A novel C-5′ substituted cinchona alkaloid-derived catalyst promotes additions of alkyl thiols to nitroolefins with excellent enantioselectivity

Article abstract of DOI:10.1039/c2cc17965b

A new bifunctional C-5′ substituted cinchona alkaloid-based catalyst promotes the first highly enantioselective additions of alkyl thiols to nitrostyrenes. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc17965b

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COMMUNICATION
A novel C-50 substituted cinchona alkaloid-derived catalyst promotes
additions of alkyl thiols to nitroolefins with excellent enantioselectivitywz
Carole Palacio and Stephen J. Connon*
Received 20th December 2011, Accepted 26th January 2012
DOI: 10.1039/c2cc17965b
A new bifunctional C-50 substituted cinchona alkaloid-based
catalyst promotes the first highly enantioselective additions of
alkyl thiols to nitrostyrenes.
devised a protocol for the catalytic asymmetric addition of
thioacetic acid to nitrostyrenes, with levels of product enantio-
meric excess up to a maximum of 78% possible. Later, Ellman
et al.9 developed chiral N-sulfinyl urea-based catalysts capable
of promoting the reaction with up to 96% product ee at ꢀ78 1C.
The process is complicated by product consuming Baylis-
Hillman-type chemistry under the reaction conditions, which limits
the product yields to 63–88%, with higher yields (up to 95%)
achievable when aliphatic nitroolefins are employed.
There has been a great deal of recent interest in the catalytic
asymmetric addition of thiols to Michael acceptors.1 Much of this
attention has been focused on the organocatalytic variant of the
process;2 however - despite considerable endeavour - the scope of
these reactions is reasonably narrow. Specifically, the asymmetric
addition of thiophenols to a range of Michael acceptors promoted
by bifunctional tertiary amine-based catalysts is now relatively
straight forward, however, in the majority of studies the less
reactive yet considerably more versatile aliphatic thiols are either
not utilised or are reported to undergo considerably less selective
addition than their aromatic counterparts.3,4 Outside of iminium
ion catalysis (enone/enal substrates),5 examples of the highly
enantioselective addition of aliphatic thiols to Michael acceptors
are very rare (Fig. 1).6 In the case of the highly synthetically
malleable 1,2-disubstituted nitroalkenes, no examples are known.7
A indirect solution to this problem has been identified
independently by Wang and Ellman: use of thioacetic acid
(2.0 equiv.) as the nucleophile allows the possibility of later
cleaving the thioester adduct hydrolytically, followed by an alkyla-
tion to give the product formally derived from the addition of an
aliphatic thiol to the nitroalkene. In 2006, the former group8
We were intrigued by and drawn to this curious general
inferiority of synthetically relevant alkyl thiols in these organo-
catalysed Michael-type processes. While it was tempting to
attribute this to the lower activity of alkyl thiols due to their
reduced acidity, pronucleophiles of both similar and higher
acidity have been shown to add to nitroolefins enantioselectively
under similar conditions in the presence of cinchona alkaloid-
based bifunctional catalysts.10,11 We therefore postulated that the
dearth of literature examples may be related to a combination of
mechanistic and stereoelectronic factors: i.e. it is likely that
catalysis by tertiary amines involving thiophenol (pKa = 6.5212)
occurs largely through specific base catalysis, while the less
acidic alkane thiols (benzyl mercaptan pKa = 9.4312) would
require proton transfer in the transition state (i.e. general base
catalysis), where stereocontrol over the formation and cleavage
of longer bonds to a 2nd row element (relative to either carbon
or other first row element based pronucleophiles) may be
beyond the abilities of previously evaluated bifunctional
catalyst systems (the relative positioning of the bifunctional
components in which are reasonably invariant) such as 1. In this
regard we note with interest that Melchiorre et al. reported that
the addition of the P-based pronucleophile diphenylphosphine
(pKa (DMSO) = 22.913)14 to nitroolefins catalysed by the
bifunctional catalyst 1 proceeded with moderate ee (36–67%).15
We recently16 designed a range of C-50-substituted cinchona
alkaloid-derived catalysts devised to introduce some variation
in this key catalyst attribute (i.e. the positioning of the
bifunctional components),17 and were naturally interested in
evaluating their potential as catalysts for the problematic
process outlined above. The results of this preliminary survey
are presented in Table 1. First it was confirmed that no back-
ground reaction between (E)-b-nitrostyrene (2) and t-butyl benzyl
mercaptan (3a)18 in the absence of catalyst occurs (entry 1). Then,
beginning with the optimum catalyst from our previous study
(i.e. 5) at 5 mol% levels in MTBE, we evaluated the addition of
Fig. 1 Organocatalytic Michael-type additions involving thiols.
