Simple diamine- and triamine-protonic acid catalysts for the enantioselective Michael addition of cyclic ketones to nitroalkenes

Article abstract of DOI:10.1021/ja062701n

Simple, chiral, pyrrolidine-based diamine and triamine derivatives that incorporate the secondary-secondary diamine motif are efficient catalysts for the highly diastereoselective and enantioselective Michael addition of cyclic ketones to 2-nitrovinyl are

Full text of DOI:10.1021/ja062701n

Published on Web 07/06/2006
Simple Diamine- and Triamine-Protonic Acid Catalysts for the
Enantioselective Michael Addition of Cyclic Ketones to Nitroalkenes
Sunil V. Pansare* and Keyur Pandya
Department of Chemistry, Memorial UniVersity of Newfoundland, St. John’s, Newfoundland, Canada A1B 3X7
Received April 18, 2006; E-mail: spansare@mun.ca
Scheme 1
Organocatalytic, asymmetric carbon-carbon and carbon-het-
eroatom bond-forming reactions have been extensively investigated
in recent years,1 and the organocatalyzed Michael addition reaction
is a continuing challenge.2 Within this category, the conjugate
addition of ketones to nitroalkenes is particularly interesting and
challenging because it generates two contiguous stereocenters in a
single step. Herein, we describe preliminary results on the highly
enantioselective conjugate addition of cyclic ketones to nitroalkenes
catalyzed at ambient temperature by structurally simple, pyrrolidine-
based amine catalysts in conjunction with a protonic acid.
Recent investigations have examined the catalysis of the ketone-
nitroalkene conjugate addition reaction with derivatives of chiral
diamines,2b,c amino acids,2d and ionic liquids,2e but a significant
Table 1
amount of effort has been devoted to the modification of the proline
motif. Chiral pyrrolidines in which a tertiary aminomethyl,3
tetrazole,4 tetrazolylmethyl,5 pyrrolidinyl,6 carboxymethyl,7 trifluo-
romethylsulfonamido,8 methylpyridyl,9 or 1-((pyrrolidin-2-yl)-
methyl)pyrrolidine10 functionality replaces the carboxyl function
in proline have been investigated. These pyrrolidine catalysts
normally require low temperature and a large excess of ketone for
good enantioselection.11 A catalyst that overcomes these limitations
would be advantageous.
entrya
cat.b
solvent
additiveb
yield
syn/antic
ee (%) synd
1
2
3
4
5
6
7
8
9
2b
2b
2b
2b
2a
2a
2a
2a
2a
2a
2c
toluene
ethanol
DMF
21
51
29
72
40
8
30
90
70
0
4/1
1/1
4/1
7/1
19/1
2/1
3/1
19/1
4/1
47
48
56
DMF
pTsOH
83e
90
We chose to investigate proline-derived triamines as organo-
catalysts for two reasons: (a) the potential for rate enhancement
by the added amine functionality in a pyrrolidine-based diamine
motif and (b) the possibility of employing a conformationally
modified, protonated form of the catalyst. Triamines 2a and 2b12
(Scheme 1) were chosen as candidates and were readily prepared
from Boc-S-proline, as shown in Scheme 1. Diamine 2c was
prepared as an analogue of 2a, lacking the tertiary amine.
Orienting experiments were conducted with cyclohexanone (3)
and the nitrostyrene 4 as the Michael acceptor. Initially, the
conjugate addition reaction was examined in a few solvents with
triamine 2b as the catalyst (Table 1). The reaction was slow and
low yields of the conjugate addition product 5 were obtained after
3 days at ambient temperature (Table 1). Surprisingly, a substantial
change in the nature of the solvent did not have a significant effect
on the enantioselectivity (entries 1 and 2), and the highest
selectivities were obtained in DMF. An improvement in selectivity
was observed when the catalyst 2a was employed in DMF. The
use of an acid6,9 (pTsOH) in conjunction with 2a or 2b had a
dramatic effect on the yield and the diastereoselectivity as well as
the enantioselectivity of this reaction (entries 4 and 8, Table 1).
The enantioselectivity with the 2b/pTsOH combination was lower
