Organic syntheses collective volume 10 jeremiah p freeman

The reaction mixture is transferred, portionwise, to a 2-L, round-bottomed flask using diethyl ether, and the solvents are removed under reduced pressure Note 9.. The resulting mixture i

Organic Syntheses, Coll Vol 10, p.1 (2004); Vol 77, p.121 (2000)

7α-ACETOXY-(1Hβ, 6Hβ)-BICYCLO[4.4.1]UNDECA-2,4,8-TRIENE

VIA CHROMIUM-MEDIATED HIGHER ORDER

CYCLOADDITION [ Bicyclo[4.4.1]undeca-3,7,9-triene-2-ol, acetate, endo- (±)- ]

Submitted by James H Rigby1 and Kevin R Fales

Checked by Robert E Lee Trout and Amos B Smith, III

1 Procedure

A Tricarbonyl(η 6 -cycloheptatriene)chromium(0) An oven-dried complexation flask (Figure 1), fitted with an additional condenser (Note 1) and gas adapter, is charged with acetonitrile (300 mL) The solvent is heated to 40°C under argon (Ar) (Note 2), chromium hexacarbonyl is added (45 g, 0.2 mol) (Note 3), and the mixture is immediately heated to reflux for 24 hr (Note 4) Toward the end of this time period (i.e., after 20 hr), the cooling jacket attached to the flask is alternately filled with water and emptied to allow for complete digestion of the starting material After complete conversion of the

chromium hexacarbonyl is evident, the free condenser is quickly changed to a 9"-Vigreux column connected through an acetone/solid carbon dioxide (CO2) condenser to a vacuum/argon line using a Firestone valve (Note 5) Vacuum ( 0.1 mm) is quickly and cautiously applied to the system while simultaneously removing the heating source (Note 6) The reaction mixture is evaporated to complete dryness by warming the reaction flask with a warm water bath as necessary (Note 7) The system is filled with argon and a previously prepared solution of cycloheptatriene (1.5 eq., 0.31 mol, 28.3 g, 32 mL) in tetrahydrofuran (THF) (50 mL) is added via syringe to the dry, bright yellow, solid tris(acetonitrile)chromium tricarbonyl intermediate This addition is best performed under a very strong flow of argon through the top joint of the reaction apparatus An additional 100 mL of THF is added to the mixture and the resulting solution is heated to reflux After 48 hr, additional cycloheptatriene (1.0 eq., 0.2 mol, 20.5 g, 23 mL) is added and the reaction is continued until complete digestion of the (CH3CN)3Cr(CO)3 intermediate is evident (Note 8) Solvent is removed under reduced pressure (Note 9), and the residue is dissolved in a mixture of hexanes (225 mL) and methylene chloride (225 mL) Celite (5.0 g) is added to the solution and the mixture is filtered through a Celite pad (5.5 cm × 1.0 cm) The filter cake is washed with methylene chloride (2 × 50 mL) and the filtrate is concentrated under reduced pressure to provide an oily red solid After the solids are dried briefly under vacuum ( 2 hr, 0.1 mm), they are triturated with chilled hexanes (100 mL), and the chilled solids are collected via vacuum filtration and washed with chilled hexanes (50 mL) The solids are dried under vacuum (0.1 mm) to yield the dark red tricarbonyl(η6-cycloheptatriene)chromium(0) (34.4-39.9 g, 75-85%, (Note 10))

Figure 1

DOI:10.15227/orgsyn.077.0121

B 7α-Acetoxy-(1Hβ, 6Hβ)-bicyclo[4.4.1]undeca-2,4,8-triene To a large, fully assembled

photochemical reaction vessel (Figure 2) are added tricarbonyl(η6-cycloheptatriene)chromium(0) (10.0

g, 0.044 mol) and hexanes (4 L, (Note 11)) While the mixture is stirred it is purged with argon for

20-30 min and then 1-acetoxy-1,3-butadiene (1.5 eq., 7.4 g, 7.8 mL, 0.66 mol) is added via syringe (Note 12) The solution is irradiated (Note 13) using a Hanovia medium pressure 450W mercury vapor lamp (Note 14) for 6 hr or longer (Note 15) until complete digestion of the starting chromium complex is noted by TLC (Note 16) The reaction mixture is transferred, portionwise, to a 2-L, round-bottomed flask using diethyl ether, and the solvents are removed under reduced pressure (Note 9) The residue is taken up in methanol (300 mL), with scraping as necessary, and the resultant slurry is stirred open to the atmosphere overnight At this time, flash grade silica gel (10.0 g, Merck 230-400 mesh) is added to the green slurry and stirring is continued as necessary for complete decomplexation of the intermediate cycloadduct complex, as noted by TLC (Note 16) The reaction mixture is filtered through a Celite pad (9 cm diameter by 1 cm deep), using additional methanol (3 × 50 mL) to rinse the flask and filter cake until the filtrate runs clear (Note 17) Solvent is removed under reduced pressure and the residue is dried overnight under 0.1 mm vacuum to remove additional traces of solvent and unreacted diene (Note 18) The product is purified via flash column chromatography (Note 19) to yield 98% pure (Note 20), 7α-acetoxy-(1Hβ, 6Hβ)-bicyclo[4.4.1]undeca-2,4,8-triene (7.7 g, 86%) (Note 21) as a white solid (mp 54-57°C)

Figure 2: Immersion well photochemical reactor

5 This item may be purchased from Ace Glass Inc., Vineland, N.J., catalog #8766-12

6 Vacuum must be applied carefully to avoid bumping, but must also be applied quickly and steadily to avoid degradation of the reaction intermediate

7 Warning! Tris(acetonitrile)chromium tricarbonyl is highly pyrophoric and degrades rapidly when exposed to oxygen, but is reasonably stable in THF solution Best yields are obtained when this intermediate is as free of acetonitrile as possible while avoiding formation of the green colored [Cr(III)]

decomposition product, which develops on contact with air.

8 The reaction is monitored by TLC (silica gel, 6:1 hexanes: ethyl acetate) Typical characteristics are

Rf = 0.15, a yellow spot [tris(acetonitrile)chromium tricarbonyl intermediate], and Rf = 0.51, a red spot (product complex) Total reaction time averaged 180 hr

9 Solvent is removed via rotary evaporator

10 This product was typically found to be ≥ 98% pure based on 1H NMR analysis, and it may be used without further purification However, the compound may be recrystallized from hexanes if necessary The complex exhibits the following characteristics: TLC: Rf = 0.51 (silica gel, 6:1 hexanes:ethyl acetate); 1H NMR (500 MHz, CD2Cl2) δ: 1.74 (d, 1 H), 2.95 (dt, 1 H, J = 9.0, 14.0), 3.40 (t, 2 H, J = 7.5), 4.87 (bs, 2 H), 6.09 (bs, 2 H) ; 13C NMR (125 MHz, CD2Cl2) δ: 23.9 (CH2), 57.1 (CH), 98.4 (CH), 101.1 (CH) ; IR (CDCl3) cm−1: 3052, 2895, 2848, 1982, 1974, 1917, 1897, 1886, 1877 ; HRMS calcd for C10H8CrO3: m/e 227.9879, found 227.9881 ; LRMS [EI] (rel %): 227.9 (19), 199.9 (13), 172.0 (15), 144.0 (74)

11 Performing this reaction at higher concentrations (i.e., in 1-2 L solvent) results in significantly increased reaction times, incomplete reaction, and increased side product formation

12 The reaction conditions given were developed using (E)-1-acetoxy-1,3-butadiene prepared according to the procedure of McDonald, et al.2 with the following modifications (unchecked)

Crotonaldehyde (105 g, 125 mL) is added by addition funnel over 1 hr to a refluxing solution of

isopropenyl acetate (2.5 mol, 250 g, 275 mL), p-toluenesulfonic acid (anhydrous, 2.0 g) and copper(II) acetate (0.5 g) The mixture is heated at reflux for 30 min and then the reaction apparatus is set up for distillation Distillation (bath temp 110-130°C) is continued for 2.5 hr until acetone and nearly all unreacted isopropenyl acetate is collected The distillation residue is cooled to 25°C and crude product

is isolated via vacuum distillation (bp 32°C, 7 mm) This crude product typically contains traces of

isopropenyl acetate and significant amounts of acetic acid The crude distillate is dissolved in diethyl ether (500 mL), and carefully mixed with saturated aqueous sodium bicarbonate solution, adding additional anhydrous sodium bicarbonate slowly to the stirring mixture until gas evolution ceases and the pH increases to 7.0 The layers are separated and the organic phase is washed with brine (300 mL) and dried with magnesium sulfate The solution is carefully concentrated, and the product is purified by distillation to yield nearly pure (E)-1-acetoxy-1,3-butadiene ( 35-50% yield) Frequently, sequential distillations of the product are necessary to ensure the purity of the product obtained Pure product exhibits the following characteristics: bp 32°/10 mm; TLC: Rf = 0.61 (silica gel, 6:1 hexanes:ethyl acetate); 1H NMR (500 MHz, CDCl3) δ: 2.14 (s, 3 H), 5.08 (dd, 1 H, J = 10.5, 0.5), 5.21 (d, 1 H, J = 17.0), 6.03 (dd, 1 H, J = 12.0, 12.0), 6.26 (ddd, 1 H, J = 21.5, 10.5, 10.5), 7.39 (d, 1 H, J = 12.5) ; 13C NMR (125 MHz, CDCl3) δ: 20.7 (CH3), 116.0 (CH), 117.3 (CH2), 131.7 (CH), 138.6 (CH), 167.8 (C) ;

IR (CDCl3) cm−1: 3091, 3074, 3041, 1660, 1097 ; HRMS m/e calcd for C6H8O2: 112.0524, found 112.0523 ; LRMS [EI] (rel %): 112.0 (57), 70.0 (100)

Alternatively, 1-acetoxy-1,3-butadiene is available as a mixture of E,Z-isomers from Aldrich Chemical Company, Inc When using the commercial reagent, 3.0 eq (14.8 g, 15.6 mL) is necessary to ensure complete reaction, as the Z isomer does not react

13 Caution: UV radiation is harmful to eyes and skin; the reaction vessel may be wrapped with

aluminum foil or the reaction conducted in a closed photochemical reaction cabinet to prevent exposure

to the harmful UV rays

14 The photochemical lamp and power supply may be purchased from Ace Glass Inc., Vineland, N.J., catalog #'s 7825-32 or 7825-40 (lamp) and 7830-60 (power supply)

15 A solid buildup occurs on the immersion well that may slow the reaction considerably To help minimize this, the submitters suggest a constant purging of the reaction mixture with argon throughout the entire reaction time

16 Typical TLC data (silica gel, 6:1 hexanes:ethyl acetate) include Rf = 0.61 (1-acetoxy-1,3-butadiene); 0.51, a red spot [tricarbonyl(cycloheptatriene)chromium]; 0.45 a yellow spot (side product that often overlaps with the starting complex); and 0.31 a yellow spot (main intermediate chromium complex)

17 Prior to and between washes, the green filter cake cracks and should be "pushed down" with a spatula to form a uniform surface prior to any subsequent washes

18 TLC at this point (silica gel, 6:1 hexanes: ethyl acetate) shows three spots (UV): Rf = 0.76 (trace orange); 0.55 (side product); 0.47 (main product)

19 Chromatography is performed as follows: a 3.5-cm ID glass column is packed with 140 g of flash grade silica gel (Merck 230-400 mesh) in petroleum ether and the sample is loaded in minimal

petroleum ether The checkers found that a 5.0-cm ID glass column packed with 170 g of Merck

70-270 mesh silica gel gave slightly better separation Care must be taken during product application to minimize silica gel column separation The column is eluted, recycling solvent as necessary, until the front running orange band is collected This band is comprised of trace amounts of unreacted tricarbonyl(cycloheptatriene)chromium Elution then proceeds using 500 mL of 49:1 petroleum ether:diethyl ether

followed by 19:1 petroleum ether:diethyl ether to obtain the product Prior to elution of the desired

[6π+4π] cycloadduct, the side product, [6π+2π] cycloadduct (A) elutes, usually streaking into the

desired product, but it is of little consequence All fractions containing the desired product are combined and the solvent is removed under reduced pressure The product sometimes solidifies during solvent removal, but may require seeding with authentic material to promote crystallization

20 The [6π+4π] cycloadduct exhibits the following characteristics: bp: 104-107°/1.3 mm; TLC: Rf = 0.47 (silica gel, 6:1 hexanes:ethyl acetate); 1H NMR (500 MHz, CDCl3) δ: 2.11 (s, 3 H), 2.12-2.15 (m, 1 H), 2.31 (bd, 1 H, J = 14.0), 2.35-2.47 (m, 2 H), 2.74 (bs, 1 H), 2.92 (bs, 1 H), 5.49 (bd, 1 H, J = 11.0), 5.60-5.65 (m, 1 H), 5.66-5.68 (m, 1 H), 5.73-5.81 (m, 2 H), 5.83-5.88 (m, 2 H) ; 13C NMR (125 MHz, CDCl3) δ: 21.4 (CH3), 31.7 (CH2), 32.9 (CH2), 37.3 (CH), 42.7 (CH), 76.7 (CH), 124.9 (CH), 127.1 (CH), 128.7 (CH), 133.1 (CH), 135.3 (CH), 137.8 (CH), 170.5 (C) ; IR (neat) cm−1: 3011, 2924, 2905,

2884, 2872, 1737, 1447, 1430, 1368, 1241, 1199, 1055, 1020 ; HRMS calcd for C13H16O2: m/e 204.11503, found 204.1149 ; LRMS [EI] (rel %): 204.1 (2), 162.1 (2), 144.1 (20), 129.0 (11), 112.0 (6), 92.0 (100) Purity was determined by 500 MHz 1H NMR, with the main impurity being the [6π+2π]

cycloadduct A

This compound exhibits the following characteristics: TLC: Rf = 0.35 (silica gel, 19:1 hexanes:ethyl acetate); 1H NMR (500 MHz, CDCl3) δ: 1.58 (ddd, 1 H, J = 13.5, 9.5, 3.5), 1.89 (d, 1 H, J = 12.0), 2.01 (ddd, 1 H, J = 13.5, 9.5, 9.5), 2.10 (s, 3 H), 2.14-2.19 (m, 1 H), 2.61 (dd, 1 H, J = 12.0, 5.5), 2.69 (ddd, 1

H, J = 16.5, 8.5, 4.0), 2.84 (ddd, 1 H, J = 19.5, 9.5, 6.0), 5.58 (d, 1 H, J = 10.0, 6.0), 5.62 (dd, 1 H, J = 12.0, 9.5), 5.72 (dd, 1 H, J = 12.0, 7.0), 5.83 (dd, 1 H, J = 12.0, 6.5), 6.10 (dd, 1 H, J = 10.5, 8.5), 7.09 (d, 1 H, J = 12.0) ; 13C NMR (125 MHz, CDCl3) δ: 20.7 (CH3), 33.3 (CH2), 36.7 (CH), 42.3 (CH2), 46.3 (CH), 54.7 (CH), 115.5 (CH), 123.3 (CH), 126.6 (CH), 135.0 (CH), 135.2 (CH), 141.0 (CH), 168.2 (C) ;

IR (neat) cm−1: 3019, 2950, 2931, 2863, 1755, 1370, 1219, 1094 ; HRMS calcd for C13H16O2: m/e 204.11503, found 204.1147 ; LRMS [EI] (rel %): 204.1 (2), 144.1 (20), 129.1 (7), 112.0 (6), 92.0 (100)

21 The yield reported is that of the submitters and is based on the use of the pure butadiene It was found by the checkers that use of a mixture of the E, Z-isomers (as purchased from Aldrich Chemical Company, Inc.) led to an average yield of 73%

(E)-1-acetoxy-1,3-Waste Disposal Information

All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995 Wastes containing chromium, aqueous solutions as well as solids, were collected and disposed of separately Prior to washing, all glassware laden with chromium by-products, were soaked overnight in a solution composed of 15-20 g of copper beads dissolved in 2 L of 50% aqueous nitric acid This solution may be kept loosely capped in a fume hood and reused several times prior to disposal

