Alpha fluorinated aromatic ketone as nucleophile in asymmetric organocatalytic c n and c c bonds formation reactions 5

After removed the solvent, the pure product 81c was obtained by flash chromatography gradient elution with hexane and EtOAc mixtures: 50/1 to 10/1.. Then the reaction solvent was remove

Chapter 5

Experimental

5.1 General Information

5.1.1 General procedures and methods

1H and 13C NMR spectra were recorded on a Bruker ACF300 (300MHz),

Bruker DPX300 (300MHz) or AMX500 (500MHz) spectrometer Chemical shifts are reported in parts per million (ppm) The residual solvent peak was used as an internal reference Low resolution mass spectra were obtained on a Finnigan/MAT LCQ spectrometer in ESI mode and a Finnigan/MAT 95XL-T mass spectrometer

in FAB mode All high resolution mass spectra were obtained on a Finnigan/MAT 95XL-T spectrometer Infrared spectra were recorded on a BIO-RAD FTS 165 FTIR spectrometer Enantiomeric excess values were determined by chiral HPLC analysis on two sets: Jasco HPLC units, including a Jasco DG-980-50 Degasser, a LG-980-02 Ternary Gradient Unit, a PU-980 Intelligient HPLC Pump, UV-975 Intelligient UV/VIS Detectors, and an AS-950 Intelligient Sampler; Dionex Ultimate 3000 HPLC units, including a Ultimate 3000 Pump, Ultimate 3000 variable Detectors Optical rotations were recorded on Jasco DIP-1000 polarimeter Melting points were determined on a BÜCHI B-540 melting point apparatus Analytical thin layer chromatography (TLC) was performed with Merck pre-coated TLC plates, silica gel 60F-254, layer thickness 0.25 mm Flash chromatography separations were performed on Merck 60 (0.040 - 0.063mm) mesh silica gel Toluene was distilled from sodium/benzophenone and stored under N2 atmosphere Dichloromethane was distilled from CaH2 and stored under

N2 atmosphere Other reagents and solvents were commercial grade and were used as supplied without further purification, unless otherwise stated

5.1.2 Materials

All commercial reagents were purchased from Sigma-Aldrich, Fluka, Alfa Aesar, Merck, TCI, and Acros of the highest purity grade They were used without further purification unless specified All solvents used, mainly hexane (Hex) and ethyl acetate (EtOAc), were distilled Anhydrous DCM was freshly distilled from CaH2 Anhydrous THF was freshly distilled from Na/benzophenone MeCN and CHCl3 were distilled from CaH2 MeOH was distilled from Mg

5.2 Preparation and Characterization of Substrates and catalysts

5.2.1 Preparation and characterization of -fluorinated aromatic ketones

The -tetralone derivatives 81c and 81g were synthesized according to the

modified reported procedure.1 To a 100 mL round bottom flask was added

4-(4-chlorophenyl)-4-oxobutanoic acid 83a (5 mol, 1.1 g), H2O (10 mL), concn HCl (8 mL) and Zn (40 mol, 2.6 g) After stirring at room temperature for half an hour, the suspension was heated to reflux The reaction was monitored by TLC Then, the resulting mixture was extracted by EtOAc for three times The crude

intermediates 84a was obtained and used directly for next step after removing the

solvents

The crude 84a and PPA (3.2 g) were placed in 50 mL round bottom flask After

stirring at 80 oC for 20 min, the mixture was heated to 110 oC for overnight Then water (15 mL) was added and the solution was exacted by EA for three times

After removed the solvent, the pure product 81c was obtained by flash

chromatography (gradient elution with hexane and EtOAc mixtures: 50/1 to 10/1)

Yield of 81c was 42%; 81g was prepared by the same procedure as 81c, yield of 81g was 50% Their spectral properties were in agreement with literature values.1

General procedure: The -fluorinated aromatic ketones 82a-82m were prepared

according to the previously reported method.2 To a 50 mL clean round bottom flask was added aromatic cyclic ketone (3.5 mmol, 1.0 equiv.), Selectfluor (1.490

g, 4.2 mmol, 1.2 equiv.) and MeOH (30 mL) The suspension was stirred under reflux condition for 2-12 hours, monitored by TLC The white insoluble material

was filtered off Then the reaction solvent was removed in vacuo and the crude

product was directly loaded onto a silica gel column, followed by gradient elution with hexane/EtOAc mixtures (50/1 ~ 10/1 ratio) After removing the solvents, pure -fluorinated aromatic cyclic ketone was obtained

