Enantioselective nitrocyclopropanation of α,β-unsaturated α-cyanoimides catalyzed by bifunctional thiourea

Article abstract of DOI:10.1055/s-0029-1217331

The organocatalyzed asymmetric cyclopropanation of bromonitromethane with α-cyano-α,β-unsaturated imides is described. In addition, the same bifunctional thiourea was revealed to be a powerful catalyst for preparing these α-cyanoimides by Knoevenagel condensation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1217331

CLUSTER
1627
Enantioselective Nitrocyclopropanation of a,b-Unsaturated a-Cyanoimides
Catalyzed by Bifunctional Thiourea
E
nantioselective
s
Nitrocyc
u
lopropanatio
b
n
of
a
,
b
-Uns
a
aturated
a
-
s
Cyanoimi
a
des Inokuma, Shota Sakamoto, Yoshiji Takemoto*
Graduate School of Pharmaceutical Sciences, Kyoto University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
Fax +81(75)7534569; E-mail: takemoto@pharm.kyoto-u.ac.jp
Received 30 January 2009
functional thiourea 1.5 We envisioned that if the same
Abstract: The organocatalyzed asymmetric cyclopropanation of
bromonitromethane with a-cyano-a,b-unsaturated imides is de-
scribed. In addition, the same bifunctional thiourea was revealed to
be a powerful catalyst for preparing these a-cyanoimides by
Knoevenagel condensation.
reaction with bromonitromethane proceeds efficiently,
there is a chance that the obtained Michael adduct A
would cyclize concurrently via the organocatalyzed in-
tramolecular SN2 reaction, to give the desired 2-nitro-
cyclopropanecarboxylic
acids
stereoselectively.
Key words: asymmetric
organocatalysis,
cyclopropanation,
However, simple a,b-unsaturated imides are not suffi-
ciently electrophilic to react with the nucleophile. There-
fore, we planned to introduce an additional small electron-
withdrawing group such as CN at the a-position of the
substrates to possibly activate the Michael acceptor
(Scheme 1). In this report, we describe highly enantiose-
lective organocatalyzed cyclopropanation with the use of
novel Michael acceptors 4.
Michael addition, a,b-unsaturated imides
2-Nitrocyclopropanecarboxylic acid derivatives are now
recognized as versatile precursors for biologically active
compounds.1 Furthermore, they are quite useful building
blocks for the synthesis of highly functionalized molecu-
lar targets.2 Therefore, the catalytic and enantioselective
construction of these motifs is a valuable challenge for
synthetic chemists.3 Asymmetric Michael addition fol-
lowed by intramolecular nucleophilic substitution is a rep-
resentative process for this purpose. There have been
several reports on the metal-free, organocatalyzed asym-
metric synthesis of 2-nitrocyclopropane derivatives.4
Connon et al. reported the asymmetric cyclopropanation
of nitroolefins with 2-iodomalonate via a chiral thiourea-
catalyzed Michael addition followed by DBU-mediated
intramolecular nucleophilic substitution.4a However, the
enantioselectivity in these reactions was moderate and en-
vironmentally hazardous hexamethylphosphoramide
(HMPA) was used in the second step. Recently, Fan et al.
successfully applied the combined use of an aminothio-
urea catalyst and hypervalent iodine such as PhI(OAc)2 to
cyclopropanation, although this method was limited to the
synthesis of malonate-derived cyclopropanes.4b Ley and
Cordova independently developed a proline-mediated
cyclopropanation of bromonitromethane to a,b-unsaturat-
ed ketones or aldehydes.4c,d Although these reactions
could be used for the efficient synthesis of the desired
nitrocyclopropanes, these methods require an additional
step for oxidation of the ketone or aldehyde into the cor-
responding carboxylic acids. Therefore, the development
of a more direct and convenient protocol for preparing 2-
nitrocyclopropanecarboxylic acids would be a consider-
able challenge.