3 Discussion

Synthetic sequences that employ a cycloaddition step benefit from the convergency and stereoselectivity that characterizes these pericyclic transformations In recent years, several new methodologies for performing so-called higher-order cycloadditions [e.g., [6π+4π], [6π+2π], [4π+4π], [4π+3π], etc.] have appeared and are now being used as key transformations in the synthesis of a

number of target molecules.3 4 5 For example, a number of reports have appeared in which the generation of specific examples of bicyclo[4.4.1]undecatriene ring systems are noted as useful intermediates in the synthesis of cerorubenate sesterterpenes6 as well as the ingenane diterpenes.7 In particular, the general utility of chromium-mediated [6π+4π] cycloaddition in the synthesis of several

bicyclo[4.4.1]undecatriene systems as potential intermediates in natural product synthesis has been demonstrated,8 including the synthesis of members of the taxane and tigliane families.9 Furthermore, studies involving cleavage of certain functionalized members of these ring systems, allows for the generation of medium-sized carbocycles.10

With these synthetic opportunities in mind, presentation of the methodology used in large scale generation of tricarbonyl(η6-cycloheptatriene)chromium(0) as well as an example of [6π+4π] cycloaddition is timely Although a specific example of the submitter's higher-order cycloaddition methodology utilizing an electron-rich diene partner is presented, comparable results have also been obtained employing an electron-poor diene, methyl sorbate, with typical yields of 80-85% on a 10-g scale.11

Key to this large scale cycloaddition chemistry is the ability to generate large quantities of

tricarbonyl(η6-cycloheptatriene)chromium(0) The submitters have found that the best results are obtained when the desired complex is generated with the highly reactive and pyrophoric complexation reagent (CH3CN)3Cr(CO)3.12 One drawback to this method, however, was the need to scrape solidified Cr(CO)6 from the reflux condenser during the early stages of the reaction, causing atmospheric exposure

to the reactants For this reason, an engineering control was instituted through development of a reaction vessel (Figure 1) containing a built-in large bore condenser, thereby obviating the need to open the system for scraping and allowing, after subsequent complexation with cycloheptatriene, the isolation of highly pure product complex with little or no additional purification necessary

References and Notes

1 Department of Chemistry, Wayne State University, Detroit, MI 48202-3489

2 McDonald, E.; Suksamrarn, A.; Wylie, R D J Chem Soc., Perk Trans I 1979, 1893

3 Recent reviews in this area include: (a) Rigby, J H In "Comprehensive Organic Synthesis";

Trost, B M.; Fleming, I.; Eds.; Pergamon Press: Oxford, 1991; Vol 5, pp 617-643;

4 Rigby J H In "Advances in Metal-Organic Chemistry"; JAI Press, Inc.: Greenwich, CT, 1995;

Vol 4, pp 89-127;

5 Rigby J H Org React 1997, 49, 331-425

6 Paquette, L A.; Hormuth S.; Lovely, C J J Org Chem 1995, 60, 4813, and references cited

therein

7 For an overview of synthetic approaches toward the ingenane diterpenes see: Rigby, J H In

"Studies in Natural Products Chemistry"; Rahman, A.-U.; Ed.; Elsevier: New York, 1993; Vol

12 (Part H), pp 233-274

8 Rigby, J H.; de Sainte Claire, V Heeg, M J Tetrahedron Lett 1996, 37, 2553

9 Rigby, J H.; Niyaz, N M.; Short K M.; Heeg, M J J Org Chem 1995, 60, 7720

10 Rigby, J H.; Ateeq, H S.; Krueger, A C Tetrahedron Lett 1992, 33, 5873

11 For general experimental details see: Rigby, J H.; Ateeq, H S.; Charles, N R.; Cuisiat, S V.;

Ferguson, M D.; Henshilwood, J A.; Krueger, A C.; Ogbu, C O.; Short, K M.; Heeg, M J J

Am Chem Soc 1993, 115, 1382

12 Tate, D P.; Knipple, W R.; Augl, J M Inorg Chem 1962, 1, 433

Appendix Chemical Abstracts Nomenclature (Collective Index Number);

(Registry Number)

Benzenesulfonic acid, 4-methyl- (9); (104-15-4)

Cupric acetate monohydrate:

Acetic acid, copper(2+) salt, monohydrate (8,9); (6046-93-1)

Copyright © 1921-2005, Organic Syntheses, Inc All Rights Reserved

Organic Syntheses, Coll Vol 10, p.9 (2004); Vol 77, p.135 (2000)

STILLE COUPLINGS CATALYZED BY CARBON WITH CuI AS A COCATALYST: SYNTHESIS OF 2-(4'-

Submitted by Lanny S Liebeskind2 and Eduardo Peña-Cabrera3 Checked by Jory Wendling and Louis S Hegedus

1 Procedure

A 200-mL, flame-dried Schlenk flask is purged with nitrogen and charged with 10.0 g (40.6 mmol)

of 4-iodoacetophenone (Note 1), 770 mg (4.1 mmol) of copper(I) iodide (CuI) (Note 2), 2.5 g (8.1 mmol) of triphenylarsine (Note 3), and 150 mL of anhydrous 1-methyl-2-pyrrolidinone (Note 4) The dark solution is degassed for 15 min (nitrogen sparge) and then 14.1 mL (44.7 mmol) of 2-(tributylstannyl)thiophene (Note 5) is added The reaction flask is immersed in a preheated oil bath at 95°C and 215 mg (0.2 mmol) of 10% palladium on activated carbon(Note 6) is added under a positive

nitrogen pressure The mixture is kept at 95°C for 24 hr (Note 7) and then allowed to cool to 25°C and diluted with 300 mL of ethyl acetate The dark mixture is poured into 200 mL of an aqueous saturated

sodium fluoride solution (Note 8) and stirred vigorously for 30 min The green-yellow heterogeneous mixture is passed through a sand pad contained in a medium-frit filter, aided by a water aspirator (Note 9) The filtrate is partitioned in a separatory funnel and the aqueous layer is extracted with two 100-mL portions of ethyl acetate The organic extracts are combined and stirred with 200 mL of fresh saturated aqueous sodium fluoride solution for 30 min The mixture is then passed through a sand pad as described above The pad is rinsed with 50 mL of ethyl acetate The mixture is partitioned again and the aqueous layer is extracted with two 50-mL portions of ethyl acetate The organic extracts are combined and washed with five 100-mL portions of water and finally with 100 mL of brine (Note 10) The dark yellow solution is dried over anhydrous magnesium sulfate (MgSO4) (Note 11) and filtered The used MgSO4 is washed with 50 mL of ethyl acetate The solvent is removed under reduced pressure to give a dark yellow solid that is dissolved in the minimum amount of dichloromethane and adsorbed onto 20 g

of silica gel (Note 12) The solvent is thoroughly removed under reduced pressure and the resulting solid is charged into a medium-pressure liquid chromatography column (silica gel, 3 × 15 cm) (Note 13) The product (6.6 g, 80%) (Note 14) is purified as described by Baeckström et al.4(Note 15)

3 Caution: Triphenylarsine is highly toxic and must be handled with gloves in a well-ventilated hood It

was purchased from Aldrich Chemical Company, Inc., and used as received

4 Anhydrous 1-methyl-2-pyrrolidinone was purchased from Aldrich Chemical Company, Inc , and used without further drying The water content was determined to be 117 ppm using a Coulomatric K-F Titrimeter

5 2-(Tributylstannyl)thiophene was purchased from Aldrich Chemical Company, Inc , and is used without additional purification

6 10% Palladium on activated carbon was purchased from Alpha Division

7 The reaction can be monitored by quenching small aliquots with water and extracting with a small amount of diethyl ether The ethereal layer is spotted on an analytical silica gel TLC plate (0.25 mm thickness, from EM Separations Technology) ( 10% ethyl acetate in hexanes, using 254 nm UV light to

DOI:10.15227/orgsyn.077.0135

visualize the spots) The following are the Rf's of the components of the mixture: 2-(tributylstannyl)thiophene (0.86), triphenylarsine (0.62), 4-iodoacetophenone (0.48), and 2-(4'-acetylphenyl)thiophene , (0.38 fluorescent) Trace amounts of 4-butylbenzophenone (Rf, 0.52) were observed at the end of the reaction

8 Caution: Sodium fluoride is highly toxic and should be handled with gloves in a well-ventilated hood

It was purchased from Spectrum Chemical Mfg Corp and used without purification

9 If crystallization underneath the frit occurs during the filtration process, the sand pad is washed with

20 mL of ethyl acetate The sand pad was changed three times during the filtration of the whole mixture

to avoid clogging

10 The washings are necessary to remove all the 1-methyl-2-pyrrolidinone

11 Anhydrous magnesium sulfate was obtained from EM Science

12 Silica gel 60, particle size 0.040-0.063 mm (230-400 mesh) was obtained from EM Separation Technology

13 The medium-pressure liquid chromatography system (MPLC) was purchased from Baeckström SEPARO AB

14 The product (a golden flaky solid) exhibits the following properties: mp 118-119°C; IR (CH2Cl2)

cm−1: 1680, 1601, 1270 ; 1H NMR (300 MHz, CDCl3) δ: 2.6 (s, 3 H), 7.1 (m, 1 H), 7.3 (d, 1 H, J = 5), 7.4 (d, 1 H, J = 3.8), 7.7 (d, 2 H, J = 8), 8.0 (d, 2 H, J = 9) ; 13C NMR (75.5 MHz, CDCl3) δ: 26.5, 124.6, 125.6, 126.4, 128.3, 129.1, 135.7, 138.7, 142.9, 197.2 Anal Calcd for C12H10OS: C, 71.30; H, 5.00; S, 15.90 Found: C, 71.14; H, 5.03; S, 15.77 (The material obtained by the checkers was a very pale yellow flaky solid.)

15 The purification was carried out using a hexanes/dichloromethane gradient (200 mL of each gradient solution) The gradient started with hexanes at a flow rate of 25 mL/min and the concentration of

dichloromethane was increased each time by 10% A total of fifty 30-mL fractions were collected Under these conditions, most of the triphenylarsine used was recovered and recycled (The checkers purified the material using conventional flash chromatography techniques The crude product adsorbed

on 20 g of flash silica gel was dry packed on a 6-cm × 14-cm column of flash silica gel Elution with

750 mL of hexanes followed by 500 mL each of a hexane/dichloromethane gradient starting with 10%

dichloromethane (CH2Cl2)/hexanes and finishing with 100% CH2Cl2 A total of fifty 100-mL fractions were collected The separation was monitored by analytical TLC as described in (Note 7).)

Waste Disposal Information

All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995

3 Discussion

The rate-enhancing influence of Cu(I) salts (the so-called "Copper Effect") in normally nonproductive and sluggish Stille couplings was first pointed out by Liebeskind et al.6 in 1990 A greater insight into this phenomenon was obtained later by Farina and co-workers.7 A number of modifications of the Stille reaction have since been reported Among them are the cross-coupling of organostannanes with organic halides promoted by stoichiometric amounts of Cu(I) salts,8 9 10 and the Cu(I)- or Mn(II)-catalyzed cross-coupling of organostannanes with iodides in the presence of sodium chloride.11

It was also discovered that aryl and vinyl iodides, bromides, and triflates participated efficiently in cross-coupling reactions with organostannanes when catalyzed by palladium-on-carbon in the presence

of Cu(I) as cocatalyst.1

The best conditions were found to be: Pd/C (0.5 mole%), Cu(I) (10 mole%), and AsPh3 (20 mole%) Besides the advantage of using a stable form of Pd(0), the yield of the products under these conditions was better than that obtained using tris(dibenzylideneacetone)palladium [Pd2(dba)3] as the source of Pd(0) Similarly, a slightly lesser amount of the homocoupled product was observed using the Pd/C protocol Although a significant amount of AsPh3 is necessary for cross-coupling to take place, it can be efficiently recovered (and recycled) at the end of the reaction by column chromatogaphy

Other products prepared using the Pd/C protocol are:

References and Notes

1 The original report was published elsewhere: Roth, G P.; Farina, V.; Liebeskind, L S.;

Peña-Cabrera, E Tetrahedron Lett 1995, 36, 2191

2 Chemistry Department, Emory University, 1515 Pierce Dr., Atlanta, GA 30322

3 Facultad de Química, Universidad de Guanajuato, Col Noria Alta S/N, Guanajuato, Gto 36000,

Mexico

4 Baeckström, P.; Stridh, K.; Li, L.; Norin, T Acta Chem Scand, Ser B 1987, B41, 442

5 Kauffman, G B.; Teter, L A Inorg Synth 1963, 7, 9

6 Liebeskind, L S.; Fengl, R W J Org Chem 1990, 55, 5359

7 Farina, V.; Kapadia, S.; Krishnan, B.; Wang, C.; Liebeskind, L S J Org Chem 1994, 59, 5905

8 Piers, E.; Romero, M A J Am Chem Soc 1996, 118, 1215,

9 Takeda, T.; Matsunaga, K.; Kabawasa, Y.; Fujiwara, T Chem Lett 1995, 771,

10 Allred, G D.; Liebeskind, L S J Am Chem Soc 1996, 118, 2748

11 Kang, S-K; Kim, J-S.; Choi, S-C J Org Chem 1997, 62, 4208

Appendix Chemical Abstracts Nomenclature (Collective Index Number);

Copyright © 1921-2005, Organic Syntheses, Inc All Rights Reserved

Organic Syntheses, Coll Vol 10, p.12 (2004); Vol 76, p.57 (1999)

ASYMMETRIC SYNTHESIS OF α-AMINO ACIDS BY THE ALKYLATION OF PSEUDOEPHEDRINE GLYCINAMIDE: L-

ALLYLGLYCINE AND N-BOC-L-ALLYLGLYCINE [ Acetamide, 2-amino-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl-, [R- (R,R)]-, 4-Pentenoic acid, 2-amino-, (R)- and 4-Pentenoic acid, 2-[[(1,1-

argon and charged with 30.8 g (0.726 mol, 2 equiv) of anhydrous lithium chloride (Note 1), 60.0 g (0.363 mol, 1 equiv) of (R,R)-(−)-pseudoephedrine(Note 2), and 500 mL of dry tetrahydrofuran (THF) (Note 3) The resulting slurry is cooled in an ice bath After 15 min, 6.89 g (0.182 mol, 0.5 equiv) of solid lithium methoxide(Note 4) is added to the reaction flask in one lot The resulting mixture is stirred

at 0°C for 10 min, after which time the pressure-equalizing addition funnel is charged with a solution of 40.4 g (0.454 mol, 1.25 equiv) of glycine methyl ester (Note 5) in 100 mL of dry THF (Note 3), and dropwise addition of this solution is initiated The addition is completed within 1 hr, and the reaction flask is maintained at 0°C for an additional 7 hr The reaction is terminated by the addition of 500 mL of water The bulk of the THF is removed from the resulting colorless solution by concentration under reduced pressure An additional 250 mL of water is added to the aqueous concentrate, and the resulting aqueous solution is transferred to a 2-L separatory funnel and extracted sequentially with one 500-mL and four 250-mL portions of dichloromethane The combined organic extracts are dried over anhydrous

potassium carbonate and filtered, and the filtrate is concentrated under reduced pressure The clear,

DOI:10.15227/orgsyn.076.0057

colorless, oily residue is dissolved in 300 mL of warm (50°C) THF (Note 3), 10 mL of water is added, and the resulting solution is allowed to cool to 23°C, whereupon the product crystallizes as its monohydrate within 1 hr The crystallization process is completed by cooling the crystallization flask to

−20°C After standing for 2 hr at −20°C, the crystals are collected by filtration and rinsed with 200 mL

of ether The crystals are dried under reduced pressure (0.5 mm) at 23°C for 2 hr to provide 62.8 g (72%) of (R,R)-(−)-pseudoephedrine glycinamide monohydrate (Note 6)