O

F

Following general procedure, 2-fluoro-3,4-dihydronaphthalen-1(2H)-one (82d) 81% yield Yellow oil; Its spectral properties were in agreement with

O

F

TsO

6-Fluoro-5-oxo-5,6,7,8-tetrahydronaphthalen-2-yl-4-methylbenzenesulfonate (82b)

The title compound was prepared according to the general procedure Yield: 71%; white solid 1HNMR (500 MHz, CDCl3, ppm): δ = 7.97 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.34(d, J = 8.1 Hz, 2H), 6.86-6.84 (m, 1H), 5.11 (ddd, J

= 5.0, 12.0, 48.0 Hz, 1H), 3.10-3.08 (m, 2H), 2.59-2.34 (m, 5H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 192.0 (d, J =14.8 Hz), 153.5, 145.9, 145.1, 132.0, 130.0, 130.0, 130.0, 128.4, 122.3, 121.0, 90.7 (d, J = 188.3 Hz), 29.8 (d, J = 19.8 Hz), 26.8 (d, J = 16.5 Hz); 19F NMR (282.4 MHz, CDCl3, ppm): -114.8~-115.0 (m); LRMS (FAB) m/z 335.1 (M + H+)

5.14 (ddd, J = 5.0, 13.0 48.5 Hz, 1H), 3.10-3.04 (m, 1H), 2.90-2.83 (m, 1H),

2.62-2.55 (m, 1H), 2.34-2.26 (m, 7H); 13C NMR (75.5 MHz, CDCl3, ppm): δ =

194.0 (d, J =14.5 Hz), 138.3, 136.6, 136.3, 131.2, 125.6, 91.0 (d, J = 187.7 Hz), 29.3 (d, J = 18.9 Hz), 24.1 (d, J = 17.8 Hz); 19F NMR (282.4 MHz, CDCl3, ppm): -114.9~-115.1 (m); LRMS (FAB) m/z 193.1 (M + H+)

Hz, 1H), 3.12-3.18 (m, 2H), 2.67-2.60 (m, 1H), 2.48-2.40 (m, 1H) 13C NMR (75.5 MHz, CDCl3, ppm): δ = 191.2 (d, J =15.2 Hz), 149.4, 147.2, 132.1, 130.3, 127.8, 123.0, 123.0, 90.5 (d, J = 189.2 Hz), 29.3 (d, J = 19.7 Hz), 26.9 (d, J =

11.2 Hz) 19F NMR (282.4 MHz, CDCl3, ppm): -115.1~-115.4 (m); LRMS (ESI) m/z 208.1 (M - H+)

1H), 7.30-7.24 (m, 2H), 5.14 (ddd, J = 5.0, 13.0 47.6 Hz 1H), 3.17-3.07 (m, 2H),

2.64-2.56 (m, 1H), 2.43-2.33 (m, 1H); 13C NMR (75.5 MHz, CDCl3, ppm): δ =

192.3 (d, J = 14.0 Hz), 161.7 (d, J = 247.3 Hz), 138.8, 132.9, 130.7, 130.6; 121.8, 121.5, 113.6 (d, J = 22.3 Hz), 90.9 (d, J = 188.5 Hz), 30.0 (d, J = 19.0 Hz), 26.3 (d, J = 16.7 Hz); 19F NMR (282.4 MHz, CDCl3, ppm): -38.1~-38.2 (m), -114.9~-115.2 (m); LRMS (ESI) m/z 181.1 (M - H+)

O

O

F

3-Fluorochroman-4-one (82h)

The title compound was prepared according to the general procedure After the

reaction solvent was removed in vacuo, then crude product was dissolved in

MeCN (3 mL), hydrolysis with 10% aqueous HCl (9 mL) for 6 hours The product was extracted with ethyl acetate, washed by brine and dried with anhydrous

