Regioselective cobalt-catalyzed addition of sulfides to unactivated alkenes

Article abstract of DOI:10.1021/jo201016z

A novel method to synthesize tertiary alkyl/aryl sulfides in a mild and regioselective manner from unactivated alkenes using cobalt catalysis is described. The methodology is compatible with sensitive functionalities and is successful with several different types of alkenes and sulfides.

Full text of DOI:10.1021/jo201016z

NOTE
pubs.acs.org/joc
Regioselective Cobalt-Catalyzed Addition of Sulfides to
Unactivated Alkenes
Vinay Girijavallabhan,* Carmen Alvarez, and F. George Njoroge
Merck Research Laboratories, Kenilworth, New Jersey 07033, United States
S Supporting Information
b
ABSTRACT: A novel method to synthesize tertiary alkyl/aryl
sulfides in a mild and regioselective manner from unactivated
alkenes using cobalt catalysis is described. The methodology is
compatible with sensitive functionalities and is successful with
several different types of alkenes and sulfides.
ulfur is found in many biologically relevant compounds, and
therefore, it is commonly used in medicinal chemistry pro-
grams in the form of sulfonamides, sulfones, sulfoxides, or
sulfides.1 Recently, our medicinal chemistry efforts were directed
toward the synthesis of tertiary alkyl/aryl sulfones of type 1 and
sulfides of type 2 (Figure 1).
our knowledge had not been previously demonstrated in the
literature.
S
Since our system 3 contained sensitive functionalities, it was
important to establish that it was compatible with the conditions
used in the cobalt-catalyzed reaction. Therefore, we chose
Carreira’s hydroazidation as a test reaction and found that it
provided a good yield of the tertiary azide 7 when used with the
cobalt catalyst 5 (Scheme 1).5 Many mechanistic studies per-
formed by the Carreira group have suggested the formation of a
cobaltÀhydride complex from the reaction of the cobalt catalyst
with phenylsilane.6 This complex undergoes regioselective olefin
hydrocobaltation, positioning the cobalt on the most substituted
carbon, followed by the interception of the organocobalt or
derived radical by the tosylazide which leads to the regioselec-
tivity found in the reaction.
Since the substrate 3 seemed amenable to this type of reaction,
the next goal was to find an appropriate sulfur reagent that could
effect the addition to the alkene bond. We envisioned that the
reaction would use a mechanism very similar to that seen in the
hydroazidation reaction and would therefore provide similar
regioselectivity. In order to understand the sulfur reactivity
required for the reaction, our first attempts involved the use of
commercially available thiophenol 8 or diphenyl disulfide 9.
Unfortunately, both of these reactions provided exclusively the
reduced alkene 10 (Figure 4).
Since the scaffold contained sensitive functionalities as well as
numerous chiral centers, a mild method of introducing sulfur into
the molecule without interfering with any sensitive functional
groups was required. Literature searches of tertiary alkyl sulfides
uncovered some examples of the synthesis of these types of
functionalities, although many of the chemistries involved were
performed on scaffolds with no heteroatoms and required harsh
conditions such as strong acids and high temperatures.2 In 2006,
Dunach and co-workers discovered a mild method of synthesiz-
ing tertiary sulfides from unactivated alkenes and thiols using
indium(III) trifluoromethanesulfonate as a Lewis acid.3 Unfor-
tunately, this method failed to provide the product 2 when it was
attempted on alkene 3, most likely due to the acid instability of 3
(Figure 2).
To overcome the aforementioned drawbacks, we needed to
discover a novel, mild method of synthesizing tertiary alkyl
sulfides. It was apparent that the most efficient method to add
sulfur to our molecule would be via a Markovnikov addition of a
sulfur reagent across the alkene 3, much like the Lewis acid
mediated processes described earlier. Since alkene 3 was not
activated by any neighboring groups, the type of sulfur reagent as
well as the method of activating the alkene to addition was critical
to the success of the hydrothiolation reaction. Recent work by
Carreira and co-workers has demonstrated that many different
types of functional groups (i.e., azides, nitriles, Cl) can be added
to unactivated olefins with complete Markovnikov selectivity
using cobalt catalysis (Figure 3).4 This work inspired us to
develop this reaction with sulfur reagents which to the best of
The failure of the diphenyl disulfide reaction, in particular,
suggested that the sulfur reagent needed to be even more reactive
in order to compete with the reduction process. According to the
mechanism of the hydroazidation reaction proposed by Carriera
in the aforementioned papers, tosyl azide worked well in the
reaction not only because the tosyl is a good leaving group but
Received: May 24, 2011
Published: June 22, 2011
r
2011 American Chemical Society
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|

The Journal of Organic Chemistry
NOTE
Scheme 1. Hydroazidation of 3
Figure 1. Tertiary sulfone and sulfide targets.
