Pyrrolidine based chiral organocatalyst for efficient asymmetric Michael addition of cyclic ketones to β-nitrostyrenes

Article abstract of DOI:10.1016/j.bmcl.2012.05.047

An efficient asymmetric Michael addition of cyclic ketones to β-nitrostyrenes using secondary diamine as an organocatalyst derived from l-proline and (R)-α-methylbenzyl amine has been described. This pyrrolidine based catalyst 1 was found to be very effec

Full text of DOI:10.1016/j.bmcl.2012.05.047

Bioorganic & Medicinal Chemistry Letters 22 (2012) 4225–4228
Contents lists available at SciVerse ScienceDirect
Bioorganic & Medicinal Chemistry Letters
journal homepage: www.elsevier.com/locate/bmcl
Pyrrolidine based chiral organocatalyst for efficient asymmetric Michael
addition of cyclic ketones to b-nitrostyrenes
Kamal Nain Singh a, , Paramjit Singh a, Pushpinder Singh a, Nand Lal b, Sandeep Kumar Sharma a
⇑
a Department of Chemistry, Punjab University, Chandigarh 160014, India
b Department of Chemistry, Government College, Chowari, Chamba 176302, Himachal Pradesh, India
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient asymmetric Michael addition of cyclic ketones to b-nitrostyrenes using secondary diamine as
Received 15 April 2012
Revised 9 May 2012
Accepted 11 May 2012
Available online 19 May 2012
an organocatalyst derived from
idine based catalyst 1 was found to be very effective to synthesize various
good yield (up to 81%) with excellent stereoselectivity (up to >99:1 dr and >99% ee).
Ó 2012 Elsevier Ltd. All rights reserved.
L
-proline and (R)-
a
-methylbenzyl amine has been described. This pyrrol-
c-nitrocarbonyl compounds in
Keywords:
Michael addition reaction
Asymmetric organocatalysis
L
-Pyrrolidine
Nitroolefins
Cyclic ketones
One of the most powerful and more economical approach for the
employed for this reaction such as aminomethyl pyrrolidine, amine
thiourea, pyrrolidinyltetrazole, pyrrolidine sulfonamide, chiral pri-
mary-secondary diamines, prolinamides etc. and significant
improvement in diastereoselectivity and enantioselectivity has
been documented.
preparation of wide variety of enantiomerically enriched com-
pounds is through asymmetric organocatalysis.1 The ease of func-
tionalization, eliminating the use of toxic transition metals and
mild reaction conditions are the distinguished features of this
methodology.2 Barbas3 and List4 independently reported the first
organocatalytic addition of ketones to trans b-nitrostyrenes using
Preliminary results were reported by Pansare and Kirby14 on the
application of pyrrolidine-based secondary–secondary diamine as
catalyst for ketone–nitroalkene conjugate addition reaction and
the role of catalyst-nitroalkene hydrogen bonding in the stereose-
lectivity of these reactions. In addition, the structural investigation
for the stereoselectivity of conformationally constrained as well as
conformationally flexible analogues of prolinamides,15 synergically
L
-proline as a catalyst with good yields, but very low enantioselec-
tivities (0–23%). Since then the tremendous use of organocatalysis,
offering high stereoselective transformations of versatile starting
materials using easy procedures and mild conditions is on the rise.
