Transition-metal-free synthesis of ynol ethers and thioynol ethers via displacement at sp Centers: A revised mechanistic pathway

Article abstract of DOI:10.1021/jo500814y

We present here valuable extensions to our previous work in preparing highly functionalized, heteroatom-substituted alkynes via displacement at an sp center. Our results show that a wide range of ynol ethers can be prepared by the same methodology and that the same protocol can be applied to the synthesis of synthetically useful thioynol ethers. We also present new observations that have led us to revise our original hypothesis in favor of a pathway involving radical intermediates.

Full text of DOI:10.1021/jo500814y

Note
pubs.acs.org/joc
Transition-Metal-Free Synthesis of Ynol Ethers and Thioynol Ethers
via Displacement at sp Centers: A Revised Mechanistic Pathway
Vincent James Gray, James Cuthbertson, and Jonathan D. Wilden*
Department of Chemistry, University College London, 20 Gordon Street, London WC1H 0AJ, U.K.
S
* Supporting Information
ABSTRACT: We present here valuable extensions to our previous work
in preparing highly functionalized, heteroatom-substituted alkynes via
displacement at an sp center. Our results show that a wide range of ynol
ethers can be prepared by the same methodology and that the same protocol can be applied to the synthesis of synthetically
useful thioynol ethers. We also present new observations that have led us to revise our original hypothesis in favor of a pathway
involving radical intermediates.
he transition-metal-free formation of carbon−carbon and
carbon−heteroatom bonds has become one of the most
these processes are radical in nature,9 we felt compelled to
critically reassess our work. We here report further findings
which led us to revise our original hypothesis in favor of a radical
mechanism, particularly in light of our most recent mechanistic
observations.10
T
debated and explored topics in organic chemistry in recent
years.1 To the surprise of many, various processes that were
previously assumed to require a transition-metal catalyst have
been found to be viable without the metal additive. Such
processes include classical palladium chemistry (e.g., Sonoga-
shira2 and Heck3 reactions) and many other TM-mediated
processes (particularly those involving copper4 or a variety of
other metals5). Most of these processes have employed sodium
and potassium tert-butoxide and an amine additive (ligand),6,7
which can sometimes result in reactions that can compete in
terms of scope and efficiency with those mediated by the metal.
Our own work in this area had focused on the preparation of tert-
butyl ynol ethers from an alkynyl sulfonamide 1, which we
suggested might proceed via an addition−elimination process to
yield the ynol ether 2 with concomitant elimination of potassium
N,N-diethylamidosulfite (Scheme 1 and Figure 1).8
We first turned our attention to the question of the critical
nature of DMF to the success of the reaction. Others had
observed that TM-free processes usually proceeded most
efficiently when a coordinating molecule (usually an amine)6,7
was added to the reaction mixture. In reevaluating our work, we
therefore hypothesized that DMF was fulfilling this role in our
reaction. In doing so, we recognized that an alternative and more
convenient solvent might be suitable for the reaction. Choosing
THF as the solvent, we explored the effect of coordinating
additives that have been employed in various TM-free processes.
We were delighted to observe that (in common with others6)
additives such as DMEDA and related amines not only allowed
the reaction to proceed, but gave the products in enhanced yield
compared to our original observation (Figure 2). Furthermore,
very little variation in yield or efficiency is observed between
those additives that promote the reaction, all of the yields being
within 5% of each other (Figure 2).
Scheme 1. Original Mechanistic Hypothesis for TM-Free
Synthesis of Ynol Ethers
Interestingly, additives appear to fall into two clear groups;
those which promote the ynol ether formation (“effective”) and
those which have no effect (“ineffective”) and only yield starting
material at the end of the reaction. Clearly, the effective additives
are all structurally related, although the exact mode of
enhancement is yet to be determined.
Having established an improved strategy for the synthesis of
ynol ethers, we then turned our attention to improving the scope
of the reaction. Given that our original reports had focused
almost exclusively on the tert-butyl variants, we were keen to
establish a protocol where primary, secondary as well as tertiary
ynol ethers could be synthesized. Using the improved protocol
outlined in Figure 2, we were pleased to observe that the ynol
ethers derived from a range of primary, secondary and tertiary
Although at the time we made a number of important
observations about this reaction, these were not always easy to
explain. In particular, the reaction seemed dependent on
potassium ions being present in the reaction medium (which
we explained somewhat via DFT studies), the process seemed
unique to DMF as the solvent, even when compared to other
highly polar aprotic solvents, and the presence of an aryl group in
the substrate appeared to be essential. Additionally, we have
made the counterintuitive observation that those alkynyl
sulfonamides bearing an electron-rich aryl group undergo the
reaction much faster than their electron-deficient counterparts.
Having observed the recent work in the area of TM-free
processes and the body of evidence that seems to be building that
Received: April 10, 2014
Published: May 19, 2014
© 2014 American Chemical Society
5869
dx.doi.org/10.1021/jo500814y | J. Org. Chem. 2014, 79, 5869−5874

The Journal of Organic Chemistry
Note
Figure 1. Range of ynol ethers 2a−j prepared by our methodology.