Figure 2. Proposed hydrothiolation reaction of compound 3.
Figure 4. Attempted hydrothiolation with readily available sulfur
reagents.
Table 1. Synthesis of Tosyl Sulfides 12À16
entry
R
yield (%)
Figure 3. Carreira reaction to functionalize unactivated alkenes.
12
13
14
15
16
Me
Et
68
62
8
also because the tosyl activated the nitrogen of the azide toward
nucleophilic attack. Since tosyl sulfides are known to react with
carbon nucleophiles to provide alkyl sulfides, they were promis-
ing substrates to test the hydrothiolation reaction hypothesis.7
Yokoyama and co-workers recently developed an efficient meth-
od of synthesizing tosyl sulfides from the corresponding dialkyl/
aryl sulfides and toluenesulfinic acid sodium salt in the pre-
sence of iodine.8 Using this methodology, several tosyl sulfides
(12À16) were synthesized in reasonable yields with the excep-
tion of the tert-butyl sulfide 14 ,which provided a low yield
possibly due to sterics (Table 1).
With these tosyl sulfides in hand, we embarked on the cobalt-
catalyzed hydrothiolation reaction. When 3 equiv of tosyl sulfide
12 was combined with compound 3 in the presence of 2 mol % of
cobalt catalyst 5 and 1.3 equiv of phenylsilane, an excellent yield
(90%) of the desired sulfide product 17 was obtained (Figure 5).
As seen in Table 2, the reaction worked well with many of the
other tosyl sulfides to provide both tertiary alkyl and aryl sulfides
(18À22). The only tosyl sulfide that did not provide the desired
product 19 was the highly hindered tert-butyl sulfide 14 (only
biproduct 10 was isolated). The reaction also provided a good
yield of the desired product 20 using the commercially available
S-phenyl benzenethiosulfonate. The electronics of the tosyl
sulfides did not seem to have a great impact on the reaction as
seen with the yields of entries 21 and 22. It is important to note
that 3 equiv of the tosyl sulfide was found to be optimal in order
to ensure complete conversion of the valuable intermediate 3 to
the sulfide products. When less than this amount was used in the
t-Bu
3-F-phenyl
85
86
4-OMe-phenyl
reaction, compound 10 was occasionally seen as a side product
(10À40%).
In order to further test the scope of the reaction, we attempted
the hydrothiolation reaction on other substituted alkenes with
varying electronics as well as sensitive functionalities. As can be
seen from Table 3, the aliphatic alkenes 24 and 25 provide good
yields of the desired product with the ester of 25 being unaffected
by the reaction conditions. The reaction also worked well on
styrene-based alkene 26 though the yield dropped slightly for
indene analogue 27 possibly due to polymerization of the indene
starting material. The reaction also provided a good yield and
complete regioselectivity when performed on a trisubstituted
alkene as shown by example 28.
The sulfides created by this reaction could be useful in the
synthesis of sulfones. As shown in Figure 6, a representative
oxidation of the sulfide 17 with m-CPBA provided an excellent
yield of the desired sulfone 29. It is reasonable to assume that
the sulfoxides could also be isolated via this protocol by using
only 1 equiv of m-CPBA, but this reaction was not attempted.
This paper has described a regioselective, novel methodology
to create secondary or tertiary alkyl or aryl sulfides from
unactivated alkene substrates with sensitive functionality. The
reaction has proven to work well with both electron-deficient and
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NOTE
Table 3. Examination of Various Alkenes in the Hydrothio-
lation Reaction
Figure 5. Successful hydrothiolation reaction with 12.
Table 2. Examination of Various Tosyl Sulfides in the
Hydrothiolation Reaction
entry
R
X
yield (%)
18
19
20
21
22
Et
Me
Me
H
70
0
t-Bu
phenyl
97
98
79
4-F-phenyl
4-OMe-phenyl
Me
Me
electron-rich sulfur electrophiles as well as different types of
substituted alkenes. This methodology provides access to com-
pounds with high levels of complexity in a mild manner and could
be useful in medicinal chemistry programs.
