Asymmetric michael additions of α-nitrocyclohexanone to aryl nitroalkenes catalyzed by natural amino acid-derived bifunctional thioureas

Article abstract of DOI:10.1021/ol302005f

A series of new thiourea catalysts prepared from natural amino acids have been applied in organocatalytic asymmetric Michael additions of α-nitrocyclohexanone to nitroalkenes. The resulting addition products are formed with excellent enantioselectivities (up to an er of 98:2) in good yields (up to 90%).

Full text of DOI:10.1021/ol302005f

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4518–4521
Asymmetric Michael Additions
of r‑Nitrocyclohexanone to Aryl
Nitroalkenes Catalyzed by Natural Amino
Acid-Derived Bifunctional Thioureas
€
Manuel Jorres, Ingo Schiffers, Iuliana Atodiresei, and Carsten Bolm*
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg1,
D-52074 Aachen, Germany
carsten.bolm@oc.rwth-aachen.de
Received July 19, 2012
ABSTRACT
A series of new thiourea catalysts prepared from natural amino acids have been applied in organocatalytic asymmetric Michael additions of
R-nitrocyclohexanone to nitroalkenes. The resulting addition products are formed with excellent enantioselectivities (up to an er of 98:2) in good
yields (up to 90%).
Organocatalysis has become a well-respected methodol-
ogy in asymmetric organic synthesis.1,2 Besides activation
via enamines or imminium ions, hydrogen bonding plays a
major role.3 Catalysts combining both a hydrogen donor
and a hydrogen acceptor are of particular interest because
they allow a simultaneous activation of two reactants.4
Excellent examples include the thioureas by Takemoto5
and Jacobsen,6 in which the H-binding cores are combined
with (di)amino-based H-acceptors.7
Initially, our work wasfocused ontheuseofbifunctional
thioureas in the enantioselective desymmetrization of
meso-anhydrides.8 Further interest in this catalyst type
(1) For recent books, see: (a) Enantioselective Organocatalysis;
Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007. (b) Organocatalysis; Reetz,
M. T., List, B., Jaroch, S., Weinmann, H., Eds.; Springer: Berlin, 2008.
(2) For selected recent reviews on organocatalysis, see: (a) Mukherjee,
S.; Yang, J. W.; Hoffmann, S.; List, B. Chem. Rev. 2007, 107, 5471. (b)
(6) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901.
ꢀ
(7) For other examples, see: (a) Vakulya, B.; Varga, S.; Csampai, A.;
ꢀ
Soos, T. Org. Lett. 2005, 7, 1967. (b) McCooey, S. H.; Connon, S. J.
€
ꢀ
Enders, D.; Grondal, C.; Huttl, M. R. M. Angew. Chem., Int. Ed. 2007,
Angew. Chem., Int. Ed. 2005, 44, 6367. (c) Andres, J. M.; Manzano, R.;
46, 1570. (c) MacMillan, D. W. C. Nature 2008, 455, 304. (d) Dondoni,
A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (e) Melchiorre, P.;
Marigo, M.; Carlone, A.; Bartoli, G. Angew. Chem., Int. Ed. 2008, 47,
6138. (f) Yu, X.; Wang, W. Chem. Asian J. 2008, 3, 516. (g) Bertelsen, S.;
Jørgensen, K. A. Chem. Soc. Rev. 2009, 38, 2178. (h) Pihko, P. M.;
Pedrosa, R. Chem.;Eur. J. 2008, 14, 5116. (d) Ma, Z.-W.; Liu, Y.-X.;
Huo, L.-J.; Gao, X.; Tao, J.-C. Tetrahedron: Asymmetry 2012, 23, 443.
(8) Schmitt, E.; Schiffers, I.; Bolm, C. Tetrahedron 2010, 66, 6349.
(9) Flock, A. M.; Krebs, A.; Bolm, C. Synlett 2010, 1219.