O
S
R1
R2
Ar
N
H
N
H
CN
+
Me
Me
N+
H
Br
NO2
–O
O
O
N+
+
CF3
R1
R2
H
Br
CN
S
F3C
N
H
N
H
NMe2
thiourea 1
S
Ar
N
N
O2N
R1
O
H
H
Me
N+
R2
Me
HBr
H
O
O
O
Br
R1
N+
CN
R2
CN
A
Scheme 1 Concept of the cyclopropanation of a-cyano-a,b-unsatu-
rated compounds catalyzed by bifunctional thiourea 1
We previously reported the enantioselective Michael ad-
dition of nitromethane to a,b-unsaturated imides with bi-
We initially examined the preparation of the requisite a-
cyano-a,b-unsaturated ester, ketone, sulfone, and imides
4a–e from benzaldehyde 2a and several a-substituted
nitriles 3a–e (Table 1).6 The treatment of 2a and ester 3a
with either ZnO7 or AcOH/morpholine provided the de-
SYNLETT 2009, No. 10, pp 1627–1630
x
x
.x
x
.2
0
0
9
Advanced online publication: 02.06.2009
DOI: 10.1055/s-0029-1217331; Art ID: Y00409ST
© Georg Thieme Verlag Stuttgart · New York

1628
T. Inokuma et al.
CLUSTER
Table 2 Screening of the Substrates
sired product 4a in moderate yield (entries 1 and 2). In the
course of our study on Knoevenagel condensation, we dis-
covered that bifunctional thiourea 1 could be used as a cat-
alyst to give 4a in better yield than with the typical
reaction conditions (entry 3).8 This reaction was success-
fully applied to the synthesis of other Michael acceptors to
give 4b–e in good yields (entries 4–7). In addition, the
corresponding E-isomers were exclusively obtained in all
cases.9
thiourea 1
(1 equiv)
NO2
Br
NO2
R
(1.5 equiv)
toluene, r.t.
Ph
R
Ph
CN
4a–e
CN
5a–e
Et3N, r.t., 40 min
100% conversion
+
Table 1 Knoevenagel Condensation of Benzaldehyde 2a and a-
Cyano Compounds 3a–e
NO2
R
O
R
method A–C
Ph
Ph
NC
3a–e
R
+
CN
6a–e
Ph
H
CN
4a–e
2a
yield (%)a dr (5/6)b
ee of 5c
O
O
Entry
4
Time (h)
O
O
CO2Me
COPh
SO2Ph
N
1
2
3
4
5
4a
4b
4c
4d
4e
26
24
24
6
29
68
0
>99:1
>99:1
–
11
47
–
N
H
F
3a
3b
3c
3d
3e
R
Entry
3
Methoda
Time (h)
Product
Yield (%)b
48
53
>99:1
71:29
71
97
1
2
3
4
5
6
7
3a
3a
3a
3b
3c
3d
3e
A
B
C
C
C
C
C
24
7
4a
4a
4a
4b
4c
4d
4e
54
22
68
85
88
59
72
25
a Isolated yield.
b Estimated from 1H NMR.
c Determined by HPLC.
26
24
17
6
Based on the ee obtained, we selected 4e as the optimal
Michael acceptor. To reduce the catalytic amount of 1, we
next examined the catalytic asymmetric cyclopropanation
of 4e in the presence of 10 mol% of 1 with several bases
(Table 3). As expected, the catalytic reaction with no ad-
ditional base resulted in the recovery of most of the start-
ing material and gave the cycloadduct 5e in 11% yield
with small amounts of Michael adduct (4%, entry 1). Al-
though the addition of 1.5 equivalents of inorganic bases
such as NaHCO3 and K2CO3 improved the yield of 5e to
37% and 27% without producing 6e, the reaction did not
proceed effectively due to the low solubility of the bases
in toluene (entries 2 and 3). Furthermore, pyridine was too
weak as a base for the reaction (entry 4). After several in-
vestigations of bases, Et3N was found to be the best addi-
tive, and gave 5e in 55% yield as a single product (entry
5). The excellent enantioselectivity of the product was
still maintained in the catalytic reaction even with an ex-
cess amount of an achiral base such as Et3N. On the other
hand, when the same reaction was performed at lower
temperature, the chemical yield was enhanced to 84%,
and we obtained a mixture of 5e and diastereomer 7e,
which was a C3 epimer of 5e, in a ratio of 63:37 (entry 6).
