Enantioselective organocatalytic direct Michael addition of nitroalkanes to nitroalkenes promoted by a unique bifunctional DMAP-thiourea

Article abstract of DOI:10.1021/ja805390k

A new catalyst is designed, synthesized, and evaluated for the asymmetric Michael addition of nitroalkanes to nitroalkenes. The obdurate nature of this reaction has made this a formidable challenge to subdue by asymmetric catalysis. The catalyst design includes a thiourea function to activate the nitroalkene by a double H-bond and a 4-dimethylaminopyridine unit to deprotonate the nitroalkane and to bind the resulting nitronate anion also by a double H-bond. The chiral scaffold for the catalyst is 2,2′-diamino-1,1′-binaphthalene (BINAM), and a bis-conjugate is prepared by the attachment of the thiourea unit and the dimethylaminopyridine moiety (DMAP) via the two amino groups. The resulting catalyst will effect the reaction of nitroalkanes to a variety of nitrostyrenes and gives excellent asymmetric inductions (91-95% ee) over a range of 10 substrates. Remarkably, the asymmetric induction increases with decreasing catalyst loading with the optimal compromise between rate and induction at a loading of 2 mol %. Copyright

Full text of DOI:10.1021/ja805390k

Published on Web 09/23/2008
Enantioselective Organocatalytic Direct Michael Addition of Nitroalkanes to
Nitroalkenes Promoted by a Unique Bifunctional DMAP-Thiourea
Constantinos Rabalakos and William D. Wulff*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
Received July 20, 2008; E-mail: wulff@chemistry.msu.edu
Scheme 1
Conjugate addition to nitroalkenes is a versatile reaction that
benefits from the high reactivity of nitroalkenes.1,2 The Michael
addition of carbonyl compounds to nitroalkenes is valued for its
ability to generate γ-nitro carbonyl compounds of the type 3 which
can serve as precursors to γ-amino carbonyl compounds upon
reduction or 1,4-dicarbonyl compounds via a Nef reaction (Scheme
1). The first report of an asymmetric catalyst for this reaction
appeared in 1996 and involved a chiral base derived from a cinchona
alkaloid.3 Since, the catalytic asymmetric addition of carbonyls to
nitroalkenes has been the subject of intense scrutiny by the chemical
community. Cumulative efforts of work appearing in 112 publica-
tions have led to the identification of several highly tuned and
refined catalysts.2,4
In contrast, only four reports describe efforts to develop chiral
catalysts for the asymmetric catalytic Michael addition of nitroal-
kanes to nitroalkenes.5 One is not a direct Michael addition since
it requires preformed silyl nitronates.5a Two involve organometallic
catalysts which are Ti/Zn5b and La5d based. The fourth involves a
modified cinchona alkaloid as an organocatalyst, but the reactions
are quite sluggish and require 6-12 d to achieve 10 turnovers.5c
This dearth of reports on the Michael addition of nitroalkanes to
nitroalkenes is surprising since 1,3-dinitro compounds of the type
5 would be a convenient source of 1,3-diamines (Scheme 1). One
reason for this may be related to the fact that the nitronate anion 6
is very prone to subsequent addition of nitroalkene leading to
oligiomers of the type 7.6 As a result this reaction has been difficult
to catalyze, and to the best of our knowledge there is only one
example of a reaction that has been effected with a substoichio-
metric amount of a nonchiral catalyst.7 Recently, we have found
that as little as 2 mol% of a simple nonchiral thiourea can accelerate
this reaction while suppressing oligomer formation.8 Herein, we
report on the development of a highly enantioselective version of
this reaction using a novel bifunctional thiourea catalyst that was
rationally designed for this particular transformation.
We focused our investigations on the design of a bifunctional
catalyst that would incorporate both a thiourea moiety and base.