(10) For other recent examples of thiourea-catalyzed Michael addi-
tion reactions, see: (a) Cao, Y.; Jiang, X.; Liu, L.; Shen, F.; Zhang, F.;
Wang, R. Angew. Chem., Int. Ed. 2011, 50, 9124. (b) Dong, X.-Q.; Fang,
X.; Wang, C.-J. Org. Lett. 2011, 13, 4426. (c) Ramireddy, N.; Abbaraju,
S.; Zhao, C.-G. Tetrahedron Lett. 2011, 52, 6792. (d) Rana, N. K.; Singh,
V. K. Org. Lett. 2011, 13, 6520. (e) Bai, J.-F.; Wang, L.-L.; Peng, L.;
Guo, Y.-L.; Jia, L.-N.; Tian, F.; He, G.-Y.; Xu, X.-Y.; Wang, L.-X.
J. Org. Chem. 2012, 77, 2947. (f) Urbanietz, G.; Cassens-Sasse, E.; Keeß,
S.; Raabe, G.; Enders, D. Adv. Synth. Catal. 2012, 354, 1481. (g) Parra,
€
Majander, I.; Erkkila, A. Top. Curr. Chem. 2010, 291, 29.
(3) For reviews on hydrogen-bonding catalysis, see: (a) Schreiner,
P. R.; Wittkopp, A. Org. Lett. 2002, 4, 217. (b) Schreiner, P. R. Chem.
Soc. Rev. 2003, 32, 289. (c) Pihko, P. M. Angew. Chem., Int. Ed. 2004, 43,
2062. (d) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
(e) Zhang, Z.; Schreiner, P. R. Chem. Soc. Rev. 2009, 38, 1187.
(4) For reviews on bifunctional hydrogen-bonding catalysis, see:
(a) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299. (b) Taylor, M. S.;
Jacobsen, E. N. Angew. Chem., Int. Ed. 2006, 45, 1520. (c) Connon, S. J.
Chem. Commun. 2008, 2499. (d) Connon, S. J. Synlett 2009, 354. (e) Lu,
L.-Q.; An, X.-L.; Chen, J.-R.; Xiao, W.-J. Synlett 2012, 23, 490.
(5) Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003,
125, 12672.
ꢁ
A.; Uria, U.; Besselievre, F.; Merino, E.; Rueping, M. Org. Lett. 2010,
12, 5680. (h) Raimondi, W.; Basl, O.; Constantieux, T.; Bonne, D.;
Rodriguez, J. Adv. Synth. Catal. 2012, 354, 563. (i) Li, X.; Zhang, Y.-Y.;
Xue, X.-S.; Jin, J.-L.; Tan, B.-X.; Liu, C.; Dong, N.; Cheng, J.-P. Eur. J.
Org. Chem. 2012, 1774.
r
10.1021/ol302005f
Published on Web 08/28/2012
2012 American Chemical Society

led us to study Michael addition reactions,9,10 which are
amongthe mostefficientmethodsforCÀC and CÀX bond
formations.11 If R-substituted cyclic ketones are applied in
such reactions, products with a quaternary stereogenic
center are formed.12,13 Additions to nitroalkenes provide
synthetically attractive intermediates with an easy-to-convert
flexible functional group.11,14 Here, we report the syntheses
of new bifunctional thioureas starting from natural amino
acid-derived N-substituted 3-amino piperidines and a
5-membered analogue, and we demonstrate their excellent
organocatalytic potential in asymmetric Michael addition
of R-nitrocyclohexanone to nitroalkenes.15,16
The N-Boc group cleavages of diamines 3aÀf were
effected with hydrochloric acid, which afforded the corre-
sponding HCl salts. Subsequent treatments of those with
triethylamine and additions of the respective thioisocya-
nates to the liberated diamines led to thioureas 4aÀs in
good to excellent yields (66À99%; Table 1).