The relative configuration of 7e was deduced from the 1H
NMR spectrum.13 The mechanism of the generation of 7e
with a decrease in the reaction temperature is unclear at
this stage, but might be attributed to deceleration of the
cyclization of the Michael adduct at low temperature.14
25
a Method A: AcOH (10 mol%), morpholine (10 mol%), toluene,
Dean–Stark; method B: ZnO (5.0 equiv), DMF, r.t.; method C: thio-
urea 1 (10 mol%), toluene, reflux.
b Isolated yield.
With the desired a,b-unsaturated nitriles 4a–e in hand, we
next studied the nitrocyclopropanation of 4a–e with bro-
monitromethane in the presence of a stoichiometric
amount of thiourea 1 (Table 2). The reaction of both me-
thyl ester 4a and phenyl ketone took place smoothly at
room temperature to give the corresponding nitrocyclo-
propanes 5a and 5b in moderate yields as a single product,
respectively, but the enantioselectivities were low to mod-
erate (entries 1 and 2). When a,b-unsaturated sulfone 4c
was used as a substrate, the desired product 5c was not ob-
tained at all (entry 3). In contrast to these results, the enan-
tioselectivity was considerably improved with a,b-
unsaturated oxazolidinone and imide 4d and 4e10 (entries
4 and 5). In the case of 4e, the major product 5e was ob-
tained with 97% ee. Although inseparable epimer 6e was
obtained as a minor product, 6e could be converted into 5e
under basic conditions. The relative configuration of 5d
was determined by X-ray crystallographic analysis,11,12
and the absolute configuration at C3 of 5a–e was assigned
to be R according to our previous report.5b
We finally investigated the scope of this catalytic reaction
with several a,b-unsaturated a-cyanoimides 4f–k bearing
Synlett 2009, No. 10, 1627–1630 © Thieme Stuttgart · New York

CLUSTER
Enantioselective Nitrocyclopropanation of a,b-Unsaturated a-Cyanoimides
Table 4 Substrate Scopes
1629
Table 3 Screening of the Additives
O
O
O
O
Br
NO2
thiourea 1
Br
NO2
thiourea 1 additive
Et3N
(10 mol%) (1.5 equiv)
(10 mol%) (1.5 equiv)
(1.5 equiv)
(1.5 equiv)
R
N
Ph
N
H
H
toluene
toluene, r.t.
CN
CN
F
F
4e
4f–k
O2N
O2N
O
O
O
O
F
O2N
O2N
O
O
O
O
F
+
Ph
N
H
Ph
N
H
+
CN
CN
R
N
H
R
N
H
F
CN
CN
5e
7e
F
5f–k
7f–k
Entry
Additive
Time (h)
Total yield 5e/7e
ee of 5e
(%)a
(%)b
Entry
R
Temp Time Yield of
ee of 5
(°C)
(h)
5 and 7a
(%)b
1
none
24
24
24
19
2
11
37
27
7
>99:1 97
>99:1 94
1
2
3
4
5
6
4-MeC6H4 (4f)
4-ClC6H4 (4g)
3-ClC6H4 (4h)
2-ClC6H4 (4i)
4-BrC6H4 (4j)
1-naphthyl (4g)
–60
24
81
(62:38)
99
98
98
98
98
98
2
NaHCO3
K2CO3
pyridine
Et3N
3
>99:1 82
>99:1 90
>99:1 96
63:37 97
–20
–20
–20
–20
–20
4
2
1
5
1
75
(60:40)
4
80
(50:50)
5
55
84
6c
Et3N
24
79
(63:37)
a Isolated yield.
b Determined by HPLC.
c The reaction was performed at –60 °C.
