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Chapter 8

Downloaded by NORTH CAROLINA STATE UNIV on September 27, 2012 | http://pubs.acs.org Publication Date: January 11, 2007 | doi: 10.1021/bk-2007-0949.ch008

Catalytic In-Situ Generation of Trifluoroacetaldehyde from Its Hemiacetal and Successive Direct Aldol Reaction with Ketones Kazumasa Funabiki and Masaki Matsui Department of Materials Science and Technology, Faculty of Engineering, Gifu University, 1-1, Yanagido, Gifu 501-1193, Japan

Trifluoroacetaldehyde ethyl hemiacetal reacted with unmodified ketones in the presence of 30 to 50 each mol% of amines and acids at ambient temperature, affording the correspondingβ-hydroxy-ß-trifluoromethylatedketones in good yields with good to excellent diastereoselectivities. Furthermore, L-proline-catalyzed asymmetric direct aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with unmodified ketones also proceeded smoothly to produce the corresponding β-hydroxy-β-trifluoromethylated ketones with good to excellent diastereo- and enantio-selectivities.

© 2007 American Chemical Society

In Current Fluoroorganic Chemistry; Soloshonok, V., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2007.

141

142

Introduction

Trifluoroacetaldehyde (CF CHO) is one of the most important C2 building block for the 'synthesis of the a-trifluoromethlyated alcohols, which are important core moieties of liquid crystals and antidepressant. Therefore, it has been widely used in aldol, Mukaiyama aldol, ene, Friedel-Crafts, Morita-BayllisHillman reaction, and so on. Despite significant progress in the area of efficient asymmetric synthesis of trifluorometylated molecules using C F C H O (1), the method for the generation of C F C H O from its hemiacetal or hydrate is still dependent on the early protocol, which includes a serious indispensable conditions such as use of an excess amount of concentrated sulfuric acid under high reaction temperature (2). Therefore, an environmentally-friendly, practical, and efficient method for the in situ generation of C F C H O attended by its simultaneous stereoselective carbon-carbon bond formation reaction is really required. Recently, we have found that a stoichiometric amount of enamines or imines are capable to in situ generation of C F C H O as well as the successive carboncarbon bond formation reaction under mild conditions, producing P-hydroxy-ptrifluoromethylated ketones in good to excellent yields (3) (Figure 1). 3


3

3

3

3

OH

2

R

+ FC 3

OEt

R

- N '

3

R . or " " x^ni N

i trifluoromethyl (syn : anti = 93 : 7, 86% de) > difluoromethyl (syn : anti = 78 : 22, 56% de) group (entries 1,4 and 5), though the reason for this ^-selective outcome is not clear at this present. Downloaded by NORTH CAROLINA STATE UNIV on September 27, 2012 | http://pubs.acs.org Publication Date: January 11, 2007 | doi: 10.1021/bk-2007-0949.ch008

3

2

£-Proline-catalyzed Asymmetric Direct Aldol Reaction of C F C H O Ethyl Hemiacetal with Ketones (9,10,11) 3

Optimization of the Reaction Conditions The results of the L-proline-catalyzed reaction of C F C H O ethyl hemiacetal l a with acetone 2a in various solvents are summarized in Table 3 (Figure 8). 3

OH T F

3

C ^ O E t 1

O IT +

30 m o l % , L - P r o l i n e ^ solvent, rt, 48 h

2a

OH \

O jl

¥ C^^^ 3

3a

Figure 8. L-Proline-catalyzed Asymmetric Direct Aldol Reaction of CF CHO Ethyl Hemiacetal with Acetone. 3

The employment of DMSO or D M F resulted in a significant loss of enantioselectivities (entries 1 and 2). Other solvents, such as acetonitrile, dichloromethane and chloroform could be used to produce the good yields of the product 3a with good enantioselectivities (entries 8-10). The reaction in THF or hexane was very sluggish and gave low yields of 3a (entries 2 and 12). The reaction in water did not proceed at all (entry 3). The reaction in benzene resulted in best enatioselectivity of 3a but with a decreased yield (entry 11). Importantly, acetone can be used as the solvent as well as a ketone donor with excellent yield in good enantioselectivity (entries 5 and 6). Lowering reaction temperature (0 °C) resulted in significant decrease of the product 3a even in the presence of a stoichiometric amount of L-proline, together with slight increase of ee (entry 7). 1