Following successful endeavors in the synthesis of ynol ethers,
we decided to explore the direct analogues with sulfur as the
heteroatom in the synthesis of thioynol ethers. These species
have received much less attention in the literature and appear to
be difficult to prepare by other methods.11 We began our studies
by examining the reaction of the potassium salts of tert-butyl thiol
(prepared from KH and the parent thiol) under the reaction
conditions outlined in Figure 3. Once again, we were pleased to
observe that the tert-butyl thioynol ethers could be obtained in
most cases in reasonable yields (Figure 4).
We then turned our attention to exploring the scope of the
thiols that could be employed in this reaction. Our initial studies
have indicated that by using the procedure outlined in Figure 4,
thioynol ethers can be obtained directly when simple primary
alkyl thiolates are used; however, when secondary alkyl thiolates
are employed, the α-addition product is isolated (Figure 5). In
common with the oxygen series,8 the α-addition products are
isolated as a single geometrical isomer, in this case the (E)-
isomer. The outcome of the reaction appears to have little or no
dependence on steric factors, and this is one observation that has
led us to revise our thinking in favor of a radical mechanism
(discussed later).
These observations led us to the hypothesis that an
intermediate vinyl anion (common also to the ynol ether
synthesis) was an intermediate in the reaction mechanism. To
test this hypothesis, we proceeded to dope the reaction medium
with first 5% H2O and then 5% D2O. As expected, in both cases
the α-addition product resulted in excellent yields with almost
complete deuterium incorporation when D2O was used.
Furthermore, the α-addition products could be converted to
Figure 2. Effect of additives in ynol ether formation.
alkoxides (generated from the parent alcohol and either KH or
potassium metal) could be prepared without incident (Figure 3).
In general, although any of the additives indicated in Figure 2 can
be employed, we have favored addition of dimethylamine to the
reaction as its volatility means that it is more easily removed than
other additives at the end of the reaction.
In nearly all cases, the ynol ether was isolated in good yield, the
only exception being when potassium trifluoroethoxide was
employed as the nucleophile, when 2 mol of the alkoxide is
incorporated into the product to yield the ketene acetal.
Presumably, on formation of the ynol ether, the additional
electron-withdrawing capacity of the trifluoroethyl group renders
the already reactive ynol ether susceptible to nucleophilic attack
at the most electron-deficient carbon atom yielding the observed
product.
Figure 3. Ynol ethers synthesized from various alkoxides.
5870
dx.doi.org/10.1021/jo500814y | J. Org. Chem. 2014, 79, 5869−5874

The Journal of Organic Chemistry
Note
Figure 4. Synthesis of tert-butyl thioynol ethers.
Figure 5. Comparison of the reactivity of primary and secondary thiols.
Scheme 2
Figure 6. Mechanistic pathway for the LDA-promoted elimination.
Figure 7. Revised mechanistic pathway involving radical intermediates.
the thioynol ether in excellent yields by treatment with LDA
(Scheme 2).
Presumably, the well-known propensity of the sulfonamide
moiety to direct metalation to adjacent carbon atoms results in
facile deprotonation (facilitated by the fact that the compound is
the appropriate geometrical isomer for such a reaction)12
followed by elimination of lithium N,N-diethylamidosulfite as
described previously (Figure 6). This approach is a reliable
method of obtaining the thioynol ethers where the initial
procedure yields predominantly the α-addition products.
5871
dx.doi.org/10.1021/jo500814y | J. Org. Chem. 2014, 79, 5869−5874

The Journal of Organic Chemistry
Note
at 50 °C for 20 min. The reaction mixture was then allowed to cool to rt,
and the contents were concentrated in vacuo. The reaction flask was
then cooled to 0 °C, and 2 M dimethylamine in THF (0.28 mL, 0.57
mmol, 2.7 equiv) was added, followed by alkynyl sulfonamide 1 (50.0
mg, 0.21 mmol, 1.0 equiv). The reaction mixture was then allowed to stir
for 10 min while warming to rt, followed by careful addition of i-PrOH
(1.0 mL) to quench any residual potassium. The reaction mixture was
then dissolved in CH2Cl2 (20 mL) and washed with water (10 mL). The
organic fraction was dried over MgSO4, filtered, and concentrated in
vacuo to give a pale yellow oil, which was purified via flash
chromatography (0−5% Et2O/PE) to give the product as a colorless
film (19.5 mg, 0.15 mmol, 70%); IR νmax (film)/cm−1 2965, 2266, 1732,
1444, 1324, 1058, 905; 1H NMR (600 MHz, CDCl3) δH 7.35 (m, 2 H),
7.26 (m, 2 H), 7.22 (m, 1 H), 3.99 (s, 3 H); 13C NMR (150 MHz,
CDCl3) δC 131.6, 128.3, 126.8, 123.8, 100.2, 66.0, 38.9; LRMS (EI) 132
(98), 105 (99), 91 (36), 89 (100), 77 (81), 63 (36); HRMS (EI) calcd
for C9H8O (M+) 132.0570, found 132.0571.
