Stereoselective synthesis of functionalised cyclopropanes from nitroalkenes via an organocatalysed Michael-initiated ring-closure approach

Article abstract of DOI:10.1016/j.tetasy.2010.04.005

Synthetically useful nitrocyclopropanes are easily obtained via Michael addition of dimethyl bromomalonate to nitrostyrenes promoted by commercially available (S)-α,α-di-β-naphthlyl-2-pyrrolidinemethanol as the catalyst, followed by DABCO-mediated intramo

Full text of DOI:10.1016/j.tetasy.2010.04.005

Tetrahedron: Asymmetry 21 (2010) 1155–1157
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Stereoselective synthesis of functionalised cyclopropanes from nitroalkenes
via an organocatalysed Michael-initiated ring-closure approach
*
Alessio Russo, Alessandra Lattanzi
Dipartimento di Chimica, Università di Salerno, Via Ponte don Melillo, 84084 Fisciano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Synthetically useful nitrocyclopropanes are easily obtained via Michael addition of dimethyl bromomal-
onate to nitrostyrenes promoted by commercially available (S)-a,a-di-b-naphthlyl-2-pyrrolidinemetha-
nol as the catalyst, followed by DABCO-mediated intramolecular nucleophilic substitution. The
functionalised nitrocyclopropanes are obtained in good yield, excellent diastereoselectivity and up to
Received 7 February 2010
Accepted 6 April 2010
Available online 4 May 2010
49% ee.
Dedicated with admiration to Professor
Henri B. Kagan on the occasion of his 80th
birthday
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
complete control of the diastereoselectivity and up to 47% ee. This
simple approach has been recently improved by Yan using 60-dem-
Chiral cyclopropane is the key-structural motif of a variety of
natural products, agrochemical targets and biologically active com-
pounds including a notable number of therapeutic agents.1 More-
over, cyclopropyl containing compounds are attractive synthetic
intermediates and building blocks.2
Consequently, many synthetic efforts have been focused on the
development of efficient and stereoselective methodologies of
cyclopropanation of alkenes essentially based through the genera-
tion of organometallic carbenoid species and ylides.3 The organo-
catalytic approach has been gaining importance in this context as
demonstrated by several reports showing the ability of various
ethyl-quinine as the catalyst and dimethyl bromomalonate as the
nucleophile.8 In this case, DABCO in DMF rather than DBU in less
environmentally friendly hexamethylphosphoramide (HMPA)
was found to be more effective conditions for the ring closure.
Excellent diastereo- and enantioselectivity and good yields of
product were obtained for a variety of aryl and heteroaromatic
nitroalkenes. A similar approach has been recently developed by
Takemoto using chiral bifunctional thioureas to access densely
functionalised cyclopropanes.9
Recently, we have demonstrated that easily accessible L-a,a-
diaryl prolinols are useful promoters of the organocatalysed Mi-
chael addition and ring-opening reactions for the formation of car-
bon–carbon and carbon–heteroatom bonds.10 Herein, we report a
further example of their potential as organocatalysts in the stereo-
selective synthesis of nitrocyclopropanes. Indeed, we previously
L
-proline derivatives to promote the process via iminium activation
a
of
,b-unsaturated aldehydes and ketones.4 Excellent results in
terms of diastereo- and enantioselectivity have been achieved by
Gaunt et al. in the cyclopropanation of acrylate esters or amides,
using in situ generation of chiral ylides by using readily available
cinchona alkaloid derivatives.5 Intramolecular variants have also
been established.6 Connon et al. reported that bifunctional cin-
chona alkaloid-derived thioureas are able to catalyse the enantio-
selective cyclopropanation of nitroalkenes with dimethyl
chloromalonate via Michael-initiated ring-closure reaction (MIRC)7
(Scheme 1).
Firstly, the enantioselective Michael addition occurs, followed
by DBU-mediated intramolecular nucleophilic substitution on the
adduct. The stereocontrol of the reaction is established through
non-covalent activation of nitroalkene and dimethyl chloromalo-
nate by the acid and basic sites of the thiourea catalyst, respec-
tively. Nitrocyclopropanes have been isolated in good yield,
demonstrated that L-a,a-diaryl prolinols behave as bifunctional
organocatalysts in the Michael addition of malonates to aryl and
heteroaryl nitroalkenes, affording the adducts in good to high yield
and moderate enantioselectivity (up to 56% ee).11 Hydrogen bond-
ing interactions of the nitroalkene and the malonate ester with the
hydroxyl group and the secondary basic moiety of the catalyst
have been suggested to be involved in substrates activation. Hence,
the sequence in Scheme 1 was thought to be a viable access to
enantiomerically enriched nitrocyclopropanes using
prolinols as a novel class of organic promoters.
a,a-diaryl
2. Results and discussion
At the outset a variety of aryl-substituted prolinols were
screened in different reaction conditions at room temperature in
the model reaction between trans-nitrostyrene 1a and dimethyl
* Corresponding author. Tel.: +39 089 969563; fax: +39 089 969603.
