Synthetic scope, computational chemistry and mechanism of a base induced 5-endo cyclization of benzyl alkynyl sulfides

Article abstract of DOI:10.1016/j.tet.2010.11.104

We present an experimental and computational study of the reaction of aryl substituted benzyl 1-alkynyl sulfides with potassium alkoxide in acetonitrile, which produces 2-aryl 2,3-dihydrothiophenes in poor to good yields. The cyclization is most efficient with electron withdrawing groups on the aromatic ring. Evidence indicates there is rapid exchange of protons and tautomerism of the alkynyl unit prior to cyclization. Theoretical calculations were also conducted to help rationalize the base induced 5-endo cyclization of benzyl 1-propynyl sulfide (1a). The potential energy surface was calculated for the formation of 2,3-dihydrothiophene in a reaction of benzyl 1-propynyl sulfide (1a) with potassium methoxide. Geometries were optimized with CAM-B3LYP/6-311+G(d,p) in acetonitrile with the CPCM solvent model. It is significant that the benzyl propa-1,2-dien-1-yl sulfane (6) possessed a lower benzylic proton affinity than the benzyl prop-2-yn-1-yl sulfane (8) thus favoring the base induced reaction of the former. From benzyl(propa-1,2-dien-1- yl sulfane (6), 2,3-dihydrothiophene can be formed via a conjugate base that undergoes 5-endo-trig cyclization followed by a protonation step.

Full text of DOI:10.1016/j.tet.2010.11.104

Tetrahedron 67 (2011) 1002e1010
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthetic scope, computational chemistry and mechanism of a base induced
5-endo cyclization of benzyl alkynyl sulfides
a
b
b
,
a
a
ꢀ
*
John M. Motto , Alvaro Castillo , Alexander Greer , Laura K. Montemayer , Erin E. Sheepwash ,
Adrian L. Schwan a
,
*
a Department of Chemistry, University of Guelph, Guelph, ON, Canada N1G 2W1
b Department of Chemistry, The City University of New York (CUNY), Brooklyn College, Brooklyn, NY 11210, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
We present an experimental and computational study of the reaction of aryl substituted benzyl 1-alkynyl
sulfides with potassium alkoxide in acetonitrile, which produces 2-aryl 2,3-dihydrothiophenes in poor to
good yields. The cyclization is most efficient with electron withdrawing groups on the aromatic ring.
Evidence indicates there is rapid exchange of protons and tautomerism of the alkynyl unit prior to
cyclization. Theoretical calculations were also conducted to help rationalize the base induced 5-endo
cyclization of benzyl 1-propynyl sulfide (1a). The potential energy surface was calculated for the for-
mation of 2,3-dihydrothiophene in a reaction of benzyl 1-propynyl sulfide (1a) with potassium meth-
oxide. Geometries were optimized with CAM-B3LYP/6-311þG(d,p) in acetonitrile with the CPCM solvent
model. It is significant that the benzyl propa-1,2-dien-1-yl sulfane (6) possessed a lower benzylic proton
affinity than the benzyl prop-2-yn-1-yl sulfane (8) thus favoring the base induced reaction of the former.
From benzyl(propa-1,2-dien-1-yl sulfane (6), 2,3-dihydrothiophene can be formed via a conjugate base
that undergoes 5-endo-trig cyclization followed by a protonation step.
Received 13 September 2010
Received in revised form 29 November 2010
Accepted 30 November 2010
Available online 7 December 2010
Keywords:
Cyclization
Computational chemistry
Tautomerism
Dihydrothiophenes
Carbanions
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
reactive functionality in the substrates, there nevertheless was
a requirement for an electron withdrawing group on the aryl ring.
2,3-Dihydrothiophenes are useful synthetic precursors for many
compounds including thiophenes,1 thionucleoside derivatives,2
and penicillin mimics.3 Synthetic routes to 2,3-dihydrothiophenes
are varied and numerous,1f,4 with based-induced cyclizations
playing an important role. Under basic conditions, starting sub-
strates usually require the presence of electron withdrawing or
other functionality to facilitate condensation chemistry or to di-
rectly participate in the cyclization.5 Some cyclizations that make
use of transition metals to target dihydrothiophenes6 do not
require such strong directing functionality.6a A radical based cy-
clization free of strong electron withdrawing groups provided
mixtures of 2,3 and 2,5-dihydrothiophenes.7
In 2000, the Schwan group reported chemistry that created 2,3-
dihydrothiophenes (2) by way of a tert-butoxide induced 5-endo
cyclization of 2-substituted arylmethyl alkynyl sulfides (1), Eq. (1).8
That reaction was thought to involve benzylic deprotonation and
cyclization at the terminal carbon of the propynyl chain, even
though the starting material did not possess unsaturation in the
terminal carbon, nor held any other skeletal functionality to bring
about carbonecarbon bond formation. Although there was no os-
tensible need for strong electron withdrawing groups or other
In the communication, some mechanistic data were offered, but
some intriguing uncertainties remained.8 How was it that the
cyclization occurred most efficiently when the starting material did
not have unsaturation at the propynyl terminus? Which tautomeric
form of the 3-carbon unit is accepting the electron density? We
now report that a broader selection of arylmethyl alkynyl sulfides
succumbs to the cyclization and we offer some mechanistic and
computational evidence concerning the mode of cyclization of the
substrates.
2 KOtBu
CH3CN
S
S
(1)
X(n)
X(n)
1
2
2. Results and discussion
2.1. Scope of the reaction
The requisite startingmaterials (1)were accessiblebyadaption of
benzylic halides or alcohols. The alcohols were converted to thio-
cyanates under Mitsunobu conditions, whereas the halides were
* Corresponding authors. E-mail address: schwan@uoguelph.ca (A.L. Schwan).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.11.104

J.M. Motto et al. / Tetrahedron 67 (2011) 1002e1010
1003
converted to thiocyanates or thiotosylates by direct substitution
with appropriate sulfur reagent.9 The ArCH2SeX reagents were then
treated with an acetylide to bring forth the benzyl alkynyl sulfides.10
Full synthetic procedures are in the Supplementary data.
The presence of the nitro groups prevented the reaction and
starting material was fully recoverable in the 2-nitro case (1r),
whereas full decomposition occurred in the 3-nitro case (1q).
Replacing the aryl groups with heteroaryl groups prevented the
reaction. Specifically, 2-bromothien-3-ylmethyl 1-propynyl sulfide,
2-furfuryl 1-propynyl sulfide, and 2-fluoro-4-iodopyrid-3-yl
1-propynyl sulfide did not cyclize. Also, positioning an iodine group
at the peri position did not prompt cyclization of 8-iodonaph-
thalen-1-ylmethyl 1-propynyl sulfide.
A selection of dihydrothiophenes has been shown to be oxi-
dizable to thiophenes.1c,eeg,12 Accordingly, we have achieved the
successful conversion of heterocycles 2b and 2h into thiophenes 3b
and 3h in 73 and 81% yields, respectively, with DDQ1e in CHCl3.
Moreover the additional functionality on the aryl unit provides
a reactive feature for further adaption toward compounds and
polymers with useful electronic properties.13
In the communication,8 many optimized reaction parameters
were reported including solvent and substrate concentration. It was
subsequently learned that KOtBu is preferred over sodium or lith-
ium tert-butoxide. Thus, treating the starting sulfides 1 with 2 equiv
of KOtBu in acetonitrile at various temperatures for 24 h affords
a dihydrothiophene (2) with the aryl group at the 2-position and
the double bond at the 4-position, Eq. (1).
The products and yields are outlined inTable 1. The products were
identified through standard spectroscopic characterization. Partic-
ularly diagnostic are the five sets of non-aryl resonances in the 1H
NMR spectrum, each of which represents one proton from the
dihydrothiophene ring. The 1H NMR spectra consistently exhibit
a ddd near 6.2 ppm, a dt near 5.6 ppm, a dd near 5.3 ppm, a ddt near
3.3 ppm, and a dddd near 2.9 ppm. The 1He1H coupling constants of
products match those of related heterocycles.5c,11 The initial notion
that a 2-substituted aryl group is required for cyclization8 was found
to be invalid, as the results show that electronwithdrawing groups at
other aryl position promote the reaction.