2,2′-Diamino-1,1′-binaphthyl (BINAM) was chosen as the chiral
scaffold whose conjugates with thioureas9 have been relatively
unexplored. Wang and co-workers developed the BINAM bifunc-
tional thiourea 8 (Figure 1) as an asymmetric catalyst for the
Morita-Baylis-Hillman reaction,10 and subsequently this catalyst
has been found useful in the asymmetric Michael addition of 1,3-
dicarbonyls to nitroalkenes.11 The same group has investigated 8
as a catalyst for the Michael addition of nitroalkanes to nitroalkenes
but found it to be a very sluggish catalyst.5c They found that the
reaction of trans-nitrostyrene with 2-nitropropane only gave a 29%
yield after 48 h for a reaction carried out neat with 10 mol% of 8.
We reasoned that catalyst 9 may have an increased efficiency for
this reaction for two reasons. The dimethylamino-pyridine (DMAP)
unit in 9 should be much more basic12 than the dimethylaryl-amine
function in 8 leading to more efficient deprotonation of the nitroalkane,
and once deprotonated, the nitronate anion of the resulting ion pair
should be able to noncovalently interact with the protonated DMAP
via two hydrogen bonds (Figure 1). We envisioned that it may be
possible for a catalyst such as 9 to interact via both components via
double H-bonds, bringing them into close proximity in the chiral pocket
and thereby influencing both the reactivity and selectivity of the
reaction. While chiral catalysts containing the DMAP unit are well-
known for a variety of reactions,13 especially the resolution of alcohols,
there is only one example for a Michael addition reaction. Kotsuki
reported that a DMAP-pyrrolidine hybrid was effective for the
Michael addition of ketones to nitroalkenes.14 In addition to chiral
DMAP catalysts, there are other related 2-aminopyridine catalysts that
have been reported.15 The chiral DMAP-thiourea hybrid (R)-9 can
be readily prepared in two steps from the commercially available 2,2′-
diamino-1,1′-binaphthyl (R)-10 in two steps (Scheme 2).
An initial screen of the bifunctional catalyst (R)-10 for the
Michael addition of nitroalkanes to nitroalkenes was quite encour-
aging. All of the reactions in Table 1 produced only small amounts
of polymer or oligiomers which can be the exclusive product when
substoichiometric amounts of a base is used as catalyst.8,16 Since
catalyst 8 is sluggish for this reaction under neat conditions,5c it
was not surprising to find that it is even more sluggish when a
solvent is used (entry 1). To optimize turnover, the reaction of
1-nitropropane and nitrostyrene was investigated with decreasing
amounts of the catalyst (R)-9, and as expected, the rate of the
reaction decreased with decreasing amounts of the catalyst.
However, the increase in asymmetric induction (and the dr) with
lower catalyst loading was surprising. The optimal catalyst loading
with regard to asymmetric induction is 0.5-2 mol% although the
reactions are too slow under these conditions to be useful. Nonetheless,
at these low catalyst loadings, the reactions are extremely clean by
1H NMR revealing only starting material and product with little or no
evidence of polymer formation.
Further optimization lead to conditions that allowed the use of
only 2 mol% catalyst and which gave high yields and excellent
asymmetric inductions for a variety of substrates (Table 2). For
example the reaction of 1-nitropropane (12a) with nitrostyrene (13)
9
13524 J. AM. CHEM. SOC. 2008, 130, 13524–13525
10.1021/ja805390k CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Michael Addition of Nitroalkanes to Nitroalkenes with
Catalyst (R)-9a
entry
Rb
nitroalkene
Ar
Adduct % yieldc syn:antid % ee syn
1
2
3
4
5
6
7
8
9
Et
13
15
16
16
17
18
19
20
21
22
13
Ph
14a
23
24
24
25
26
27
28
29
30
14c
80
60
55
94e
72
84
75f
75f
69
78
78
84:16
85:15
80:20
80:20
81:19
74:26
83:17
87:13
90:10
74:26
90:10
95
94
94
94
94
92
92
93
94
92
91
Et
Et
Et
Et
Et
Et
Et
Et
4-MeOC6H4
2-MeOC6H4
2-MeOC6H4
4-MeC6H4
2-CIC6H4
4-CIC6H4
4-BrC6H4
3-BrC6H4
2-BrC6H4
Ph
10 Et
11 n-Pr
Figure 1. Design of a new bifunctional thiourea/DAMP catalyst for nitro-
group activation.
