Intermolecular cross-double-Michael addition between nitro and carbonyl activated olefins as a new approach in C-C bond formation

Article abstract of DOI:10.1021/ol702059x

(Chemical Equation Presented) A novel intermolecular cross-double-Michael addition between nitro and carbonyl activated olefins has been developed through Lewis base catalysis. The reaction took place with a large group of β-alkyl nitroalkenes and α,β-uns

Full text of DOI:10.1021/ol702059x

ORGANIC
LETTERS
2007
Vol. 9, No. 22
4495-4498
Intermolecular Cross-Double-Michael
Addition between Nitro and Carbonyl
Activated Olefins as a New Approach in
C−C Bond Formation
Xiaohua Sun,† Sujata Sengupta,† Jeffrey L. Petersen,† Hong Wang,‡
James P. Lewis,‡ and Xiaodong Shi*,†
C. Eugene Bennett Department of Chemistry and Department of Physics,
West Virginia UniVersity, Morgantown, West Virginia 26506
xiaodong.shi@mail.wVu.edu
Received August 21, 2007
ABSTRACT
A novel intermolecular cross-double-Michael addition between nitro and carbonyl activated olefins has been developed through Lewis base
catalysis. The reaction took place with a large group of
compound in good to excellent yields.
â-alkyl nitroalkenes and r,â-unsaturated ketone/esters, producing an allylic nitro
Efficient C-C bond formation and implementation of diverse
functionality are two crucial aspects in organic synthesis.1
In the last two decades, tandem (or cascade or sequential)
reactions of designated precursors brought great attention to
the construction of complicated organic molecules.2 Signifi-
cant progress has been made using this strategy in the total
synthesis of natural products and biological activated mol-
ecules.3 Meanwhile, intermolecular sequential reactions
across different reactants have been developed into many
powerful methodologies, including the Mannich reaction,4
the Baylis-Hillman reaction,5 and the Robinson annulations,6
etc. The fact that tandem reactions of different substrates
can rapidly combine organic functionalities within “one step”
provides undeniable benefits as a simple, efficient, and atom-
economical approach in organic synthesis.
Our interests in developing new organic reactions with
the capability of rapid functional group construction origi-
nated from the Lewis base (LB) mediated Baylis-Hillman
reaction (reaction A). As shown in reaction B, the successful
intermolecular cross-double-Michael addition will lead to
very attractive products in one step and provide a highly
efficient novel methodology in complex molecule synthesis.
† C. Eugene Bennett Department of Chemistry.
‡ Department of Physics.
(1) (a) Corey, E. J. Angew. Chem., Int. Ed. 1991, 30, 455-465. (b)
Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed.
2001, 40, 4544-4568. (c) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem.
ReV. 2001, 101, 2067-2096. (d) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D.
Angew. Chem., Int. Ed. 2005, 44, 4442-4489.
(2) (a) Nicolaou, K. C.; Montagnon, T.; Snyder, S. A. Chem. Commun.
2003, 551-564. (b) Nicolaou, K. C.; Edmonds, D. J.; Bulger, P. G. Angew.
Chem., Int. Ed. 2006, 45, 7134-7186.
(3) (a) Zu, L. S.; Wang, J.; Li, H.; Xie, H. X.; Jiang, W.; Wang, W. J.
Am. Chem. Soc. 2007, 129, 1036-1037. (b) Nicolaou, K. C.; Lim, Y. H.;
Piper, J. L.; Papageorgiou, C. D. J. Am. Chem. Soc. 2007, 129, 4001-
4013. (c) Baran, P. S.; Maimone, T. J.; Richter, J. M. Nature 2007, 446,
404-408.
According to the literature, the only successful example
using this strategy is the homodimerization of enones by
10.1021/ol702059x CCC: $37.00
© 2007 American Chemical Society
Published on Web 10/02/2007