1-Propoxy-2-phenylethyne (3b). Synthesized using 1 as limiting
reagent (50.0 mg, 0.21 mmol, 1.0 equiv): colorless film, 23.2 mg, 69%;
IR νmax (film)/cm−1 2968, 2261, 1724, 1323, 1064, 754; 1H NMR (600
MHz, CDCl3) δH 7.34 (d, J = 7.1 Hz, 2 H), 7.26 (t, J = 7.1 Hz, 2 H), 7.21
(t, J = 7.1 Hz, 1 H), 4.12 (t, J = 6.5 Hz, 2 H), 1.84 (sex., J = 7.2 Hz, 2 H),
1.02 (t, J = 7.2 Hz, 3 H); 13C NMR (150 MHz, CDCl3) δC 131.6, 128.3,
126.6, 124.2, 99.1, 80.8, 39.6, 22.4, 10.0; LRMS (EI) 160 (35), 118
(100), 117 (25), 90 (20), 90 (16); HRMS (EI) calcd for C11H12O (M+)
160.0883, found 160.0886.
The course of our work has led us to revise our original
hypothesis in favor of a related addition−elimination pathway,
but one that proceeds via a radical process. Our most recent work
(along with a growing body of work in the literature) suggests
that potassium alkoxides (and certainly thiolates) have inherent
electron-transfer ability and might feasibly promote a single
electron transfer to the alkynyl sulfonamide. This process is
highly reminiscent of dissolving metal reduction of alkynes to
yield trans-alkenes via a single electron transfer pathway.
Additionally, the observation that doping the reaction mixture
with 5% water results in the anti-Michael products being isolated
as single geometrical isomers is consistent with a trans-disposed
radical anion intermediate as shown in Figure 7. The resulting
highly electrophilic heteroatom-centered radical can then
combine with the vinyl radical anion at the site of greatest
electron density. This might also explain why the more electron-
rich species react faster than those alkynyl sulfonamides bearing
an electron-withdrawing group. Furthermore, the observation
that excess O2 and radical inhibitors such as galvinoxyl inhibit the
reaction led us to propose the revised mechanism outlined in
Figure 7.
It is noteworthy that others working in this area while studying
similar systems, have postulated a reaction mechanism involving
a polar mechanism via coordination of a potassium bound
alkoxide to the sulfonyl unit. Given our mechanistic observations
in this paper and our previous studies which suggest the
potassium counterion is essentially dissociated from the oxygen
anion, we feel that the radical mechanism (Figure 7) that results
from an initial single electron transfer from the alkoxide to the
acetylene is a more accurate description of the observed behavior
in these systems.
1-(Neopentyloxy)-2-phenylethyne (3c). Synthesized using 1 as
limiting reagent (50.0 mg, 0.21 mmol, 1.0 equiv): colorless film, 24.9 mg,
63%; IR νmax (film)/cm−1 2968, 2259, 1728, 1326, 1069, 904; 1H NMR
(600 MHz, CDCl3) δH 7.32 (d, J = 7.9 Hz, 2 H), 7.25 (t, J = 7.9 Hz, 2 H),
7.20 (t, J = 7.9 Hz, 1 H), 3.88 (s, 2 H), 1.01 (s, 9 H); 13C NMR (150
MHz, CDCl3) δC 131.5, 128.3, 126.6, 124.2, 100.3, 89.5, 38.7, 32.6, 26.1;
LRMS (EI) 188 (6), 159 (5), 119 (10), 118 (100), 90 (43); HRMS (EI)
calcd for C13H16O (M+) 188.1196, found 188.1193.
( )-(Hexan-3-yloxy)ethynyl)benzene (3d). Synthesized using 1 as
limiting reagent (50.0 mg, 0.21 mmol, 1.0 equiv): colorless oil, 27.6 mg,
65%; IR νmax (film)/cm−1 2963, 2254, 1461, 1324, 1063, 753; 1H NMR
(600 MHz, CDCl3) δH 7.33 (d, J = 7.3 Hz, 2 H), 7.24 (t, J = 7.3 Hz, 2 H),
7.19 (t, J = 7.3 Hz, 1 H), 4.05 (tt, J = 7.5, 4.9 Hz, 1 H), 1.80−1.83 (m, 2
H), 1.72 (m, 1 H), 1.60 (m, 1 H), 1.52 (m, 1 H), 1.44 (m, 1 H), 1.01 (t, J
= 7.4 Hz, 3 H), 0.97 (t, J = 7.3 Hz, 3 H); 13C NMR (150 MHz, CDCl3)
δC 131.5, 128.2, 126.4, 124.6, 97.8, 91.0, 40.8, 35.2, 26.5, 18.6, 14.1, 9.6;
LRMS (EI) 202 (6), 145 (6), 119 (8), 118 (100), 86 (30); HRMS (EI)
calcd for C14H18O (M+) 202.1352, found 202.1349.
CONCLUSIONS
■
We have significantly improved the scope and applicability of our
original methodology in the synthesis of a wide range of ynol
ethers derived from primary, secondary and tertiary alkoxides.
Furthermore, we have applied the same methodology to the
synthesis of thioynol ethers along with a strategy to synthesize
both α-addition products and the thioynol ethers via sequential
addition−elimination. The course of our work has given us cause
to reassess the mechanistic pathway and to revise our original
hypothesis in favor of an addition−elimination pathway
involving radical intermediates.