E-mail address: lattanzi@unisa.it (A. Lattanzi).
0957-4166/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2010.04.005

1156
A. Russo, A. Lattanzi / Tetrahedron: Asymmetry 21 (2010) 1155–1157
CO2Me
NO2
MeO2C
R
MeO2C
O
O
1) catalyst
CH2Cl2, -30°C
CO2Me
NO2
Cl
3) DBU
HMPA
NO2
+
MeO
OMe
R
2) filter
R
Cl
2
1
3
de>98%, 14-47% ee
R= aryl, heteroaryl, alkyl
catalysts used: bifunctional thioureas derived from cinchona alkaloids
Scheme 1. MIRC strategy to nitrocyclopropanes.
bromomalonate 2 for the conjugate addition process, whereas the
ring-closure step was carried out on the crude mixture using DAB-
CO in DMF as a solvent (Table 1).
robenzene (entry 13). Catalyst loading can be eventually reduced
to 15 mol % without significantly affecting the efficiency of the pro-
cess (entry 14).
Catalysts 4a–d led exclusively to trans-nitrocyclopropane prod-
uct 3a, as confirmed by 1H NMR analysis, as the prevalent (2S,3R)-
enantiomer in generally good yield over the two steps and up to
To investigate the scope of the stereoselective nitrocyclopro-
pane MIRC approach, the reaction of compound 2 with a series of
trans-nitroalkenes was explored under optimised reaction condi-
tions (Table 2).14
31% ee (entries 1–4).12 Commercially available
a,a-(2-naph-
thyl)prolinol 4e significantly improved the ee of the product (entry
5). More sterically demanding perhydroindolinol 4f, recently em-
ployed as silyl ether derivative in enamine catalysis,13 proved to
be poorly efficient compared to prolinols 4a–e. The reaction using
the most effective catalyst 4e, carried out at ꢀ16 °C led to a negli-
gible enhancement of the enantioselectivity (entry 7). The reaction
performed with diethyl bromomalonate proceeded sluggishly (en-
try 8). Alternative solvents were detrimental in all respects (entries
9 and 10). Various aromatic solvents were also checked (entries
11–13) and amongst them, the best result was achieved with chlo-
Electron-donating or withdrawing substituents at the para-po-
sition on the phenyl ring were generally well tolerated, achieving
the products in good yield and up to 49% ee (entries 2–6). A lower
efficiency in terms of yield and enantiocontrol was observed in the
case of ortho-phenyl substituted compounds or the sterically hin-
dered 1-naphthyl-derivative (entries 7 and 8), in analogy to previ-
ously reported findings on the same process promoted by
cinchona-derived thioureas and 60-demethyl-quinine. Heteroaryl
nitroalkenes afforded comparable results (entries 9 and 10), while
the b-alkyl substituted nitroalkene did not react, which was in
Table 1
Optimisation study for the synthesis of model nitrocyclopropane 3a promoted by catalyst 4a
CO2Me
NO2
MeO2C
Ph
O
O
4
1) (30 mol%)
solvent
+
NO2
MeO
OMe
Ph
2) DABCO
DMF, rt, 16 h
Br
2
3a
1a
H
HO
Ph
4a
Ar=Ph
Ar=3,3'-(Me)2C6H3
OH
Ar
4f
4b
Ph
N
H
4c
Ar=4-MeOC6H4
N
Ar
H
H
4d
4e
Ar=4-tBuC6H4
Ar=2-naphthyl
Entry
4
Solvent
T (°C)
tb (h)
Yield 3ac (%)
ee 3ad (%) (abs. conf.)