action of an organophosphine, which is referred to as the
Rauhut-Currier reaction.7 Although this reaction was first
discovered in 1963, no related reactions have been reported
until very recently, when the Krische group,8 the Miller
group,9 and the Wang group10 developed effective intra-
molecular asymmetric cyclization of R,â-unsaturated ketones.
In addition, the Kwon group successfully applied organo-
phosphine catalysts to promote both intermolecular and
intramolecular allene-alkene coupling.11 These remarkable
works re-emphasize the advantages of this reaction as a very
attractive approach in C-C bond construction. However, to
date, there is still a lack of effective methodology for efficient
intermolecular cross-coupling of different activated olefins,
especially non-ketone/aldehyde Michael receptors, which
essentially will provide more functionality in the final
products.12 In this paper, we report the first successful
intermolecular double-Michael addition between nitro and
carbonyl activated olefins through LB-catalyzed cascade
reactions.
The biggest challenge for the cross-double-Michael ad-
dition is the control of sequential addition across the two
Michael receptors. Assuming that the EWG1 activated alkene
is more reactive than the EWG2 activated alkene, the
nucleophilic addition of the LB catalyst will first attack the
EWG1 olefin, forming the carbanion intermediate. However,
the carbanion intermediate will most likely react with the
EWG1 activated olefin (homoaddition) rather than the EWG2
activated olefins (desired heteroaddition). This fundamental
challenge was associated with all of these types of reactions
and directly resulted in no observation of successful hetero-
double-Michael addition in the literature, although this
methodology is extremely interesting for synthetic organic
chemists.
erization of nitroalkene dominated, and only a trace amount
of the desired product was obtained, except when both
proline and NaN3 were used as the catalysts, which produced
32% of the desired product as a single E isomer (determined
by NOE) (Scheme 1). No product was isolated if only proline
or only NaN3 was used as the catalyst.
Scheme 1
Monitoring this reaction in d6-DMSO by NMR revealed
that almost all the â-nitrostyrene was consumed in 1 h, and
formation of product 3 was not observed until 2 h later, when
most of 1a had already been consumed (Supporting Informa-
tion). These results strongly implied that the addition of
nitrocarbanion 4 to â-nitrostyrene (which leads to the
polymerization) is in equilibrium, and intermediate nitro-
alkene oligomers can dissociate and reproduce the nitro-
carbanion 4, leading to the addition of a less reactive enone
Michael receptor. Therefore, the key for successful inter-
molecular hetero-double-Michael addition is to avoid the
polymerization and “quench” the equilibrium by a kinetically
irreversible step. Thus, the R-methyl-â-nitrostyrene 1b was
employed to react with enone 2a. The purpose for using 1b
is to: (a) slow the nitroalkene polymerization and (b)
introduce an irreversible step by the alkyl group â-elimina-
tion. As expected, the allylic nitro product 5a was formed
in good yields. The results of reaction condition screening
are shown in Table 1.
Among all of the tested Lewis bases, the secondary amines
were the only effective catalysts that promoted this reaction
(entries 1, 4, and 5). The non-nucleophilic amine (DIPEA,
entry 7) and primary amine (glycine, entry 6) did not promote
this reaction, while the nucleophilic tertiary amine (DABCO,
entry 3) promoted the reaction with slow kinetics and poor
yield. The inorganic base (NaOt-Bu, entry 8) gave significant
polymerization of 1b with no desired product obtained.
Meanwhile, other nucleophilic bases (entry 9), including
DMAP, imidazole, NMI, PPh3, and P(OMe)3, all proved as
noneffective catalysts for this reaction. Combination of
proline (0.2 equiv) and other Lewis bases revealed modified
reaction conditions (entries 10-14), and NaN3 was selected
as the best adduct. Finally, the solvent screening gave DMSO
as the most effective solvent. With the best reaction
conditions, various nitroalkenes and R,â-unsaturated ketones
and esters were applied to investigate the reaction substrate
scope, and the results are summarized in Table 2.
To investigate this reaction, we first studied the reaction
between the nitro and carbonyl activated olefins. It is well-
known that the nitroalkenes are more reactive Michael
receptors than enones, which makes the sequential addition
across the two alkenes possible. The â-nitrostyrene was then
used to react with various carbonyl-activated alkenes, includ-
ing cyclohexenone, methyl acrylate, and methyl vinyl ketone.
Meanwhile, various Lewis bases were applied to promote
this reaction, including DMAP, PPh3, DABCO, imidazole,
and NMI. However, among all the tested conditions, polym-
(4) (a) Hijicek, I. Chem. Listy 2005, 99, 298-317. (b) Hajicka, J. Chem.
Listy 2005, 99, 317-317.
(5) (a) Methot, J. L.; Roush, W. R. AdV. Synth. Catal. 2004, 346, 1035-
1050. (b) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003,
103, 811-891.
(6) Jansen, B. J. M.; Hendrikx, C. C. J.; Masalov, N.; Stork, G. A.;
Meulemans, T. M.; Macaev, F. Z.; de Groot, A. Tetrahedron 2000, 56,
2075-2094.
(7) Rauhut, M. M.; Currier, H. U.S. 3074999, Jan. 22, 1963.
(8) Wang, L. C.; Luis, A. L.; Agaplou, K.; Jang, H. Y.; Krische, M. J.
J. Am. Chem. Soc. 2002, 124, 2402-2403.
(9) Aroyan, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 256-257.
(10) (a) Zu, L.; Li, H.; Xie, H.; Wang, J.; Jiang, W.; Tang, Y.; Wang,
W. Angew. Chem., Int. Ed. 2007, 46, 3732-3734. (b) Li, H.; Zu, L.; Xie,
H.; Wang, J.; Jiang, W.; Wang, W. Org. Lett. 2007, 9, 1833-1835.
(11) (a) Zhu, X. F.; Schaffner, A. P.; Li, R. C.; Kwon, O. Org. Lett.
2005, 7, 2977-2980. (b) Zhu, X. F.; Henry, C. E.; Wang, J.; Dudding, T.;
Kwon, O. Org. Lett. 2005, 7, 1387-1390. (c) Zhu, X. F.; Lan, J.; Kwon,
O. J. Am. Chem. Soc. 2003, 125, 4716-4717.
As shown in Table 2, various nitroalkenes and R,â-
unsaturated ketones/esters are all suitable for this transforma-
tion. Good to excellent yields were obtained in most cases,
(12) Enders, D.; Huttl, M. R. M.; Grondal, C.; Raabe, G. Nature 2006,
441, 861-863.
4496
Org. Lett., Vol. 9, No. 22, 2007