( )-(Nonan-2-yloxy)ethynyl)benzene (3e). Synthesized using 1 as
limiting reagent (50.0 mg, 0.21 mmol, 1.0 equiv): colorless oil, 36.4
1
mg,71%; IR νmax (film)/cm−1 2928, 2253, 1724, 1264, 1063, 753; H
NMR (600 MHz, CDCl3) δH 7.33 (d, J = 7.1 Hz, 2 H), 7.25 (t, J = 7.1 Hz,
2 H), 7.20 (t, J = 7.1 Hz, 1 H), 4.25 (sex., J = 6.1 Hz, 1 H), 1.82 (m, 1 H),
1.58 (m, 1 H), 1.42 (d, J = 6.1 Hz, 3 H), 1.27−1.40 (m, 10 H), 0.88 (t, J =
6.2 Hz, 3 H); 13C NMR (150 MHz, CDCl3) δC 131.5, 128.3, 126.4,
124.5, 97.6, 86.2, 41.1, 35.6, 31.9, 29.5, 29.3, 25.3, 22.8, 19.5, 14.2; LRMS
(CI) 245 (25), 237 (37), 147 (26), 119 (100), 91 (20); HRMS (CI)
calcd for C17H24O (M + H)+ 245.1899, found 245.1892.
EXPERIMENTAL SECTION
■
General Experimental Methods. All reactions were carried out at
atmospheric pressure, under argon, unless otherwise stated. Normal-
phase silica gel (BDH) was used for flash chromatography. Reactions
were monitored by thin-layer chromatography (TLC) using plates
precoated with silica gel 60 F254 on aluminum visualized by UV (254
nm) and chemical stain (potassium permanganate). Mass spectra were
measured in EI and CI mode. Electron-spray ionization spectra were
1-(−)-Menthoxy-2-phenylethyne (3f).14 Synthesized using 1 as
limiting reagent (50.0 mg, 0.21 mmol, 1.0 equiv): colorless oil, 35.5 mg,
66%; IR νmax (film)/cm−1 2951, 2869, 2248, 1730, 1460, 1317, 1062; 1H
NMR (600 MHz, CDCl3) δH 7.34 (d, J = 7.3 Hz, 2 H), 7.25 (t, J = 7.3 Hz,
2 H), 7.20 (t, J = 7.3 Hz, 1 H), 3.96 (td, J = 11.0, 4.5 Hz, 1 H), 2.34 (m, 1
H), 2.23 (sept. d, J = 7.0, 2.7 Hz, 1 H), 1.67−1.73 (m, 2 H), 1.43−1.55
(m, 2 H), 1.27 (q, J = 11.0 Hz, 1 H), 1.04 (qd, J = 13.1, 3.5 Hz, 1 H), 0.98
(d, J = 6.6 Hz, 3 H), 0.96 (d, J = 6.9 Hz, 3 H), 0.89 (m, 1 H), 0.88 (d, J =
6.9 Hz, 3 H); 13C NMR (150 MHz, CDCl3) δC 131.7, 128.3, 126.4,
124.6, 97.8, 88.7, 47.2, 40.9, 40.0, 34.1, 31.8, 26.1, 23.5, 22.2, 20.8, 16.6;
LRMS (CI) 256 (15), 237 (20), 139 (100), 118 (15), 83 (15); HRMS
(CI) calcd for C18H24O (M+) 256.1821, found 256.1813; [α]D = −58 (c
1.1, cyclohexane) [lit.14 [α]D = −60 (c 1.5, cyclohexane)].
measured on a LC-TOF mass spectrometer. H NMR and 13C NMR
1
spectra were recorded at 500 or 600 MHz and 125 or 150 MHz,
respectively, at ambient temperature. All chemical shifts were referenced
to the residual proton impurity of the deuterated solvent. Coupling
constants, J, are quoted in hertz to one decimal place. Infrared spectra
were obtained on a FTIR Spectrometer operating in ATR mode.
Melting points are uncorrected.
General Procedure for the Synthesis of Ynol Ethers 3a−h. 1-
Methoxy-2-phenylethyne (3a).13 To a flame-dried, 25 mL round-
bottomed flask purged with argon were added anhydrous methanol
(36.3 mg, 1.13 mmol, 5.4 equiv) and anhydrous THF (0.3 mL). Freshly
cut potassium metal (44.0 mg, 1.13 mmol, 5.4 equiv) was then carefully
added and the reaction mixture stirred at rt for 10 min, followed by reflux
Trimethyl(2-((phenylethynyl)oxy)ethyl)silane (3g). Synthesized
using 1 as limiting reagent (50.0 mg, 0.21 mmol, 1.0 equiv): colorless
film, 22.9 mg, 50%; IR νmax (film)/cm−1 2948, 2256, 1724, 1639, 1316,
5872
dx.doi.org/10.1021/jo500814y | J. Org. Chem. 2014, 79, 5869−5874

The Journal of Organic Chemistry
Note
1062; 1H NMR (600 MHz, CDCl3) δH 7.34 (d, J = 7.0 Hz, 2 H), 7.25 (t,
J = 7.0 Hz, 2 H), 7.20 (t, J = 7.0 Hz, 1 H), 4.24 (m, 2 H), 1.25 (m, 2 H),
0.10 (s, 9 H); 13C NMR (150 MHz, CDCl3) δC 131.6, 128.3, 126.6,
124.3, 98.8, 77.9, 40.5, 18.2, −1.3; LRMS (CI) 219 (66), 191 (51), 175
(33), 119 (38), 101 (30); HRMS (CI) calcd for C13H19OSi (M + H)+
219.1205, found 219.1209.