Dehydration of the monohydrate is initiated by suspending the crystalline solid (62.8 g) in 1.2 L of

dichloromethane ; the resulting suspension is stirred vigorously for 1 hr to break up any large lumps of solid After 1 hr of vigorous stirring, 60 g of anhydrous potassium carbonate is added to the fine dispersion (Note 7) After the suspension is stirred for 10 min, it becomes translucent At this point the mixture is filtered through 40 g of Celite in a 10 cm-i.d Büchner funnel fitted with a Whatman #1 filter paper The clear, colorless filtrate is concentrated under reduced pressure The oily residue is dissolved

in 200 mL of toluene , and the resulting solution is concentrated to remove any residual

dichloromethane The oily concentrate is then dissolved in 175 mL of hot (60°C) toluene , and the resulting solution is allowed to cool slowly to 23°C Crystallization of the product may occur spontaneously within 1-3 hr at 23°C; however, if necessary, it can be initiated by scratching the side of the flask until crystals are observed Once crystallization is initiated, the crystals are broken up periodically with a spatula to obtain a fine powder that is easily manipulated After 30 min from the onset of crystallization, the flask is cooled to −20°C under an argon atmosphere to complete the crystallization process After standing at −20°C for 2 hr, the crystals are collected by filtration and rinsed with 200 mL of ether The product is dried by transferring the solid to a 500-mL, round-bottomed flask fitted with a vacuum adapter and evacuating the flask (0.5 mm) After 1 hr at 23°C, the flask is immersed in an oil bath at 60°C (Note 8) After 12 hr, the flask is cooled to 23°C to afford 53.8

g (67% overall) of anhydrous (R,R)-(−)-pseudoephedrine glycinamide(Note 9)

B Pseudoephedrine L -allylglycinamide A 1-L, single-necked, round-bottomed flask is equipped with a Teflon-coated magnetic stirring bar and a rubber septum through which is placed a needle connected to a source of vacuum and argon The system is evacuated, the flask is flame-dried and then allowed to cool to 23°C under reduced pressure When the reaction flask has cooled to 23°C, it is flushed with argon and charged with 200 mL of dry THF (Note 3) and 63.0 mL (0.450 mol, 1.025 equiv) of diisopropylamine (Note 10) The resulting solution is cooled to 0°C in an ice bath With efficient stirring, the solution is deoxygenated at 0°C by alternately evacuating the reaction vessel and flushing with argon three times After the solution is deoxygenated, 167 mL (0.439 mol, 1 equiv) of a 2.63 M solution of butyllithium in hexanes (Note 11) and (Note 12) is added via syringe over a 20-min period After the addition is complete, the solution is stirred at 0°C for 15 min

Separately, a 2-L, three-necked, round-bottomed flask is equipped with an inlet adapter connected

to a source of vacuum and argon, two rubber septa, and a Teflon-coated magnetic stirring bar The flask

is charged with 57.2 g (1.35 mol, 6 equiv) of anhydrous lithium chloride (Note 1) and, with efficient stirring of the solid, the reaction vessel is evacuated and flame-dried The flask and its contents are allowed to cool to 23°C under reduced pressure When the flask has cooled to 23°C, it is flushed with

argon, 50.0 g (0.225 mol, 1 equiv) of solid (R,R)-(−)-pseudoephedrine glycinamide is added, and one of the septa is replaced with a Teflon thermometer adapter fitted with a thermometer for internal measurement of the reaction temperature The solids are suspended in 500 mL of dry THF (Note 3) and the resulting milky-white slurry is cooled to an internal temperature of 0°C in an ice bath With efficient stirring, the slurry is deoxygenated by alternately evacuating the reaction vessel and flushing with argon

three times

The two reaction flasks are connected via a wide-bore (14 gauge) cannula so that one end of the cannula is immersed in the lithium diisopropylamide solution and the other is suspended above the (R,R)-(−)-pseudoephedrine glycinamide-lithium chloride slurry The flask containing the lithium diisopropylamide solution and its ice bath are raised to a height just above that of the flask containing the glycinamide slurry The reaction flask containing the glycinamide slurry is very briefly evacuated to initiate siphon transfer of the lithium diisopropylamide solution Once the siphon flow is established, the flask containing the glycinamide slurry is flushed with argon By raising or lowering the height of the flask containing the lithium diisopropylamide solution, the rate of addition is modulated so that the

temperature of the reaction mixture does not rise above 5°C (approximately 45 min addition time) (Note 13) After the addition is complete, the reaction mixture is stirred at 0°C for 30 min (Note 14) To the resulting pale yellow suspension is added 19.5 mL (0.225 mol) of allyl bromide (Note 15) via syringe over a 20-min period The rate of addition of allyl bromide is also modulated to prevent the internal reaction temperature from rising above 5°C (Note 16) After the addition of allyl bromide is complete, the reaction mixture is stirred for 45 min at 0°C The reaction is terminated by the addition of

500 mL of water The resulting biphasic mixture is slowly acidified by the addition of 300 mL of 3 M aqueous hydrochloric acid solution The biphasic mixture is transferred to a 2-L separatory funnel and is extracted with 1 L of ethyl acetate The organic layer is separated and extracted sequentially with 300

mL of 3 M aqueous hydrochloric acid solution and 300 mL of 1 M aqueous hydrochloric acid solution The aqueous layers are combined and cooled to an internal temperature of 5°C by stirring in an ice bath The cold aqueous solution is then cautiously made basic (pH 14) by the slow addition of 120 mL of aqueous 50% sodium hydroxide solution The temperature of the solution should not be allowed to rise above 25°C during the addition of base The basic solution is extracted sequentially with one 500-mL portion and four 250-mL portions of dichloromethane(Note 17) The combined organic layers are dried over anhydrous potassium carbonate and filtered, and the filtrate is concentrated under reduced pressure The oily residue is dissolved in 200 mL of toluene , and the resulting solution is concentrated under reduced pressure to remove residual dichloromethane and diisopropylamine The solid residue is recrystallized by suspending it in 100 mL of toluene and heating the resulting suspension until the solids dissolve (ca 70°C) The recrystallization mixture is allowed to cool to 23°C After 3 hr, when crystallization of the product is nearly complete, the recrystallization flask is cooled to 0°C in an ice bath to complete the recrystallization process After standing at 0°C for 1 hr, the crystals are collected

by filtration and rinsed sequentially with two 50-mL portions of cold (0°C) toluene and one 100-mL portion of ether at 23°C The crystals are dried under reduced pressure (0.5 mm) at 23°C for 2 hr to provide 31.3 g ( 53%) of diastereomerically pure pseudoephedrine L-allylglycinamide(Note 18) The mother liquors are concentrated and the oily residue is dissolved in 50 mL of toluene at 23°C The resulting solution is cooled to −20°C and seeded with authentic pseudoephedrine L-allylglycinamide After standing at −20°C for 6 hr, the crystals that have formed are collected by filtration and rinsed with

25 mL of cold (0°C) toluene and 50 mL of ether at 23°C The product is dried under reduced pressure (0.5 mm) at 23°C for 2 hr to afford a second crop of the alkylation product The second crop of crystals ( 4.8 g) is recrystallized a second time by suspending it in 20 mL of toluene and warming to ca 70°C to dissolve the solids (Note 19) The resulting solution is allowed to cool slowly to 23°C, whereupon the product crystallizes within 1 hr The recrystallization flask is cooled to −20°C to complete the crystallization process After standing at −20°C for 90 min, the crystals are collected by filtration and washed sequentially with two 10-mL portions of cold (0°C) toluene and one 25-mL portion of ether The crystals are dried under reduced pressure (0.5 mm) at 23°C for 2 hr to afford 3.6 g ( 6%) of diastereomerically pure pseudoephedrine L-allylglycinamide To obtain additional product, the mother liquors are concentrated under reduced pressure and the oily residue is purified by chromatography on silica gel (100 g, 5-cm i.d column) eluting with 4% methanol , 4% triethylamine and 92%

dichloromethane The oily residue obtained after concentration of the appropriate fractions is dissolved

in 25 mL of warm (50°C) toluene The resulting solution is cooled to −20°C and held at that temperature for 12 hr The crystals that form are collected by filtration and rinsed with 20 mL of cold (0°C) toluene and 30 mL of ether at 23°C The crystals are dried under reduced pressure (0.5 mm) at 23°C for 2 hr to provide an additional 5.0 g ( 8%, total yield: 39.1-42.0 g, 66-71%) of diastereomerically pure pseudoephedrine L-allylglycinamide

C L -Allylglycine A 1-L, single-neck, round-bottomed flask equipped with an efficient reflux condenser, a Teflon-coated magnetic stirring bar and a heating mantle is charged with 25.0 g (0.0953 mol) of pseudoephedrine L-allylglycinamide and 500 mL of water The resulting suspension is heated to reflux, causing the solids to dissolve to afford a colorless, homogeneous solution After 10 hr at reflux, the reaction mixture is allowed to cool to 23°C, whereupon (R,R)-(−)-pseudoephedrine is observed to crystallize (Note 20) Concentrated aqueous ammonium hydroxide solution (10 mL) is added (Note 21), whereupon the resulting aqueous slurry is transferred to a 1-L separatory funnel and extracted with three 200-mL portions of dichloromethane , reserving the aqueous layer The three organic layers are individually and sequentially extracted with a single aqueous solution prepared by combining 250 mL

of water and 5 mL of concentrated aqueous ammonium hydroxide solution The aqueous extract is combined with the aqueous extract reserved earlier and the resulting solution is concentrated under

reduced pressure to provide a white solid residue The solid is triturated, sequentially, with one

100-mL and one 50-100-mL portion of absolute ethanol The triturated solid is collected by filtration and dried under reduced pressure (0.5 mm) at 23°C for 2 hr to afford 10.2 g (93%) of L-allylglycine of ≥99% ee (Note 22) If desired, (R,R)-(−)-pseudoephedrine can be recovered from the organic extracts The organic extracts are combined and dried over anhydrous potassium carbonate and filtered, and the filtrate is concentrated under reduced pressure to afford a solid The solid is recrystallized by dissolving

it in a minimum volume of hot water (ca 350 mL) The resulting solution is allowed to cool slowly to 23°C, by which time extensive crystallization of (R,R)-(−)-pseudoephedrine has occurred The recrystallization flask is cooled to 0°C in an ice bath After standing at 0°C for 1 hr, the crystals are collected by filtration and dried under reduced pressure (0.5 mm) at 23°C for 2 hr to afford 10.8 g of pure (R,R)-(−)-pseudoephedrine (mp 116-117°C) The mother liquors are concentrated and a second crop of crystals (2.6 g, total yield 13.4 g, 85%) is obtained in a similar manner by recrystallization from

ca 75 mL of water

D N-Boc- L -allylglycine A 1-L, single-neck, round-bottomed flask equipped with an efficient reflux condenser, a Teflon-coated magnetic stirring bar and a heating mantle is charged with 14.7 g (0.056 mol, 1 equiv) of pseudoephedrine L-allylglycinamide and 224 mL (0.112 mol, 2 equiv) of 0.5 M aqueous sodium hydroxide solution The resulting slurry is heated to reflux whereupon a clear, colorless homogeneous solution is obtained After 2 hr at reflux, the reaction mixture is cooled to 23°C, inducing the crystallization of (R,R)-(−)-pseudoephedrine (Note 20) The reaction suspension is transferred to a 1-L separatory funnel and is extracted sequentially with one 200-mL and one 100-mL portion of

dichloromethane , reserving the aqueous layer The two organic layers are individually and sequentially extracted with a single 150-mL portion of water The aqueous layer is combined with the earlier aqueous extract and the resulting solution is reserved If desired, (R,R)-(−)-pseudoephedrine can be recovered from the organic extracts, as follows The organic extracts are combined and dried over anhydrous potassium carbonate and filtered, and the filtrate is concentrated under reduced pressure to afford a solid The solid is recrystallized by dissolving it in a minimum volume of hot water (ca 250 mL) The resulting solution is allowed to cool slowly to 23°C, by which time extensive crystallization of

(R,R)-(−)-pseudoephedrine has occurred The recrystallization flask is cooled to 0°C in an ice bath After standing at 0°C for 1 hr, the crystals are collected by filtration and are dried under reduced pressure (0.5 mm) at 23°C for 2 hr to afford 6.2 g (67%) of pure (R,R)-(−)-pseudoephedrine (mp 116-117°C) The mother liquors are concentrated and a second crop of crystals (1.5 g, total yield 7.7 g, 83%)

is obtained in a similar manner by recrystallization from ca 50 mL of water

The combined aqueous layers are transferred to a 1-L, round-bottomed flask and 9.40 g (0.112 mol,

2 equiv) of solid sodium bicarbonate is added The resulting solution is reduced to a volume of approximately 150 mL by concentration under reduced pressure A Teflon-coated magnetic stirring bar

is added, and the aqueous mixture is cooled to 0°C in an ice bath To the cooled solution is added, sequentially, 150 mL of p-dioxane (Note 23) and 13.4 g (0.0615 mol, 1.1 equiv) of di-tert-butyl dicarbonate(Note 24) The reaction mixture is stirred for 90 min at 0°C, at which time the ice bath is removed and the solution is allowed to warm to 23°C After stirring for 90 min at 23°C, the reaction mixture is diluted with 200 mL of water and the resulting solution is transferred to a 1-L separatory funnel and extracted sequentially with one 400-mL and one 200-mL portion of ethyl acetate , reserving the aqueous layer The two organic layers are individually and sequentially extracted with a single 100-

mL portion of 0.1 M aqueous sodium hydroxide solution The aqueous layer is combined with the aqueous extract reserved earlier and the resulting solution is stirred while cooling in an ice bath Before acidification of the aqueous layer, 100 mL of ethyl acetate is added to prevent excessive frothing The resulting biphasic mixture is carefully acidified by the slow addition of 250 mL of a 1 M aqueous

hydrochloric acid solution until the aqueous layer is pH 1 The biphasic mixture is transferred to a 2-L separatory funnel, 400 mL of ethyl acetate is added, and, after thorough mixing, the layers are separated The organic layer is extracted with 200 mL of water The two aqueous layers are individually and sequentially extracted with a single 200-mL portion of ethyl acetate The organic layers are combined, and the resulting solution is dried over anhydrous sodium sulfate and filtered The filtrate is concentrated under reduced pressure The residue is dissolved in 100 mL of toluene , and the resulting solution is concentrated The residue is then sequentially dissolved in and then concentrated from 100

mL of toluene , 100 mL of dichloromethane , and two 100-mL portions of ether , in order to remove residual dioxane and ethyl acetate The oily residue is dried under reduced pressure (55°C, 0.2 mm) for

12 hr to afford 11.8 g (97%) of analytically pure N-Boc-L-allylglycineas a viscous oil (Note 25).