Na2SO4 The solvent was evaporated under vacuum The residue was purified by column chromatography; using 20:1 ethyl acetate-hexanes gave the pure product Yield: 64%; white solid 1HNMR (300 MHz, CDCl3, ppm): δ = 7.93 (dd, J =8, 3

Hz, 1H), 7.57-7.51 (m, 1H), 7.26-7.00 (m, 1H), 5.14 (ddd, J = 5, 8, 48 Hz, 1H),

4.69-4.50 (m, 1H) Its spectral properties were in agreement with literature values.2

O

F

3-Fluoro-6-methylchroman-4-one (82i)

The title compound was prepared according to the general procedure as 82h

Yield: 58%; white solid 1HNMR (500 MHz, CDCl3, ppm): δ = 7.71 (d, J = 1.2

Hz, 1H), 7.34 (dd, J = 2.2, 8.5 Hz, 1H), 6.91 (d, J = 8.5, 1H), 5.14 (ddd, J = 4.0,

9.0, 46.9 Hz, 1H), 4.60-4.56 (m, 1H), 4.53-4.50 (m, 1H), 2.32 (s, 3H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 187.1 (d, J =15.6 Hz), 159.3, 137.8, 131.8, 127.0, 118.9, 117.6, 85.6 (d, J = 187.7 Hz), 68.6 (d, J = 25.9 Hz), 20.3; 19F NMR (282.4 MHz, CDCl3, ppm): -127.9~-128.2 (m); LRMS (FAB) m/z 181.0 (M + H+)

O

O

F Cl

6-Chloro-3-fluorochroman-4-one (82j)

The title compound was prepared according to the general procedure as 82h

Yield: 79%; white solid 1HNMR (500 MHz, CDCl3, ppm): δ = 7.87 (d, J = 2.6

Hz, 1H), 7.47 (dd, J = 2.6, 8.9 Hz, 1H), 6.98 (d, J = 8.9, 1H), 5.14 (ddd, J = 6.0,

9.0, 46.8 Hz, 1H), 4.66-4.53 (m, 2H); 13C NMR (75.5 MHz, CDCl3, ppm): δ =

185.8 (d, J =16.2 Hz), 159.6, 136.6, 127.9, 126.8, 120.1 119.6, 85.2 (d, J = 188.5 Hz), 68.8 (d, J = 25.8 Hz); 19F NMR (282.4 MHz, CDCl3, ppm): -127.5~-127.8 (m); LRMS (ESI) m/z 199.1 (M - H+)

O

F F

6-Fluoro-3-fluorochroman-4-one (82k)

The title compound was prepared according to the general procedure as 82h

Yield: 65%; white solid 1HNMR (500 MHz, CDCl3, ppm): δ = 7.55 (dd, J = 3.0, 8.0 Hz, 1H), 7.28-7.24 (m, 1 H), 7.02-6.99 (m, 1H), 5.19 (ddd, J = 4.4, 9.0, 46.7

2-Fluoro-1-(3-(trifluoromethyl)phenyl)propan-1-one (82o)

Yield (two steps): 24.4%; yellow oil 1HNMR (300 MHz, CDCl3, ppm): δ = 8.25

(s, 1H), 8.20-8.17 (m, 1H), 7.87-7.85 (m, 1H), 7.66-7.61 (m, 1H), 5.66 (ddd, J = 6.9, 13.6, 48.4Hz, 1H), 1.68 (dd, J = 6.9, 24.1 Hz, 1H); 19F NMR (282.4 MHz,

Procedure for synthesis of di-3-ethylpentan-3-yl azodicarboxylate 106 was

described as followed:

3-Ethylpentan-3-yl-1H-imidazole-1-carboxylate 102 was prepared according

to the previously reported method.4 1,1’-Carbonyldiimidazole 100, CDI (4.9 g, 30

mmol, 1.0 equiv.) was added to a 100 mL flame dried round bottom flask under

N2 atmosphere Dry toluene (40 mL) and 3-ethylpentan-3-ol 101(8.2 mL, 60

mmol, 2.0 equiv.) was added to the suspension dropwise, followed by KOH (16.8

mg, 0.018 mmol, 0.006 equiv.) The reaction mixture was stirred at 60 oC for overnight (A clear solution was formed one hour later) The reaction solvent was

removed in vacuo The residue was dissolved in DCM, and the organic layer was

washed with brine three times and dried over Na2SO4 The crude product was obtained after removing the solvent Flash chromagraphy over silica gel using