Table 1. Screening of the Reaction Conditionsa
Table 2. Reaction Substrate Scopea-c
Lewis base
(equiv)
co-cat
time convn yield
solvent
(1.0 equiv) (h)b
(%)c
93
55
(%)d
1
2
3
4
5
6
7
8
9
DMSO L-Pro (0.2)
DMSO NaN3 (1.0)
-
-
4
9
80
6
DMSO DABCO (1.0)
DMSO pyrrolidine (0.2)
DMSO pyrrolidine (0.2)
DMSO glycine (1.0)
DMSO DIPEA (1.0)
DMSO NaOt-Bu (1.0)
DMSO other basese
-
-
AcOH
-
-
12 50
20
60
81
4
4
72
100
20 trace trace
20 trace trace
-
-
4
100
trace
20 trace trace
10 DMSO L-Pro (0.2)
11 DMSO L-Pro (0.2)
12 DMSO L-Pro (0.2)
13 DMSO L-Pro (0.2)
14 DMSO L-Pro (0.2)
DIPEA
DMAP
PPh3
NaN3
DABCO
NaN3
NaN3
NaN3
NaN3
NaN3
4
4
4
3
4
100
100
100
100
100
76
86
83
90
21
15 THF
16 H2O
L-Pro (0.2)
L-Pro (0.2)
20 trace trace
20 trace trace
5
20 40
5
17 MeOH L-Pro (0.2)
18 MeNO2 L-Pro (0.2)
19 acetone L-Pro (0.2)
95
72
31
8
9
a Reactions were carried out at room temperature, 1b/2a ) 1:2.
b Reaction time was determined by TLC. c Conversion based on the
consumption of the starting material 1b from NMR. d 5a as a mixture of
syn/anti diastereomers (dr ) 1:1), and the NMR yield was determined by
1,3,5-trimethoxybenzene as the internal standard. e Other bases tested
include 1.0 equiv of DMAP, imidazole, NMI, PPh3, and P(OMe)3.
a Same conditions as in Table 1. b Isolated yield. c The relative
stereochemistry of 5d was determined by X-ray crystallography.
including kinetically hindered cyclopentene 5c and â-disub-
stituted enone 5p. Similar reactivities between enone and
ester were observed (5e and 5f), which clearly indicated that
the formation of iminium between enone and proline was
unnecessary for the reaction. This result is consistent with
the fact that low enantioselectivity (<5% ee) was observed
in all tested cases. Similar to other nitro chemistry, low
diastereoselectivity was obtained due to the acidic proton
on the nitro carbon (e.g., 5a and 5l) or the similar stereo
effect by alkyl and nitro groups (e.g., 5g and 5m). However,
the low dr could be a small problem since the two
diastereomers can be either separated or converted into the
same product through readily available nitro chemistry. Three
examples are shown in Scheme 2 to convert the allylic nitro
compounds into amine (lactam), allylic alcohol, and enone
with good yields.
(Hu¨nig's base, entry 7) and the primary amine (entry 6) did
not catalyze this reaction and revealed the importance of the
catalyst nucleophilicity for effective promotion of the reac-
tion. Meanwhile, the addition of acid to pyrrolidine acceler-
ated the reaction (entry 5), providing additional evidence that
Scheme 2
Considering the fact that proline itself can promote this
reaction without NaN3 (Table 1, entry 1), the secondary
amine most likely serves as the LB catalyst while NaN3 helps
by tuning the reaction acidity for optimal performance. One
key mechanistic question is whether this reaction underwent
nucleophilic addition to nitroalkene followed by the second
Michael addition or just through γ-carbon deprotonation.
As indicated in Table 1, the secondary amines were the
only effective catalysts. Both the non-nucleophilic amine
Org. Lett., Vol. 9, No. 22, 2007
4497