’ EXPERIMENTAL SECTION
General Details. Dry solvents were purchased and used without
further purification. Other solvents or reagents were used as obtained
except when otherwise noted. Analytical thin layer chromatography
(TLC) was performed on precoated silica gel plates and was accom-
plished with UV light or by staining with basic KMnO4 solution,
methanolic sulfuric acid, or Vaughn’s reagent. Column chromatography
was performed silica gel 60 (particle size 0.040À0.055 mm, 230À400
mesh) or using an automated chromatographic system. NMR specra
were recorded in CDCl3 or DMSO-d6 in 400 MHz (1H NMR), and 100
MHz (13C NMR). Low- and high-resolution mass spectra were obtained
using electron spray or FAB ionization methods.
Figure 6. Oxidation of sulfide 17 to sulfone 29.
(9.5 g, 70 mmol), and N,O-dimethylhydroxylamine hydrochloride (7.27 g,
75 mmol) were suspended in methylenechloride(250mL) andtreatedwith
triethylamine (21 mL, 150 mmol). The reaction was stirred overnight at
room temperature and then quenched with water. The organic layer was
washed with saturated sodium bicarbonate, water, and brine, dried over
sodium sulfate, and concentrated. Column chromatography (1:1 hexanes/
ethyl acetate) provided compound 3B as a thick colorless oil (13.5 g, 78%):
1H NMR (CDCl3, 400 MHz) δ 6.15 (m, 1H), 4.7 (m, 1H), 4.45 (m, 1H),
4.15 (m, 1H), 3.7 (s, 3H), 3.4 (m, 1H), 3.2 (s, 3H), 2.5 (m, 1H), 1.8 (m,
1H), 1.45 (s, 3H), 1.4 (s, 9H), 1.25 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 175.9, 155.3, 110.8, 87.2, 84.0, 78.9, 61.6, 56.6, 47.7, 32.3, 32.1, 28.5, 26.7,
24.4; HRMS (ESI) calcd for C16H29N2O6 ([M + H]+) 345.2020, found
345.2025.
tert-Butyl (3aS,4R,6R,6aR)-2,2-dimethyl-6-(prop-1-en-2-
yl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ylcarbamate
(3).
Step 2. Compound 3B (2.3 g, 6.66 mmol) was dissolved in THF
(50 mL) and cooled in an ice bath. A solution of 3 M methylmagnesium
bromide in diethyl ether (13.3 mL, 40 mmol) was added dropwise, and
after 30 min, the reaction was allowed to warm to room temperature and
stirred for another 1 h. The reaction was then quenched with saturated
ammonium chloride solution and extracted with ethyl acetate twice.
The combined organic layers were dried over sodium sulfate and con-
centrated. Column chromatography (3:1 hexanes/ethyl acetate) pro-
1
vided compound 3C as a white solid(1.8 g, 90%): H NMR (CDCl3,
400 MHz) δ 5.2 (bs, 1H), 4.75 (m, 1H), 4.4 (m, 1H), 4.1 (m, 1H), 3.15
(m, 1H), 2.35 (m, 1H), 2.25 (s, 3H), 1.85 (m, 1H), 1.45 (s, 3H), 1.4
(s, 9H), 1.25 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 210.5, 155.5,
Step 1. Compound 3A (15.0 g, 50 mmol), 1-ethyl-3-(3-dimethylami-
nopropyl) carbodiimide (11.4 g, 60 mmol), 95% 1-hydroxybenzotriazole
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NOTE
111.3, 86.4, 82.0, 58.8, 56.8, 30.9, 29.3, 28.4, 26.7, 24.4; HRMS (ESI)
calcd for C15H26NO5 ([M + H]+) 300.1805, found 300.1808.
127.1, 21.6, 18.1; HRMS (ESI) calcd for C8H11O2S2 ([M + H]+)
203.0195, found 203.0194.
Step 3. Triphenylphosphonium bromide (29.2 g, 84 mmol) was
suspended in THF (300 mL). A 0.5 M solution of potassium hexam-
ethyldisilazide (160 mL) was added slowly, and the yellow solution was
stirred for 30 min at room temperature and then cooled on an ice bath.
