N-(heteroarenesulfonyl)prolinamides-catalyzed aldol reaction between acetone and aryl trihalomethyl ketones

Article abstract of DOI:10.1021/ol2001039

Enantiomerically enriched trihalomethyl-substituted alcohols having a quaternary chiral carbon center can be prepared by the catalytic enantioselective cross-aldol reaction of acetone with trihalomethyl ketones by using N-(8-quinolinesulfonyl)prolinamide as an organocatalyst. The MO calculations elucidate that the hydrogen bonding between the sulfonimide proton and the 8-quinolyl nitrogen atom plays an important role in exerting the enantioselectivity of the reaction.

Full text of DOI:10.1021/ol2001039

ORGANIC
LETTERS
2011
Vol. 13, No. 7
1662–1665
N-(Heteroarenesulfonyl)prolinamides-
Catalyzed Aldol Reaction between
Acetone and Aryl Trihalomethyl Ketones
Noriyuki Hara, Ryota Tamura, Yasuhiro Funahashi, and Shuichi Nakamura*
Department of Frontier Materials, Graduate School of Engineering,
Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-8555, Japan
snakamur@nitech.ac.jp
Received January 17, 2011
ABSTRACT
Enantiomerically enriched trihalomethyl-substituted alcohols having a quaternary chiral carbon center can be prepared by the catalytic
enantioselective cross-aldol reaction of acetone with trihalomethyl ketones by using N-(8-quinolinesulfonyl)prolinamide as an organocatalyst.
The MO calculations elucidate that the hydrogen bonding between the sulfonimide proton and the 8-quinolyl nitrogen atom plays an important role
in exerting the enantioselectivity of the reaction.
Since the enantioselective aldol reaction with organoca-
talysts is recognized as one of the most powerful car-
bon-carbon bond-forming reactions,1 the organocataly-
tic asymmetric aldol reaction to ketones as electrophiles
has thus been investigated,2 as it provides efficient access to
chiral tertiary alcohols. However, it is still a challenging
research field due to the poor reactivity of ketones as
electrophiles and the difficulty of the differentiation of
the reactive carbonyl face. Therefore, expanding the scope
of the organocatalytic aldol reaction with ketones is highly
desirable. Although chiral tertiary trihalomethyl carbinols
are versatile building blocks in organic synthesis,3 there
have been only three examples of the cross-aldol reaction
with ketones having trihalomethyl groups. Ya-Wen and
co-workers have reported the L-proline-catalyzed enantio-
selective aldol reaction of acetone with 2,2,2-trifluoro-
1-arylethanones as trihalomethyl ketones to give products
with moderate enantioselectivity (up to 64% ee).4 More
recently, highly enantioselective organocatalytic aldol
reactions between R,β-unsaturated trifluoromethyl ketones
and ketones have been reported.5 On the other hand, there
are no reports on the reaction of trichloromethyl ketones
probably due to their low reactivities and difficulties in
obtaining high enantioselectivity. Although pioneering
studies have been performed, the development of highly
enantioselective catalyst systems with wide substrate toler-
ance is still a challenging research. Recently, we reported
that N-(2-thiophenesulfonyl)prolinamide acted as a highly
efficient organocatalyst for the reaction of acetone or
(1) For reviews, see: (a) Asymmetric Organocatalysis; Berkessel, A.,
€
Groger, H., Eds.; Wiley-VCH: New York, 2005. (b) Enantioselective
Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, Germany,
2007. (c) Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638–
4660.
ꢀ
ꢀ
(2) For reviews, see: (a) Guillena, G.; Najera, C.; Ramon, D. J.
Tetrahedron: Asymmetry 2007, 18, 2249. (b) Bella, M.; Gasperi, T.
Synthesis 2009, 1583. (c) Adachi, S.; Harada, T. Eur. J. Org. Chem.
