Organocatalytic, asymmetric, one-pot, three-component Mannich reaction of hydroxyacetone

Article abstract of DOI:10.1080/00397910802323098

The direct three-component asymmetric Mannich reactions of hydroxyacetone with anilines and aromatic aldehydes in the presence of (2S,5S)-5- (methoxycarbonyl)pyrrolidine-2-carboxylic acid afforded syn-1,2-amino alcohols in good-to-excellent yields (55～91%

Full text of DOI:10.1080/00397910802323098

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Organocatalytic, Asymmetric,
One-Pot, Three-Component
Mannich Reaction of
Hydroxyacetone
Qing Gu a , Ling-Xia Jiang a , Kui Yuan a , Lei Zhang a
& Xin-Yan Wu a
a Laboratory for Advanced Materials and Institute of
Fine Chemicals, East China University of Science and
Technology , Shanghai, China
Published online: 31 Oct 2008.
To cite this article: Qing Gu , Ling-Xia Jiang , Kui Yuan , Lei Zhang & Xin-Yan
Wu (2008) Organocatalytic, Asymmetric, One-Pot, Three-Component Mannich
Reaction of Hydroxyacetone, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 38:23, 4198-4206, DOI:
10.1080/00397910802323098
To link to this article: http://dx.doi.org/10.1080/00397910802323098
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Synthetic Communications1, 38: 4198–4206, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802323098
Organocatalytic, Asymmetric, One-Pot,
Three-Component Mannich Reaction
of Hydroxyacetone
Qing Gu, Ling-Xia Jiang, Kui Yuan, Lei Zhang, and Xin-Yan Wu
Laboratory for Advanced Materials and Institute of Fine Chemicals, East
China University of Science and Technology, Shanghai, China
Abstract: The direct three-component asymmetric Mannich reactions of hydro-
xyacetone with anilines and aromatic aldehydes in the presence of (2S,5S)-5-
(methoxycarbonyl)pyrrolidine-2-carboxylic acid afforded syn-1,2-amino alcohols
in good-to-excellent yields (55ꢀ91%) and up to 98% ee.
Keywords: Amino alcohol, asymmetric Mannich reaction, enantioselectivity,
hydroxyacetone, organocatalysis
INTRODUCTION
The asymmetric Mannich reaction is one of the most powerful carbon–
carbon bond-forming reactions for the construction of optically
enriched nitrogen-containing compounds.[1] The ideal Mannich reac-
tion would involve a catalytic process employing directly the unmodi-
fied carbonyl donor, amine, and acceptor aldehyde in one pot.[2] The
first example of direct enantioselective Mannich-type reactions was
reported Yamasaki and co-workers using heterodimetallic complexes
as catalysts.[3] Recently asymmetric reactions catalyzed by metal-free
organic molecules have become increasingly popular. The direct
organocatalytic three-component Mannich reaction was reported first
Received February 27, 2008.
Address correspondence to Xin-Yan Wu, Laboratory for Advanced Materials
and Institute of Fine Chemicals, East China University of Science and Technology,
Shanghai 200237, China. E-mail: xinyanwu@ecust.edu.cn
4198

Organocatalytic Mannich Reaction
4199
by List[4] and was followed by the excellent work of several groups.[5–12]
L-Proline,[4–9] proline-derived tetrazole,[10] acylic amino acids and their
derivatives,[11] and chiral phosphoric acids[12] were developed as enan-
tioselective catalysts for the direct, one-pot, three-component Mannich
reactions. Although 1,2-amino alcohol can be constructed via Mannich
reaction of hydroxyacetone to imines, hydroxyacetone was seldom
used as donor in the asymmetric, catalyzed, direct Mannich
reactions.[4b,11b,13]
To the best of our knowledge, most of the reported proline-based
organocatalysts were designed by changing the carboxylic acid func-
tion of proline, and less attention has been paid to the modification
on five-membered ring of proline.[14–17] The steric features of a substi-
tuent at the 5-position of the pyrrolidine can be used to fix the con-
formation of the enamine intermediate for Mannich reaction.[16] Thus
we designed (2S,5S)-5-(methoxycarbonyl)pyrrolidine-2-carboxylic acid
(1) as organocatalyst for the direct, one-pot, three-component
Mannich reaction with hydroxyacetone as donor to furnish chiral
1,2-amino alcohols.
RESULTS AND DISCUSSION
Initially a three-component Mannich reaction of 4-nitrobenzaldehyde,
para-methoxyaniline, and hydroxyacetone was carried out at room tem-
perature with 20 mol% of 1 in dimethyl sulfoxide (DMSO). The Man-
nich adducts were obtained in 74% yields with 85=15 dr (syn=anti) and
60% ee for the syn-isomer (Table 1, entry 1). Similar to L-proline, orga-
nocatalyst 1 provided syn-Mannich product in the reactions of hydro-
xyketone as donor. It was reported that (3R,5R)-5-methyl-b-proline
was ineffective in the Mannich-type reactions of ketones originated
from relatively slow formation of the enamine intermediates, due to
the steric hindrance of the 5-methyl group.[18] Our result suggested that
the carboxyl group at the 5-position of proline in trans configuration
would not block the formation of (E)-enamine intermediate or inflect
the syn-selectivity.
The enantioselectivity of the syn-isomer increased to 76% ee when
4 A molecular sieves were added (entry 2). It should be noted that the
˚
molecular sieves play a special role in the transition state other than
desiccants (entry 3 vs. 4). The reaction temperature had effect on the
enantioselectivity. Decreasing the reaction temperature to 10 ꢀC, the cor-
responding syn-amino alcohol was afforded in 86% ee (entry 3). Among
the solvents screened, N,N-dimethylformamide (DMF) provided good
enantioselectivity (entry 5). Other solvents, including MeOH, CH3CN,

