Acid-base organocatalysts for the aza-Morita-Baylis-Hillman reaction of nitroalkenes

Article abstract of DOI:10.1016/j.tetasy.2010.05.027

A new class of acid-base chiral organocatalysts 1a and 2 for aza-Morita-Baylis-Hillman (aza-MBH) reaction of conjugated nitroalkenes is described. The acidic phenolic hydroxy groups and basic imidazole unit cooperatively activate nitroalkenes to promote the aza-MBH reaction in good yields with moderate enantioselectivities.

Full text of DOI:10.1016/j.tetasy.2010.05.027

Tetrahedron: Asymmetry 21 (2010) 891–894
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Acid–base organocatalysts for the aza-Morita–Baylis–Hillman reaction
of nitroalkenes
*
*
Shinobu Takizawa , Atsushi Horii, Hiroaki Sasai
The Institute of Scientific and Industrial Research (ISIR), Osaka University, Mihogaoka, Ibaraki, Osaka 567-0047, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
A new class of acid–base chiral organocatalysts 1a and 2 for aza-Morita–Baylis–Hillman (aza-MBH) reac-
tion of conjugated nitroalkenes is described. The acidic phenolic hydroxy groups and basic imidazole unit
cooperatively activate nitroalkenes to promote the aza-MBH reaction in good yields with moderate
enantioselectivities.
Received 27 April 2009
Accepted 17 May 2010
Available online 16 June 2010
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
The aza-Morita–Baylis–Hillman (aza-MBH) reaction is recog-
nized as one of the most useful and atom-economical carbon–car-
N
N
bon bond forming reactions between the a-position of an electron-
N
H
N
H
OH
OH
OH
OH
deficient alkene and an imine catalyzed by nucleophilic amines or
phosphines.1 The aza-MBH adducts are highly functionalized
allylic amines, which prove to be valuable building blocks for bio-
logically important compounds and natural products.2 To date, a
number of attractive systems have been developed for this asym-
metric catalytic process.3 Recently Xu et al. reported the first enan-
tioselective aza-MBH reaction of the b-methyl substituted
nitroalkene, although the applicability of their catalysts has been
limited to trisubstituted b-styrene derivatives.4 No reaction was
observed when disubstituted nitroalkenes were used as starting
materials. To the best of our knowledge, research on the enantiose-
lective coupling of simple conjugated nitroalkenes and imines has
not been reported. Obtaining efficient chiral catalysts for the aza-
MBH reaction of simple conjugated nitroalkenes has been a chal-
lenge in organic synthesis.
1a
2
Figure 1. Acid–base organocatalysts for the aza-MBH reaction of nitroalkenes.
reaction-promoting functionality, could be introduced onto the
3-position of BINOL as a chiral Brønsted acid, using an appropriate
spacer (Fig. 2).
As the first step toward the development of the acid–base type
organocatalyst, imidazole6 units were attached through an aro-
matic ring to the 3-position of (S)-BINOL. The synthetic procedure
for organocatalysts 1a7 and 28 is shown in Scheme 1.9 The reaction
of prototypical substrates 2-(2-nitrovinyl)furan 10a and 4-bro-
mobenzyl N-tosylimine 11a was initially attempted using organo-
catalyst 1a or 2. As expected, organocatalyst 1a, with a 2-(1H-
imidazol-4-yl)phenyl group at the 3-position of BINOL, promoted
the reaction to give 12a in 23% yield with 38% ee (Table 1, entry
5). In contrast, organocatalysts 1b–c,10,11 in which the possibility
of synergistic cooperation between the Brønsted acid and the Le-
wis base in an intramolecular manner was eliminated, resulted
in low asymmetric induction or no reaction (entries 6 and 7). The
reaction was mediated by a mixed reagent (S)-BINOL (10 mol %)
and imidazole (10 mol %) and produced 12a in racemic form (entry
4). These results indicate that the introduction of acid–base units
at the appropriate positions on one chiral skeleton improves the
asymmetric induction efficiency. Known chiral organocatalysts
Herein, BINOLate organocatalysts 1a and 2 (Fig. 1) bearing an
imidazole unit are expected to be effective for promoting the enan-
tioselective aza-MBH reaction of conjugated nitroalkenes and N-
tosylimines.
