Enantioselective aza-Henry reaction with acyclic guanidine-thiourea bifunctional organocatalyst

Article abstract of DOI:10.1002/adsc.200800692

A highly enantioselective aza-Henry reaction of imines with nitromethane was achieved with a reactive guanidine-thiourea bifunctional organocatalyst affording β-nitroamines with high enantioselectivity (up to 96% ee). The diastereo- and enantioselective v

Full text of DOI:10.1002/adsc.200800692

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DOI: 10.1002/adsc.200800692
Enantioselective Aza-Henry Reaction with Acyclic Guanidine-
Thiourea Bifunctional Organocatalyst
Keisuke Takadaa and Kazuo Nagasawaa,*
a
Department of Biotechnology and Life Science; Graduate School of Engineering; Tokyo University of Agriculture and
Technology (TUAT), 2-24-16 Naka-cho, Koganei, Tokyo 184-8588, Japan
Fax : (+81)-42-388-7295; e-mail: knaga@cc.tuat.ac.jp
Received: November 9, 2008; Revised: January 5, 2009; Published online: February 6, 2009
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200800692.
Abstract: A highly enantioselective aza-Henry reac-
tion of imines with nitromethane was achieved with
a reactive guanidine-thiourea bifunctional organo-
catalyst affording b-nitroamines with high enantio-
selectivity (up to 96% ee). The diastereo- and enan-
tioselective version of this reaction with nitroal-
kanes also proceeded selectively (up to 99:1 dr with
99% ee).
as well as diastereo- and enantioselective, Henry reac-
tions under liquid-liquid biphasic conditions.[9] In this
reaction, the catalyst 1a, which has long alkyl chain
on the guanidine moiety, forms a chiral surfactant.
This surfactant and potassium iodide as an additive
were effective for preventing the retro-reaction pro-
cess, resulting in the observed high enantioselectivity.
In contrast, the aza-Henry reaction does not involve a
retro process, so here, we newly explored the solid-
liquid biphasic aza-Henry reaction in the presence of
a guanidine-thiourea bifunctional organocatalyst.
We investigated the catalytic activity and enantiose-
lectivity in the reaction of imine 2a[10] and nitrome-
thane 3a catalyzed by the guanidine-thiourea com-
pounds 1 (Figure 1), focusing on the substituents of
Keywords: aza-Henry reaction; guanidines; organic
catalysts; phase-transfer catalyst; thioureas
The aza-Henry reaction is a fundamental carbon- the guanidine group and the chiral spacer (Table 1).
carbon bond-forming reaction in synthetic organic First, the effects of the R1 and R2 groups on guanidine
chemistry,[1] providing a synthetically useful chiral in- were explored. The mono-substituted guanidines 1a
termediate for b-nitro amines.[2] Since the pioneering and 1b (5 mol%) efficiently catalyzed the reaction
catalytic asymmetric version of the reaction by Shiba- within 30 min under Cs2CO3-THF biphasic conditions
sakiꢀs group, using a heterobimetallic catalyst,[3] many at 08C, but the enantioselectivity was poor (entries 1
further developments have been reported.[4] Among and 2). In the case of bis-substituted guanidine 1c, the
them, an organocatalytic aza-Henry reaction was re- enantioselectivity was increased to 74% ee (entry 3).
ported for the first time by Takemoto et al. using a Drastic improvements of both catalytic activity and
chiral thiourea-N-dimethylamine group-conjugated enantioselectivity were seen with cyclic amine-substi-
catalyst.[5] Recently, various types of organocatalytic tuted guanidines 1d and 1e (entries 4-7). In particular,
aza-Henry reactions have been reported, including 1d having a pyrrolidine ring gave b-nitroamine 4a in
the use of bisamidine,[6] Cinchona alkaloid deriva- 92% yield with 93% ee. When the reaction tempera-
tives[7] and (thio)urea as catalysts.[8] Although high ture was lowered to À108C, the enantioselectivity in-
enantio- and/or diastereoselectivities have been creased to 96% without any decrease of the chemical
achieved, limited substrate generality and low catalyt- yield. When the catalyst loading of 1d was decreased
ic activity are still issues. Herein, we describe the to 3 mol%, the chemical yield and enantioselectivity
highly enantioselective aza-Henry reaction of both ar- were slightly decreased to 91% and 90% ee (entry 6).
omatic and aliphatic imines with nitromethane in the Next, the chiral spacer (R3) was varied. The catalysts
presence of an active bifunctional organocatalyst. A 1f and 1g, which have alanine- and valine-derived
highly diastereo- and enantioselective version of the chiral spacers (R3 =Me, i-Pr), respectively, gave 4a
reaction with aromatic imines is also described.
with high yield, but the enantioselectivity was only
Recently we have developed a guanidine-thiourea moderate (entries 8 and 9). Since the catalysts 1h and
bifunctional acyclic catalyst, 1a, for enantioselective, 1i,[9d] lacking the thiourea or guanidine group, did not
Adv. Synth. Catal. 2009, 351, 345 – 347
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345