1
2
3
4
5
6
4a
4b
4c
4d
4e
4f
4e
4e
4e
4e
4e
4e
4e
4e
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
CH2Cl2
THF
p-Xylene
Anisole
Chlorobenzene
Chlorobenzene
18
18
18
18
18
18
ꢀ16
18
18
18
18
18
18
18
91
95
76
65
67
64
110
86
70
66
72
45
65
75
68
70
81
90
67
51
56
25
30
36
58
38
75
62
28 (2S,3R)
31 (2S,3R)
21 (2S,3R)
29 (2S,3R)
40 (2S,3R)
9 (2S,3R)
7
43 (2S,3R)
8e
9
—
f
33 (2S,3R)
rac
40 (2S,3R)
36 (2S,3R)
43 (2S,3R)
40 (2S,3R)
10
11
12
13
14g
a
Conjugate addition was performed with 1a (0.2 mmol), dimethyl bromomalonate (0.22 mmol), 4 (0.06 mmol) in chlorobenzene (0.4 mL). The intramolecular cyclo-
propanation on the crude mixture was performed using DABCO (0.15 mmol) in DMF (1 mL).
b
Reaction time of the first step.
Combined yield of two steps.
c
d
Determined by HPLC analysis. Absolute configuration was determined by comparison of specific rotation and elution order of HPLC retention times with those reported in
the literature.7
e
Reaction performed with diethyl bromomalonate.
Not determined.
15 mol % of catalyst was used.
f
g

A. Russo, A. Lattanzi / Tetrahedron: Asymmetry 21 (2010) 1155–1157
1157
Table 2
Stereoselective cyclopropanation of trans-nitroalkenes mediated by catalyst 4ea
CO2Me
MeO2C
O
O
4e
1)
(30 mol%)
chlorobenzene, 18°C
+
NO2
(R)
(R)
MeO
OMe
R
2) DABCO, DMF
rt, 16h
NO2
R
Br
2
1
3
Entry
R
tb (h)
Yield 3c (%)
ee 3d (%) (abs. conf.)
1
2
3
4
5
6
7
8
9
Ph
65
65
69
69
85
77
77
87
75
73
68
69
63
61
50
45
49
68
—
43 (2S,3R)
44 (2S,3R)
35 (2S,3R)
46 (2S,3R)
49 (2S,3R)
49 (2S,3R)
35 (2S,3R)
17 (2S,3R)
42 (2S,3R)
32 (2S,3R)
—
4-CH3C6H4
4-CF3C6H4
4-BrC6H4
4-CH3OC6H4
4-ClC6H4
2-ClC6H4
1-Naphthyl
2-Furyl
112
112
98
10
11
2-Thienyl
Cyclohexyl
a
Conjugate addition was performed with 1 (0.2 mmol), dimethyl bromomalonate 2 (0.22 mmol), 4e (0.06 mmol) in chlorobenzene (0.4 mL). The intramolecular cyclo-
propanation on the crude mixture was performed using DABCO (0.15 mmol) in DMF (1 mL) affording exclusively trans-3.
b
Reaction time of the first step.
Combined yield of two steps.
c
d
Determined by HPLC analysis. Absolute configuration was determined by comparison of specific rotation and elution order of enantiomers via chiral HPLC with those
reported in the literature.7
Ed. 2008, 47, 8460; (d) Charette, A. B.; Molinaro, C.; Brochu, C. J. Am. Chem. Soc.
2001, 123, 12168; (e) Aggarwal, V. K.; Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.;
Porcelloni, M. Angew. Chem., Int. Ed. 2001, 40, 1430; (f) Davies, H. M. L.;
Bruzinski, P. R.; Lake, D. H.; Kong, N.; Fall, M. J. J. Am. Chem. Soc. 1996, 118,
6897; (g) Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.-B.; Itoh, K. J. Am.
Chem. Soc. 1994, 116, 2223.
agreement with our previous findings on conjugate addition of
malonate esters to nitroalkenes promoted by the same catalysts
(entry 11). Finally, the Michael addition to the trisubstituted al-
kene trans-b-methyl-b-nitrostyrene did not proceed. Although
the levels of enantioselectivity are still moderate, a,a-diaryl-proli-
4. For selected examples, see: (a) Companyó, X.; Alba, A.-N.; Cárdenas, F.;
Moyano, A.; Rios, R. Eur. J. Org. Chem. 2009, 3075; (b) Ibrahem, I.; Zhao, G. L.;
Rios, R.; Vesely, J.; Sunden, H.; Dziedzic, P.; Córdova, A. Chem. Eur. J. 2008, 14,
7867; (c) Wascholowski, V.; Hansen, H. M.; Longbottom, D. A.; Ley, S. V.
Synthesis 2008, 1269; (d) Xie, H.; Zu, L.; Li, H.; Wang, J.; Wang, W. J. Am. Chem.
