Catalytic asymmetric addition of thiols to nitrosoalkenes leading to chiral non-racemic α-sulfenyl ketones

Article abstract of DOI:10.1021/ol2012633

The first asymmetric organocatalytic sulfenylation of in situ derived nitrosoalkenes leading to chiral nonracemic α-sulfenylated ketones is described. The transformation proceeds in an umpolung fashion, relative to enolate/azaenolate methods, and uses simple thiols, thereby obviating the need for electrophilic sulfur reagents.

Full text of DOI:10.1021/ol2012633

ORGANIC
LETTERS
2011
Vol. 13, No. 15
3810–3813
Catalytic Asymmetric Addition of Thiols to
Nitrosoalkenes Leading to Chiral
Non-Racemic r-Sulfenyl Ketones
John M. Hatcher, Mark C. Kohler, and Don M. Coltart*
Department of Chemistry, Duke University, Durham, North Carolina 27708,
United States
don.coltart@duke.edu
Received May 15, 2011
ABSTRACT
The first asymmetric organocatalytic sulfenylation of in situ derived nitrosoalkenes leading to chiral nonracemic R-sulfenylated ketones is
described. The transformation proceeds in an umpolung fashion, relative to enolate/azaenolate methods, and uses simple thiols, thereby
obviating the need for electrophilic sulfur reagents.
The R-functionalization of ketones in an umpolung
sense, wherein a nucleophilic species adds to an electro-
philic R-carbon, provides an attractive alternative to en-
olate/azaenolate-based methods and is well suited to
catalysis. We are currently exploring ways to achieve this
through the use of activated alkenes (e.g., azo- and
nitrosoalkenes) obtained by the oxidation of hydrazones
and related compounds.1 Recent reports by Jørgensen,2
Deng,3 and Fu4 highlight the general importance of
asymmetric sulfenylation reactions. Chiral nonracemic
sulfur-containing compounds are important both bio-
logically5 and in a synthetic context6 through their use as
chiral auxiliaries,7 ligands for metal catalysis,8 and
organocatalysts.9 We reasoned that the umpolung strategy
we are investigating could provide the basis for the devel-
opment of a novel approach to the asymmetric synthesis of
R-sulfenylated ketones. Such compounds are normally
obtained from the addition of an electrophilic sulfur
species to a preformed enolate/azaenolate.10,11 Unfortu-
nately, no general and effective method is available to
(9) McGarrigle, E. M.; Aggarwal, V. K. In Enantioselective Organo-
catalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007; Chapter 10.
(10) For example, see: (a) Wladislaw, B; Marzorati, L.; Di Vitta, C.
Org. Prep. Proced. Int. 2007, 39, 447–494. (b) Trost, B. M. Chem. Rev.
1978, 78, 363–382. (c) Trost, B. M. Acc. Chem. Res. 1978, 11, 453–461.
(d) Corey, E. J.; Knapp, S. Tetrahedron Lett. 1976, 4687–4690.
(e) Seebach, D.; Teschner, M. Chem. Ber. 1976, 109, 1601–1616.
(11) For asymmetric methods employing chiral auxiliaries, see: (a)
(1) Hatcher, J. M.; Coltart, D. M. J. Am. Chem. Soc. 2010, 132, 4546–
4547.
(2) Marigo, M; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794–797.
(3) Liu, Y.; Sun, B.; Wang, B.; Wakem, M.; Deng, L. J. Am. Chem.
Soc. 2009, 131, 418–419.
€
Enders, D.; Schafer, T.; Mies, W. Tetrahedron 1998, 54, 10239–10252.
(4) Sun, J.; Fu, G. C. J. Am. Chem. Soc. 2010, 132, 4568–4569.
(5) (a) Chatgilialoglu, C.; Asmus, K.-D. Sulfur-Centered Reactive
Intermediates in Chemistry and Biology; Springer: New York, 1991. (b)
Bruice, T. C.; Benkovic, S. J. Bioorganic Mechanisms; Benjamin: New
York, 1966; Vol. 1, Chapter 3.
(6) Toru, T.; Bolm, C. Organosulfur Chemistry in Asymmetric Synth-
esis; Wiley-VCH: Weinheim, Germany, 2008.
(7) Roos, G. Compendium of Chiral Auxiliary Applications; Elsevier
Science: Amsterdam, 2001.
(b) Youn, J.-H.; Herrmann, R.; Ugi, I. Synthesis 1987, 159–161. For an
asymmetric method employing a stoichiometric chiral ligand, see:(c)
Yura, T.; Iwasawa, N.; Clark, R.; Mukaiyama, T. Chem. Lett. 1986,
1809–1812. For an asymmetric method employing a chiral sulfenylating
reagent, see: (d) Hiroi, K.; Nishida, M.; Nakayama, A.; Nakazawa, K.;
Fujii, E.; Sato, S. Chem. Lett. 1979, 969–972.
(12) Use of the Enders SAMP/RAMP auxiliaries has proven effective
in delivering R-sulfenylated SAMP/RAMP hydrazones (48ꢀ87% yield;
dr = 95.5:4.5 to 98:2). However, complications during auxiliary removal
result in low yields of the corresponding R-sulfenylated ketones or in
compromised enantiomer ratios. See ref 11a.
(8) Pellissier, H. Chiral Sulfur Ligands: Asymmetric Catalysis; Royal
Society of Chemistry: Cambridge, U.K., 2009.
r
10.1021/ol2012633
Published on Web 06/29/2011
2011 American Chemical Society

