Selectivity reversal during thia-Michael additions using tetrabutylammonium hydroxide: Operationally simple and extremely high turnover

Article abstract of DOI:10.1055/s-0033-1341106

The use of tetrabutylammonium hydroxide as a novel and exceedingly efficient thia-Michael addition catalyst is herein described. This extremely simple methodology allows for the conjugate addition of a wide variety of mercaptan nucleophiles, and functions remarkably well with a very wide range of both classical and non-classical Michael acceptors. Contradistinctive to current literature reports, the use of this catalyst more efficiently promotes the addition of more basic thiols. This methodology is especially attractive and operationally simple, as it generally proceeds with only 1 mol% catalytic loading and without excess reagent, and the produced products typically require no purification. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1341106

PAPER
▌1725
pSaepelrectivity Reversal during Thia-Michael Additions Using Tetrabutylammonium
Hydroxide: Operationally Simple and Extremely High Turnover
Extremely Efficient Thia-Michael Catalysis with TBA-OH
Daniel R. Nicponski,* Jennifer M. Marchi
Herbert C. Brown Center for Borane Research, Department of Chemistry, Purdue University, 560 Oval Dr., West Lafayette, IN, 47907, USA
E-mail: drn2@purdue.edu
Received: 30.01.2014; Accepted after revision: 13.03.2014
been shown to catalyze thia-Michael additions efficient-
Abstract: The use of tetrabutylammonium hydroxide as a novel
ly.19 While these reports have offered an excellent ad-
and exceedingly efficient thia-Michael addition catalyst is herein
vancement in the promotion of this reaction, the requisite
use of silica gel chromatography for these methods signif-
described. This extremely simple methodology allows for the con-
jugate addition of a wide variety of mercaptan nucleophiles, and
functions remarkably well with a very wide range of both classical icantly retracts from their attraction. As such, further pro-
and non-classical Michael acceptors. Contradistinctive to current
literature reports, the use of this catalyst more efficiently promotes
the addition of more basic thiols. This methodology is especially at-
plicit carbonyl functionalities are highly desirable.
tractive and operationally simple, as it generally proceeds with only
motional methods that provide pure products directly and
expand the generality of this methodology away from ex-
We began our studies by considering the model reaction
of cyclopent-2-en-1-one (1) with one equivalent of ben-
zenethiol (pKa ≈ 6.6) in alcoholic solvents. Without the
aid of an additional catalyst, only trace amounts of thia-
Michael product 2 were observable by TLC analysis after
two hours (Table 1, entry 1). An observation we made
during work on an unrelated project involving mostly P–
C bond formation indicated to us that an aqueous solution
of tetrabutylammonium hydroxide (TBA-OH) in an alco-
holic solvent could potentially serve as an effective cata-
lyst for this reaction.
1 mol% catalytic loading and without excess reagent, and the pro-
duced products typically require no purification.
Key words: thia-Michael reaction, conjugate addition, catalysis,
green chemistry, high turnover number, selectivity reversal
The Michael addition of nucleophiles to α,β-unsaturated
systems is one of the most important bond forming pro-
cesses in synthetic organic chemistry. Of special interest
are the sulfur variants of this reaction, historically referred
to as the thia-Michael reaction, which provide access to β-
thiocarbonyl compounds.1 These highly interesting com-
pounds are of great importance, as they often possess bio-
logical and pharmacological activity,2 and can also be
used as auxiliaries in further synthetic manipulation.3
Typically, thia-Michael reactions are promoted by: cer-
tain bases;1a,2c,4 the fluoride ion;5 functionalized clays6 and
silica gel,4b,7 iodine,8 lanthanum salts;9 Brønsted–Lowry
acids;10 or metals such as copper,11 cadmium,12 bismuth,13
ruthenium,14 or vanadium.15 (The direct addition of thio-
late anions has also been described.16) The use of these
catalysts often requires harsh conditions, elevated temper-
atures, prolonged reaction times, or special precautions
such as the employment of inert atmosphere techniques,
tedious purification methods, or pH-altered media. Fur-
thermore, superstoichiometric quantities of catalysts or
reagents are frequently required for full promotion. For
these reasons, new and improved catalysts for this reac-
tion are still being sought. In designing such catalysts,
special consideration should be given to the cost and
atom-economy of potential promoters.17 Additionally, the
choice of solvent and catalyst should be made with the
consideration of potential environmental impact in
mind;18 very high catalytic turnover is especially critical
when making considerations for scale-up to an industrial
level. In certain cases, the use of water as a solvent has
Table 1 Optimization of Reaction Parameters
O
O
HSPh (1 equiv)
TBA-OH (x mol%)
solvent
SPh
1
2
Entry
Solvent
TBA-OH (mol%) Time (min) Yield (%)
1
2
3
4
5
6
7
ROH
–
120
<1
<1
1
trace
>99
>99
>99
>99
>99
>99
MeOH
EtOH
EtOH
EtOH
EtOH
EtOH
10
10
5
1
2
0.1
0.01
5
10
Testing this theory, we found that the addition of 10 mol%
of an aqueous solution of tetrabutylammonium hydroxide
was found to offer complete formation of the addition
product almost instantaneously. With this in mind, we
performed an optimization study to improve the efficacy
of this novel catalyst (Table 1). We noted that, under cat-
alytic conditions, the reaction proceeded readily in alco-
holic solvents such as methanol and ethanol (entries 2 and
SYNTHESIS 2014, 46, 1725–1730
Advanced online publication: 11.04.2014
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1341106; Art ID: SS-2014-M0082-OP
© Georg Thieme Verlag Stuttgart · New York

1726
D. R. Nicponski, J. M. Marchi
PAPER
Table 2 Application of Thia-Michael Catalysis Conditions to a
Variety of Mercaptans (continued)
3), but opted for the use of the latter, as it is a preferred
solvent from an environmental standpoint. Remarkably,
we found that even 0.01 mol% (10,000 TON) of tetrabu-
tylammonium hydroxide catalyst could effectively pro-
mote the reaction (entry 7). Tetrabutylammonium
hydroxide is not reported to possess any RCRA-classified
hazards,20 it is a readily available and inexpensive re-
agent,21 its use does not require special techniques or con-
siderations, and it can be readily removed due to its
insolubility in diethyl ether.
