Highly enantioselective direct aldol reaction catalyzed by cinchona derived primary amines

Article abstract of DOI:10.1039/b711164a

Highly enantioselective aldol reactions of aldehydes with cyclic ketones catalyzed by a primary amine derived from cinchonine are reported. Aromatic aldehydes reacted with various cyclic ketones cleanly to afford the anti-aldol adducts in up to 99% yield,

Full text of DOI:10.1039/b711164a

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Highly enantioselective direct aldol reaction catalyzed by cinchona derived
primary amines†
Bao-Lei Zheng, Quan-Zhong Liu,* Chuan-Sheng Guo, Xue-Lian Wang and Long He
Received 20th July 2007, Accepted 6th August 2007
First published as an Advance Article on the web 14th August 2007
DOI: 10.1039/b711164a
Highly enantioselective aldol reactions of aldehydes with
cyclic ketones catalyzed by a primary amine derived from
cinchonine are reported. Aromatic aldehydes reacted with
various cyclic ketones cleanly to afford the anti-aldol adducts
in up to 99% yield, with good diastereoselectivities (up to 9 : 1)
and excellent enantioselectivities (up to 99% ee).
asymmetric aldol reaction presents the most versatile protocols
for the preparation of optically enriched b-hydroxyl ketones. To
our knowledge, although Barbas et al. firstly employed the amine
in the direct aldol reaction,12 there is no report of asymmetric
aldol reactions catalyzed by cinchonine derived amines. To probe
the potential application of cinchona derived amines in direct aldol
reactions, we initiated an enantioselective aldol reaction between
aldehydes and cyclic ketones. Herein, we disclose our preliminary
results toward this work.
We were pleased to find that 9-amino-9-deoxy-epi-cinchonine 1
(Fig. 1, 10 mol%) exhibited high catalytic activity for the asym-
metric aldol reaction of 4-nitrobenzaldehyde with cyclohexanone
at room temperature. The corresponding adduct was cleanly
isolated in 74% yield with a promising 87% ee after 39 h and
the anti-isomer was favorably formed with 1.6 : 1 dr (entry 1,
Table 1). The enantioselectivity increased to 95% ee when the
reaction was conducted in the presence of TFA (10 mol%), and 1
(10 mol%) with dr 6.9 : 1 (entry 2, Table 1). The employment of
triflic acid (10 mol%) further enhanced the enantioselectivity and
reactivity. The amount of triflic acid used considerably affected
the reactivity of the catalyst. Fifteen mol% of acid in combination
with 10 mol% of catalyst was suitable for the reaction in terms
of enantioselectivity, diastereoselectivity and reactivity (99% ee,
9 h, entry 5, Table 1). To our surprise, the reaction was very slow
when 20 mol% of triflic acid was used (15 h, 77% yield, entry 6).
Although 9-amino-9-deoxy-epi-cinchonidine (2) gave 94% of ee,
the adduct with the opposite configuration was obtained (entry 8).
Since the pioneering work of List et al.1 with enantioselective aldol
reactions in the presence of proline as catalyst, organocatalysts
have demonstrated their significant importance in asymmetric
C–C or heteroatom–C bond formation. In both types of trans-
formations, the amino acid proline has been widely employed
as a versatile organocatalyst.2 Despite the high efficiency shown
in a series of reactions, proline suffers from serious problems
such as poor solubility in organic solvents, a tendency to react
with electron-deficient aromatic aldehydes to form iminium salts
that decarboxylate even at room temperature,3 and difficulties
in modulating its reactivity through structure modification. To
solve these problems, Maruoka and coworkers reported a novel
organocatalyst derived from optically pure binaphthol.4 Another
alternative was the transformation of proline to its prolinamide
derivatives.5 Recently, Chen’s group developed a simple primary–
tertiary diamine-Brønsted acid catalyst that has been successfully
applied in direct aldol reactions.6 The catalytic system is highly
efficient for both linear and cyclic aliphatic ketones.
Cinchona derivatives have been versatile catalysts in many
organic transformations due to their excellent performance. Cin-
chona derived amines such as 1 and 2 can also be readily prepared
from a known protocol.7 These amines have been employed as
efficient organocatalysts in enantioselective Michael reactions
in high yields and enantioselectivities via enamine or iminium
intermediates. For example, Chen developed a highly efficient
enantioselective Michael addition of a,a-dicyanoalkene8 as well
as 1,3-dicarbonyl compounds9 to a,b-unsaturated ketones using
cinchonine derived amines as the organocatalyst. Connon and
McCooey developed a highly enantioselective addition of alde-
hydes and ketones to nitroolefins catalyzed by readily accessible
alkaloid derivatives.10 Very recently, Melchiorre et al. reported an
organocatalytic asymmetric Friedel–Crafts alkylation of indoles
with a,b-unsaturated ketones by the successful application of an
iminium ion activation strategy toward enones using the salt
formed with this amine and N-protected phenyl glycine.11 The
Fig. 1 Structure of amines derived from cinchona.