2009, 3661 and references cited therein. (d) Hayashi, Y.; Sekizawa, H.;
Yamaguchi, J.; Gotoh, H. J. Org. Chem. 2007, 72, 6493. (e) Itoh, T.;
Ishikawa, H.; Hayashi, Y. Org. Lett. 2009, 11, 3854. (f) Chen, W.-B.; Du,
X.-L.; Cun, L.-F.; Zhang, X.-M.; Yuan, W.-C. Tetrahedron 2010, 66,
1441. (g) Jiang, Z.; Lu, Y. Tetrahedron Lett. 2010, 51, 1884.
(3) (a) Corey, E. J.; Link, J. O. J. Am. Chem. Soc. 1992, 114, 1906. (b)
Khrimian, A. P.; Oliver, J. E.; Waters, R. M.; Panicker, S.; Nicholson,
J. M.; Klun, J. A. Tetrahedron: Asymmetry 1996, 7, 37. (c) Fujisawa, T.;
Ito, T.; Fujimoto, K.; Shimizu, M.; Wynberg, H.; Staring, E. G. J.
Tetrahedron Lett. 1997, 38, 1593. (d) Wang, Z.; Campagna, S.; Yang, K.;
Xu, G.; Pierce, M. E.; Fortunak, J. M.; Confalone, P. N. J. Org. Chem.
2000, 65, 1889. (e) Jiang, B.; Si, Y.-G. Adv. Synth. Catal. 2004, 346, 669.
(f) Bejot, R.; Tisserand, S.; Reddy, L. M.; Barma, D. K.; Baati, R.;
Falck, J. R.; Mioskowski, C. Angew. Chem., Int. Ed. 2005, 44, 2008.
(4) Li-Hua, Q.; Zong-Xuan, S.; Chang-Qing, S.; Yan-Hua, L.; Ya-
Wen, Z. Chin. J. Chem. 2005, 23, 584.
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Zhang, D.; Yuan, C. Tetrahedron 2008, 64, 2480.
r
10.1021/ol2001039
Published on Web 03/02/2011
2011 American Chemical Society

aldehydes with isatin derivatives.6,7 We herein report the
efficient synthesis of chiral tertiary alcohols or amines
having a trihalomethyl group by the enantioselective reac-
tion of trihalomethyl ketones or imines with acetone using
N-(heteroarenesulfonyl)prolinamides (Scheme 1).
Table 1. Enantioselective Addition of Acetone to 2,2,2-Tri-
fluoro-1-phenylethanone 1a in the Presence of Various Orga-
nocatalysts 3,4
Scheme 1. Construction of a Quaternary Chiral Carbon Center
by Asymmetric Aldol Reaction to Trihalomethyl Ketones
entry catalyst (mol %) TFA (mol %) time (h) yield (%)a ee (%)b
1c
2
3
4
5
6
7
8
9
3 (10)
12
36
48
48
48
48
48
48
72
120
97
89
83
88
85
91
92
86
88
81
27
45
60
75
67
83
89
87
86
84
The fluoroalkyl group is one of the most attractive
functional groups in organic chemistry because fluoroalk-
yl-containing molecules often play an important role in
material, agricultural, and medicinal chemistry.8 Espe-
cially, the synthesis of chiral trifluoromethylated com-
pounds having a quaternary chiral center is highly
desirable.9 Therefore, we first examined the reaction of
2,2,2-trifluoro-1-phenylethanone 1a with acetone in the
presence of 10 mol % of various chiral organocatalysts 3,4.
The results are shown in Table 1. L-Proline 3 was an active
catalyst, but exhibited poor asymmetric inducibility (entry
1). Enantioselectivity was improved in the reaction per-
formed at a lower temperature, although the reactivity was
lower (entry 2). The reaction using the TFA salt of N-
(p-toluenesulfonyl)prolinamide (4a) proceeded to give pro-
duct 2a with moderate enantioselectivity (entry 3).10 To
improve enantioselectivity, we optimized the arenesulfonyl
group of chiral organocatalysts (entries 4-7). Finally, the
chiral organocatalyst N-(8-quinolinesulfonyl)prolinamide
(4e) proved to be the catalyst of choice, and under the same
reaction condition, afforded 2a in 92% yield with 89% ee
(entry 7). Importantly, by lowering the catalyst loading to
5, 2, and 1 mol % (entries 8-10), which represents the
lowest catalyst loading employed in the asymmetric aldol
reaction to ketones, there was no significant loss of en-
antioselectivity and yield.
