Effect of high pressure on the organocatalytic asymmetric michael reaction: Highly enantioselective synthesis of γ-nitroketones with quaternary stereogenic centers

Article abstract of DOI:10.1021/ol201275h

The significant effect of hydrostatic pressure on the difficult organocatalytic 1,4-conjugate addition of nitroalkanes to prochiral sterically congested β,β-disubstituted enones is demonstrated. This approach allows for the synthesis of γ-nitroketones con

Full text of DOI:10.1021/ol201275h

ORGANIC
LETTERS
2011
Vol. 13, No. 14
3624–3627
Effect of High Pressure on the
Organocatalytic Asymmetric Michael
Reaction: Highly Enantioselective
Synthesis of γ-Nitroketones with
Quaternary Stereogenic Centers
ꢀ
Piotr Kwiatkowski,* Krzysztof Dudzinski, and Dawid Łyzwa
_
Faculty of Chemistry, University of Warsaw, Pasteura 1, 02-093 Warsaw, Poland
pkwiat@chem.uw.edu.pl
Received May 12, 2011
ABSTRACT
The significant effect of hydrostatic pressure on the difficult organocatalytic 1,4-conjugate addition of nitroalkanes to prochiral sterically
congested β,β-disubstituted enones is demonstrated. This approach allows for the synthesis of γ-nitroketones containing quaternary
stereogenic centers with good yields, excellent enantioselectivity, and low loading (1À5 mol %) of simple chiral primary amine catalysts.
The high-pressure methodology in liquid systems has
been quite well recognized as a very powerful tool in
organic synthesis,1 but the influence of pressure on asym-
metric metallo-1a,2 and organocatalytic3 reactions still
remains a poorly explored area of catalysis. These facts,
as well as the remarkable progress made in organocatalysis
in recent years,4 prompted us to study the effect of pressure
on selected difficult organocatalytic reactions requiring a
high catalyst loading, long reaction time, and reactions
which are still beyond the reach of classical organocata-
lysis. Increased pressure can assist in overcoming organo-
catalytic reactions with a negative volume of activation,1
which are ineffective under thermal conditions because of
steric and electronic constraints.
The high-pressuretechniquewas successfullyintroduced
to organic synthesis by Dauben in the mid-1970s.5 In the
early 1980s Matsumoto3a investigated the first high-
pressure asymmetric organocatalytic reaction, including
natural cinchona alkaloids as catalysts in Michael-type
reactions, with a positive influence on the rate but unfortu-
nately with low or moderate enantioselectivity. The litera-
ture also describes a few other examples of high-pressure
asymmetric organocatalytic reactions catalyzed by chiral
tertiary or secondary amines, usually with low or moderate
enantioselectivity.3bÀf,h To date, the highest positive effect
of pressure on the asymmetric organocatalytic process was
observed by Hayashi3g in a Mannich-type reaction cata-
lyzed by proline.
(1) (a) Van Eldik, R., Klarner, F. G., Eds. High Pressure Chemistry:
Synthetic Mechanistic and Supercritical Applications; Wiley-VCH: Wein-
heim, 2002. (b) Matsumoto, K., Acheson, R. M., Eds. Organic Synthesis at
High Pressure; Wiley: New York, 1991. (c) Jurczak, J., Baranowski, B., Eds.
High Pressure Chemical Synthesis; Elsevier: Amsterdam, 1989.
(2) Reiser, O. Top. Catal. 1998, 5, 105.
(3) For examples of enantioselective organocatalytic reactions under
high pressure, see: (a) Matsumoto, K.; Uchida, T. Chem. Lett. 1981,
1673. (b) Sera, A.; Takagi, K.; Katayama, H.; Yamada, H.; Mataumoto,
K. J. Org. Chem. 1988, 53, 1157. (c) Oishi, T.; Oguri, H.; Hirama, M.
Tetrahedron: Asymmetry 1995, 6, 1241. (d) Marko, I. E.; Giles, P. R.;
Hindley, N. J. Tetrahedron 1997, 53, 1015. (e) Misumi, Y.; Bulman,
R. A.; Matsumoto, K. Heterocycles 2002, 56, 599. (f) Sekiguchi, Y.;
Sasaoka, A.; Shimomoto, A.; Fujioka, S.; Kotsuki, H. Synlett 2003,
1655. (g) Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N. J. Am. Chem.
Soc. 2003, 125, 11208. (h) Hayashi, Y.; Tsuboi, W.; Shoji, M.; Suzuki, N.
Tetrahedron Lett. 2004, 45, 4353.