disfavors the carbanion path. To further investigate the
mechanism, compound 1i was synthesized and applied into
the reaction with 2a as a comparison with the reaction
between 1b and 2a. As shown in Scheme 3, a clear kinetic
Scheme 4. Computational Studies Revealed the Unfavored
Equilibrium for the Carbanion Second Michael Addition
Scheme 3. Possible Reaction Mechanism
In conclusion, by introducing the â-alkyl group in the
nitroalkene, we developed the first successful intermolecular
double-Michael addition. Many different nitro- and carbonyl-
activated olefins were suitable for this reaction. The products
are synthetically attractive and can be readily converted into
many other complex building blocks. Although the reaction
mechanism remains to be further elucidated, this reaction
provides a new approach for C-C bond formation under
mild, efficient, and atom-economic reaction conditions.
Asymmetric synthesis and conversion of the final product
into other attractive building blocks are under investigation.
Acknowledgment. We thank the C. Eugene Bennett
Department of Chemistry, the Eberly College of Arts and
Science, and the WV Nano Initiative at West Virginia
University for the financial support.
difference was observed between 1b and 1i. These experi-
mental results strongly suggested the LB nucleophilic mech-
anism as proposed. This hypothesis was further supported
by computational studies. An energetically unfavored equi-
librium between allylic nitro carbanion and enone was
observed (Scheme 4), which may explain why the simple
deprotonation of the γ-carbon could not lead to the desired
product.
Supporting Information Available: Experimental and
computational details, spectrographic data, and XRD infor-
mation. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL702059X
4498
Org. Lett., Vol. 9, No. 22, 2007