Chiral primary amine catalyzed asymmetric direct cross-aldol reaction of acetaldehyde

Article abstract of DOI:10.1002/ejoc.201100267

The first primary aminocatalytic direct cross-aldol reaction of acetaldehyde is presented. Among the various vicinal diamines screened, the L-tert-leucine derivative 1c in conjunction with (H₄SiW ₁₂O₄₀)_0.25 was identified as the optimal catalyst; good catalytic activity (up to 99% yield in 4 h), and high enantioselectivities (up to 92% ee) were achieved for a range of donors, including aromatic aldehydes and isatin derivatives. Aqueous acetaldehyde solution and paraldehyde can be conveniently applied in this system.

Full text of DOI:10.1002/ejoc.201100267

FULL PAPER
DOI: 10.1002/ejoc.201100267
Chiral Primary Amine Catalyzed Asymmetric Direct Cross-Aldol Reaction of
Acetaldehyde
Shenshen Hu,[a] Long Zhang,[a] Jiuyuan Li,[a] Sanzhong Luo,*[a] and Jin-Pei Cheng*[a]
Keywords: Aldehydes / Aldol reactions / Amines / Asymmetric catalysis / Organocatalysis
The first primary aminocatalytic direct cross-aldol reaction of
acetaldehyde is presented. Among the various vicinal di-
enantioselectivities (up to 92% ee) were achieved for a range
of donors, including aromatic aldehydes and isatin deriva-
tives. Aqueous acetaldehyde solution and paraldehyde can
amines screened, the
L-tert-leucine derivative 1c in conjunc-
tion with (H4SiW12O40 0.25
)
was identified as the optimal cata- be conveniently applied in this system.
lyst; good catalytic activity (up to 99% yield in 4 h), and high
aldol reactions have often been applied in the asymmetric
synthesis of aza-sugars.[9] However, despite these advances
and the prevalence of organocatalysis, to our surprise, there
have been no reports on primary amine catalyzed acetalde-
hyde aldol reactions.[10]
Inspired by the primary amino catalysts found in Nature,
we previously developed the vicinal primary–tertiary di-
amines 1 and 2 as both functional and mechanistic mimics
of natural aldolases.[11,12] To further expand their applica-
tions in some organocatalytic reactions such as those men-
tioned above, we explored the use of these chiral primary
amines in the acetaldehyde aldol reaction (Scheme 1). In-
deed, vicinal diamines such as 1 were found to be effective
catalysts for the acetaldehyde aldol reaction, showing much
improved activity over typical secondary amines[6,7] and en-
abling the cross-aldol reactions with aromatic aldehydes
and isatin derivatives.
Introduction
The aldol reaction, first discovered by Wurtz in 1872,[1]
is one of the most important methods for carbon–carbon
bond formation both in nature and in modern organic syn-
thesis.[2] During the past decade, enamine-based organocat-
alysts have enabled a range of asymmetric direct aldol reac-
tions.[3] Nevertheless, the direct cross-aldol reactions of
acetaldehyde, which is the simplest enolizable carbonyl
compound, are being known to be difficult.[4] The funda-
mental challenge is to suppress undesired side reactions,
such as multi/poly-aldolization, dehydration, and polymeri-
zation of the products. The direct asymmetric self-aldoliza-
tion of acetaldehyde was first reported by Barbas and co-
workers who used l-proline as the catalyst and obtained
(+)-(5S)-hydroxy-(2E)-hexenal with low conversion and
moderate enantioselectivity.[5] In 2008, Hayashi and co-
workers reported the first example of an asymmetric direct
cross-aldol reaction of acetaldehyde with the aid of a diaryl-
prolinol-based catalyst.[6] Subsequently, the cross-aldol re-
action between acetaldehyde (as the nucleophile) and a
ketone (as an electrophile) were also achieved by the appli-
cation of chiral secondary amine organocatalysts.[7]
The acetaldehyde-dependent aldol reaction is also an en-
zymatic process. In nature, 2-deoxyribose-5-phosphate al-
dolase (DERA) is the only known aldolase that utilizes an
aldehyde (acetaldehyde) as the donor. In the enzymatic
pathway, the ε-primary amine of a lysine residue is the cata-
lytic functional group, promoting the reaction through the
proved enamine intermediate.[8] In the 1990s, DERA-based
Scheme 1. Direct cross-aldol reaction of acetaldehyde catalyzed by
primary amines.
Results and Discussion
[a] Beijing National Laboratory for Molecular Sciences (BNLMS),
CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences,
Beijing 100190, P. R. China
Initial Trial and Screening of the Catalysts
We started the study with our previously developed pri-
mary amine catalyst 1a, in the presence of trifluorometh-
anesulfonic acid (TfOH), and investigated the cross-aldol
reaction between acetaldehyde and p-nitrobenzaldehyde as
E-mail: luosz@iccas.ac.cn
chengjp@most.cn
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100267.