O
O
HSR (1 equiv)
TBA-OH (1 mol%)
EtOH
1
SR
Entry Product
Time
Yielda (%)
O
O
9
10
11
12
30 min
98
Table 2 Application of Thia-Michael Catalysis Conditions to a
Variety of Mercaptans
OEt
S
O
O
HSR (1 equiv)
TBA-OH (1 mol%)
O
CO2Me
EtOH
10
90 min
90 min
>99
71
NHAc
1
SR
S
Entry Product
Time
2 min
Yielda (%)
>99
O
O
11d
O
S
1
2
a Yield of pure product.
S
b Thiol (4 equiv) was used.
c Thiol (0.25 equiv) was used.
d Thiol (1.5 equiv) was used.
O
e A 92:8 mixture of linkage isomers (S/O) was obtained in a total of
98% yield.
2
3
4
1 min
>99
73
OMe
S
O
We were pleased to discover such excellent catalytic ac-
tivity, and so desired to generalize this protocol by exten-
sion to a variety of mercaptan nucleophiles. To this end,
we studied the reaction of 1 with a variety of structurally
and electronically tuned thiols (Table 2). For this study,
we opted to employ the use of 1 mol% tetrabutylammoni-
um hydroxide, as we felt it offered an excellent compro-
mise between catalytic loading, physical measurability,
and reaction time. We were gratified to see that a wide va-
riety of thiol-containing compounds were well tolerated in
this reaction. Whereas the highly electron-deficient (more
acidic; pKa ≈ 4.6) 2,4,5-trichlorobenzenethiol functioned
only moderately well in this reaction (entry 3), the much
more electron-rich 4-methoxybenzenethiol (less acidic;
pKa ≈ 6.8) was complete almost instantaneously and in
quantitative yield (entry 2). This comes in stark contrast to
literature reports which indicate that more electron-poor
(more acidic) thiols are better substrates for such reac-
tions.22 With this data in hand, we suspected that less acid-
ic aliphatic thiols (typical pKa ≈ 10) would be excellent
substrates for this reaction. Indeed, the use of benzylic
(entry 4; pKa ≈ 9.9) and other aliphatic thiols (entries 5–
10; pKa values ≈ 10.5, 9.4, 9.4, 9.6, 8.2, 9.1) gave excel-
lent yields and rapid completion times. Gratifyingly, stoi-
chiometric alterations allowed for the controlled
formation of either the monomeric (entry 6) or dimeric
(entry 7) compounds when ethane-1,2-dithiol was used,
furnishing excellent yields. The reaction of 2-mercapto-
ethanol (entry 8), while rapid and high-yielding, unex-
Cl
3
30 min
Cl
S
Cl
O
OMe
4
5
6
7
8
9
2 h
2 h
90
89
92
97
98e
S
O
5
S
O
6b
2 h
SH
S
O
O
7c
3 h
S
S
O
8d
30 min
OH
S
Synthesis 2014, 46, 1725–1730
© Georg Thieme Verlag Stuttgart · New York

PAPER
Extremely Efficient Thia-Michael Catalysis with TBA-OH
1727
pectedly furnished a 92:8 mixture favoring the S-linkage chromatographic purification procedures, provides access
isomer. The use of ethyl 2-mercaptoethanoate provided a to a wide range of molecular scaffoldings rapidly in very
nearly quantitative yield of the expected product (entry 9). high yields and in an environmentally friendly manner.
N-Acetyl-protected cysteine also functioned well in this We feel as though this novel methodology is an excellent
reaction, furnishing an unresolved mixture of diastereo- expansion upon existing catalytic options and will provide
mers in essentially perfect yield (entry 10). In agreement chemists with an additional synthetic tool.
with our observations that more acidic thiols gave the op-
Table 3 Extension of Thia-Michael Reaction of Benzenethiol to Ad-
ditional Michael Acceptors
posite of the expected reactivity, using thioacetic acid (en-
try 11; pKa ≈ 3.3) diminished conversion was also
observed. In almost all of the above cases, no purification
beyond a simple water–diethyl ether partition was re-
quired.