Keisuke Takada and Kazuo Nagasawa
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The scope of imine substrates was examined under
the optimized conditions (Table 1, entry 5). Every re-
action was completed within 30 min (Table 2, en-
tries 1–6). Aliphatic and aromatic imines gave the cor-
responding aza-Henry products 4 in good yield (82–
96%) with high enantioselectivity (90–96% ee). The
diastereo- and enantioselective version of the aza-
Henry reaction was also explored with imines 2e–g
and nitroalkanes 3b–d (Table 2, entries 7–13). In all
cases, the anti-b-nitro amines 4 were obtained in good
yield (81–94%) and with high diastereo- and enantio-
selectivities (90:10–99:1 dr, 96–99% ee).
In summary, we have developed a highly enantiose-
lective aza-Henry reaction by using the newly devel-
oped guanidine-thiourea bifunctional organocatalyst
1d. This reaction is applicable to various aliphatic and
aromatic imines. The diastereo- and enantioselective
version of this reaction with nitroalkanes and aromat-
Table 2. Catalytic asymmetric aza-Henry reaction of imines
2 with nitroalkanes 3.[a]
Figure 1. Structures of guanidine-thiourea bifunctional cata-
lysts 1a–g and monofunctional catalysts 1h and 1i.
Table 1. Substituent effects on yield and enantioselectivity in
the reaction 2a and 3a with catalysts 1.[a]
Entry
R1
R2
Yield [%][b]
ee [%][c]
dr[d]
1
2b
2c
2d
2e
2f
2g
2e
2e
2e
2f
2f
2g
2g
3a
3a
3a
3a
3a
3a
3b
3c
3d
3b
3c
3b
3c
84 (4b)
92 (4c)
82 (4d)
96 (4e)
85 (4f)
88 (4g)
94 (4h)
90 (4i)
85 (4j)
89 (4k)
89 (4l)
81 (4m)
94 (4n)
95
96
90
96
90
96
99
99
98
99
97
97
96
–
–
–
–
–
–
Entry
Catalyst
Yield [%][b]
ee [%][c]
2
3[e]
4
1
2
3
4
1a
1b
1c
1d
1d
1d
1e
1f
1g
1h
1i
89
90
61
92
92
91
80
90
91
76
88
9
17
74
93
96
90
85
71
71
0
5
6
7[f]
8[g]
9[g]
10[h]
11[h]
12
13
99:1
99:1
94:6
92:8
90:10
96:4
95:5
5[d]
6[e]
7
8
9
10
11
12
[a]
Reactions were carried out on a 0.1 mmol scale in 1.0 mL
of THF.
Isolated yield.
[a]
Reactions were carried out on a 0.1 mmol scale in 1.0 mL
of THF.
Isolated yield.
[b]
[c]
[b]
[c]
Enantiomeric excesses were determined by chiral HPLC
Enantiomeric excess was determined by chiral HPLC an-
analysis.[5b,7a,8a]
alysis.[7a]
[d]
Diastereomer ratios were determined by HPLC analy-
sis.[5b,8a]
Reaction was run at 08C.
Reaction was run at À108C with Cs2CO3 (50 mol%).
Reaction was run at À208C with Cs2CO3 (50 mol%).
Reaction was run at À258C with Cs2CO3 (50 mol%) for
2 h.
[d]
[e]
Reaction was run at À108C.
3 mol% catalyst was used at À108C.
[e]
[f]
[g]
[h]
show any asymmetric induction, the guanidine and
thiourea groups in 1d were considered to act coopera-
tively in the asymmetric induction (entries 10 and 11).
346
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Enantioselective Aza-Henry Reaction with Acyclic Guanidine-Thiourea
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ic imines also proceeded with extremely high selectiv-
ities.
Experimental Section
Typical Procedure for Enantioselective Aza-Henry
Reaction
To a mixture of (S,S)-1d (4.8 mg, 5 mmol), Cs2CO3 (32.6 mg,
0.1 mmol) and imine (2a) (21.2 mg, 0.1 mmol) in THF
(1 mL) was added nitromethane (3a) (54 mL, 1.0 mmol) at
À108C. The resulting mixture was stirred vigorously at
À108C for 30 min. To the reaction mixture was added satu-
rated aqueous NH4Cl, and the organic layer was extracted
with ethyl acetate. The extracts were dried over MgSO4, fil-
tered and concentrated under vacuum. The residue was pu-
rified by column chromatography on silica gel (n-hexane/
ethyl acetate=50:1 to 25:1) to give nitroamine 4a; yield:
25.3 mg (92%). The enantiomeric excess of 4a (96% ee) was
determined by means of chiral HPLC analysis [Chiral AD-
H, 0.46 cm (f)ꢂ25 cm (L), n-hexane/2-propanol=90:10,
0.8 mLminÀ1, major; 12.3 min, minor; 9.4 min].[7a]
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Acknowledgements
This research was supported in part by grants from Uehara
Memorial Foundation and the Nagase Science and Technolo-
gy Foundation.
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