Eur. J. Org. Chem. 2011, 3347–3352
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3347

S. Luo, J.-P. Cheng et al.
FULL PAPER
a model reaction. Although 1a/TfOH was previously shown leucine, was identified as the optimal catalyst, which pro-
to be an effective catalyst in the syn-selective cross-aldol vided 82% yield and 86% ee with 2-sulfobenzoic acid (2-
reaction of aldehydes,[11f] this catalytic system showed low SBA) as the acidic additive (Table 1, Entry 6).
activity in the reaction between acetaldehyde and p-ni-
trobenzaldehyde under the same conditions, giving only
trace amounts of the desired product (Table 1, Entry 3). In
our continuing studies, it was found that substantial activity
and enantioselectivity could be achieved by changing the
acidic additives from TfOH to 2-sulfobenzoic acid (2-SBA)
(Table 1, Entry 4).
Table 1. Catalyst screening for direct cross-aldol reaction of acetal-
dehyde.
Entry[a]
Catalyst[b]
Yield [%][c]
ee [%][d]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
l-Ala-OH
l-Phe-OH
1a/TfOH
1a/2-SBA
1b/2-SBA
1c/2-SBA
1d/2-SBA
1e/2-SBA
1f/2-SBA
1g/2-SBA
1h/2-SBA
2a/2-SBA
2b/2-SBA
2c/2-SBA
2d/2-SBA
2e/2-SBA
3a/2-SBA
3b/2-SBA
4/2-SBA
trace
trace
trace
81
76
82
60
74
47
62
66
71
62
74
64
41
14
34
n.a.
n.a.
n.a.
Figure 1. Chiral primary amines used in this study.
73 (R)
80 (R)
86 (R)
75 (S)
68 (R)
71 (R)
62 (R)
53 (R)
71 (S)
66 (S)
68 (S)
72 (S)
66 (S)
46 (S)
85 (S)
34 (S)
30 (S)
n.a.
Optimization of Reaction Conditions
During the course of the catalyst screening, minor
amounts of a dehydration byproduct and self-condensation
products of acetaldehyde were observed in the catalysis of
1c/2-SBA. Bearing in mind the dramatic effect of acidic ad-
ditives in the primary–tertiary diamine catalytic system,[11]
we then examined a range of acidic additives to further im-
prove the catalytic efficiency and suppress the side reac-
tions.[13] In the present case, we were delighted to find that
the use of silicontungstic acid (H4SiW12O40), which was
previously used as a catalyst support for chiral amines,[14]
led to a much cleaner reaction, with slightly improved ac-
44
8
trace
5/2-SBA
6/2-SBA
[a] Reagents and conditions (unless otherwise stated): p-nitrobenz- tivity and enantioselectivity than that of 2-SBA and TfOH
aldehyde
(0.4 mmol),
acetaldehyde
(1.6 mmol),
catalyst
(Table 1, Entry 6 vs. 1 and 2). In the presence of 1c/
(H4SiW12O40)0.25, the reaction proceeded cleanly to afford
83% yield and 86% ee in 5 h. In comparison, the reaction
(0.04 mmol), DMF (0.4 mL), 25 °C, 8 h. [b] 2-SBA: 2-sulfobenzoic
acid. [c] Isolated yield. [d] Determined by chiral HPLC.
With 2-SBA as the selected acidic additive, a range of required 24 h for complete conversion with typical second-
chiral primary amines were then examined (Figure 1). Pri- ary amine catalysts such as diarylprolinol.[6]
mary–tertiary vicinal diamines such as 1, 2, and 3 were
The use of other solvents in the model reaction with cata-
found to be viable catalysts for this type of cross-aldol reac- lyst 1c/(H4SiW12O40)0.25 was examined, and the activity of
tion, with moderate to good activity and good enantio- the reaction was found to be highly solvent-dependent,
selectivity (Table 1, Entries 4–18). Other types of primary probably due to the different solubility of 1c/
amines, such as natural primary amino acids, primary sec- (H4SiW12O40)0.25. The catalyst 1c/(H4SiW12O40)0.25 tends to
ondary diamines 4, aminoquinuclidine 5, and primary aggregate in chlorinated solvents and showed poor solubil-
amino amide 6 were much less active, with low stereoselecti- ity in less polar solvents, such as toluene, diethyl ether, and
vity, which highlights the critical role of the primary–terti- tetrahydrofuran (THF), leading to poor catalytic efficiency
ary vicinal diamines in this reaction. Among the primary– (Table 2, Entries 8–13). Although the reactions seem to
tertiary vicinal diamines screened, diamine organocatalysts favor polar solvents such as N,N-dimethylformamide
1 derived from amino acids were apparently superior, both (DMF) and MeCN, probably due to their better solvating
in terms of enantioselectivity and activity, to those of 2 and ability for 1c/(H4SiW12O40)0.25, the solvent screening did
3 (Table 1, Entries 4–11 vs. 12–18), and the catalytic efficacy not show any clear improvement on the catalytic results
steadily improved when the bulkiness of the R3 group in (Table 2, Entries 6 and 7). The employment of neat condi-
diamines 1 was increased (Table 1, Entries 4, 5, and 6). tions (with 16 equiv. of acetaldehyde) was found to afford a
Eventually, chiral primary amine 1c, derived from l-tert- slightly increased ee with a quantitative yield in 2 h
3348
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3347–3352

Asymmetric Cross-Aldol Reaction of Acetaldehyde
(Table 2, Entry 14). The enantioselectivity could be further substrates.[6] No further aldolization of the cross-aldol
improved to 92% ee at lower temperatures (10 °C; Table 2, products was observed, and only trace amounts of dehy-
Entry 15). It should be pointed out that the use of a large dration products were detected in some cases. It was also
excess of acetaldehyde is not essential in this case; thus, the noted that the activity and selectivity were relatively low
loading could be significantly reduced, because the reaction with ortho-substituted aromatic aldehydes compared with
was equally fast with 4 equiv. of acetaldehyde (Table 2, En- those of para-substituted aldehydes (Table 3, Entry 1 vs. 3
try 6). In addition, industrial sources of acetaldehyde, such and Entry 7 vs. 11), which may be rationalized by consider-
as aqueous acetaldehyde and paraldehyde, could be equally ing the steric effect of the ortho substituent as illustrated in
applied in the catalytic system 1c/(H4SiW12O40)0.25, with ac- TS-II (Scheme 2). The reaction of electron-rich aldehydes,
ceptable enantioselectivity and activity under the developed such as 2-naphthaldehyde, also proceeded smoothly with
conditions, without further optimization (Table 2, En- moderate yield and good ee (Table 3, Entry 13) over several
tries 17 and 18). Because analytically pure acetaldehyde is batch additions of acetaldehyde. In our studies, aliphatic
inexpensive and readily available, neat conditions were em- aldehydes appeared to be poor acceptors due to their low
ployed for subsequent studies.