School of Chemistry, Centre for Synthesis and Chemical Biology,
Trinity Biomedical Sciences Institute, University of Dublin,
Trinity College, Dublin 2, Ireland. E-mail: connons@tcd.ie;
Fax: +35316712826
w This article is part of the ChemComm ‘Chirality’ web themed issue.
z Electronic supplementary information (ESI) available: experimental
procedures and characterisation data. CCDC 859316. For ESI and
crystallographic data in CIF or other electronic format see DOI:
10.1039/c2cc17965b
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2849–2851 2849

Table 1 Preliminary catalyst evaluation
Table 2 Investigation of substrate scope
Loading Conc.
(mol%) (M)
Yield ee
t (h) (%)a (%)b
Entry
Product
1
10
0.02
20
96
90
2
3
4
20
0.01
68
68
68
98
84
97
86
91
90
20
20
0.007
0.01
Cat.
(mol%) Prod.
Conc.
(M)
Yield ee
t (h) (%)a (%)b
Entry
Solv.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19c
20c
21c
22c
23c
24d
25d
26d
— (0)
5 (5)
5 (5)
5 (5)
5 (5)
5 (5)
5 (5)
5 (5)
5 (5)
6 (5)
7 (5)
8 (5)
9a (5)
9b (5)
1 (5)
10 (5)
11 (5)
12 (5)
12 (5)
12 (5)
12 (5)
12 (5)
12 (5)
12 (5)
12 (5)
12 (10)
4a
4a
4b
4c
4d
4e
4d
4d
4d
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
4a
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
THF
0.37
0.44
0.4
0.37
0.37
0.4
16
16
16
16
16
16
40
40
40
16
16
16
16
16
16
21
21
16
72
72
24
72
72
72
72
24
0
498
498
498
498
85
0
32
25
4
3
0
5
4
7
1
0.37
498
498
498
498
498
498
498
498
498
498
498
498
498
498
498
498
498
498
79
CH2Cl2 0.37
PhMe
0.37
0.37
0.37
0.37
0.37
0.37
0.37
0.37
0.37
0.37
0.37
0.37
0.37
0.37
5
6
10
20
0.02
0.01
20
68
93
99
92
90
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
Et2O
8
17
33
ꢀ8
ꢀ1
ꢀ8
4
51
71
69
63
75
78
88
63
92
7
8
10
10
10
0.02
0.02
0.02
20
20
20
91
82
98
96
93
90
PhMe
CHCl3
CH2Cl2 0.37
CH2Cl2 0.04
CH2Cl2 0.004
CH2Cl2 0.02
498
Determined by 1H NMR spectroscopy using styrene as an internal
a
b
c
d
standard. Determined by CSP-HPLC. At ꢀ30 1C. At ꢀ78 1C.
a range of thiols (3a–e) of variable acidity to 2. The general trend
observed in previous studies is reversed in the presence of catalyst
5: alkyl thiols 3a and 3b undergo moderately selective reaction
(entries 2–3), while more acidic thiols 3d and 3e furnish either
racemic or almost racemic products (entries 5–6).
9
10
20
20
0.01
0.01
96
96
56
77
94
89
Interestingly the hindered thiol 3c proved a poor substrate
(entry 4) and the failure of thiophenol to add enantioselectively
to 2 is not solvent-specific (entries 7–9). Next a catalyst screen
was undertaken: catalysts devoid of the C-50 urea (i.e. 6 and 7,
entries 10–11) promoted efficient but unselective reactions, and
while the C-50- bis-urea substituted catalyst 8 fared marginally
better (entry 12), it represented no improvement upon 5.
Variation of the C-9 substituent of catalyst 5 proved instructive:
11
a
b
Isolated yield after chromatography. Determined by CSP-HPLC.
c
2850 Chem. Commun., 2012, 48, 2849–2851
This journal is The Royal Society of Chemistry 2012

use of the methoxy-substituted catalyst 9a (entry 13) led to
slightly higher product ee, whereas the corresponding benzoyl
analogue 9b is a poor catalyst from a stereoselectivity standpoint.