(2,2-Bis(2,2,2-trifluoroethoxy)vinyl)benzene (3h). Synthesized
using 1 as limiting reagent (50.0 mg, 0.21 mmol, 1.0 equiv): yellow
oil, 33.4 mg, 53%; IR νmax (film)/cm−1 2935, 1725, 1450, 1152, 1065,
1015; 1H NMR (600 MHz, CDCl3) δH 7.42 (d, J = 7.4 Hz, 2 H), 7.30 (t,
J = 7.4 Hz, 2 H), 7.16 (t, J = 7.4 Hz, 1 H), 4.87 (s, 1 H), 4.21 (q, J = 8.3
Hz, 2 H), 4.28 (q, J = 7.9 Hz, 2 H); 13C NMR (150 MHz, CDCl3) δC
155.1, 133.5, 128.6, 127.6, 125.9, 123.3 (q, J = 275.0 Hz), 122.8 (q, J =
275.0 Hz), 85.8, 66.4 (q, J = 36.0 Hz), 64.3 (q, J = 36.0 Hz); LRMS (EI)
300 (100), 217 (38), 189 (70), 136 (20), 118 (16); HRMS (EI) calcd for
C12H10O2F6 (M+) 300.0579, found 300.0577.
1593, 1574, 1490, 1456, 1365, 1256, 1161, 1114, 1047; 1H NMR (600
MHz, CDCl3) δH 7.38 (dd, J = 7.7, 1.7 Hz, 1 H), 7.25 (t, J = 7.8 Hz, 1 H),
6.89 (t, J = 7.4 Hz, 1 H), 6.86 (d, J = 8.4 Hz, 1 H), 3.87 (s, 3 H), 1.49 (s, 9
H); 13C NMR (150 MHz, CDCl3) δC 160.0, 132.9, 129.2, 120.5, 113.3,
110.7, 92.5, 83.1, 55.9, 48.7, 30.4; LRMS (EI) 220 (32), 164 (100), 148
(40), 135 (15), 131 (29), 121 (19); HRMS (EI) calcd for C13H16OS
(M+) 220.0916, found 220.0915.
((2-Bromophenyl)ethynyl)(tert-butyl)sulfane (4f). Synthesized
using 1f as limiting reagent (60.0 mg, 0.19 mmol, 1.0 equiv): pale
yellow oil, 36.8 mg, 72%; IR νmax (film/cm−1) 2962, 2922, 2898, 2863,
2169, 1465, 1365, 1161, 1046, 1025; 1H NMR (600 MHz, CDCl3) δH
7.56 (d, J = 8.1 Hz, 1 H), 7.42 (dd, J = 8.0, 1.3 Hz, 1 H), 7.24 (t, J = 7.6
Hz, 1 H), 7.12 (dt, J = 7.9, 1.5 Hz, 1 H), 1.53 (s, 9 H); 13C NMR (150
MHz, CDCl3) δC 132.7, 132.4, 128.8, 127.1, 126.0, 124.8, 94.9, 84.8,
49.4, 30.6; LRMS (EI) 270 (10), 268 (9), 214 (53), 212 (52), 132 (31),
86 (30), 84 (48); HRMS (EI) calcd for C12H13BrS (M+) 267.9916,
found 267.9916.
General Procedure for the Synthesis of Alkynyl Sulfides. tert-
Butyl(phenylethynyl)sulfane (4a).15 A 25 mL three-necked flame-dried
flask was charged with a stirring bar and tert-butyl thiol (87.0 mg, 0.96
mmol, 4.0 equiv), followed by anhydrous THF under argon. To the
mixture was added KH (39.0 mg, 0.96 mmol, 4.0 equiv, supplied as a
30% weight dispersion in mineral oil which was rinsed with PE and dried
between filter paper immediately prior to use) as a single portion. The
reaction mixture was stirred at rt for 10 min and then gently heated to 50
°C. The white suspension was stirred at 50 °C for 20 min before being
allowed to cool first to rt and then to −40 °C. Dimethylamine solution
(2.0 M in THF, 0.24 mL, 0.48 mmol, 2.0 equiv) was added via syringe,
followed immediately after by alkynyl sulfonamide 1a (58 mg, 0.24
mmol, 1.0 equiv). The solution was allowed to warm to rt over 10 min
and then carefully quenched with i-PrOH (1 mL). The crude mixture
was diluted in CH2Cl2 (20 mL) and washed with water (10 mL) and
brine (10 mL). The organic portions were combined, dried over MgSO4,
filtered, and concentrated in vacuo. The crude product was purified via
column chromatography (EtOAc/PE) to yield the alkynyl sulfide as a
pale yellow oil: 29.7 mg, 64%; IR νmax (film)/cm−1 2963, 2922, 2897,
2164, 1596, 1487, 1456, 1365, 1162; 1H NMR (600 MHz, CDCl3) δH
7.44−7.42 (m, 2 H), 7.32−7.28 (m, 3 H), 1.48 (s, 9 H); 13C NMR (150
MHz, CDCl3) δC 131.4, 128.4, 128.0, 123.9, 96.2, 79.1, 48.6, 30.5;
LRMS (EI) 190 (19), 134 (100), 84 (23), 57 (33); HRMS (EI) calcd for
C12H14S (M+) 190.0816, found 190.0813.