activity and the associated side reactions.
Table 3. Substrate scope of aromatic aldehydes.
Table 2. Optimization of the reaction conditions.
Entry[a]
R
t
[h]
Product
Yield
[%][b]
ee
[%][c]
Entry[a]
Acid[b]
Solvent
t
Yield
ee
1
2
3
4-O2NC6H4
3-O2NC6H4
2-O2NC6H4
4-NCC6H4
4-F3CC6H4
4-BrC6H4
4
4
6
7a
7b
7c
7d
7e
7f
99
99
92
97
89
77
83
62
34
58
48
97
62
92
89
81
85
90
90
91
87
80
69
77
87
82
[h] [%][c] [%][d]
1
2
3
4
5
6
7
8
9
2-SBA
TfOH
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
toluene
THF
5
5
5
5
5
5
5
5
5
5
5
5
5
2
4
24
24
24
73
62
83
56
69
89
75
45
27
24
24
51
56
99
99
96
82
79
86
87
84
88
89
87
86
71
90
82
72
84
82
89
92
75
87
79
4
24
12
48
48
60
40
60
48
2
5[d]
6[d]
7[d]
8
(H3PW12O40)0.33
(H3PMo12O40)0.33
(H4SiMo12O40)0.25
(H4SiW12O40)0.25
(H4SiW12O40)0.25
(H4SiW12O40)0.25
(H4SiW12O40)0.25
(H4SiW12O40)0.25
(H4SiW12O40)0.25
4-ClC6H4
7g
7h
7i
3,4-Cl2C6H3
2,6-Cl2C6H3
2-FC6H4
2-ClC6H4
4-pyridyl
9
10
11
12
13[e]
7j
7k
7l
10
11
12
13
14[e]
15[e,f]
16[e,g]
17[h]
18[i]
Et2O
CH3Cl
2-naphthyl
72
7m
(H4SiW12O40)0.25 ClCH2CH2Cl
[a] Reagents and conditions (unless otherwise stated): aromatic al-
dehyde (0.4 mmol), acetaldehyde (0.4 mL), catalyst 1c/
(H4SiW12O40)0.25 (0.04 mmol), 10 °C. [b] Isolated yield. [c] Deter-
mined by chiral HPLC. [d] Determined by HPLC after conversion
of the primary hydroxy group into the monobenzoyl ester.[6] [e] The
reaction was carried out at 25 °C; acetaldehyde (0.2 mL) was added
three times at 24 h intervals.
(H4SiW12O40)0.25
(H4SiW12O40)0.25
(H4SiW12O40)0.25
(H4SiW12O40)0.25
(H4SiW12O40)0.25
(H4SiW12O40)0.25
CH2Cl2
–
–
–
–
–
[a] Reagents and conditions (unless otherwise stated): p-nitrobenz-
aldehyde (0.4 mmol), acetaldehyde (1.6 mmol), catalyst 1c/additive
acid (0.04 mmol), solvent (0.4 mL), 25 °C. [b] 2-SBA: 2-sulfo-
benzoic acid. [c] Isolated yield. [d] Determined by chiral HPLC. [e]
Acetaldehyde (0.4 mL) was used. [f] The reaction was carried out
at 10 °C. [g] The reaction was carried out at 0 °C. [h] Aqueous
acetaldehyde (40%, 0.4 mL) was used at 25 °C. [i] Paraldehyde
(0.4 mL) was used at 25 °C.
Substrate Scope
With the optimal conditions in hand, the scope of the
direct aldol reaction of acetaldehyde was then examined
with respect to both aromatic aldehydes and isatin deriva-
tives in the presence of 10 mol-% 1c/(H4SiW12O40)0.25. The
reaction with aromatic aldehydes, including heteroaromatic
aldehyde, proceeded quite smoothly to give the desired al-
dol products with up to 99% yield and 92% ee (Table 3).