Soc. 2007, 129, 10886; (e) Hartikka, A.; Arvidsson, P. I. J. Org. Chem. 2007, 72,
5874; (f) Johansson, C. C. C.; Bremeyer, N.; Ley, S. V.; Owen, D. R.; Smith, S. C.;
Gaunt, M. J. Angew. Chem., Int. Ed. 2006, 45, 6024; (g) Kojima, S.; Suzuki, M.;
Watanabe, A.; Ohkata, K. Tetrahedron Lett. 2006, 47, 9061; (h) Deng, X.-M.; Cai,
P.; Ye, S.; Sun, X.-L.; Liao, W.-W.; Li, K.; Tang, Y.; Wu, Y.-D.; Dai, L.-X. J. Am.
Chem. Soc. 2006, 128, 9730; (j) Kunz, R. K.; MacMillan, D. W. C. J. Am. Chem. Soc.
2005, 127, 3240.
5. Papageorgiou, C. D.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2003, 42, 828.
6. Bremeyer, N.; Smith, S. C.; Ley, S. V.; Gaunt, M. J. Angew. Chem., Int. Ed. 2004, 43,
2681.
7. McCooey, S. H.; McCabe, T.; Connon, S. J. J. Org. Chem. 2006, 71, 7494.
8. Xuan, Y.-n.; Nie, S.-z.; Dong, L.-t.; Zhang, J.-m.; Yan, M. Org. Lett. 2009, 11, 1583.
9. Inokuma, T.; Sakamoto, S.; Takemoto, Y. Synlett 2009, 1627.
10. (a) Lattanzi, A. Org. Lett. 2005, 7, 2579; (b) Russo, A.; Lattanzi, A. Adv. Synth.
Catal. 2008, 350, 1991; (c) Lattanzi, A.; Della Sala, G. Eur. J. Org. Chem. 2009,
1845; For a review, see: (d) Lattanzi, A. Chem. Commun. 2009, 1452.
11. Lattanzi, A. Tetrahedron: Asymmetry 2006, 17, 837.
nols afford comparable results to cinchona alkaloid derived thio-
ureas as catalysts, working at room temperature and using more
environmentally friendly reaction conditions for the ring-closure
step.
3. Conclusion
In conclusion, we have shown that besides cinchona-modified
alkaloids and chiral thioureas,
a,a-diaryl prolinols are a new
class of organocatalysts employable in the stereoselective MIRC
approach to cyclopropanes. A convenient protocol to synthetically
useful nitrocyclopropanes has been developed by using commer-
cially available a,a-(2-naphthyl)prolinol and bromomalonate with
easily accessible trans-nitrostyrenes. The functionalised products
are obtained as diastereoisomerically pure trans-isomers, in good
yield and moderate enantioselectivity. We are currently working
on the improvement of MIRC strategy for the stereoselective
cyclopropanation of electron-poor alkenes.
12.
A control experiment was carried out with catalyst 4a (0.06 mmol) and
compound 2 (0.24 mmol) stirred in toluene at room temperature for 72 h. 1H
NMR analysis of the crude reaction mixture substantially showed the
resonances of the catalyst and compound
2 and resonances of a side-
product, which might correspond to the N-alkylated catalyst. Catalyst 4a was
recovered after silica gel chromatography in 76% yield. The alkylation of the
secondary amine moiety of catalysts 4 is a negligible process with respect to
Brønsted base activation of compound 2.
Acknowledgements
MIUR and University of Salerno are acknowledged for financial
support.
13. Luo, R.-S.; Weng, J.; Ai, H.-B.; Lu, G.; Chan, A. S. C. Adv. Synth. Catal. 2009, 351,
2449.
14. Representative procedure for the stereoselective synthesis of nitrocyclopropanes: A
References
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dimethyl bromomalonate (28.8
0.060 mmol) in chlorobenzene (400
a
stirring bar was charged with
L, 0.22 mmol) and catalyst 4e (21.2 mg,
L) and stirred at room temperature. The
1 (0.20 mmol),
l
l
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reaction was quenched until almost complete consume of 1 as monitored by
TLC (petroleum ether/diethyl ether 7/3). The reaction mixture was diluted with
DMF (1 mL) and DABCO (22.4 mg, 0.20 mmol) was added at room temperature.
Stirring was maintained overnight, then the reaction mixture was diluted with
EtOAc (30 mL). The organic layer was washed with water (40 mL ꢁ 4), dried
over Na2SO4, and concentrated under vacuum. The residue was purified by
flash column chromatography (petroleum ether/diethyl ether 9/1) to give the
product. Spectroscopic and analytical data of compounds trans-3 matched
those reported in the literature.7,8