2. Results and discussion
Our work has focused on developing bifunctional catalysts that
can promote enantioselective carbon–carbon bond forming reac-
tions via a dual activation mechanism.5 We envisioned that locat-
ing both acid and base units on one chiral skeleton would facilitate
synergistic cooperation. A Lewis base unit, which would act as a
13,3e 14,3m 15,3d and 163a–c for the aza-MBH reaction of
unsaturated carbonyl compounds were ineffective in this reaction
a,b-
* Corresponding authors. Tel.: +81 6 6879 8466; fax: +81 6 6879 8469 (S.T.).
E-mail address: taki@sanken.osaka-u.ac.jp (S. Takizawa).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.05.027

892
S. Takizawa et al. / Tetrahedron: Asymmetry 21 (2010) 891–894
R1
R1
NHTs
R2
NTs
R2
aza-MBH Reaction
+
NO2
Nitroalkene
NO2
Allyl Amine
Imine
Acid-Base Organocatalyst
retro-Michael
Reaction
Michael
Reaction
LB: Lewis Base
Proton Transfer
R1
R1
LB
OH
LB
NTs
R2
NTs
R2
Mannich
Reaction
OH
O
N
O
N
OH
OH
O
O
I
II
Figure 2. Acid–base organocatalyzed aza-MBH reaction of nitroalkenes.
TEA (1.1 eq)
(Boc)2O (1.1 eq)
DMAP (0.01 eq)
N
N
Br
Br
MeCN, 0 oC to rt, 14 h
Quant
N
3
4
N
H
Boc
O
B
4 (1.0 eq)
N
O
Pd(PPh3)4 (10 mol%)
K3PO4 (1.5 eq)
TFA, rt, 0.5 h
74%
N
OMOM
OMOM
OMOM
(S)-1a
Boc
toluene/H2O, reflux, 12 h
30%
OMOM
5
6
O
B
i) n-BuLi (1.1 eq)
ii) B(OMe)3 (1.5 eq)
Pinacol (1.5 eq)
4 (1.0 eq)
O
Pd(PPh3)4 (10 mol%)
K3PO4 (1.5 eq)
Acetic acid (3.0 eq)
OMOM
OMOM
OMOM
OMOM
toluene/H2O, reflux, 12 h
20%
66%
7
8
N
TFA, rt, 0.5 h
67%
N
OMOM
OMOM
(S)-2
Boc
9
Scheme 1. Synthesis of organocatalysts 1a and 2.
(entries 9–12). Among the acid–base organocatalysts we designed,
catalyst 2 bearing an H8-BINOL12 backbone also exhibited an
acceptable outcome (entry 8), affording product 12a in 56% yield
and 51% ee. The absolute configurations of the major adduct 12a
obtained with catalyst (S)-1a were opposite to those obtained with
(S)-2, which contains the H8-BINOL backbone (entries 5 and 8).

