Chiral amine organocatalysts for the syn-aldol reaction involving substituted benzaldehydes and hydroxyacetone

Article abstract of DOI:10.1016/j.tetasy.2011.05.021

A new series of cyclohexanediamine organocatalysts that contain the primary amine functionality has been designed, synthesized and tested as catalysts for the asymmetric aldol reaction involving hydroxyacetone and a variety of substituted benzaldehydes. H

Full text of DOI:10.1016/j.tetasy.2011.05.021

Tetrahedron: Asymmetry 22 (2011) 1051–1054
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Chiral amine organocatalysts for the syn-aldol reaction involving
substituted benzaldehydes and hydroxyacetone
⇑
Dhruba Sarkar, Kurt Harman, Subrata Ghosh, Allan D. Headley
Department of Chemistry, Texas A&M University-Commerce, Commerce, TX 75429-3011, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 14 April 2011
Accepted 27 May 2011
A new series of cyclohexanediamine organocatalysts that contain the primary amine functionality has
been designed, synthesized and tested as catalysts for the asymmetric aldol reaction involving hydrox-
yacetone and a variety of substituted benzaldehydes. High enantioselectivites and diasteroselectivites
were obtained using catalyst 1a for these reactions. A key step in this reaction for the formation of the
syn-product is the formation of a stable intramolecular hydrogen bonded Z-enamine isomer, which in
addition to the steric bulk of the catalyst, serve to dictate the course of the stereochemical outcome of
the reaction.
Ó 2011 Elsevier Ltd. All rights reserved.
1. Introduction
development of such organocatalysts that are tunable for different
reaction types continue to be a challenging task.
A major challenge for chemists over the years is the develop-
ment of appropriate amines to serve as effective catalysts for asym-
metric synthesis. The action of such catalysts mimics enzymatic
enamine catalysis in biological systems.1 In biological systems,
the excellent stereocontrol that results from the direct asymmetric
aldol reaction is key for the enzymatic aldolase reaction.2 Through
the pioneering work of List et al.3 enamine-based compounds have
gained widespread use as catalysts for a wide variety of asymmetric
reactions.4 For these enamine-based organocatalysts, a key step is
the use of chiral secondary amines, such as pyrrolidine derivatives;
it has been demonstrated that such organocatalysts are efficient
catalysts for the aldol reaction.5 According to the Houk–List model,
these catalysts are believed to stabilize the transition states of these
reactions via the formation of hydrogen bonds. In our research
group, we have developed various tunable chiral pyrolidine ionic
liquid catalysts that are effective catalysts for various asymmetric
reactions.6
In recent years, the application of primary amino acid
derivatives as organocatalysts has received much attention due
to their stereochemical selectivity for some direct aldol reactions.7
Achieving the goal of controlling the stereochemistry of asymmet-
ric aldol reactions continues to be a major challenge for chemists.
Several efficient asymmetric methodologies for this reaction using
various organocatalysts have been developed, but the use of
primary amine-based organocatalysts for the asymmetric
aldol reactions has received far less attention.8 The design and
The direct asymmetric aldol reaction is highly important be-
cause it provides an efficient method to synthesize optically active
b-hydroxy carbonyls and as a result, has received much attention.
Herein we report the design and synthesis of a series of organocat-
alysts derived from amino acids and cyclohexanediamine that are
effective and result in high enantioselectivity for syn-aldol prod-
ucts for the reactions of
a-hydroxyacetone and various aromatic
aldehydes. The synthesis of the organocatalysts is outlined in
Scheme 1.
2. Results and discussion
Since it is known that hydrogen bonds play an important role in
the stabilization of the transition states for reactions involving cat-
alysts of this type, R1 was selected to convey different acidities to
the N–H of the catalyst. It was expected that 1g and 1f would exhi-
bit the greatest acidity due to the presence of two trifluoromethyl
substituents and the sulfone and carbonyl groups, respectively. As
a result, they were expected to form effective hydrogen bonds to
stabilize the transition state. On the other hand, the N–H of organ-
ocatalysts 1c should be the least acidic. The R2 group was selected
to convey different steric bulks to the catalyst. From Table 1, 1d
and 1e should exhibit the most steric bulk owing to the presence
of the tert-butyl and benzyl groups, respectively, which are bonded
to the carbon adjacent to the stereogenic center of the catalyst.