4200
Q. Gu et al.
Table 1. Optimization of reaction conditions
Entry
Solvent
Time (h)
Yield (%)a
dr (syn=anti)b
Ee (%)c
1
DMSO
DMSO
DMSO
DMSO
DMF
CH3OH
CH3CN
CH2Cl2
Toluene
36
36
36
36
48
30
30
30
30
74
73
72
70
59
48
48
60
43
85=15
84=16
82=18
84=16
72=28
78=22
64=36
47=53
61=39
60
76
86
69
71
6
24
9
31
2d
3d,e
4e,f
5
6
7
8
9
aIsolated yield after silica-gel column chromatography.
bDetermined by HPLC analysis.
cEe values of syn-isomer, determined by HPLC using chiralpak AD-H column.
d
˚
4 A Molecular sieves were added.
eThe reaction was carried out at 10 ꢁC.
fPerformed imine was used.
CH2Cl2 and toluene, were found to be less satisfactory in terms of the
yield and the enantioselectivity (entries 6–9 vs. 1).
Under the optimized reaction conditions, a variety of aromatic
aldehydes were reacted with para-methoxyaniline and hydroxyacetone
(Table 2). The Mannich products were obtained in moderate to good
yields with up to 95% ee and diasteromer ratio (dr) ranging from
78=22 to 94=6. The stereochemical outcome depends significantly on
the electronic properties of the substituent on benzaldehyde. Electron-
withdrawing groups had a positive effect on the enantioselectivities
(entries 1–9 vs. 10 and 11).
Also, several different phenylamine components were investigated.
As shown in Table 3, the Mannich products were achieved in good to
excellent yields with up to 98% ee. The structure of the amine component
has a considerable effect on the Mannich reaction. Compared to para-
methoxyphenylamine, other anilines studied provided better diastero-
and enantioselectivities.

Organocatalytic Mannich Reaction
4201
Table 2. Three-component direct asymmetric Mannich reactions of different
aromatic aldehydes
Entry
R
Time (h)
Yield (%)a
dr (syn=anti)b
Ee (%)c
1
2
3
4
5
6
7
8
9
4-NO2
3-NO2
2-NO2
4-CN
3-CN
4-F
4-Cl
2-Cl
4-Br
H
4-Me
36
48
60
60
48
48
60
48
60
72
72
72
66
76
70
60
75
71
57
62
70
55
82=18
88=12
94=6
90=10
94=6
84=16
82=18
80=20
89=11
80=20
78=22
86
91
95
85
77
72
65
67
64
33
26
10
11
aIsolated yield after column chromatography.
bDetermined by HPLC analysis.
cEnantiomeric excess of syn-product was determined by HPLC using Chiralcel
OD-H or Chiralpak AD-H column.
CONCLUSION
Organocatalyst 1 was efficient for three-component, direct, asymmetric
Mannich reactions of hydroxyacetone, the Mannich products were
achieved in good yields with up to 94=6 dr and 98% ee.
EXPERIMENTAL
General Considerations
DMSO and DMF were dried over CaH2 and distilled under reduced pres-
sure. Toluene and THF were distilled from sodium-benzophenone.
Dichloromethane and acetonitrile were distilled from CaH2. NMR spec-
tra were recorded with a Bruker spectrometer at 500 MHz, and chemical

4202
Q. Gu et al.
Table 3. Three-component direct asymmetric Mannich reactions of different
amine components
Entry
R0
Time (h)
Yield (%)a
dr (syn=anti)b
Ee (%)c
1
2
3
4
5
6
4-MeO
3-MeO
4-Me
2,4-Me2
H
36
36
36
48
48
48
72
88
81
77
71
91
82=18
90=10
85=15
85=15
88=12
85/15
86
98
87
87
93
93
4-Cl
aIsolated yield after silica-gel column chromatography.
bDetermined by HPLC analysis.
cEe values of syn-isomer, determined by HPLC using Chiralpak AD-H column.
shifts were reported in parts per million (d) relative to the internal
standard Me4Si (0 ppm). IR spectra were recorded on Nicolet Magna-I
550 spectrometer. Mass spectra were recorded on Micromass LCT spec-
trometer with EI resource. High-performance liquid chromatography
(HPLC) analysis was performed on a Waters 510 with 2487 detector
using Daicel Chiralcel OD-H or Chiralpak AD-H column.
Materials
All starting materials were obtained commercially and used directly.
Scheme 1. Synthesis of organocatalyst 1.