HSPh (1 equiv)
TBA-OH (1 mol%)
EWG
EWG
SPh
EtOH
Excited by this initial success, we became interested in ex-
tending this methodology to include several additional
Michael reaction acceptors. To this end, we considered
the reaction of benzenethiol with a variety of Michael ac-
ceptor groups-both classical and non-classical (Table 3).
Entry Michael acceptor Product
Time Yielda
(h)
(%)
O
SPh
Ph
O
1
13
7 h
>99
Ph
As can be seen from Table 3, a wide variety of both clas-
sical (entries 1–7) and non-classical (entries 8–11)
Michael systems were readily reactive under the reaction
conditions. For example, simple α,β-unsaturated carbon-
yls (entries 1–3) underwent smooth Michael addition,
even with a high degree of steric hindrance at the β-posi-
tion (entry 1). In the case of methyl vinyl ketone (MVK),
a significant degree of polymerization occurred (entry 2).
Excellent chemoselectivity was obtained in the reaction
with ethyl propiolate (entry 4), as monoaddition occurred
exclusively. In accord with literature reports,23 the Z-iso-
mer was the major product. The addition onto other accep-
tors such as dimethyl ethylidenemalonate (entry 5),
succinimide (entry 6), and acrylonitrile (entry 7) were
very facile, providing essentially quantitative yields in
each case. As expected, the addition onto 3-vinylcyclo-
hex-2-en-1-one provided the 1,6-addition product exclu-
sively (entry 8). While the addition onto phenyl vinyl
sulfoxide partially functioned (entry 9), it did not com-
plete, even under extended reaction times.24 Conversely,
the reaction with phenyl vinyl sulfone was nearly flaw-
less, providing quantitative yield of the expected product
within two hours. Likewise, the reaction of benzenethiol
with allenyldiphenylphosphine oxide (entry 11) also pro-
ceeded in excellent yield. While the Michael reactions of
this particular compound with the four principle chalo-
genides have been previously described,25 only moderate
yields were obtained in each case, and the use of pre-
O
O
2
3
14
15
3 h
4 h
72d
59e
SPh
O
O
t-BuO
SPh
t-BuO
O
O
SPh
O
4
5
16 10 min >99f
EtO
EtO
O
O
O
MeO
OMe
MeO
OMe
17
18
4 h
99
SPh
O
O
HN
HN
6
1 min >99
SPh
O
N
O
N
7
8
19
20
1 h
2 h
>99
>99
SPh
O
O
SPh
O
O
9
21 35 h
69e
99
S
S
Ph
Ph
SPh
O
O
O
O
formed anions was a requisite. As such, this current pro- 10
cedure offers significant improvements in accessing these
types of compounds. Just as with the previous group of
compounds, the majority of these products required no ad-
ditional purification beyond a simple water–diethyl ether
S
22
23
2 h
2 h
S
Ph
Ph
Ph
Ph
SPh
SPh
O
P
O
P
11
99
Ph
Ph
a Yield of pure compound.
partition to provide analytically pure compound.
b 5 mol% catalyst was used.
c MVK (1.5 equiv) was used.
In conclusion, we have demonstrated that the use of tetra-
butylammonium hydroxide in extremely low catalytic
loadings can catalyze the thia-Michael reactions of a wide
variety of mercaptans with both classical and non-classi-
cal Michael acceptors. This remarkably simple methodol-
ogy, which usually required no tedious workup or
d A significant amount of polymerization occurred.
e The reaction did not complete under the chosen conditions.
f The product was obtained as an intractable (Z/E, 85:15) mixture of
geometrical isomers.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1725–1730

1728
D. R. Nicponski, J. M. Marchi
PAPER
All reagents were purchased from Sigma-Aldrich, Fisher-Acros,
Strem Chemical, or Alfa-Aesar, and were used without further pu-
rification unless otherwise noted. All reactions were performed at
r.t. All TLC analysis was performed using 60Å, Glass-backed TLC
plates (250 μm thickness, F-254 indicator); PMA = phosphomolyb-
dic acid. 1H, 13C, and 31P NMR spectra were recorded at r.t., on ei-
ther Varian Inova 300 MHz, Bruker ARX400, or Bruker DRX500
spectrometers referenced to either the deuterated residual solvent
peak, or to TMS.
13C NMR (75 MHz, CDCl3): δ = 216.1, 158.4, 129.6, 129.5, 113.7,
55.1, 45.4, 39.5, 37.0, 35.1, 29.5.
LRMS (ESI+): m/z [M + Na]+ calcd: 259.1; found: 259.1.
3-(Hexylthio)cyclopentan-1-one (6)
Yield: 216 mg (89%); Rf = 0.73 (hexane–EtOAc, 70:30, stain =
PMA, p-anisaldehyde, KMnO4).