The cyclization represents a rare instance where CeC bond
formation occurs without the need for functionality directly par-
ticipating in condensation or other reactive chemistry. Apparently,
after deprotonation, the unsaturation of the 3-carbon substituent
on sulfur is sufficient to activate ring closure.
Table 1
Cyclization data for benzyl 1-alkynyl sulfides
#
Product
Temp (ꢀC)a
Yieldb
S
2.2. Mechanism and computations
X(n)
Theoretical calculations have been conducted to help rationalize
the base induced 5-endo cyclization of benzyl 1-alkynyl sulfides,
which led us to the mechanistic proposal in Scheme 1, slightly
modified from that reported in the original communication of
2000.8 Model system 1a was used to mimic the core of benzyl
alkynyl sulfides bearing substituents on the aryl ring. Because it
was impractical to compute the reaction with the potassium tert-
butoxide base, the potential energy surface was calculated for the
formation of 2,3-dihydrothiophene 2a in a reaction of 1a with po-
tassium methoxide. Geometries were optimized with CAM-B3LYP/
6-311þG(d,p)14e16 in acetonitrile with the CPCM solvent model.17
X¼2-H
Reflux
28c,d
2a
b
c
d
e
X¼2-I
0
0
0
75
74
74
0
X¼2-Br
X¼2-Cl
X¼2-Me
X¼2-Ph
Reflux
Refluxe
Reflux
Reflux
rt
f
41c,d
45
64
68
45
59
66
45f
68
44c,d
54c
0
g
h
i
j
k
l
m
n
o
p
q
r
X¼2-F
X¼2-CN
X¼3-I
X¼4-I
rt
X¼3-CF3
X¼2-SPh
X¼2-S(O)Ph
X¼2-S(O)2Ph
X¼2,5-(OMe)2
X¼3,5-(OMe)2
X¼3-NO2
X¼2-NO2
Reflux
Reflux
Reflux
Reflux
reflux
Reflux
Reflux
Reflux
0
S
s
0
72
Br
S
S
t
60f,g
47
Br
I
S
u
0
69h
iPr
a
Reaction temperature. Compounds 1 were stirred for 24 h unless otherwise
indicated.
b
c
Yield is of isolated material unless otherwise indicated.
Yield based on consumed starting material.
Product could not be separated from starting material. Product was assigned
Scheme 1.
d
based in the characteristic 1H NMR peaks.
The calculated structures are shown in Fig. 1 where Kþe
interactions are foundforall structures. Itis interesting to note that
cation interactions are influenced less by inductive effects and more
p
e
Refluxed for 8 h.
Mixture of diastereomers (1:1).
Refluxed for 6 h.
Ratio of isomers based on double bond position: 2,3/2,5¼1/1.7.
p-
f
g
h
by through-space effects between the metal ion and substituents on

1004
J.M. Motto et al. / Tetrahedron 67 (2011) 1002e1010
Fig. 1. Optimized CPMC-CAM-B3LYP/6-311þG(d,p) geometries for the KOMe-induced cyclization of 1a. Calculations were carried out in acetonitrile. Kþ, KOMe, and MeOH mol-
ꢁ
ecules were modeled explicitly. Bolded numbers aligned near the structures are bond distances in A. Unbolded numbers on some of the structures are the atom numbers referred to
in Table 2.
the aromatic rings,18 and that the nitro substituent causes the ring to
have a very weak -cation interaction. Because of the complexity of
the PES for the parent system 1a, a computational examination of
substituent effects was beyond the scope of our study.
The energetic features of the reaction are shown in Fig. 2. From
Fig. 2A it is clear that allenyl species 6 plays a key role in the cy-
clization process to 2,3-dihydrothiophene 2a because it is stabilized
compared to 8.
that the preferred tautomeric state of the 3-carbon unit was the
1-propynyl form as propargyl or allenyl tautomers were never
observed by 1H NMR of the cyclization mixture contents. Such an
observation is fully consistent with past literature that indicates the
conjugated form is the more thermodynamically stable.19 Similarly,
the computed protonationedeprotonation equilibria, which in-
volve 1a, 4-8 show relatively low activation energies of
0.4e8.2 kcal/mol and provide an explanation of how proton or
deuterium can be incorporated in all CeH sites except on the
phenyl ring.
In the condensed phase, our computations did not find a tran-
sition state(s) for the isomerization of 2a to 14. Additional control
experiments on 2b in CD3CN, revealed minimal incorporation of
D into the material. The 2,3-dihydro isomer (2b) is not amenable to
migration of the double bond because its exchange is quite slow.
We did not probe the equilibrium between 2b and 14b due to this
slow exchange. The rate of H/D exchange of the starting material is
substantially more rapid. It can be noted that re-exposure of 14u
(2,5-dihydro isomer of 2u) to the reaction conditions causes the 2u/
14u isomer ratio to be re-established. However, 2u does not
exchange when re-exposed to the reaction conditions in CD3CN.
Attempts to prepare 14a in order to study its exchange and isom-
erization behavior were not successful.
p
The formation of 4 from 1a is a ‘dead end’ and did not convert to
cyclic products. Allene 6 is formed in a two-step process from 1a via
intermediate 5. A transition state for the loss of a benzylic proton
from 6 has an activation barrier of 7.9 kcal/mol (Fig. 2B). Upon
formation of deprotonated allene 9, it can undergo a unimolecular
5-endo-trig cyclization yielding anion 10, followed by protonation
to form 2a. While the thia-Wittig rearrangement has been eluci-
dated yielding 11 (Fig. 2C), the experimental data suggest a rapid
protonation of 10 and the formation of 2a. An alternative mecha-
nism involves the conversion of deprotonated alkyne 12 via
a 5-endo-dig cyclization to give 13 followed by protonation to form
14; however, the path to 12 is higher in energy.
Control experiments were performed in order to provide further
understanding of the reaction mechanism. When the reaction was
performed in CD3CN, the products possessed essentially full deu-
teration at the non-aryl carbons, a result consistent with significant
solvent intervention. Indeed, deuterium exchange experiments
showed that methyl hydrogens of thioethers 1a,b,i,j each ex-
changed with half-lives of ca. 25 s at ꢁ10 ꢀC, whereas benzyl hy-
drogen exchange was faster, completing in <25 s at the same
temperature. The onset of product was scaled to be substantially
longer at the same temperature. Related experiments reaffirmed
The reaction is most certainly a base mediated cyclization onto
the terminus of the three carbon unit. The experimental exchange
and computational data suggest that the propynyl/allenyl/prop-
argyl equilibrium is dynamic, with the propynyl as the most pop-
ulated entity (Fig. 2A). From Fig. 2, it is evident that formation of
allenyl species is favored to the propargyl species and accounts for
the path to 2,3-dihydrothiophene product in acetonitrile. 2,3-

J.M. Motto et al. / Tetrahedron 67 (2011) 1002e1010
1005
TS1a/5
12
Proton loss
9
B
A
8.2
4
TS7/8
TS8/12
TS1a/4
7.3
8
6.8
+ MeOH, K+
6.9
12
12.0
6.4
10.5
TS5/6
5.2
+ KOMe
TS6/7
TS6/9
+
+ MeOH, K
9
7
7.9
4.9
7.5
4.3
5
3.6
8
5.6
+
+ MeOH, K+
+ MeOH, K
+ KOMe
6
+ MeOH, K+
1a
0.4
+ KOMe
0.0
6
+ KOMe
0.0
+ KOMe
5-endo dig
5-endo trig
C
cyclization
TS12/13
17.9
TS9/10
16.4
12
3.0
9
0.0
TS13/15
TS10/11
-5.9
-2.7
+
+ MeOH, K
13
10
+
+ MeOH, K
-8.0
-9.0
+
+ MeOH, K
+
+ MeOH, K
11
+
15
+ MeOH, K
-27.5
+
-31.2
+ MeOH, K
Fig. 2. AeC. CPCM-CAM-B3LYP/6-311þG(d,p) optimized potential energy surface in kcal/mol including thermal corrections for enthalpy (273.15 K). KOMe, Kþ, and MeOH molecules
were modeled explicitly. Transition states were confirmed by intrinsic reaction coordinate (IRC) calculations.
dihydrothiophene 2a and 2,5-dihydrothiophene 14 are essentially
isoenergetic. The relative energies of these two dihydrothiophene
products were calculated to be within 2.8 kcal/mol of each other
(Table S1). A change in the solvent or benzyl alkynyl sulfide struc-
ture may shift the reaction to propargyl species and the path to 2,5-
dihydrothiophene product. The more rapid exchange at the
benzylic site suggests that benzylic anions are available to attack
the terminus of the 3-carbon unit when unsaturation is available
(see Fig. 2C).