20:1 EtOAc-hexane gave 3-ethylpentan-3-yl 1H-imidazole-1-carboxylate 102

( 5.1 g, 82%) as a pure, colorless oil

Bis(3-Ethylpentan-3-yl)hydrazine-1,2-dicarboxylate 103 was prepared using

a slightly modified protocol that was previously reported.4 Hydrazine hydrate (2.4g, 47.6 mmol, 2.0 equiv.) and 95% ethanol (12 mL) was added to a 50 mL round bottom flask The reaction flask was cooled in an ice bath, and

3-ethylpentan-3-yl 1H-imidazole-1-carboxylate 102 (5.0 g, 23.8 mmol, 1 equiv.)

was added in one batch After stirring for half an hour, a solution of 3.8 g (35.7 mmol, 1.5 equiv.) of Na2CO3 in 15 mL of water was added dropwise When the

solution of Na2CO3 was added completely, the reaction solution was warmed to

room temperature and stirred for 2 hours The reaction solvent was removed in

vacuo and the residue was dissolved in Et2O The mixture was extracted with

Et2O The organic layer was washed with saturated brine for three times and dried over Na2SO4 Then, the organic layers were concentrated to give an off-white

liquid with 70% yield The crude 3-ethylpentan-3-yl hydrazinecarboxylate 103

can be used for next step without purification

3-Ethylpentan-3-yl hydrazinecarboxylate 103 (384 mg, 2.2 mmol, 1.0 equiv.),

HOAc (264 mg, 4.4 mmol, 2 equiv.) and water 2 mL were added to a 25 mL round bottom flask The solution was cooled in an ice bath, followed by the addition of NaNO2 (167 mg, 2.4 mmol, 1.1 equiv.) in three batches The reaction mixture was stirred at 0 oC for one hour; water (2 mL) was added The mixture was extracted with Et2O The organic layer was washed with saturated brine for three times, dried over Na2SO4, and concentrated to give an off-white liquid The crude

3-ethylpentan-3-yl carbonazidate 104 can be used for next step directly

3-Ethylpentan-3-yl hydrazinecarboxylate 103 (282 mg, 1.6 mmol, 1.0 equiv.), 3-ethylpentan-3-yl carbonazidate 104 (300 mg, 1.6 mmol, 1.0 equiv.) and pyridine

(0.7 mL) were added to a 25 mL round bottom flask at room temperature The solution was stirring at room temperature for 4 days The reaction solvent was

removed in vacuo The residue was dissolved in Et2O, and the organic layer was washed by the solution of CuSO4 and brine for three times, followed by dried over

Na2SO4 and concentrated to give brown oil Purification by flash chromatography

by gradient elution with hexane/EA mixtures (50/1 ~ 5/1 ratio) afforded

bis(3-ethylpentan-3-yl) hydrazine-1,2-dicarboxylate 105 as a yellow oil The yield

of three steps from 103 is 32%

Di-3-ethylpentan-3-yl-azodicarboxylate 106 (EocN=NEoc) was prepared

using a related protocol.4 Under N2 atmosphere, to a 25 mL flame dried round

bottom flask was added bis(3-ethylpentan-3-yl) hydrazine-1,2-dicarboxylate 105

(1.2 g, 3.6 mmol, 1 equiv.), pyridine (0.3 mL, 4.0 mmol, 1.1 equiv.) and DCM (60 mL) The mixture was cooled in ice bath Br2 dissolved in DCM (15 mL) was added dropwise over an hour Then the solution was warmed to room temperature

smoothly The reaction was monitored by TLC After 105 was consumed

completely, the reaction mixture was diluted with DCM and washed with 2x30

mL 1N HCl solution, satd NaHCO3 (2x30 mL) and brine (2x40 mL), followed by dried over Na2SO4 and concentrated to give a yellow solid, which was

recrystallized from hexane yielding di-3-ethylpentan-3-yl-azodicarboxylate 106

(0.9 g, 80%) as light yellow crystals

(75.5 MHz, CDCl3, ppm): δ = 146.5, 136.9, 130.1, 117.0, 93.7, 26.8, 7.5; LRMS (FAB) m/z 211.1 (M + H+)