Organocatalytic Mannich Reaction
4203
General Procedure for Synthesis of 1 (Scheme 1)
Aqueous NaOH (1.0 M, 11.6 mL) was added dropwise to a solution of
compound 2[19] (2.02 g, 6.94 mmol) in methanol (16 mL) was added and
stirred at room temperature for 3 days. The resulting mixture was con-
centrated, and the residue was dissolved in water (10 mL). The aqueous
solution was washed with EtOAc and acidified to pH 2 by diluted hydro-
chloride (1.0 M). After saturating with NaCl, the aqueous solution was
extracted with EtOAc. The combined organic layers were dried over
anhydrous Na2SO4. After filtration and removal of solvent, the residue
was purified by column chromatography on silica gel (3:1 PE=EA þ 1%
HOAc) to afford 3 as a white solid. Yield: 79% (1.51 g). Mp: 99–
101 ꢁC. [a]D ꢂ 83.0 (c 1.38, CHCl3). 1H NMR (D2O, d ppm) 7.30–
14
7.25 (m, 2 H), 7.25–7.15 (m, 1 H), 7.20–7.15 (m, 2 H), 4.15 (q, J ¼ 6.7 Hz,
Hz, 1 H), 3.85 (dd, J ¼ 9.7, 1.2 Hz, 1 H), 3.60 (d, J ¼ 7.6 Hz, 1 H), 3.50 (s,
3 H), 2.55–2.45 (m, 1 H), 2.05–1.95 (m, 2 H), 1.80–1.75 (m, 1 H), 1.30 (s,
3 H). IR (film, cmꢂ1) 3059m, 3027m, 2952m, 2874m, 1732s, 1622w,
1492w, 1454m, 1373m, 1310m, 1206s, 1165s, 1092w, 1060w, 993w,
767s, 704s. MS (ESI) m=z (rel intensity): 278 ([M þ 1]þ, 100), 279
([M þ 2]þ, 14). HRMS: calcd. for C15H20NO4(M þ H): 278.1392; found:
278.1354.
In a flame-dried flask, a solution of compound 3 (1.50 g,
5.4 mmol) in anhydrous MeOH (20 mL) was hydrogenated over 26%
Pd(OH)2=C (0.25 g, 17% wt) for 15 h. The catalyst was removed by fil-
tering through a Celite1 pad. The solvents were removed in vacuo to
give a solid, then washed successively with CH2Cl2 and MeOH to
afford pure 1 as a white solid. Yield: 34% (270 mg). Mp 184–186 ꢁC.
14
½aꢃD ꢂ 87.8 (c 0.88, CH3OH). 1H NMR (D2O, d ppm) 4.56 (dd,
J ¼ 7.8, 7.4 Hz, 1 H), 4.23 (t, J ¼ 7.50 Hz, 1 H), 3.80 (s, 3 H), 2.44–
2.35 (m, 2 H), 2.20–2.00 (m, 2 H). IR (film, cmꢂ1) 3421s, 3006s,
2991s, 2958s, 2935s, 2782m, 1743s, 1623s, 1563s, 1460m, 1440m,
1408s, 1389s, 1364m, 1295m, 1227s, 1155m, 1105w, 1072m, 1018s. MS
(EI) m=z (rel intensity): 128 ([M-COOH]þ, 20), 114 ([M-COOCH3]þ,
61), 68 ([M-COOH-COOCH3]þ, 100). HRMS: calcd. for C7H11NO4(M):
173.0688; found: 173.0699.
General Procedure for Mannich Reaction
˚
The solution of organocatalyst 1 (0.05 mmol), 4 A molecule seives
(12 mg), and hydroxyacetone (0.2 mL) in anhydrous DMSO (2 mL) was
stirred for 5 min, then the aniline (0.25 mmol) and aromatic aldehyde
(0.25 mmol) were added, and the reaction mixture was stirred at 10 ꢁC

4204
Q. Gu et al.
(monitored by thin-layer chromatography, TLC). The reaction mixture
was treated with saturated ammonium chloride solution (2 mL) and
extracted with ethyl acetate (3 ꢄ 5 mL). The combined organic phases
were washed with brine (2 ꢄ 5 mL) and dried (Na2SO4), concentrated,
and purified by column chromatography on silica gel to afford the
desired product. The ratio of diasteroisomers and the enantiomeric
excesses were determined by chiral HPLC.
ACKNOWLEDGMENT
We thank the National Natural Science Foundation of China (20402004)
and the Science Foundation of Shanghai Municipality (06ZR14028) for
financial support.
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