While there is ongoing interest in assessing endo versus exo
cyclization preferences for single species,20 we were not able to
locate literature analyses of competitive endo cyclizations of
equilibrating species. Given our findings, the chemistry at hand
The transitions states TS9/10 and TS12/13 differ only by a few
kcal/mol. Furthermore, many of the calculated parameters are quite
similar in the two transition states. For instance, the degrees of
rehybridization of the benzylic carbon in the transitions states,
as measured by changing dihedral angles, are essentially
indistinguishable. However, the transition state differences worth
noting relate to C-C bond formation, C(3)-S bond lengthening and
the bending of the three carbon unit (Table 2).
ꢁ
Transition state TS9/10 exhibits CeC bond forming at 2.37 A, C
ꢁ
(3)eS bond lengthening of 0.13 A and a bend of the allene unit to
ꢀ
ꢁ
134 . As a comparison, TS12/13 has closer CeC contacts at 2.33 A,
ꢁ
extra lengthening of C(3)eS (0.21 A) and a lesser degree of bending
at the sp. hybridized carbon (137ꢀ). Clearly, TS12/13 calls upon and
benefits from the extra lengthening of the C(3)eS bond and there is
less inclination to bend at the allenyl/propynyl central carbon. Both
of these features permit advanced CeC bond formation in the
transition state. The TS9/10 transition state is achieved with more
bending at the allenyl carbon but with less developed CeC bond
formation and does not require as much C(3)eS bond lengthening.
The data suggest the allene is more receptive to cyclization than
the propynyl unit, as it demonstrates a greater propensity to bend
during the cyclization. It is possible that such behavior would also
come into play with other 5-endo-dig/trig cyclizations, such as with
systems absent of sulfur or any other atom that could accommodate
electron density.
does not present
a true competition, nevertheless our de-
termination of transition state energies and parameters permit
a comparison of two different but closely related entities. The
simplicity of the system may serve as a model for other funda-
mental cyclizations affording five-membered rings.
Baldwin’s rules suggest the 5-endo-dig cyclization should be
allowed, and the 5-endo-trig should not.21 However, the 5-endo-trig
example in the current paper is allene-based with a geometry very
close to the alkyne tautomer and was not specifically addressed by
Baldwin.22 As such, the cyclization tendencies of this comparison
are difficult to distinguish without the assistance of computational
chemistry.

1006
J.M. Motto et al. / Tetrahedron 67 (2011) 1002e1010
Table 2
Selected computation data for cyclizationsa
9
12
Original bond lengths of key atoms
C(2)eC(1)
C(3)eC(2)
S(4)eC(3)
1.30
1.30
1.80
C(2)eC(1)
C(3)eC(2)
S(4)eC(3)
1.20
1.45
1.86
Original indication of planarity of anion
3-C Bond angle
C(7)eC(6)eC(5)eH(17)
C(8)eC(6)eC(5)eH(17)
C(1)eC(2)eC(3)
ꢁ164.7
C(7)eC(6)eC(5)eH(18)
C(8)eC(6)eC(5)eH(18)
C(1)eC(2)eC(3)
ꢁ171.3
20.00
178.6
14.3
179.6
TS9/10
TS12/13
Bond lengths of key bonds
C(2)eC(1)
C(3)eC(2)
S(4)eC(3)
C(5)eC(1)
C(1)eC(2)eC(3)
C(7)eC(6)eC(5)eH(17)
C(8)eC(6)eC(5)eH(17)
1.36
1.29
1.94
C(2)eC(1)
C(3)eC(2)
S(4)eC(3)
C(5)eC(1)
C(1)eC(2)eC(3)
C(7)eC(6)eC(5)eH(18)
C(8)eC(6)eC(5)eH(18)
1.24
1.42
2.04
2.33
137.0
173.0
Bond forming distance
3-C Bond angle
Rehybridization dihedral angles
2.37
133.8
173.5
ꢁ8.33
ꢁ8.2
10
13
Bond lengths of key atoms
C(1)eC(2)
C(2)eC(3)
C(3)eS(4)
C(3)eC(2)eC(1)
1.52
1.33
1.86
C(2)eC(1)
C(3)eC(2)
S(4)eC(3)
C(3)eC(2)eC(1)
1.34
1.49
1.90
3-C Bond angle
109.5
112.4
a
ꢁ
The numbering scheme is shown in Fig. 1. Bond distances in A. Bond angles and dihedral angles in degrees.
3. Conclusions
4.2. Computational methods
A simple base-induced transition metal free 5-endo cyclization
of benzyl 1-alkynyl sulfides (1) proceeds without the need for
activating of electron withdrawing substituents directly attached to
skeletal carbons. The 2,3-dihydrothiophene products (2) can be
readily forwarded to 2-aryl thiophenes. Computational chemistry
was performed to assist in the understanding of mechanism of
cyclization and establish, which allenyl/propargyl tautomer is likely
involved in the cyclization.
It is significant that the allenyl species 6, formed in a stepwise
path via 5, is more stable than the propargyl species 8. The weaker
benzylic proton affinity of 6 than 8 favors the base induced reaction
of 6. From allenyl species 6, 2,3-dihydrothiophene 2a can be formed
in three steps, including base 9, which undergoes a 5-endo-trig
cyclization to 10.
Density Functional Theory (DFT) calculations were conducted
using the Gaussian 09 suite of programs.15 The CAM-B3LYP method
corrected for the long-range deficiencies of B3LYP and provided
results close to coupled cluster calculations.23 Condensed phase
calculations for acetonitrile were carried out with the conductor-
like polarizable continuum model (CPCM) of Cossi and co-
workers17 with the smoothing formalism that Karplus and York
developed.14e The solute molecular cavity was specified using the
Bondi radii values.24 The computed values include thermal
(273.15 K) corrections for enthalpy. Transition states were con-
firmed by examining the negative eigenvalue of the hessian matrix
and by intrinsic reaction coordinate (IRC) calculations. GaussView
5 was used for the visualization of the molecules and the vibra-
tional modes.16
There are some shortcomings with the B3LYP functional.25 For
example, medium and long-range electron correlation errors are
common.26 The CAM-B3LYP functional was selected because of its
good performance in calculations of electronic polarizabilities, as
well as long-range exchange interactions by a Coulomb attenuating
method, and medium-range interactions with an error fitting
function.14d,27
Table 3 shows that the CAM-B3LYP calculation predicts greater
stability of propyne versus allene, which is opposite to that found
by experimental, and M05-2X and CCSD(T) methods.29e31 The
relative energetics of MP4,19b CCSD(T), and CAM-B3LYP calculations
are quite similar to each other for methyl prop-1-yn-1-yl sulfane
and methyl propa-1,2-dien-1-yl sulfane. However, our CAM-B3LYP
calculations are not expected to have greater accuracy than ∼4 kcal/
mol. The average errors of B3LYP in thermochemistry calculations
were ∼3.6 kcal/mol (from a database of 177 reactions).28
4. Experimental
4.1. General
Melting points were determined using a MEL-TEMP melting
point apparatus and are uncorrected. Infrared (IR) spectra were
obtained on a Bomem FTIR spectrometer either neat or in a solution
cell (CH2Cl2 or CDCl3). NMR spectra for 1H and 13C NMR were
recorded on a Bruker spectrometer at 400 and 100.6 MHz in CDCl3
solution and are reported in parts per million
d (ppm) relative to
tetramethylsilane internal standard or CDCl3 at 7.26 ppm. Ele-
mental analyses were performed by MHW labs of Phoenix, AZ.
Mass spectrometry was performed at the McMaster Regional
Centre for Mass Spectrometry, McMaster University or the WAT-
SPEC Mass Spectrometry Facility at the University of Waterloo.
Diethyl ether and tetrahydrofuran (THF) were freshly distilled from
sodium and benzophenone. Methylene chloride was freshly dis-
tilled from calcium hydride. Acetonitrile was distilled from calcium
4.3. General procedure for the cyclization of benzyl propynyl
sulfides
ꢁ
hydride and stored over 4 A molecular sieves under an N2 atmo-
sphere. Potassium tert-butoxide was stored in a vial in a desiccator
with anhydrous CaSO4. All air and water sensitive reagents were
transferred using oven-dried nitrogen-purged glass syringes. Flash
chromatography was performed on new mesh Type 60 A silica gel.