Table 1. Syntheses of Thioureas from N-Boc-Protected Cyclic
Diamines
The preparation of enantiomerically pure 3-amino-
substituted cyclic amines from R-amino acids was first
reported by Moon and Lee.17,18 Following their procedure
with slight modifications, N-Boc-protected diamines 3aÀf
were accessible in good yields (Scheme 1). Accordingly,
starting from L-aspartic acid (1a) and L-glutamic acid (1b)
the syntheses of pyrrolidine 3a and piperidines 3bÀf
proceeded via amino diols 2a and 2b, respectively. Dime-
sylations of the latter followed by cyclizations of the
doubly activated substrates upon treatment with primary
amines gave access to 3aÀf in overall yields of up to 71%
(over five steps).
entry
diamine
R1
R2
product yielda (%)
1
2
3a (n = 1) Me
3b (n = 2) Me
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
4a
4b
4c
4d
4e
4f
86
81
66
82
92
94
89
67
98
99
95
70
96
97
79
96
94
99
97
3
3c (n = 2) i-Pr 3,5-(CF3)2C6H3
3d (n = 2) t-Bu 3,5-(CF3)2C6H3
4
5
3e (n = 2) Cy
3f (n = 2) Bn
3b (n = 2) Me
3b (n = 2) Me
3b (n = 2) Me
3b (n = 2) Me
3b (n = 2) Me
3b (n = 2) Me
3b (n = 2) Me
3b (n = 2) Me
3b (n = 2) Me
3b (n = 2) Me
3b (n = 2) Me
3b (n = 2) Me
3,5-(CF3)2C6H3
3,5-(CF3)2C6H3
C6H5
6
7
4g
4h
4i
8
p-(CH3)C6H4
p-(CF3)C6H4
p-(NO2)C6H4
p-ClC6H4
9
10
11
12
13
14
15
16
17
18
19
4j
4k
4l
Scheme 1. Syntheses of N-Boc-Protected 3-Amino Cyclic
Amines from Natural Amino Acids
3,5-Cl2C6H3
p-FC6H4
4m
4n
4o
4p
4q
4r
4s
2-naphthyl
2,6-(CH3)2C6H3
Bn
i-Bu
CH2Cy
3d (n = 2) t-Bu Bn
a After column chromatography.
With the goal of evaluating the organocatalytic potential of
the newly prepared thioureas, they were tested in Michael
addition reactions of R-nitrocyclohexanone (5) to 2-fluoro-β-
nitrostyrene (6a) (Table 2). The transformation was expected
to reveal eventual catalytic activities of 4aÀsandtobe agood
indicator for the intrinsic stereoselectivity during the CÀC
bond formation affording dinitrocyclohexanone 7a having
two stereogenic centers with one being quaternary.
(11) For reviews with a focus on Michael-type additions to nitroalk-
enes, see: (a) Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem.
2002, 1877. (b) Tsogoeva, S. B. Eur. J. Org. Chem. 2007, 1701. (c) Almasi,
D.; Alonso, D. A.; Najera, C. Tetrahedron: Asymmetry 2007, 18, 299.
(d) Vicario, J. L.; Badia, D.; Carrillo, L. Synthesis 2007, 2065.
(e) Sulzer-Mosse, S.; Alexakis, A. Chem. Commun. 2007, 3123.
(12) For the formation of quaternary centers in organic synthesis,
see: (a) Quaternary Stereocenters: Challenges and Solutions for Organic
Synthesis; Christoffers, J., Baro, A., Eds.; Wiley-VCH: Weinheim, 2005.
(b) Christoffers, J.; Baro, A. Adv. Synth. Catal. 2005, 347, 1473. (c) Cozzi,
P. G.; Hilgraf, R.; Zimmermann, N. Eur. J. Org. Chem. 2007, 5969.
(d) Bella, M.; Gasperi, T. Synthesis 2009, 1583.
