Highly enantioselective organocatalytic sulfa-michael addition to α, β-unsaturated ketones

Article abstract of DOI:10.1021/jo902634a

"Chemical Equation Presented" A cinchona alkaloid-derived urea was found to be an efficient organocatalyst for catalyzing enantioselective conjugate addition between thiols and various α,β-unsaturated ketones to provide optically active sulfides with high

Full text of DOI:10.1021/jo902634a

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Highly Enantioselective Organocatalytic
Sulfa-Michael Addition to r,β-Unsaturated Ketones
Nirmal K. Rana,†,§ Sermadurai Selvakumar,†,§ and
Vinod K. Singh*,†,‡,§
†Department of Chemistry, Indian Institute of Technology,
Kanpur, India 208 016, and ‡Indian Institute of Science
Education and Research Bhopal, ITI (Gas Rahat) Building,
Govindpura, India 462 023
FIGURE 1. Homochiral Bronsted acids.
Successful catalytic systems for the asymmetric version of
this reaction include cinchona alkaloid derivatives,4 hetero-
bimetallic complexes,5 chiral metal complexes,6 and organo-
catalysts.7 Despite all the progress made in this area, most of
the current catalytic systems have certain limitations such as
lower substrate scope, low reaction temperatures, relatively
high catalyst loading (∼20 mol %), and use of additives such
as molecular sieves. Hence, it is desirable to develop a
catalytic system that can overcome some of the limitations
associated with the existing methodologies. Recently, chiral
bifunctional thiourea derivatives8 have appeared to be effi-
cient organocatalysts for the different Michael addition
reaction. Among them, cinchona alkaloid-derived thioureas
have found wide applications in many enantioselective
transformations.9 As a part of our ongoing program on the
development of homochiral Bronsted acids for asymmetric
catalysis, we have investigated the reaction of thiols with R,β-
unsaturated ketones catalyzed by homochiral Bronsted acids
vinodks@iitk.ac.in
Received December 13, 2009
A cinchona alkaloid-derived urea was found to be an efficient
organocatalyst for catalyzing enantioselective conjugate addi-
tion between thiols and various R,β-unsaturated ketones to
provide optically active sulfides with high chemical yields (up to
>99%) and enantiomeric excess (up to >99% ee). The reac-
tion was performed with 0.1 mol % of catalyst in toluene at
room temperature. A transition state model has been proposed
to explain the stereochemical outcome of the reaction.
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The catalytic asymmetric Michael addition is one of the
most powerful transformations in asymmetric synthesis.1 In
recent years, a remarkable progress has been made in
organocatalytic version of this reaction.2 Among various
type of this reaction, sulfa-Michael addition provides direct
access to optically active sulfides that are versatile precursors
for the synthesis of biologically interesting compounds.3
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107, 5713–5743. (c) Takemoto, Y. Org. Biomol. Chem. 2005, 3, 4299–4306.
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§ Fax: þ91-512-2597436.
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2000, 56, 8033–8061. (b) Krause, N.; Hoffmann-Roder, A. Synthesis 2001,
171–196.
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Tetrahedron: Asymmetry 2007, 18, 299–365. (b) Tsogoeva, S. B. Eur. J. Org.
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2007, 3123–3133.
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DOI: 10.1021/jo902634a
r
Published on Web 02/24/2010
J. Org. Chem. 2010, 75, 2089–2091 2089
2010 American Chemical Society