S. Takizawa et al. / Tetrahedron: Asymmetry 21 (2010) 891–894
893
N
N
H
N
N
N
N
H
OH
OH
OH
OH
OH
OH
1b
1c
13
OH
N
PPh2
O
PPh2
OH
OH
OH
N
14
15
16
Table 1
Enantioselective aza-MBH reaction of 3a with 4a using organocatalysts
Table 2
Effect of solvent and temperature on the reaction
Catalyst 1a or 2 (10 mol%)
12a
10a + 11a
NTs
O
O
Solvents, rt, 72 h
NHTs
*
Organocatalyst
CH2Cl2, rt, 72h
+
Entry
Solvent
MeCN
Catalysts
Yielda (%)
eeb,c (%)
Br
NO2
1
2
3
4
5
6
7
8
9
10
11d
12
13d
14
1a
2
1a
2
NR
Trace
NR
19
—
53 (+)
—
NO2
10a
Br
11a
12a
THF
31 (+)
47 (ꢀ)
21 (+)
45 (ꢀ)
37 (+)
47 (ꢀ)
55 (+)
60 (+)
45 (ꢀ)
—
Entry
Organocatalyst (10 mol %)
Yielda (%)
eeb,c (%)
Toluene
1a
2
30
55
1
2
None
(S)-BINOL
Imidazole
(S)-BINOL + imidazole
1a
1b
1c
2
13
14
15
16
NR
NR
25
21
23
12
NR
56
NR
NR
NR
NR
—
—
—
rac
38 (ꢀ)
5 (ꢀ)
—
51 (+)
—
Chlorobenzene
1a
2
64
34
3
CHCl3
CCl4
1a
2
48
67
4d
5
2
35
6
7
8
9
10
11
12
1a
1a
2
81
NR
77
20 (+)
—
—
—
a
b
c
Isolated yield.
Determined by HPLC (Daicel Chiralcel OD-H).
The sign of specific rotation is indicated in parentheses.
d
a
b
c
At 0 °C for 168 h.
Isolated yield.
Determined by HPLC (Daicel Chiralcel OD-H).
The sign of specific rotation is indicated in parentheses.
10 mol % of (S)-BINOL and 10 mol % of imidazole were used.
d
4-methoxy-1-(2-nitrovinyl)benzene 10b and 2,4-dimethoxy-1-(2-
nitrovinyl)benzene 10c produced the corresponding adducts 12h
and 12i but with low yields and enantioselectivities (entries 13
and 14). When using (2-nitrovinyl)benzene 10d as a substrate,
no reaction was observed (entry 15).
Encouraged by the results obtained with 1a and 2, the effect of
other reaction conditions were investigated (Table 2). Halogenated
solvents such as chlorobenzene, CHCl3, and CCl4 (entries 7–14),
along with toluene (entries 5 and 6), gave relatively good results
compared with MeCN (entries 1 and 2) and THF (entries 3 and
4). The product was obtained with 60% ee when using 2 at 0 °C (en-
try 11), although lower reaction temperature drastically dimin-
ished the reaction rates (entries 11 and 13).
Next, we investigated the substrate scope of this catalyst sys-
tem under the optimized reaction conditions (Table 3).13 Regard-
less of whether the aromatic substituent R2 of 11 is electron
withdrawing or electron donating, organocatalysts 1a and 2 pro-
moted the reaction (entries 1–10). 2-Naphthyl N-tosylimine 11g
could be used as a substrate (entries 11 and 12). The reactions of
3. Conclusion
In conclusion, acid–base organocatalysts (S)-3-(2-(1H-imidazol-
4-yl)phenyl)BINOL 1a and (S)-3-(2-(1H-imidazol-4-yl)phenyl)-
5,5’,6,6’,7,7’,8,8’-octahydro-BINOL 2 for the aza-MBH reaction of
conjugated nitroalkenes have been prepared. The acid–base func-
tionalities suitably positioned on the skeleton work synergistically
to furnish the product with up to 60% ee. Efforts are currently
underway to improve the catalytic efficacy and investigate the
reaction mechanism.