Scheme 2. Proposed transition states.
The reactions between isatin derivatives and acetalde-
In these cases, the catalytic activity of primary amine 1c hyde were also examined under the optimal conditions. The
was quite high compared with previous reports on the same reactions were completed within 6 h, giving the desired
Eur. J. Org. Chem. 2011, 3347–3352
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3349

S. Luo, J.-P. Cheng et al.
FULL PAPER
Table 4. Substrate scope of isatin derivatives.
Entry[a]
R
X
t [h]
Product
Yield [%][b]
ee [%][c]
1
2[d]
3[d]
4
H
H
H
Me
Bn
H
4-Br
5-Br
H
2
6
6
6
6
8a
8b
8c
8d
8e
90
92
92
92
97
69
80 (96)
82 (92)
80
5
H
77
[a] Reagents and conditions (unless otherwise stated): isatin derivative (0.4 mmol), acetaldehyde (0.4 mL), catalyst/additive (0.04 mmol),
10 °C. [b] Isolated yield. [c] Determined by chiral HPLC. [d] Value in parentheses is ee obtained after a single recrystallization.
products 8a–e with excellent yields and moderate ee aromatic aldehydes, the combined use of readily available
(Table 4). Although the best enantiomeric excess of this sys- and simple catalysts with exceptionally high activity should
tem was approximately 80% ee, it could be readily improved be of significant practical value.
to more than 90% ee after a single recrystallization
(Table 4, Entries 2 and 3). These products are valuable in-
termediates for the synthesis of convolutamydines E and
Experimental Section
B.[7c,7d] Compared with the reported catalytic protocols for
General Information: Commercial reagents were used as received,
the same reactions,[7c,7d] 1c/(H4SiW12O40)0.25 demonstrated
unless otherwise indicated. 1H and 13C NMR spectra were recorded
much better activity, albeit with lower enantioselectivity.
with a 300 MHz instrument (Bruker DMX 300) as noted, and were
internally referenced to the residual protic solvent signals. Chemical
shifts are reported in ppm from tetramethylsilane with solvent reso-
nance as the internal standard. The following abbreviations were
used to designate the chemical shift multiplicities: s = singlet, d =
doublet, t = triplet, m = multiplet, br. = broad. All first-order split-
ting patterns were assigned on the basis of the appearance of the
multiplet. Splitting patterns that could not be easily interpreted are
designated as multiplet (m) or broad (br.). HPLC analysis was per-
formed by using Chiralcel columns. Absolute configurations were
determined by correlation to values reported in the literature.[6] Pri-
mary amines 1a,[11d,11f] 2,[11a–11c,11e] 3,[15] 4,[16] 5, aldol products of
aromatic aldehydes[6] 7a, 7b, 7c, 7e, 7f, 7i, 7k, 7l, 7n, and isatin
derivatives 9a–e[7] have previously been reported. Primary amines
1b–d, 6, and aldol products 7d, 7g, 7h, 8j are new compounds.
Proposed Transition State
By comparing the optical rotation with the known prod-
uct, the absolute configuration of 7 and 8 was determined
to be (R).[17] Enamine transition states TS-I and TS-II are
proposed to account for the observed stereoselectivity
(Scheme 2). Consistent with previous reports,[6,11] the pro-
tonated amino group plays significant roles in the stereo-
control through hydrogen bonding with the carbonyl
group of the aldehyde acceptor. In addition, the large steric
bulk of the tert-butyl group, together with the substituent
on the tertiary amines would also favor the approach of
the acceptor to the enamine face. Clearly, in line with this
hypothesis, the ortho-substituted aromatic aldehyde (e.g., 2-
chlorobenzaldehyde) gave a much lower enantioselectivity
than its para-substituted analogue (e.g., 4-chlorobenzalde-
hyde), probably as a result of the steric interference between
the ortho substituent and the tertiary amino group (TS-II
in Scheme 2).
Typical Procedure for the Synthesis of Catalyst 1c: The amino acid
derivative 1c was synthesized according to the published pro-
cedure.[11d] To a solution of N-Boc-l-tert-leucine (9.24 g, 40 mmol)
in anhydrous CH2Cl2 (60 mL) at 0 °C, was slowly added N,NЈ-dicy-
clohexylcarbodiimide (DCC; 8.66 g, 42 mmol) in anhydrous
CH2Cl2 (40 mL). After stirring for 30 min, diethylamine (2.92 g,
40 mmol) in anhydrous CH2Cl2 (20 mL) was added in about 1 h,
and the solution was stirred at room temperature for an additional
12 h. The white solid formed was filtered and washed with CH2Cl2
(2ϫ20 mL). The organic layers were combined and washed with
2% HCl (10 mL), 4% NaHCO3 (20 mL), and brine (20 mL), then
dried with anhydrous Na2SO4. After removal of the solvent, the
residue was purified by flash chromatography and directly used for
next step. To the obtained product was added MeOH (80 mL), then
CH3COCl (10 mL) slowly. The solution was heated to reflux for
1 h, and then cooled to room temperature. The solvent was re-
moved, CH2Cl2 (120 mL) and H2O (80 mL) were added, and the
pH value was adjusted to 12 by the addition of K2CO3. The aque-
ous phase was extracted with CH2Cl2 (40 mL), and the organic
layers were combined and dried with anhydrous Na2SO4. After re-
Conclusions
We present herein the first biomimetic primary amine
catalyzed cross aldol reactions of acetaldehyde. A vicinal
primary–tertiary diamine derived from l-tert-leucine, in
concert with H4SiW12O40, was identified as the optimal
catalytic system, facilitating the direct cross-aldol reaction
of acetaldehyde with a range of substrates, including aro-
matic aldehydes and isatin derivatives, with up to 99% yield
and 92% ee. Although the substrate scope is still limited to moval of the solvent, the residue was purified by flash chromatog-
3350 Eur. J. Org. Chem. 2011, 3347–3352
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Asymmetric Cross-Aldol Reaction of Acetaldehyde
raphy to afford the intermediate compound (8.58 g, 75% yield). To
the above-obtained intermediate (8.58 g) in anhydrous THF
(60 mL) at 0 °C was added LiAlH4 (1.14 g, 30 mmol) in portions,
then the solution was heated to reflux for 4 h. After cooling to
room temperature, saturated aqueous Na2SO4 (4 mL) was added.