Analytical thin-layer chromatography (TLC) was performed using
0.25 mm Merck Kieselgel 60 F254 glass-backed plates.
In a flame-dried rbf is placed the benzyl propynyl sulfide
(1 equiv) in dry CH3CN (1 mL per 5 mg of substrate). In a second
flask is placed KOtBu (2.0 equiv) in dry CH3CN (1 mL per 5 mg of
substrate). The solution of the substrate is added to the KOtBu
solution via syringe and the reaction is stirred at rt or reflux for
24 h. Upon completion of the reaction, de-ionized water (DI) H2O is
ꢁ

J.M. Motto et al. / Tetrahedron 67 (2011) 1002e1010
1007
Table 3
Relative energies of propyne and allene, and of methyl prop-1-yn-1-yl sulfane and methyl propa-1,2-dien-1-yl sulfane
Method
E (kcal/mol)
Ref.
·
propyne
allene
Experimental
ꢁ1.4
ꢁ1.4
ꢁ1.2
0.8
29
30
31
This work
CCSD(T)/cc-pVQZ//MP2/cc-pVTZ
M05-2X/6-311þG(2df,2p)
CAM-B3LYP/6-311þG(d,p)
CH3S
CH3S
methyl prop-1-yn-1-yl sulfane
·
methyl propa-1,2-dien-1-yl sulfane
MP4/6-31þG(d)//RHF/6-31þG(d)
1.3
1.8
3.4
2.6
1.3
0.6
19b
19b
This work
This work
This work
This work
IEFPCM-MP4/6-31þG(d)//PCM-RHF/6-31þG(d)
CAM-B3LYP/6-311þG(d,p)
CPCM-CAM-B3LYP/6-311þG(d,p)
CCSD(T)/cc-pVQZ//MP2/cc-pVTZ
CPCM-CCSD(T)/cc-pVQZ//CPCM-MP2/cc-pVTZ
added and the layers separated. The aqueous layer is extracted with
EtOAc (3ꢂ). The organics are combined, washed with DI H2O (1ꢂ),
satd aq NaCl (1ꢂ), dried over MgSO4, and concentrated. See Table 1
for additional detail.
J¼6.0, 2.6 and 1.7 Hz, 1H, vinyl H), 5.61 (dt, J¼6.0 and 2.9 Hz, vinyl
H), 5.27 (dd, J¼9.7 and 4.9 Hz, 1H, CH), 3.27 (ddt, J¼16.8, 9.7 and
2.6 Hz, 1H, CH2), 2.86 (dddd, J¼16.8, 4.9, 2.9 and 1.7 Hz, 1H, CH2). 13
C
NMR (100.6 MHz, CDCl3), d: 142.5, 132.7, 128.7, 128.1, 127.9, 125.4,
123.3, 120.4, 50.8, 42.3. IR (neat, cmꢁ1) 3062, 2938, 2896, 2842,
1588, 1567, 1467, 1440, 1265, 1025. EIMS, m/z (%): 242 (20, Mþ for
81Br), 240 (21, Mþ for 79Br), 161 (37), 128 (100), 116 (18), 115 (24), 84
(22), 51 (15), 49 (23), 47 (16), 45 (29). Anal. Calcd for C10H9BrS: C,
49.81; H, 3.76. Found: C, 49.79; H, 3.88.
4.3.1. 2-Phenyl-2,3-dihydrothiophene (2a). The reaction of benzyl
1-propynyl sulfide 1a (337 mg, 2.08 mmol) with KOtBu (467 mg,
4.16 mmol) in refluxing acetonitrile yielded 2,3-dihydrothiophene
2a (57.8 mg; 17%) and recovered starting material (132 mg) after
flash chromatography. The yield based on recovered starting ma-
terial was 28%. Spectral data were obtained as a mixture of the two
4.3.4. 2-(2-Chlorophenyl)-2,3-dihydrothiophene (2d). The reaction
of 2-chlorobenzyl propynyl sulfide (1d) (231 mg, 1.18 mmol) with
KOtBu (264 mg, 2.35 mmol) in acetonitrile yielded 2,3-dihy-
drothiophene 2d (171 mg; 74%) as a yellow liquid after flash
compounds. 1H NMR (400 MHz, CDCl3),
d
: 7.41 (d, J¼7.4 Hz, 1H, Ar
H), 7.30e7.33 (m, 2H, Ar H), 7.23e7.26 (m, 2H, Ar H), 6.23 (dt, J¼6.0
and 2.4 Hz, 1H, vinyl H), 5.59 (dt, J¼6.0 and 2.4 Hz, 1H, vinyl H), 4.91
(dd, J¼9.6 and 7.3 Hz, 1H, CH), 3.20 (ddt, J¼16.5, 9.6, and 2.4 Hz, 1H,
CH2), 2.93 (ddt, J¼16.5, 7.3, and 2.4 Hz, 1H, CH2). Partial 13C NMR
chromatography. 1H NMR (400 MHz, CDCl3),
d
: 7.62 (dd, J¼7.6 and
1.7 Hz, 1H, Ar H), 7.36 (dd, J¼7.6 and 1.4 Hz, 1H, Ar H), 7.25 (dt, 7.6
and 1.4 Hz, 1H, Ar H), 7.19 (dt, J¼7.6 and 1.7 Hz, 1H, Ar H), 6.24 (ddd,
J¼6.0, 2.6 and 1.8 Hz, 1H, vinyl H), 5.60 (dt, J¼6.0 and 3.0 Hz, 1H,
vinyl H), 5.31 (dd, J¼9.7 and 5.1 Hz, 1H, CH), 3.26 (ddt, J¼16.7, 9.7
and 2.6 Hz,1H, CH2), 2.87 (dddd, J¼16.7, 5.1, 3.0 and 1.8 Hz,1H, CH2).
(100.6 MHz, CDCl3), d: 128.6, 127.4, 127.0, 125.6, 120.5, 52.7, 43.9.
4.3.2. 2-(2-Iodophenyl)-2,3-dihydrothiophene (2b). The reaction of
2-iodobenzyl propynyl sulfide (1b) (194 mg, 0.674 mmol) with
KOtBu (180 mg, 1.35 mmol) yielded 2,3-dihydrothiophene 2b
(180 mg; 75%) as a yellow liquid after flash chromatography. 1H
13C NMR (100.6 MHz, CDCl3),
d: 140.8, 132.7, 129.4, 128.4, 127.9,
127.2, 125.4, 120.4, 48.1, 42.2. IR (neat, cmꢁ1) 3070, 2939, 2896,
2842, 1472, 1444, 1051, 1037. EIMS, m/z (%): 196 (7, Mþ for 37Cl), 194
(7, Mþ for 35Cl), 86 (31), 84 (46), 58 (22), 51 (20), 49 (72), 47 (15), 43
(100), 42 (15). HREIMS: calcd for C10H9ClS: 196.0113. Found:
196.0101.
NMR (400 MHz, CDCl3),
d
: 7.84 (dd, J¼7.7 and 1.1 Hz, 1H, Ar H), 7.61
(dd, J¼7.7 and 1.6 Hz, 1H, Ar H), 7.33 (dt, J¼7.7 and 1.1 Hz, 1H Ar H),
6.94 (dt, J¼7.7 and 1.6 Hz, 1H, Ar H), 6.25 (ddd, J¼6.0, 2.6 and 1.7 Hz,
1H, vinyl H), 5.63 (dt, J¼6.0 and 2.8 Hz, 1H, vinyl H), 5.13 (dd, J¼9.7
and 5.0 Hz, 1H, CH), 3.27 (ddt, J¼16.8, 9.7, and 2.8 Hz, 1H CH2), 2.83
(dddd, J¼16.8, 5.0, 2.8, and 1.7 Hz, 1H, CH2). 13C NMR (100.6 MHz,
4.3.5. 2-(2-Phenylphenyl)-2,3-dihydrothiophene (2f). The reaction
of 2-phenylbenzyl propynyl sulfide (1f) (157 mg, 0.659 mmol) with
KOtBu (148 mg, 1.32 mmol) in refluxing acetonitrile yielded a mix-
ture of 2,3-dihydrothiophene 2f (38.6 mg; 25%) and recovered
starting material (63.2 mg) after flash chromatography. The yield
based on recovered starting material was 41%. Spectral data
obtained as a mixture of dihydrothiophene 2f and benzyl propynyl
CDCl3), d: 145.6, 139.4, 128.9, 128.7, 127.5, 125.4, 120.4, 99.9, 56.0,
42.9. IR (neat, cmꢁ1) 3060, 2937, 2894, 2844,1583, 1563, 1463, 1436,
1012. EIMS, m/z (%): 288 (7, Mþ), 161 (37), 128 (100), 127 (23), 116
(17), 115 (39), 89 (19), 85 (18), 77 (32), 63 (25), 62 (15), 51 (32), 50
(28), 45 (31). HREIMS: Calcd for C10H9SI: 287.9470. Found:
287.9457.