894
S. Takizawa et al. / Tetrahedron: Asymmetry 21 (2010) 891–894
Table 3
Substrate scope using organocatalysts 1a and 2
R1
R1
NHTs
NTs
R2
10 mol % of catalyst 1a (or 2)
*
+
R2
CCl4 (or CHCl3), rt
NO2
10
NO2
11
12
Entry
R1
R2
Cat
Time (h)
Yielda (%)
eeb,c (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
2-Furyl 10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
10a
Ph 11b
11b
4-F–C6H4 11c
11c
4-Cl–C6H4 11d
11d
4-MeO–C6H4 11e
11e
4-NC–C6H4 11f
11f
2-Naphthyl 11g
11g
4-Br–C6H4 11a
11a
11a
1a
2
1a
2
1a
2
1a
2
1a
2
1a
2
1a
1a
1a
72
120
96
120
72
72
96
168
72
72
72
120
72
72
72
77
54
77
60
94
76
35
14
98
85
89
47
23
16
NR
12b
12b
12c
12c
12d
12d
12e
12e
12f
57 (ꢀ)
57 (+)
51 (ꢀ)
47 (+)
47 (ꢀ)
51 (+)
43 (ꢀ)
40 (+)
51 (ꢀ)
47 (+)
47 (ꢀ)
47 (+)
29 (ꢀ)
21 (ꢀ)
—
12f
12g
12g
12h
12i
4-MeO–C6H4 10b
2,4-diMeO–C6H3 10c
Ph 10d
a
b
c
Isolated yield.
Determined by HPLC (Daicel Chiralcel OD-H).
The sign of specific rotation is indicated in parentheses.
6. (a) Luo, S.; Zhang, B.; He, J.; Janczuk, A.; Wang, P. G.; Chenga, J.-P. Tetrahedron
Lett. 2002, 43, 7369; (b) Deb, I.; Dadwal, M.; Mobin, S. M.; Namboothiri, I. N. N.
Org. Lett. 2006, 8, 1201; (c) Mohan, R.; Rastogi, N.; Namboothiri, I. N. N.; Mobin,
S. M.; Panda, D. Bioorg. Med. Chem. 2006, 14, 8073; (d) Rastogi, N.; Mohan, R.;
Panda, D.; Mobin, S. M.; Namboothiri, I. N. Org. Biomol. Chem. 2006, 4, 3211; (e)
Deb, I.; Shanbhag, P.; Mobin, S. M.; Namboothiri, I. N. N. Eur. J. Org. Chem. 2009,
14, 4091.
Acknowledgments
This work was supported by a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports, Science
and Technology, Japan, and Takeda Science Foundation. We thank
the technical staff of the Comprehensive Analysis Center of ISIR,
Osaka University.
7. (S)-1a: 1H NMR (270 MHz, CDCl3): d 6.48–7.75 (17H, m); 13C NMR (37.7 MHz,
CDCl3): d 153.0, 149.3, 135.7, 135.2, 134.4, 134.0, 133.5, 131.3, 130.9, 130.2,
128.9, 128.7, 128.5, 128.0, 127.9, 127.7, 126.9, 126.5, 124.8, 124.7, 123.7, 123.1,
118.3, 113.1; HRMS (ESI) m/z calcd for C29H21N2O2, 429.1525 [(M+H)+]: found,
429.1515; ½a 2D0
¼ ꢀ56:3 (c 0.5, CHCl3).
ꢁ
References
8. (S)-2: 1H NMR (270 MHz, CDCl3): d 6.66–7.64 (9H, m), 2.74 (4H, br s), 2.18 (4H,
br s), 1.20–1.70 (8H, m); 13C NMR (37.7 MHz, CDCl3): d 148.3, 147.7, 136.4,
136.3, 135.8, 134.9, 134.1, 131.0, 130.8, 130.6, 129.5, 129.3, 129.3, 127.9, 127.3,
127.1, 127.0, 126.2, 125.1, 122.7, 121.6, 119.0, 28.9, 26.9, 23.0, 22.9, 22.6;
HRMS (ESI) m/z calcd for C29H29N2O2, 437.2151 [(M+H)+]: found, 437.2169;
1. (a) Morita, K.-I.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc. Jpn. 1968, 41, 2815; (b)
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Asymmetry 2006, 17, 578; (l) Liu, Y.-H.; Chen, L.-H.; Shi, M. Adv. Synth. Catal. 2006,
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½ ꢁ ¼ ꢀ109 (c 0.5, CHCl3).