3 (10)
4a (10)
4b (10)
4c (10)
4d (10)
4e (10)
4e (5)
8
8
8
8
8
4
4e (2)
1.6
0.8
10
4e (1)
a Yield of isolated 2a after purification on silica gel. b Ee was
determined by HPLC analysis. c The reaction was carried out at room
temperature.
With these optimized conditions, the reaction of a series
of fluoroalkyl ketones and acetone using organocatalyst 4e
was examined (Table 2). The reaction of various aryl tri-
fluoromethyl ketones 1a-h gave products 2a-h in high
yield with high enantioselectivity (entries 1-7). The
Table 2. Enantioselective Addition of Acetone to Various
Fluoroalkyl Ketones 1a-i
(6) (a) Nakamura, S.; Hara, N.; Nakashima, H.; Kubo, K.; Shibata,
N.; Toru, T. Chem.;Eur. J. 2008, 14, 8079. (b) Hara, N.; Nakamura, S.;
Shibata, N.; Toru, T. Chem.;Eur. J. 2009, 15, 6790. (c) We also
developed montmorillonite entrapped N-(2-thiophenesulfonyl)-
prolinamide, see: Hara, N.; Nakamura, S.; Shibata, N.; Toru, T. Adv.
Synth. Catal. 2010, 352, 1621.
entry
ketone 1
product 2
time (h)
yeld (%)a
ee (%)b
(7) Recently, Carter, Cheong, and co-workers have reported N-(2-
pyridinesulfonyl)prolinamide as a organocatalyst, see: Yang, H.;
Mahapatra, S.; Cheong, P. H.; Carter, R. G. J. Org. Chem. 2010, 75, 7279.
(8) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneuer, V. Chem.
Soc. Rev. 2008, 37, 320. (b) Organofluorine Compounds in Medicinal and
Biochemical Applications; Filler, R., Kobayashi, Y., Yagupolskii, L. N.,
Eds.; Elsevier: Amsterdam, The Netherlands, 1993. (c) Organofluorine
Compounds: Chemistry and Applications; Hiyama, T., Ed.; Springer: New
York, 2000.
(9) Recently, our group has reported the enantioselective nucleophi-
lic addition to trifluoromethyl ketones using organocatalysts, see: (a)
Ogawa, S.; Shibata, N.; Inagaki, J.; Nakamura, S.; Toru, T.; Shiro, M.
Angew. Chem., Int. Ed. 2007, 46, 8666. (b) Nakamura, S.; Hyodo, K.;
Nakamura, Y.; Shibata, N.; Toru, T. Adv. Synth. Catal. 2008, 350, 1443.
(10) The addition of a substoichiometric amount of TFA is impor-
tant, because TFA activates the background reaction of 1a with acetone.
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
48
48
48
48
48
48
48
48
48
92
61
91
76
87
88
95
81
91
89
86
86
90
88
84
85
77
92
1g
1h
1i
2g
2h
2i
a Yields of isolated 2 after purification on silica gel. b Ee was
determined by HPLC analysis.
Org. Lett., Vol. 13, No. 7, 2011
1663

heteroatom containing arylaldehyde 1h also resulted in a
good enantioselectivity (entry 8). The reaction with fluor-
oalkyl ketone 1i also gave product 2i in high yield with high
enantioselectivity (entry 9).