(4) (a) Dalko, P. I., Ed. Enantioselective Organocatalysis;
Wiley-VCH: Weinheim, 2007. (b) List, B., Ed. Asymmetric Organoca-
talysis; Topics in Current Chemistry, Vol. 291; Springer-Verlag: Berlin,
2009.
(5) Dauben, W. G.; Kozikowski, A. P. J. Am. Chem. Soc. 1974, 96,
3664.
r
10.1021/ol201275h
Published on Web 06/14/2011
2011 American Chemical Society

1,4-conjugate addition of nitroalkanes to prochiral steri-
cally congested β,β-disubstituted enones, catalyzed by
simple chiral primary amines 1aÀ1h (Figure 1).12,13 We
have found that a combination of pressure and bifunc-
tional catalysis with primary amines derived from cincho-
na alkaloids can remarkably accelerate the reaction rate.
This approach allows for efficient asymmetric synthesis of
γ-nitroketones14 containing all-carbon quaternary stereo-
genic centers with high enantioselectivity.
Scheme 1. Creation of All-Carbon Quaternary Stereocenters by
1,4-Conjugate Addition to β,β-Disubstituted Enones
In our high-pressure studies we focused attention on
challenging 1,4-conjugate additions of carbon nucleo-
philes to prochiral β,β-disubstituted Michael acceptors
enabling the generation of quaternary stereogenic centers
(Scheme 1).6 Asymmetric organocatalytic Michael-type
reactions are practically restricted to β-monosubstituted
unsaturated carbonyl compounds and nitroalkenes.7 The
literature describes only a few examples of such organoca-
talytic reactions of sterically congested β,β-disubstituted
acceptors with C-nucleophiles,6c,8 usually with a very
limited scope, and some examples of intramolecular
reactions,9 e.g. DielsÀAlder, FriedelÀCrafts, and Stetter.
Moreover, this type of Michael acceptors was also applied
in asymmetric organocatalytic hydrogenation10 and some
additions of heteronucleophiles including epoxidation and
aziridination.11 In contrast, transition-metal-catalyzed
asymmetric conjugate addition reactions to β,β-disubsti-
tuted Michael acceptors have been quite extensively ex-
plored in recent years.6d
Figure 1. Organocatalysts examined in the Michael reaction.
As a model reaction for our studies, we chose the
addition of nitromethane to 3-methylcyclohexenone (2a,
Table 1). This particular reaction was investigated by the
research groups of Ley8a,b and Amedjkouh8c in the pre-
sence of chiral secondary amines. More promising results
were obtained recently by Ye’sgroup,8d with10À20 mol %
of the primary amine-thiourea catalyst containing 1,2-
diaminocyclohexane and a cinchona alkaloid moiety.
The product 3a was isolated after 5 days with 82% yield
and 94% ee; however, the presented scope of enones is
limited only to 3-n-alkylcyclohexenones.
Inthiscommunicationwedemonstrate thepositiveeffect
of hydrostatic pressure (up to 10 kbar) on enantioselective
(6) (a) Christoffers, J., Baro, A., Eds. Quaternary Stereocenters:
Challenges and Solutions for Organic Synthesis; Wiley-VCH: Weinheim,
2005. (b) Trost, B. M.; Jiang, C. Synthesis 2006, 369. (c) Bella, M.; Gasperi,
T. Synthesis 2009, 1583. (d) Hawner, C.; Alexakis, A. Chem. Commun.
2010, 7295. (e) Das, J. P.; Marek, I. Chem. Commun. 2011, 4593.
(7) Almasi, D.; Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry
2007, 18, 299.
In our preliminary investigations we applied 5 mol %
of simple chiral primary amines 1aÀf as catalysts with
TFA as a cocatalyst (Figure 1, Table 1). Screening under
ambient conditions revealed a very low conversion of
3-methylcyclohexenone. In contrast, application of 10
kbar of pressure and a catalytic amount of 1,2-diamines
1bÀf remarkably accelerated the reaction rate (Table 1).
The best results in terms of conversions were observed
with amines 1c, 1e, and 1f. The significantly lower yield
(8) (a) Mitchell, C. E. T.; Brenner, S. E.; Ley, S. V. Chem. Commun.
2005, 5346. (b) Mitchell, C. E. T.; Brenner, S. E.; Garcia-Fortanet, J.;
Ley, S. V. Org. Biomol. Chem. 2006, 4, 2039. (c) Malmgren, M.;
Granander, J.; Amedjkouh, M. Tetrahedron: Asymmetry 2008, 19,
1934. (d) Li, P.; Wang, Y.; Liang, X.; Ye, J. Chem. Commun. 2008,
3302. (e) Wascholowski, V.; Hansen, H. M.; Longbottom, D. A.; Ley,
S. V. Synthesis 2008, 1269. (f) Bernardi, L.; Fini, F.; Fochi, M.; Ricci, A.
Synlett 2008, 1857. (g) Procopio, A.; De Nino, A.; Nardi, M.; Oliverio,
M.; Paonessa, R.; Pasceri, R. Synlett 2010, 1849.