Compound 3C (10.0 g, 33.3 mmol) was dissolved in THF (100 mL)
and added dropwise to the stirring solution over a 15 min period. The
reaction was stirred for 1 h on the ice bath and then warmed to room
temperature and stirred for another 2 h. The reaction was then quenched
with saturated ammonium chloride solution and extracted with ethyl
acetate twice. The combined organic layers were dried over sodium
sulfate and concentrated. Column chromatography (4:1 hexanes/ethyl
acetate) provided compound 3 as a white solid (7.1 g, 72%): 1H NMR
(CDCl3, 400 MHz) δ 4.7 (s, 1H), 4.6 (s, 1H), 4.35 (t, J = 6.25 Hz, 1H),
4.28À4.2 (m, 1H), 3.82À3.74 (m, 1H), 2.45À2.38 (m, 1H), 2.2À2.1
(m, 1H), 1.6 (s, 3H), 1.52À1.42 (m, 1H), 1.35 (s, 3H), 1.3 (s, 9H), 1.1
(s, 3H); 13C NMR (CDCl3, 100 MHz) δ 155.5, 145.4, 112.6, 110.2,
85.6, 82.9, 79.5, 57.0, 50.6, 35.3, 28.3, 27.3, 24.9, 21.7; HRMS (ESI)
calcd for C16H28NO4 ([M + H]+) 298.2013, found 298.2015.
S-Ethyl 4-Methylbenzenesulfonothioate (13). Compound 13 (4.26 g,
62%) was obtained as a colorless oil using the general procedure A: 1H
NMR (CDCl3, 400 MHz) δ 7.8 (d, 3J = 8.6 Hz, 2H), 7.35 (d, 3J = 8.2 Hz,
3
2H), 3.0À2.95 (m, 2H), 2.42 (s, 3H), 1.25 (t, J = 7.5 Hz, 3H); 13C
NMR (CDCl3, 100 MHz) δ 144.6, 141.9, 129.9, 126.9, 30.5, 21.8, 14.1;
HRMS (ESI) calcd for C9H13O2S2 ([M + H]+) 217.0351, found
217.0352.
S-tert-Butyl 4-Methylbenzenesulfonothioate (14). Compound 14
(624 mg, 8%) was obtained as a colorless oil using the general procedure
A: 1H NMR (CDCl3, 400 MHz) δ 7.8 (d, 3J = 8.3 Hz, 2H), 7.32 (d, 3J =
8.2 Hz, 2H), 2.42 (s, 3H), 1.42 (s, 9H); 13C NMR (CDCl3, 100 MHz)
δ 144.3, 143.9, 129.6, 127.0, 55.0, 30.9, 21.7; HRMS (ESI) calcd for
C11H17O2S2 ([M + H]+) 245.0665, found 245.0664.
S-3-Fluorophenyl 4-Methylbenzenesulfonothioate (15). Com-
pound 15 (7.67 g, 85%) was obtained as a white solid using the general
1
procedure A: H NMR (CDCl3, 400 MHz) δ 7.46 (m, 2H), 7.4À7.3
(m 1H), 7.25À7.20 (m, 2H), 7.2À7.14 (m, 2H), 7.1À7.05 (m, 1H),
2.42 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 163.5, 161.0, 145.1, 140.1,
132.29, 132.25, 130.6, 129.5, 127.5, 123.0, 118.7, 118.5, 21.6; HRMS
(ESI) calcd for C13H12FO2S2 ([M + H]+) 283.0257, found 283.0255.
S-4-Methoxyphenyl 4-Methylbenzenesulfonothioate (16). Com-
pound 16 (10.5 g, 86%) was obtained as a white solid using the general
procedure A (reaction was performed in 1.3Â scale): 1H NMR(DMSO-d6,
400 MHz) δ 7.4 (m, 4H), 7.2 (m, 2H), 6.95 (m, 2H), 3.79 (s, 3H), 2.4
(s, 3H); 13C NMR (DMSO-d6, 100 MHz) δ 162.6, 145.4, 140.0, 138.4,
130.2, 127.6, 118.1, 115.7, 56.0, 21.5; HRMS (ESI) calcd for
C14H15O3S2 ([M + H]+) 295.0457, found 295.0455.