We next investigated the effect of solvent on the reaction,
with screening results summarized in Table 2. All the solvents
tested gave almost the same enantioselectivities. Good yields were
obtained in THF, toluene, and water with different reaction times
of 4 to 23 h and dr ranging from 4.8–9.8 : 1. The reaction
was apparently retarded by DMSO and DMF with yields of
only ∼70% after a long reaction time (44–45 h). Water had a
significant impact on reaction speed, but a deleterious effect on
diastereoselectivity. From these results, solvent had little effect
College of Chemistry and Chemical Engineering, China West Normal
University, Nanchong, 637002, China. E-mail: quanzhongliu@sohu.com;
Fax: +86-817-2582029; Tel: +86-817-2568081
† Electronic supplementary information (ESI) available: Catalysts and
conditions, screening studies, experimental procedures, and full charac-
terization of products. See DOI: 10.1039/b711164a
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◦
◦
Table 1 Reactions between 4-nitrobenzaldehyde and cyclohexanone
the ee dropped significantly (40 C, 92% ee, 2.0 : 1 dr vs. 60 C,
86% ee, 1.7 : 1 dr. See ESI†) It is noteworthy that only 5 mol%
of amine 1 can catalyze the reaction affording the product in 81%
yield and 98% ee, although the reaction was not as fast (entry 13).
Thus, 10 mol% of catalyst in combination with 15 mol% triflic acid,
cyclohexanone as solvent, and room temperature were chosen for
the optimal conditions.
The optimized protocol was then expanded to a wide variety
of aldehydes and cyclic ketones (Table 3‡). The results of these
trials indicated that the reaction is dramatically dependent on
the electronic effect of the substituent. For example, 4-, 3-,
2-nitrobenzaldehyde and 4-trifluoro-methylbenzaldehyde under-
went aldol reaction smoothly with cyclohexanone in good to
excellent yields (74–99%) and excellent enantioselectivities (97–
99% ee, entries 1, 5, 6 and 9, Table 3). Unsubstituted aromatic
aldehydes were less reactive, because benzaldehyde, furyl-aldehyde,
and 1-naphthylaldehyde afforded only low to moderate yields, but
very good enantioselectivities (entries 11–13). The substrates with
electron donating groups at the aromatic ring were not suitable
for the reaction. For example, 4-methoxy-benzaldehyde reacted
with cyclohexanone for 48 h yielding the corresponding product
in only 19% yield and 89% ee (entry 15, Table 3). Cyclopentanone
was also employed in the aldol reaction which showed less desired
enantioselectivity compared to cyclohexanone in our catalytic
system. 4- and 2-nitrobenzaldehyde afforded the corresponding
product in 86% and 84% ee respectively (entries 2 and 7). In
almost all cases, the diastereoselectivity is not high, with the
structures of both aldehydes and ketones having significant impact
on the dr value. The highest diastereomeric ratio was observed
when 4-nitrobenzaldehyde and cyclohexanone were combined
(entry 1, Table 3). We also tested the catalytic system in the aldol
Entry
Acid (%)
Yield (%)
ee (%)
dr
1a
2
3
4
5
—
74
55
99
97
99
77
81
76
87
95
98
98
99
98
98
−94
1.6 : 1
6.9 : 1
6.3 : 1
9.4 : 1
9.2 : 1
8.9 : 1
7.8 : 1
9.9 : 1
TFA (10)
TfOH (5)
TfOH (10)
TfOH (15)
TfOH (20)
TfOH (7.5)
TfOH (15)
6
7b
8c
a Unless otherwise stated, the reaction was carried out with 0.25 mmol
of 4-nitrobenzaldehyde and 0.5 mL (4.8 mmol) of cyclohexanone, the
enantioselectivity was measured using chiral AD-H, dr was measured
according to 1H NMR of crude product. b In the presence of 5 mol%
of catalyst 1. c Catalyst 2 used instead.
