Cyclohexane-1,2-diamines: Efficient catalysts for the enantioselective conjugate addition of ketones to Nitro Olefins

Article abstract of DOI:10.1002/ejoc.200801263

Simple monosulfonated cyclohexane-1,2-diamines are highly enantioselective organocatalysts for the conjugate addition of ketones to nitro olefins. By focusing on aromatic ketones as the most challenging substrates, selectivities of up to 98 % ee can be ac

Full text of DOI:10.1002/ejoc.200801263

SHORT COMMUNICATION
DOI: 10.1002/ejoc.200801263
Cyclohexane-1,2-diamines: Efficient Catalysts for the Enantioselective
Conjugate Addition of Ketones to Nitro Olefins
Ramesh Rasappan[a] and Oliver Reiser*[a]
Keywords: Organocatalysis / Enantioselectivity / Conjugate addition / Amines
Simple monosulfonated cyclohexane-1,2-diamines are highly
enantioselective organocatalysts for the conjugate addition
of ketones to nitro olefins. By focusing on aromatic ketones
as the most challenging substrates, selectivities of up to 98%
ee can be achieved for the title reaction. Moreover, a three-
component process between the primary amine catalyst, the
nitroalkene, and the ketone, which results in the irreversible
formation of pyrrols has been recognized as a reaction path-
way for catalyst deactivation.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Very recently, the simple diamine 3 was reported in an
elegant study to be effective in catalyzing the addition of
acyclic methyl ketones to nitroalkenes in up to 87% ee,[13]
which prompted us to disclose our own study. Focusing es-
pecially on aromatic methyl ketones as the more challenging
substrates, we wish to disclose 4d[14] as an effective catalyst
that gives rise to selectivities of up to 98% ee for the title
transformation and to provide some insight into the mecha-
nism by identifying a reaction pathway that causes catalyst
deactivation.
Introduction
Conjugate addition reactions of aldehydes and ketones
to nitro olefins promoted by organocatalysts have been ex-
tensively studied.[1,2] While secondary amines such as pro-
line give good results with aldehydes and cyclic ketones as
substrates, acyclic ketones have proved to be more difficult
substrates.[3–7] For the latter, thiourea catalysts, flanked on
both sides with chiral directing groups and bearing, in ad-
dition, a primary amino group[8–10] such as 1[8] and 2,[9]
have been successfully developed (Figure 1). In general, pri-
mary amines are increasingly recognized as powerful organo-
catalysts.[11,12]
Results and Discussion
We began our study by screening catalyst 4a for the ad-
dition of acetone (7a) to β-nitrostyrene (6a) in different sol-
vents (Table 1) and suggest that toluene is the most suitable
with respect to yields and selectivity to give rise to 8a (80%
yield, 73% ee, Entry 8). The use of additives, which proved
to be successful with other catalysts for this transforma-
tion,[9,15–22] did not lead to further improvement (Entries 9
and 10). Under solvent-free conditions, equimolar amounts
of benzoic acid seem to be beneficial in terms of enantio-
selectivity (Entries 5 and 6); however, the results that were
achieved under the latter conditions were inferior with re-
spect to yield.
By varying the aromatic group of the sulfonamide in 4,
the isopropyl-substituted derivative 4d was found to signifi-
cantly improve the enantioselectivity of 8a to 87% ee, and
by using 20 mol-% of this catalyst, quantitative conversion
was achieved (Table 2, Entry 4). Further attempts to opti-
mize the results by screening additives for this catalyst,
however, were again unsuccessful. While acceleration of the
rate of reaction occurs in the presence of protic additives,
an undesirable decrease in enantioselectivity was observed
(Entries 5–12).
Figure 1. Organocatalysts for the conjugate addition of carbonyl
compounds to nitroalkenes.
[a] Institut für Organische Chemie, Universität Regensburg,
Universitätsstr. 31, 93053 Regensburg, Germany
Fax: +49-941-943-4121
E-mail: Oliver.Reiser@chemie.uni-regensburg.de
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2009, 1305–1308
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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R. Rasappan, O. Reiser
SHORT COMMUNICATION
Table 1. Conjugate addition of acetone to β-nitrostyrene with 4a.
Table 3. Conjugate addition of aromatic ketones to β-nitrostyrenes
with 4d.
Entry Loading(4a) [mol-%] Solvent
Additive[a]
Yield [%] ee [%][b]
1
2
3
4
5
6
7
8
9
10
10
10
10
10
15
15
15
15
15
15
EtOH
CH2Cl2
hexane
THF
neat
neat
–
–
–
–
29
51
0
43
82
68
26
62
–
33
32
71
58
73
62
61
–
PhCOOH
H2O, AcOH 84
–
PhCOOH
H2O, AcOH 58
neat
toluene
toluene
toluene
80
44
[a] Equimolar amounts with respect to catalyst 4a were employed.
[b] Determined by HPLC (Chiralpak AS-H); the configuration of
8a was assigned by comparing optical rotation data and HPLC
retention times with literature data.[8–10]
Table 2. Screening of catalysts 4.
Entry Catalyst Time [h]
Additive (mol-%) Yield [%][a] ee [%][b]
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4d
4d
4d
4d
4d
4d
4d
4d
62
62
44
62
10
60
70
60
70
48
48
70
–
–
–
–
96
88
86
98
92
35
79
57
84
97
99
62
73
74
70
87
64
82
85
74
58
82
76
75
PhCOOH (10)
PhCOOH (20)
AcOH (10)
AcOH (20)
4 Å MS
MgSO4
H2O (1000)
H2O (20)
9
10
11
12
[a] Isolated yield. [b] The ee values were determined by HPLC (Chi-
ralpak AS-H).
Turning to the more challenging aromatic ketones, we
were pleased to note that with catalyst 4d enantioselectivi-
ties of up to 98% ee were achieved; however, as expected
these substrates turned out to be less reactive (Table 3).
Raising of the reaction temperature to 35 °C was found to
give improved yield, whilst retaining the high selectivities
observed at 20 °C, but even higher temperatures were not
tolerated well (Entries 1–4). Under the optimized condi-
tions, 8b–8k were obtained in 94–98% ee with acceptable
yields (Entries 2, 5–13). Besides β-nitrostyrene (6a), the p-
bromophenyl and the 2-furyl analogs 6b and 6c, respec-
tively, could be employed as nitroalkenes, while the more
electron-rich p-methoxyphenyl derivative 6d proved to be
[a] Isolated yield. [b] Determined by HPLC (Chiralpak AS-H). [c]
20 °C. [d] 50 °C. [e] 70 °C.
The modest turn over cycles and frequencies achieved,
not reactive enough to undergo the conjugate addition reac- which is a general phenomenon with primary amine organo-
tion (Entries 12–14).
catalysts,[3–7] prompted us to investigate the fate of catalyst
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Eur. J. Org. Chem. 2009, 1305–1308