The solid formed was filtered and washed with THF several times.
The organic layers were combined and dried with anhydrous
Na2SO4. The solvent was removed, and pure catalyst 1c (3.97 g)
was obtained as a colorless oil by distillation under reduced pres-
sure (77% yield). [α]2D0 = +124.1 (c = 0.50, MeOH). 1H NMR
(1R)-1-(4-Cyanophenyl)propane-1,3-diol (7d): [α]2D0 = +16.4 (c =
0.54, MeOH). The enantiomeric excess (85% ee) was determined
by HPLC (AS-H column; 210 nm; 2-propanol/n-hexane, 1:9; 25 °C;
1.0 mL/min), tR = 32.92 min (major isomer), tR = 38.75 min (minor
isomer). 1H NMR (300 MHz, CDCl3): δ = 1.91–1.96 (m, 2 H,
CH2), 2.38 (br. s, 1 H, OH), 3.56 (br. s, 1 H, OH), 3.87–3.90 (t, J
= 5.40 Hz, 2 H, CH2), 5.01–5.15 (t, J = 6.00 Hz, 1 H, CH), 7.47–
7.49 (d, J = 8.10 Hz, 2 H, ArH), 7.64–7.62 (d, J = 8.10 Hz, 2 H,
ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 40.1, 61.3, 73.5,
110.0, 118.8, 126.3, 132.2. 149.7 ppm. HRMS: clacd. for
(300 MHz, CDCl3): δ = 0.89 (s, 9 H, CH3), 0.97–1.02 (t, J = C10H11NO2 [M] 177.0790; found 177.0792.
6.90 Hz, 6 H, CH3), 1.49 (br., 2 H, NH2), 2.07–2.15 (m, 1 H, CH),
(1R)-1-(4-Chlorophenyl)propane-1,3-diol (7g): [α]2D0 = +18.2 (c =
0.50, MeOH). The enantiomeric excess (91% ee) was determined
by HPLC after conversion of the primary hydroxy group into the
monobenzoyl ester (AS-H column; 210 nm; 2-propanol/n-hexane,
2.34–2.45 (m, 3 H, CH2, CH2), 2.53–2.67 (m, 3 H, CH2, CH2) ppm.
13C NMR (75 MHz, CDCl3): δ = 12.2, 26.4, 33.2, 47.5, 55.6,
57.4 ppm. HRMS: calcd. for C10H25N2 [M + 1] 173.2012; found
173.2013.
3:97; 25 °C; 1.0 mL/min), tR = 40.48 min (major isomer), tR
=
(S)-N1,N1-Diethyl-3-methylbutane-1,2-diamine (1b): [α]2D0 = +96.2 (c
1
44.70 min (minor isomer). H NMR (300 MHz, CDCl3): δ = 1.86–
2.02 (m, 2 H, CH2), 2.23 (br. s, 1 H, OH), 3.00 (br. s, 1 H, OH),
3.85–3.89 (m, 2 H, CH2), 4.94–4.98 (m, 1 H, CH), 7.29–7.35 (m, 4
H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 40.4, 61.3, 73.6,
127.0, 128.6, 133.2, 142.8 ppm. HRMS: calcd. for C9H11ClO2 [M]
186.0448; found 186.0451.
1
= 0.50, MeOH). H NMR (300 MHz, CDCl3): δ = 0.90–0.92 (d, J
= 6.90 Hz, 6 H, CH3), 0.97–1.02 (t, J = 6.90 Hz, 6 H, CH3), 1.46–
1.57 (m, 3 H, CH, NH2), 2.10–2.18 (m, 1 H, CH), 2.35–2.47 (m, 3
H, CH2, CH2), 2.53–2.65 (m, 3 H, CH2, CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 12.2, 18.3, 19.6, 32.3, 47.6, 56.3, 58.4 ppm.
HRMS: calcd. for C9H23N2 [M + 1] 159.1861; found 159.1856.