a 2D0
9. Known compounds 3, 5 and 7 were synthesized following their reported
procedures. Compound 3, Young, M. B.; Barrow, J. C.; Glass, K. L.; Lundell, G. F.;
Newton, C. L.; Pellicore, J. M. Rittle, K. E.; Selnick, H. G. Stauffer, K. J.; Vacca, J. P.;
Williams, P. D.; Bohn, D.; Clayton, F. C.; Cook, J. J.; Krueger, J. A.; Kuo, L. C. S.;
Lewis, D.; Lucas, B. J.; McMasters, D. R.; Miller-Stein, C.; Pietrak, B. L.; Wallace,
A. A.; White, R. B.; Wong, B.; Yan, Y.; Nantermet, P. G. J. Med. Chem. 2004, 47,
2995. Compound 5, Ma, L.; Jin, R.-Z.; Lü, G.-H.; Bian, Z.; Ding, M. X.; Gao, L.-X.
Synthesis 2007, 2461. Compound 7, Takasaki, M.; Motoyama, Y.; Yoon, S.-H.;
Mochida, I.; Nagashima, H. J. Org. Chem. 2007, 72, 10291.
10. (S)-1b: 1H NMR (270 MHz, CDCl3): d 7.08–7.77 (17H, m); 13C NMR (37.7 MHz,
CDCl3): d 153.1, 146.9, 138.0, 134.8, 133.7, 133.0, 131.6, 130.7, 130.5, 130.2,
129.1, 129.1, 128.6, 128.5, 128.1, 126.9, 126.8, 125.8, 124.4, 124.2, 123.9, 123.5,
128.5, 118.3, 114.1, 112.2; HRMS (ESI) m/z calcd for C29H21N2O2, 429.1525
[(M+H)+]: found, 429.1511; ½a 2D0
¼ ꢀ94:8 (c 0.5, CHCl3).
ꢁ
11. (S)-1c: 1H NMR (270 MHz, CDCl3): d 6.96–7.94 (17H, m); 13C NMR (37.7 MHz,
CDCl3): d 154.6, 151.3, 138.5, 136.8, 135.7, 134.7, 132.7, 132.2, 131.0, 130.7,
130.4, 130.3, 129.0, 128.9, 127.3, 126.9, 125.5, 125.5, 125.3, 124.2, 123.9, 119.2,
116.9, 114.8; HRMS (ESI) m/z calcd for C29H21N2O2, 429.1525 [(M+H)+]: found,
429.1511; ½a 2D0
¼ ꢀ104 (c 0.5, CHCl3).
ꢁ
12. Cram, D. J.; Helgeson, R. C.; Peacock, S. C.; Kaplan, L. J.; Domeier, L. A.; Moreau,
P.; Koga, K.; Mayer, J. M.; Chao, Y.; Siegel, M. G.; Hoffman, D. H.; Sogah, G. D. Y.
J. Org. Chem. 1978, 43, 1930.
13. General experimental procedure (Table 3): To
a solution of organocatalyst
(10 mol %) in solvent (0.2 mL) was added nitroalkene 10 (0.2 mmol) and imine
11 (0.1 mmol) at rt. The reaction mixture was stirred until the reaction had
reached completion by monitoring with TLC analysis. The mixture was directly
purified by flash column chromatography (SiO2, n-hexane/EtOAc = 7/2) to give
the corresponding adduct 12 as a yellow solid. All products were characterized
by 1H, 13C NMR, MS, and IR spectroscopy, and were identical in all respects
with reported by Namboothiri et al.6d Determination of absolute configurations
of 12 is now in progress.
4. Wang, X.; Chen, Y.-F.; Niu, L.-F.; Xu, P.-F. Org. Lett. 2009, 11, 3310.
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Rajesh, D.; Onitsuka, K.; Suzuki, T.; Mikami, M.; Yamataka, H.; Jayaprakash, D.;
Sasai, H. Tetrahedron 2008, 64, 3361; (b) Takizawa, S.; Matsui, K.; Sasai, H. J.
Synth. Org. Chem. Jpn. 2007, 65, 1089.