As expected, representative traditional literature catalyst systems
characterised by functionality capable of donating two hydrogen
bonds at C-9 (i.e. 1,3c,10a,b,19 1020 and 11,21 entries 15–17 respec-
tively) failed to promote this reaction involving an alkyl thiol
enantioselectively.
2010, 49, 4290; (h) S. Bonollo, D. Lanari, F. Pizzo and L. Vaccaro,
Org. Lett., 2011, 13, 2150.
3 (a) Non-nitroalkene electrophiles: H. H. Hiemstra and H. Wynberg,
J. Am. Chem. Soc., 1981, 103, 417; (b) P. McDaid, Y. Chen and
L. Deng, Angew. Chem., Int. Ed., 2002, 41, 338; (c) B.-J. Li, L. Jiang,
M. Liu, Y.-C. Chen, L.-S. Ding and Y. Wu, Synlett, 2005, 603;
(d) D. Enders and K. Hoffman, Eur. J. Org. Chem., 2009, 1665;
(e) N. K. Rana, S. Selvakumar and V. K. Singh, J. Org. Chem., 2010,
75, 2089; (f) Q.-L. Pei, H.-W. Sun, Z.-J. Wu, X.-J. Du, X.-M. Zhang
and W.-C. Yuan, J. Org. Chem., 2011, 76, 7849; (g) J. M. Hatcher,
M. C. Kohler and D. Coltart, Org. Lett., 2011, 13, 3810;
(h) X.-Q. Dong, X. Fang and C.-J. Wang, Org. Lett., 2011, 13, 4426.
4 (a) Nitroalkene electrophiles: M. Meciarova, S. Toma and P. Kotrusz,
Org. Biomol. Chem., 2006, 4, 1420; (b) S. Shirakawa, A. Moriyama and
S. Shimizu, Eur. J. Org. Chem., 2008, 5957; (c) J. Wang, H. Xie, H. Li,
L. Zu and W. Wang, Angew. Chem., Int. Ed., 2008, 47, 4177;
(d) Y. Gao, Q. Ren, H. Wu, M. Li and J. Wang, Chem. Commun.,
2010, 46, 9232; (e) X.-F. Wang, Q.-L. Hua, Y. Cheng, X.-L. An,
Q.-Q. Yang, J.-R. Chen and W.-J. Xiao, Angew. Chem., Int. Ed., 2010,
49, 8379.
5 (a) T. Ishino and T. Oriyama, Chem. Lett., 2007, 36, 550; (b) A. Kumar
and Akanksha, Tetrahedron, 2007, 63, 11086; (c) P. Ricci, A. Carlone,
G. Bartoli, M. Bosco, L. Sambri and P. Melchiorre, Adv. Synth. Catal.,
2008, 350, 49; (d) P. Galzerano, F. Pesciaioli, A. Mazzanti, G. Bartoli
and P. Melchiorre, Angew. Chem., Int. Ed., 2009, 48, 7892;
(e) M. Yoshida, Y. Ono and S. Hara, Tetrahedron Lett., 2010,
51, 5134; (f) X. Tian, C. Cassani, Y. Liu, A. Moran, A. Urakawa,
P. Galzerano, E. Arceo and P. Melchiorre, J. Am. Chem. Soc., 2011,
133, 17934.
Given the importance of the C-9 unit in the case of catalyst
5, it was decided to prepare an analogue with augmented steric
bulk at this position. Gratifyingly, installation of a large
(TBDPS) silyl-group resulted in a new catalyst (12) capable
of generating 4a in significantly improved enantiomeric excess
(entry 18). Enantioselectivity increased further at ꢀ30 1C
(entry 19) and a subsequent solvent screen (entries 20–23)
and temperature/concentration optimisation experiments
(entries 24–26) allowed conditions to be identified under which
12 (at 5 mol% loading) could promote the formation of 4a in
quantitative yield and 92% ee in 24 h.
With a useful protocol now in hand, attention turned to the
question of substrate scope (Table 2). We were pleased to find
that products derived from the addition of 3a to both activated
(13–15, entries 1–3) deactivated (16, entry 4) and heterocyclic
(both p-excessive and p-deficient, 17–19, entries 5–7) nitroolefins
could be generated in excellent yield and enantioselectivity.