sulfide 1f. 1H NMR (400 MHz, CDCl3),
d: 7.51e7.17 (m, 9H, Ar H’s),
4.3.3. 2-(2-Bromophenyl)-2,3-dihydrothiophene (2c). The reaction
of 2-bromobenzyl propynyl sulfide (1c) (209 mg, 0.867 mmol) with
KOtBu (195 mg, 1.73 mmol) in acetonitrile yielded 2,3-dihyr-
othiophene 2c (154 mg; 74%) as a yellow liquid after flash chro-
6.18 (dt, J¼4.6 and 2.0 Hz, 1H, vinyl H), 5.51 (dt, J¼4.6 and 3.1 Hz,
vinyl H), 4.97 (dd, J¼9.5 and 7.3 Hz,1H, CH), 3.06e2.93 (m, 2H, CH2).
4.3.6. 2-(2-Fluorophenyl)-2,3-dihydrothiophene (2g). The reaction
of 2-fluorobenzyl propynyl sulfide (1g) (204 mg, 1.13 mmol) with
KOtBu (255 mg, 2.27 mmol) in refluxing acetonitrile yielded 2,3-
dihydrothiophene 2g (92 mg; 45%) as a yellow liquid after flash
matography. 1H NMR (400 MHz, CDCl3),
d: 7.62 (dd, J¼7.7 and
1.6 Hz, 1H, Ar H), 7.55 (dd, J¼7.7 and 1.2 Hz, 1H, Ar H), 7.29 (dt, J¼7.7
and 1.2 Hz, 1H, Ar H), 7.11 (dt, J¼7.7 and 1.6 Hz, 1H, Ar H), 6.24 (ddd,

1008
J.M. Motto et al. / Tetrahedron 67 (2011) 1002e1010
chromatography. 1H NMR (400 MHz, CDCl3),
d
: 7.56 (dt, J¼7.7 and
2.91 (dddd, J¼16.6, 6.5, 2.8, and 2.2 Hz, 1H). 13C NMR (100.6 MHz,
1.7 Hz, 1H), 7.26e7.20 (m, 1H), 7.12 (t, J¼7.7 Hz, 1H), 7.02 (ddd,
J¼10.3, 8.2, and 1.1 Hz, 1H), 6.42 (ddd (app. dt), J¼6.1, 2.3, and
2.3 Hz, 1H), 5.60 (dt, J¼6.1 and 2.8 Hz, 1H), 5.20 (dd, J¼9.7 and
6.1 Hz), 3.22 (dddd (apparent ddt), J¼16.6, 9.7 and 2.6 Hz, 1H), 2.90
(dddd (apparent ddt), J¼16.6, 6.1, 2.6, 1H). 13C NMR (100.6 MHz,
CDCl3),
d
: 144.6, 130.8(q, J13Ce19F¼32.3 Hz), 130.4, 129.1, 125.5, 124.2,
124.0 (q, J13Ce19F¼272.1 Hz), 123.8, 120.3, 51.8, 43.9. IR (neat, cmꢁ1):
3066, 2930, 1716,1613,1596,1492, 1450,1329,1261, 1166,1125, 1098,
1073, 1002, 902, 804, 739, 702. CIMS m/z (%): 231 (10, (MþH)þ), 230
(59, Mþ),197 (12),177 (16), 86 (24), 84 (38), 51 (35), 49 (100), 47 (17),
30 (22). HRCIMS: calcd for C11H9F3S: 230.0377. Found: 230.0372.
CDCl3),
d
: 159.6 (d, J13Ce19F¼246.3), 130.4 (d, J13Ce19F¼13.5 Hz),
128.7 (d, J13Ce19F¼8.2 Hz), 128.2 (d, J13Ce19F¼3.3 Hz), 125.3, 124.3 (d,
J13Ce19F¼3.3 Hz), 120.4, 115.2 (d, J13Ce19F¼22.1 Hz), 44.2 (d,
J13Ce19F¼2.8 Hz), 42.5. IR (CDCl3, cmꢁ1): 3066, 3044, 2932, 2892,
2840, 1717, 1614, 1585, 1488, 1456, 1278, 1264, 1230, 1173, 1094,
1035, 1006, 832, 805. CIMS, m/z (%): 181.0 (24, (MþH)þ), 180.0 (100,
Mþ), 179.0 (15, (MꢁH)þ), 147.1 (40), 146.1 (14), 49.0 (22). Anal. Calcd
for C10H9SF: C, 66.64%, H: 5.03%. Found: C, 66.41%; H, 5.13%.
4.3.11. 2-(Phenylthio)phenyl-2,3-dihydrothiophene (2l). The reaction
of 2-(phenylthio)benzyl propynyl sulfide (1l) (210 mg, 0.77 mmol)
with KOtBu (172 mg,1.53 mmol) in refluxing acetonitrile yielded 2,3-
dihydrothiophene 2l (137 mg, 66%) as a yellow oil after flash chro-
matography. 1H NMR (400 MHz, CDCl3),
d: 7.72 (dd, J¼7.9, 1Hz, 1H),
7.38e7.14 (m, 8H), 6.21 (ddd, J¼6.1, 2.2, and 2.0 Hz,1H), 5.56 (dt, J¼6.1
and 2.7 Hz, 1H), 5.50 (dd, J¼9.9 and 5.6 Hz, 1H), 3.13 (ddt, J¼16.8, 9.9,
and 2.7 Hz, 1H), 2.82 (dddd, J¼16.8, 5.0, 2.7, and 2.0 Hz, 1H). 13C NMR
4.3.7. 2-(2-Cyanophenyl)-2,3-dihydrothiophene (2h). The reaction
of 2-cyanobenzyl propynyl sulfide (1h) (239 mg, 1.27 mmol) with
KOtBu (286 mg, 2.55 mmol) in acetonitrile yielded 2,3-dihy-
drothiophene 2h7a (153 mg, 64%) as a white solid (mp 83e84.5 ꢀC)
(100.6 MHz, CDCl3), d: 145.7, 136.5, 134.0, 132.1, 129.4, 129.1, 128.9,
128.0, 127.7, 126.4, 125.5, 120.3, 48.6, 43.0. IR (CDCl3, cmꢁ1): 3057,
3016, 2926, 2839, 1717, 1581, 1476, 1466, 1439, 1328, 1301, 1277, 1194,
1158, 1083, 1068, 1057, 1038, 1024, 1000, 738. CIMS, m/z (%): 271 (97,
(MþH)þ), 270 (100, Mþ), 242 (27), 223 (20), 215 (17), 214 (25), 197
(29),193(75),161 (48),160(30),147 (17),128(33),115 (16). Anal. Calcd
for C16H14S2: C, 71.07%; H, 5.22%. Found: C, 70.92%; H, 5.30%.
after flash chromatography. 1H NMR (400 MHz, CDCl3),
d: 7.75 (d,
J¼8.0Hz, 1H), 7.63e7.54 (m, 2H), 7.34 (t, J¼7.6 Hz, 1H), 6.24 (ddd
apparent dt, J¼6.0 and 2.1 Hz, 1H), 5.58 (dt, J¼6.0 and 2.7 Hz, 1H),
5.26 (dd, J¼9.9 and 5.5 Hz, 1H), 3.34 (ddt, J¼16.8, 9.9, and 2.5 Hz,
1H), 2.87 (dddd (apparent ddt), J¼16.8, 5.5, and 2.6 Hz, 1H). 13C
4.3.12. 2-(Phenylsulfinyl)phenyl-2,3-dihydrothiophene (2m). The re-
action of 2-(phenylsulfinyl)benzyl propynyl sulfide (1m) (119 mg,
0.41 mmol) with KOtBu (93.5 mg, 0.83 mmol) in refluxing acetoni-
trile yielded 2,3-dihydrothiophene 2m (528 mg, 45%) as a white
solid and a 1:1 mixture of diastereomers after flash chromatography
on silica gel (20e40% hexanes eluent). 1H NMR (400 MHz, CDCl3,
NMR (100.6 MHz, CDCl3), d: 147.5, 133.4, 132.7, 127.7, 127.6, 125.4,
120.1, 117.5, 111.0, 49.2, 43.5. IR (CH2Cl2, cmꢁ1): 3018, 2843, 2226,
1599, 1482, 1449, 1212, 1166, 1041, 1003. CIMS, m/z (%): 188.1 (27,
(MþH)þ), 187.0 (56, Mþ), 186.0 (100, (MꢁH)þ), 154.1 (21). Anal.