2 Notes

1 Reagent-grade anhydrous lithium chloride (Mallinckrodt Inc.) is further dried by transferring the solid

to a flask equipped with a vacuum adapter The flask is evacuated (0.5 mm) and immersed in an oil bath

at 150°C After 12 hr at 150°C, the flask is allowed to cool to 23°C and is flushed with argon for storage

2 (R,R)-(−)-Pseudoephedrine was used as received from Aldrich Chemical Company, Inc

3 Tetrahydrofuran was obtained from EM Science and was distilled under nitrogen (atmospheric pressure) from sodium benzophenone ketyl

4 Lithium methoxide was purchased from Aldrich Chemical Company, Inc , and used as received

Butyllithium (BuLi) (10 M in hexanes) may be substituted for lithium methoxide in this reaction and produces a more rapid reaction For example, the use of 0.25 equiv of 10 M BuLi requires only 1-2 hr for complete reaction and affords 65-69% yield of anhydrous pseudoephedrine glycinamide on a 40-60-

g scale.2 The submitters describe the use of lithium methoxide as a less hazardous alternative to the highly pyrophoric 10 M BuLi

5 Glycine methyl ester is prepared by the method of Almeida et al.3 In a mortar and pestle, 80 g of

glycine methyl ester hydrochloride (used as received from Aldrich Chemical Company, Inc.) is ground

to a fine powder The powder is suspended in 600 mL of dry ether in a 1-L Erlenmeyer flask equipped with a Teflon-coated magnetic stirring bar Gaseous ammonia is bubbled rapidly through the vigorously stirred suspension After 2 hr, the addition of ammonia is discontinued, the product slurry is filtered through a coarse-fritted glass filter, and the filtrate is concentrated under reduced pressure at 23°C The liquid residue is distilled under reduced pressure (54-55°C at 18 mm) to provide 51.3 g (90%) of glycine methyl ester as a colorless liquid Glycine methyl ester will polymerize upon storage at room temperature, but may be stored at −20°C for short periods (up to two weeks) without significant decomposition

6 The monohydrate and anhydrous product show identical spectroscopic properties (Note 9) The monohydrate exhibits the following physical properties: mp 83-85°C; Anal Calcd for C12H18N2O2·H2O,

C, 59.93; H, 8.32; N, 11.66; Found C, 59.81; H, 8.42; N, 11.51

7 Alternatively, azeotropic drying with acetonitrile may be employed in lieu of

dichloromethane/potassium carbonate.2 A solution of 50.3 g of (R,R)-(−)-pseudoephedrine glycinamide monohydrate in ca 200 mL of acetonitrile is concentrated under reduced pressure The oily residue is dissolved in 250 mL of toluene and the resulting solution is concentrated under reduced pressure The oily residue obtained may be carried on directly in the alkylation procedure with only a slight decrease

in yield from the procedure described above Alternatively, anhydrous (R,R)-(−)-pseudoephedrine glycinamide may be precipitated and the resulting solid dried and carried forward as outlined above

8 Proper drying of (R,R)-(−)-pseudoephedrine glycinamide is essential to achieve high yields in the subsequent alkylation step Complete drying may not be achieved at temperatures below 50°C To prevent melting of the solid product, it should not be heated above 65°C A preliminary indication of the hydration state of the product is its melting point Material that is partially hydrated routinely has a melting point that is depressed relative to that of pure anhydrous product (mp 78-80°C) A more accurate determination of the water content may be obtained either from C,H,N analysis or by Karl Fischer titration The product is somewhat hygroscopic It may be weighed on the open benchtop without significant hydration; however, it should be stored under argon The glycinamide should be redried at 60°C under reduced pressure (0.5 mm) if it has been stored for an extended period, or if the yield of the subsequent alkylation reaction is lower than expected

9 The product shows the following physical and spectroscopic properties: mp 78-80°C; [α]23

D −101.2° (CH3OH, c 1.2); TLC Rf = 0.18 (5% CH3OH, 5% NEt3, 90% CH2Cl2); IR (neat) cm−1: 3361, 2981, 1633,

1486, 1454, 1312, 1126, 1049, 926, 760, 703 ; 1H NMR (1:1 ratio of rotamers, CDCl3) δ: 0.99 (d, 1.5 H,

J = 6.7), 1.09 (d, 1.5 H, J = 6.7), 2.11 [s(br), 3 H], 2.79 (s, 1.5 H), 2.97 (s, 1.5 H), 3.37 (d, 0.5 H, J = 17.1), 3.46 [d(obs)], 1 (H, J = 16.6), 3.72 (d, 0.5 H, J = 15.5), 3.88 (m, 0.5 H), 4.53-4.63 (m, 1.5 H), 7.29-7.40 (m, 5 H) ; 13C NMR (CDCl3) δ: 14.4, 15.3, 27.1, 30.1, 43.4, 43.7, 57.2, 57.5, 74.9, 75.8, 126.7, 126.9, 127.9, 128.2, 128.5, 128.7, 142.1, 142.3, 173.5, 174.1 Anal Calcd for C12H18N2O2: C, 64.84; H, 8.16; N, 12.60 Found: C, 64.65; H, 8.25; N, 12.53

10 Diisopropylamine was purchased from Aldrich Chemical Company, Inc , and distilled under

nitrogen (atmospheric pressure) from calcium hydrideprior to use

11 It is absolutely imperative that the solution of butyllithiumbe accurately titrated If an excess of

butyllithium (or LDA) is used, reduced yields will result as a consequence of a decomposition reaction that releases pseudoephedrine This is easily monitored by TLC analysis ( 5% methanol , 5%

triethylamine , and 90% dichloromethane eluent; UV and ninhydrin visualization) It should be noted that even optimal reaction conditions produce small amounts of this cleavage product (2-4%); however, the amount of cleavage is greatly enhanced in the presence of excess base To titrate the alkyllithium solution we recommend the method of Watson and Eastham.4 5 A standard solution of 1.00 M 2-butanol

(freshly distilled from calcium hydride) in toluene (freshly distilled from calcium hydride) is prepared in

a volumetric flask A 50-mL, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar and a rubber septum is charged with 5 mg of 2,2'-dipyridyl and 20 mL of ether The flask is flushed with argon, and a small amount (ca 0.5 mL) of the standard 1.00 M solution of 2-butanol in toluene is added to the solution The butyllithium solution to be titrated is added slowly, dropwise, to a single-drop end point that turns the solution dark red This initial titration eliminates complications due to moisture

or oxygen and should not be used in the calculation of the titer of the butyllithium solution Several repetitions of the titration cycle are conducted using the same indicator solution by using accurate, air-tight syringes and alternately adding aliquots of 1.00-M 2-butanol solution (1-2.5 mL) followed by titration of the butyllithium to a dark-red end point

12 The checkers employed 163 mL of a 2.70-M solution of butyllithium in hexanes whose titer was determined by the procedure given in (Note 11)

13 The addition required 80 min in the hands of the checkers

14 The reaction mixture was stirred for 40 min at 0°C by the checkers

15 Allyl bromide was purchased from Aldrich Chemical Company, Inc , and was distilled under argon

(atmospheric pressure) from calcium hydride immediately prior to use

16 The allyl bromide addition required 30 min in the hands of the checkers

17 The pH of the aqueous layer is checked after each extraction to ensure that it is >12 If necessary, the pH of the aqueous layer is readjusted to 14 by the addition of aqueous 50% sodium hydroxide

solution

18 The product shows the following physical and spectroscopic properties: mp 71-73°C; [α]23

D −86.4° (CH3OH, c 1.1); TLC Rf = 0.59 (5% CH3OH, 5% NEt3, 90% CH2Cl2); IR (neat) cm−1: 3354, 3072, 2978,

1632, 1491, 1453, 1109, 1051, 918, 762, 703 ; 1H NMR (3:1 rotamer ratio, CDCl3) major rotamer δ: 1.03 (d, 3 H, J = 6.4), 2.13 (m, 1 H), 2.23 (m, 1 H), 2.87 (s, 3 H), 3.65 (dd, 1 H, J = 7.5, 5.3), 4.55-4.59 (m, 2 H), 5.07-5.14 (m, 2 H), 5.64-5.85 (m, 1 H), 7.23-7.38 (m, 5 H); minor rotamer δ: 0.96 (d, 3 H, J = 6.7), 2.61-2.66 (m, 2 H), 2.93 (s, 3 H), 3.69 (m, 1 H), 4.03 (m, 1 H) ; 13C NMR (CDCl3) major rotamer δ: 14.4, 31.4, 39.6, 51.2, 57.6, 75.5, 118.1, 126.5, 127.6, 128.2, 133.7, 142.1, 176.1; minor rotamer δ: 15.5, 27.0, 39.8, 51.0, 74.9, 117.9, 126.8, 128.1, 128.5, 134.7, 141.8, 175.1 Anal Calcd for

C15H22N2O2: C, 68.67; H, 8.45; N, 10.68 Found: C, 68.57; H, 8.59; N, 10.70 Determination of the diastereomeric purity of the product by NMR is complicated by the presence of amide rotamers The diastereomeric purity of the product may be determined accurately and conveniently by preparing the corresponding diacetate and analyzing by capillary gas chromatography To prepare the diacetate, a 10-

mL, round-bottomed flask equipped with a Teflon-coated magnetic stirring bar and a rubber septum is charged with a 16-mg sample of the alkylation product to be analyzed and 1 mL of pyridine The product is acetylated by adding 1 mL of acetic anhydride and a catalytic amount ( 5 mg) of 4-(N,N-dimethylamino)pyridine The reaction mixture is stirred under argon for 1 hr and excess acetic anhydride is quenched by addition of 15 mL of water The reaction mixture is extracted sequentially with one 30-mL portion and one 20-mL portion of ethyl acetate The two organic extracts are individually and sequentially extracted with a single 15-mL portion of aqueous saturated sodium bicarbonate solution; the organic extracts are combined, dried over anhydrous sodium sulfate and filtered The filtrate is concentrated under reduced pressure, and the residue is dissolved in ethyl acetate

for capillary gas chromatographic analysis Analysis was carried out using a Chirasil-Val capillary column (25 m × 0.25 mm × 0.16 μm, available from Alltech Inc.) under the following conditions: oven temp 220°C, injector temp 250°C, detector temp 275°C The following retention times were observed: (R,R)-(−)-pseudoephedrine glycinamide diacetate, 6.69 min; (R,R)-(−)-pseudoephedrine L-allylglycinamide diacetate, 6.94 min; (R,R)-(−)-pseudoephedrine D-allylglycinamide diacetate, 6.32 min Note that the retention times can vary greatly with the age and condition of the column The checkers obtained the following values using an identical new column from Alltech with a flow rate of 4 mL/min, split ratio of 50:1, and an injection volume of 1 μL: retention times (min) 18.33 (D-allyl

isomer), 19.24 (glycinamide SM), 20.24 (L-allyl isomer).

19 The second crop of product crystals (mp 69-71°C) was contaminated with 2% of the starting material, (R,R)-(−)-pseudoephedrine glycinamide (as determined by GC analysis, (Note 18)), and was recrystallized to provide analytically pure product

20 Although the pseudoephedrine may be recovered by filtration at this stage, the recovery is not quantitative (ca 50-60%) A more efficient recovery is achieved by the extraction procedure described

21 Ammonium hydroxide is added to decrease the solubility of pseudoephedrine in the aqueous phase and to minimize the formation of emulsions

22 The product shows the following spectroscopic and physical properties: mp 275-280°C (dec.); lit.6

241-243°C (dec.); lit.7 283°C (dec.); [α]23

D −37.2° (H2O, c 4); lit.8 [α]23

D −37.1 (H2O, c 4) (Note 26); IR (KBr) cm−1: 3130, 2605, 1586, 1511, 1406, 1363, 1345, 1307, 919, 539 ; 1H NMR (D2O) δ: 2.50 (m, 2 H), 3.67 (dd, 1 H, J = 7.0, 5.1), 5.13 (d, 1 H, J = 10.0), 5.14 (d, 1 H, J = 18.6), 5.64 (m, 1 H) ; 13C NMR (D2O) δ: 35.6, 54.6, 120.9, 132.0, 175.1 Anal Calcd for C5H9NO2: C, 52.16; H, 7.88; N, 12.17 Found:

C, 52.15; H, 7.74; N, 12.03

The product is determined to be ≥99% ee by HPLC analysis on a Crownpak CR(+) column (pH 1.5 HClO4 mobile phase, 0.4 mL/min, 205 nm detection) The minor enantiomer was identified by comparison with an authentic sample prepared from (S,S)-(+)-pseudoephedrine glycinamide The following retention times are observed: D-allylglycine, 4.68 min; L-allylglycine, 5.45 min Using an identical new column and the identical eluent at a flow rate of 0.8 mL/min, the checkers observed retention times of 13.86 min for D-allylglycine and 15.19 min for L-allylglycine

23 Reagent grade p-dioxane was used as received from Mallinckrodt Inc

24 Di-tert-butyl dicarbonate was used as received from Aldrich Chemical Company, Inc

25 If necessary, residual ether may be removed by placing the oily product under reduced pressure (0.5 mm) and warming briefly with a heat gun The oily residue is typically found to be analytically pure product and requires no purification The product shows the following physical and spectroscopic characteristics: [α]23

H, 8.14; N, 6.56

In order to determine the enantiomeric excess of the product, the Boc protective group must be removed prior to HPLC analysis The sample is prepared by dissolving 23 mg of N-Boc allylglycine in 1 mL of

tetrahydrofuran and adding 2 mL of a 3 M aqueous hydrochloric acid solution The mixture is allowed

to stir at 23°C for 1 hr and then is concentrated under reduced pressure to provide a solid residue The solid is dissolved in water for HPLC analysis The product is determined to be ≥99% ee by analysis on a Crownpak CR(+) column (Note 22) and (Note 27)

26 The checkers obtained material having mp 240-242°C and [α]23

D −3.7° to −3.8° (CH2Cl2, c 1.1), all of which were determined to be ≥

99% ee by HPLC analysis on a Crownpak CR(+) column (Note 22)

Waste Disposal Information

All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995

3 Discussion

This procedure describes a highly practical method for the asymmetric synthesis of α-amino acids

by the alkylation of the chiral glycine derivative, pseudoephedrine glycinamide.10 This methodology has been used for the synthesis of a wide variety of α-amino acids and is distinguished by the fact that the glycine amino group is not protected in the alkylation reaction The method employs pseudoephedrine

as a chiral auxiliary Pseudoephedrine is readily available and inexpensive in both enantiomeric forms, and many of its N-acyl derivatives are crystalline solids The procedure that is described here for the enolization of pseudoephedrine glycinamide is modified from our previously reported metalation conditions9 by reaction temperature (0°C versus −78°C employed earlier) and the order of mixing of reagents (addition of lithium diisopropylamide to pseudoephedrine glycinamide versus addition of

pseudoephedrine glycinamide to lithium diisopropylamide) This modified procedure is more convienient for large-scale synthesis and is less sensitive to small errors in the titer of the butyllithium

solution The alkylation reaction proceeds in high yield using a wide variety of electrophiles and with excellent diastereoselectivity Like the alkylation substrates, the products of the alkylation reaction are frequently crystalline and are readily recrystallized to ≥99% de

The preparation of the alkylation substrate, pseudoephedrine glycinamide, is achieved in a single step from readily available and inexpensive reagents This reaction accomplishes amide bond formation between the secondary amino group of pseudoephedrine and the carboxyl group of glycine methyl ester

without protection of the glycine amino group This is possible, it is speculated, by the operation of a base-catalyzed mechanism involving transesterification of the methyl ester with the hydroxyl group of

pseudoephedrine, followed by intramolecular O N acyl transfer Pseudoephedrine glycinamide of both enantiomeric forms is easily prepared in large quantities by this procedure

A particularly advantageous feature of this method for the synthesis of α-amino acids is the simplicity and mildness of the hydrolysis of the pseudoephedrine amide bond to reveal the α-amino acid Two hydrolysis protocols are described, one for the isolation of enantiomerically pure α-amino acids, and the other for the preparation of N-acyl-α-amino acids of ≥99% ee Simply heating aqueous solutions of the alkylation products results in spontaneous cleavage of the amide bond (presumably by intramolecular N O acyl transfer, followed by hydrolysis of the resulting α-amino ester) and is ideal for isolation of the free α-amino acid under salt-free conditions, thus obviating the need for ion-exchange chromatography Heating the alkylation products in the presence of alkali accelerates the cleavage reaction and allows the direct N-acylation of the hydrolysis products by the addition of an acylating agent to the aqueous alkaline α-amino acid solution N-Protected α-amino acids are thus prepared in a single synthetic operation Both hydrolysis procedures are highly efficient and proceed without significant racemization (≤1%) In both procedures, the chiral auxiliary is easily recovered in crystalline form in high yield

References and Notes

1 Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena,

CA 91125

2 Myers, A G.; Yoon, T.; Gleason, J L Tetrahedron Lett 1995, 36, 4555

3 Almeida, J F.; Anaya, J.; Martin, N.; Grande, M.; Moran, J R.; Caballero, M C Tetrahedron:

Asymmetry 1992, 3, 1431

4 Watson, S C.; Eastham, J F J Organomet Chem 1967, 9, 165;

5. Gall, M.; House, H O Org Synth., Coll Vol VI 1988, 121

6 Broxterman, Q B.; Kaptein, B.; Kamphius, J.; Schoemaker, H E J Org Chem 1992, 57, 6286

7 Fluka Chemical Guide, 1995-1996, 70

8 Black, S.; Wright, N G J Biol Chem 1955, 213, 39

9 Williams, R M.; Im, M.-N J Am Chem Soc 1991, 113, 9276

10 Myers, A G.; Gleason, J L.; Yoon, T J Am Chem Soc 1995, 117, 8488

Appendix Chemical Abstracts Nomenclature (Collective Index Number);