76
(58:42)
81
different aryl groups as the b-substituent under the opti-
mized conditions (Table 4).15 Regardless of the electron-
withdrawing and electron-donating groups of the aryl
group, the catalytic reaction of 4f–g and 4j proceeded in
good yield without affecting the stereoselectivity (entries
1, 2, and 5). The substituted position (2-, 3-, 4-) of the
chloride group did not significantly affect either the chem-
ical yield or the ee (entries 2–4). Furthermore, imide 4k
bearing a naphthyl group could be converted to the corre-
sponding cyclopropane 5k in excellent ee. Although the
diastereoselectivity should be improved, we have devel-
oped the thiourea-catalyzed enantioselective cyclopropa-
nation of bromonitromethane and a,b-unsaturated imides
4 in the presence of Et3N.
(73:27)
a Isolated yield.
b Determined by HPLC.
References
(1) (a) Andres, N.; Wolf, H.; Zähner, H.; Rössner, E.; Zeek, A.;
König, W. A.; Sinnwell, V. Helv. Chim. Acta 1989, 72, 426.
(b) Rössner, E.; Zeek, A.; König, W. A. Angew. Chem., Int.
Ed. Engl. 1990, 29, 64. (c) Gootz, T. D.; Brighty, K. E. Med.
Res. Rev. 1996, 16, 433. (d) Brighty, K. E.; Castaldi, J. M.
Synlett 1996, 1097. (e) Zlatopolskiy, B. D.; Loscha, K.;
Alvermann, P.; Kozhushkov, S. I.; Nikolaev, S. V.; Zeeck,
A.; de Meijere, A. Chem. Eur. J. 2004, 10, 4708.
(2) (a) Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini,
M. Chem. Rev. 2005, 105, 933. (b) Gnad, F.; Reiser, O.
Chem. Rev. 2003, 103, 1603. (c) Rosini, G.; Ballini, R.
Synthesis 1988, 833.
In conclusion, we have developed highly reactive and ste-
reoselective Michael acceptors such as 4e–g. These sub-
strates could be easily prepared by Knoevenagel
condensation with bifunctional thiourea. Optically active
2-nitrocyclopropanecarboxylic acids were also synthe-
sized with the same thiourea in excellent enantioselectiv-
ities.
(3) (a) Pellisier, H. Tetrahedron 2008, 64, 7041. (b) For an
example, see: Donaldson, W. A. Tetrahedron 2001, 57,
8589. (c) Moreau, B.; Charette, A. B. J. Am. Chem. Soc.
2005, 127, 18014.
(4) (a) McCooey, S. H.; McCabe, T.; Connon, S. J. J. Org.
Chem. 2006, 71, 7494. (b) Fan, R.; Ye, Y.; Li, W.; Wang, L.
Adv. Synth. Catal. 2008, 350, 2488. (c) Hansen, H. M.;
Longbottom, D. A.; Ley, S. V. Chem. Commun. 2006, 4838.
(d) Vesely, J.; Zhao, G.; Bartoszewicz, A.; Cordova, A.
Tetrahedron Lett. 2008, 49, 4209.
Acknowledgment
This work was supported in part by Scientific Research on Priority
Areas: Advanced Molecular Transformations of Carbon Resources
(19020027) and Targeted Proteins Research Program. T.I. thanks
the JSPS for a Fellowship.
Synlett 2009, No. 10, 1627–1630 © Thieme Stuttgart · New York

1630
T. Inokuma et al.
CLUSTER
(5) (a) Xie, J.; Yoshida, K.; Takasu, K.; Takemoto, Y.
Tetrahedron Lett. 2008, 49, 6910. (b) Inokuma, T.; Hoashi,
Y.; Takemoto, Y. J. Am. Chem. Soc. 2006, 128, 9413.
(c) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc.