First, thiourea 4a derived from N-methylpyrrolidine 3a
and 3,5-bis(trifluoromethyl)phenyl thioisocyanate was
(15) For a review on conjugate additons of nitroalkanes to electron-
poor alkenes, see: Ballini, R.; Bosica, G.; Fiorini, D.; Palmieri, A.;
Petrini, M. Chem. Rev. 2005, 105, 933.
(16) In an early example of an organocatalytic asymmetric Michael
addition of 2-nitrocycloalkanones to methyl vinyl ketone, see: Latvala,
A.; Stanchev, S.; Linden, A.; Hesse, M. Tetrahedron: Asymmetry 1993, 4,
173.
(13) For selected recent examples of Michael additions to R-substituted
cyclic ketones, see: (a) Zhang, Z.-H.; Dong, X.-Q.; Chen, D.; Wang,
C.-J. Chem.;Eur. J. 2008, 14, 8780. (b) Luo, J.; Xu, L.-W.; Hay,
ꢀ
R. A. S.; Lu, Y. Org. Lett. 2009, 11, 437. (c) Manzano, R.; Andres,
(17) Moon, S.-H.; Lee, S. Synth. Commun. 1998, 28, 3919.
(18) For recent publications on 3-amino-substituted cyclic amines,
ꢀ
J. M.; Muruzabal, M. D.; Pedrosa, R. Adv. Synth. Catal. 2010, 352, 3364.
(d) Dong, X.-Q.; Teng, H.-L.; Tong, M.-C.; Huang, H.; Taoa, H.-Y.;
Wang, C.-J. Chem. Commun. 2010, 46, 6840. (e) Hong, B.-C.; Kotame,
P.; Lee, G.-H. Org. Lett. 2011, 13, 5758.
(14) (a) Ono, N. The Nitro Group in Organic Synthesis; Wiley-VCH:
New York, 2001. (b) Ballini, R.; Petrini, M. Tetrahedron 2004, 60, 1017.
~
see: (a) Camps, P.; Galdeano, C.; Munoz-Torrero, D.; Rull, J.; Calvet,
T.; Font-Bardia, M. Tetrahedron: Asymmetry 2011, 22, 745. (b) Cochi,
A.; Pardo, D. G.; Cossy, J. Eur. J. Org. Chem. 2012, 2023. (c) Sakurai,
R.; Sakai, K.; Kodama, K.; Yamaura, M. Tetrahedron: Asymmetry
2012, 23, 221.
Org. Lett., Vol. 14, No. 17, 2012
4519

applied. To our delight, the reaction proceeded at room
temperature and was complete after 17 h (Table 2, entry 1).
Product 7a was isolated in 78% yield, and its dr and er were
94:6 and 85:15, respectively. No reaction occurred in the
absence of the catalyst. Both yield and stereoselectivity
were improved in catalyses with pyrrolidine-based thiour-
eas. For example, the direct analogue to 4a, thiourea 4b,
gave 7a in 90% yield (Table 2, entry 2). While the dr was
identical (94:6), the er raised to 94:6. Increasing the steric
bulk of the substituent at the endocyclic nitrogen of the
catalystled tofurther improvements(Table2, entries 3À6).
Hence, the best result (with respect to yield and er) was
achieved with thiourea 4d having an N-tert-butyl substi-
tuent. With 10 mol % of that catalyst, 7a was obtained in
91% yield with dr and er values of 90:10 and 97:3,
respectively (Table 2, entry 4).19 Attempts to further
optimize the catalyst structure by modifying the thiourea
aryl fragment remained unsuccessful.20 As shown in a
series of N-methyl-substituted piperidine-based thioureas
(Table 2, entries 7À15), the yields in the formation of 7a
varied and the diastereselectivities were high. However, the
enantioselectivity did not improve. Interestingly, an ex-
change of the thiourea aryl by a benzyl group did lead to
the desired increase in stereoselectivity, and, with 4p,
product 7a was obtained in 91% yield having a dr of
94:6 and an er of 96:4 (Table 2, entry 16). With respect to
the yield (90%) and er (97:3), almost the same values were
observed in a catalysis with thiourea 4s which combined
theN-tert-butyl-substitutedpiperidine corewiththebenzyl
substituent (Table 2, entry 19). To our surprise, the dr
(82:18) was remarkably low here.