1H NMR (300 MHz, CDCl3): δ = 3.46 (p, J = 6.9 Hz, 1 H), 2.64–
2.54 (m, 3 H), 2.49–2.31 (m, 2 H), 2.20 (m, 2 H), 1.96 (m, 1 H), 1.60
(p, J = 7.1 Hz, 2 H), 1.44–1.27 (m, 6 H), 0.89 (t, J = 6.8 Hz, 3 H).
TBA-OH-Catalyzed Thia-Michael Addition 2–23; General Pro-
cedure
13C NMR (75 MHz, CDCl3): δ = 216.2, 45.8, 40.4, 37.1, 31.4, 31.3,
Into a round-bottom flask charged with a magnetic stirbar was add-
ed an appropriate Michael acceptor (1.0 equiv). This material was
dissolved in enough EtOH to produce a 0.1 M solution. After stir-
ring to ensure dissolution, mercaptan (1.0 equiv) was added, and the
mixture was stirred until homogenous. After this time, TBA-OH (40
wt% in H2O, 1 mol% ) was added in one portion, and the mixture
was stirred until deemed complete by TLC analysis. The mixture
was then partitioned between deionized H2O (50 mL) and Et2O (50
mL). After removing the organic layer, the residual product was ex-
tracted from the aqueous layer using an additional portion of Et2O
(50 mL). The combined organic layers were then washed with de-
ionized H2O (50 mL) then brine (50 mL). After drying (MgSO4), the
crude product was concentrated under reduced pressure, then, if
necessary, purified via column chromatography.
29.9, 29.6, 28.6, 22.5, 14.1.
LRMS (ESI+): m/z [M + Na]+ calcd: 223.1; found: 223.1.
3-[(2-Mercaptoethyl)thio]cyclopentan-1-one (7)
Yield: 198 mg (92%); Rf = 0.45 (hexane–EtOAc, 70:30, stain =
PMA, p-anisaldehyde, KMnO4).
1H NMR (400 MHz, CDCl3): δ = 3.50 (p, J = 6.3 Hz, 1 H), 2.91–
2.73 (m, 4 H), 2.62 (dd, J = 18.4, 7.1 Hz, 1 H), 2.50–2.34 (m, 2 H),
2.26–2.18 (m, 2 H), 1.96 (m, 1 H), 1.74 (t, J = 7.7 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 216.2, 45.8, 40.5, 37.1, 35.5, 30.1,
24.9.
LRMS (ESI+): m/z [M + Na]+ calcd: 199.0; found: 199.0.
1,2-Bis[(3-oxocyclopentyl)thio]ethane (8)7
Yield: 76 mg (98%); Rf = 0.13 (hexane–EtOAc, 70:30, stain =
PMA, p-anisaldehyde, KMnO4).
1H NMR (400 MHz, CDCl3): δ = 3.52 (p, J = 6.2 Hz, 2 H), 2.82 (s,
4 H), 2.63 (dd, J = 18.2, 6.8 Hz, 2 H), 2.50–2.37 (m, 4 H), 2.27–2.19
(m, 4 H), 1.98 (m, 2 H).
13C NMR (101 MHz, CDCl3): δ = 216.1, 45.8, 40.7, 37.1, 31.6, 30.1.
LRMS (ESI+): m/z [M + Na]+ calcd: 281.1; found: 281.0.
3-(Phenylthio)cyclopentan-1-one (2)4a
Yield: 58 mg (>99%); Rf = 0.46 (hexane–EtOAc, 85:15, stain =
PMA, p-anisaldehyde, KMnO4).
1H NMR (400 MHz, CDCl3): δ = 7.42–7.24 (m, 5 H), 3.89 (p, J =
6.0 Hz, 1 H), 2.60 (dd, J = 18.7, 7.7 Hz, 1 H), 2.48 (dt, J = 18.2, 7.6
Hz, 1 H), 2.38–2.17 (m, 3 H), 2.02 (m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 216.3, 134.2, 131.9, 129.1, 127.4,
45.2, 43.3, 36.7, 29.3.
LRMS (ESI+): m/z [M + Na]+ calcd: 215.0; found: 215.0.
3-[(2-Ethoxy-2-oxoethyl)thio]cyclopentan-1-one (10)
Yield: 242 mg (>99%); Rf = 0.41 (hexane–EtOAc, 70:30, stain =
PMA, p-anisaldehyde, KMnO4).
1H NMR (300 MHz, CDCl3): δ = 4.20 (q, J = 7.1 Hz, 2 H), 3.64 (p,
J = 7.1 Hz, 1 H), 3.29 (m, 2 H), 2.66 (dd, J = 18.5, 7.4 Hz, 1 H), 2.41
(m, 2 H), 2.23 (m, 2 H), 1.98 (m, 1 H), 1.30 (t, J = 7.1 Hz, 3 H).
3-[(4-Methoxyphenyl)thio]cyclopentan-1-one (3)15
Yield: 271 mg (>99%); Rf = 0.53 (hexane–EtOAc, 70:30, stain = p-
anisaldehyde, vanillin, KMnO4).