These organocatalysts were screened using a-hydroxyacetone and
4-nitrobenzaldehyde and the results are shown in Table 1.
From Table 1, catalysts 1d and 1e gave the lowest ee, compared
to catalyst 1a; this observation indicates that the steric bulk at the
R2 position does not play a major role in the stereochemical control
⇑
Corresponding author.
E-mail address: Allan_Headley@tamu-commerce.edu (A.D. Headley).
0957-4166/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2011.05.021

1052
D. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1051–1054
O
R2
NH
NH
R1
OH
1)
NHBoc
NH2
NH2
NH
R1
R1-Cl, DCM
0-25 o
DCC, DCM,
0-25 oC
NH2
R2
C
O
NH2
2) 30% TFA, DCM
2
1 (yields up to 95%)
3 (yields up to 80%)
R1
R2
Catalyst
R1
R2
Catalyst
O
S
O
C
1e
1a
CH(CH3)2
CH(CH3)2
CH2C6H5
CH(CH3)2
O
CF3
O
O
C
1b
C
1f
CF3
CF3
O
CH(CH3)2
C(CH3)3
1c
1d
C
O
S
O
1g
CH(CH3)2
C
O
CF3
Scheme 1. Synthesis of various primary amine organocatalysts.
Table 1
Table 2
Results from the screening of the catalysts shown in Scheme 1 using hydroxyacetone
and nitrobenzaldehyde
Aldol reaction of hydroxyacetone with various aromatic aldehydes using catalyst 1a
O
O
OH
O
15 mol% Catalyst 1a
O
OH
O
15 mol% Catalyst 1a
OH
+
O
H
DCM, rt, 48-72 hrs
H
OH
+
DCM, rt, 48-72 hrs
NO2
OH
X
OH
4a
X
NO2
ee%b
5
6
5a
4a
6a
Entry
X
Product
Yield (%)
syn/antia
ee%b
Entry
Catalyst
Yield (%)
syn/antia
1
2
3
4
5
6
7
4-NO2
2-NO2
4-CN
2-Cl
4-Cl
4-CF3
4-OCH3
6a
6b
6c
6d
6e
6f
74
60
58
55
58
60
48
88/12
90/10
79/21
90/10
69/31
90/10
70/30
75
81
69
84
52
93
91
1
2
3
4
5
6
7
1a
1b
1c
1d
1e
1f
74
98
56
84
88
75
65
88/12
86/14
78/22
81/19
73/27
79/21
81/19
75
64
60
40
54
75
75
6g
1g
Determined by 1H NMR.
Determined by chiral HPLC of the product.
a
Determined by 1H NMR.
Determined by chiral HPLC of the product.
a
b
b
of the reaction. Catalysts 1f and 1g gave comparable ee and syn/
anti products to those of catalyst 1a. This observation indicates that
the acidity of the amine functionality bonded to R1, does not play a
major role in the stereochemical outcome of the reaction. Since
catalyst 1a was found to give the best combination of results for
this reaction (yield, diastereoselectivity and enantioselectivity), it
was chosen as the catalyst to analyze its effects on the aldol reac-
Due to the hydrogen bond that is formed between the OH-
group and the acidic hydrogen, the Z-isomer is the more stable
one, compared to the E-isomer. It has been shown that a similar
type of hydrogen bond accounts for the stability the Z-isomer of
the enamines of a
-hydroxyacetone9 and nitroethane amine anhy-
dride.10 The reaction of the Z-isomer with the substrate aldehyde
produces two possible transitions states, as shown in Figure 2.
From Figure 2, it is obvious that the N–H acidic hydrogen can
interact with the carbonyl oxygen to form the more stable transi-
tion state, which explains why the syn-products are formed for
the reactions shown in Table 2. On the other hand, the less stable
transition state does not have a similar type of interaction, as
shown in Figure 2. From the transition state model shown in Fig-
ure 2, it is obvious as to why the increased acidity of the N–H of
the amine that is bonded to R1 of catalyst 1f and 1g does not play
tion using
a-hydroxyacetone and a wide range of aromatic alde-
hydes, that have both electron-withdrawing and electron-
donating groups; the results are shown in Table 2.
