Alpha fluorinated aromatic ketone as nucleophile in asymmetric organocatalytic c n and c c bonds formation reactions 2

Chapter 2 Enantioselective H/D exchange reaction catalyzed by chiral bicyclic guanidine... 2.2.2 Optimization studies on asymmetric H/D exchange reaction Scheme 2.6 Chiral bicyclic gu

Chapter 2

Enantioselective H/D exchange reaction catalyzed

by chiral bicyclic guanidine

Enantioselective H/D exchange reaction

28

Hydrogen/deuterium (H/D) exchange between organic compounds and deuterium sources is very important for a wide range of applications such as protein dynamics, labeled drugs and mechanistic studies of organic reactions Recently, there are only scattered reports of organic base-mediated H/D exchange reactions

The initial experiment was established by Drueckhammer and his coworkers1 in

1998 The H/D exchange reaction was performed between various -substituted

propionate ethyl thioesters 75 and CD3OD catalyzed by triethylamine in

toluene-d 8 The -thio derivatives (X = PhS, PhCH2S), as well as the halo and azido compounds showed half-lives for H/D exchange of a few hours while the

-aryl compounds showed half-lives of 2.5 days or more These studies were used for further understanding of the utility of thioesters as substrates in enzymatic dynamic resolution procedures (Scheme 2.1)

O

SEt

X

CH3

CD3OD

toluene-d 8

O SEt X

CH3 D

+ CD3OH

X = PhS, PhCH2S, halogen,N3,Ar t1/2(h): 1.3-108

Scheme 2.1 H/D exchange of -substituted propionate ethyl thioesters

Babas et al.2 reported the deuterium exchange experiments of trifluoroethyl thioesters catalyzed by 50 mol% Oct3N The H/D exchange reaction was utilized for studying the role of -proton acidity of the thioesters and its influence on

reactivity and enantioselectivity in the Michael reaction There was a correlation

between the exchange rate and the Michael reaction (Scheme 2.2 Eq 1 vs Eq 2)

The trifluoroethyl thioester of propoinic acid (77: R1 = Me) did not undergo

-proton exchange and was not active in the Michael reaction (Scheme 2.2)

O

S

Oct3N

Toluene-d 8

O S

O S

+

77: R1= Ar, Me

R1= Ar, t 1/2 = 5min-230min

R1= Me, t 1/2 = >5000min

O

S

77: R1= Ar, Me

PhCO2H (10 mol%) MeOH,RT

O S

R1

R2

R1= Ar, yield:45-88%; ee: 33-98%

R1= Me, No reaction N

Ar Ar

cat: 76

1

2

Scheme 2.2 H/D exchange of trifluoroethyl thioester

Scheme 2.3 H/D exchange of ketones

Recently, Mioskowski and his coworkers3 reported the high level of deuterium

Enantioselective H/D exchange reaction

30

incorporation of aromatic 80a-80d and aliphatic ketones 80e-80f, which were

performed in CDCl3 with TBD (triazabicyclo[4,4,0]dec-5-ene) as organic base catalyst It is the first example using aprotic media CDCl3 as deuterium source for

H/D exchange reaction of ketones TBD, a much stronger base (pKa = 26.2), led

to the high deuterium incorporation for all the ketone substrates via deprotonation/deuteriation process

ketones

2.2.1 Synthesis of -fluorinated aromatic cyclic ketones and chiral bicyclic

guanidine catalyst

-Tetralone derivatives 81a-81g, 81l were easily transformed into fluorinated ketones 82a-82g, 82l using fluorinating reagent Selectfluor according to the

reported procedure4 (Scheme 2.4 Eq 1) For the uncomercially available substrates

81c and 81g, we prepared them from the substituted 4-oxo-4-phenylbutanoic acid

83 in a two-step protocol Intermediates 84 were prepared by the reduction of 83,

followed cyclization in polyphospheric acid (PPA) at 110 oC to give the desired

products 81c and 81g (Scheme, 2.4 Eq 3)5

The fluorinated chroman-4-one derivatives 82h-82k were synthesized from the commercially available starting material 81h-81k Because dimethylketal form

were formed partly in the crude -fluorinated ketone products, the hydrolysis step

with 10% HCl aq was necessary for achieving the pure products 82h-82k

(Scheme 2.4 Eq 2)

Scheme 2.4 Fluorination of ketones

Scheme 2.5 Synthesis of the chiral bicyclic guanidine 25

The chiral bicyclic guanidine was prepared by the well-established procedure published in our lab6 N-Tosyl aziridine 86 was readily prepared from its corresponding commercially available α-amino alcohol 85 via a two-step protocol Triamine unit 87 was easily obtained by treating N-tosyl aziridine 86 in MeOH

saturated with NH3 gas in a sealed vessel After removing the solvent and the residue was dissolved in MeCN and refluxed for 3 days The subsequent removal