150


Table 3. I-Proline-catalyzed Asymmetric Direct Aldol Reaction of CF3CHO Ethyl Hemiacetal with Acetone Entry"

Solvent

Yield (%)

R:F

Ee

1 2 3 4 5 6 r 8 9 10 11 12

DMSO DMF H 0 THF Acetone Acetone Acetone MeCN CH C1

96 94 0 19 97 96 18 64 45 31 32 19

50.3 : 49.7 52.0: 48.0

2.8 4.0

-

-

68.7 : 31.3 67.6: 32.4 69.2: 30.8'' 71.3 : 28.7 70.7: 29.2 73.9: 26.1 72.8: 27.2 75.8: 24.2 73.0: 27.0

37.4 35.2 38.4* 42.6 41.5 47.8 45.6 51.6 46.0

2

2

2

CHCI3

Benzene Hexane

b

c

a

All the reaction was carried out with CF CHO ethyl hemiacetal l a (1 mmol) with Zproline (30 mol%) in the mixed solvent of dry acetone 2a (2 ml) and solvent (8 ml) or dry acetone (10 ml). * Determined by F NMR using benzotrifluoride as an internal standard. Determined by HPLC analysis with DAICEL CHIRALCEL OD-H (hexane:/PrOH=95/5) after p-chlorobenzoylation. Determined by GC with InterCap CHIRAMIX (GL Science). Carried out with Z-proline (100 mol%) at 0 °C for 96 h. 3

19

c

d

e

Other CF3CHO derivatives, such as hydrate (75 wt%) and 2,2,2trifluoroethyl hemiacetal (88 wt%) as well as pentafluoropropionaldehyde hydrate Id were also examined, as shown in Figure 9. Hemiacetals are la,c much effective than hydrate lb to produce almost quantitative yields of 3a. However, there is only slight difference in ee of 3a. Pentafluoropropionaldehyde hydrate Id also reacted with acetone to give 69% yield of aldol product 6a with slight higher enantioselectivity. The absolute configuration of the major aldol product 3a generated by the reaction could be determined unambiguously as R by the comparision with the reported values of the optical rotation (12).

I-Proline-catalyzed Asymmetric Direct Aldol Reaction with Ketones The catalytic asymmetric direct aldol reaction of C F C H O ethyl hemiacetal with unmodified other ketones 2 are described in Figures 10 and 11. Interestingly, cyclopentanone 2b also nicely underwent the Z-prolinecatalyzed direct aldol reaction with C F C H O ethyl hemiacetal la as well as pentafluoropropionaldehyde hydrate Id to give the corresponding aldol product 3b, 6b in 77-96% yields with excellent syw-diastereoselectivities (dr = 94-98 : 26) as well as high enantioselectivities (er = 88.6-88.8 : 11.2-11.4). The reason for sjw-selectivities in the reaction with cyclopentanone is unclear at this present. 3

3


151

OH I F

3

O M +

C " \ ) X


A

^

1

0

/

O H O = |T

r

r^~48h

1

"

F

3

C

2a X = H 2

OH 7

3

V

^

. 97% yield, R : 5 = 70.6 : 2 9 . 4 , 4 1 . 2 % ee

O ]T

_ ^ 30 mol%, I-Prohne ^ 1

+

CF CF "T>H

/

3a

64% yield, R : 5 = 68.9 : 31.1, 37.8% ee

X = CH CF

3

„ _ 30mol%, L-Proline^

A

/

rt,48h

2

Id

O H =

r

C F

3

2a

0 If

C F 2 ^ ^ ^ 6a

69% yield

R: S = 72.0 2 8 . 0 44.0% ee

Figure 9. L-Proline-catalyzed Asymmetric Direct Aldol Reaction of Other CF CHO Derivatives and Pentafluoropropionaldehyde Hydrate with Acetone. 3

OH

OH

X + R f T > X

6

rt, 48 h 3b,6b

2b

la : R f= C F , X = Et 3

a

C

2

0

b

77 % y i e l d , Syn : Anti = 94 : 6 ,

C

R : 5 = 88.6 : 11.4 , 77.2%

Determined by

1

9

F N M R using benzotrifluonde as an internal standard.