An important observation from Table 2 is the relatively high
diastereoselectivity achieved with this catalyst for such a wide
range of substrates. This observation can be explained by the close
examination of the possible enamine isomers of catalyst 1a, which
are shown in Figure 1.

D. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1051–1054
1053
O
O
H
H
H
H
H
N
N
N
H
H
N
H
H
H
H
O
CH3
CH3
O
N
N
O
O
OH
H
H
S
S
O
CH3
CH3
cis-isomer
trans-isomer
Figure 1. Conformers for the enamine intermediate from catalyst 1a.
Figure 2. Proposed transition states for the aldol reaction of hydroxyacetone with aromatic aldehydes using catalyst 1a.
a major role in the outcome of the reactions, compared to catalyst
1a, since the hydrogen is more removed from the carbonyl oxygen.
The reaction involving the electron-donating 4-methoxbenzalde-
hyde (entry 7) resulted in similar stereochemical outcomes as
those involving the electron-withdrawing 4-trifluoromethylbenz-
aldehyde (entry 6); the reactions of 4-nitrobenzaldehyde (entry
1) resulted in different stereochemical outcomes to those of 4-cya-
nobenzaldehyde (entry 3). This observation would imply that the
electronic effect does not play a major role in the stereochemical
determining step of the reaction. As a result, there seems to be
no direct correlation between the nature of the substituents of
the phenyl ring and the stereochemical outcome of these reactions,
similar observations have been made for comparable reactions.8a,b
was washed with water and the solvent was removed at reduced
pressure. The residue was purified through column chromatogra-
phy on silica gel (eluent, ethyl acetate/methanol 3:1) to give the
mono-substituted aminocyclohexane 3. The corresponding amino
acid (15 mmol) and N,N0-dicyclohexylcarbodiimide (DCC) (3.11 g,
15 mmol) were dissolved in dichloromethane (30 mL) and cooled
to 0 °C. After the solution was stirred for 30 min, a solution of 3
(10 mmol) in 20 mL dichloromethane was added dropwise over
15 min. After the addition was complete, the mixture was warmed
to room temperature and stirred for another 12 h. After filtration
and removal of solvent at reduced pressure, the residue was puri-
fied by flash column chromatography on silica gel (eluent, hexane/
ethyl acetate 2:1) to provide the protected catalyst, which was dis-
solved (8 mmol) in a mixture of TFA/CH2Cl2 30% (20 mL), and stir-
red for 12 h at room temperature. The mixture was made basic by
the addition of sodium bicarbonate and after filtration, the solvent
was removed at reduced pressure and was purified through flash
column chromatography on silica gel (eluent, ethyl acetate/metha-
nol 5:1) to yield the catalysts 1 shown in Table 1.
3. Conclusion
In conclusion, this new series of cyclohexanediamine organo-
catalysts, which contain the primary amine functionality gives
high enantioselectivites, diastereoselectivites and relatively good
yields for the asymmetric syn-aldol reaction involving
a-hydrox-
yacetone and a wide variety of substituted benzaldehydes. The for-
mation of the more stable Z-enamine conformer, combined with
the steric bulk of the catalyst, plays an important role in controlling
the stereochemical outcome of the reaction.
4.2. Catalyst 1a
White solid: mp: 143–144 °C; ½a D20
ꢀ
¼ þ30:2 (c 0.51, CH2Cl2); 1H
NMR (400 MHz, CDCl3) d 0.89 (d, J = 7.2 Hz, 3H), 0.98 (d, J = 6.8 Hz,
3H), 1.13–1.71 (m, 8H), 1.91–2.04 (m, 2H), 2.28–2.32 (m, 1H), 2.42
(s, 3H), 3.04–3.14 (m, 2H), 2.47–3.68 (m, 2H), 7.26–7.35 (m, 3H),
7.60 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) d 19.8, 24.5,
24.6, 24.9, 32.6, 33.2, 33.9, 49.1, 52.4, 58.1, 60.4, 126.7, 126.8,
129.5, 129.6, 139.2, 143.0, 175.6; HRMS (ESI) m/z (%) calcd for
4. Experimental
4.1. General procedure for the synthesis of the catalysts
C
18H30N3O3S (MH+) 368.2002, found 368.1995.