Bis(3-Ethylpentan-3-yl) hydrazine-1,2-dicarboxylate 105

Yield of three steps from 9: 32%; yellow oil; 1HNMR (500 MHz, CDCl3, ppm):

δ = 6.25 (s 1H), 1.62 (q, J = 7.5 Hz, 6H), 0.83 (t, J = 7.5 Hz, 9H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 155.3, 89.1, 27.0, 7.6; LRMS (ESI) m/z 339.0 (M + Na+)

O

N

Et3CO N

O OCEt3

Di-3-ethylpentan-3-yl azodicarboxylate 106

Yield: 80%; yellow crystal; 1HNMR (500 MHz, CDCl3, ppm): δ = 1.96 (q, J = 7.5 Hz, 6H), 0.91 (t, J = 7.5 Hz, 9H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 159.3, 95.1, 26.8, 7.5; LRMS (ESI) m/z 336.7 (M + Na+)

5.2.2 Preparation and characterization of catalysts

Bicyclic guanidine 25 was prepared according to the published procedure.5

Pentanidines 163a-163e were synthesized by the similar procedures Among of them, 163c and 163d were prepared by myself (163a and 163e by Dr Fu; 163b by

Dr Chen).6

1 NH3(g) MeOH

Ar Ar

Ar R

R

HCl

imidazoline salt

Lawessen' reagent

Ar Ar

RHN NHR

S

2 NaOH(5 M) THF, RT

(COCl)2toluene

80oC

158

4ÅMS MeCN reflux

oC, and the mixture was allowed to reflux for 1 hour Then, the concentrated HCl

(0.03 mL) was added to the mixture and stirred over night After cooling down to room temperature, the product was filtered by suction on a Buchner funnel and

washed by cold acetone for three times Yellow solid 156b was obtained with 86%

yield and used for next step

In a 50 mL RBF was placed 156b (569 mg, 1.6 mmol), MeI (0.2 mL, 2 equiv.)

and 1.5 mL methanol at 0 oC The mixture was stirred at room temperature for 12

hours After removed the solvent, the crude product 157b was obtained as oil and

used for next step directly

In a 100 mL seal tube was placed 157b (1.6 mmol) and MeOH (4 mL) three

balloons of ammonia gas were bubbled into the mixture at 0 oC Then, the resulting mixture was heated to reflux for three days Off-white solid came out

from the reaction mixture After filtration, salt of white solid 158 was obtained with quantitive yield Pure 158 was achieved after basification with NaOH (5M)

in THF at room temperature for 5 hours at room temperature

To a 25 mL RBF containing (1S,2S)-1,2-bis(4-methoxyphenyl)ethane-1,2-diamine

155b (816 mg, 3 mmol), K2CO3 (4.1 g, 10 equiv.) and DMF (5 mL) was added benzyl bromide (0.7 mL, 2 equiv.) by dropwise The reaction was monitored by

TLC The resulting mixture was extracted by EtOAc and the crude product 159b

(R = Bn) was obtained with 64% yield after the solvent was evaporated in vacuo

159b (870 mg, 1.9 mmol), triphosgene (571 mg, 1.9 mmol), Et3N (0.8 mL, 6 equiv.) and DCM (6 mL) were placed in a 25 mL RBF at 0 oC Then, the resulting mixture was stirred at room temperature for overnight Extracted by DCM, the

pure product 160b (R = Bn) was purified by flash chromatography by gradient

elution with hexane/EtOAc mixtures (50/1 ~ 5/1 ratio) Yellow oil was obtained with 73% yield

To a 25 mL RBF containing 160b (618 mg, 1.3 mmol) and o-xylene (6 mL)

was added Lawessen’s reagent (1.0 g, 2 equiv.) The resulting mixture was heated

to 145 oC for 12 hours And the reaction was monitored by TLC and quenched by MeOH After removing the solvent, the crude product was loaded on the colomn and flashed by gradient elution with hexane/EA mixtures (50/1 ~ 8/1 ratio) Pure

product 161b (R = Bn) was obtained with 79% yield

Under N2 atmosphere, 161b (R = Bn) (499 mg, 1 mmol), oxalyl dichloride (0.8

mL, 9 mmol) and toluene (6 mL) were placed in a 25 mL RBF The resulting mixture was heated to 80 oC for 2 days and a half Another batch of oxalyl dichloride (0.15 mL) was added to the mixture The reaction was monitored by