(Registry Number)

Methanol, lithium salt (8,9); (865-34-9)

Glycine methyl ester (8,9); (616-34-2)

Butylamine, N,N-dimethyl-, lithium salt (8);

2-Propanamine, N-(1-methylethyl)-, lithium salt (9); (4111-54-0)

Formic acid, oxydi-, di-tert-butyl ester (8);

Dicarbonic acid, bis(1,1-dimethylethyl) ester (9), (24424-99-5)

Glycine methyl ester hydrochloride:

Glycine methyl ester, hydrochloride (8,9); (5680-79-5)

Organic Syntheses, Coll Vol 10, p.12 (2004); Vol 77, p.22 (2000)

SYNTHESIS AND DIASTEREOSELECTIVE ALKYLATION OF

((1S,2S)-coated magnetic stirring bar is charged with 21.3 g (129 mmol) of (1S,2S)-(+)-pseudoephedrine (Note 1) and 250 mL of tetrahydrofuran(Note 2) The flask is placed in a water bath at 23°C, and to the well-stirred solution, 18.0 g (138 mmol) of propionic anhydride(Note 3) is added by a Pasteur pipette in 1-

mL portions over approximately 5 min The flask is sealed with a rubber septum containing a needle adapter to an argon-filled balloon, and the clear, colorless solution is allowed to stir at 23°C for an additional 10 min The rubber septum is removed, and the reaction solution is neutralized by the addition of 400 mL of saturated aqueous sodium bicarbonate solution After thorough mixing (Note 4), the biphasic mixture is poured into a separatory funnel and extracted with three portions of ethyl acetate

(250 mL, 150 mL, and 150 mL, respectively) The combined organic extracts are dried over anhydrous

sodium sulfate , filtered, and concentrated under reduced pressure to afford a white solid Residual solvent is removed under vacuum (0.5 mm) for 3 hr The solid residue is dissolved in 125 mL of hot (110°C) toluene in a 250-mL Erlenmeyer flask, and the flask is placed in a water bath at 80°C This bath

is allowed to cool slowly to 23°C Extensive crystallization occurs as the solution cools Crystallization

is completed by cooling the flask to −20°C After 10 hr, the crystals are collected by filtration and rinsed with 100 mL of cold (0°C) toluene The crystals are dried under reduced pressure (0.5 mm) at 23°C for

3 hr to afford 27.2 g (95%) of the (1S,2S)-pseudoephedrinepropionamide as a white solid (Note 5)

B [1S(R),2S]-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N,2-dimethylbenzenepropionamide, pseudoephedrine-(R)-2-methylhydrocinnamamide] A flame-dried, 2-L, three-necked, round-bottomed

[(1S,2S)-flask equipped with a mechanical stirrer and an inlet adapter connected to a source of argon is charged with 25.0 g (590 mmol) of anhydrous lithium chloride(Note 6) and sealed with a rubber septum The inlet adapter is removed and replaced with a rubber septum containing a needle adapter to an argon-filled balloon The reaction flask is charged with 31.3 mL (223 mmol) of diisopropylamine(Note 7) and

120 mL of tetrahydrofuran(Note 2) The mixture is cooled to −78°C in a dry ice-acetone bath, and 85.1

mL (207 mmol) of a 2.43 M solution of butyllithium in hexanes (Note 8) is added via cannula over 10 min The resulting suspension is warmed to 0°C in an ice-water bath and is held at that temperature for

5 min, then cooled to −78°C An ice-cooled solution of 22.0 g (99.4 mmol) of pseudoephedrinepropionamide in 300 mL of tetrahydrofuran(Note 2) is transferred to the cold reaction mixture by cannula over 10 min The reaction mixture is stirred at −78°C for 1 hr, at 0°C for 15 min, at 23°C for 5 min, and finally is cooled to 0°C, whereupon 17.7 mL (149 mmol) of benzyl bromide(Note 9) is added over 3 min via syringe After 15 min, 5 mL of saturated aqueous ammonium chloride

(1S,2S)-solution is added, and the reaction mixture is poured into a 2-L separatory funnel containing 800 mL of saturated aqueous ammonium chloride solution and 500 mL of ethyl acetate The aqueous layer is

DOI:10.15227/orgsyn.077.0022

separated and extracted further with two 150-mL portions of ethyl acetate The combined organic extracts are dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to afford a yellow solid Residual solvent is removed under vacuum (0.5 mm) for 3 hr The solid residue is dissolved in 100 mL of hot (110°C) toluene in a 250-mL Erlenmeyer flask, and the flask is placed in a water bath at 80°C The bath is allowed to cool slowly to 23°C Extensive crystallization occurs as the solution cools Crystallization is completed by cooling the flask to −20°C After 10 hr, the crystals are collected by filtration and are rinsed with 100 mL of cold (0°C) toluene The crystals are dried under reduced pressure (0.5 mm) at 23°C for 3 hr to afford 27.8 g (90%) of the desired (1S,2S)-pseudoephedrine-(R)-2-methylhydrocinnamamide as a white solid (Note 10) The diastereomeric excess (de) of this product is determined to be ≥99% (Note 11)

2 Notes

1 (1S,2S)-(+)-Pseudoephedrine was obtained from Aldrich Chemical Company, Inc , and was used without further purification

2 Tetrahydrofuran was distilled from sodium benzophenone ketyl under an atmosphere of nitrogen

3 Propionic anhydride was obtained from Aldrich Chemical Company, Inc , and used without further purification

4 Because of the large volume of CO2 released during the neutralization of propionic acid, care should

be taken that the propionic acid is quenched before the reaction mixture is sealed and shaken inside a separatory funnel

5 The product exhibits the following properties: mp 114-115°C; 1H NMR (300 MHz, C6D6) δ: 0.53 (d, J

= 6.7), 0.9-1.1 (m), 1.22 (t, J = 7.3), 1.73 (m), 2.06 (s), 2.40 (m), 2.77 (s), 3.6-3.75 (m), 4.0-4.2 (m), 4.51 (t, J = 7.2), 4.83 (br), 6.95-7.45 (m) ; 13C NMR (75 MHz, CDCl3) δ: 9.0, 9.4, 14.2, 15.2, 26.6, 27.3, 27.6, 32.1, 57.7, 58.1, 75.0, 76.1, 126.3, 126.7, 127.4, 127.9, 128.1, 128.3, 141.5, 142.2, 174.8, 175.8 (The 1H and 13C NMR spectra are complex due to amide geometrical isomerism); IR (neat) cm−1: 3380 (OH), 2979, 1621 (C=O), 1454, 1402, 1053, 702 ; HRMS (FAB) m/z 222.1490 [(M+H)+ calcd for

C13H20NO2: 222.1495] Anal Calcd for C13H19NO2: C, 70.56; H, 8.65; N, 6.33 Found: C, 70.55; H, 8.50; N, 6.35

6 Anhydrous lithium chloride (99+%, A.C.S reagent grade) was purchased from Aldrich Chemical Company, Inc , and was further dried as follows The solid reagent is transferred to a flask fitted with a vacuum adapter The flask is evacuated (0.5 mm) and immersed in an oil bath at 150°C After heating for 12 hr at 150°C, the flask is allowed to cool to 23°C and is flushed with argon for storage

7 Diisopropylamine was distilled from calcium hydride under an atmosphere of nitrogen

8 Butyllithium (2.5 M solution in hexanes) was purchased from Aldrich Chemical Company, Inc , and was titrated against diphenylacetic acid 2

9 Benzyl bromide was obtained from Aldrich Chemical Company, Inc , and purified by passage through 5 g of activated basic aluminum oxide

10 The product exhibits the following properties: mp 136-137°C; 1H NMR (300 MHz, C6D6) δ: 0.59 (d,

J = 6.8), 0.83 (d, J = 7.0), 1.02 (d, J = 6.5), 1.05 (d, J = 7.0), 2.08 (s), 2.45-2.59 (m), 2.70 (s), 2.75 (m), 3.01 (m), 3.36 (dd, J = 13.1, 6.92), 3.80 (m), 3.96 (m), 4.25 (br), 4.45 (m), 6.9-7.4 (m) ; 13C NMR (75 MHz, CDCl3) δ: 14.3, 15.5, 17.4, 17.7, 27.1, 32.3, 38.1, 38.9, 40.0, 40.3, 58.0, 75.2, 76.4, 126.2, 126.4, 126.8, 127.5, 128.26, 128.31, 128.6, 128.9, 129.2, 139.9, 140.5, 141.1, 142.3, 177.2, 178.2 (The 1H and

13C NMR spectra are complex due to amide geometrical isomerism); IR (neat) cm−1: 3384 (OH), 3027,

chlorotrimethylsilane After 10 min, the cloudy reaction mixture is quenched with 5 mL of water, and the mixture is transferred to a 125-mL separatory funnel with 50 mL of 50% ethyl acetate-hexanes The organic layer is separated and extracted further with 5 mL of water followed by 5 mL of brine The organic layer is dried over anhydrous sodium sulfate, filtered, and concentrated The oily residue is dissolved in ethyl acetate for capillary gas chromatographic analysis The analysis is carried out using a Chirasil-Val capillary column (25 m × 0.25 mm × 0.16 μm, Alltech, Inc.) under the following

conditions: oven temp 200°C, injector temp 250°C, detector temp 275°C The following retention times were observed: 8.60 min (minor diastereomer), 9.27 min (major diastereomer) It should be noted that the retention times can vary greatly depending on the age and condition of the column

Dichloromethane was purchased from EM Science and was distilled from calcium hydride under an atmosphere of nitrogen Triethylamine and chlorotrimethylsilane were purchased from Aldrich Chemical Company, Inc , and were distilled from calcium hydride under an atmosphere of nitrogen

Waste Disposal Information

All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995

3 Discussion

This procedure describes the use of pseudoephedrine as a chiral auxiliary for the asymmetric alkylation of carboxylic acid amides In addition to the low cost and availability in bulk of both enantiomeric forms of the chiral auxiliary, pseudoephedrine, a particular advantage of the method is the facility with which the pseudoephedrine amides are formed In the case of carboxylic acid anhydrides, the acylation reaction occurs rapidly upon mixing with pseudoephedrine Because pseudoephedrine amides are frequently crystalline materials, the acylation products are often isolated directly by crystallization, as illustrated in the procedure above

Pseudoephedrine amides undergo highly diastereoselective and efficient alkylation reactions Like the alkylation substrates, the alkylation products are frequently crystalline compounds, and can often be isolated in ≥99% de by direct crystallization from the crude reaction mixture The procedure described above is representative of this methodology and can be generally employed with a wide range of pseudoephedrine amides and alkylating agents.3 , 4 The transformation of the alkylation products into highly enantiomerically enriched alcohols, aldehydes, and ketones, provides access to a large number of useful intermediates for organic synthesis, as described in the accompanying procedure

References and Notes

1 Division of Chemistry and Chemical Engineering, California Institute of Technology, Pasadena,

CA 91125

2 Kofron, W G.; Baclawski, L M J Org Chem 1976, 41, 1879

3 Myers, A G.; Yang, B H.; Chen, H.; Gleason, J L J Am Chem Soc 1994, 116, 9361

4 Myers, A G.; Yang, B H.; Chen, H.; McKinstry, L.; Kopecky, D J.; Gleason, J L J Am Chem

Soc 1997, 119, 6496

Appendix Chemical Abstracts Nomenclature (Collective Index Number);

Propanoic acid, anhydride (9); (123-62-6)

Organic Syntheses, Coll Vol 10, p.23 (2004); Vol 79, p.196 (2002)

2-AMINO-3-FLUOROBENZOIC ACID

[ Benzoic acid, 2-amino-3-fluoro- ]

Submitted by Martin Kollmar, Richard Parlitz, Stephan R Oevers, and Günter Helmchen1 Checked by Hui Li and Marvin J Miller

1 Procedure

A N-(2-Fluorophenyl)-2-(hydroxyimino)acetamide (2) Solution A: A 2-L, three-necked,

round-bottomed flask fitted with a condenser and a thermometer is charged with 62.0 g (0.89 mol) of

hydroxylamine hydrochloride , 256.7 g (1.80 mol) of anhydrous sodium sulfate , 79.5 g (0.41 mol) of

2,2,2-trichloro-1-ethoxyethanol (Note 1) and 1125 mL of water To aid dissolution, the mixture is heated to approximately 40°C and stirred vigorously with the help of a mechanical stirrer (Note 2) Solution B: 30 g (0.27 mol) of 2-fluoroaminobenzene(Note 3) is added dropwise slowly into a 500-mL, one-necked, round-bottomed flask containing a vigorously stirred mixture of 150 mL of water and 75

mL of concd hydrochloric acid(Note 4) Solution B is added in one portion to solution A The mixture

is vigorously stirred and heated to reflux After 1 to 2 min the mixture turns milky and a white precipitate accompanied by a small amount of brown by-product is formed (Note 5) The oil bath is removed and the flask is cooled rapidly (ice bath) to room temperature (20°C) (Note 6) After 60 hr at room temperature the precipitate is removed by filtration and washed with ice-cold water (Note 7) After drying over phosphorus pentoxide (P4O10), 43.6 g (86%) of product, mp 116-117°C, is obtained (Note 8) Crystals glued together by brown by-product, mainly consisting of the product, can be used in the next step without further purification Nearly colorless product is obtained by recrystallization from

ethanol

B 7-Fluoroisatin (3) A 250-mL, three-necked, round-bottomed flask fitted with a condenser and a

thermometer is charged with 100 mL of concd sulfuric acid After heating to 70°C, 30.0 g (0.165 mol)

of anilide 2 (Note 9) is added over a period of 1 hr The resulting deep red solution is heated to 90°C (Note 10) for 60 min (Note 11) and then is cooled to room temperature (20°C) over an ice bath (Note 12) The mixture is then added rapidly to a vigorously stirred mixture of 1.0 L of ice water and 200 mL

of ethyl acetate (Note 13) The organic phase is separated and the almost black aqueous phase is extracted twice with 200 mL of ethyl acetate(Note 14) The combined red organic phases are dried with

sodium sulfate The solvent is removed under reduced pressure and the crude product is dried at low pressure, whereupon 12.9 to 15.7 g (47-57%) of an orange powder, mp 186-190°C, is obtained (Note

DOI:10.15227/orgsyn.079.0196

15) The crude product is sufficiently pure for the next step Further purification is possible by recrystallization from acetone/water

C 2-Amino-3-fluorobenzoic acid (4) A 500-mL, three-necked, round-bottomed flask fitted with an

addition funnel and a thermometer, is charged with 15.0 g (0.09 mol) of 7-fluoroisatin (3) and 200 mL

of 1 M aqueous sodium hydroxide solution (Note 16); 22 mL of hydrogen peroxide (30%) solution (0.20 mol hydrogen peroxide) is added dropwise over 45 min The temperature of the reaction mixture rises to 30° or 40°C After 1.5 hr the reaction is complete (Note 17) To the pale orange, clear reaction mixture 3 M hydrochloric acid is added until a pH of ca 7.5 is reached The mixture is treated with charcoal, stirred for a while, filtered and the clear filtrate is further acidified to pH 4-5, when the now pale yellow solution becomes cloudy again Finally, at pH 1 the beige 3-fluoroanthranilic acid (4)

precipitates Bubbles are observed during acidification After an hour of stirring, the product is collected

on a funnel and dried over P4O10; yield: 11.64 to 13.3 g (84-96%) of pure 3-fluoroanthranilic acid (4),

3 The quality of the commercially available (colorless) 2-fluoroaminobenzene (1) is sufficient (Fluka

Chemical Company) Older or colored material requires distillation prior to use (bp 171°C, d = 1.15)