1H NMR (400 MHz, CDCl3): δ = 7.39 (d, J = 8.7 Hz, 2 H), 6.86 (d,
J = 8.7 Hz, 2 H), 3.80 (s, 3 H), 3.72 (p, J = 6.1 Hz, 1 H), 2.55–2.41
(m, 2 H), 2.31–2.15 (m, 3 H), 1.97 (m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 216.1, 170.3, 61.6, 45.4, 41.0,
37.2, 33.3, 29.6, 14.3.
LRMS (ESI+): m/z [M + Na]+ calcd: 225.1; found: 225.0.
13C NMR (101 MHz, CDCl3): δ = 216.8, 159.9, 135.8, 124.1, 114.8,
55.4, 45.2, 44.8, 36.9, 29.3.
LRMS (ESI+): m/z [M + Na]+ calcd: 245.1; found: 245.1.
Methyl N-Acetyl-S-(3-oxocyclopentyl)cysteine (11)
Yield: 316 mg (>99%); Rf = 0.38, EtOAc, stain = p-anisaldehyde,
KMnO4).
1H NMR (400 MHz, CDCl3): δ = 6.32 (m, 1 H), 4.85 (m, 1 H), 3.79
(s, 3 H), 3.49 (m, 1 H), 3.13–2.98 (m, 2 H), 2.61 (m, 1 H), 2.40 (m,
2 H), 2.19 (m, 2 H), 2.06 (s, 3 H), 1.93 (m, 1 H).
3-[(2,4,5-Trichlorophenyl)thio]cyclopentan-1-one (4)
Yield: 263 mg (73%); Rf = 0.46 (hexane–EtOAc, 80:20, stain =
PMA, p-anisaldehyde, KMnO4).
1H NMR (300 MHz, CDCl3): δ = 7.58 (s, 1 H), 7.50 (s, 1 H), 4.06
(m, 1 H), 2.76 (dd, J = 18.6, 7.3 Hz, 1 H), 2.65–2.30 (m, 4 H), 2.13
(m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 215.9, 170.8, 170.3, 52.2, 51.7,
45.1, 40.2, 36.5, 29.3, 26.2, 22.4.
LRMS (ESI+): m/z [M + Na]+ calcd: 282.1; found: 282.1.
13C NMR (75 MHz, CDCl3): δ = 214.9, 134.4, 134.0, 131.9, 131.6,
131.1, 44.9, 42.4, 36.8, 29.3.
LRMS (ESI+): m/z [M + Na]+ calcd: 316.9; found: 317.0; [M + Na
+ 2]+ calcd: 318.9; found: 319.0; [M + Na + 4]+ calcd: 320.9; found:
321.0.
3-(Acetylthio)cyclopentan-1-one (12)26
Yield: 137 mg (71%); Rf = 0.53 (hexane–EtOAc, 70:30, stain = I2,
p-anisaldehyde, KMnO4).
1H NMR (400 MHz, CDCl3): δ = 3.99 (p, J = 7.3 Hz, 1 H), 2.67 (dd,
J = 18.7, 7.7 Hz, 1 H), 2.46–2.29 (m, 2 H), 2.28 (s, 3 H), 2.26–2.10
(m, 2 H), 1.91 (s, 1 H).
3-{[(4-Methoxyphenyl)methyl]thio}cyclopentan-1-one (5)
Yield: 260 mg (90%); Rf = 0.50 (hexane–EtOAc, 70:30, stain =
PMA, p-anisaldehyde, KMnO4).
1H NMR (300 MHz, CDCl3): δ = 7.18 (d, J = 8.6 Hz, 2 H), 6.79 (d,
J = 8.6 Hz, 2 H), 3.72 (s, 3 H), 3.67 (d, J = 3.9 Hz, 2 H), 3.21 (p, J =
6.9 Hz, 1 H), 2.48–2.03 (m, 5 H), 1.85 (m, 1 H).
13C NMR (101 MHz, CDCl3): δ = 215.7, 195.2, 44.6, 39.2, 37.6,
30.6, 29.6.
LRMS (ESI+): m/z [M + Na]+ calcd: 181.0; found: 181.0.
Synthesis 2014, 46, 1725–1730
© Georg Thieme Verlag Stuttgart · New York

PAPER
Extremely Efficient Thia-Michael Catalysis with TBA-OH
1729
3-Phenyl-3-(phenylthio)propanal (13)27
Yield: 184 mg (>99%); Rf = 0.61 (hexane–EtOAc, 70:30, stain = I2,
p-anisaldehyde, KMnO4).
1H NMR (400 MHz, CDCl3): δ = 9.62 (s, 1 H), 7.31–7.13 (m, 10 H),
4.68 (t, J = 7.4 Hz, 1 H), 2.99 (d, J = 7.4 Hz, 2 H).
13C NMR (101 MHz, CDCl3): 199.4, 140.5, 133.4, 133.3, 129.1,
128.9, 128.6, 127.9, 127.7, 49.1, 47.2.
LRMS (ESI+): m/z [M + Na]+ calcd: 265.1; found: 265.1.
13C NMR (101 MHz, CDCl3): δ = 133.1, 131.0, 129.2, 127.4, 118.1,
29.9, 18.0.
LRMS (ESI+): m/z [M + Na]+ calcd: 186.0; found: 186.1.