Calcd for C11H9SN: C, 70.55%, H: 4.84%. Found: C, 70.53%; H, 5.04%.
mixture of isomers),
d: 7.95e7.93 (m, 1H), 7.86e7.84 (m, 1H),
4.3.8. 2-(3-Iodophenyl)-2,3-dihydrothiophene (2i). The reaction of
3-iodobenzyl propynyl sulfide (1i) (591 mg, 2.05 mmol) with KOtBu
(460 mg, 4.10 mmol) in acetonitrile yielded 2,3-dihydrothiophene
2i (402 mg, 68%) as a yellow oil after flash chromatography. 1H NMR
7.73e7.71 (m, 2H), 7.60e7.56 (m, 2H), 7.50e7.45 (m, 5H), 6.17 (ddt,
J¼8.4, 5.9, and 2.2 Hz 1H), 5.57 (dt, J¼5.9 and 2.8 Hz, 0.5H), 5.42 (ddt
(apparent dt), J¼8.4 and 2.3 Hz, 0.5H), 5.31e5.28 (m, 0.5H), 3.25 (ddt,
J¼16.8,10.0, and 2.6 Hz, 0.5H), 2.94 (dddd, J¼16.8, 5.7, 3.2, and 2.5 Hz,
0.5H), 2.80 (ddt, J¼16.8, 10.0, and 2.6 Hz, 0.5H), 2.51 (dddd, J¼16.8,
5.7, 3.2, 2.5, 0.5H). 13C NMR (100.6 MHz, CDCl3, mixture of isomers),
(400 MHz, CDCl3),
d
: 7.92 (s, 1H), 7.75 (d, J¼7.9 Hz, 1H), 7.53 (d,
J¼7.9 Hz, 1H), 7.22 (t, J¼7.9 Hz, 1H), 6.40 (ddd (apparent dt), J¼6.1
and 2.2 Hz, 1H), 5.74 (dt, J¼6.1 and 2.7 Hz, 1H), 4.96 (dd, J¼9.7 and
6.7 Hz, 1H), 3.37 (ddt, J¼16.6, 9.7, and 2.2 Hz, 1H), 3.05 (dddd (ap-
parent ddt), J¼16.6, 6.7, and 2.7 Hz, 1H). 13C NMR (100.6 MHz,
d: 144.9, 144.6, 142.7, 142.5, 141.8, 132.1, 132.0, 131.3, 131.2, 129.4,
129.0, 128.7, 128.6, 128.4, 127.7, 126.0, 125.5, 125.3, 125.2, 125.0, 120.4,
119.6, 46.3, 46.0, 44.0, 43.7. IR (CDCl3, cmꢁ1): 3057, 2927, 2839, 1582,
1472, 1442, 1328, 1306, 1279, 1260, 1191, 1159, 1122, 1083, 1035, 998,
960, 918, 850. CIMS, m/z (%): 288.1 (3, (MþH)þ), 287 (19, Mþ), 242
(22), 235 (11), 233 (19), 217 (12), 200 (24),199 (21),197 (45),194 (13),
193 (100), 192 (23),191 (57), 184 (12), 162 (10), 161 (68), 160 (57), 159
(18), 147 (40), 134 (15), 128 (65), 116 (14), 115 (39). HRCIMS: calcd for
C16H15S2O: 287.0564. Found: 287.0563.
CDCl3), d: 145.9, 136.4, 135.9, 130.3, 126.3, 125.5, 120.3, 94.4, 51.7,
43.8. IR (neat, cmꢁ1): 3052, 2925, 2836, 1714, 1587, 1563, 1471, 1421,
1263, 1193, 1065, 994, 882, 781. CIMS, m/z (%): 305 (70, (MþNH3)þ),
289 (14, (MþH)þ),161 (6),128 (7). Anal. Calcd for C10H9SI: C, 41.68%;
H, 3.15%. Found: C, 41.48%; H, 3.25%.
4.3.9. 2-(4-Iodophenyl)-2,3-dihydrothiophene (2j). The reaction of
4-iodobenzyl propynyl sulfide (1j) (556 mg, 1.93 mmol) with KOtBu
(433 mg, 3.86 mmol) in acetonitrile yielded 2,3-dihydrothiophene
2j (250 mg, 45%) as a yellow oil after flash chromatography. 1H NMR
4.3.13. 2-(Phenylsulfonyl)phenyl-2,3-dihydrothiophene (2n). The re-
action of 2-(phenylsulfonyl)benzyl propynyl sulfide (1n) (207 mg,
0.69 mmol) with KOtBu (154 mg,1.37 mmol) in refluxing acetonitrile
yielded 2,3-dihydrothiophene 2n (141 mg, 68%) as a yellow solid
after flash chromatography on silica gel (mp 109e113 ꢀC). 1H NMR
(400 MHz, CDCl3),
d
: 7.80 (d, J¼8.4 Hz, 2H), 7.32 (d, J¼8.4 Hz, 2H),
6.40 (ddd (apparent dt), J¼6.1 and 2.0 Hz, 1H), 5.74 (dt, J¼6.1 and
2.7 Hz, 1H), 4.99 (dd, J¼9.7 and 6.7 Hz, 1H), 3.36 (ddt, J¼16.6, 9.7,
and 2.4 Hz, 1H), 3.03 (dddd (apparent ddt), J¼16.6, 6.7, and 2.4 Hz,
(400 MHz, CDCl3),
d
: 8.17 (dd, J¼8.0 and 1.2 Hz, 1H), 7.87e7.82 (m,
1H). 13C NMR (100.6 MHz, CDCl3),
d: 143.3, 137.6, 128.9, 125.5, 120.3,
3H), 7.62e7.51 (m, 4H), 7.44 (dt, J¼8.0 and 1.2 Hz, 1H), 6.12 (ddd,
J¼6.0, 2.0, and 2.0 Hz,1H), 5.66 (dd, J¼10.3 and 5.0 Hz, 1H), 5.46 (ddd
(apparent dt), J¼6.0 and 2.7 Hz, 1H), 3.09 (ddt, J¼17.1, 10.3, 2.7), 2.69
92.6, 51.9, 43.8. IR (neat, cmꢁ1): 3054, 3019, 2927, 2854, 1900, 1713,
1584, 1564, 1484, 1434, 1400, 1277, 1259, 1102, 1005, 943, 911, 857,
818, 780. EIMS, m/z (%): 288 (78, Mþ), 161 (8), 128 (100), 115 (30).
HREIMS Calcd for C10H9SI: 287.9466. Found: 287.9470.
(dddd, J¼17.1, 5.0, 2.7, and 2.0 Hz,1H).13C NMR (100.6 MHz, CDCl3),
d:
144.7, 141.6, 137.0, 134.5, 133.3, 129.6, 129.3, 128.9, 127.6, 127.4, 125.3,
119.9, 45.7, 44.4. IR (CDCl3, cmꢁ1): 3072, 2935, 2846, 2686, 1590,
1571, 1470, 1447, 1315, 1156, 1126, 1091, 1058. CIMS m/z (%): 303 (67,
(MþH)þ), 302 (21, Mþ), 238 (32), 237 (19), 233 (11), 214 (16), 192
(17), 191 (100), 166 (16), 165 (11), 161 (19), 160 (61), 129 (12), 128 (41),
125 (16),116 (15),115 (37), 91 (25), 78 (17), 77 (25). HRCIMS: calcd for
C16H15O2S2: 303.0513. Found: 303.0530.
