since reported a range of bases and nucleophiles to effect
the elimination and subsequent addition.10 A variety of
indolenine precursors have also been reported to be
generated using both acidic11 and basic12 reaction condi-
tions. Though a broad scope of additions has already been
demonstrated (Grignard, nitroalkane, malonate, malono-
nitriles), there have been very few asymmetric variations
reported.13-16 More recently, a Brønsted-base catalyzed
asymmetric addition of malononitrile using a cinchona based
thiourea catalyst was reported with high selectivity.17 This
has prompted us to report our findings on the catalytic,
enantioselective Michael addition of arylnitromethanes to
indolenine intermediates. In the context of BAM (Bis(AMi-
dine)) catalysis,18 this is the first report of their use as chiral
Brønsted bases.19
To gauge the reactivity of nitroalkanes with sulfone 5a using
a BAM catalyst, the Petrini protocol was utilized for direct
comparison. In this experiment using dichloromethane, conver-
sion to the desired nitroalkane alkylation product (6a) was
observed, but with low enantioselectivity (20% ee, Table 1,
(3) Isolation and biological activity: Cui, C.-B.; Kakeya, H.; Osada, H.
Tetrahedron 1996, 52, 12651–12666. Kondoh, M.; Usui, T.; Mayumi, T.;
Osada, H. J. Antibiot. 1998, 51, 801–804. Syntheses of 3: Edmondson, S. D.;
Danishefsky, S. J. Angew. Chem., Int. Ed. 1998, 37, 1138–1140. Edmondson,
S.; Danishefsky, S. J.; Sepp-Lorenzino, L.; Rosen, N. J. Am. Chem. Soc.
1999, 121, 2147–2155. Overman, L. E.; Rosen, M. D. Angew. Chem., Int.
Ed. 2000, 39, 4596–4599. Sebahar, P. R.; Williams, R. M. J. Am. Chem.
Soc. 2000, 122, 5666–5667. Von, N. F.; Danishefsky, S. J. Angew. Chem.,
Int. Ed. 2000, 39, 2175–2178. Bagul, T. D.; Lakshmaiah, G.; Kawabata,
T.; Fuji, K. Org. Lett. 2002, 4, 249–251. Meyers, C.; Carreira, E. M. Angew.
Chem., Int. Ed. 2003, 42, 694–696. Miyake, F. Y.; Yakushijin, K.; Horne,
D. A. Org. Lett. 2004, 6, 4249–4251. Marti, C.; Carreira, E. M. J. Am.
Chem. Soc. 2005, 127, 11505–11515. Wang, S.; Ding, K.; Lu, Y.;
Nikolovska-Coleska, Z.; Qiu, S.; Wang, G.; Qin, D.; Shangary, S.
Preparation of spirotryprostatin A derivatives as inhibitors of MDM2. WO/
2006/091646, August 8, 2006. Trost, B. M.; Stiles, D. T. Org. Lett. 2007,
9, 2763–2766.
Table 1. Optimization of Enantioselective Additions to
Sulfonylmethyl Indolesa
(4) For a recent review: Bandini, M.; Eichholzer, A. Angew. Chem.,
Int. Ed. 2009, 48, 9608–9644.
(5) For recent reviews see: Jørgensen, K. A. Synthesis 2003, 1117–1125.
Bandini, M.; Melloni, A.; Umani-Ronchi, A. Angew. Chem., Int. Ed. 2004,
43, 550–556.
entry
catalyst
base
temp (°C)
M
ee (%)b
(6) Bandini, M.; Garelli, A.; Rovinetti, M.; Tommasi, S.; Umani-Ronchi,
A. Chirality 2005, 17, 522–529. Herrera, R. P.; Sgarzani, V.; Bernardi, L.;
Ricci, A. Angew. Chem., Int. Ed. 2005, 44, 6576–6579. Zhuang, W.; Hazell,
R. G.; Jørgensen, K. A. Org. Biomol. Chem. 2005, 3, 2566–2571. Jia, Y.-
X.; Zhu, S.-F.; Yang, Y.; Zhou, Q.-L. J. Org. Chem. 2006, 71, 75–80. Lu,
S.-F.; Du, D.-M.; Xu, J. Org. Lett. 2006, 8, 2115–2118. Ganesh, M.; Seidel,
D. J. Am. Chem. Soc. 2008, 130, 16464–16465. Itoh, J.; Fuchibe, K.;
Akiyama, T. Angew. Chem., Int. Ed. 2008, 47, 4016–4018. Liu, H.; Lu,
S.-F.; Xu, J.; Du, D.-M. Chem. sAsian J. 2008, 3, 1111–1121. Yuan, Z.-
L.; Lei, Z.-Y.; Shi, M. Tetrahedron: Asymmetry 2008, 19, 1339–1346.
McKeon, S. C.; Mueller-Bunz, H.; Guiry, P. J. Eur. J. Org. Chem. 2009,
4833–4841. Yokoyama, N.; Arai, T. Chem. Commun. 2009, 3285–3287.
Wang, X.-F.; Chen, J.-R.; Cao, Y.-J.; Cheng, H.-G.; Xiao, W.-J. Org. Lett.
2010, 12, 1140–1143.