TLC After removing the solvent, the crude imidazoline salt product 162b (R = Bn)

was obtained and used for next step directly

Under N2 atmosphere, 158b (227 mg, 2 equiv.) and imidazoline salt product 162b (R = Bn) (204 mg, 1 equiv.), 4Å MS (500 mg) and MeCN (5 mL) were placed in a flame-dried RBF The resulting mixture was refluxed for one day and monitored by TLC After removing the solvent, the residue was loaded on the colomn flashed by gradient elution with DCM/MeOH mixtures (100/1 ~ 8/1 ratio)

Pure product 163C (R = Bn) was obtained with 60% yield

S

(4S,5S)-4,5-bis(4-methoxyphenyl)imidazolidine-2-thione (156b)

1HNMR (300 MHz, CDCl3, ppm): δ = 7.16-7.14 (m 2H), 6.88-6.75 (m, 2H), 4.70

(s, 1 H), 3.78 (s, 3H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 183.2, 159.8, 130.8, 127.7, 114.4, 69.9, 55.3;

exchange reaction and characterization of deuterated products

82a-d 1

O F D Br

O

F

82a

N N N H

tBu tBu

25 (30 mol%)

ClCH2CH2Cl, 0oC 15h

D2O (150 equiv.) Br

To a solution of 30 mol% chiral guanidine 25 (2.7 mg, 0.012 mmol) in 0.8 mL

of ClCH2CH2Cl (DCE), D2O (0.12 mL, 6 mmol) was added Then, the reaction mixture was cooled to 0 oC After stirring at 0 oC for 20 min, 82a (9.7 mg, 0.04

mmol) was added in two batches This resulting solution was stirred for 15 hours

at 0 oC The reaction mixture was purified by flash chromatography on silica gel

eluting with hexane/EtOAc (30/1 to 5/1) to give 82a-d 1 (13 mg) as an off-white solid with 96% yield The deuteration incorporation was determined by 1H NMR spectroscopy by comparing the relative intensity to a non-exchangeable proton in the molecule

The product 82a-d 1 was obtained as an off-white solid Yield: 96% ee: 24%; 100%D

1 H NMR (500 MHz, CDCl3, ppm): δ = 8.2 (s, 1H), 7.63 (d, J = 8.2 Hz, 1H), 7.16 (d, J =

8.2 Hz, 1H), 3.12-3.02 (m, 2H), 2.61-2.54 (m, 1H), 2.40-2.31 (m, 1H)

The ee was determined by HPLC analysis PHENOMENEX Lux 5u Amylose-2 (4.6 mm

i.d x 250 mm, 4.6 mm i.d x 250 mm); Hexane/2-propanol = 95/5; flow rate 0.5 ml/min; 25°C; 254 nm; retention time: major isomer: 50.0 min; minor isomer: 46.8 min

O F D TsO

The product 82b-d 1 was obtained as white solid Yield: 98% ee: 30%; 95%D

1 H NMR (300 MHz, CDCl3, ppm): δ = 7.97 (d, J = 8.6 Hz, 1H), 7.73 (d, J = 8.3 Hz, 1H), 7.34(d, J = 8.1 Hz, 2H), 6.86-6.84 (m, 1H), 3.10-3.08 (m, 2H), 2.59-2.34 (m, 5H)

The ee was determined by HPLC analysis PHENOMENEX Lux 5u Amylose-2 (4.6 mm

i.d x 250 mm, 4.6 mm i.d x 250 mm); Hexane/2-propanol = 92/8; flow rate 0.8 ml/min; 25°C; 254 nm; retention time: major isomer: 124.3 min; minor isomer: 132.8 min