conduct this transformation asymmetrically,11,12 and a
catalytic asymmetric process has never been reported. In
what follows, we describe the first catalytic asymmetric
sulfenylation of in situ derived nitrosoalkenes, leading to
chiral nonracemic R-sulfenylated ketones. This method
reliably delivers high levels of asymmetric induction and
occurs under mild and operationally simple conditions.
Moreover, the transformation proceeds in an umpolung
fashion, relative to conventional enolate/azaenolate meth-
ods, using simple thiols.
Scheme 1. Proposed Catalytic Asymmetric Umpolung Sulfe-
nylation
Figure 1. Amino (thio)urea catalysts 6ꢀ15.
transformation, we were particularly interested in chiral
amino (thio)ureas (cf. Figure 1). Such compounds should
provide greater structural organization than simple chiral
amines during the key bond-forming step as a result of
hydrogen bonding (cf. 4 and 5, Scheme 1) and facilitate
intracomplex attack of the nucleophile.
N-Sulfonyl azo- and nitrosoalkenes undergo conjugate
addition by certain nucleophiles.1,13 Addition of benzene
thiol to R-chloro N-sulfonyl hydrazones can be achieved
using Et3N.13a However, greater than 2 equiv of base are
needed to ensure in situ formation of both the azoalkene
intermediate and the corresponding ammonium thiolate.
We theorized that if the activated olefin were generated
(1f2, Scheme 1) irreversibly14 prior to the thiolate addition
step, then a catalytic amount of a chiral amine could be used,
leading to an asymmetric sulfenylation reaction (2 f 3).
Moreover, a racemic halogen species (1) would be adequate
as the olefin precursor. As potential catalysts for this
The general structure of the catalysts we required for our
work is well-known in the context of certain bifunctional
catalysts, which have been used to facilitate a variety of
transformations.15 Although our mechanistic proposal de-
viates from the mechanism that appears operative in those
reports, the catalysts they employed provided us with an
excellent starting point from which to launch our studies.
Thus, we began by investigating the sulfenylation of R-
chloro oxime 16 and R-chloro N-sulfonyl hydrazone 17
using the readily accessible compound 615a as a potential
asymmetric catalyst (Table 1). The intermediate nitroso- and
azoalkenes, respectively, were generated by treatment with
NaHCO3. Gratifyingly, compound 6 indeed catalyzed the
formation of the desired product enantioselectively begin-
ning from substrate 16. However, no asymmetric induction
resulted under the same conditions in the case of substrate
17. The structurally related urea catalyst 7 was also tried
with R-chloro oxime 16 but gave poorer asymmetric
induction than its thiourea counterpart (6). Several other
amino thioureas were tested as catalysts for the transfor-
mation (see Table 1), but only 14 and 153 showed a clear
improvement in enantioselectivity over 6. Notably, cata-
lysts 14 and 15 were complementary to 6 with regard to the
absolute sense of asymmetric induction, offering a con-
venient way of accessing either enantiomer of 18.
(13) For example, see: (a) Reese, C. B.; Sanders, H. P. J. Chem. Soc.,
Perkin Trans. 1 1982, 2719–2724. (b) Cacchi, S.; Misiti, D.; Felici, M.
Synthesis 1980, 147–149. (c) Sacks, C. E.; Fuchs, P. L. J. Am. Chem. Soc.
1975, 97, 7372–7374. (d) Korboukh, I.; Kumar, P.; Weinreb, S. M.
J. Am. Chem. Soc. 2007, 129, 10342–10343. (e) Ohno, M.; Torimitsu, S.;
Naruse, N.; Okamoto, M.; Saki, I. Bull. Chem. Soc. Jpn. 1966, 39, 1129–
1134.
(14) Cf. Rosini, G.; Baccolini, G. J. Org. Chem. 1974, 39, 826–828
and references therein.
(15) For example, see: (a) Schreiner, P. R.; Wittkopp, A. Org. Lett.
2002, 4, 217–220. (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007,
107, 5713–5743. (c) Zhang, Z.; Schreimer, P. R. Chem. Soc. Rev. 2009,
ꢀ
ꢀ
38, 1187–1198. (d) Vakulya, B.; Varga, S.; Csampai, A.; Soos, T. Org.
Lett. 2008, 7, 1967–1969. (e) Andres, J. M.; Manzano, R.; Pedrosa, R.
Chemistry 2008, 14, 5116–5119. (f) Tan, K. L.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 2007, 46, 1315–1317. (g) Lubkoll, J.; Wennemers, H.
Angew. Chem., Int. Ed. 2007, 46, 6841–6844. (h) Song, J.; Wang, Y.;
Deng, L. J. Am. Chem. Soc. 2006, 128, 6048–6049. (i) Inokuma, T.;
Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2006, 128, 9413–9419. (j)
Okino, T.; Hoashi, Y.; Furukawa, T.; Xu, X.; Takemoto, Y. J. Am.
Chem. Soc. 2005, 127, 119–125. (k) Wang, J.; Li, H.; Yu, X.; Zu, L.;
Wang, W. Org. Lett. 2005, 7, 4293–4296. (l) Wang, J.; Li, H.; Duan, W.;
Zu, L.; Wang, W. Org. Lett. 2005, 7, 4713–4716. (m) McCooey, S. H.;
Connon, S. J. Angew. Chem., Int. Ed. 2005, 44, 6367–6370. (n) Song, J.;
Ye, J.; Dixon, D. J.; Hynes, P. S. Chem. Commun. 2005, 4481–4483. (o)
Okino, T.; Hoashi, Y.; Takemoto, Y. J. Am. Chem. Soc. 2003, 125,
12672–12673.
To further investigate the effect of temperature and
solvent, the transformation between 16 and benzene thiol
was studied using catalyst 6 (Table 2). Interestingly, no
Org. Lett., Vol. 13, No. 15, 2011
3811