(1R)-1-(3,4-Dichlorophenyl)propane-1,3-diol (7h): [α]2D0 = +50.2 (c =
0.68, MeOH). The enantiomeric excess (87% ee) was determined
by HPLC (AS-H column; 210 nm; 2-propanol/n-hexane, 1:9; 25 °C;
0.5 mL/min), tR = 18.69 min (major isomer), tR = 19.98 min (minor
isomer). 1H NMR (300 MHz, CDCl3): δ = 1.84–1.94 (m, 2 H,
CH2), 2.60 (br. s, 1 H, OH), 3.59 (br. s, 1 H, OH), 3.84 (m, 2 H,
CH2), 4.88–4.92 (m, 1 H, CH), 7.15–7.18 (m, 1 H, ArH), 7.39–7.46
(m, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 40.3, 61.4,
73.1, 125.0, 127.7, 130.4, 131.3, 132.6, 144.6 ppm. HRMS: calcd.
for C9H11Cl2O2 [M] 220.0058; found 220.0061.
(R)-N1,N1-Diethyl-3-phenylethane-1,2-diamine (1d): [α]2D0 = –73.5 (c
1
= 0.50, MeOH). H NMR (300 MHz, CDCl3): δ = 1.02–1.07 (t, J
= 6.90 Hz, 6 H, CH3), 1.92 (br., 2 H, NH2), 2.41–2.57 (m, 4 H,
CH2), 2.62–2.74 (m, 2 H, CH2), 4.03–4.08 (m, 1 H, CH), 7.21–7.40
(m, 5 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 12.1, 47.5,
53.8, 62.5, 126.8, 127.1, 128.5, 144.8 ppm. HRMS: calcd. for
C12H21N2 [M + 1] 193.1705; found 193.1699.
(S)-2-Amino-1-(azepan-1-yl)-3-phenylpropan-1-one (6): [α]2D0 = +68.6
(c = 0.50, MeOH). 1H NMR (300 MHz, CDCl3): δ = 1.47–1.76 (m,
10 H, overlapped with the peak of H2O, NH2, CH2), 2.74–2.81 (m,
1 H, CH2), 2.99–3.05 (m, 1 H, CH2), 3.20–3.34 (m, 1 H, CH2),
3.34–3.42 (m, 2 H, CH2), 3.43–3.60 (m, 1 H, CH2), 3.88–3.92 (t, J
= 7.20 Hz, 1 H, CH), 7.21–7.31 (m, 5 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 12.1, 47.5, 53.8, 62.5, 126.8, 127.1, 128.5,
144.8 ppm. HRMS: calcd for C15H23N2O [M + 1] 247.1810; found
247.1804.
(1R)-1-(2-Fluorophenyl)propane-1,3-diol (7j): The enantiomeric ex-
cess (69% ee) was determined by HPLC (AS-H column; 210 nm; 2-
propanol/n-hexane, 1:9; 25 °C; 1.0 mL/min), tR = 10.02 min (minor
isomer), tR = 11.18 min (major isomer). 1H NMR (300 MHz,
CDCl3): δ = 1.99–2.04 (m, 2 H, CH2), 2.34 (br. s, 1 H, OH), 3.09
(br. s, 1 H, OH), 3.84–3.91 (m, 2 H, CH2), 5.27–5.31–4.92 (t, J =
6.00 Hz, 1 H, CH), 6.99–7.05 (m, 1 H, ArH), 7.14–7.29 (m, 2 H,
ArH), 7.52–7.57 (m, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 39.0, 61.6, 68.5, 115.1, 115.4, 124.3, 124.4, 127.1, 127.2, 128.8,
128.9 ppm. HRMS: calcd. for C9H11FO2 [M] 170.0743; found
170.0745.
Typical Procedure for the Direct Cross-Aldol Reaction of Acetalde-
hyde: Catalyst 1c (6.9 mg, 0.04 mmol), H4SiW12O40 (28.8 mg,
0.04 mmol), and 4-nitrobenzaldehyde (60.4 mg, 0.4 mmol) were
mixed together in acetaldehyde (0.4 mL, 99% extra pure, Aldrich)
at 10 °C. The mixture was stirred for 4 h, then excess acetaldehyde
was removed in vacuo. MeOH (2 mL) and NaBH4 (37 mg,
1.0 mmol) were added, and the resulting mixture was stirred at 0 °C
for an additional 10 min before quenching by addition of water.
The organic materials were extracted with CH2Cl2 three times, and
the combined organic extracts were dried with anhydrous Na2SO4
and concentrated under vacuo. The residue was purified by flash
chromatograph on silica gel to afford pure product 7a.
Supporting Information (see footnote on the first page of this arti-
cle): Detailed results of acid screening, determination of the abso-
lute configuration of 7a and 8b, NMR spectra of the chiral primary
amines and cross-aldol products, and HPLC traces of the cross-
aldol products.