87:13 (Table 2, entry 20), all stereoselectivities were low
to moderate.
Table 2. Catalyst Screeninga
entry
cat.
yield of 7ab (%)
dr (anti:syn)c
erc
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
4a
4b
4c
4d
4e
4f
4g
4h
4i
78
90
76
91
72
79
56
33
65
25
84
79
82
82
84
91
58
74
90
64
23
17
89
31
94:6
94:6
90:10
90:10
90:10
94:6
88:12
92:8
93:7
95:5
93:7
91:9
93:7
89:11
95:5
94:6
93:7
92:8
82:18
92:8
66:34
87:13
94:6
92:8
85:15
94:6
96:4
97:3
96:4
94:6
88:12
88:12
91:9
89:11
91:9
92:8
92:8
89:11
87:13
96:4
With the goal to compare the aformentioned results with
those obtainable with related and established catalyst
structures, compounds 8À12 became part of the screening
process (Table 2, entries 20À24). Those included selenour-
ea 8,21 thiophosphinamide 9,22 and sulfonamide 10, which
all contained the N-methyl-substituted piperidine core.
Furthermore, Takemoto’s thiourea 115 and the Jørgensen/
Hayashi catalyst 1223 were tested. None of these com-
pounds, however, proved superior over the newly reported
thioureas 4, and, with the exception of selenourea 8 which
gave 7a in 64% yield with a dr of 92:8 and an er of
4j
4k
4l
4m
4n
4o
4p
4q
4r
4s
8d
92:8
92:8
97:3
87:13
50:50
40:60
22:78
56:44
9d
10d
11
12
(19) Use of ent-4d gave 7a with a dr of 95:5 and an er of 3:97 in 81%
yield. Why in this case the yield and the dr differed from the result with 4d
remain uninvestigated.
a Use of 0.3 mmol of 5 and 0.2 mmol of 6a in 1 mL of solvent. b After
column chromatography. c Determined by HPLC of the crude product
using a chiral stationary phase. d For synthetic details, see the Support-
ing Information.
(20) For effects of electronic variations of thiourea moieties, see:
(a) Li, X.; Deng, H.; Zhang, B.; Li, J.; Zhang, L.; Luo, S.; Cheng, J.-P.
Chem.;Eur. J. 2010, 16, 450. (b) Jakab, G.; Tancon, C.; Zhang, Z.;
Lippert, K. M.; Schreiner, P. R. Org. Lett. 2012, 14, 1724.
(21) To the best of our knowledge, this is the first reported use of a
selenourea in an asymmetric organocatalysis. Unfortunately, compound
8 appeared to decompose under the applied reaction conditions. The
synthesis of 8 involved the addition of 3b to phenyl isoselenocyanate.
For preparative aspects of isoselenocyanates, see: Barton, D. H. R.;
Parekh, S. I.; Tajbakhsh, M.; Theodorakis, E. A.; Tse, C.-L. Tetrahedron
1994, 50, 639.
(22) For recent examples of (thio)phosphorodiamide-catalyzed
Michael additions to nitroolefins, see: Wu, R.; Chang, X.; Lu, A.; Wang,
Y.; Wu, G.; Song, H.; Zhou, Z.; Tang, C. Chem. Commun. 2011, 47,
5034.
(23) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen,
K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (b) Hayashi, Y.; Gotoh,
H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212.
On the basis of the results of the catalyst screening
summarized in Table 2, thiourea 4d was chosen for the
subsequent studies.