* Determined by

1

9

F NMR.

0

c

9 6 % y i e l d * , Syn : Anti = 9 8 . 2*, R. 5 = 88.8 : 11.2 , 77.6% ee

Id : R f = C F C F , X = H 3

O

30 m o l % , L - P r o l i n e

Determined by G C with InterCap C H I R A M I X ( G L Science).

Figure 10. L-Proline-catalyzed Asymmetric Direct Aldol Reaction with Cyclopentanone.


152 Cyclohexanone 2c reacted smoothly, via the proposed transition state by List and Houk (13), with the C F C H O ethyl hemiacetal l a as well as pentafluoropropionaldehyde hydrate Id in the presence of 30 mol% of Z-proline to produce 3c,6c in 68-71% yields with high ^/-selectivities (dr = 96-99 : 4-1) with excellent enantioselectivities (er = 95.5-96.7 : 3.3-4.5). 3

O H


Y

JJ

R f ^ O X

+

Q

1

O

=

il

rt,48h

'

2c

l a : R f = C F , X = Et 3

3c,6c

0

6 8 % y i e l d , Syn • Ann

Id : R f = C F C F , X - H 3

OH 30mol%,Z.-Proline

2

= 4 : 96*,

0

C

R : 5 = 95.5 . 4.5 ,

71% y i e l d , Syn • Anti = 1 : 99*,

R:

S=

° D e t e r m i n e d by

1 9

F N M R using b e n z o t n f l u o n d e as an internal standard.

* D e t e r m i n e d by

1 9

F N M R

c

c

9\.0%ee C

96.7 : 3.3 , 93.4%

c

ee

D e t e r m i n e d by G C with C h i r a l s i l - D e x C B ( C h r o m p a c k ) .

Figure 11. L-Proline-catalyzed Asymmetric Direct Aldol Reaction with Cyclohexanone. Unfortunately, the reaction of diethyl ketone 2d as a linear disubstituted ketone with hemiacetal l a did not proceed at all.

a,a-

Conclusions

In summary, we have achieved that the direct aldol reaction of C F C H O ethyl hemiacetal with unmidified ketones by the use of small amount of acids and amines without any strong acid and high reaction temperature, producing Phydroxy-P-trifluoromethylated ketones in good yields. Furthermore, commercially available I-proline-catalyzed asymmetric aldol reaction of C F C H O ethyl hemiacetal with unmodified ketones also succeeded to produce 0hydroxy-P-trifluoromethylated ketones in good to excellent diastereo- and/or enatioselectivies. 3

3

Acknowledgements

This work was partially supported by a Grant-in-Aid from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the O G A W A


153 Science and Technology Foundation and Gifu University. We are grateful to the Central Glass Co., Ltd., for the gift of C F C H O hemiacetal and hydrate as well as financial support. We also thank my coworkers, Messrs. H . Yamamoto, H . Nagaya, and Ms. M . Ishihara for their contribution. 3


References

1.

2.

3.

4.

5. 6. 7. 8. 9.