tert-Butyl (3aS,4R,6R,6aR)-6-(2-azidopropan-2-yl)-2,2-
dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ylcar-
bamate (7). Compound 5 (18 mg, 0.03 mmol) was dissolved
in ethanol (2 mL) and then treated sequentially with compound 3
(300 mg, 1 mmol) dissolved in ethanol (8 mL), tosyl azide (497 mg,
2.5 mmol), and phenylsilane (0.16 mL, 1.3 mmol). The reaction was
allowed to stir at room temperature for 1.5 h and was quenched with
brine and extracted with ethyl acetate. The combined organic layers were
dried over sodium sulfate and concentrated. Column chromatography
(4:1 hexanes/ethyl acetate) provided compound 7 as a colorless oil
(275 mg, 81%): 1H NMR (CD3OD, 400 MHz) δ 4.45 (t, 3J = 6.8 Hz,
1H), 4.25 (t, 3J = 6.2 Hz, 1H), 3.8 (m, 1H), 2.1 (m, 1H), 2.0 (m, 1H),
General Procedure B for Hydrosulfuration Reactions. tert-
Butyl (3aS,4R,6S,6aR)-2,2-Dimethyl-6-(2-(methylthio)propan-2-yl)-
tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ylcarbamate (17). Com-
pound 5 (18 mg, 0.03 mmol) was dissolved in ethanol (2 mL) and then
treated sequentially with compound 3 (300 mg, 1 mmol) dissolved in
ethanol (8 mL), compound 12 (3 mmol), and phenylsilane (0.16 mL,
1.3 mmol). The reaction was allowed to stir at room temperature for 1.5 h,
quenched with brine, and extracted with ethyl acetate. The combined
organic layers were dried over sodium sulfate and concentrated. Column
chromatography (4:1 hexanes/ethyl acetate) provided compound 17
(310 mg, 90%) as a thick colorless oil:1H NMR (CDCl3, 400 MHz) δ
4.8 (bs, 1H, NH), 4.5 (t, J = 6.25 Hz, 1H), 4.2 (t, J = 7.03 Hz 1H), 3.8 (m,
1H), 2.25 (m, 1H), 2.1 (m, 1H), 2.0 (s, 3H), 1.6À1.5 (m, 1H), 1.45
(s, 3H), 1.38 (s, 9H), 1.21 (s, 3H); 13C NMR (CDCl3, 100 MHz)
δ 155.4, 113.0, 84.8, 80.0, 79.2, 57.0, 53.0, 44.8, 33.6, 28.4, 27.6, 26.7,
26.4, 25.2, 10.8; HRMS (ESI) calcd for C17H32NO4S ([M + H]+)
346.2047, found 346.2048.
1.46 (s, 3H), 1.44 (s, 9H), 1.36 (s, 3H), 1.3 (s, 3H), 1.27 (s, 3H); 13
C
NMR (CD3OD, 100 MHz) δ 156.5, 112.9, 84.6, 79.6, 78.7, 61.4,
56.2, 52.9, 32.6, 27.2, 26.4, 23.9, 23.7, 23.6; HRMS (ESI) calcd for
C16H29N4O4 ([M + H]+) 341.2183, found 341.2182.
tert-Butyl (3aS,4R,6R,6aR)-6-isopropyl-2,2-dimethyltetra-
hydro-3aH-cyclopenta[d][1,3]dioxol-4-ylcarbamate (10).
Compound 5 (18 mg, 0.03 mmol) was dissolved in ethanol (2 mL)
and then treated sequentially with compound 3 (300 mg, 1 mmol) dis-
solved in ethanol (8 mL), diphenyl disulfide (535 mg, 2.5 mmol), and
phenylsilane (0.16 mL, 1.3 mmol). The reaction was allowed to stir at
room temperature for 1.5 h, quenched with brine and, extracted with
ethyl acetate. The combined organic layers were dried over sodium
sulfate and concentrated. Column chromatography (4:1 hexanes/ethyl
acetate) provided compound 7 as a white solid (254 mg, 85%). 1H NMR
(CDCl3, 400 MHz) δ 4.75 (bs, 1H), 4.3À4.2 (m, 2H), 3.8 (m, 1H),
2.25 (m, 1H), 1.65 (m, 1H), 1.5À1.45 (m, 1H), 1.45 (s, 3H), 1.4
(s, 9H), 1.3À1.2 (m, 1H), 1.25 (s, 3H), 0.96 (d, 3J = 6.4 Hz, 3H), 0.85
(d, 3J = 7.3 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 155.5, 113.0, 85.0,
80.1, 79.5, 56.9, 53.8, 46.3, 33.7, 28.3, 27.9, 27.6, 27.3, 25.3, 21.7, 14.4;
HRMS (ESI) calcd for C16H30NO4 ([M + H]+) 300.2169, found
300.2170.