At first, (1R,2R)-1,2-diaminocyclohexane 2 (2.28 g, 20 mmol)
was added to dichloromethane. The mixture was cooled to 0 °C
and a solution of acetyl chloride/tosyl chloride (6.7 mmol) in
10 mL of dichloromethane was added dropwise over 30 min. After
the addition was complete, the mixture was allowed to warm to
room temperature and stirred overnight. The resulting solution
4.3. Catalyst 1b
White solid: mp: 178–179 °C; ½a D20
ꢀ
¼ ꢁ24:7 (c 0.2, MeOH); 1H
NMR (400 MHz, CDCl3)
d 0.47 (d, J = 6.8 Hz, 3H), 0.86 (d,

1054
D. Sarkar et al. / Tetrahedron: Asymmetry 22 (2011) 1051–1054
J = 7.2 Hz, 3H), 1.24–1.84 (m, 8H), 1.91–2.04 (m, 2H), 2.16–2.34 (m,
1H), 3.02–3.14 (m, 1H), 3.20 (d, J = 3.2 Hz, 1H), 3.47–3.49 (m, 1H),
3.74–3.84 (m, 1H), 4.067–4.08 (m, 1H), 7.26–7.60 (m, 3H), 7.80–
7.82 (m, 2H); 13C NMR (100 MHz, CDCl3) d 19.7, 24.4, 24.9, 25.7,
30.5, 32.1, 32.3, 52.0, 56.3, 60.0, 127.0, 128.3, 131.2, 134.0, 156.7,
167.0; HRMS (ESI) m/z (%) calcd for C18H28N3O2 (MH+) 318.2176,
found 318.2181.
(s, 1H), 8.32(s, 2H); 13C NMR (100 MHz, CDCl3) d 16.0, 19.7, 24.3,
24.4, 24.9, 32.9, 33.1, 33.9, 52.1, 59.5, 121.1, 123.9, 125.6, 125.7,
126.9, 132.5, 132.8, 145.6, 176.2; HRMS (ESI) m/z (%) calcd for
C
19H26F6N3O3S (MH+) 490.1593, found 490.1595.
4.9. General procedure for the aldol reaction of hydroxyacetone
Catalyst 1a (9 mg, 0.03 mmol), hydroxyacetone (37 mg,
0.4 mmol), and 4-nitrobenzaldehyde (30, 0.2 mmol) were mixed
in 0.4 mL of DCM at room temperature. The mixture was stirred
for 48 h and directly purified by flash chromatography to afford
the aldol adduct 6a as a white solid (yield 74%). The syn/anti ratio
was determined by 1H NMR spectroscopy of the crude mixture, the
enantiomeric excess (ee) was determined by HPLC on a chiral
phase.
4.4. Catalyst 1c
White solid: mp: 181–182 °C; ½a D20
ꢀ
¼ ꢁ24:4 (c 0.21, CH2Cl2); 1H
NMR (400 MHz, CD3OD) d 0.95 (d, J = 7.2 Hz, 3H), 0.99 (d, J = 7.2 Hz,
3H), 1.31–1.84 (m, 8H), 2.03–2.15 (m, 2H), 2.36 (s, 3H), 3.20 (d,
J = 3.2 Hz, 1H), 3.46 (d, J = 5.2 Hz 1H), 3.77–3.91 (m, 2H), 4.55 (s,
1H), 7.24 (d, J = 8.0 Hz, 2H), 7.69 (d, J = 8.0 Hz, 2H); 13C NMR
(100 MHz, CDCl3) d 19.7, 21.3, 24.4, 24.9, 30.5, 32.1, 32.3, 33.9,
52.0, 55.9, 60.0, 127.0, 128.9, 131.2, 141.5, 166.9, 175.8; HRMS
Acknowledgments
(ESI) m/z (%) calcd for
C
19H30N3O3 (MH+) 332.2332, found
332.2337.