4.3.10. 3-(Trifluoromethyl)phenyl-2,3-dihydrothiophene (2k). The re-
action of 3-(trifluoromethyl)benzyl propynyl sulfide (1k) (218 mg,
0.95 mmol) with KOtBu (213 mg, 1.89 mmol) in refluxing acetonitrile
yielded 2,3-dihydrothiophene 2k (122 mg, 59%) as a yellow oil after
flash chromatography. 1H NMR (400 MHz, CDCl3),
d: 7.65 (s, 1H), 7.59
(d, J¼7.7 Hz,1H), 7.51 (d, J¼7.7 Hz,1H), 7.43 (t, J¼7.7 Hz,1H), 6.24 (ddd
(apparent dt), J¼6.1 and 2.2 Hz, 1H), 5.59 (dt, J¼6.1 and 2.8 Hz, 1H),
4.91 (dd, J¼9.7 and 6.5 Hz,1H), 3.24 (ddt, J¼16.6, 9.7, and 2.6 Hz,1H),
4.3.14. 2,5-Dimethoxyphenyl-2,3-dihydrothiophene (2o). The re-
action of 2,5-dimethoxybenzyl propynyl sulfide (1o) (300 mg,

J.M. Motto et al. / Tetrahedron 67 (2011) 1002e1010
1009
1.35 mmol) with KOtBu (304 mg, 2.71 mmol) in refluxing acetoni-
trile yielded a mixture of 2,3-dihydrothiophene 2o (81 mg; 27%)
and recovered starting material (115 mg) after flash chromatogra-
phy. The yield based on recovered starting material was 44%. 1H
J¼6.2 and 1.7 Hz, 1H, vinyl H), 5.68 (dd, J¼6.2 and 2.8 Hz, 1H, vinyl
H), 5.35 (d, J¼8.8 Hz, 1H, CH), 3.38 (m, 1H, CH), 1.55 (m, 2H, CH2),
1.30e1.05 (m, 2H, CH2), 0.78 (t, J¼7.2 Hz, 3H, CH3). Data for trans-
2u: 1H NMR (400 MHz, CDCl3),
d
: 7.83 (dd, J¼7.8 and 1.1 Hz, 1H, Ar
NMR (400 MHz, CDCl3),
d
: 7.09 (d, J¼2.9 Hz, 1H, Ar H), 6.73e6.80
H), 7.54 (dd, J¼7.8 and 1.6 Hz, 1H, Ar H), 7.32 (dt, J¼7.8 and 1.1 Hz,
1H, Ar H), 6.93 (dt, J¼7.8 and 1.6 Hz, 1H, Ar H), 6.19 (dd, J¼6.0 and
1.3 Hz, 1H, vinyl H), 5.65 (dd, J¼6.0 and 2.9 Hz, 1H, vinyl H), 4.73 (d,
J¼4.0 Hz, 1H, CH), 3.14 (m, 1H, CH), 1.63 (m, 2H, CH2), 1.42 (sextet,
J¼7.4 Hz, 2H, CH2), 0.93 (t, J¼7.4 Hz, 3H, CH3). 13C NMR (100.6 MHz,
(m, 2H, Ar H), 6.21 (ddd, J¼6.0, 2.6, and 1.8 Hz, 1H, vinyl H), 5.60 (dt,
J¼6.0 and 2.9 Hz, 1H, vinyl H), 5.24 (dd, J¼9.6 and 5.6 Hz, 1H, CH),
3.81 (s, 3H, OCH3), 3.77 (s, 3H, OCH3), 3.15 (ddt, J¼16.6, 9.6 and
2.6 Hz,1H, CH2), 2.87 (dddd, J¼16.6, 5.6, 2.9 and 1.8 Hz,1H, CH2). 13
C
NMR (100.6 MHz, CDCl3),
d
: 148.5, 125.4, 122.7, 120.7, 113.6, 113.2,
CDCl3), d: 146.1, 139.3, 128.8, 127.9, 125.1, 124.4, 100.0, 61.2, 55.9,
112.2, 111.4, 56.1, 55.7, 45.1, 41.7. IR (neat, cmꢁ1) 3004, 2941, 2910,
2837, 1499, 1220, 1048. GC/MS, m/z (%): 222 (100, Mþ), 189 (69), 174
(45), 158 (24), 146 (9), 115 (8), 91 (9), 45 (10).
36.2, 20.6, 14.2. IR (neat, cmꢁ1) 3047, 2959, 2930, 2873, 1463, 1010,
911. EIMS, m/z (%): 330 (56, Mþ), 287 (100), 160 (56), 128 (19), 115
(34). Data for 14u: 1H NMR (400 MHz, CDCl3),
d: 7.80 (dd, J¼7.7 and
1.1 Hz, 1H, Ar H), 7.34 (dt, J¼7.7 and 1.1 Hz, 1H, Ar H), 7.26 (dd, J¼7.7
and 1.8 Hz,1H, Ar H), 6.92 (ddd, J¼7.7, 7.5, and 1.8 Hz,1H, Ar H), 5.80
(d, J¼1.0 Hz, 1H, CH), 5.50 (d, J¼5.1 Hz, 1H, vinyl H), 3.89 (m, 1H,
CH2), 3.77 (d (br), J¼14.3 Hz, 1H, CH2), 2.01e1.93 (m, 1H, CH2),
1.88e1.81 (m,1H, CH2),1.58e1.35 (m, 2H, CH2), 0.88 (t, J¼7.3 Hz, 3H,
4.3.15. 3,5-Dimethoxyphenyl-2,3-dihydrothiophene (2p). The re-
action of 3,5-dimethoxy benzyl propynyl sulfide (1p) (270 mg,
1.22 mmol) with KOtBu (275 mg, 2.45 mmol) in refluxing acetoni-
trile yielded 2,3-dihydrothiophene 2p (113 mg, 42%) as a colorless
oil after flash chromatography on silica gel. The yield based on re-
CH3). 13C NMR (100.6 MHz, CDCl3),
d: 146.0, 145.4, 139.2, 129.0,
covered starting material was 54%. 1H NMR (400 MHz, CDCl3),
d:
129.0, 128.7, 124.2, 100.6, 63.8, 37.7, 31.6, 21.2, 13.9. IR (neat, cmꢁ1
)
6.57 (d, J¼2.3 Hz, 2H), 6.36 (t, J¼2.3 Hz, 1H), 6.21 (dt, J¼6.1 and
2.2 Hz, 1H), 5.57 (dt, J¼6.1 and 3.0 Hz, 1H), 4.84 (dd, J¼9.6 and
7.3 Hz, 1H), 3.78 (s, 6H), 3.17 (ddt, J¼16.6, 9.6, and 2.7 Hz, 1H), 2.92
(dddd, J¼16.6, 7.3, 2.7, and 2.2 Hz, 1H). 13C NMR (100.6 MHz, CDCl3),
3058, 2962, 2933, 2875, 2850, 1584, 1563, 1463, 1436, 1011, 832,
792. Anal. Calcd for C13H15IS: C, 47.28; H, 4.58. Found: C, 47.15; H,
4.46.
d: 168.2, 160.8, 145.7, 125.5, 120.6, 105.0(2), 99.2(2), 55.3, 52.9, 43.7.
4.4. General procedure for the oxidation of 2-aryl-2,3-
dihydrothiophenes
IR (CDCl3, cmꢁ1): 3073, 3008, 2960, 2940, 2840, 1607, 1596, 1469,
1431, 1350, 1205, 1196, 1157, 1067, 940, 927, 848, 836. CIMS, m/z (%):
223 (40, (MþH)þ), 222 (51, Mþ), 189 (100), 174 (19), 158 (10).
HRCIMS: calcd for C12H14O2S: 222.0715. Found: 222.0715.
To a solution of DDQ (1.6 equiv) was added a solution of the
dihydrothiophene (1.0 equiv) in CHCl3. The reaction is stirred at rt
for 24 h. Upon completion of the reaction, the solution is filtered
and diluted with CH2Cl2 and washed with DI H2O (4ꢂ). The organic
solution is then washed with satd aq NaCl (1ꢂ), dried over MgSO4,
and concentrated.