Table 2 Effect of solvent on the reaction
Entry
Solvent
Time/h
Yield (%)a
ee (%)b
drc
1
2d
Neat
THF
9
17
45
44
23
4
22
20
12
19
24
38
96
23
99
98
77
74
94
97
84
79
82
98
94
90
11
81
99
99
97
97
98
97
98
98
98
98
97
98
91
98
9.2 : 1
9.8 : 1
3.5 : 1
5.0 : 1
8.6 : 1
4.8 : 1
7.0 : 1
6.6 : 1
7.5 : 1
8.1 : 1
4.1 : 1
5.0 : 1
2.4 : 1
7.8 : 1
3d
DMSO
DMF
Toluene
H2O
CHCl3
EtOH
CH2Cl2
Et2O
4d
Table 3 Enantioselective direct aldol reaction of aldehydes and cyclic
ketones
5d
6d
7d
8d
9d
10d
11e
12f
13g
14h
DMF-H2O
Neat
Neat
Entry
R
X
Yield (%)
ee (%) anti–syn dr
Neat
a Isolated yield. b Determined by chiral AD-H. c Determined by 1H NMR.
d The reaction was carried out with 0.25 mmol of aldehyde, 0.5 mL of
cyclohexanone and 1 mL of solvent. e Volume ratio 1 : 1◦. f The reaction
was carried out at 0 ◦C. g The reaction carried out at −16 C. h 5 mol% of
catalyst 1 was used.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16d
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
4-NO2C6H4
3-NO2C6H4
2-NO2C6H4
2-NO2C6H4
2-NO2C6H4
4-CF3C6H4
4-FC6H4
C6H5
Fural
1-Naphthyl
4-Cl
4-CH3OC6H4
4-NO2
CH2
99
70
92
38
74
98
99
44
99
58
31
39
55
70
19
25
99 : 65
86 : 67
91 : 78
94 : 57
97 : 25
97 : n.d.
84 : 63
87 : 71
98 : 58
94 : 29
86 : 54
63 : 94
93 : 16
91 : 16
89 : 14
56
9.2 : 1
a
—
5.0 : 1
5.4 : 1
3.0 : 1
3.2 : 1
7.5 : 1
2.4 : 1
3.2 : 1
2.3 : 1
1.7 : 1
1.0 : 1
1 : 2.5
4.9 : 1
4.1 : 1
3.7 : 1
—
Oc
Sb
CH2
CH2
a
—
Oc
CH2
CH2
CH2
CH2
CH2
CH2
CH2
on enantioselectivity but greatly affected the reaction time and
dr. Neat cyclohexanone was suitable as both reactant as well as
solvent in terms of enantioselectivity and catalyst reactivity.
Although the enantioselectivities were excellent in all cases, the
diastereomeric ratio was only about 90 : 10. To further improve the
diastereoselectivity, we investigated the effect of temperature on
the reaction. To our disappointment, the reaction proceeded very
slowly under low temperature with decreased diastereoselectivity.
For example, the reaction carried out at −16 ◦C for 96 h afforded
only 11% yield (91% ee, 2.4 : 1 dr, entry 13). At higher temperature,
a Cyclopentanone used. b 2 Equivalents of ketone used. c 5 Equivalents of
ketone used. d Neat acetone used instead of cyclic ketone in the presence
of 10 mol% of catalyst and 15 mol% of triflic acid.
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reaction with acetone, but unfortunately, a 25% yield and 56% ee
were obtained when neat acetone was applied under the optimal
conditions.
In conclusion, an enantioselective direct aldol reaction of
cyclic ketones with different aromatic aldehydes catalyzed by
cinchona derived amines has been reported with high yields, good
diastereoselectivity, and up to 99% ee. The aromatic aldehydes
with electron withdrawing groups are suitable substrates for this
reaction. This provides a practical and convenient method for the
synthesis of optically enriched hydroxyl ketones.
2 (a) A. Corvoda, B. Zhou, I. Ibrahem, E. Reyes, M. Engqvist and W.-W.
Liao, Chem. Commun., 2005, 3586–3588; (b) Z. Jiang, Z. Liang, X. Wu
and Y. Lu, Chem. Commun., 2006, 2801–2803; (c) A. Corvoda, B. Zhou,
P. Dziedzic, I. Ibrahem, E. Reyes and Y. Xu, Chem.–Eur. J., 2006, 12,
5385–5397; (d) B. List, Synlett, 2001, 1675–1686; (e) H. Gro¨ger and J.
Wilken, Angew. Chem., Int. Ed., 2001, 40, 529–532; (f) M. Movassaghi
and E. N. Jacobsen, Science, 2002, 298, 582–583; (g) A. S. Paraskar,
Synlett, 2003, 582–583; (h) B. List, Chem. Commun., 2006, 819–824.
3 F. Orsini, F. Pelizzoni, M. Forte, R. Destro and P. Gariboldi, Tetrahe-
dron, 1988, 44, 519–541.
4 (a) T. Kano, J. Takai, O. Tokuda and K. Maruoka, Angew. Chem., Int.
Ed., 2005, 44, 3055–3057; (b) T. Kano, O. Tokuda and K. Maruoka,
Tetrahedron Lett., 2006, 47, 7423–7426.