3-[2-(Phenylthio)ethyl]cyclohex-2-en-1-one (20)32
Yield: 201 mg (>99%); Rf = 0.28 (hexane–EtOAc, 80:20, stain =
vanillin, KMnO4).
1H NMR (300 MHz, CDCl3): δ = 7.25–7.06 (m, 5 H), 5.78 (s, 1 H),
2.96 (t, J = 7.5 Hz, 2 H), 2.41 (t, J = 7.5 Hz, 2 H), 2.24 (t, J = 5.9
Hz, 2 H), 2.16 (t, J = 5.8 Hz, 2 H), 1.85 (p, J = 5.9 Hz, 2 H).
4-(Phenylthio)butan-2-one (14)28
Yield: 185 mg (72%); Rf = 0.51 (hexane–EtOAc, 70:30, stain =
p-anisaldehyde, KMnO4).
13C NMR (75 MHz, CDCl3): δ = 199.0, 163.1, 135.3, 129.5, 128.8,
126.4, 126.2, 37.3, 37.2, 31.0, 29.4, 22.5.
1H NMR (300 MHz, CDCl3): δ = 7.35–7.16 (m, 5 H), 3.13 (t, J = 7.2
Hz, 2 H), 2.75 (t, J = 7.3 Hz, 2 H), 2.14 (s, 3 H).
13C NMR (75 MHz, CDCl3): δ = 206.3, 135.5, 129.3, 128.8, 126.1,
43.0, 30.1, 27.4.
LRMS (ESI+): m/z [M + Na]+ calcd: 203.1; found: 203.0.
LRMS (ESI+): m/z [M + Na]+ calcd: 255.1; found: 255.1.
Phenyl 2-(Phenylthio)ethyl Sulfone (22)33
Yield: 248 mg (>99%); Rf = 0.35 (hexane–EtOAc, 75:25, stain =
PMA, p-anisaldehyde, KMnO4).
1H NMR (400 MHz, CDCl3): δ = 7.85 (d, J = 7.8 Hz, 2 H), 7.62 (m,
1 H), 7.52 (t, J = 7.6 Hz, 2 H), 7.23–7.18 (m, 5 H), 3.30 (m, 2 H),
3.14 (m, 2 H).
tert-Butyl 3-(Phenylthio)propanoate (15)29
Yield: 140 mg (59%); Rf = 0.33 (hexane–CH2Cl2, 60:40, stain =
KMnO4).
13C NMR (101 MHz, CDCl3): δ = 138.3, 133.9, 133.3, 129.8, 129.3,
1H NMR (300 MHz, CDCl3): δ = 7.37–7.15 (m, 5 H), 3.12 (t, J = 7.4
Hz, 2 H), 2.53 (t, J = 7.4 Hz, 2 H), 1.44 (s, 9 H).
129.1, 127.9, 126.9, 55.4, 26.1.
LRMS (ESI+): m/z [M + Na]+ calcd: 301.0; found: 301.0.
13C NMR (75 MHz, CDCl3): δ = 170.8, 135.5, 129.9, 128.9, 126.3,
80.9, 35.6, 29.3, 28.2.
LRMS (ESI+): m/z [M + Na]+ calcd: 261.1; found: 261.1; [M + K]+
Diphenyl[2-(phenylthio)prop-2-en-1-yl]phosphine Oxide (23)25a
Yield: 290 mg (>99%); Rf = 0.44 (hexane–EtOAc, 50:50, stain =
PMA, p-anisaldehyde, KMnO4).
calcd: 277.1; found: 277.1.
1H NMR (300 MHz, CDCl3): δ = 7.70–7.64 (m, 4 H), 7.41–7.29 (m,
6 H), 7.19–7.10 (m, 5 H), 5.45 (d, J = 3.8 Hz, 1 H), 4.98 (d, J = 3.9
Hz, 1 H), 3.19 (d, JH-P = 13.2 Hz, 2 H).
13C NMR (75 MHz, CDCl3): δ = 134.5 (d, JC-P = 9.0 Hz), 132.6,
132.1, 131.6, 131.3, 130.8, 130.7, 128.9, 128.2, 128.1, 127.8, 118.3,
37.4, 37.2 (d, JC-P = 65.3 Hz).
Ethyl (Z)-3-(Phenylthio)prop-2-enoate (16)23
Yield: 318 mg (>99%); Rf = 0.56 (hexane–EtOAc, 80:20, stain =
KMnO4).
1H NMR (300 MHz, CDCl3): δ = 7.44–7.26 (m, 6 H), 7.21 (d, J =
10.1 Hz, 1 H), 5.87 (d, J = 10.1 Hz, 1 H), 4.20 (q, J = 7.1 Hz, 2 H),
1.27 (t, J = 7.1 Hz, 3 H).
31P NMR (121 MHz, CDCl3): δ = 29.2.
13C NMR (75 MHz, CDCl3): δ = 166.2, 149.4, 135.9, 130.8, 129.1,
128.0, 113.2, 60.2, 14.4.
LRMS (ESI+): m/z [M + Na]+ calcd: 373.1; found: 373.1.