We gratefully acknowledge the financial support of this re-
search by the Robert A. Welch Foundation (T-1460) and NSF-REU
(Grant No. 0851966).
4.5. Catalyst 1d
White solid: mp: 181–182 °C; ½a D20
ꢀ
¼ ꢁ25:6 (c 0.3, MeOH); 1H
References
NMR (400 MHz, CDCl3) d 0.81 (s, 9H), 1.26–1.42 (m, 6H), 1.77–
1.83 (m, 2H), 2.00–2.03 (m, 1H), 2.32 (d, J = 12.4 Hz, 1H), 3.00 (s,
1H), 6.79 (s, 2H), 7.10 (d, J = 5.2 Hz, 1H), 7.27–7.47 (m, 3H), 7.78–
7.82 (m, 2H); 13C NMR (100 MHz, CDCl3) d (ppm) 24.4, 24.9, 26.5,
32.1, 32.2, 34.0, 52.2, 55.9, 64.1, 127.0, 128.3, 131.3, 134.1, 137.8,
167.1, 175.1; HRMS (ESI) m/z (%) calcd for C19H30N3O2 (MH+)
332.2332, found 332.2332.
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4.6. Catalyst 1e
White solid: mp: 166–167 °C; ½a D20
ꢀ
¼ þ2:5 (c 0.95, MeOH); 1H
NMR (400 MHz, CDCl3) d 1.26–1.61 (m, 8H), 1.67–1.91 (m, 3H),
2.17–2.3 (m, 2H), 3.1–3.15 (dd, J = 3.6 and 14.0 Hz, 1H), 3.52–
3.54 (m, 1H), 3.84 (s, 2H), 7.07 (d, J = 7.2 Hz, 2H), 7.16–7.24 (m,
3H), 7.38–7.44 (m, 2H), 7.52 (d, J = 6.4 Hz, 1H), 7.84 (d, J = 8 Hz,
2H); 13C NMR (100 MHz, CDCl3) d 24.5, 24.9, 32.0, 33.4, 40.8,
52.0, 56.0, 56.4, 126.7, 127.0, 128.5, 128.7, 129.0, 131.3, 134.0,
137.8, 167.0, 175.7; HRMS (ESI) m/z (%) calcd for C22H28N3O2
(MH+) 366.2176, found 366.2182.
4.7. Catalyst 1f
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White solid: mp: 186–187 °C; ½a D20
ꢀ
¼ þ8:3 (c 0.12, MeOH); 1H
NMR (400 MHz, CDCl3) d (ppm) 0.45 (d, J = 6.8 Hz, 3H), 0.90 (d,
J = 6.8 Hz, 3H), 1.24–1.51 (m, 6H), 1.78–2.04 (m, 3H), 2.28–2.36
(m, 1H), 2.43 (d, J = 13.2 Hz 1H), 3.27 (d, J = 8.4 Hz, 2H), 7.72 (d,
J = 7.2 Hz, 1H), 7.97 (s, 1H) 8.08 (d, J = 5.2 Hz, 1H), 8.34 (s, 2H);
13C NMR (100 MHz, CDCl3) d 15.3, 19.5, 24.1, 24.9, 30.17, 31.78,
31.9, 51.8, 58.0, 59.7, 124.6, 127.6, 131.7, 132.0, 136.3, 163.6,
179.9; HRMS (ESI) m/z (%) calcd for
454.1924, found 454.1929.
C
20H26F6N3O2 (MH+)
4.8. Catalyst 1g
White solid: mp: 147–138 °C; ½a D20
ꢀ
¼ þ48:6 (c 0.21, MeOH); 1
H
NMR (400 MHz, CDCl3) d 0.86 (d, J = 6.9 Hz, 3H), 1.00 (d, J = 7.1 Hz,
3H), 1.16–1.36 (m, 6H), 1.64–1.73 (m, 3H), 1.92–1.99 (m, 2H), 2.33
(s, 1H), 3.24 (s, 1H), 3.66–3.75 (m, 2H), 7.58 (d, J = 6.8 Hz, 1H), 8.02
9. Ramasastry, S. S. V.; Zhang, H.; Tanaka, F.; Barbas, C. F., III J. Am. Chem. Soc. 2007,
129, 288–289.
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