(9) (a) Kerr, M. S.; Rovis, T. J. Am. Chem. Soc. 2004, 126, 8876. (b)
Wilson, R. M.; Jen, W. S.; MacMillan, D. W. C. J. Am. Chem. Soc. 2005,
127, 11616. (c) Banwell, M. G.; Beck, D. A. S.; Willis, A. C. Arkivoc
2006, 163. (d) Xu, D.-Q.; Xia, A.-B.; Luo, S.-P.; Tang, J.; Zhang, S.;
Jiang, J.-R.; Xu, Z.-Y. Angew. Chem., Int. Ed. 2009, 48, 3821. (e) Zhang,
E.; Fan, C.-A.; Tu, Y.-Q.; Zhang, F.-M.; Song, Y.-L. J. Am. Chem. Soc.
2009, 131, 14626.
(10) (a) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2005, 127, 32. (b) Yang, J. W.; Hechavarria Fonseca, M. T.;
Vignola, N.; List, B. Angew. Chem., Int. Ed. 2005, 44, 108. (c) Tuttle,
J. B.; Ouellet, S. G.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128,
12662. (d) Martin, N. J. A.; List, B. J. Am. Chem. Soc. 2006, 128, 13368.
(e) Martin, N. J. A.; Ozores, L.; List, B. J. Am. Chem. Soc. 2007, 129,
8976. (f) Martin, N. J. A.; Cheng, X.; List, B. J. Am. Chem. Soc. 2008,
130, 13862.
(11) (a) Wang, X.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2008,
130, 6070. (b)Zhang, F.-G.; Yang, Q.-Q.;Xuan, J.; Lu, H.-H.;Duan, S.-W.;
Chen, J.-R.; Xiao, W.-J. Org. Lett. 2010, 12, 5636. (c) Pesciaioli, F.; De
Vincentiis, F.; Galzerano, P.; Bencivenni, G.; Bartoli, G.; Mazzanti, A.;
Melchiorre, P. Angew. Chem., Int. Ed. 2008, 47, 8703. (d) Lu, H.-H.;
Zhang, F.-G.; Meng, X.-G.; Duan, S.-W.; Xiao, W.-J. Org. Lett. 2009,
11, 3946.
(12) For a review on organocatalysis with primary amines, see: (a)
Jiang, L.; Chen, Y.-C. Catal. Sci. Technol. 2011, 1, 354. (b) Xu, L.-W.;
Luo, J.; Lu, Y. Chem. Commun. 2009, 1807. (c) Peng, F.; Shao, Z. J. Mol.
Catal. A: Chemical 2008, 285, 1. (d) Chen, Y.-C. Synlett 2008, 1919.
(13) For selected examples of organocatalytic 1,4-conjugate addition
of nitroalkanes, catalyzed by chiral primary amines, see: (a) Lv, J.;
Zhang, J.; Lin, Z.; Wang, Y. Chem.;Eur. J. 2009, 15, 972. (b) Mei, K.;
Jin, M.; Zhang, S.; Li, P.; Liu, W.; Chen, X.; Xue, F.; Duan, W.; Wang,
W. Org. Lett. 2009, 11, 2864. (c) Dong, L.-T.; Lu, R.-J.; Du, Q.-S.;
Zhang, J.-M.; Liu, S.-P.; Xuan, Y.-N.; Yan, M. Tetrahedron 2009, 65,
4124. (d) Liu, C.; Lu, Y. Org. Lett. 2010, 12, 2278. (e) Cui, H.-F.; Li, P.;
Wang, X.-W.; Chai, Z.; Yang, Y.-Q.; Cai, Y.-P.; Zhu, S.-Z.; Zhao, G.
Tetrahedron 2011, 67, 312. (f) Reference 8d.
(14) (a) Roca-Lopez, D.; Sadaba, D.; Delso, I.; Herrera, R. P.;
Tejero, T.; Merino, P. Tetrahedron: Asymmetry 2010, 21, 2561. (b)
Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.; Petrini, M. Chem.
Rev. 2005, 105, 933.