tert-Butyl((4-methoxyphenyl)ethynyl)sulfane (4b). Synthesized
using 1b as limiting reagent (50.0 mg, 0.19 mmol, 1.0 equiv): pale
yellow oil, 13.3 mg, 32%; IR νmax (film)/cm−1 2963, 2163, 1603, 1507,
1288, 1247, 1162, 1026; 1H NMR (600 MHz, CDCl3) δH 7.39 (d, J = 8.6
Hz, 2 H), 6.83 (d, J = 8.6 Hz, 2 H), 3.81 (s, 3 H), 1.46 (s, 9 H); 13C NMR
(150 MHz, CDCl3) δC 159.6, 133.4, 116.0, 114.0, 95.9, 77.0, 55.4, 48.4,
30.4; LRMS (EI) 220 (30), 164 (100), 149 (53), 97 (22), 86 (23), 84
(38); HRMS (EI) calcd for C13H16SO (M+) 220.0916, found 220.0912.
((4-Bromophenyl)ethynyl)(tert-butyl)sulfane (4c). Synthesized
using 1c as limiting reagent (60.0 mg, 0.16 mmol, 1.0 equiv): pale
yellow oil, 30.0 mg, 59%; νmax (film/cm−1) 2962, 2922, 2861, 2163,
1584, 1482, 1456, 1393, 1365, 1240, 1162, 1069; 1H NMR (600 MHz,
CDCl3) δH 7.43 (d, J = 8.4 Hz, 2 H), 7.27 (d, J = 8.4 Hz, 2 H), 1.47 (s, 9
H); 13C NMR (150 MHz, CDCl3) δC 132.8, 131.6, 122.8, 122.1, 95.2,
80.7, 48.8, 30.5; LRMS (EI) 270 (22), 268 (21), 214 (100), 212 (97),
169 (10), 167 (10), 132 (28); HRMS (EI) calcd for C12H13BrS (M+)
267.9916, found 267.9915.
tert-Butyl((3-methoxyphenyl)ethynyl)sulfane (4g). Synthesized
using 1g as limiting reagent (45.0 mg, 0.17 mmol, 1.0 equiv): pale
yellow oil, 18.4 mg, 49%; IR νmax (film)/cm−1 2962, 2158, 1601, 1573,
1456, 1365, 1283,1042; 1H NMR (600 MHz, CDCl3) δH 7.21 (t, J = 7.9
Hz, 1 H), 7.03 (d, J = 7.6 Hz, 1 H), 6.95 (s, 1 H), 6.85 (ddd, J = 8.3, 2.6,
0.9 Hz, 1 H), 3.80 (s, 3 H), 1.48 (s, 9 H); 13C NMR (150 MHz, CDCl3)
δC 159.4, 129.5, 124.8, 124.0, 116.2, 114.6, 96.2, 79.0, 55.4, 48.6, 30.5;
LRMS (CI) 220 (50), 164 (100), 135 (6), 86 (4), 84 (4); HRMS (CI)
calcd for C13H16OS (M+) 220.0922, found 220.0921.
tert-Butyl(p-tolylethynyl)sulfane (4h). Synthesized using 1h as
limiting reagent (55.0 mg, 0.22 mmol, 1.0 equiv): yellow oil, 32.7 mg,
73%; IR νmax (film/cm−1) 2963, 2922, 2897, 2864, 2164, 1508, 1455,
1365, 1162, 1020; 1H NMR (500 MHz, CDCl3) δH 7.33 (d, J = 8.1 Hz, 2
H), 7.11 (d, J = 8.1 Hz, 2 H), 2.34 (s, 3 H), 1.47 (s, 9 H); 13C NMR (150
MHz, CDCl3) δC 138.2, 131.5, 129.1, 120.8, 96.3, 78.0, 48.4, 30.4, 21.6;
LRMS (EI) 204 (16), 148 (100), 86 (49), 84 (77); HRMS (EI) calcd for
C13H16S (M+) 204.0967, found 204.0969.
General Procedure for the Synthesis of Alkynyl Sulfides 5a−
d. To a flame-dried flask under argon were added thiol (4.0 equiv) and
anhydrous THF (0.70 mL). To the stirring solution was added
potassium hydride (4.0 equiv) as a single portion to give a bubbling,
white paste. The mixture was stirred at rt for 10 min and then gently
warmed to 30 °C for 20 min. The resulting solution was allowed to cool
to rt and was then cooled further to −40 °C using a dry ice/acetonitrile
bath. To the cooled solution was added dimethylamine (2.0 M in THF,
2.0 equiv), followed by sulfonamide 1 as a single portion. The reaction
mixture was allowed to warm to rt over 10 min and then quenched by
the addition of i-PrOH (1.0 mL). The crude mixture was diluted with
CH2Cl2 (20 mL), washed with water (10 mL) and then brine (10 mL),
and then dried over MgSO4. The crude material was filtered,
concentrated in vacuo and purified by column chromatography
(EtOAc/PE or CH2Cl2/MeOH) to yield the alkynyl sulfides 5a−d.