4.3.16. 2-(1-Bromonaphth-2-yl)-2,3-dihydrothiophene (2s). The re-
action of 1-bromonaphth-2-yl propynyl sulfide (1s) (209 mg,
0.716 mmol) with KOtBu (161 mg, 1.43 mmol) yielded 2,3-dihy-
drothiophene 2s (150 mg; 72%) as a yellow liquid after flash chro-
matography. 1H NMR (400 MHz, CDCl3),
d
: 8.33 (d, J¼8.5 Hz, 1H, Ar
4.4.1. Oxidation of dihydrothiophene 2b. To a solution of 2b
H), 7.79 (m, 3H, Ar H), 7.59 (m, 1H, Ar H), 7.50 (m, 1H, Ar H), 6.30
(ddd, J¼6.0, 2.5, and 1.9 Hz, 1H, vinyl H), 5.70 (dd, J¼10.0 and 5.2 Hz,
1H, CH), 5.65 (dt, J¼6.0 and 2.8 Hz, 1H, vinyl H), 3.38 (ddt, J¼16.9,
10.0 and 2.5 Hz, 1H, CH2), 2.95 (dddd, J¼16.9, 5.2, 2.8 and 1.9 Hz, 1H,
(205 mg, 0.71 mmol, 1.0 equiv) in CHCl3 (15 mL) was added DDQ
(258 mg, 1.14 mmol, 1.6 equiv) and the reaction was stirred for 24 h.
Workup as indicated and flash chromatography on silica gel (100%
hexane eluent) provided thiophene 3b (149 mg, 73%) as a colorless
CH2). 13C NMR (100.6 MHz, CDCl3),
d: 140.7, 133.8, 132.5, 128.3,
oil. 1H NMR (400 MHz, CDCl3),
d
: 7.98 (dd, J¼7.9 and 0.8 Hz,1H), 7.45
128.0, 127.8, 127.5, 126.4, 125.7, 125.3, 122.5, 120.5, 51.6, 43.0. IR
(neat, cmꢁ1) 3060, 2933, 2901, 2844,1502,1330,1259, 818. EIMS, m/
z (%): 292 (12, Mþ for 81Br), 290 (12, Mþ for 79Br), 211 (39), 179 (15),
178 (100), 165 (19). Anal. Calcd for C14H11BrS: C, 57.74; H, 3.81.
Found: C, 57.90; H, 4.00.
(dd, J¼7.4 and 1.8 Hz, 1H), 7.39 (m, 2H), 7.21 (dd, J¼3.6 and 1.1 Hz,
1H), 7.12 (dd, J¼5.1 and 3.6 Hz, 1H), 7.02 (dt, J¼7.4 and 1.8 Hz, 1H).
13C NMR (100.6 MHz, CDCl3),
d: 144.9, 139.9, 139.4, 131.3, 129.4,
128.1, 127.6, 126.8, 125.9, 99.6. IR (neat, cmꢁ1): 3146, 3119, 2915,
2848, 1723,1680,1594,1501,1435,1408,1375, 1243,1212,1151, 1131,
1071, 1011, 937, 886, 809, 739. CIMS, m/z (%): 287 ((MþH)þ, 30), 286
(Mþ, 39), 161 (100), 160 (19). Anal. Calcd for C10H7SI: C, 41.98%; H,
2.47%. Found: C, 41.79%; H, 2.60%.
4.3.17. 2,6-Bis(2,3-dihydro-5-thienyl)-2-bromobenzene (2t). The re-
action of 2,6-bis(1-propynylthio)-2-bromobenzene (1t) (201 mg,
0.616 mmol) with KOtBu (277 mg, 2.47 mmol) yielded 2,3-dihy-
drothiophene 2t (93.4 mg; 47%) as yellow liquid after flash chro-
4.4.2. Oxidation of dihydrothiophene 2h. To
a solution of 2h
matography. 1H NMR (400 MHz, CDCl3),
d
: 7.51 (d, J¼7.5 Hz, 2H, Ar
(120 mg, 0.64 mmol, 1.0 equiv) in CHCl3 (15 mL) was added DDQ
(233 mg, 1.03 mmol, 1.6 equiv) and the reaction was stirred for 24 h.
Workup as indicated and flash chromatography on silica gel (5e10%
EtOAc/hexane eluent) provided thiophene 3h32 (96.3 mg, 81%) as
H), 7.26 (t, J¼7.5 Hz, 1H, Ar H), 6.22 (m, 2H, vinyl H’s), 5.61 (m, 2H,
vinyl H’s), 5.34 (dt, J¼9.5 and 3.9 Hz, 2H, CH), 3.26 (m, 2H, CH2), 2.85
(m, 2H, CH2). 13C NMR (100.6 MHz, CDCl3),
d: 143.1, 143.0, 128.6,
127.8, 127.8, 127.0, 126.8, 125.5, 125.3, 120.6, 120.4, 51.6, 51.5, 42.3,
a colorless oil. 1H NMR (400 MHz, CDCl3),
d
: 7.72 (dd, J¼8.0 and
42.2. IR (neat, cmꢁ1) 3072, 2933, 2896, 2843, 1415, 1021, 792.
1.0 Hz, 1H), 7.63 (dd, J¼3.7 and 1.0 Hz, 1H), 7.60e7.55 (m, 2H), 7.42
(dd, J¼5.1 and 1.0 Hz, 1H), 7.37 (t, J¼6.1 and 1.6 Hz, 1H), 7.14 (dd,
4.3.18. 2-(2-Iodophenyl)-3-propyl-2,3-dihydrothiophenes (2u) and
2-(2-iodophenyl)-3-propyl-2,5-dihydrothiophene (2u0). The reaction
of 2-iodobenzyl hexynyl sulfide (1u) (453 mg, 1.37 mmol) with
KOtBu (308 mg, 2.75 mmol) in acetonitrile at rt yielded 2,3-dihy-
drothiophenes 2u (69 mg; 15%) and 2,5-dihydrothiophene 14u
(302 mg; 67%) as a yellow liquids after two flash chromatographies.
J¼5.1 and 3.7 Hz, 1H). 13C NMR (100.6 MHz, CDCl3),
d: 139.3, 137.4,
134.2, 132.9, 129.6, 128.1, 127.5 (2), 127.2, 118.8, 109.9. IR (neat,
cmꢁ1): 3108, 3074, 2224, 1595, 1565, 1528, 1482, 1444, 1354, 1277,
1247, 1213, 1189, 1166, 1107, 1042, 962, 853, 836, 761.
Acknowledgements
Data for cis-2u: 1H NMR (400 MHz, CDCl3),
1.2 Hz, 1H, Ar H), 7.74 (dd, J¼7.7 and 1.6 Hz, 1H, Ar H), 7.38 (dt, J¼7.7
and 1.2 Hz, 1H, Ar H), 6.95 (dt, J¼7.7 and 1.6 Hz, 1H, Ar H), 6.29 (dd,
d
: 7.82 (dd, J¼7.7 and
The content is solely the responsibility of the authors and does
not necessarily represent the official views of the National Institute

1010
J.M. Motto et al. / Tetrahedron 67 (2011) 1002e1010
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of General Medical Sciences or the National Institutes of Health.
Computational support was provided by the Graduate Center
computational facility and the City University of New York’s High
11. Pretsch, E.; Clerc, T.; Seibl, J.; Simon, W. Tables of Spectral Data for Structure
Determination of Organic Compounds: 13C NMR, 1H NMR, IR, MS, UV/VIS. Chemical
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Shoji, Y.; Yoshio, M.; Yasuda, T.; Funahashi, M.; Kato, T. J. Mater. Chem. 2010, 20,
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National Institutes of Health (SC1 GM093830) for support. ALS
thanks the Natural Sciences and Engineering Research Council
(NSERC) of Canada for financial support. LKM also thanks NSERC for
a Postgraduate scholarship.
Supplementary data
15. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Scalmani, G.; Barone, V.; Mennucci, B.; Petersson, G. A.; Na-
katsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng,
G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.; Hasegawa, J.;
Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery,
J. A., Jr.; Peralta, J. E.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.; Kudin, K.
N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.; Raghavachari, K.; Rendell, A.;
Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi, M.; Rega, N.; Millam, N. J.; Klene, M.;
Knox, J. E.; Cross, J. B.; Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.;
Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.; Salvador, P.; Dan-
Supplementary data associated with this article can be found in
online version at doi:10.1016/j.tet.2010.11.104. These data include
MOL files and InChiKeys of the most important compounds
described in this article.
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