4 Dissolution of aniline 1 is exothermic and it should therefore be added in small portions Complete

dissolution is essential in order to avoid the formation of dark tar-like by-products

5 The longer the solution boils the more tar-like by-product is formed One to two min of boiling are necessary and sufficient for complete conversion of the reactants

6 The reaction mixture must not be cooled to 0°C as this leads to the precipitation of inorganic salts

7 The long period is necessary to obtain maximum yield

8 Spectral characteristics are as follows: IR (KBr) cm−1 : 3390 m (O-H), 1660 s (C=O), 1618 s (C=N),

1546, 1486, 1460 s (C=C), 1260 s (C-F)], 1021 m [ν(N-O)], 756 s [ν(C-H)arom] ; 1H NMR (CD3OD, 500.13 MHz) δ: 7.09 (m, 3 H, H-3, H-4, H-5), 7.53 (s, 1 H, HC=NOH), 7.94 (m, 1 H, H-6) ; 13C NMR (CD3OD,75.47 MHz) δ: 116.33 (d, 2JF,3 = 19.8, C-3), 124.76 (C-5), 125.47 (d, 3JF,6 = 4.0, C-6), 126.53 (d, 2JF,1 = 11.3, C-1), 126.99 (d, 3JF,4 = 7.9, C-4), 144.01 (HC=NOH), 155.42 (d, 1JF,2 = 245.3, C-2), 162.88 (C=O)

9 Anilide 2 has to be completely dry Residual water reacts violently with the acid with heat generation

causing decomposition

10 By-products form if the temperature is too high Anilide 2 does not dissolve completely if the

temperature is below 50°C and then the reaction does not go to completion

11 The progress of the reaction can be monitored by hydrolysis of a sample, extraction with ethyl acetate , and TLC [silica gel Macherey, Nagel & Co "Polygram Sil G/UV 254", petroleum ether/ethyl acetate/acetic acid 99:50:1, UV visualization, Rf (2) = 0.40, Rf (3) = 0.31 (yellow spot)]

12 If the temperature is too high, tar-like by-products form If the solution is cooled to 0°C, hydrolysis does not take place because the sulfuric acid does not mix with the hydrolysis solution and mainly

oxime 5 is obtained

13 The presence of ethyl acetate is essential as otherwise the yellow oxime 5 (mp 233-235°C) is formed

in yields of 20-30% Ethyl acetate is added in order to extract the isatin 3 from the aqueous phase immediately upon formation Oxime 5 is probably formed by reaction of isatin 3 with hydroxylamine

generated by decomposition of unreacted anilide 2.2

Spectral characteristics of 7-fluoroisatin 3-oxime (5) are as follows: TLC: silica gel Macherey, Nagel &

Co "Polygram Sil G/UV 254", petroleum ether/ethyl acetate PE/EE 2:1 elution, 2 drops of glacial acetic acid , UV visualization, Rf = 0.19; IR (KBr) cm−1: ≈3500 m, br (OH), 1723 s (C=O), 1640 s (C=N),

1596, 1494, 1445 m (C=C), 1208 m (C-F), 942 m (N-O), 794 w νC-Harom) ; 1H NMR (acetone-d6, 500.13 MHz) δ: 7.06 (ddd, 1 H, 4J5,F + 4.6, 3J4,5 = 7.5, 3J5,6 = 8.5, H-5), 7.20 (ddd, 1 H, 4J4,6 =1.1, 3J5,6 = 8.5, 3J6,F = 10.1, H-6), 7,83 (dd, 1 H, 4J4,6 = 1,0, 3J4,5 = 7.0, H-4), 10.14 (bs, 1 H, N-H), 12.75 (bs, 1H, N-OH) ; 13C NMR (acetone-d6, 125.76 MHz) δ: 115.75 (d, 3JF,3 = 4.2, C-3a), 115.96 (C-6), 120.33 (C-5), 120.43 (C-4), 126.40 (d, 2JF,8 = 13.4, C-7a), 140.65 (d, 4JF,2 = 4.1, C-3), 143.85 (d, 1JF,7 = 243,2, C-7), 161.71 (C-2) ; HR-MS (EI, direct insert): m/z 180.03322 (M+ exact mass calcd for C8H5O2N2F: 180.0335), 163.0070 (M+ - OH), 152.0365 (M+ - CO), 135.0359 (M+ - CO2H), 108.0271 (M+ - CO - OH

- HCN) Anal Calcd for C8H5FN2O2: C, 53.43; H, 2.80; N, 15.55 Found: C, 53.34; H, 3.08; N, 15.28

14 If the aqueous phase is extracted more than twice, the yield may rise, but the oxime 5 and other

by-products are extracted as well

15 Spectral characteristics are as follows: IR (KBr) cm−1: 3446 w (NH-CO), 1737 s (C3=O), 1637 s (C2=O), 1602, 1495, 1452 m (C=C), 1209 m (C-F), 780 w (C-H)arom ; 1H NMR (acetone-d6, 500.13 MHz) δ: 7.14 (ddd, 1 H, 4J5,F = 4.2, 3J4,5 = 7.7, 3J5,6 = 8.3, H-5), 7.39 (dd, 1 H, 4J4,6 = 1.1, 3J4,5 = 7.4, H-4), 7.48 (ddd, 1 H, 4J4,6 = 1.0, 3J4,5 = 8.4, 3J6,F = 10.2, H-6), 10.45 (bs, 1 H, N-H) ; 13C NMR (acetone-d6, 125.76 MHz) δ: 119.15 (d, 3JF,3 = 3.4, C-3a), 119.26 (d, 4JF,4 = 3.5, C-4), 122.52 (d, 3JF,5 = 5.3, C-5), 123.57 (d, 2JF,6 = 17.6, C-6), 136.20 (d, 2JF,8 = 13.9, C-7a), 146.38 (d, 1JF,7 = 246.8, C-7), 157.29 (C-2), 181.70 (d, 4JF,2 = 4.5, C-3)

16 Previously3 3 N or 10 N NaOH was used The submitters found that this reaction also proceeds to completion at room temperature in 1 N NaOH solution

17 Monitoring was carried out by extracting acidified samples with ethyl acetate and TLC [silica gel Macherey, Nagel & Co "Polygram Sil G/UV 254", petroleum ether/ethyl acetate/acetic acid 99:50:1, visualization of spots by UV Rf = 0.37 (spot shows strong blue fluorescence)]

18 Spectral characteristics of 4 are as follows: IR (KBr) cm−1: 3500-3391 m (NH2), 3085 m, br (CO2H), 1678 s (C=O), 1630 w (C-NH2)], 1590, 1562, 1476 m (C=C)], 780 w (C-Harom) ; 1H NMR (acetone-

-d6, 500.13 MHz) δ: 6.58 (ddd, 1 H, 4J5,F = 4.9, 3J5,6 = 7.9, 3J4,5 = 8.0, H-5), 6.84 (bs, 1 H), 7.19 (ddd, 1 H,

4J4,6 = 1.3, 3J4,5 = 8.0, 3J4,F = 11.6, H-4), 7.31 (bdd, 1 H), 7.63 (bd, 1 H), 7.67 (ddd, 1 H, 3J6,F = 1.3, 4J4,6 = 1.3, 3J5,6 = 7.9, H-6) ; 13C NMR (acetone-d6, 125.76 MHz) δ: 108.71 (d, 3JF,1 = 4.5, C-1), 110.30 (d, 3JF,5

= 7.0, C-5), 114.51 (d, 2JF,4 = 18.5, C-4), 122.97 (d, 4JF,6 = 3.0, C-6), 136.35 (d, 2JF,2 = 14.0, C-2), 147.55 (d, 1JF,3 = 237.4, C-3), 165.27 (d, 4JF,7 = 3.4, C-7)

Waste Disposal Information

All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995

3 Discussion

Anthranilic acids are important intermediates for the preparation of heterocycles The previously described procedure,3 used here as the starting point, works well for compounds not containing electron-withdrawing substituents This modified procedure thus extends the range of applicability

2-Amino-3-fluorobenzoic acid is an important intermediate in the synthesis of derivatives of indole , such as the potent and selective thromboxane/prostaglandin endoperoxide receptor antagonist L-670,5964 or the anti-inflammatory agent Etodolac.5 Compounds of this type have therapeutic applications 2-Amino-3-fluoro-benzoic acid is also an important precursor for the synthesis of fluoroacridines, which can be converted to interesting tridentate ligands, such as Acriphos.6

The steps described above at least triple yields that were previously reported;3 in particular the yield

of the second step is improved significantly No chromatography is required for purification and all reactions can be carried out on a larger scale, the only limiting factor being the scale of the laboratory equipment Of advantage is the use of water as solvent in all three steps

In order to assess the generality of this procedure for the preparation of acceptor-substituted anthranilic acids it was applied to 2-amino-3-chlorobenzoic acid , which was obtained with excellent overall yield of 53% (lit.3: 16%)

References and Notes

1 Organisch-Chemisches Institut der Universität Heidelberg, Im Neuenheimer Feld 270, D-69120

Heidelberg, Germany and (S.R.O.) Max-Planck-Institut für Kohlenforschung,

Kaiser-Wilhelm-Platz 1, D-45470 Mühlheim an der Ruhr, Germany

2 Wibaut, J P.; Geerling, M C Rec Trav Chim 1931, 50, 41

3 (a) Holt, S J.; Sadler, P W Proc Roy Soc B 1958, 148, 481; (b) McKittrick, B.; Failli, A.;

Steffan, R J.; Soll, R M.; Hughes, P.; Schmid, J.; Asselin, A A.; Shaw, C.C.; Noureldin, R.;

Gavin, G J Heterocycl Chem 1990, 27, 2151

4 Ford-Hutchinson, A W.; Girard, Y.; Lord, A.; Jones, T R.; Cirino, M.; Evans, J F.; Gillard, J.;

Hamel, P.; Leveille, C.; Masson, P.; Young, R Can J Physiol Pharmacol., 1989, 67, 989

5 (a) Demerson, C A.; Humber, L G.; Philipp, A H.; Martel, R R J Med Chem 1976, 19, 391;

(b) Humber, L G.; Med Res Rev 1987, 7, 1

6 Hillebrand, S.; Bartkowska, B.; Bruckmann, J.; Krüger, C.; Haenel, M W Tetrahedron Lett

1998, 39, 813

Appendix Chemical Abstracts Nomenclature (Collective Index Number);

(Registry Number)

2-Amino-3-fluorobenzoic acid:

Anthranilic acid, 3-fluoro- (8);

Benzoic acid, 2-amino-3-fluoro- (10); (825-22-9)

1H-Indole-2,3-dione, 7-fluoro-, 3-oxime (13); (143884-84-8)

Copyright © 1921-2005, Organic Syntheses, Inc All Rights Reserved

Organic Syntheses, Coll Vol 10, p.29 (2004); Vol 76, p.46 (1999)

(1S,2R)-1-AMINOINDAN-2-OL [ 1H-Inden-2-ol, 1-amino-2,3-dihydro-(1S-cis)- ]

Submitted by Jay F Larrow1 , Ed Roberts2 , Thomas R Verhoeven2 , Ken M Ryan2 , 3 , Chris H Senanayake2 , 4 , Paul J Reider2 , and Eric N Jacobsen1

Checked by Stephanie A Lodise and Amos B Smith, III

1 Procedure

A (1S,2R)-Indene oxide A 500-mL, three-necked, round-bottomed flask equipped with an

overhead mechanical stirrer, a 125-mL addition funnel, and a thermocouple is charged with indene

((Note 1), 29.0 g, 0.25 mol, 1 equiv), dichloromethane (CH2Cl2) (30 mL), butylsalicylidene)-1,2-cyclohexanediaminomanganese(III) chloride (0.953 g, 1.5 mmol, 0.6 mol% , (Note 2)), and 4-phenylpyridine N-oxide ((Note 3), 1.28 g, 7.5 mmol, 3.0 mol%) under a nitrogen (N2) atmosphere The resulting brown mixture is cooled to −5°C, and then a cold sodium hypochlorite

(S,S)-(N,N')-bis(3,5-di-tert-(NaOCl) solution (191 mL, 1.7 M, 1.3 equiv, (Note 4)) is added slowly with vigorous stirring while maintaining the reaction temperature between 0°C and 2°C (Note 5) Upon complete addition of the bleach, the reaction is stirred for an additional 1 hr at 0°C At this point, hexanes (200 mL) are added in one portion with stirring, and the reaction mixture is filtered through a pad of Celite on a large Büchner funnel The filter cake is washed with dichloromethane (2 × 50 mL), and the filtrate is transferred to a 500-mL separatory funnel The lower aqueous layer is removed, and the brown organic layer is washed with aqueous saturated sodium chloride (NaCl) solution (100 mL) The organic layer is dried over

sodium sulfate (Na2SO4), filtered, and concentrated by rotary evaporation A small amount of calcium hydride (CaH2) (100 mg) is added to the brown residue, and the epoxide is isolated by short path

DOI:10.15227/orgsyn.076.0046

vacuum distillation, bp 58-60°C (0.025 mm), to yield 24.0 g of epoxyindane (84-86% ee) as a colorless to slightly yellow liquid (0.197 mol, 71% yield, (Note 6), (Note 7), and (Note 8))

B (1S,2R)-1-Aminoindan-2-ol (crude) A dry, 1000-mL, three-necked, round-bottomed flask

equipped with a large magnetic stir bar, a 250-mL addition funnel, a 50-mL addition funnel, and a thermocouple is charged with dry acetonitrile (100 mL , (Note 9)) and cooled to −5°C under a N2atmosphere The mixture is stirred vigorously, and slow addition of fuming sulfuric acid (20 mL, 0.4 mol, 2 equiv, 27-33% SO3, (Note 10)) is begun, followed by dropwise addition of a solution of the epoxide (26.0 g, 0.197 mol) in dry hexanes (200 mL, (Note 9)) The reagents are added simultaneously

at a rate such that the reaction temperature is maintained between 0 and 5°C After the additions are complete, the reaction mixture is warmed to room temperature and stirred for 1 hr Water (100 mL) is added via the addition funnel over 10-15 min, and the resulting biphasic mixture is stirred for an additional 30 min The lower aqueous phase is separated, diluted with 100 mL of water and concentrated by distillation at atmospheric pressure to a head temperature of 100°C The mixture is heated at reflux for 3 hr, after which time the mixture is cooled to room temperature The crude aqueous solution of aminoindanol is used without further purification in the next step (Note 11)

C (1S,2R)-1-Aminoindan-2-ol (100% ee) A 500-mL, three-necked, round-bottomed flask equipped

with a large magnetic stir bar, a 125-mL addition funnel, a pH probe, and a thermocouple is charged with the hydrolysis solution from Part B and 1-butanol (100 mL) Sodium hydroxide (80 mL of an aqueous 50% solution, (Note 12)) is added slowly with external ice bath cooling to maintain the temperature below 30°C until the reaction mixture reaches a pH of 12-13 The upper 1-butanol layer is separated, and the aqueous layer is extracted with another 100 mL of 1-butanol The combined butanol

extracts are diluted with methanol (200 mL), and vacuum-filtered through a Büchner funnel into a

2000-mL, three-necked, round-bottomed flask equipped with a mechanical overhead stirrer, 250-mL addition funnel, and reflux condenser The reaction mixture is stirred vigorously and heated to reflux, and a solution of L-tartaric acid (35.5 g, 0.24 mol, 1.2 equiv) in methanol (200 mL) is added over 15-30 min while reflux is maintained Heating is discontinued until a thick but stirrable slurry is formed (Note 13) The suspension is reheated to reflux for 2 hr (Note 14) At this point, the mixture is cooled to room temperature and allowed to stand for 1 hr The resulting solids are collected on a Büchner funnel and washed with methanol (2 × 100 mL) The white solid thus obtained is then dried under reduced pressure

to yield 47.4 g of the 1:1 tartrate salt (Note 15)