LRMS (ESI+): m/z [M + Na]+ calcd: 231.0; found: 231.0.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
m
tgioSrantnugIifoop
r
itmnatr
Dimethyl 2-[1-(Phenylthio)ethyl]malonate (17)
Yield: 168 mg (99%); Rf = 0.52 (hexane–CHCl3, 30:70, stain =
PMA, p-anisaldehyde, KMnO4).
1H NMR (400 MHz, CDCl3): δ = 7.49–7.26 (m, 5 H), 3.79–3.65 (m,
References
s, s, 2 H, 3 H, 3 H), 3.55 (d, J = 8.7 Hz, 1 H), 1.36 (d, J = 6.9 Hz, 3
H).
13C NMR (101 MHz, CDCl3): δ = 167.9, 167.6, 133.8, 132.7, 128.9,
(1) (a) Bakuzis, P.; Bakuzis, M. L. F. J. Org. Chem. 1981, 46,
235. (b) Houghton, T. J.; Choi, S.; Rawal, V. H. Org. Lett.
2001, 3, 3615.
(2) (a) Naidu, B. N.; Sorenson, M. E.; Bronson, J. J.; Pucci, M.
J.; Clark, J. M.; Ueda, Y. Bioorg. Med. Chem. Lett. 2005, 15,
2069. (b) Sun, C.; Aspland, S. E.; Ballatore, C.; Castillo, R.;
Smith, A. B. III; Castellino, A. J. Bioorg. Med. Chem. Lett.
2006, 16, 104. (c) Sani, M.; Candiana, G.; Pecker, F.;
Malpezzi, L.; Zanda, M. Tetrahedron Lett. 2005, 46, 2393.
(3) Eliel, E. L.; Morris-Natschke, S. J. Am. Chem. Soc. 1984,
106, 2937.
(4) (a) Rana, N. K.; Selvakumar, S.; Singh, V. K. J. Org. Chem.
2010, 75, 2089. (b) Abbasi, M. Tetrahedron Lett. 2012, 53,
3683. (c) Rosenker, C. J.; Krenske, E. H.; Houk, K. N.;
Wipf, P. Org. Lett. 2013, 15, 1076.
128.0, 57.3, 52.5, 52.5, 42.9, 19.1.
LRMS (ESI+): m/z [M + Na]+ calcd: 291.1; found: 291.1.
2-(Phenylthio)succinimide (18)30
Yield: 219 mg (>99%); Rf = 0.38 (hexane–EtOAc, 70:30, stain =
p-anisaldehyde, I2, KMnO4).
1H NMR (400 MHz, CDCl3): δ = 9.38 (s, 1 H), 7.49–7.32 (m, 5 H),
4.08 (dd, J = 9.1, 4.4 Hz, 1 H), 3.14 (dd, J = 18.8, 9.1 Hz, 1 H), 2.66
(dd, J = 18.8, 4.4 Hz, 1 H).
13C NMR (101 MHz, CDCl3): δ = 176.8, 175.8, 133.8, 130.6, 129.4,
129.0, 45.2, 37.1.
LRMS (ESI+): m/z [M + Na]+ calcd: 230.0; found: 230.1.
(5) Kuwajima, I.; Mirofushi, T.; Nakamura, E. Synthesis 1976,
602.
(6) Laszlo, P.; Montaufier, M.-T.; Randriamahefa, S. L.
Tetrahedron Lett. 1990, 31, 4867.
3-(Phenylthio)propionitrile (19)31
Yield: 163 mg (>99%).
1H NMR (400 MHz, CDCl3): δ = 7.46 (s, 6 H), 3.05 (t, J = 7.0 Hz,
2 H), 2.55 (t, J = 7.0 Hz, 2 H).
(7) Khan, A. T.; Ghosh, S.; Choudhury, L. H. Eur. J. Org.
Chem. 2006, 2226.
(8) Chu, C.-M.; Gao, S.; Sastry, M. N. V.; Yao, C.-F.
Tetrahedron Lett. 2005, 46, 4971.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 1725–1730

1730
D. R. Nicponski, J. M. Marchi
PAPER
(9) (a) Kobayashi, S.; Ogawa, C.; Kawamura, M.; Sugiura, M.
Synlett 2001, 983. (b) Kumar, A.; Ahmad, I.; Rao, M. S. J.
Sulfur Chem. 2009, 30, 570.
(21) When purchased as a 40% wt. solution in water from Sigma-
Aldrich Chemical Company, TBA-OH is ≈ $240/mol. Price
obtained on March 30, 2014.
(10) (a) Chen, W.; Shi, L. Catal. Commun. 2008, 9, 1079.
(b) Chaudhuri, M. K.; Hussain, S. J. Mol. Catal. A: Chem.
2007, 269, 214. (c) Wabnitz, T. C.; Spencer, J. B. Org. Lett.
2003, 5, 2141.
(11) Garg, S. K.; Kumar, R.; Chakraborti, A. K. Tetrahedron
Lett. 2005, 46, 1721.
(12) Saito, M.; Nakajima, M.; Hashimoto, S. Tetrahedron 2000,
56, 9589.