Rana et al.
JOCNote
TABLE 1. Optimization of Reaction Condition for the Enantioselective
TABLE 2. Enantioselective Michael Addition of Different Aryl Thiols
to Cyclohexenonea
Michael Addition of Thiol to r,β-Unsaturated Enonesa
ee (%)b
entry
Ar
C6H5
2-MeC6H4
4-MeC6H4
2,4-Me2C6H3
2,6-Me2C6H3
2-EtC6H4
2-naphthyl
4-tBuC6H4
2-MeOC6H4
4-MeOC6H4
2-FC6H4
time (h)
product
yield (%)
ee (%)b
entry
catalyst
mol (%)
time (h)
yield (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1e
1f
10
5
1
0.5
0.5
2
2
2
12
12
2
2
2
2
2
4
2
2
2
5
>99
>99
>99
>99
>99
98
69
75
86
1
2
3
4
5
6
7
8
5
7
7
9
10
8
6
8
10
8
5
5
5
6
6
10
10
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
>99
>99
>99
>99
>99
>99
97
>99
>99
>99
>99
>99
>99
>99
>99
95
94
95
92
88
99
90
93
92
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.1
88
61c
81d
66e
66f
30
95
>99
>99
>99
>99
>99
>99
>99
>99
>99
>99
9
9
97
10
11
12
13
14
15
16
17
-70
-44
92
84
4
8
10
94
10
11
12
13
14
15
16
17
>99
90
91
85
91
92
90
89
4-FC6H4
2,4-F2C6H3
2-ClC6H4
4-ClC6H4
2-BrC6H4
4-BrC6H4
1g
1h
1i
1e
97
aReactions were carried out on a 0.5 mmol scale with 0.6 mmol of
thiol in 1 mL of toluene at room temperature, unless noted otherwise.
aReactions were carried out on a 0.5 mmol scale with 0.6 mmol of
thiol in 1 mL of toluene at room temperature, unless noted otherwise.
bDetermined by HPLC using chiral column.
b
c
Determined by HPLC using chiral column. 4 A molecular sieves were
˚
added. dReaction was carried out at 0 °C. eReaction was carried out at
-15 °C. fCH2Cl2 was used as a solvent.
bond donating arms were screened in the above reaction, and
the results are summarized in Table 1. However, the enan-
tioselectivities varied greatly depending on the organocata-
lyst used. The poor enantioselectivity with catalysts 1b-d
and 1g-i emphasize the correct relative orientation of acidic
and basic functional groups and importance of double
hydrogen bonding in the catalyst’s chiral scaffold. The lower
enantiomeric excess with catalyst 1f clearly indicates that
CF3 substituent on the aromatic ring is crucial for the
observed enantioselectivity (Table 1, entries 12 and 13).
Finally, we were pleased to find that lowering the catalyst
loading to 0.1 mol % had a positive effect on the enantios-
electivity and the product 2a was obtained in 94% ee while a
good level of conversion was maintained (Table 1, entry 17).
Having identified the optimized condition for this reaction, a
variety of aromatic thiols were then tested by using cyclohex-
enone as an acceptor (Table 2). High enantioselectivities were
obtained in almost all the cases. It is noteworthy that not only
the steric hindrance of the substituents at the aromatic rings but
also the electronic nature has no effect on the enantioselectivity.
To extend the scope of the reaction, Sulfa-Michael addi-
tion of other cyclic and acyclic enones was studied (Table 3).
Excellent enantioselectivities were achieved with wide vari-
ety of cyclic and acyclic enones. Interestingly, 4,4-dimethyl
cyclohexenone furnished the corresponding Michael adducts
in excellent enantioselectivities (up to >99% ee) and yields
(Table 3, entries 1-8). Apart from cyclohexenone, cyclic
enones such as cyclopentenone and cycloheptenone also
afforded the Michael adducts in high enantioselectivities
(Table 3, entries 9-15). The reaction was then extended to
acyclic enones and a variety of aryl thiols were screened.
Again, high enantioselectivities were obtained in almost all
the cases (Table 3, entries 16-21).
(Figure 1). In this Note, we wish to report the highly
enantioselective organocatalytic conjugate addition of thiols
with R,β-unsaturated ketones.
At the outset, sulfa-Michael reaction of thiophenol with
cyclohexenone was examined using thiourea 1a. Treatment
of thiol with cyclohexenone in the presence of 10 mol % of
the catalyst 1a in toluene at room temperature furnished
Michael adduct 2a in 69% ee (Table 1, entry 1). To
our delight, on decreasing the catalyst loading from 10 to
0.5 mol %, the enantioselectivity increased to a great extent,
with no appreciable change in chemical yield of the reaction
(Table 1, entries 2-4). Increase in enantioselectivity with low
catalyst loading indicates the formation of a more stereo-
controlled transition state at low local catalyst concentra-
˚
tion. Addition of 4 A molecular sieves had negative effect on
the enantioselectivity of the reaction (Table 1, entry 5). Role
of water on the enantioselectivity enhancement was not
clear. But, we believe that it plays a crucial role in stabilizing
the transition state via weak hydrogen bonding. However,
using water as a reaction medium led to racemic product.10
Lowering the reaction temperature to 0 °C and -15 °C did
not show any effect on the chemical yield, but the enantios-
electivity decreased when the reactions were carried out at
lower temperatures (Table 1, entries 6 and 7). However, on
changing the reaction medium to CH2Cl2,10 the product was
formed in high yield and moderate enantioselectivity
(Table 1, entry 8).
After optimizing reaction conditions with 1a, various
chiral Brønsted acid catalysts 1b-i with different hydrogen
(10) Other solvents were also screened for this reaction using the catalyst
1a, but its enantioselectivity was found to be inferior in comparison to
toluene: H2O (0%), EtOH (0%), CH3NO2 (17%), DCE (65%), THF (45%),
o-xylene (62%), CHCl3 (42%), and CH3CN (16%).
The proposed transition state model to explain the stereo-
chemical outcome of the reaction is shown in Figure 2. We
2090 J. Org. Chem. Vol. 75, No. 6, 2010