General Procedure A (Synthesis of Tosyl Sulfides). S-Methyl
4-Methylbenzenesulfonothioate (12). Sodium 4-methylbenzenesulfi-
nate (compound 11) (10.0 g, 56 mmol), dimethyl disulfide (1.59 g,
17 mmol), and iodine (8.06 g, 32 mmol) were dissolved in methylene
chloride (200 mL) and the mixture stirred for 5 h. The reaction was
quenched with 10% aqueous sodium thiosulfate and extracted with
methylene chloride. The organic layer was dried over sodium sulfate and
concentrated. Column chromatography (20:1 hexanes/ethyl acetate)
provided compound 12 as a yellow solid (4.39 g, 68%): 1H NMR
(CDCl3, 400 MHz) δ 7.8 (d, 3J = 8.5 Hz, 2H), 7.34 (d, 3J = 8.3 Hz, 2H),
2.48 (s, 3H), 2.44 (s, 3H); 13C NMR (CDCl3, 100 MHz) δ 144.8, 129.9,
tert-Butyl (3aS,4R,6S,6aR)-6-(2-(ethylthio)propan-2-yl)-2,2-dimeth-
yltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ylcarbamate (18). Com-
pound 18 (251 mg, 70%) was obtained as a colorless oil using the general
1
procedure B: H NMR (CDCl3, 400 MHz) δ 4.7 (bs, 1H, NH), 4.52
(dd, J = 7.03, 5.47 Hz, 1H), 4.23 (t, J = 6.25 Hz, 1H), 3.85 (m, 1H),
2.6À2.5 (m, 2H), 2.32 (m, 1H), 2.12 (m, 1H), 1.59 (m, 1H), 1.5 (s, 3H),
1.42 (s, 9H), 1.32 (s, 3H), 1.3 (s, 3H), 1.28 (s, 3H), 1.22(t, 3J = 7.0 Hz,
3H); 13C NMR (CDCl3, 100 MHz) δ 155.5, 113.3, 85.1, 80.2, 79.4, 56.9,
53.9, 46.2, 33.8, 28.2, 27.9, 27.5, 27.3, 25.3, 21.8, 14.4; HRMS (ESI)
calcd for C18H34NO4S ([M + H]+) 360.2203, found 360.2204.
tert-Butyl (3aS,4R,6S,6aR)-2,2-Dimethyl-6-(2-(phenylthio)propan-
2-yl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ylcarbamate (20).
Compound 20 (394 mg, 97%) was obtained as a thick colorless oil
using the general procedure B: 1H NMR (CDCl3, 400 MHz) δ 7.55À
7.52 (m, 2H), 7.4À7.25 (m, 3H), 4.7 (bs, 1H, NH), 4.6 (dd, J = 7.8, 6.26
Hz, 1H), 4.25 (dd, J = 7.82, 6.25 Hz, 1H), 3.85 (m, 1H), 2.4 (m, 1H), 2.2
(m, 1H), 1.7 (m, 1H), 1.5 (s, 3H), 1.42 (s, 9H), 1.3 (s, 3H), 1.2 (m, 6H);
13C NMR (CDCl3, 100 MHz) δ 155.5, 138.0, 131.5, 129.0, 128.5, 113.0,
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NOTE
84.8, 80.3, 79.8, 57.0, 53.4, 50.1, 34.0, 28.5, 28.0, 27.7, 27.5, 25.4; HRMS
(ESI) calcd for C22H34NO4S ([M + H]+) 408.2203, found 408.2203.
tert-Butyl (3aS,4R,6S,6aR)-6-(2-(3-Fluorophenylthio)propan-2-yl)-
2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ylcarbamate
(21). Compound 21 (417 mg, 98%) was obtained as a thick colorless oil
using the general procedure B: 1H NMR (CDCl3, 400 MHz) δ 7.35À
7.25 (m, 3H), 7.05 (m, 1H), 4.7 (bs, 1H, NH), 4.6 (dd, J = 7.8, 5.5 Hz,
1H), 4.28 (dd, J = 7.03, 6.25 Hz, 1H), 3.81 (m, 1H), 2.35 (m, 1H), 2.19
(m, 1H), 1.62 (m, 1H), 1.5 (s, 3H), 1.42 (s, 9H), 1.3 (s, 3 H), 1.22 (m,
6H); 13C NMR (CDCl3, 100 MHz) δ 163.5, 160.5, 133.6, 129.8, 129.6,
124.6, 124.4, 116.2, 116.0, 113.2, 84.8, 80.0, 79.5, 57.0, 53.0, 50.5, 33.4,
28.2, 27.4, 25.2; HRMS (ESI) calcd for C22H33FNO4S ([M + H]+)
426.2109, found 426.2108.