Organocatalysts have also been used in the synthesis of natural
products such as (+)-Augustureine,5a (À)-brasoside5b and chiral
baclofen,5c,d a potent GABAs receptor agonist that is used for the
treatment of spinal cord injury-induced spasm. A large number of
chiral amine derivatives derived from aminoacids have been devel-
oped to affect several highly useful transformations, including al-
provides a foresight to synthesize and evaluate chiral L-pyrrolidine
based diamine 1 as an organocatalyst. Although the corresponding
amide 215 has shown excellent yield and diastereoselectivity, but
the observed enantioselectivity was up to 81%. A distinct trend in
enantioselectivity and reactivity versus catalyst side chain pKa va-
lue was established by Yu et al.16 and this interestingly reveals that
higher pKa value in the catalyst’s side chain favours higher enanti-
oselectivity and reactivity (Fig. 1). Theoretical studies have also im-
plied the role of hydrogen bonding and/or the steric interactions in
deciding the stereoselectivity.17 We explored the use of conforma-
tionally flexible chiral secondary–secondary diamine 1 as the
organocatalyst, which was found to have higher pKa value for side
chain (pKa = 34),18 in Michael addition reactions of ketones with
substituted b-nitrostyrenes and found that the corresponding
dol, Mannich and Michael reactions,
compounds, b-functionalizations of ,b unsaturated carbonyl com-
pounds, Diel–Alder reactions, epoxidation reactions and many
more.6–10 The asymmetric Michael addition11 involving
-enoliz-
able ketones to electron deficient nitroolefins, has received much
attention because the corresponding adducts, -nitro carbonyl
a-alkylations of carbonyl
a
a
c
compounds, constitute important building blocks in organic syn-
thesis.12 Many efficient and selective organocatalysts13 have been
c
-nitroketones are obtained in good yield with high stereoselectiv-
⇑
Corresponding author. Tel.: +91 172 2534438; fax: +91 172 2222918.
E-mail address: kns@pu.ac.in (K.N. Singh).
ity up to >99% ee and >99:1 dr.
0960-894X/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.bmcl.2012.05.047

4226
K. N. Singh et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4225–4228
Table 1
Screening of solventsa
H
N
H
N
N
H
N
H
O
NO2
O
O
NO2
(20 mol%)
solvent, rt
1
pKa=34
pKa=13
+
1
2
7a
5a
6a
Time (h)
Figure 1. Side chain pKa values of organocatalyst 1 and the earlier known catalyst 2.
Entry
Solvent
Yieldb (%)
eec (%)
drd (syn/anti)
1
2
3
4
5
6
7
8
CHCl3
DCE
THF
Et2O
DMF
Toluene
MeOH
EtOH
24
24
36
36
36
24
36
36
53
58
49
44
32
68
Traces
Traces
98
98
99
>99
99
>99
—
99:1
99:1
99:1
99:1
98:2
>99:1
—
The chiral catalyst 1 was easily prepared according to Scheme 1.
Commercially available L
-proline was reacted with Boc-anhydride19
and the N-Boc protected proline 3 was activated towards nucleo-
philic attack by reaction with ethyl chloroformate and then treated
with (R)-a-methyl benzylamine in the presence of triethyl amine to
afford the corresponding amide 4 in 85% yield.20 N-Boc deprotec-
—
—
tion with formic acid20 and further reduction of amide 2 by LiAlH4
21
a
Reaction conditions: nitrostyrene (1.6 mmol), cyclohexanone (3.2 mmol), cat-
afforded the desired chiral catalyst 1 in 40% overall yield.
The activity of catalyst 1 was investigated by using cyclohexa-
none (5a) and b-nitrostyrene (6a) under different solvent
conditions (Table 1). Initial trials using 20 mol % of catalyst 1 in
chloroform at room temperature and without any other additive
gave the desired Michael adduct 7a in 53% yield with high syn
diastereoselectivity (99:1 dr) and good enantioselectivity (98% ee)
(Table 1, entry 1).
Best results were obtained in toluene with improved yield and
stereoselectivity (Table 1, entry 6). The reaction proceeded to mod-
erate extent in solvents like THF, Et2O and DMF (Table 1, entries
3–5) while in protic polar solvents, that is methanol and ethanol
(Table 1, entries 7 and 8) only trace amount of the Michael adduct
was formed. In most of the solvents, high enantioselectivity was
observed irrespective of the yield.