Rana et al.
JOCNote
TABLE 3. Enantioselective Michael Addition between Different Aryl
Thiols and Enonesa
has been explained with the help of a transition state model.
This protocol offers several advantages such as operational
simplicity, mild reaction conditions, low catalyst loading
(0.1 mol %), and high enantioselectivities (up to >99% ee)
and yields.
Experimental Section
General Procedure for the Enantioselective Organocatalytic
Michael Addition of Thiols with r,β-Unsaturated Ketones. 1.
Thiophenol (66 mg, 0.6 mmol) was added to a mixture of 2-
cyclohexenone 8a (48 mg, 0.5 mmol) and the catalyst 1e (50 μL
0.01 M stock solution in dry toluene, 0.289 mg, 0.0005 mmol) in
dry toluene (1.0 mL) at the room temperature. The reaction
mixture was stirred, and the progress of the reaction was
monitored by TLC. After the completion of the reaction, the
reaction mixture was concentrated in vacuum, and the crude
product was purified over silica gel by column chromatography.
The product 2a was obtained in >99% (102 mg) yield and 94%
ee. The enantiomeric excess of the Michael adduct was deter-
mined by chiral HPLC on chiralpak AD column [n-hexane/
2-propanol 98:2]; flow rate 1 mL/min; λ = 254 nm; tR(major) =
13.85 min (S), tR(minor) = 17.98 min (R); [R]D25 = -85.2 (c 1.0,
1
CHCl3). H NMR (500 MHz, CDCl3): δ 1.66-1.77 (m, 2H),
2.11-2.16 (m, 2H), 2.26-2.39 (m, 3H), 2.66-2.69 (m, 1H),
3.39-3.42 (m, 1H), 7.26-7.35 (m, 3H), 7.41-7.42(m, 2H). 13
C
NMR (125 MHz, CDCl3): δ 24.0, 31.2, 40.8, 46.1, 46.7, 127.7,
129.0, 132.9, 133.2, 208.7. IR (NaCl cell, CH2Cl2, cm-1): 2943,
1712. HRMS (ESþ) calcd for C12H15OS [M þ H]þ: 207.0844;
found: 207.0845.
2. 2-Thionaphthol (96 mg, 0.6 mmol) was added to a mixture
of (E)-4,4-dimethyl-1-phenylpent-2-en-1-one 8e (94 mg, 0.5 mmol)
and the catalyst 1e (50 μL 0.01 M stock solution in dry toluene,
0.289 mg, 0.0005 mmol) in dry toluene (1.0 mL) at the room
temperature. The reaction mixture was stirred, and the progress of
the reaction was monitored by TLC. After the completion of the
reaction, the reaction mixture was concentrated in vacuum and the
crude product was purified over silica gel by column chromato-
graphy. The product 6a was obtained in 95% (166 mg) yield and
82% ee. The optical purity was determined by HPLC on chiralpak
AD column [n-hexane/2-propanol 95:5]; flow rate 1 mL/min; λ =
254 nm; tR(minor) = 8.40 min (S); tR(major) = 9.54 min (R);
[R]D25 = -125.4 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ
1.08 (s, 9H), 3.34-3.36 (m, 2H), 4.01 (dd, J = 7.5, 5.5 Hz, 1H),
7.37-7.42 (m, 4H), 7.49-7.55 (m, 2H), 7.67-7.73 (m, 3H), 7.83-
7.89 (m, 3H). 13C NMR (125 MHz, CDCl3): δ 27.9, 36.3, 41.2,
55.5, 125.7, 126.4, 127.4, 127.7, 128.2, 128.4, 128.6, 128.7, 128.9,
132.0, 133.1, 133.8, 134.8, 137.3, 198.8. IR (KBr pellet, cm-1):
2923, 1590; mp = 65 °C. HRMS (ESþ) calcd for C23H25OS [M þ
H]þ: 349.1626; found: 349.1626.
aReactions were carried out on a 0.5 mmol scale with 0.6 mmol of
thiol in 1 mL of toluene at room temperature, unless noted otherwise.
bDetermined by HPLC using chiral column.
Acknowledgment. V.K.S. thanks the Department of
Science and Technology, India, for a research grant through
J. C. Bose fellowship. N.K.R. and S.S. thank the Council of
Scientific and Industrial Research, New Delhi, for research
fellowships.
FIGURE 2. Proposed transition state model.
believe that the enone is activated by the urea moiety through
double hydrogen bonding, while the thiol is activated by the
basic quinuclidine nitrogen atom and the approach of thiol
to the Si face of enone leads to the formation of the major
stereoisomer.
In conclusion, we have developed a highly enantioselective
organocatalytic sulfa-Michael addition to enones promoted
by a quinine-derived urea catalyst. The stereochemical outcome
Supporting Information Available: General experimental
1
procedures, characterization data including H NMR spectra,
13C NMR spectra for all new compounds, and HPLC chroma-
tograms for Michael adducts. This material is available free of
charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 6, 2010 2091