tert-Butyl (3aS,4R,6S,6aR)-6-(2-(4-Methoxyphenylthio)propan-2-yl)-
2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ylcarbamate
(22). Compound 22 was obtained as a white solid using the general
procedure B: 1H NMR (CD3OD, 400 MHz) δ 7.45 (m, 2H), 6.9 (m,
2H), 4.55 (dd, J = 7.82, 5.47 Hz, 1H), 4.28 (t, 1H), 3.8 (s, 3H), 2.20 (m,
1H), 2.1 (m, 1H), 1.65 (m, 1H), 1.45 (m, 12H), 1.28 (s, 3H), 1.2 (s, 3H),
1.18 (s, 3H); 13C NMR (CD3OD, 100 MHz) δ 161.1, 157.0, 139.4,
122.4, 114.4, 114.2, 113.1, 84.9, 80.3, 79.1, 56.9, 54.8. 53.1, 49.3, 33.7,
27.8, 27.6, 27.2, 26.9, 26.1, 24.5; HRMS (ESI) calcd for C23H36NO5S
([M + H]+) 438.2309, found 438.2311.
tert-Butyl (3aS,4R,6S,6aR)-2,2-Dimethyl-6-(2-(methylsulfonyl)pro-
pan-2-yl)tetrahydro-3aH-cyclopenta[d][1,3]dioxol-4-ylcarbamate
(29). Compound 17 (160 mg, 0.465 mmol) was dissolved in methylene
chloride (8 mL) and treated with 77% m-CPBA (259 mg, 1.16 mmol).
After being stirred at room temperature for 2 h, the reaction mixture was
washed with 1 M potassium carbonate solution, dried over sodium
sulfate, and concentrated. Column chromatography (2:1 ethyl acetate/
hexanes) provided compound 29 (173 mg, 99%) as a colorless oil:
1H NMR (CDCl3, 400 MHz) δ 4.95 (bs, 1H, NH), 4.5 (m, 1H), 4.35
(m, 1H), 3.8 (m, 1H), 2.8 (s, 3H), 2.4 (m, 2H), 1.65 (m, 1H), 1.45 (s,
3H), 1.4 (s, 3H), 1.38 (s, 9H), 1.33 (s, 3H), 1.23 (s, 3H); 13C NMR
(CDCl3, 100 MHz) δ 113.5, 84.0, 79.6, 79.4, 62.6, 56.5, 48.0, 35.5,
34.0, 28.3, 27.5, 25.2, 21.0, 18.5; HRMS (ESI) calcd for C17H32NO6S
([M + H]+) 378.1945, found 378.1945.
’ ASSOCIATED CONTENT
Supporting Information. 1H NMR and 13C NMR spec-
S
b
tra. This material is available free of charge via the Internet at
http://pubs.acs.org.
’ AUTHOR INFORMATION
GeneralProcedureCforHydrosulfurationReactions. Phenyl-
(2,4,4-trimethylhexan-2-yl)sulfane (24). Compound 5 (7 mg, 0.012
mmol) was dissolved in ethanol (1 mL) and then treated sequentially
with 2,4,4-trimethylhex-1-ene (72 mg, 0.57 mmol) dissolved in ethanol
(1 mL), S-phenyl benzenesulfonothioate (350 mg, 1.42 mmol), and
phenylsilane (0.091 mL, 0.74 mmol). The reaction was allowed to stir at
room temperature for 1.5 h, quenched with brine, and extracted with
ethyl acetate. The combined organic layers were dried over sodium
sulfate and concentrated. Column chromatography (hexanes) provided
compound 24 (128 mg, 95%) as a colorless oil: 1H NMR (CDCl3, 400
MHz) δ 7.6À7.5 (m, 2H), 7.4À7.2 (m, 3H), 1.7 (s, 2H), 1.4À1.25 (m, 8
H), 1.0 (s, 6H), 0.8 (t, J = 7.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ
137.8, 129.0, 128.6, 128.3, 52.5, 51.0, 37.0, 35.2, 30.4, 28.5, 8.5; HRMS
(ESI) sample run in the presence of acetic acid therefore calcd for
C15H25OS ([M + H]+) 253.1621, found 253.1616.
Corresponding Author
*E-mail: vinay.girijavallabhan@merck.com.
’ REFERENCES
(1) (a) Gleason, J. G. Org. Compd. Sulphur, Selenium, Tellurium
1975, 3, 190–218. (b) Parry, R. J. Tetrahedron 1983, 39 (8), 1215–1238.
(c) Prinsep, M. R. Stud. Nat. Prod. Chem. 2003, 28, 617–751.
(2) (a) Naya, K.; Okayama, T.; Fujiwara, M.; Nakata, M.; Ohtsuka,
T.; Kurio, S. Bull. Chem. Soc. Jpn. 1990, 63 (8), 2239–2245. (b) Ipatieff,
V. N.; Pines, H.; Friedman, B. S. J. Am. Chem. Soc. 1938, 60, 2731–2734.
(3) (a) Weiwer, M.; Chaminade, X.; Bayon, J. C.; Dunach, E. Eur. J.