electronic properties of the thiols used. Interestingly, how-
ever, the two most sterically hindered thiols underwent the
addition reaction with relatively low enantioselectivity
(entries 7 and 8). Of the thiols examined, the best enantio-
selectivity resulted with the use of benzene thiol and 2-mer-
captothiophene (entries 1 and 2).
Table 1. Survey of Conditions for Asymmetric R-Sulfenylation
entry
substrate (Y)
catalyst
product
era
yield (%)
Table 3. Scope of the Asymmetric R-Sulfenylation Reaction
with Various Thiols
1
16 (O)
6
18
19
18
18
18
18
18
18
18
18
18
10:90
49:51
32:68
14:86
77:23
56:44
53:47
91:9
86
74
82
84
78
70
72
84
82
86
84
2
17 (NSO2Tol)
6
3
16
16
16
16
16
16
16
16
16
7
4
8
5
9
6
10
11
12
13
14
15
7
era
yield (%)
8
entry
thiol (R =)
product
9
90:10
94:6
1
2
3
4
5
6
7
8
9
10
Ph
18
20
21
22
23
24
25
26
27
28
94:6
86
84
85
88
82
86
76
78
79
86
10
11
2-Thienyl
93:7
94:6
4-F-C6H4
90:10
91:9
a Determined by chiral HPLC analysis.
2-Thiazole
4-MeO-C6H4
4-CF3-C6H4
2,6-(Me)2-C6H4
CPh3
89:11
87:13
80:20
70:30
69:31
65:35
improvement in asymmetric induction resulted at tempera-
tures above or below ꢀ30 °C (entries 1ꢀ4).16 This was also
true of the various solvents tried for the reaction at ꢀ30 °C
(entries 5ꢀ9), each of which gave inferior results in compar-
ison to CH2Cl2 with regard to both asymmetric induction
and yield.
4-NO2-C6H4
3,4-(CF3)2-C6H4
a Determined by chiral HPLC analysis.
We next turned our attention to investigating the scope
of the reaction with different R-chloro oximes and benzene
thiol (Table 4). The transformation extended to the use of
other cyclic R-chloro oximes (entries 2 and 3), although the
asymmetric induction was compromised somewhat for the
five-membered system (33). We were pleased to find that
the reaction could also be conducted in an asymmetric
fashion with acyclic R-chloro oximes. In this case, the best
results were obtained when there was a clear steric distinc-
tion between the R and R0 substituents (cf. 42). Presumably
this is due to a bias for the formation of the most sterically
favored olefin configuration of the nitrosoalkenes, during
deprotonation of the R-chloro oximes.
Having established an effective catalytic asymmetric sul-
fenylation reaction, we investigated the hydrolysis of the
product oximes to ensure that they could be converted to the
corresponding R-sulfenyl ketones without compromising
the integrity of the new stereogenic center. After some
experimentation, we were led to the use of IBX,17 which
allowed us to generate the R-sulfenyl ketones from the
oximes without epimerization and in high yield (Table 4).
Initial investigations into the mechanism of the trans-
formation were conducted as follows. First, to confirm
that the nitrosoalkene was indeed formed and the putative
electrophile in the reaction, a solution of 16 in CDCl3
(distilled over CaH2) was treated with saturated aqueous
NaHCO3 and then dried (MgSO4). The product of this
Table 2. Effect of Solvent and Temperature on the Asymmetric
R-Sulfenylation of 16 Catalyzed by 6
entry
solvent
temp (°C)
era
yield (%)
1
2
3
4
5
6
7
8
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
Et2O
23
4
20:80
12:88
10:90
10:90
20:80
26:74
25:75
12:88
20:80
76
80
86
81
68
24
23
82
70
ꢀ30
ꢀ78
ꢀ30
ꢀ30
ꢀ30
ꢀ30
ꢀ30
MeCN
toluene
THF
a Determined by chiral HPLC analysis.
Since the best result of our study to this point was obtained
using catalyst 14 in CH2Cl2 at ꢀ30 °C, these conditions were
used to investigate the scope of the reaction with various
thiols (Table 3). Both electron-rich and -deficient systems
reacted effectively. No trend could be ascertained in these
initial studies with regard to asymmetric induction, and the
(17) Bose, D. S.; Srinivas, P. Synlett 1998, 977–978.
(18) Francotte, E.; Merenyi, R.; Viehe, H. Helv. Chim. Acta 1981, 64,
1208–1218.
(16) Studies are underway to determine if this temperature effect
translates to other catalysts.
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Org. Lett., Vol. 13, No. 15, 2011