On the other hand, trichloromethyl-containing com-
pounds have also been found to be useful in medicinal
chemistry.11 Furthermore, these compounds are impor-
tant synthetic intermediates; they can be converted to
R-amino acids, R-hydroxy acids, oxiranes, and R-fluoro
acids.3 Therefore, we next examined the reaction of tri-
chloromethyl ketones 5a-i with acetone using various
organocatalysts 3,4 (Table 3). Moderate enantioselectivity
tallography (see the Supporting Information), and the
stereochemistry of other products was tentatively assumed
by analogy. These results are the first example of a highly
enantioselective aldol reaction of trichloromethyl ketones
using organocatalysts.
To expand the scope of the catalyst system, we examined
the enantioselective Mannich-type reaction of a ketimine
with acetone. Although there are only a few reports for the
enantioselective Mannich-type reaction with ketimines,12
the reaction of 2,2,2-trifluoro-1-phenylethanimine 7 with
acetone was catalyzed by 5 mol % of organocatalysts 4e to
give product 8 in high yield with high enantioselectivity
(eq 1). The stereochemical outcome of the reaction is in
agreement with the reaction of trichloromethyl ketone 5h.
Table 3. Enantioselective Addition of Acetone to 1-Aryl-2,2,2-
trichloroethanone 5a-i
The enantioselective reaction of trihalomethyl ketones
or a ketimine with acetone using organocatalyst 4e having
a heteroarenesulfonyl group gave products in good yield
with good enantioselectivity, although the reaction using
organocatalyst 4a did not afford a good result (Table 1,
entry 3 vs 7). Therefore, the heteroarenesulfonyl group
plays an important role in exerting enantioselectivity of the
reaction. To clarify the structure of the related compounds
derived from 4e, we studied the MO calculation of catalyst
4e and enamine intermediate 9 prepared from 4e with
acetone by Gaussian 0913 B3LYP/6-311þG** after con-
formational analyses. The most stable structures for 4e are
depicted in Figure 1. Two nitrogens for quinoline (N1) and
entry
5
catalyst
time (h)
yield (%)a
ee (%)b
1
2
5a
5a
5a
5a
5a
5b
5c
5d
5e
5f
3
66
48
45
16
51
54
70
50
33
74
86
87
94
83
46
66
89
85
93
93
96
95
94
93
91
92
96
90
4c
4d
4e
4e
4e
4e
4e
4e
4e
4e
4e
4e
3
66
4
48
5
144
144
144
48
6
7
8
9
48
10
11
12
13
48
5g
5h
5i
48
48
48
a Yield of isolated 2a after purification on silica gel. b Ee was
determined by HPLC analysis.
was obtained in the reaction with L-proline 3 (entry 1). The
reaction with organocatalysts having heteroarenesulfonyl
groups showed moderate yield and high enantioselectivity
as well as the reaction of 1-aryl-2,2,2-trifluoroethanone
(entries 2-4). We found that N-(8-quinolinesulfonyl)pro-
linamide (4e) is an efficient organocatalyst in the reaction
of 5a with acetone (entry 4). The yield of product 6a can be
improved with a longer reaction time (entry 5). The reac-
tion of various trichloromethyl ketones 5b-i gave pro-
ducts 6b-i in good yield with high enantioselectivity
(entries 6-12), although the reaction with trichloromethyl
ketones 5b,c having an electron-donating substitution
attached to the para-position of the benzene ring decreased
the reaction rate and yield (entries 6 and 7). The absolute
configuration of product 6h was determined by X-ray crys-
Figure 1. Optimized structure for catalyst 4e.
pyrrolidine (N2) arranged to the hydrogen on sulfonimide.
In the optimized structure, the distance between the sulfo-
ꢀ
˚
nimide hydrogen and nitrogens (N1, N2) is 2.267 A and
2.181 A, respectively. Furthermore, the NBO analysis14 for
ꢀ
˚
(12) (a) Zhuang, W.; Saaby, S.; Jørgensen, K. A. Angew. Chem., Int.