Org. Chem. 2007, 15, 2464–2469. (b) Weiwer, M.; Coulombel, L.;
Dunach, E. Chem. Commum. 2006, 3, 332–335.
(4) (a) Gaspar, B.; Carreira, E. M. Ange. Chem. Int. Ed. 2008,
47, 5758–5760. (b) Gaspar, B.; Waser, J.; Carreira, E. M. Synthesis
2007, 24, 3839–3845. (c) Gaspar, B.; Carreira, E. M. Ange. Chem. Int. Ed.
2007, 46, 4519–4522. (d) Waser, J; Nambu, H.; Carreira, E. M. J. Am.
Chem. Soc. 2005, 127, 8294–8295.
(5) Synthesis of the catalyst can be found in: Morris, G. A.; Zhou, H.;
Stern, C. L.; Nguyen, S. T. Inorg. Chem. 2001, 40, 322–3227.
(6) Mechanistic elucidation can be found in the following: Waser, J.;
Gaspar, B.; Nambu, H.; Carriera, E. M. J. Am. Chem. Soc. 2006, 128,
11693–11712.
(7) (a) Kohei, O.; Shiro, T. Tetrahedron. 2009, 65 (11), 2244–2253.
(b) Piller, F. M.; Knochel, P. Org. Lett. 2009, 11 (2), 445–448.
(8) Fujiki, K.; Tanifuji, N; Sasaki, Y.; Yokoyama, T. Synthesis 2002,
3, 343–348.
Ethyl 4-Methyl-4-(phenylthio)pentanoate (25). Compound 25 (123
mg, 86%) was obtained as a lightly yellow colored oil using the general
procedure C: 1H NMR (CDCl3, 400 MHz) δ 7.5 (m, 2H), 7.4À7.3 (m,
3H), 4.15 (q, J = 7 Hz, 2H), 2.6 (t, J = 7.82 Hz, 2H), 1.8 (t, J= 7.81Hz, 2H),
1.26 (t, J = 7.03 Hz, 3H), 1.23 (s, 6H); 13C NMR (CDCl3, 100 MHz)
δ 173.9, 137.9, 131.8, 129.5, 128.5, 60.0, 48.5, 37.0, 30.5, 28.4, 14.0; HRMS
(ESI) calcd for C14H21O2S ([M + H]+) 253.1257, found 253.1256.
Phenyl(2-phenylpropan-2-yl)sulfane (26). Compound 26 (101 mg,
78%) was obtained as a lightly yellow colored oil using the general
procedure C: 1H NMR (CDCl3, 400 MHz) δ 7.5 (m, 3H), 7.35À7.15
(m, 6H), 7.1 (m, 1H), 1.3 (s, 6H); 13C NMR (CDCl3, 100 MHz)
δ 146.7, 137.0, 129.1, 128.6, 127.5, 127.1, 126.5, 125.5, 43.8, 25.3;
HRMS (ESI) calcd for C15H15S ([M + H]+) 227.0889, found 227.0887.
(2,3-Dihydro-1H-inden-1-yl)(phenyl)sulfane (27). Compound 27
(66 mg, 51%) was obtained as a lightly yellow colored oil using the
1
general procedure C: H NMR (CDCl3, 400 MHz) δ 7.4 (m, 2H),
7.35À7.18 (m, 7H), 4.8 (m, 1H), 3.0 (m, 1H), 2.85 (m, 1H), 2.55 (m,
1H), 2.22 (m, 1H); 13C NMR (CDCl3, 100 MHz) δ 143.8, 142.8, 131.4,
128.9, 127.8, 126.5, 125.0, 124.8, 51.8, 33.6, 30.8; HRMS (ESI) calcd for
C15H15S ([M + H]+) 227.0889, found 227.0888.
(2-Methylheptan-2-yl)(phenyl)sulfane (28). Compound 28 (114
mg, 90%) was obtained as a lightly yellow colored oil using the general
procedure C: 1H NMR (CDCl3, 400 MHz) δ 7.52 (m, 2H), 7.35
(m, 3H), 1.5À1.45 (m, 4H), 1.4À1.25 (m, 4H), 1.24 (s, 6H), 0.92
(t, J = 7.0 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 137.5, 132.4, 128.5,
128.3, 49.4, 42.4, 32.3, 28.7, 24.5, 22.7, 14.2.
6446
dx.doi.org/10.1021/jo201016z |J. Org. Chem. 2011, 76, 6442–6446