Product ee was Z90% in all cases save that of the nitro-
substituted 14. Of particular synthetic utility is the use of alkane
thiol derivatives which can serve as synthetic equivalents for H2S:
i.e. sulfides containing photo-cleavable22 (i.e. 20, entry 8) and
acid/Hg2+-labile23 (i.e. 21, entry 9) functionality can be prepared
in excellent yield and ee using this methodology through the
selection of the appropriate thiol. Non-benzylic alkane thiols
are also compatible (22–23, entries 10–11).
6 (a) D. Leow, S. Lin, S. K. Chittimalla, X. Fu and C.-H. Tan,
Angew. Chem., Int. Ed., 2008, 47, 5641; (b) Y. Liu, B. Sun, B. Wang,
M. Wakem and L. Deng, J. Am. Chem. Soc., 2009, 131, 418; (c) L. Dai,
H. Yang and F. Chen, Adv. Synth. Catal., 2010, 352, 2137; (d) L. Dai,
H. Yang and F. Chen, Eur. J. Org. Chem., 2011, 5071.
7 It should be noted that a single example of an organocatalytic
asymmetric addition of a benzyl mercaptan derivative to a
b,b-disubstituted nitroalkene has been reported. This addition
required higher nucleophile and catalyst loadings, proceeded at a
slower rate and was less enantioselective (87% ee) than the
corresponding addition of thiophenol derivatives, see: H.-H. Lu,
F.-G. Zhang, X.-G. Meng, S.-W. Duan and W.-J. Xiao, Org. Lett.,
2009, 11, 3946.
8 H. Li, L. Zu, J. Wang and W. Wang, Tetrahedron Lett., 2006, 47, 3145.
9 K. L. Kimmel, M. T. Robak and J. A. Ellman, J. Am. Chem. Soc.,
2009, 131, 8754.
10 (a) For selected examples see: S. H. McCooey and S. J. Connon,
Angew. Chem., Int. Ed., 2005, 44, 6367; (b) J. Ye, D. J. Dixon and
P. S. Hynes, Chem. Commun., 2005, 4481; (c) T.-Y. Liu, H.-L. Cui,
Q. Chai, J. Long, B.-J. Li, Y. Wu, L.-S. Ding and Y.-C. Chen,
Chem. Commun., 2007, 2228.
11 For a potential caveat see: S. H. McCooey, T. McCabe and
S. J. Connon, J. Org. Chem., 2006, 71, 7494.
12 M. M. Kreevoy, E. T. Harper, R. E. Duvall, H. S. Wilgus III and
L. T. Ditsch, J. Am. Chem. Soc., 1960, 82, 4899.
13 J.-N. Li, L. Liu, Y. Fu and Q.-X. Guo, Tetrahedron, 2006, 62, 4453.
14 The pKa of thioacetic acid, thiophenol and benzylmercaptan
in DMSO are 5.2, 10.3 and 15.3 respectively: F. G. Bordwell,
Acc. Chem. Res., 1988, 21, 456.
15 G. Bartoli, M. Bosco, A. Carlone, M. Locatelli, A. Mazzanti,
L. Sambri and P. Melchiorre, Chem. Commun., 2007, 722.
16 C. Palacio and S. J. Connon, Org. Lett., 2011, 13, 1298.
17 (a) For previous examples see: S. Brandes, M. Bella, A. Kjoersgaard
and K. A. Jørgensen, Angew. Chem., Int. Ed., 2006, 45, 1147;
(b) X. Liu, B. Sun and L. Deng, Synlett, 2009, 1685.
18 A less malodorous alternative to benzyl mercaptan.
19 B. Vakulya, S. Varga, A. Csampai and T. Soos, Org. Lett., 2005,
7, 1967.
In summary, prompted by a curious dependence of enantio-
selectivity on the acidity of thiol nucleophiles in many organo-
catalytic conjugate additions, we have developed (to the best of
our knowledge) the first general, highly efficient and enantio-
selective organocatalytic system for the addition of previously
problematic alkane thiols to nitrostyrenes. The process is
promoted by a readily prepared novel C-50 substituted bifunctional
cinchona alkaloid catalyst and is of broad scope: a range of alkane
thiols (including those containing cleavable benzyl substituents)
and a variety of electron deficient, electron rich and heterocyclic
nitrostyrenes are compatible. We would like to thank the Irish
Research Council for Science Engineering and Technology for
funding and Dr T. McCabe for X-ray analysis.
Notes and references
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c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 2849–2851 2851