Acknowledgments
(1R)-1-(4-Nitrophenyl)propane-1,3-diol
(7a):
Yield:
78 mg
(0.039 mmol, 99%);[6] pale-yellow liquid. [α]2D0 = +20.2 (c = 0.5,
MeOH). The enantiomeric excess (92% ee) was determined by
HPLC (OJ-H column; 254 nm; 2-propanol/n-hexane, 1:9; 25 °C;
1.0 mL/min), tR = 20.75 min (major isomer), tR = 25.38 min (minor
isomer). 1H NMR (300 MHz, CDCl3): δ = 1.93–1.99 (m, 2 H,
CH2), 2.36 (s, 1 H, OH), 3.62 (s, 1 H, OH), 3.89–3.90 (d, J =
2.22 Hz, 2 H, CH2), 5.07–5.11 (m, 1 H, CH), 7.53–7.56 (d, J =
8.76 Hz, 2 H, ArH), 8.18–8.21 (d, J = 8.73 Hz, 2 H, ArH) ppm.
13C NMR (75 MHz, CDCl3): δ = 40.2, 61.3, 73.3, 123.7, 126.4,
147.2, 151.7.
This work was supported by the National Natural Science Founda-
tion of China (NSFC) (20702052, 20972163, and 21025208), the
Ministry of Science and Technology (MoST) (2011CB808600) and
the Chinese Academy of Sciences.
[1] A. Wurtz, Bull. Soc. Chim. Fr. 1872, 17, 436.
[2] For reviews on asymmetric direct aldol reaction, see: a) Modern
Aldol Additions (Ed.: R. Mahrwald), Wiley-VCH, Weinheim,
2004; b) C. Palomo, M. Oiabide, J. M. Garcia, Chem. Eur. J.
2002, 8, 36–44; c) T. D. Machajewski, C.-H. Wong, Angew.
Eur. J. Org. Chem. 2011, 3347–3352
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3351

S. Luo, J.-P. Cheng et al.
FULL PAPER
Chem. Int. Ed. 2000, 39, 1352–1374; d) T. Mukiyama, Angew. [10]
Chem. Int. Ed. 2004, 43, 5590; e) S. E. Denmark, R. A. Stav-
enger, Acc. Chem. Res. 2000, 33, 432–440; f) Y. M. A. Yamada,
For a kinetic study on primary amino acid mediated self-con-
densation of acetaldehyde, see: B. B. Nozière, A. Córdova, J.
Phys. Chem. A 2008, 112, 2827–2837.
N. Yoshikawa, H. Sasai, M. Shibasaki, Angew. Chem. Int. Ed.
Engl. 1997, 36, 1871; g) J. S. Johnson, D. A. Evans, Acc. Chem.
Res. 2000, 33, 325–335; h) B. M. Trost, C. S. Brindle, Chem.
Soc. Rev. 2010, 39, 1600–1632; i) S. Saito, H. Yamamoto, Acc.
Chem. Res. 2004, 37, 570–579.
[11]
a) S. Luo, H. Xu, J. Li, L. Zhang, J.-P. Cheng, J. Am. Chem.
Soc. 2007, 129, 3074–3075; b) S. Luo, H. Xu, L. Zhang, J. Li,
J.-P. Cheng, Org. Lett. 2008, 10, 653–656; c) S. Luo, H. Xu, L.
Chen, J.-P. Cheng, Org. Lett. 2008, 10, 1775–1778; d) J. Li, S.
Luo, J.-P. Cheng, J. Org. Chem. 2009, 74, 1747–1750; e) S. Luo,
Y. Qiao, L. Zhang, J. Li, X. Li, J.-P. Cheng, J. Org. Chem. 2009,
74, 9521–9523; f) J. Li, N. Fu, X. Li, S. Luo, J.-P. Cheng, J.
Org. Chem. 2010, 75, 4501–4507.
[3] For reviews on chiral amine catalyzed asymmetric direct aldol
reactions, see: a) P. L. Dalko, L. Moisan, Angew. Chem. Int. Ed.
2004, 43, 5138–5176; b) Asymmetric Organocatalysis, (Eds. A.
Berkessel, H. Groger), Wiley-VCH, Weinheim, 2005; c) B. List,
Acc. Chem. Res. 2004, 37, 548–557; d) B. List, Chem. Commun.
2006, 819–824; e) W. Notz, F. Tanaka, C. F. Barbas III, Acc.
Chem. Res. 2004, 37, 580–591; f) S. Mukherjee, J. W. Yang, S.
Hoffmann, B. List, Chem. Rev. 2007, 107, 5471–5569; g) G.
Guillena, C. Nájera, D. J. Ramón, Tetrahedron: Asymmetry
2007, 18, 2249–2293; h) L. M. Geary, P. G. Hultin, Tetrahe-
dron: Asymmetry 2009, 20, 131–173; for leading examples, see:
i) B. List, R. A. Lerner, C. F. Barbas III, J. Am. Chem. Soc.
2000, 122, 2395–2396; j) H. Torri, M. Nakadai, K. Ishihara, S.
Saito, H. Yamamoto, Angew. Chem. Int. Ed. 2004, 43, 1983–
1986; k) Z. Tang, Z.-H. Yang, X.-H. Chen, L.-F. Cun, A.-Q.
Mi, Y.-Z. Jiang, L.-Z. Gong, J. Am. Chem. Soc. 2005, 127,
9285–9289; l) Y. Hayashi, S. Aratake, T. Okano, J. Takahashi,
T. Sumiya, M. Shoji, Angew. Chem. Int. Ed. 2006, 45, 5527–
5529.