Next, using toluene as solvent, the effect of catalyst loading was
examined and the results are summarized in Table 2. A decrease in
catalyst loading resulted in lowering of yield even after prolonging
the reaction time, without affecting stereoselectivity (Table 2, en-
tries 1 and 2). Increase in catalyst loading, that is up to 30 mol %
did not show any synergic effect on reaction time, yield and stere-
oselectivity (Table 2, entry 4). Hence, the use of 20 mol % of catalyst
1 and toluene as a solvent at room temperature provided the best
optimized reaction conditions.
alyst 1 (20 mol %), solvent (10.0 mL), rt.
b
Isolated yield.
c
Determined by chiral HPLC using Chiralpak AS-H column.
Determined by 1H NMR analysis of crude sample.
d
Table 2
Effect of catalyst loadinga
Entry Catalyst 1 (mol %) Time (h) Yieldb (%) eec (%) drd (syn/anti)
1
2
3
4
5
48
36
24
24
41
61
68
70
99
99
>99
>99
99:1
99:1
>99:1
>99:1
10
20
30
a
Reaction conditions: nitrostyrene (1.6 mmol), cyclohexanone (3.2 mmol), tol-
uene (10.0 mL), rt.
b
Isolated yield.
c
Determined by chiral HPLC using Chiralpak AS-H column.
d
Determined by 1H NMR analysis of crude sample.
and the results are shown in Table 3. The catalyst 1 was tolerant
to a broad range of nitro-olefins derived from aromatic systems
bearing electron-donating as well as electron-withdrawing groups
with different substitution patterns (Table 3). The furyl and
napthyl derivatives of nitrostyrenes afforded the corresponding
products 7f and 7g in good yield but somewhat decreased enantio-
meric excess (Table 3, entries 6, 7). However, in case of cyclopenta-
To further explore the scope of this asymmetric Michael reac-
tion, various nitro-olefins and cyclic ketones were investigated
H
O[CO2C(CH3)3]2
1. ClCO2C2H5 / TEA / DCM
N
COOH
COOH
N
H
N
N
H2N
2.
Boc
Boc
O
(85%)
4
3
(83%)
HCOOH
H
N
H
N
LiAlH4
N
H
N
H
O
(80%)
2
1
(70%)
Scheme 1. Synthesis of catalyst 1.

K. N. Singh et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4225–4228
4227
Table 3
Asymmetric Michael addition using catalyst 1a
Ar
O
n
O
n
NO2
NO2
1
(20 mol%)
Toluene,rt
+
Ar
n=2; 5a
7a-j
6a-j
n=1; 5b
Entry
5
6 (Ar)
Time (h)
7b (%Yield)
ee (%)
dre (syn/anti)
1
2
3
4
5
6
7
8
9
10
5a
5a
5a
5a
5a
5a
5a
5a
5b
5b
C6H5
24
34
30
28
30
32
25
24
28
24
7a (68)
7b (60)
7c (71)
7d (74)
7e (81)
7f (69)
7g (69)
7h (75)
7i (61)
7j (78)
>99c
98c
99d
>99c
88c
85c
79c
98c
53c
87c
>99:1
99:1
99:1
99:1
98:2
97:3
95:5
99:1
63:37
61:39
4-OCH3C6H4
3,4-(OCH3)2C6H3
3-OCH3C6H4
4-ClC6H4
2-Furyl
1-Naphthyl
Benzo[d][1,3]dioxol-5-yl
C6H5
Benzo[d][1,3]dioxol-5-yl
a
b
c
Reaction conditions: nitroalkene (1.6 mmol), ketone (3.2 mmol), catalyst 1 (20 mol %) Toluene (10.0 mL), rt.
Isolated yield.
Determined by chiral HPLC using Chiralpak AS-H column.
Determined by chiral HPLC using Chiralcel OD column.