1c
2
3
4
5
6
7
8
4c
4c
4c
4c
4c
4c
4c
4a
4b
4c
4c
KF/Alumina
KF/Alumina
KF/Alumina
KF/Alumina
KF
Na2CO3
K2CO3
K2CO3
rt
rt
-20
-78
rt
rt
rt
rt
rt
0.2
0.2
0.2
0.2
0.1
0.1
0.2
0.2
0.2
0.1
0.1
20
60
57
49
68
61
70
56
73
78
81
9d
10
11d
K2CO3
K2CO3
K2CO3
rt
rt
(7) Additions of indole to R,ꢀ-disubstituted nitrostyrenes: Bandini, M.;
Melchiorre, P.; Melloni, A.; Umani-Ronchi, A. Synthesis 2002, 1110–1114.
Ballini, R.; Clemente, R. R.; Palmieri, A.; Petrini, M. AdV. Synth. Catal.
2006, 348, 191–196. Kusurkar, R.; Alkobati, N.; Gokule, A.; Chaudhari,
P.; Waghchaure, P. Synth. Commun. 2006, 36, 1075–1081. Kantam, M. L.;
Laha, S.; Yadav, J.; Srinivas, P. Synth. Commun. 2009, 39, 4100–4108.
Ye, M.-C.; Yang, Y.-Y.; Tang, Y.; Sun, X.-L.; Ma, Z.; Qin, W.-M. Synlett
2006, 1240–1244. Habib, P. M.; Kavala, V.; Raju, B. R.; Kuo, C.-W.;
Huang, W.-C.; Yao, C.-F. Eur. J. Org. Chem. 2009, 4503–4514. An elegant
asymmetric, tandem FC/Henry reaction: Arai, T.; Yokoyama, N. Angew.
Chem., Int. Ed. 2008, 47, 4989–4992.
a All reactions were performed using 2 equivalents of phenylni-
tromethane on a 0.1 mmol scale and resulted in less than 1.5:1 dr material
and between 30-80% yield. Absolute stereochemistry assigned by cor-
relation. See Supporting Information for details. b Enantiomeric ratios were
measured using chiral stationary phase HPLC and are reported for the major
diastereomer. c Dichloromethane was used instead of toluene. d One equiv-
alent of phenylnitromethane was used.
(8) Enantioselective additions have been reported using nitroalkenes
bearing an additional activating group (-CO2R): Sui, Y.; Liu, L.; Zhao, J.-
L.; Wang, D.; Chen, Y.-J. Tetrahedron 2007, 63, 5173–5183.
(9) Ballini, R.; Palmieri, A.; Petrini, M.; Torregiani, E. Org. Lett. 2006,
8, 4093–4096.
entry 1). Use of toluene improved selectivity to 60% ee (Table
1, entry 2). Attempts to improve enantioselection by lowering
the temperature provided lower conversion and enantioselection
(Table 1, entries 3-4), likely due to the heterogeneity of the
reaction mixture and the sluggish elimination step. There was
no change in diastereoselection throughout the reaction opti-
mization process.20 Considering the possibility that the sto-
(10) For a review: Palmieri, A.; Petrini, M.; Shaikh, R. R. Org. Biomol.
Chem. 2010, 8, 1259–1270. For other works Palmieri, A.; Petrini, M. J.
Org. Chem. 2007, 72, 1863–1866. Ballini, R.; Palmieri, A.; Petrini, M.;
Shaikh, R. AdV. Synth. Catal. 2008, 350, 129–134. Palmieri, A.; Petrini,
M.; Shaikh, R. R. Synlett 2008, 2008, 1845–1851. Ballini, R.; Gabrielli,
S.; Palmieri, A.; Petrini, M. AdV. Synth. Catal. 2010, 352, 2459–2462.
Marsili, L.; Palmieri, A.; Petrini, M. Org. Biomol. Chem. 2010, 8, 706–
712.
(11) Cozzi, P.; Benfatti, F.; Zoli, L. Angew. Chem., Int. Ed. 2009, 48,
1313–1316. Campetella, S.; Palmieri, A.; Petrini, M. Eur. J. Org. Chem.
2009, 2009, 3184–3188. Boas, U.; Brask, J.; Jensen, K. J. Chem. ReV. 2009,
109, 2092–2118.
(13) Proline catalyzed (enamine) additions: Shaikh, R.; Mazzanti, A.;
Petrini, M.; Bartoli, G.; Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47,
8707–8710.
(14) Preliminary results using NHC: Li, Y.; Shi, F. Q.; He, Q. L.; You,
S. L. Org. Lett. 2009, 11, 3182–3185.
(12) Semenov, B. B.; Granik, V. G. Pharm. Chem. J. 2004, 38, 287–
310. Semenov, B.; Smushkevich, Y.; Levina, I.; Kurkovskaya, L.; Lysenko,
K.; Kachala, V. Chem. Heterocycl. Compd. 2005, 41, 730–738. Matsuo,
J.-I.; Tanaki, Y.; Ishibashi, H. Tetrahedron 2008, 64, 5262–5267.
(15) Enantioselective addition of N-Bz enamines to indolyl alcohols
using a chiral phosphoric acid: Guo, Q.-X.; Peng, Y.-G.; Zhang, J.-W.;
Song, L.; Feng, Z.; Gong, L.-Z. Org. Lett. 2009, 11, 4620–4623.
Org. Lett., Vol. 12, No. 24, 2010
5745