Table 4. Scope of the Asymmetric R-Sulfenylation Reaction
with Various Thiols
Scheme 2. (a) Determination of Absolute Stereochemistry;
(b) Proposed Nitrosoalkenes Intermediates
umpolung sulfenylation method. Using a related approach,
we were able to establish that the major enantiomer
of the ketone (38) produced from R-chloro oxime 36
(Table 3, entry 4) also had the R-configuration at the new
stereogenic center (see (R)-38, Scheme 2a).19 Since sulfeny-
lation of both acyclic compound 36 and cyclic compound
16 gave the same sense of chirality at the newly formed
stereogenic center, we assume that, like the cyclic R-chloro
oximes, the acyclic systems also react via the nitrosoalkene
in which the nitrogen and the R-alkyl substituent have
the E-configuration about the carbonꢀcarbon bond
(cf. Scheme 2b).
In conclusion, we have developed the first catalytic
asymmetric approach to the sulfenylation of in situ derived
nitrosoalkenes, leading to chiral nonracemic R-sulfenylated
ketones. The transformation proceeds in an umploung
fashion, relative to conventional enolate/azaenolate meth-
ods, using simple thiols and known derivatives of readily
accessible cinchona alkaloids as catalysts. Further mechan-
istic studies of this transformation are underway, as are
studies on the use of different electrophiles and nucleophiles,
and the exploration and development of improved catalysts.
a Determined by chiral HPLC analysis.
reaction exhibited 1H NMR data consistent with the
corresponding nitrosoalkene.18 In a second set of experi-
ments, racemic 18 was prepared and combined with
catalyst 14 in CH2Cl2. The product composition was
analyzed after 1 h and showed a 50:50 mixture of
enantiomers, indicating that no enantiomeric enrichment
had occurred. This supports the notion that, for the
enantioselective transformation, asymmetric induction re-
sults during addition of the ammonium thiolate to the
nitrosoalkene.
The absolute stereochemistry of the addition reaction
was determined using our recently developed method for
asymmetric ketone R-functionalization,19 as outlined in
Scheme 2a. To do so, cyclohexanone was converted to N-
amino cyclic carbamate (ACC) hydrazone 47 by condensa-
tion with ACC auxiliary 46. Sulfenylation of this compound
via the derived azaenolate gave 48 as a single diastereomer,
and the crystal structure of this compound was obtained.20
Hydrolysis of 48 then gave (S)-29 as the major enantiomer,21
which was the opposite of that formed from the present
Acknowledgment. J.M.H. holds a C. R. Hauser Fellow-
ship and M.C.K. a Burroughs-Wellcome Fellowship (Duke
University). We thank Cyndie Seraphin (Duke University)
for conducting certain experiments, and Christopher R.
Brue and Dr. Kristin Kirschbaum (University of Toledo)
for X-ray crystalography.
Supporting Information Available. Experimental pro-
cedures and analytical data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) (a) Lim, D.; Coltart, D. M. Angew. Chem., Int. Ed. 2008, 47,
5207–5210. (b) Krenske, E. H.; Houk, K. N.; Lim, D.; Wengryniuk,
S. E.; Coltart, D. M. J. Org. Chem. 2010, 75, 8578–8584.
(20) See the Supporting Information for details.
(21) Some epimerization occurred during hydrolysis.
Org. Lett., Vol. 13, No. 15, 2011
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