Determined by 1H NMR analysis of crude sample.
d
e
none (5b), there was a significant decrease in stereoselectivity (Ta-
ble 3, entries 9, 10), which is by and large the case with other
organocatalysts also.22
For the observed stereochemical results, the putative mecha-
nism based upon Seebach,s model23 as shown in Scheme 2 is pro-
posed. Firstly, the catalyst 1 and cyclohexanone forms a chiral
enamine 8. Michael reaction of this enamine with nitro-olefin
leads to the formation of adduct 9 via the acyclic synclinal transi-
tion state A. The adduct 9 upon hydrolysis affords the desired prod-
uct 7 and regenerates catalyst 1 which continues the subsequent
catalytic cycle. In the transition state A, the bulky groups (–CH3
and –Ph) shield the Si-face of enamine double bond, thus forcing
H
N
N
H2O
NO2
Ar
O
8
N
H
N
H
N
H
N
O
N
N
N
Ar
Ar
H
O
NO2
State
A
1
9
H2O
O
Ar
NO2
7
Scheme 2. Putative mechanism.

4228
K. N. Singh et al. / Bioorg. Med. Chem. Lett. 22 (2012) 4225–4228
Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. and references
therein.
8. For excellent reviews on iminium catalysis, see: (a) Lelais, G.; MacMillan, D. W.
C. Aldrichimica Acta 2006, 39, 79; (b) Erkkilä, A.; Majander, I.; Pihko, P. M. Chem.
Rev. 2007, 107, 5416.
9. For reviews on enamine-SOMO catalysis, see: (a) Bertelsen, S.; Nielsen, M.;
Jorgensen, K. A. Angew. Chem., Int. Ed. 2007, 46, 7356; (b) Beeson, T. D.;
Mastracchio, A.; Hong, J.; Ashton, K.; MacMillan, D. W. C. Science 2007, 316,
582; (c) Jang, H.; Hong, J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2007, 129, 7004;
(d) Sibi, M. P.; Hasegawa, M. J. Am. Chem. Soc. 2007, 129, 4124; (e) Kim, H.;
MacMillan, D. W. C. J. Am. Chem. Soc. 2008, 130, 398.
10. (a) Hong, B.; Wu, M.; Tseng, H.; Liao, J. Org. Lett. 2006, 8, 2217; (b) Bertelsen, S.;
Marigo, M.; Brandes, S.; Dinir, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128,
12973.
11. For reviews on asymmetric 1,4-conjugate addition reactions, see: (a) Berner, O.
M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 1877, 2002; (b) Tsogoeva, S. B. Eur.
J. Org. Chem. 2007, 1701; (c) Vicario, J. L.; Badía, D.; Carillo, L. Synthesis 2007,
2065; (d) Almasi, D.; Alonso, D. A.; Nájera, C. Tetrahedron: Asymmetry 2007, 18,
299; (e) Roca-Lopez, D.; Sadaba, D.; Delso, I.; Herrera, R. P.; Tejero, T.; Merino,
P. Tetrahedron: Asymmetry 2010, 21, 2561.
12. (a) Calderari, G.; Seebach, D. Helv. Chim. Acta 1995, 58, 1592; (b) Sibi, M. P.;
Manyem, S. Tetrahedron 2000, 56, 8033; (c) Ono, N. The Nitro Group in Organic
Synthesis; Wiley-VCH: New York, 2001; (d) Christoffers, J.; Baro, A. Angew.
Chem., Int. Ed. 2003, 42, 1688; (e) Czekelius, C.; Carreira, E. M. Angew. Chem., Int.
Ed. 2005, 44, 612.
the nitro-olefin to approach from the Re-face to give the major
enantiomer. Meanwhile, the secondary NH group present in 8
activates and orientates the nitro-olefins through hydrogen bond-
ing.24,25 This also explains the failure of reaction in polar protic
solvents like MeOH and EtOH which may inhibit the enamine for-
mation or the subsequent hydrogen bonding in A. In catalyst 1,
replacing (R)-a-methyl benzylamine with (S)- or racemic a-methyl
benzylamine had no effect on the yield and stereoselectivity of the
reaction, thus indicating that this chiral centre plays no significant
role. Finally, it seems to be the combined effect of steric factors and
intermolecular hydrogen bonding which leads to the higher stere-
oselectivity in the reaction and furnish the S, R- product.26
In conclusion, we have developed a simple and effective chiral
diamine organocatalyst for the direct asymmetric Michael addi-
tions of cyclic ketones to nitroolefins. Further applications of this
organocatalyst in other reactions are being investigated.