5.4 Protocol for bicyclic guanidine catalyzed asymmetric C-N bond formation reaction and characterization of products

2-Fluoro-3,4-dihydronaphthalen-1(2H)-one 82d (33.0 mg, 0.2 mmol, 4.0 equiv.) and 25 (1.12 mg, 0.005 mmol, 0.1 equiv) were dissolved in THF (0.4 ml) and

stirred at 0 oC for 20 min, then di-3-ethylpentan-3-yl azodicarboxylate 106 (17.0

mg, 0.05 mmol, 1.0 equiv.) was added The reaction mixture was stirred at 0 oC

and monitored by TLC After 45 hours, upon complete consumption of 106, the

reaction solvent was removed in vacuo and the crude product was directly loaded

onto a short silica gel column, followed by gradient elution with hexane/DCM

mixtures (100/1 - 10/1 ratio) After removing the solvent, product 108d (21.5 mg)

was obtained as off-white oil in 86% yield

Characterization of adducts

O

F N NH Eoc

Eoc Br

(S)-Bis(3-ethylpentan-3-yl)1-(7-bromo-2-fluoro-1-oxo-1,2,3,4-tetrahydronaph thalen-2-yl)hydrazine-1,2-dicarboxylate (108a) Light yellow solid 90% ee,

mp: 96-98oC, [α]29

D = -64.7 (c 2.1, CHCl3); 1H NMR (500 MHz, CDCl3, ppm): δ =

8.10-8.03 (m, 1H), 7.56-7.54 (m, 1H), 7.11 (dd, J = 8.0, 30.2 Hz, 1H), 6.47-6.43

(br, 1H), 3.55-3.50 (m, 1.4H), 2.95-2.77 (m, 1.6H), 2.29-2.25 (m, 1H), 1.90-1.65 (m, 12H), 0.87 – 0.66 (m, 18H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 186.9

(dd, J = 21.6, 33.9 Hz), 154.1 (d, J = 52.4 Hz), 152.5 (d, J = 10.6 Hz), 141.9 (d, J

= 166.3 Hz), 136.1 (d, J = 41.6 Hz), 133.2 (d, J = 112.8 Hz), 131.0, 130.7, 130.3, 130.0, 120.5 (d, J = 8.5 Hz), 102.2 (dd, J = 158.2, 221.2 Hz), 93.8 ( J = 14.6 Hz), 89.6, 89.5, 32.9 (d, J = 28.0 Hz), 27.0, 26.7, 26.5, 25.4 (d, J = 7.6 Hz), 7.6, 7.5,

7.4; 19F NMR (282.4 MHz, CDCl3, ppm): 50.6, -51.8; IR (film): 3406, 2972,

2944, 2883, 1732, 1643, 1458, 1383, 1345, 1296, 1231, 1133 cm-1; LRMS (ESI) m/z 555.2, 557.1 (M-H+), HRMS (ESI) m/z 579.1860 (M + Na+), calc for

C26H38N2 F1O579Br1 23Na1 579.1840

The ee was determined by HPLC analysis PHENOMENEX Lux 5u Cellulose-2

(4.6 mm x 250 mm); Hexane/2-propanol = 99/1; flow rate 0.5 ml/min; 25 °C; 254 nm; retention time: major isomer: 41.1 min; minor isomer: 22.9 min

O

F N NH Eoc

7.34-7.32 (m, 2H), 6.89-6.82 (m, 2H), 6.40 (br, 1H), 3.53-3.44 (m, 1.4H), 2.89-2.78 (m, 1.6H), 2.46 (s, 3H), 2.27 (m, 1H), 1.89-1.67 (m, 12H), 0.88 – 0.64 (m, 18H); 13C NMR (75.5 MHz, CDCl3, ppm): δ = 187.1 (dd, J = 20.8, 47.9 Hz),

154.4, 153.8, 153.2, 152.8, 152.5, 146.1, 145.7, 144.1, 132.1, 131.2, 130.4, 130.2,

129.9, 128.5, 128.4, 122.0, 121.8, 120.8, 120.6, 102.2 (dd, J = 144.5, 220.7 Hz), 93.9 (d, J = 51.5 Hz), 89.6, 32.9 (d, J = 28.1 Hz), 27.0, 26.7, 26.4, 25.8 (d, J = 7.5