Cyclohexane-1,2-diamines as Efficient Catalysts
4d in the title reaction. Indeed, we were able to identify Table 4. Catalyst deactivation by formation of pyrrole 9a.
the irreversible formation of pyrroles in a three-component
reaction between the catalyst, the nitroalkene, and the aro-
matic ketone as a novel pathway for the catalyst deactiva-
tion (Scheme 1).[23] For example, reaction of 6b and 7b in
the presence of 4d (20 mol-%) gave rise to 9b in 30% yield
based on the amount of catalyst employed. We propose the
formation of intermediate 11 formed by addition of in situ
Entry Additive (mol-%)
Yield 9 [%][a] Yield 8b [%] ee [%][b]
formed enamine 10 to the nitroalkene, which can either un-
dergo hydrolysis to the desired product 8 or can alterna-
tively undergo ring closure with formal elimination of
HNO2 and oxidation to form pyrrole 9.
1
2
3
–
30
27
30
0
72
58
45
0
96
96
95
–
PhCOOH
AcOH
4
TFA
5
6
7
8
HCOOH
PTSA
2-ClC6H4COOH
MeOH
0
0
30
26
24
0
6
18
20
0
–
10
57
64
58
56
53
62
61
92
93
96
95
93
93
93
92
9
NH4Cl
10
11
12
13
TBBP (20)
TBBP (15)
TBBP (10)
TBBP (5)
[a] Based on 4d. [b] Determined by HPLC (Chiralpak AS-H).
Conclusions
In conclusion, we have shown that a simple primary
amine catalyst can afford excellent enantioselectivity in the
conjugate addition of aromatic ketones and nitroalkenes.
For the first time, the formation of a pyrrole side product
as a mode for catalyst deactivation was observed. Further
studies focusing on the development and exploration of di-
amines as organocatalysts are currently under way.
Experimental Section
Supporting Information (see footnote on the first page of this arti-
cle): Full experimental procedures and characterization data for
compounds 4, 5, 8 and 9.
Scheme 1. Catalyst deactivation by irreversible formation of pyr-
rols.
Acknowledgments
The mechanistic proposal put forward (Scheme 1) sug-
gests that protic additives should accelerate hydrolysis to
yield 8. On the other hand, protonation could also facilitate
the extrusion of nitrous acid as a first step towards the for-
mation of pyrroles 9. When the various acids, protic sol-
vents, or salts were screened, the pyrrole side products were
still observed (Table 4). A notable exception was found with
3,3Ј,5,5Ј-tetrabromo-2,2Ј-biphenol[7] (TBBP), which was
This work was supported by the Deutsche Forschungsgemeinschaft
(SPP 1179 Organokatalyse), the Deutsche Akademische Aus-
tauschdienst (DAAD; fellowship for R. R.), and the Fonds der
Chemischen Industrie.
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R. Rasappan, O. Reiser
SHORT COMMUNICATION
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Received: December 18, 2008
Published Online: February 3, 2009
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Eur. J. Org. Chem. 2009, 1305–1308