(83%) than with the 2a/pTsOH combination (>99%). Use of 2,4-
dinitrobenzenesulfonic acid decreased the enantioselectivity and
trifluoroacetic acid deactivated the catalyst. Selectivity with catalyst
2c was comparable to 2a. Although 2a provided 5 with 90% ee in
toluene without any added acid, the enantioselectivity with 2a/
pTsOH in DMF was >99%. The poor solubility of the 2a/pTsOH
salt in toluene precluded further studies in this solvent. The
toluene
iPrOH
DMF
DMF
DMF
25
73
pTsOH
>99e
83e
f
10
11
DMF
DMF
TFA
pTsOH
86
19/1
>99e
a 1.1 equiv of ketone. b 20 mol %. c 1H NMR of crude products. d Chiral
HPLC analysis. e 5 equiv of ketone. f 2,4-dinitrobenzenesulfonic acid.
observation that 2a and 2c are better catalysts than 2b highlights
the importance of the secondary-secondary diamine motif, which
was examined by Yamamoto in asymmetric aldol reactions.13
However, this class of diamines has been mostly overlooked in
organocatalytic conjugate addition studies and, in one earlier
investigation, generated aminals of the carbonyl substrates.14
The catalysts 2a or 2c in conjunction with pTsOH in DMF were
employed in the conjugate addition of a few cyclic ketones to a
variety of 2-nitrovinyl arenes at ambient temperature. In all cases,
the syn diastereomer was obtained as the major product, and good
diastereoselectivities and enantioselectivities were observed. These
results are summarized in Table 2.
Enantioselectivities for nitroalkenes with substitution at the
4-position in the phenyl ring were very high. Moving the substituent
to the 2-position lowered the enantioselectivity (Table 2, entries 4,
5, 7, 8, 11, and 13). In one case, the use of methanesulfonic acid
instead of pTsOH significantly increased the diastereoselectivity
as well as the enantioselectivity (Table 2, entries 5 and 6).
Interestingly, increasing the size of the acid additive decreased the
9
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J. AM. CHEM. SOC. 2006, 128, 9624-9625
10.1021/ja062701n CCC: $33.50 © 2006 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Enantioselective Conjugate Addition of Cyclic Ketones to
Nitroalkenes Catalyzed by 2a or 2ca
Figure 1. Transition state assemblies for conjugate additions with proto-
nated 2a or 2c.
secondary amine delivers the nitroalkene by hydrogen bonding to
provide the major product in all cases. For ortho-substituted
nitroalkenes, a nonhydrogen-bonded assembly such as B may
compete with A to avoid steric interactions (R′-R′′) with a large
acid counterion. This would reduce the enantioselection. In a
noncoordinating solvent, an internally hydrogen-bonded ethylene-
diamine unit (C) may explain the higher enantioselection with 2a
as compared to 2c.
In conclusion, we have developed simple, protonated triamine
and diamine catalysts for the highly enantioselective conjugate
addition of cyclic, six-membered ketones to nitroalkenes. The main
advantages of these catalysts are the ease of synthesis and very
good enantioselection at ambient temperature. For unhindered
nitroalkenes, the enantioselection with these simple catalysts at
ambient temperature is better than the enantioselection with
structurally more complex pyrrolidine catalysts at subambient
temperatures.9,10 We are investigating the efficacy of these and
related catalysts in other organocatalytic reactions.
Acknowledgment. These investigations were supported by the
Natural Sciences and Engineering Research Council of Canada
(Grant 298911-04).
Supporting Information Available: Experimental methods and
spectroscopic data for all compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
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The stereochemical outcome may be explained by a synclinal
transition state assembly15 A (Figure 1) in which a protonated
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