Ed. 2004, 43, 4476. (b) Sukach, V. A.; Golovach, N. M.; Pirozhenko,
V. V.; Rusanov, E. B.; Vovk, M. V. Tetrahedron: Asymmetry 2008, 19,
761. (c) Jiang, B.; Dong, J. J.; Si, Y. G.; Zhao, X. L.; Huang, Z. G.; Xua,
M. Adv. Synth. Catal. 2008, 350, 1360. (d) Baudequin, C.; Zamfir, A.;
Tsogoeva, S. B. Chem. Commun. 2008, 4637.
(11) (a) Prakash, G. K. S.; Hu, J. In Science of Synthesis; Thieme:
Stuttgart, Germany, 2005; Vol. 22, p 617. (b) Darko, L. L. J. Med. Chem.
1971, 14, 527.
1664
Org. Lett., Vol. 13, No. 7, 2011

4e estimated that the energy of interaction between lone
pairs (LP) of both nitrogens and σ* orbital for the
Nimide-H bond was 3.21 and 4.33 kcal/mol, respectively.
These results imply that the hydrogen on sulfonimide in 4e
makes hydrogen bonding to both nitrogens in quinoline
and pyrrolidine.
The optimized structure for enamine intermediate 9 also
shows hydrogen bonding between the nitrogen in quino-
line and the hydrogen on sulfonimide, although the nitro-
gen in the pyrrolidine ring is separated from the
sulfonimide hydrogen becauseoftheformation ofenamine
(Figure 2). The NBO analysis for enamine 9 also shows the
interaction between the lone pair of quinoline nitrogen and
the σ* orbital for the Nimide-H bond. The stabilizing
energy for their hydrogen bonding was estimated to be
8.45 kcal/mol.
Figure 3. Assumed transition state for the cross-aldol reaction of
1a with acetone, using 4e.
play an important role in transition states. There are two
plausible transition states TS-S and TS-R. The reaction
with 4e proceeds more preferably through TS-S giving
(S)-2a, because TS-R, whichgives (R)-2a, isdestabilizedby
steric repulsion between the bulky trifluoromethyl groups
and methyl or the 8-quinolyl groups in enamine 9.15
In conclusion, we have developed a highly enantioselec-
tive construction of a quaternary carbon center by the
reaction of trihalometyl ketones and a ketimine with
acetone (up to 96% ee). We have identified 8-quinoline-
sulfonylated catalyst 4e to be a privileged organocatalyst
for the reaction with various trihalometyl ketones and
ketimine. Further studies are in progress to study the
potential of these catalytic systems in other processes.
Acknowledgment. This work was supported by the
Tatematsu Foundation. We are grateful to Zeon Co. for
a gift of CPME.
Figure 2. Optimized structure for enamine intermediate 9.
From the above considerations, the assumed transition
states for the enantioselective aldol reaction of trifluoro-
methyl ketones with acetone are shown in Figure 3. The
hydrogen bonding between the sulfonimide proton and the
8-quinolyl nitrogen atom in the organocatalysts 4e would
Supporting Information Available. Representative ex-
perimantal procedures, HPLC analyses, and NMR spec-
tra of the products. This material is available free of
charge via the Internet at http://pubs.acs.org.
(13) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.;
Petersson, G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.;
Izmaylov, A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.;
Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakaji-
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Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Ragha-
vachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi,
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Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salva-
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(15) It is reasonable that the phenyl group is effectively a smaller
group than the trifluoromethyl group. The order of relative sizes for
trihalomethyl and phenyl group are CCl3 > CF3 > Ph as indicated by
the following reports, see: (a) Corey, E. J.; Cheng, X.-M.; Cimprich,
K. A.; Sarshar, S. Tetrahedron Lett. 1991, 32, 6835. (b) Ramachandran,
P. V.; Teodorovic, A. V.; Brown, H. C. Tetrahedron 1993, 49, 1725. (c)
Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986. (d) Tur,
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F.; Mansilla, J.; Lillo, V. J.; Saa, J. M. Synthesis 2010, 1909. This
assumption is in good agreement with the better enantioselectivity
obtained from the reaction with trichloromethyl ketones 5 than that
with trifluoromethyl ketones 1.
Org. Lett., Vol. 13, No. 7, 2011
1665