A 300-mL, three-necked, round-bottomed flask equipped with a large magnetic stir bar, a 125-mL addition funnel, a pH probe, and a thermocouple is charged with the aminoindanol-tartrate salt Water (95 mL, 2:1 v/w) is added, and the mixture is stirred under a N2 atmosphere Aqueous sodium hydroxide

(50 wt-%, 23 mL, 2 equiv, (Note 12) and (Note 16)) is added with external ice bath cooling until the reaction mixture reaches pH 12-13, resulting in precipitation of the aminoindanol free base The mixture

is cooled to 0°C and allowed to stand at that temperature for an additional 30 min The white to tan solid

is collected by vacuum filtration, washed with ice-cold water (20 mL), and air-dried on the filter The solid is dissolved in hot toluene (1:10 w/v, (Note 17)), and the resulting solution is allowed to cool to room temperature, then further cooled to 4°C for 1 hr The resulting white solid is collected by vacuum filtration, washed with cold toluene (20 mL), and dried under reduced pressure The total yield of

aminoindanol (100% ee, (Note 18)) is 17.2 g, mp 122-124°C (Note 19)

2 Notes

1 Technical grade indene (92%) was obtained from Aldrich Chemical Company, Inc , and was passed through a 10 × 10-cm column of basic alumina to remove highly colored impurities The compound was then distilled under a N2 atmosphere from a small amount of CaH2 The distillate was stored under N2 at 4°C

2 The epoxidation catalyst was prepared according to the published procedures.5 6 Alternatively, research quantities can be purchased from Aldrich Chemical Company, Inc., or bulk quantities can be purchased from ChiRex Ltd, Dudley, UK

3 4-Phenylpyridine N-oxide was purchased from Aldrich Chemical Company, Inc., and used as received Other pyridine N-oxide derivatives have been used with success in the epoxidation reaction The choice of the pyridine N-oxide derivative has been demonstrated to have a small yet measurable

impact on both the rate of reaction and the enantiomeric excess of the product epoxide.7 8 9

4 Commercial 10-13% NaOCl was purchased from Aldrich Chemical Company, Inc , and stored at 4°

C The concentration of bleach was determined according to the method of Kolthoff and Belcher.10

To a 250-mL Erlenmeyer flask containing a magnetic stir bar was added 2 mL of the commercial NaOCl solution, 100 mL of water, 1.5 mL of concd HCl , and 7 g of potassium iodide The resulting dark brown solution was titrated with a 1 M solution of sodium thiosulfate (Na2S2O3) The endpoint is reached when the solution becomes colorless Using the following equations, the concentration of the NaOCl solution can be calculated OCl− + 2I− + 2H+ H2O + Cl− + I2 2S2O3 + I2 S4O6 + 2I−

The solution (191 mL) used by the submitters was found to be 1.7 M in NaOCl and was then made 0.2

M in sodium hydroxide (NaOH) by the addition of 1.52 g of solid NaOH

5 The epoxidation reaction is exothermic The bleach is added over a period of 2-2.5 hr in order to maintain the desired temperature range If the rate of addition appears to be faster, then the rate of stirring should be increased to ensure proper mixing of the biphasic mixture

6 The physical properties are as follows: 1H NMR (400 MHz, CDCl3) δ: 2.95 (dd, 1 H, J = 2.9, 18.2), 3.19 (d, 1 H, J = 18.2), 4.10 (t, 1 H, J = 2.9), 4.25 (m, 1 H), 7.15-7.25 (m, 3 H), 7.48 (d, 1 H, J = 7.4) ;

13C NMR (100 MHz, CDCl3) δ: 34.5, 57.5, 59.0, 125.0, 126.0, 126.1, 128.4, 140.8, 143.4 ; IR (NaCl): ν (cm−1) 3045, 3029, 2913, 1474, 1466, 1419, 1372, 1230, 1175, 1000, 983 ; [α]23

D +23.3° (hexanes, c

1.31); HRMS (CI, cool probe): calcd for C9H12NO [M+NH4] 150.0919, observed 150.0913

7 The enantiomeric excess of the epoxide is determined by HPLC analysis using a Chiracel OB column (25 cm × 4.6 mm, Daicel) eluted with EtOH/hexanes (5:95) at 1 mL/min, while monitoring at 254 nm The retention times of the epoxide enantiomers are 11.1 (1S,2R) and 15.3 (1R,2S) min

8 The submitters distilled the epoxyindane at lower pressure, bp 47-48°C (0.005 mm)

9 Solvents were freshly distilled from CaH2 prior to reaction

10 Fuming sulfuric acid was purchased from Aldrich Chemical Company, Inc , and used as received Approximately 10% of the acid is added before addition of the epoxide solution is begun

11 The weight of the hydrolysis mixture is 225-250 g

12 Slightly more or less NaOH solution may be required to reach the desired pH range

13 The precipitation of the diastereomeric salt is rapid, and the solid may need to be broken up with a spatula in order to maintain proper mixing Additional methanol may be added if needed

14 The salt that precipitates initially is not diastereomerically pure, and the additional reflux period is necessary to allow equilibration to the diastereomerically pure material

15 The salt is isolated as a methanol solvated complex, FW = 331

16 The pH of the initial mixture is approximately 3.5 The free base begins to precipitate around pH 8.5

17 The product is recrystallized from toluene in order to remove any of the trans isomer, as well as to dry the product The hot mixture should be heated long enough to azeotropically remove water from the product

18 The stereochemical purity of the product is determined by reacting a sample of the product (15 mg) with 2,4-dinitrofluorobenzene (13 μL) in CH2Cl2 (5 mL) The yellow solution is diluted with ethanol

(1:10), then analyzed by HPLC on an N-naphthylleucine column (4.6 × 25 mm, Regis) eluted with IPA/hexanes (8:92) at 1 mL/min while monitoring at 350 nm The retention times of the trans enantiomers are 17.4 and 19.1 min, while those of the cis enantiomers are 24.4 (1R,2S) and 27.1 (1S,2R) min The product is enantio- and diastereomerically pure after recrystallization from toluene

19 The physical properties are as follows: 1H NMR (400 MHz, CD3OD) δ: 2.88 (dd, 1 H, J = 2.9, 16.1), 3.05 (dd, 1 H, J = 5.4, 16.1), 4.13 (d, 1 H, J = 5.0), 4.39 (m, 1 H), 7.17-7.22 (m, 3 H), 7.38 (m, 1 H) ; 13C NMR (100 MHz, CD3OD) δ: 40.0, 60.4, 75.2, 125.3, 126.1, 127.8, 128.6, 141.8, 145.1 ; IR (NaCl): ν (cm−1) 3343, 3290, 3170-3022, 2918, 1618, 1605, 1474, 1344, 1180, 1058 ; [α]23

D −41.2° (MeOH, c

1.00, MeOH); HRMS (CI, cool probe): calcd for C9H12NO [M+H] 150.0919, observed 150.0913

Waste Disposal Information

All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995

3 Discussion

The development of practical routes to the title compound has been the focus of intensive research effort since cis-aminoindanol was identified as a critical component of the highly effective HIV protease inhibitor indinavir (Crixivan®).11 , 12 Reported routes include racemate synthesis followed by resolution via diastereomeric salts,12 enzymatic resolution,13 14 and asymmetric hydroxylation.15 However, the use

of a modified Ritter reaction to convert indene oxide to the corresponding cis-amino alcohol as described in this procedure constitutes the most direct and economical route devised thus far.16 17 The application of the (salen)Mn-catalyzed epoxidation reaction18 19 20 21 22 in the first step allows access to the requisite epoxide in good yield and good enantiomeric excess, thus rendering the overall process highly efficient A final purification of the amino alcohol product involving formation of the L-tartrate salt serves to enhance both the chemical and stereochemical purity of the final product

In addition to serving as a key stereochemical controlling element for synthesis of indinavir,7 , 8 , 9 the title compound has proven to be a remarkably versatile chiral ligand and auxiliary for a range of asymmetric transformations including Diels-Alder reactions,23 24 25 26 27 carbonyl reductions,28 29 30

diethylzinc additions to aldehydes,31 and enolate additions.32 33 34 35 36

References and Notes

1 Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138

2 Merck Research Laboratories, Department of Process Research, Rahway, NJ 07065

3 Present address: Merck & Co., Stonewall Plant, Route 340 South, Elkton, VA 22827;

4 Present address: Sepracor, Inc., 33 Locke Drive, Marlboro, MA 01752

5 Larrow, J F.; Jacobsen, E N.; Gao, Y.; Hong, Y.; Nie, X.; Zepp, C M J Org Chem 1994, 59,

1939-1942;

6. Larrow, J F.; Jacobsen, E N Org Synth 1998, 75, 1

7 Senanayake, C H.; Smith, G B.; Ryan, K M.; Fredenburgh, L E.; Liu, J.; Roberts, F E.;

Hughes, D L.; Larsen, R D.; Verhoeven, T R.; Reider, P J Tetrahedron Lett 1996, 37,

3271-3274;

8 Hughes, D L.; Smith, G B.; Liu, J.; Dezeny, G C.; Senanayake, C H.; Larsen, R D.;

Verhoeven, T R.; Reider, P J J Org Chem 1997, 62, 2222-2229;

9 Bell, D.; Davies, M R.; Finney, F J L.; Geen, G R.; Kincey, P M.; Mann, I S Tetrahedron

Lett 1996, 37, 3895-3898

10 Kolthoff, I M.; Belcher, R "Volumetric Analysis, Volume III"; Interscience Publishers: New

York, 1957, pp 262-263

11 Vacca, J P.; Dorsey, B D.; Schleif, W A.; Levin, R B.; McDaniel, S L.; Darke, P L.; Zugay,

J.; Quintero, J C.; Blahy, O M.; Roth, E.; Sardana, V V.; Schlabach, A J.; Graham, P I.; Condra, J H.; Gotlib, L.; Holloway, M K.; Lin, J.; Chen, I.-W.; Vastag, K.; Ostovic, D.;

Anderson, P S.; Emini, E A.; Huff, J R Proc Natl Acad Sci U.S.A 1994, 91, 4096-4100

12 Thompson, W J.; Fitzgerald, P M D.; Holloway, M K.; Emini, E A.; Darke, P L.; McKeever,

B M.; Schlief, W A.; Quintero, J C.; Zugay, J A.; Tucker, T J.; Schwering, J E.; Homnick, C

F.; Nunberg, J.; Springer, J P.; Huff, J R J Med Chem 1992, 35, 1685-1701

13 Didier, E.; Loubinoux, B.; Ramos Tombo, G M.; Rihs, G Tetrahedron 1991, 47, 4941-4958;

14 Takahashi, M.; Ogasawara, K Synthesis 1996, 954-958

15 Boyd, D R.; Sharma, N D.; Bowers, N I.; Goodrich, P A.; Groocock, M R.; Blacker, A J.;

Clarke, D A.; Howard, T.; Dalton, H Tetrahedron: Asymmetry 1996, 7, 1559-1562

16 Senanayake, C H.; Roberts, F E.; DiMichele, L M.; Ryan, K M.; Liu, J.; Fredenburgh, L E.;

Foster, B S.; Douglas, A W.; Larsen, R D.; Verhoeven, T R.; Reider, P J Tetrahedron Lett

1995, 36, 3993-3996;

17 Senanayake, C H.; DiMichele, L M.; Liu, J.; Fredenburgh, L E.; Ryan, K M.; Roberts, F E.;

Larsen, R D.; Verhoeven, T R.; Reider, P J Tetrahedron Lett 1995, 36, 7615-7618

18 Jacobsen, E N.; Zhang, W.; Muci, A R.; Ecker, J R.; Deng, L J Am Chem Soc 1991, 113,

7063-7064;

19 Jacobsen, E N.; Deng, L.; Furukawa, Y.; Martínez, L E Tetrahedron 1994, 50, 4323-4334

20 For reviews, see: Jacobsen, E.N In "Catalytic Asymmetric Synthesis"; Ojima, I., Ed.; VCH: New

York, 1993; Chapter 4.2;

21 Jacobsen, E N In "Comprehensive Organometallic Chemistry II"; Wilkinson, G.; Stone, F G

A.; Abel, E W.; Hegedus, L S., Eds.; Pergamon: New York, 1995; Vol 12, Chapter 11.1;

22 Katsuki, T Coord Chem Rev 1995, 140, 189-214

23 Davies, I W.; Senanayake, C H.; Castonguay, L.; Larsen, R D.; Verhoeven, T R., Reider, P J

Tetrahedron Lett 1995, 36, 7619-7622;

24 Davies, I W.; Gerena, L.; Castonguay, L.; Senanayake, C H.; Larsen, R D.; Verhoeven, T R.,

Reider, P J J Chem Soc.,Chem Commun 1996, 1753-1754;

25 Davies, I W.; Senanayake, C H.; Larsen, R D.; Verhoeven, T R., Reider, P J Tetrahedron

Lett 1996, 37, 1725-1726;

26 Ghosh, A K.; Mathivanan, P.; Cappiello, J Tetrahedron Lett 1996, 37, 3815-3818;

27 Ghosh, A K.; Mathivanan, P Tetrahedron: Asymmetry 1996, 7, 375-378

28 Hong, Y.; Gao, Y.; Nie, X.; Zepp, C M Tetrahedron Lett 1994, 35, 6631-6634;

29 DiSimone, B.; Savoia, D.; Tagliavini, E.; Umani-Ronchi, A Tetrahedron: Asymmetry 1995, 6,

301-306;

30 Ghosh, A K.; Chen, Y Tetrahedron Lett 1995, 36, 6811-6814

31 Solà, L.; Vidal-Ferran, A.; Moyano, A.; Pericàs, M A.; Riera, A Tetrahedron: Asymmetry 1997,

8, 1559-1568 See also ref 7b

32 Askin, D.; Eng, K K.; Rossen, K.; Purick, R M.; Wells, K M.; Volante, R P.; Reider, P J

Tetrahedron Lett 1994, 35, 673-676;

33 Askin, D.; Wallace, M A.; Vacca, J P.; Reamer, R A.; Volante, R P.; Shinkai, I J Org Chem

1992, 57, 2771-2773;

34 Maligres, P E.; Upadhyay, V.; Rossen, K.; Cianciosi, S J.; Purick, R M.; Eng, K K.; Reamer,

R A.; Askin, D.; Volante, R P.; Reider, P J Tetrahedron Lett 1995, 36, 2195-2198;

35 Ghosh, A K.; Onishi, M J Am Chem Soc 1996, 118, 2527-2528;

36 Ghosh, A K.; Duong, T T.; McKee, S P J Chem Soc., Chem Commun 1992, 1673-1674

Appendix Chemical Abstracts Nomenclature (Collective Index Number);

Pyridine, 4-phenyl-, 1-oxide (8,9); (1131-61-9)

Sodium hypochlorite solution:

Hypochlorous acid, sodium salt (8,9); (7681-52-9)

AcetonitrileTOXIC(8,9); (75-05-8)

Sulfuric acid, fuming:

Sulfuric acid, mixt with

sulfur trioxide (9); (8014-95-7)

L-Tartaric acid:

Tartaric acid, L- (8);

Butanedioic acid, 2,3-dihydroxy-, [R-(R,R)]- (9); (87-69-4)

Copyright © 1921-2005, Organic Syntheses, Inc All Rights Reserved

Organic Syntheses, Coll Vol 10, p.35 (2004); Vol 75, p.223 (1998)

SYNTHESIS OF ISOQUINOLINONES FROM QUININE: 4a(S), 8a(R)-2- BENZOYLOCTAHYDRO-6(2H)-ISOQUINOLINONE [ 6(2H)-Isoquinolinone, 2-benzoyloctahydro-, (4aS-cis)- ]

cis-4a(S),8a(R)-PERHYDRO-6(2H)-Submitted by Darrell R Hutchison, Vien V Khau, Michael J Martinelli, Naresh K Nayyar, Barry C Peterson, and Kevin A Sullivan1