a Unless otherwise specified, all reactions were run at 0.2 M in
nitroalkene with 30 equiv of 12 and 2 mol% of catalyst (R)-9 for 40 h.
b 12a R ) Et, 12c R ) n-Pr. c Combined isolated yields of syn and anti
isomers after silica gel chromatography. d Calculated from the weights
of the separated diastereomers except entries 1-4 which were
determined by 1H NMR on the crude reaction mixture. e Reaction time
was 60 h, and the concentration of nitroalkene was 0.33 M. f Reaction
time was 17 h.
Scheme 2
acceleration a formidable challenge. The successful catalyst design
described herein should find applications in other reactions requiring
bifunctional catalysts with both H-bond donors and a Brønsted base.
Table 1. Preliminary Screen with Nitroalkanes and Nitrostyrenea
Acknowledgment. This work was supported by NIH Grant GM
63019.
Supporting Information Available: Synthetic procedures and
spectral data for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
entry Rb catalyst cat (mol%) solvent % yieldc syn:anti % ee syn % ee anti
1
2
3
4
5
6
7
8
9
Et
Et
Et
Et
Et
Et
Et
Et
Et
8
9
9
9
9
9
9
9
9
9
9
20
20
100
20
10
5
CH2Cl2
0
-
59:41
39:61
60:40
71:29
76:24
82:18
-
78
70
82
84
90
94
94
95
62
81
-
nd
63
70
60
70
nd
nd
nd
60
79
CH2Cl2 90
benzene 60
benzene 80
benzene 40
benzene 70
benzene 43
References
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2
1
benzene <30 87:13
0.5 benzene 18d
86:14
57:43
55:45
10 Me
11 n-Pr
10
20
benzene 100
benzene 96
a Unless otherwise specified, all reactions were run at 0.1 M in 13
with 10 equiv of 12 and with either (R)-8 or (R)-9 as catalyst at 25 °C
for 12-15 h. nd
) not determined. Entries 5-9 did not go to
completion. b 12a R ) Et, 12b R ) Me, 12c R ) n-Pr. c Determined by
1H NMR with triphenylmethane as internal standard. d Reaction time
was 40 h.
(10) Wang, J.; Li, H.; Yu, X.; Zu, L.; Wang, W. Org. Lett. 2005, 7, 4293.
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is 9.2 (H2O).
went to completion when the concentration was increased to 0.2
M, the amount of excess nitroalkane was increased to 30 equiv,
and the reaction time extended to 40 h (entry 1, Table 2 vs entry
7, Table 1). With these conditions, excellent enantioselectivities
were observed over a range of electron-rich and -poor nitrostyrenes
including those that are ortho-substituted.17
In summary, a new catalyst has been developed that will effect
the Michael addition of nitroalkanes to nitroalkenes with excellent
asymmetric inductions (91-95% ee). Remarkably, the asymmetric
induction increases with decreasing catalyst loading with the optimal
compromise between rate and induction at a loading of 2 mol%.
The obdurate nature of this reaction has made attempts at its
(13) Wurz, R. P. Chem. ReV. 2007, 107, 5570.
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(17) One attempt with a ꢀ-alkyl substituted nitroalkene gave a much less selective
outcome. Reaction of 1-nitro-1-pentene under the conditions in entry 1 of
Table 2 (24 h) gave the Michael adduct in 66% yield with a dr of 58:42
and 42% ee for the major diastereomer.
JA805390K
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J. AM. CHEM. SOC. VOL. 130, NO. 41, 2008 13525