Org. Lett., Vol. 13, No. 14, 2011
3625

Table 1. Catalyst Screening in the Model Reactiona
10 kbar
1 bar
acid
yield
(conv)
(%)b
amine
additive
(5 mol %)
yield
(%)b
ee
(%)c
entry
(5 mol %)
1d
2
1a
1b
1c
1d
1e
1f
TFA
<1
2
11 (23)
55 (60)
55 (95)
70 (77)
55 (99)
78 (91)
75 (99)
80 (96)
36 (89)
36 (43)
34 (S)
98 (R)
75 (R)
82 (S)
73 (S)
96 (R)
98 (R)
98 (R)
85 (R)
92 (R)
TFA
3
TFA
6f
Figure 2. Effect of pressure on the model reaction.
4
TFA
9g
<1
1
5
TFA
ee). Promising results were observed with quinidine-
derived thiourea 1i (Table 1, entry 10);16 however, the use
of natural cinchonidine under the same conditions resulted
in low yield and enantioselectivity (<10%, 18% ee).
The model reaction is very efficient under 10 kbar even
with 1 mol % of 1f during20h(Table2, entry4) and5mol%
after 5 h (entry 6). Comparable results are also attain-
able under lower pressure (4À8 kbar, entries 7 and 8). We
alsodemonstratedthatthismethodologyis applicablewith
1À2 mol % of 1f for multigram scale synthesis (20 mmol)
with good yield (>75%) and >97% ee.15 For comparison
the reaction with 10 mol % of catalyst 1f under atmo-
spheric pressure at 60 °C allows product 3a with 25% yield
(entry 10).
6
TFA
7
1f
BzOH
BzOH
No acid
No acid
3
8e
9
1f
<2
1
1f
10
1i
<0.1
a Reaction conditions: 2a (1 mmol, c = 1.0 mol/L), nitromethane (2
mmol), amine 1 (0.05 mmol), acid (0.05 mmol) in toluene (ca. 0.75 mL),
20À25 °C, 20 h, 10 kbar (or 25 °C, 24 h, 1 bar). b Determined by GC
analysis with internal standard. c Determined by GC analysis using
β-dex 225 column. d 2.5 mol % of TFA was used. e 2 mol % of 1f and
2 mol % of benzoic acid was used. f 83% ee at 1 bar. g 80% ee at 1 bar.
than those by conversion with some catalysts (Table 1,
entries 3 and 5) can be explained by subsequent nitro-
methane (2 equiv) addition to the carbonyl group.3e The
highest efficiency in terms of yield and enantioselectivity
was achieved with 9-amino-9-deoxy-epi-cinchonine 1f
(entry 6). After screening of an acid additive we found that
the addition of a weaker acid (e.g., benzoic) gave higher
conversion and enantioselectivity (entry 7).15 To our sur-
prise, lowering the catalyst loading to 2 mol % in fact
improved the yield to 80% (entry 8). A higher concentra-
tion of catalyst 1f gave practically full conversion and
promoted the subsequent Henry reaction, lowering the
yield of the desired product. Reaction without an acid
additive is less enantioselective and favors byproduct for-
mation (entry 9).
Table 2. Model Reaction Optimization Studiesa
mol % of
1 1.5
conv
(%)b
yield
(%)b,c
ee
(%)d
3
entry amine
BzOH
pressure
1
1f
1g
1h
1f
1f
1f
1f
1f
1f
1f
2
10 kbar
10 kbar
10 kbar
10 kbar
10 kbar
10 kbar
8 kbar
4 kbar
1 bar
96
96
96
87
27
93
96
80
5
87 (85) 98 (R)
91 98 (R)
90 (87) 97 (S)
2
2
3
2
4
1
84
26
87
88
75
4
98
5
0.2
5
98
6e
7
98
We studied the influence of pressure in more detail, with
2 mol % of catalyst 1f 1.5 BzOH. Figure 2 illustrates that
5
98.5
98
8f
9g
10h
2
3
10
10
∼98
98
pressure increase has a significant effect on the reaction
rate with enantioselectivity kept on a very high level (98 (
1% ee). We found that 8À10 kbar of pressure and 2 mol %
of amine 1f with an excess of benzoic acid in the range of
3À4 mol % are optimal for the model reaction (Table 2,
entry 1).15
1 bar
26
25
a Reaction conditions: 2a (1 mmol, c = 1.0 mol/L), nitromethane (2
mmol), amine 1 1.5 BzOH in toluene (ca. 0.75 mL), 20À25 °C, 20 h.
3
b Determined by GC analysis with internal standard. c Numbers in
parentheses refer to isolated yield of 3a starting from 3 mmol of 2a.
d Determined by GC analysis using β-dex 225 column. e 5 h. f Reaction
carried out at 60 °C. g 24 h. h Reaction carried out at 60 °C, 24 h.