Acknowledgments
13. (a) Cobb, A. J. A.; Shaw, D. M.; Longbottom, D. A.; Gold, J. B.; Ley, S. V. Org.
Biomol. Chem. 2005, 3, 84; (b) Betancort, J. M.; Sakthivel, K.; Thayumanavan, R.;
Tanaka, F.; Barbas, C. F., III Synthesis 2004, 1509; (c) Huang, H.; Jacobsen, E. N. J.
Am. Chem. Soc. 2006, 128, 7170; (d) Cao, C. L.; Ye, M. C.; Sun, X. L.; Tang, Y. Org.
Lett. 2006, 8, 2901; (e) Jiang, X. X.; Zhang, Y. F.; Chan, A. S. C.; Wang, R. Org. Lett.
2009, 11, 153; (f) Wang, C.; Yu, C.; Liu, C. L.; Peng, Y. G. Tetrahedron Lett. 2009,
50, 2363; (g) Liu, J.; Yang, Z. G.; Liu, X. H.; Wang, Z.; Liu, Y. L.; Bai, S.; Lin, L. L.;
Feng, X. M. Org. Biomol. Chem. 2009, 7, 4120; (h) Maya, V.; Singh, V. K. Org. Lett.
2007, 9, 1117; (i) Kokotos, C. G.; Limnios, D.; Triggidou, D.; Trifonidou, M.;
Kokotos, G. Org. Biomol. Chem. 2011, 9, 3386; (j) Tsakos, M.; Kokotos, C. G. Eur. J.
Org. Chem. 2012, 576.
We acknowledge financial support vide scheme no. 01(2138)/
07/EMR-II from CSIR, New Delhi, India. S. K. Sharma is thankful
to DST, New Delhi for providing research fellowship (DST/INSPIRE
fellowship/2011/150).
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.bmcl.2012.05.
047.
14. Pansare, S. V.; Kirby, R. L. Tetrahedron 2009, 65, 4557.
15. Kelleher, F.; Kelly, S.; Watts, J.; McKee, V. Tetrahedron 2010, 66, 3525.
16. Yu, C.; Qiu, J.; Zheng, F.; Zhong, W. Tetrahedron Lett. 2011, 52, 3298. No
explanation for the increase in enantioselectivity with increase in pKa value in
the side chain is offered; see also Ref. 14.
References and notes
17. (a) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 12911; (b) Wang, J.;
Li, H.; Lou, B.; Zu, L.; Guo, H.; Wang, W. Chem. Eur. J. 2006, 12, 4321.
18. The pKa values of 1 and 2 were calculated using the SPARC software: Hilal, S.;
Karickhoff, S. W.; Carreira, L. A. Quant. Struct. Act. Relat. 1995, 14, 348. http://
ibmlc2.chem.uga.edu/sparc/.
19. Pettit, R. G.; Singh, S. B.; Herald, D. L.; Williams, P. L.; Kantoci, D.; Burkett, D. D.;
Barkóczy, J.; Hogan, F.; Wardlaw, T. R. J. Org. Chem. 1994, 59, 6287.
20. Maya, V.; Raj, M.; Singh, V. K. Org. Lett. 2007, 9, 2593.
1. For selected reviews on organocatalysis, see: (a) Dalko, P. I.; Moisan, L. Angew.
Chem., Int. Ed. 2004, 43, 5138; (b) Seayad, J.; List, B. Org. Biomol. Chem. 2005, 3,
719; (c) List, B.; Yang, J. W. Science 2006, 313, 1584; (d) Enders, D.; Grondal, C.;
Hüttl, M. R. M. Angew. Chem., Int. Ed. 2007, 46, 1570; (e) Pellissier, H.