Enantioselective H/D exchange reaction

32

of tosyl groups was conducted in liquid ammonia in the presence of sodium After the final cyclization step, the triamine intermediate was cyclized to give the chiral

bicyclic guanidine 25 It was basified with 5M KOH aqueous solution or solid

K2CO3 (Scheme 2.5)

2.2.2 Optimization studies on asymmetric H/D exchange reaction

Scheme 2.6 Chiral bicyclic guanidine 25 catalyzed asymmetric H/D exchange

reaction in different conditions

7-Bromo-2-fluoro-3,4-dihydronaphthalen-1(2H)-one 82a was selected for the

model H/D exchange reaction catalyzed by the chiral bicyclic guanidine catalyst

25 The deuterium incorporation was monitored by 1H NMR and enantioselectivity was checked by chiral HPLC The initial experiment was carried out in THF in the presence of 100 equivalents D2O catalyzed by 30 mol% chiral guanidine at room temperature After 24 hours, over 95% deuterium

incorporation of 82a-d 1 was obtained with 4.8% ee When the temperature was

lowered to 0 oC, the enantioselectivity increased to 9% ee

Three more reactions were also carried out for comparison (Scheme 2.7) When

-fluorinated ketone 82a was treated with 30 mol% chiral bicyclic guanidine

catalyst in the presence of 100 equivalents H2O, there was no enantioselectivity over 24 h (Scheme 2.7 Eq 1) The same result was observed when the racemic

82a-d 1 was treated with 100 equivalents D2O under the same catalytic conditions

(Scheme 2.7 Eq 2) However, there was some enantioselectivity (9% ee) when the

racemic 82a-d 1 was treated with 100 equivalents H2O (Scheme 2.7 Eq 3) So the H/D exchange process is enantioselective

82a

82a-d 1(racemic)

N N N H

tBu tBu

25: 30 mol%

O

F H

O F H THF/H2O (100 equiv.)

0oC

N N N H

tBu tBu

25: 30 mol%

O

F D

O F D THF/D2O (100 equiv.)

0oC

No ee

No ee

Br

Br

N N N H

tBu tBu

25: 30 mol%

O

F D

O F D(H) THF/H2O (100 equiv.)

0oC

24 h, 3% ee

6 d, 9% ee

82a-d 1(racemic)

1

2

3

Scheme 2.7 Chiral bicyclic guanidine 25 catalyzed asymmetric H/H, D/D and

H/D exchange reaction (THF/H2O = 200μL/μL)

In our optimization studies with -fluorinated ketone 82a, we screened different solvents for asymmetric H/D exchange reaction at room temperature (Table 2.1) The chlorinated solvents gave much better enantioselectivities with high deuterium incorporation (entries 1, 5, 7) The racemic product was obtained when trifluoroethanol was used as solvent (entry 6) For deuterated solvents

(entries 9-10), ee values dropped a few percents comparing to corresponding

Enantioselective H/D exchange reaction

34

non-deuterated ones When the reaction temperature was lowered to -20 oC, no enatioselectivity was observed (entry 11) Moreover, the catalyst loading did not affect the enantioselectivity too much (entries 12-13)

Table 2.1 Optimization of the asymmetric H/D exchange reaction of -fluorinated

ketone 82a in different conditions (Scheme 2.6)

entry solvent 25/mol % D2O temp/oC incorporation

yield/%a ee/%b

2 THF 30 100 0 >95 9

a Monitored by 1H NMR; b Chiral HPLC analysis

The effect of the amount of D2O on the asymmetric H/D exchange reaction was investigated As shown in Figure 2.1, the enantioselectivities increased when the amount of D2O increased from 10 equivalents to 80 equivalents Nevertheless, the

ee values changed a little from 80 equivalents to 170 equivalents and reached to

the highest 24.4% ee (150 equiv D2O) When more than 200 equivalents D2O was

used in the reaction, the ee values dropped a lot At last, we used 150 equivalents

D2O as the optimal amount for the following reactions

Figure 2.1 Asymmetric H/D exchange reaction of -fluorinated ketone 82a in

different amount of D2O Determined by 1H NMR and Chiral HPLC analysis

To determine the optimal reaction time, the asymmetric H/D exchange reaction was carried out at different durations ranging from 1 h to 36 h (Table 2.2) At the beginning of the reaction, we observed that the enantioselectivity increased

sharply from 1 h to 5 h and reached the maximum at about 9 h with 26% ee After

the -fluorinated ketone 82a was fully converted to the deuterated product 82a-d1,

the ee value of the deuterated product decreased slowly We stopped monitoring the experiment at 36 h but the trend indicated that the ee will approach 0% with

prolonged reaction time

Enantioselective H/D exchange reaction

36

Table 2.2 Optimization of the asymmetric H/D exchange reaction of -fluorinated

ketone 82a in different reaction time

entry Reaction time/h Incorporation yield/%a ee/%b

a Determined by 1H NMR b Chiral HPLC analysis

82a-d 1

O

F D Br

15 h, 24% ee, 100% D

O F D

24 h, 30% ee, >95% D

TsO

O F D

24 h, 7% ee, 67% D

O F D

14 h, 3% ee, 70% D

CH3

O F D

24 h, 5% ee, 100% D

O

F D

24 h, 0% ee, 100% D

O F D

14 h, 13% ee, 53% D

O

O F D

24 h, 0% ee, 100% D

O

F

N N N H

25: 30 mol%

82

O F D

82-d 1

DCE, 0oC

150 equiv.)