2003, 125, 12672.
determined to be trans. Then, 7e was deduced to be a C1
epimer of 5e.
(14) We tried the one-pot process of Knoevenagel reaction and
cyclopropanation. But, disappointingly, we obtained the
same product 5e with lower ee (58% yield, 63:37 dr, 17%
ee).
(6) Jones, G. Org. React. 1967, 15, 204.
(7) Knoevenagel Reaction Catalyzed by Thiourea 1
A mixture of 3e (40.2 mg, 0.195 mmol), benzaldehyde 2a
(22 mL, 0.215 mmol), and(rac)-thiourea 1 (8.1 mg, 0.0195
mmol) in toluene (2.0 mL) was stirred at 80 °C for 25 h.
After the reaction mixture was concentrated in vacuo, the
residue was purified by silica gel column chromatography
with hexane–EtOAc (3:1) to afford 4e (41.5 mg, 72%) as
white needles.
(15) General Procedure for the Thiourea-Catalyzed
Nitrocyclopropanation
To a mixture of 4e (29.7 mg, 0.1 mmol) and thiourea 1 (4.7
mg, 10 mol%) in toluene (0.1 M) were added
bromonitromethane (10 mL, 0.15 mmol) and Et3N (20 mL,
0.15 mmol) at –60 °C during the indicated period. The
reaction mixture was directly purified by silica gel column
chromatography with hexane–EtOAc (3:1) to afford 5e (19
mg, 53%, 97% ee) as white amorphous solids and 7e (11 mg,
31%, 90% ee) as a brown oil.
(E)-N-(2-Cyano-3-phenylacryloyl)-2-fluorobenzamide
(4e)
White needles; Rf = 0.54 (hexane–EtOAc, 1:1); mp 186–188
°C. 1H NMR (500 MHz, CDCl3): d = 9.96 (d, J = 16.3 Hz, 1
H) 8.47 (s, 1 H), 8.16 (td, J = 6.3, 1.7 Hz, 1 H), 8.02 (d,
J = 8.0 Hz, 2 H), 7.65–7.60 (m, 2 H), 7.55 (dd, J = 8.0, 7.2
Hz, 2 H), 7.36 (td, J = 7.7, 7.2 Hz, 1 H), 7.25 (dd, J = 12.0,
8.0 Hz). 13C NMR (126 MHz, CDCl3): d = 161.5, 161.0 (2
C), 160.6 (d, J = 249 Hz), 158.3, 156.4, 135.6 (d, J = 9.9
Hz), 133.9, 132.7, 131.3, 129.2, 125.6 (d, J = 3.0 Hz), 116.0
(d, J = 10.2 Hz), 116.5 (d, J = 24.6 Hz), 116.0, 103.4. IR
(KBr): 3364, 1737, 1513, 1289 cm–1. MS–FAB+: m/z (%) =
295(10) [MH+], 154 [100]. Anal. Calcd for C17H11FN2O2C:
69.38, H: 3.77, N: 9.52. Found C: 69.57, H: 3.81, N: 9.55.
(8) Moison, H.; Boullet, F.; Foucaud, A. Tetrahedron 1987, 43,
537.
1-Cyano-2-nitro-3-phenylcyclopropanecarbonyl)-2-
fluorobenzamide (5e; Major Diastereomer)
White amorphous solids; Rf = 0.48 (hexane–EtOAc, 1:1);
[a]D26 –19.01 (c 0.71, CHCl3). 1H NMR (500 MHz, CDCl3):
d = 9.41 (d, J = 16.3 Hz, 1 H), 8.14 (dt, J = 6.0, 1.7 Hz, 1 H),
7.64–7.67 (m, 1 H), 7.48–7.40 (m, 5 H), 7.36 (dd, J = 7.7,
7.4 Hz, 1 H), 7.23 (dd, J = 12.3, 8.4 Hz, 1 H), 5.41 (d, J = 6.4
Hz, 1 H), 4.34 (d, J = 6.4 Hz, 1 H). 13C NMR (126 MHz,
CDCl3): d = 161.9, 161.8, 160.8 (d, J = 241 Hz), 159.7,
136.4 (d, J = 9.9 Hz), 132.9, 129.6, 129.2 (d, J = 24.6 Hz),
128.0, 125.6 (d, J = 3.6 Hz), 118.1 (d, J = 9.9 Hz), 116.7 (d,
J = 24.6 Hz), 112.2, 68.4, 37.7, 35.9. IR (CHCl3): 3400
(NH), 2247 (CN), 1699 (C=O), 1617 (NO2), 1559 (C=O).