(13) (a) Srivastava, N.; Banik, B. K. J. Org. Chem. 2003, 68,
2109. (b) Alam, M. M.; Varala, R.; Adapa, S. R.
Tetrahedron Lett. 2003, 44, 5115.
(14) Zhang, H.; Zhang, Y.; Liu, L.; Xu, H.; Wang, Y. Synthesis
2005, 2129.
(15) Chen, C.-T.; Lin, Y.-D.; Liu, C.-Y. Tetrahedron 2009, 65,
10470.
(16) Whitehead, A.; Moore, J. D.; Hanson, P. R. Tetrahedron
Lett. 2003, 44, 4275.
(17) (a) Trost, B. M. Science (Washington, D.C.) 1991, 254,
1471. (b) Trost, B. M. Angew. Chem. Int. Ed. 1995, 34, 259.
(18) (a) Nicponski, D. R.; Ramachandran, P. V. Future Med.
Chem. 2011, 3, 1469. (b) Capello, C.; Fischer, U.;
Hungerbühler, K. Green Chem. 2007, 9, 927. (c) Anastas, P.
T.; Warner, J. C. Green Chemistry: Theory and Practice;
Oxford University Press: Oxford, 1998.
(22) (a) Adam, W.; Nava-Salgado, V. O. J. Org. Chem. 1995, 60,
578. (b) In accord with this observation, the reaction of 2-
mercaptopyrimidine (pKa ≈ 1.6) only furnished a 42% yield
of product after a reaction time of 3 days when catalyzed
with 5 mol% TBA-OH.
(23) (a) Randive, N. A.; Kumar, V.; Nair, V. A. Monatsh. Chem.
2010, 141, 1329. (b) Sarrafi, Y.; Sadatshahabi, M.;
Alimohammadi, K.; Tajbakhsh, M. Green Chem. 2011, 13,
2851. (c) Downey, C. W.; Craciun, S.; Neferu, A. M.;
Vivelo, C. A.; Mueller, C. J.; Southall, B. C.; Corsi, S.;
Etchill, E. W.; Sault, R. J. Tetrahedron Lett. 2012, 53, 5763.
(24) Actually, reports detailing the Michael acceptor capabilities
of α,β-unsaturated sulfoxides are quite rare in the literature,
perhaps indicating the difficulty of such additions. For
known examples, see: (a) Gusarova, N. K.; Chernysheva, N.
A.; Khil’ko, M. Ya.; Yas’ko, S. V.; Sinegovskaya, L. M.;
Chipanina, N. N.; Korchevin, N. A.; Trofimov, B. A. Russ.
J. Gen. Chem. 2005, 75, 1247. (b) Tanikaga, R.; Sugihara,
H.; Tanaka, K.; Kaji, A. Synthesis 1977, 299. (c) Trofimov,
B. A.; Gusarova, N. K.; Efremova, G. G.; Amosova, S. V.;
Kletsko, F. P.; Vlasova, N. N.; Voronkov, M. G. Zh. Org.
Khim. 1980, 16, 2538.
(25) (a) Wu, Z.; Huang, X. Synlett 2005, 526. (b) Denmark, S. E.;
Marlin, J. E. J. Org. Chem. 1991, 56, 1003.
(19) (a) Khatik, G. L.; Kumar, R.; Chakraborti, A. K. Org. Lett.
2006, 8, 2433. (b) Yadav, J. S.; Swamy, T.; Reddy, B. V. S.;
Rao, D. K. J. Mol. Catal. A: Chem. 2007, 274, 116.
(20) Information obtained from the commercially available
MSDS for this compound. See also List of Lists,
Consolidated List of Chemicals Subject to the Emergency
Planning and Community Right-To-Know Act (EPCRA),
Comprehensive Environmental Response, Compensation
and Liability Act (CERCLA) and Section 112 (r) of the
Clean Air Act, available from the US EPA website:
http://www.epa.gov/oem/docs/chem/title3_Oct_2006.pdf
Accessed on March 30, 2014.
(26) Rana, N. K.; Unhale, R.; Singh, V. K. Tetrahedron Lett.
2012, 53, 2121.
(27) Ménand, M.; Dalla, V. Synlett 2005, 95.
(28) Rajabi, F.; Razavi, S.; Luque, R. Green Chem. 2010, 12,
786.
(29) Tye, H.; Skinner, C. L. Helv. Chim. Acta 2002, 85, 3272.
(30) Barrett, A. G. M.; Broughton, H. B.; Attwood, S. V.;
Gunatilaka, A. A. L. J. Org. Chem. 1986, 51, 495.
(31) Chen, X.; She, J.; Shang, Z.; Wu, J.; Zhang, P. Synthesis
2008, 3931.
(32) Winkler, J. D.; Lee, E. C. Y. J. Am. Chem. Soc. 2006, 128,
9040.
(33) Gelat, F.; Jayashankaran, J.; Lohier, J.-F.; Gaumont, A.-C.;
Perrio, S. Org. Lett. 2011, 13, 3170.
Synthesis 2014, 46, 1725–1730
© Georg Thieme Verlag Stuttgart · New York