Checked by Zehong Wan and Amos B Smith, III

1 Procedure

A Quininone (1) A 2-L, three-necked, round-bottomed flask (Note 1) equipped with a mechanical stirrer, reflux condenser and a thermocouple is charged with 112.2 g (0.61 mol) of benzophenone(Note 2) and 600 mL of toluene(Note 3) under a positive pressure of nitrogen (N2) Quinine, 111.11 g (0.31 mol) (Note 4), is then added in one portion (Note 5), followed by 87.1 g (0.78 mol) of potassium tert-butoxide(Note 6) added in one portion The slurry is heated to reflux with an electric mantle for 8 hr (Note 7) The reaction mixture is allowed to cool overnight to room temperature and then to 5-10°C

DOI:10.15227/orgsyn.075.0223

with an ice-water mixture 2 N Hydrochloric acid (HCl), 400 mL , is added slowly keeping the temperature below 20°C The contents of the flask are transferred to a 2-L separatory funnel with 300

mL of 2 N HCl After two layers separate, the lower aqueous layer is collected in a 3-L Erlenmeyer flask, and the organic layer is washed with 2 N HCl (2 × 250 mL) The combined aqueous layers are cooled to 0-5°C and treated dropwise with 260 mL of 5 N sodium hydroxide (NaOH) with stirring to pH 9.5 An oil initially separates that becomes a yellow solid after vigorous stirring at 0-5°C The solid is filtered using a Büchner funnel, rinsed with water (2 × 200 mL), and dried in an oven at 60°C for 48 hr

to afford the ketone 1 as a light yellow solid weighing 97.9 g (98%, (Note 8))

B N-Benzoylmeroquinene tert-butyl ester (2) A 2-L, three-necked, round-bottomed flask is

equipped with a mechanical stirrer, subsurface glass-fritted gas tube for oxygen (O2) addition (the gas tube is also connected to a bubbler containing silicone oil to monitor the flow of oxygen gas), and a thermocouple The flask is charged with 800 mL of tetrahydrofuran (THF) and 200 mL of tert-butyl alcohol (tert-BuOH) The solution is purged with O2 under stirring for 15 min and then treated with 78.4

g of potassium tert-butoxide (0.70 mol) in one portion (Note 9) The yellow reaction mixture is cooled (ice bath) while the O2 addition is continued for another 15 min Crude quininone 1, 90.0 g, (0.28 mol)

is then added portionwise over 10 min with continued O2 addition, resulting in a blood red mixture, concomitant with an exotherm to 35°C (Note 10) After the solution is stirred for 1.5 hr at ambient temperature, the gas purge is stopped and 80 mL of glacial acetic acid (HOAc) is added carefully with vigorous stirring Volatile material is removed under reduced pressure at ≤ 50°C from the resulting thick slurry that is then suspended in 400 mL of water The pH is adjusted to 10 by the addition of 60 mL of concd ammonium hydroxide (NH4OH) and the aqueous solution is extracted with ether (4 × 200 mL), washed with a saturated solution of brine (3 × 250 mL, (Note 11)), dried over sodium sulfate (Na2SO4), filtered and concentrated (Note 12) to furnish meroquinene tert-butyl ester as a viscous oil (40.5 g, 64% crude recovery, (Note 13)) A 1-L, three-necked, round-bottomed flask equipped with a mechanical stirrer, thermocouple, addition funnel, condenser, and N2 inlet is charged with 40.5 g (0.18 mol) of crude meroquinene tert-butyl ester and 235 mL of dichloromethane (CH2Cl2) (Note 14) Pyridine, 16.0

mL, (0.19 mol), (Note 15) is added, followed by dropwise addition of 25.0 mL (0.21 mol) of benzoyl chloride (Note 15) at a rate to maintain a gentle reflux over 15 min Upon complete addition, the reaction mixture is stirred at ambient temperature for 2 hr (Note 16) and washed successively with H2O (200 mL), 1 N HCl (2 × 150 mL), 2 N NaOH (2 × 150 mL), and brine (300 mL) The organic phase is dried over Na2SO4, filtered and concentrated to give the thick brown oily benzamide 2 (61.2 g, 100%,

(Note 17))

C 4a(S),8a(R)-2-Benzoyl-1,3,4,4a,5,8a-hexahydro-6(2H)-isoquinolinone (3) A 1-L, three-necked,

round-bottomed flask is equipped with a mechanical stirrer, Teflon-coated thermocouple, 500-mL addition funnel and a N2 inlet Concentrated sulfuric acid (H2SO4), 275 mL is added to the flask and the flask is cooled to 0°C under N2 The addition funnel is charged with a solution of 56.0 g (0.17 mol) of crude benzamide 2 in 60 mL of CH2Cl2, that is added dropwise over 15 min, maintaining the internal temperature between 0-10°C Upon complete addition, the cooling bath is removed and the reaction mixture is stirred vigorously for another 2 hr (Note 18) as the temperature rises to 30°C The reaction mixture is poured onto 1 kg of crushed ice with stirring and when the ice has melted the two layers are separated The aqueous phase is extracted further with CH2Cl2 (4 × 200 mL) The combined organic phases are washed with water (2 × 500 mL), brine (500 mL), dried over Na2SO4, filtered, and concentrated to a light brown semisolid (Note 19) that is dissolved in 100 mL of CH2Cl2 and

precipitated with 250 mL of hexanes to furnish 34.7 g (80%) of enone 3 as light yellow crystals (Note 20)

D 4a(S),8a(R)-2-Benzoyloctahydro-6(2H)-isoquinolinone (4) Palladium (Pd), 10% on carbon, 4.0

g , (Note 21) is placed in a 500-mL Parr bottle under N2 and carefully wetted with 50 mL of cold denatured ethanol (EtOH) A slurry of 34.7 g of enone 3 (0.14 mol) in denatured EtOH (250 mL) is

added and the Parr shaker apparatus assembled After the system is purged with nitrogen-hydrogen (N2/H2), the reaction is shaken at 50 psi H2 and 50°C until H2 uptake is complete (1 hr, (Note 22)) The catalyst is filtered over a Celite pad (Note 23) and rinsed with warm chloroform (CHCl3) (4 × 75 mL) The filtrate is concentrated under reduced pressure, dissolved in 90 mL of CH2Cl2 and crystallized with

200 mL of hexanes The crystalline solid is filtered, rinsed with hexanes and dried to afford 34.3 g (98%, (Note 24)) of the ketone 4, representing a 51% yield over four steps.

2 Notes

1 All glass apparatus was dried thoroughly under a flow of dry N2 All ground glass joints were tightly sealed with Teflon tape and then wrapped with Parafilm All the preparations were performed in an efficient fume hood while wearing gloves and adequate eye protection

2 Benzophenone purchased from Aldrich Chemical Company, Inc was used as received

3 Toluene, dichloromethane, acetic acid, ammonium hydroxide, concentrated H2SO4, 5 N NaOH and 37% HCl were purchased from Mallinckrodt Inc ; tetrahydrofuran, tert-butyl alcohol, anhydrous

Na2SO4, and NaCl were purchased from EM Science ; potassium tert-butoxide was purchased from Aldrich Chemical Company, Inc ; hexanes was purchased from Baxter , and dry O2 was purchased from Air Products All these reagents were used as received

4 Quinine (purity 90%) purchased from Aldrich Chemical Company, Inc , was used as received

5 A mild endotherm was noted: the temperature fell from 22°C to 19°C

6 The color changed to yellowish brown immediately upon addition of potassium tert-butoxide and a mild exotherm was noted, as the temperature rose to 29°C

7 The slurry became very thick as the temperature approached reflux, requiring vigorous stirring The color of the mixture gradually changed to dark orange and at the end of the reaction the color was fluorescent orange

8 The material was sufficiently pure as determined by HPLC (Zorbax C-8 column RX 25 cm; flow rate 2.5 mL/min; mobile phase acetonitrile/water (1:1); UV detection at 254 nm showed four peaks tR(min.)

at 0.9 (quinine), 1.3 (quininone), 4.4 (toluene), 5.4 (benzophenone) A part of this material (8.0 g) was dissolved in 250 mL of diethyl ether at room temperature, left in a freezer for 48 hr, and 6.9 g of light yellow solid was obtained upon filtration; mp 102-104°C

9 The reaction mixture displayed an exotherm from ambient temperature to 35°C

10 Quininone was added at a rate to keep the temperature below 25°C; otherwise the yield of this step was much lower Oxygen uptake increased upon the addition of quininone, but slowed as the reaction proceeded (15 min)

11 If three phases result, add the minimum amount of water (100 mL) that affords two phases (some color in the aqueous phase was noted) Additional quantities of water should be avoided because of the high water solubility of the product

12 The product was concentrated under reduced pressure at room temperature, but concentration at higher temperature resulted in a lower yield (35-40%)

13 Any attempts to purify the product by distillation resulted in lower yields because of pyrolysis The undistilled product was sufficiently pure for most purposes The yield range was 60-75%; 1H NMR (500 MHz, CDCl3) δ: 1.32-1.63 (m, 11 H), 2.02-2.30 (m, 4 H), 2.63-3.06 (m, 4 H), 4.90-5.18 (m, 2 H), 6.01-6.10 (m, 1 H) ; 13C NMR (125 MHz, CDCl3) δ: 28.1, 28.9, 35.7, 39.4, 43.0, 46.1, 51.4, 80.1, 116.6, 137.2, 172.3

14 Six volumes of CH2Cl2 are used to ensure efficient stirring, since a solid separates after the addition

2 H), 5.79-5.92 (m, 1 H), 7.31-7.41 (m, 5 H) ; 1H NMR (CD3SOCD3, 25°C) δ: 1.39 (m, 11 H ), 2.55 (m, 4 H), 2.90-3.50 (m, 3 H), 4.21-4.42 (m, 1 H), 4.90-5.12 (m, 2 H), 5.76-5.94 (m, 1 H), 7.31-7.41 (m, 5 H) ; 1H NMR (CD3SOCD3, 90°C) δ: 1.39-1.51 (m, 11 H), 2.04-2.21 (m, 3 H), 2.41-2.49 (m, 1 H), 3.06 (ddd, 1 H, J = 2.7, 3.7 and 10.7), 3.24 (dd, 1 H, J = 3.2 and 13.2), 3.91-4.00 (m, 2 H), 5.02-5.13 (m,

2.02-2 H), 5.78-5.87 (m, 1 H), 7.31-7.41 (m, 5 H) ; 13C NMR (CDCl3, 125 MHz) δ: 28.1, 35.8, 38.7, 42.2, 46.0, 47.5, 52.4, 80.4, 118.1, 127.0, 128.3, 129.4, 134.7, 136.2, 170.8, 171.8

18 The color of the reaction mixture changed from light yellow to dark brown at the end of the reaction with the formation of solid particles The reaction appeared complete by TLC analysis (silica gel 60 F-

254 precoated plates, hexanes:ethyl acetate, 2:8, freshly prepared); Rf for benzoyl derivative = 0.74, Rffor enone = 0.25

19 HPLC of the crude product indicated the presence of only cis isomer; no trans isomer was detected

in the crude product; 1H NMR (500 MHz, CDCl3) δ: 1.52-1.82 (m, 2 H), 2.47-2.56 (m, 3 H), 2.82-2.96 (m, 1 H), 3.21-3.41 (m, 1 H), 3.50 (dd, 1 H, J = 13.5 and 4.1), 3.52-3.72 (m, 1 H), 4.35-4.45 (m, 1 H), 6.09 (d, 1 H, J = 9.7), 6.85-7.05 (m, 1 H), 7.27-7.42 (m, 5 H) ; 1H NMR (CD3SOCD3, 25°C) δ: 1.35-1.70 (m, 2 H), 2.46-2.50 (m, 3 H), 2.82 (m, 1 H), 3.22-4.08 (m, 4 H), 5.98 (m, 1 H), 6.92 (m, 1 H), 7.34-7.44 (m, 5 H) ; 1H NMR (CD3SOCD3, 90°C) δ: 1.46-1.59 (m, 2 H), 2.48-2.50 (m, 2 H), 2.80 (m, 1 H), 3.01 (m, 1 H), 3.22-3.31 (m, 1 H), 3.51 (dd, 1 H, J = 4.2 and 13.4), 3.60-3.64 (m, 1 H), 3.84-3.87 (m, 1 H), 5.9 (dd, 1 H, J = 2.2 and 10.1), 6.77 (dd, 1 H, J = 3.0 and 9.8), 7.33-7.45 (m, 5 H) ; 13C NMR (125 MHz, CDCl3) δ: 27.2, 33.8, 37.0, 41.8, 44.9, 46.2, 126.8, 128.6, 129.8, 131.0, 135.8, 150.6, 170.8, 198.1

20 If there was no crystallization, a few crystals of crude product were added to the flask to initiate crystallization The mp was 148-150°C (lit.2 mp 150-152°C)

21 Palladium on activated carbon (10%) was purchased from Aldrich Chemical Company, Inc , and used as received

22 After 75 min an aliquot was drawn and analyzed by 1H NMR which indicated the presence of enone (< 5%); another 1.0 g of Pd was added and the mixture heated at 50°C/50 psi of H2 for another 45 min

23 The palladium on activated carbon (10%) was not allowed to become completely dry because of its flammable nature

24 The data for the pure product is: mp 179-181°C (lit.2 mp 182-183°C); 1H NMR (500 MHz, CDCl3) δ: 1.49-1.60 (m, 2 H), 2.01-2.13 (m, 2 H), 2.25-2.60 (m, 6 H), 3.03-3.22 (m, 2 H), 3.61-3.81 (m, 1 H), 4.45-4.59 (m, 1 H), 7.28-7.41 (m, 5 H) ; 1H NMR (CD3SOCD3, 25°C) δ: 1.30-1.62 (m, 2 H), 1.82 (m, 2 H), 2.18-2.65 (m, 6 H), 3.04 (m, 1 H), 3.20 (m, 1 H), 3.48 (m, 1 H), 4.22 (m, 1 H), 7.32-7.48 (m, 5 H) ;

1H NMR (CD3SOCD3, 90°C) δ: 1.34-1.52 (m, 2 H), 1.66-1.78 (m, 1 H), 1.80-2.02 (m, 1 H), 2.20-2.31 (m, 2 H), 2.31-2.37 (m, 2 H), 2.48-2.57 (m, 2 H), 3.00-3.12 (m, 1 H), 3.27 (dd, 1 H, J = 3.6 and 13.2), 3.88 (m, 2 H), 7.30-7.50 (m, 5 H) ; 13C NMR (125 MHz, CDCl3) δ: 25.5, 26.6, 27.6, 35.0, 37.4, 39.8, 45.9, 47.2, 126.8, 128.5, 129.6, 136.1, 171.0, 210.5

Waste Disposal Information

All toxic materials were disposed of in accordance with "Prudent Practices in the Laboratory"; National Academy Press; Washington, DC, 1995

3 Discussion

3

In this procedure, quinine is oxidatively degraded to meroquinene esters that are subsequently cyclized to N-acylated cis-decahydroisoquinolones in excellent overall yield, while maintaining the cis stereochemistry at the ring juncture Furthermore, with the commercial availability of quinine, high overall yields, and ease of isolations, meroquinene and subsequent products are attractive members of a practical "chiral pool"

Oxidation of the quinine C-9 hydroxy substituent to the ketone is best accomplished using the Woodward4 benzophenone/potassium t-butoxide method, now using toluene The other oxidation methods investigated (Swern, Jones, ROCl variations) were less effective or limited because of the poor solubility of the substrate Thermodynamic equilibration of these ketones has also been reported.4

Quininone, the most readily available member of the series, was used for the autoxidation studies The Doering autoxidation procedure,5 that employs only tert-BuOH, was modified to include a THF:tert-BuOH (4:1) mixture as the solvent Likewise, the pressurized Parr bottle setup as described5

was replaced with a simple subsurface gas addition; the solvent was presaturated with O2 gas, (compressed air could also be used as the O2 source) followed by t-BuOK addition and continued O2 gas purge The autoxidations could likewise be conducted in the presence of ethanol or methanol, thereby producing the corresponding ethyl or methyl esters Formation of these esters could occur via the reactive intermediate bicyclic lactam.5