Ethyl(phenylethynyl)sulfane (5a).15 Synthesized using 1a as limiting
reagent (45.0 mg, 0.19 mmol, 1.0 equiv): colorless oil, 18.0 mg, 59%; IR
νmax (film)/cm−1 2965, 2926, 2869, 2165, 1595, 1486, 1442, 1375, 1263,
1069; 1H NMR (600 MHz, CDCl3) δH 7.42−7.40 (m, 2 H), 7.31−7.28
(m, 3 H), 2.82 (q, J = 7.3 Hz, 2 H), 1.46 (t, J = 7.3 Hz, 3 H); 13C NMR
(150 MHz, CDCl3) δC 131.5, 128.4, 128.1, 123.6, 93.6, 79.3, 30.1, 14.9;
LRMS (CI) 224 (23), 163 (100), 134 (45), 129 (49); HRMS (CI) calcd
for C10H11S (M + H+) 163.0576, found 163.0573.
tert-Butyl((4-(trifluoromethyl)phenyl)ethynyl)sulfane (4d). Synthe-
sized using 1d as limiting reagent (18.0 mg, 0.06 mmol, 1.0 equiv):
colorless oil, 9.40 mg, 62%; IR νmax (film/cm−1) 2964, 2926, 2861, 2163,
1614, 1458, 1367, 1322, 1165, 1127, 1105, 1066, 1017; 1H NMR (600
MHz, CDCl3) δH 7.55 (d, J = 8.3 Hz, 2 H), 7.49 (d, J = 8.3 Hz, 2 H), 1.49
(s, 9 H); 13C NMR (150 MHz, CDCl3) δC 131.2, 129.3 (q, J = 32.7 Hz),
127.6, 125.3 (q, J = 3.6 Hz), 125.0 and 123.1 (q, J = 272.0 Hz), 95.3, 82.8,
49.0, 30.5; LRMS (EI) 258 (44), 202 (100), 183 (20), 173 (22), 157
(18), 130 (19); HRMS (EI) calcd for C13H13F3S (M+) 258.0685, found
258.0685.
Benzyl(phenylethynyl)sulfane (5b).16 Synthesized using 1a as
limiting reagent (36.0 mg, 0.15 mmol, 1.0 equiv): colorless oil, 7.4
mg, 24%; IR νmax (film)/cm−1 3061, 3029, 2925, 2853, 2166, 1596, 1487,
1453, 1419, 1237, 1201, 1070; 1H NMR (600 MHz, CDCl3) δH 7.40−
7.27 (m, 10 H), 4.02 (s, 2 H); 13C NMR (150 MHz, CDCl3) δC 136.7,
131.4, 129.3, 128.7, 128.4, 128.2, 127.9, 123.5, 94.7, 79.2, 40.6; LRMS
(CI) 224 (58), 213 (30), 191 (100), 181 (10), 147 (17); HRMS (CI)
calcd for C15H12S (M+) 224.0654, found 224.0651.
Hexyl(phenylethynyl)sulfane (5c). Synthesized using 1a as limiting
reagent (45.0 mg, 0.19 mmol, 1.0 equiv): pale yellow oil, 24.3 mg, 62%;
IR νmax (film)/cm−1 2956, 2927, 2856, 2166, 1595, 1486, 1464, 1441,
1378, 1259, 1069; 1H NMR (600 MHz, CDCl3) δH 7.41−7.39 (m, 2 H),
7.30−7.27 (m, 3 H), 2.80 (t, J = 7.4 Hz, 2 H), 1.80 (quint, J = 7.4 Hz, 2
tert-Butyl((2-methoxyphenyl)ethynyl)sulfane (4e). Synthesized
using 1e as limiting reagent (56.0 mg, 0.21 mmol, 1.0 equiv): colorless
oil, 23.7 mg, 51%; IR νmax (film/cm−1) 2961, 2923, 2898, 2863, 2167,
5873
dx.doi.org/10.1021/jo500814y | J. Org. Chem. 2014, 79, 5869−5874

The Journal of Organic Chemistry
Note
H), 1.48−1.43 (m, 2 H), 1.34−1.32 (m, 4 H), 0.90 (t, J = 7.0 Hz, 3 H);
13C NMR (150 MHz, CDCl3) δC 131.5, 128.4, 128.0, 123.7, 92.9, 79.8,
(tt, J = 7.2, 3.5 Hz, 1 H), 2.11 (m, 2 H), 1.83 (dt, J = 13.5, 3.7 Hz, 2 H),
1.67−1.63 (m, 1 H), 1.56 (dq, J = 11.9, 3.4 Hz, 2 H), 1.37 (tq, J = 11.9,
3.4 Hz, 2 H), 1.30−1.24 (m, 1 H); 13C NMR (150 MHz, CDCl3) δC
131.5, 128.4, 128.0, 123.8, 94.5, 78.7, 47.8, 33.1, 26.2, 25.6; LRMS (EI)
216 (26), 134 (100); HRMS (EI) calcd for C14H16S (M+) 216.0967,
found 216.0968.