[12]
For recent reviews on primary amine catalysis, see: a) F. Peng,
Z. Shao, J. Mol. Catal. A 2008, 285, 1–13; b) L.-W. Xu, J. Luo,
Y. Lu, Chem. Commun. 2009, 1807–1821; c) L.-W. Xu, Y. Lu,
Org. Biomol. Chem. 2008, 6, 2047–2053; d) Y.-C. Chen, Synlett
2008, 1919; for recent selected examples of primary amine cata-
lyzed direct aldol reaction, see: e) A. L. W. Demuynck, J. Vand-
erleyden, B. F. Sels, Adv. Synth. Catal. 2010, 352, 2421–2426;
f) A. Córdova, W. Zou, P. Dziedzic, I. Ibrahem, E. Reye, Y.
Xu, Chem. Eur. J. 2006, 12, 5383–5387; g) K. Nakayama, K.
Maruoka, J. Am. Chem. Soc. 2008, 130, 17666–17667; h) J.
Zhou, V. Wakchaure, P. Kraft, B. List, Angew. Chem. Int. Ed.
2008, 47, 7656–7658; i) J. Li, Z. Yang, Z. Wang, F. Wang, X.
Chen, X. Liu, X.-M. Feng, J. Am. Chem. Soc. 2008, 130, 5654–
5655; j) S. S. V. Ramasatry, H. Zhang, F. Tanaka, C. F.
Barbas III, J. Am. Chem. Soc. 2007, 129, 288–289; k) X.-Y. Xu,
Y.-Z. Wang, L.-Z. Gong, Org. Lett. 2007, 9, 4247–4249; l)
S. S. V. Ramasastry, K. Albershofer, N. Utsumi, C. F.
Barbas III, Org. Lett. 2008, 10, 1621–1624; m) X. Wu, Z. Ma,
Z. Ye, S. Qian, G. Zhao, Adv. Synth. Catal. 2009, 351, 158–
162; n) H. Huang, E. N. Jacobson, J. Am. Chem. Soc. 2006,
128, 7170–7171; o) C. G. Kokotos, G. Kokotos, Adv. Synth.
Catal. 2009, 351, 1355–1362; p) D. A. Yalalov, S. B. Tsogoeva,
S. Schmatz, Adv. Synth. Catal. 2006, 348, 826–832.
[4] For reviews on organocatalytic reactions with acetaldehyde,
see: B. Alcaide, P. Almendros, Angew. Chem. Int. Ed. 2008, 47,
4632–4634.
[5] A. Córdova, W. Notz, C. F. Barbas III, J. Org. Chem. 2002, 67,
301–303.
[6] Y. Hayashi, T. Itoh, S. Aratake, H. Ishikawa, Angew. Chem.
Int. Ed. 2008, 47, 2082–2084.
[7] a) T. Itho, H. Ishikawa, Y. Hayashi, Org. Lett. 2009, 11, 3854–
3857; b) W.-B. Chen, L.-X. Du, L.-F. Cun, X.-M. Zhang, W.-
C. Yuan, Tetrahedron 2010, 66, 1441–1446; c) N. Hara, S. Nak-
amura, N. Shibata, T. Toru, Chem. Eur. J. 2009, 15, 6790–6793;
d) N. Hara, S. Nakamura, N. Shibata, T. Toru, Adv. Synth.
Catal. 2010, 352, 1621–1624.
[13]
See the Supporting Information for details on the screening of
other acidic additives.
[14] a) S. Luo, J. Li, H. Xu, L. Zhang, J.-P. Cheng, Org. Lett. 2007,
9, 3675–3678; b) J. Li, S. Hu, S. Luo, J.-P. Cheng, Eur. J. Org.
Chem. 2009, 132–140; c) J. Li, X. Li, P. Zhou, L. Zhang, S.
Luo, J.-P. Cheng, Eur. J. Org. Chem. 2009, 4486–4493.
[15] J. Li, N. Fu, L. Zhang, P. Zhou, S. Luo, J.-P. Cheng, Eur. J.
Org. Chem. 2010, 6840–6849.
[16] S. Hu, J. Li, J. Xiang, J. Pan, S. Luo, J.-P. Cheng, J. Am. Chem.
Soc. 2010, 132, 7216–7228.
[17] See the Supporting Information for details.
Received: February 26, 2011
[8] A. Heine, G. Desantis, J. G. Luz, M. Mitchell, C.-H. Wong,
I. A. Wilson, Science 2001, 294, 369–374.
[9] a) H. J. M. Gijsen, C.-H. Wong, J. Am. Chem. Soc. 1994, 116,
8422–8423; b) H. J. M. Gijsen, C.-H. Wong, J. Am. Chem. Soc.
1995, 117, 2947–2948; c) C.-H. Wong, E. Garcia-Junceda, L.
Chen, O. Blanco, H. J. M. Gijsen, D. H. Steensma, J. Am.
Chem. Soc. 1995, 117, 3333–3339; d) H. J. M. Gijsen, C.-H.
Wong, J. Am. Chem. Soc. 1995, 117, 7585–7591; e) T. D. Ma-
chajewski, C.-H. Wong, Synthesis 1999, 1469–1472.
Published Online: May 12, 2011
3352
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 3347–3352