Next, thesubstrate scope withrespect to the nitroalkenes
was studied. In general, the reaction conditions were kept
unchanged, except for the temperature which was lowered
from ambient temperature to 0 °C and the substrate ratio
which now involved a 1.5 fold excess of the nitroalkene. To
our delight, all compounds, including 2-furyl-substituted
4520
Org. Lett., Vol. 14, No. 17, 2012

starting from 3.6 mmol of 2-fluoro-β-nitrostyrene (6a),
0.927 g (83%) of product 7a with an er of 98:2 was obtained.
Apparently, the up-scaling was unproblematic.
Table 3. Substrate Scopea
Finally, the relative and absolute configuration of
Michael adduct 7c was determined to be S,S by X-ray
crystallographic analysis (Figure 1).24
entry nitroalkene
Ar
product yieldb (%) drc
erc
1
2
3
4
4
6
7
8
9
6a
6b
6c
6d
6e
6f
o-FC6H4
C6H5
7a
7b
7c
7d
7e
7f
90
77
58
75
73
82
88
78
73
91:9 98:2d
99:1 97:3
89:11 97:3d
93:7 97:3
91:9 97:3
88:12 97:3
97:3 98:2
93:7 98:2
97:3 96:4
o-ClC6H4
p-FC6H4
p-ClC6H4
p-BrC6H4
p-MeOC6H4
p-MeC6H4
2-furyl
6g
6h
6i
7g
7h
7i
a Use of 5 (0.4 mmol), 6 (0.6 mmol), and thiourea 4d (0.04 mmol) in
DCM (2 mL) at 0 °C. b After column chromatography. c Determined by
HPLC of the crude product on a chiral stationary phase; dr values refer
to anti:syn ratios. d The er of the product could be improved to >99.5:0.5
(as single diastereomer) by recrystallization from Et2O.
Figure 1. X-ray crystal structure of 7c.
In summary, we prepared new bifunctional thioureas
using N-alkylated 3-amino-substituted pyrrolidines and
piperidines derived from L-aspartic and L-glutamic acid,
respectively. Their applications in organocatalytic asym-
metric Michael additions of R-nitrocyclohexanone (5) to
aryl nitroalkenes 6aÀi provided products with excellent
stereoselectivities in high yields.
nitroalkene 6i, reacted well, and the corresponding addi-
tion products 7aÀi were obtained in yields ranging be-
tween 58% and 90% (Table 3). Although the catalysis with
o-fluoro-substituted nitroalkene 6a provided 90% of 7a
(Table 3, entry 1), the low yield (58%) in the conversion of
the nitroalkene 6c with the o-chloro substituent (Table 3,
entry 3) appeared to indicate that steric reasons played an
important role in the catalysis of the CÀC bond-forming
process. For the yields of the addition products, neither
electron-withdrawing nor electron-donating substituents
on the aryl of the nitroalkenes seemed to matter to a large
extent. The diastereoselectivities were generally high, leading
to dr values of about 90:10. All enantioselectivities were
above an er of 96:4. Also in that respect, o-fluoro-substituted
product 7a gave the best result (er of 98:2), which was
identical to the corresponding data for products 7g and 7h
(Table 3, entries 1, 7, and 8). It was also confirmed that the
reaction could be performed on an enlarged scale. Thus,
Acknowledgment. We thank Mr. Aboul-Kata and Mrs.
Hoffmann (both RWTH Aachen University) for their
experimental work in this project, and we are grateful to
Dr. Husmann (RWTH Aachen University) for fruitful
discussions and Dr. Kleine as well as Dr. Priebbenow
(both RWTH Aachen University) for proofreading the
manuscript.
Supporting Information Available. Experimental pro-
cedures, full characterization of new products, copies of
NMR spectra, er determinations, and X-ray crystal data
for 7c (CIF). This material is available free of charge via
the Internet at http://pubs.acs.org.
(24) CCDC (7c) 897030 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
datarequest/cif.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 17, 2012
4521