We also tested other derivatives of cinchona alkaloids
1gÀi. Application of pseudoenantiomeric catalyst 1h re-
sulted in opposite enantioselectivity (Table 2, entry 3, 97%
Having established the optimal conditions for high-
pressure asymmetric reactions of 3-methylcyclohexenone
(2a) with nitromethane, we extended investigations of the
Michael reaction toothernitroalkanes and enones. Ketone
(15) For more details, see Supporting Information.
ꢀ
ꢀ
(16) Vakulya, B.; Varga, S.; Csaampai, A.; Soos, T. Org. Lett. 2005,
7, 1967.
3626
Org. Lett., Vol. 13, No. 14, 2011

2a reacts with higher nitroalkanes, e.g. nitroethane17 and
2-nitropropane, under 10 kbar of pressure with very high
yield and enantioselectivity (Scheme 2).
The organocatalytic high-pressure method can also be
employed for selected reactions of nitromethane with
acyclic β,β-disubstituted enones (6aÀc, Scheme 3). This
group of enones is generally less reactive in the presence of
catalyst 1f in comparison to cyclic ones. The best results in
terms of yield and enantioselectivity was obtained with
ketone 6a containing an electron-withdrawing group in the
Scheme 2. Reaction of 2a with Higher Nitroalkanes
β-position (74%, 97% ee with 5 mol % of 1f BzOH).
3
Enones with aryl and alkyl substituents in the β-position
require a higher loading of catalyst (10 mol %). For
instance, the Michael reaction of ketone 6b, containing a
thienyl group, furnished product 7b with high enantios-
electivity and moderate yield. The situation is more com-
plicated with enones having two different alkyl groups in
the β-position (e.g., 6c). Starting from the E-isomer of 6c
we obtained acceptable yields and an enantioselectivity up
to 80%. Surprisingly, with the Z-isomer the same direction
of asymmetric induction was observed but with very low
enantioselectivity.15 Such results can be explained by E/Z-
isomerization of enone 6c in the presence of a catalyst dur-
ing the reaction and the higher reactivity of the E-isomer.15
We focused more attentiononreactionsof nitromethane
with various β,β-disubstituted enones, especially cyclic
enones. As shown in Figure 3, this reaction works well
for a broad range of 3-substituted cyclohexenones usually
affording good to very good yields and enantioselectivity
(usually >95% ee, products 3bÀh).
Scheme 3. Reactions of Acyclic Enones with Nitromethane
In conclusion, we have developed efficient high-pressure
enantioselective organocatalytic 1,4-conjugate addition of
nitromethane to prochiral sterically hindered β,β-enones.
This approach works especially well with various cyclic
enones and allows for the synthesis of γ-nitroketones
containing quaternary stereogenic centers with good
yields, excellent enantioselectivity, and low loading of a
simple catalyst (1À5 mol %). We also presented promising
preliminary results of the reaction with acyclic enones.
Moreover, this work demonstrates the significant effect of
hydrostatic pressure on the rate of an organocatalytic
reaction while retaining very high enantioselectivity. To
the best of our knowledge, this is the first example of
pressure influence studies on an organocatalytic reaction
proceeding via an iminium activation mode.
Figure 3. Products of nitromethane reaction with cyclic enones
catalyzed by 2À5 mol % of 1f 1.5 BzOH (isolated yield given).
3
Cyclohexenones containing more sterically demanding
substituents (e.g., i-Pr) and aryl groups in the 3-position are
less reactive, and to obtain a good yield they require 5 mol %
of catalyst 1f and in some cases more than 2 equiv of
nitromethane.15 This protocol also works quite effectively
with more substituted cyclohexenones like isophorone (see
product 3e) and regioselectively with 2,6,6-trimethylcyclo-
hexene-1,4-dione (see product 3i). Moreover, we demon-
strated that this approach is readily applicable with five- and
seven-membered cyclic enones (see products 3j and 3k).
Acknowledgment. We are grateful to the National Science
Centre (Grant No. N N204 145740) and Foundation for
Polish Science for financial support. Dedicated to Professor
Janusz Jurczak on the occasion of his 70th birthday.
Supporting Information Available. Experimental pro-
cedures and analytical data. This material is available free
of charge via the Internet at http://pubs.acs.org.
(17) The use of 1-nitroalkanes (e.g., EtNO2) introduces two stereo-
genic centers, unfortunately with no diastereoselectivity because of
unselective formation of the center with the nitro group.
Org. Lett., Vol. 13, No. 14, 2011
3627