R1

R1

Scheme 2.8 Chiral bicyclic guanidine 25 catalyzed asymmetric H/D exchange

reaction

Based on the optimized reaction conditions, -fluorinated ketones 82a-82h and

82l were chosen as substrates for the asymmetric H/D exchange reaction (Scheme

2.8) The highest enantioselectivity of 30% ee was obtained with -fluorinated

ketone 82b For substrate 82f with a strong electron-withdrawing nitro group on

the aromatic ring, there was no enantioselectivity observed The -fluorinated

4-chromanone derivative 82h was not effective, either

2.3 DFT calculation for the enantioselective H/D exchange

reaction

The asymmetric deuterium exchange reaction of -fluorinated ketone was further examined by density functional theory (DFT) calculations.7 As these reactions were conducted in the presence of water (H2O or D2O), both the direct

and water-assisted protonation/deprotonation of 82b by chiral guanidine 25 were

evaluated In the direct process, two transition states, S-TS and R-TS, were located for S-1b and R-1b, with an overall activation free energy of 19.9 and 21.2

kcal/mol, respectively When a water molecule participates in the protonation/deprotonation reaction, overall activation free energy is lowered to

16.4 and 17.0 kcal/mol, for S-82b and R-82b, respectively Transition states

S-H2O-TS and R-H2 O-TS support the model of bifunctional activation by

guanidine catalyst 25,8 and more importantly, suggest that in the presence of water, the water-assisted protonation/deprotonation processes are more favorable than direct ones (Figure 2.2) Isotope effects were estimated by frequency

Enantioselective H/D exchange reaction

38

calculations on S-H2O-TS and R-H2 O-TS geometries with all protic hydrogen

atoms replaced by deuterium atoms The results indicate that overall activation free energies for both deuterated transition states are increased by 1.3 kcal/mol

Figure 2.2 Transition states for the protonation/deprotonation process

Non-hydrogen bonded hydrogen atoms are omitted for clarity Relative energies are shown in parentheses Dotted lines provide visual guides for the bond breaking and forming processes

All these results collectively accounted for the experimental observations: 1)

While the protonation of the enolate intermediate (after 82b is deprotonated) to

form S-82b is kinetically favored by 0.6 kcal/mol, the deprotonation of S-82b also proceeds faster than R-82b by 0.6 kcal/mol As a result, no changes in ee can be

expected when racemic 82b is treated with H2O in the presence of catalyst 25; 2)

Since the dedeuteration of 82b-d 1 is approximately seven times slower than the

deprotonation of 82b, enantiomerically enriched 82b-d 1 will be produced upon the

deprotonation of 82b and deuteration of the resulting enolate intermediate; 3)

However, 82b-d 1 also undergoes racemization reaction and as the deuterated

product increases, racemization will become more pronounced which will lead to

lower ee of 82b-d 1 , and eventually racemic 82b-d 1

2.4 Summary

In summary, we have developed an asymmetric H/D exchange reaction via

deprotonation/deuteration reaction catalyzed by chiral bicyclic guanidine 25 The

best enantioselectivity was 30% for deuterated products 82b-d 1 The level of deuteration at various time points was monitored using HPLC and 1H NMR The

results showed the racemization of the product 82b-d 1 occurred and the trend

seemed to indicate that the ee will approach 0% if the time of experiment is long

enough We also examined the asymmetric deuterium exchange reaction of

-fluorinated aromatic ketone by DFT calculations The computational results

explained the asymmetric H/D exchange experiment well, and the S absolute

configuration of products was achieved

Enantioselective H/D exchange reaction

40

References:

1 Um, P.-J.; Drueckhammer, D G J Am Chem Soc 1998, 120, 5605

2 Alonso, D A.; Kitagaki, S.; Utsumi, N.; Barbas III, C F Angew Chem Int

Ed 2008, 47, 4588

3 Sabot, C.; Kumar, K A.; Antheaume, C.; Mioskowski, C J Org Chem 2007,

72, 5001

4 Stavber, S.; Jereb, M.; Zupan, M Synthesis, 2002, 17, 2609

5 Owton, W M.; Brunavs, M Synth Commun 1991, 21, 981

6 Ye, W.; Leow, D.; Goh, S L M.; Tan, C.-T.; Chian, C.-H.; Tan, C.-H

Tetrahedron Lett 2006, 47, 1007

7 DFT calculations were performed by employing the Gaussian 09 program The B3LYPmethod was applied with 6-31G (d) Pople basis set

8 Lee, R.; Lim, X.; Chen, T.; Tan, G K.; Tan, C.-H Tetrahedron Lett 2009, 50,

1560