Hz), 21.7, 7.6, 7.5, 7.4; 19F NMR (282.4 MHz, CDCl3, ppm): 50.5, -52.0; IR (film): 3325, 2966, 2925, 2854, 1730, 1606, 1457, 1380, 1233, 1190, 1134 cm-1; LRMS (ESI) m/z 671.9 (M+Na+), HRMS (ESI) m/z 671.2794 (M + Na+), calc for

C33H45N2 F1O823Na132S1 671.2773

The ee was determined by HPLC analysis CHIRALCEL AD-H (4.6 mm i.d x

250 mm); Hexane/2-propanol = 70/30; flow rate 0.2 ml/min; 25 °C; 254 nm; retention time: major isomer: 42.1 min; minor isomer: 53.1 min

O

F N NH Eoc

Eoc Cl

= 21.0, 39.2 Hz), 154.1 (d, J = 50.5 Hz), 152.5, 152.4, 141.3 (d, J = 168 Hz), 133.7, 133.4, 132.9, 132.6, 132.6, 132.1, 129.9 (J = 20.8 Hz), 127.7 (d, J = 21.6 Hz), 102.2 (dd, J = 158.0, 220.9 Hz), 89.4 (d, J = 13.0 Hz), 89.5, 89.2, 32.8 (d, J = 27.8 Hz), 26.9, 26.6, 26.4, 25.2 (d, J = 5.1 Hz), 7.5, 7.4, 7.3, 7.3; 19F NMR (282.4 MHz, CDCl3, ppm): 50.8, -51.9; IR (film): 3306, 2973, 2944, 2884, 1733, 1599,

1476, 1485, 1346, 1299, 1233, 1134 cm-1; LRMS (FAB) m/z 511.1 (M - H+), HRMS (FAB) m/z 511.2366 (M - H+), calc for C26H37N2 F1O535Cl1 511.2391

The ee was determined by HPLC analysis PHENOMENEX Lux 5u Cellulose-2

(4.6 mm x 250 mm); Hexane/2-propanol = 85/15; flow rate 0.2 ml/min; 25 °C;

254 nm; retention time: major isomer: 24.3 min; minor isomer: 21.1 min

O

F

NNHEoc Eoc

(S)-bis(3-ethylpentan-3-yl)1-(2-fluoro-1-oxo-1,2,3,4-tetrahydronaphthalen-2-y l)hydrazine-1,2-dicarboxylate (108d) Off-white oil; 94% ee, [α]29D = +4.7 (c

1.0, CHCl3); 1H NMR (500 MHz, CD2Cl2, ppm): δ = 7.88 (dd, J = 7.7, 16.5 Hz,

1H), 7.50-7.46 (m, 1H), 7.34-7.22 (m, 2H), 6.48 (br, 1H), 3.52-3.34 (m, 1.4H), 2.99-2.84 (m, 1.6H), 2.30-2.25 (m, 1H), 1.87-1.66 (m, 12H), 0.86-0.64 (m, 18H);

13C NMR (75.5 MHz, CD2Cl2, ppm): δ = 188.6 (dd, J = 20.8, 38.7 Hz), 155.8,

154.9, 154.3, 153.2, 143.5 (d, J = 108.5 Hz), 133.8 (d, J = 28.5 Hz), 133.0, 128.9, 128.6, 127.1, 103.0 (dd, J = 96.9, 219.2 Hz), 92.9 (d, J = 38.4 Hz), 89.8 (,d, J = 13.3 Hz), 33.6 (d, J = 26.9 Hz), 27.5, 27.2, 27.0, 26.7 (d, J = 7.0 Hz), 7.9, 7.8, 7.8,

7.7; 19F NMR (282.4 MHz, CD2Cl2, ppm): 50.8, -50.7; IR (film): 3405, 2972,

2944, 2884, 1732, 1712, 1643, 1457, 1290, 1234 cm-1; LRMS (ESI) m/z 500.9 (M + Na+), HRMS (ESI) m/z 501.2743 (M + Na+), calc for C26H39N2 F1O523Na1

501.2735

The ee was determined by HPLC analysis CHIRALCEL AD-H + IA (4.6 mm i.d

x 250 mm, 4.6 mm i.d x 250 mm); Hexane/2-propanol = 85/15; flow rate 0.2 ml/min; 25 °C; 254 nm; retention time: major isomer: 86.5 min; minor isomer: 107.6 min