5 (a) Z. Tang, F. Jiang, L.-T. Yu, A.-Q. Mi, Y.-Z. Jiang and Y.-D. Wu,
J. Am. Chem. Soc., 2003, 125, 5262–5263; (b) Z. Tang, H. Jiang, X. Cui,
L.-Z. Gong, A.-Q. Mi, Y.-Z. Jiang and Y.-D. Wu, Proc. Natl. Acad. Sci.
U. S. A., 2004, 101, 5755–5760; (c) D. Gryko and R. Lipin´ski, Adv.
Synth. Catal., 2005, 347, 1948–1952; (d) H.-M. Guo, L.-F. Cun, L.-Z.
Gong, A. Q. Mi and Y.-Z. Jiang, Chem. Commun., 2005, 1450–1452;
(e) Z. Tang, Z.-H. Yang, X.-H. Chen, L.-F. Cun, A.-Q. Mi, Y.-Z. Jiang
and L.-Z. Gong, J. Am. Chem. Soc., 2005, 127, 9285–9289; (f) J.-R.
Chen, H.-H. Lu, X.-Y. Li, L. Cheng, J. Wan and W.-J. Xiao, Org. Lett.,
2005, 7, 4543–4545; (g) S. Singh Chimni, D. Mahajan and V. V. Suresh
Babu, Tetrahedron Lett., 2005, 46, 5617–5619; (h) S. Samanta, J. Liu,
R. Dodda and C.-G. Zhao, Org. Lett., 2005, 7, 5321–5323; (i) L. He, Z.
Tang, L.-F. Cun, A.-Q. Mi, Y.-Z. Jiang and L.-Z. Gong, Tetrahedron,
2006, 62, 346–351; (j) M. Jiang, S.-F. Zhu, Y. Yang, L.-Z. Gong, X.-G.
Zhou and Q.-L. Zhou, Tetrahedron: Asymmetry, 2006, 17, 384–387.
6 S.-Z. Luo, H. Xu, J.-Y. Li, L. Zhang and J.-P. Chen, J. Am. Chem. Soc.,
2007, 129, 3074–3075.
Acknowledgements
We are grateful for financial support from the Sichuan Provincial
Science Foundation for Outstanding Youth (grant: 05ZQ026-008)
and Key Project of the Education Department of Sichuan Province
(2006A081).
Notes and references
‡ General procedure for the aldol reaction: to a mixture of catalyst
1 (0.025 mmol) and TfOH (0.0375 mmol) was added cyclohexanone
(1 mL), cyclopentanone (1 mL), tetrahydro-4H-puran-4-one (1.25 mmol)
or tetrahydrothiopuran-4-one (0.50 mmol). The reaction mixture was
stirred for 5 min in a closed system and then aldehyde (0.25 mmol) was
added. The reaction mixture was stirred for 9–166 h (monitored by TLC).
The reaction was quenched with saturated ammonium chloride solution
(10 mL) and extracted with ethyl acetate (3 × 15 mL). The combined
organic layer was dried (Na2SO4 and concentrated in vacuo). The crude
product was purified by flash column chromatography to give pure aldol
7 H. Brunner, J. Bugler and B. Nuber, Tetrahedron: Asymmetry, 1995, 6,
1699–1702.
8 J.-W. Xie, W. Chen, R. Li, M. Zeng, W. Du, L. Yue, Y.-C. Chen, Y. Wu,
J. Zhu and J.-G. Deng, Angew. Chem., Int. Ed., 2007, 46, 389–392.
9 J.-W. Xie, L. Yue, W. Chen, W. Du, J. Zhu, J.-G. Deng and Y.-C. Chen,
Org. Lett., 2007, 9, 413–415.
10 S. J. Connon and S. H. McCooey, Org. Lett., 2007, 9, 599–602.
11 G. Bartoli, M. Bosco, A. Carlone, F. Pesciaioli, L. Sambri and P.
Melchiorre, Org. Lett., 2007, 9, 1403–1405.
1
adduct. Diastereoselectivity was determined by H NMR analysis of the
crude aldol product.
1 (a) B. List, R. A. Lerner and C. F. Barbas, III, J. Am. Chem. Soc., 2000,
122, 2395–2396; (b) K. Sakthivel, W. Notz, T. Bui and C. F. Barbas, III,
J. Am. Chem. Soc., 2001, 123, 5260–5261.
12 N. Mase, F. Tanaka and C. F. Barbas, III, Org. Lett., 2003, 5, 4369–
4372.
This journal is
The Royal Society of Chemistry 2007
Org. Biomol. Chem., 2007, 5, 2913–2915 | 2915
©