MS–FAB–: m/z (%) = 352(100) [M – H]. HRMS–FAB–: m/z
calcd for C18H11FN3O4 [M – H]: 352.0733; found: 352.0699.
HPLC: Daicel Chiralcel AS-H; hexane–i-PrOH (90:10), 1
mL min–1, 254 nm: tR(minor) = 67.8 min; tR(major) = 76.1
min.
(9) Hayashi, T. J. Org. Chem. 1966, 31, 3253.
(10) o-Fluorobenzimide is a better substrate for asymmetric
Michael addition than nonsubstituted benzimide due to the
intramolecular hydrogen bond between imide proton and
fluoro atom, see: Inokuma T., Nagamoto Y., Sakamoto S.,
Miyabe H., Takasu K., Takemoto Y.; Heterocycles; 2009, in
press
(11) CCDC 717740 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from the Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/data_request/cif.
(12) The methanolysis [cat. Er(OTf)3, MeOH, 60 °C] of 4d and
4e provided the same product 4a. Therefore, we concluded
that the compounds 4a, 4d, and 4e have the same relative
configuration. In addition, the minor product 6e was
converted into 5e by the treatment with a catalytic amount of
Et3N. The result suggests that 6e was a C2 epimer of 5e.
(13) The relative configuration of 7e was assigned as follows:
From the coupling constant of C2 and C3 protons (5e: 6.4
Hz, 7e: 6.6 Hz) in 1H NMR, the relative configuration
between the phenyl and nitro group of both 5e and 7e was
1-Cyano-2-nitro-3-phenylcyclopropanecarbonyl)-2-
fluorobenzamide (7e; Minor Diastereomer)
Brown oil; Rf = 0.40 (hexane–EtOAc, 1:1); [a]D26 +91.9 (c
0.19, CHCl3). 1H NMR (500 MHz, CDCl3): d = 9.35 (d,
J = 15.8 Hz, 1 H), 8.10 (dt, J = 6.6, 1.4 Hz, 1 H), 7.61–7.65
(m, 1 H), 7.27–7.36 (m, 5 H), 7.26 (dd, J = 10.1, 6.0 Hz, 1
H), 7.19 (dd, J = 8.3, 4.0 Hz, 1 H), 5.79 (d, J = 6.6 Hz, 1 H),
4.45 (d, J = 6.6 Hz, 1 H). 13C NMR (126 MHz, CDCl3):
d = 161.6, 161.8, 159.4 (d, J = 263 Hz), 158.7, 136.5 (d,
J = 9.9 Hz), 132.9, 129.6, 129.2 (d, J = 24.6 Hz), 128.0,
125.6 (d, J = 3.6 Hz), 118.4 (d, J = 9.9 Hz), 116.6 (d,
J = 24.6 Hz), 112.5, 65.1, 41.1, 34.1. IR (CHCl3): 3400
(NH), 2244 (CN), 1699 (C=O), 1615 (NO2), 1563 (C=O).
MS–FAB–: m/z (%) = 352(20) [M – H]. HRMS–FAB–: m/z
calcd for C18H11FN3O4 [M – H]: 352.0733; found: 352.0722.
HPLC: Daicel Chiralcel AS-H; hexane–i-PrOH (90:10), 1
mL min–1, 254 nm: tR(minor) = 91.0 min; tR(major) = 103.9
min.
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