Tetrahedron 2007, 63, 9267; (f) MacMillan, D. W. C. Nature 2008, 455, 304; (g)
Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638; (h) Enders, D.;
Wang, C.; Liebich, J. X. Chem. Eur. J. 2009, 15, 11058; (i) Chai, Z.; Zhao, G. Catal.
Sci. Technol. 2012, 2, 29.
21. Asami, M.; Ohno, H.; Kobayashi, S.; Mukaiyama, T. Bull. Chem. Soc. Jpn. 1869,
1978, 51.
2. Jain, S. L.; Modak, A.; Bhaumik, A. Green Chem. 2011, 13, 586.
3. Sakthivel, K.; Notz, W.; Bui, T.; Barbas, C. F., III J. Am. Chem. Soc. 2001, 123, 5260.
4. List, B.; Pojarlieve, P.; Martin, H. J. Org. Lett. 2001, 3, 2423.
22. Saha, S.; Seth, S.; Moorthy, J. N. Tetrahedron Lett. 2010, 51, 5281.
23. Seebach, D.; Golinski, J. Helv. Chim. Acta 1981, 64, 1413.
5. (a) Fustero, S.; Moscardo, J.; Jimenez, D.; Peerez-Carrion, M. D.; Sanchez-
Rosesllo, M.; del Pozo, C. Chem. Eur. J. 2008, 14, 9868; (b) de Figueiredo, R. M.;
Christmann, M. Eur. J. Org. Chem. 2007, 16, 2575; (c) Zu, L.; Xie, H.; Li, H.; Wang,
J.; Wang, W. Adv. Synth. Catal. 2007, 349, 2660; (d) Tsakos, M.; Kokotos, C. G.
Adv. Synth. Catal. 2012, 354, 740.
24. (a) Pansare, S. V.; Lingampally, R. Org. Biomol. Chem. 2009, 7, 319; (b) 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; (c) Xu, D. Q.; Wang, L. P.; Luo, S. P.; Wang, Y. F.; Zhang, S.; Xu, Z.
Y. Eur. J. Org. Chem. 2008, 1049; (d) Chen, J.-R.; Fu, L.; Zou, Y.-Q.; Chang, N.-J.;
Rong, J.; Xiao, W.-J. Org. Biomol. Chem. 2011, 9, 5280.
6. For selected reviews on asymmetric aminocatalysis, see: (a) List, B. Chem.
Commun. 2006, 819; (b) Barbas, C. F., III Angew. Chem., Int. Ed. 2008, 47, 42; (c)
Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008,
47, 6138; (d) Bertelsen, S.; Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178; (e)
Melchiorre, P. Angew. Chem., Int. Ed. 2009, 48, 1360; (f) Yang, H.; Carter, R. G.
Synlett 2010, 2827.
7. For reviews on chiral amines as enamine catalysts, see: (a) List, B. Acc. Chem.
Res. 2004, 37, 548; (b) Notz, W.; Tanaka, F.; Barbas, C. F., III Acc. Chem. Res. 2004,
37, 580; (c) Guillena, G.; Ramón, D. J. Tetrahedron: Asymmetry 2006, 17, 1465;
(d) Marigo, M.; Jørgensen, K. A. Chem. Commun. 2001, 2006; (e) Mukherjee, S.;
25. Although in some publications (Ref. 24a,c,d) the plausible transition state is
shown to involve both oxygen atoms of the nitro group in the hydrogen
bonding, in this case it seems more rational to propose transition state A in
which only one oxygen atom of nitro group forms a hydrogen bond. Such a
transition state has been supported on the basis of theoretical calculations as
well as stereochemical aspects: (a) Yalalov, D. A.; Tsogoeva, S. B.; Schmatz, S.
Adv. Synth. Catal. 2006, 348, 826; (b) Ref. 13i.
26. The configuration of chiral centres in 7 was assigned as on the basis of
comparison of retention times in chiral HPLC with those reported in
literature.13i,16,22