For recent reviews, see. (a) Iseki, K . Tetrahedron 1998, 54, 13887-13914. (b) Soloshonok, V . In Enantiocontrolled Synthesis of Fluoro-organic Compounds, Soloshonok, V . A . Ed.; John Wiley & Sons, Chichester, 1999, pp 230-262. (c) Mikami, K . In ref. 1b, pp 557-574. (c) Ishii, A.; Mikami, K . In Asymmetric Fluoroorganic Chemistry: Synthesis, Application, and Future Directions, Ramachandran, P. V . Ed.; ACS Symposium Series 746, Washington, DC, 1999, pp 60-73. (d) Mikami, K . In ref. 1c, pp 255-269. (e) Mikami, K . ; Itoh, Y . ; Yamanaka, M . Chem. Rev. 2004, 141, 1-16. (f) Mikami, K . ; Itoh, Y . ; Yamanaka, M . In Fluorine-Containing Synthons, Soloshonok, V . A . Ed.; A C S Symposium ries 911, Washington D C , 2005, pp 356-367. (a) Braid, M.; Iserson, H.; Lawlor, F. E. J. Am. Chem. Soc. 1954, 76, 4027. (b) Henne, A . L . ; Pelley, R. L . ; Alm, R. M. J. Am. Chem. Soc. 1950, 72, 3370-3371. (c) Shechter, H.; Conrad, F. J. Am. Chem. Soc. 1950, 72, 33713373. (a) Funabiki, K.; Nojiri, M . ; Matsui, M.; Shibata, K. Chem. Commum. 1998, 2051-2052. (b) Funabiki, K.; Matsunaga, K.; Matsui, M.; Shibata, K . Synlett 1999, 1477-1479. (c) Funabiki, K . ; Matsunaga, K.; Nojiri, Hashimoto, W.; Yamamoto, H.; Shibata, K.; M . ; Matsui, M. J. Org. Chem. 2003, 68, 28532860. (d) Funabiki, K . In ref. 1f, pp 342-355. (a) Funabiki, K.; Hashimoto, W.; Matsui, M. Chem. Commun. 2004, 20562057. (b) Funabiki, K.; Hasegawa, K.; Murase, Y . ; Nagaya, H.; Matsui, M. J. Fluorine Chem. (special issue) in press. And Ref. 3d. Funabiki, K . ; Honma, N.; Hashimoto, W.; Matsui, M. Org. Lett. 2003, 5, 2059-2061. (a) Trost, B . M . Science 1991, 254, 1471-1477. (b) Trost, B . M . Angew. Chem. Int. Ed. Engl. 1995, 34, 259-281. Funabiki, K.; Nagaya, H.; Ishihara, M . ; Matsui, M . Tetrahedron, in press. MacPhee, J. A . ; Panaye, A.; Dubois, J. - E . Tetrahedron 1978, 34, 35533562. (a) Funabiki, K . ; Yamamoto, H . ; Nagamori, M . ; Matsui, M . US 2005119507 A1. (b) Funabiki, K.; Yamamoto, H.; Matsui, M. submitted for publication.



154 10. During our work, an example dealing with the catalytic generation of trifluoroacetaldehyde as well as only one proline-derived tetrazole catalyzed direct aldol reaction with cyclopentanone has been reported, see. Torii, H . ; Nakadai, M.; Ishihara, K.; Saito, S.; Yamamoto, H . Angew. Chem. Int. Ed. 2004, 43, 1983-1986. 11. For L-proline-catalyzed asymmetric direct aldol reaction of trifluoropyruvate with aldehydes, see: Bøgevig, A . ; Kumaragurubaran, N.; Jørgensen, K . A . Chem. Commun. 2002, 620-621. For L-proline-catalyzed asymmetric Mannich reaction of trifluoromethylated imines with acetone, see: Funabiki, K.; Nagamori, M.; Goushi, S.; Matsui, M. Chem. Commun. 2004, 1928-1929. For L-proline-catalyzed asymmetric Mannich reaction of trifluoromethylated imines with aldehydes, see: Fustero, S.; Jimenez, D.; Sanz-Cervera, J. F.; Sánchez-Roselló, M.; Estenban, E.; Simón-Fuentes, A . Org. Lett. 2005, 7, 3433-3436. 12. Bucciarelli, M.; Forni, A.; Moretti, I.; Prati F.; Torre, G. Biocatalysis 1994, 9, 313-320. 13. Bahmanyar, S.; Houk, K . N.; Martin, H . J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475-2479.


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