35.9, 31.4, 29.4, 28.1, 22.7, 14.2; LRMS (CI) 218 (100), 134 (10), 129
(4); HRMS (CI) calcd for C14H18S (M+) 218.1124, found 218.1123.
N,N-Diethyl-2-((phenylethynyl)thio)ethanamine (5d). Synthesized
using 1a as limiting reagent (45.0 mg, 0.19 mmol, 1.0 equiv): pale yellow
oil, 23.3 mg, 56%; IR νmax (film)/cm−1 2968, 2932, 2803, 2164, 1595,
1487, 1442, 1383, 1285, 1200, 1068; 1H NMR (600 MHz, CDCl3) δH
7.40−7.38 (m, 2 H), 7.30−7.27 (m, 3 H), 2.89 (app. s, 4 H), 2.59 (q, J =
7.2 Hz, 4 H), 1.06 (t, J = 7.2 Hz, 6 H); 13C NMR (150 MHz, CDCl3) δC
131.5, 128.4, 128.1, 123.6, 92.9, 79.6, 52.1, 47.3, 33.5, 12.1; LRMS (CI)
234 (100), 218 (13), 205 (81), 161 (7); HRMS (CI) calcd for
C14H20NS (M + H+) 234.1311, found 234.1310.
General Procedure for the Synthesis of α-Addition Products
6a and 6b. To a flame-dried flask under argon was added thiol (4.0
equiv) and anhydrous THF (0.7 mL). To the solution was added
potassium hydride (4.0 equiv) as a single portion to give a white paste.
The mixture was stirred at rt for 10 min and then gently warmed to 30
°C for 20 min. The resulting solution was allowed to cool to rt, and was
then cooled further to −40 °C. To the cooled solution was added
dimethylamine (2.0 M in THF, 2.0 equiv), followed by a solution of
sulfonamide 1 (dissolved in 95% THF, 5% H2O; 1 mL) as a single
portion. The reaction mixture was allowed to warm to rt over 10 min and
then quenched by the addition of i-PrOH (1 mL). The crude mixture
was diluted with CH2Cl2 (20 mL) and washed with water (10 mL) and
then brine (10 mL), then dried over MgSO4. The crude material was
filtered, concentrated in vacuo ,and purified by column chromatography
(EtOAc/PE) to yield the alkynyl sulfides 6a and 6b.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra are provided. This material is provided
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: j.wilden@ucl.ac.uk.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge UCL for providing studentships for
J.C. and V.J.G. and Dr. A. Aliev for spectroscopic support.
■
REFERENCES
■
(1) Arancon, R. A. D.; Lin, C. S. K.; Vargas, C.; Luque, R. Org. Biomol.
Chem. 2014, 12, 10−35.
(2) Appukkuttan, P.; Dehaen, W.; Van der Eycken, E. Eur. J. Org. Chem.
2003, 4713−4716.
( )-(E)-N,N-Diethyl-1-(isopropylthio)-2-phenylethenesulfona-
mide 6a. Synthesized using 1a as limiting reagent (36.0 mg, 0.15
mmol); colorless oil, 42.7 mg, 89%; IR νmax (film)/cm−1 2970, 2930,
(3) Rueping, M.; Leiendecker, M.; Das, A.; Poisson, T.; Bui, L. Chem.
Commun. 2011, 47, 10629−10631.
1
2867, 1446, 1320, 1201, 1138.1016; H NMR (600 MHz, CDCl3) δH
(4) Jin, G.; Zhang, X.; Cao, S. Org. Lett. 2013, 15, 3114−3117.
(5) Sun, C.-L.; Li, H.; Yu, D.-G.; Yu, M.; Zhou, X.; Lu, X.-Y.; Huang, K.;
Zheng, S.-F.; Li, B. J.; Shi, Z.-J. Nat. Chem. 2010, 2, 1044−1049.
(6) Liu, W.; Cao, H.; Zhang, H.; Zhang, H.; Chung, K. H.; He, C.;
Wang, H.; Kwong, F. Y.; Lei, A. J. Am. Chem. Soc. 2010, 132, 16737−
16740.
8.03 (s, 1 H), 7.95 (m, 2 H), 7.42−7.38 (m, 3 H), 3.67 (sept, J = 6.6 Hz, 1
H), 3.38 (q, J = 7.1 Hz, 4 H), 1.23−1.20 (m, 12 H); 13C NMR (150
MHz, CDCl3) δC 144.8, 134.5, 133.5, 131.0, 130.3, 128.5, 43.1, 40.4,
23.0, 14.9; LRMS (CI) 313 (39), 177 (100), 135 (12); HRMS (CI)
calcd for C15H23NO2S2 (M+) 313.1165, found 313.1166.
( )-(E)-1-(Cyclohexylthio)-N,N-diethyl-2-phenylethenesulfona-
mide (6b). Synthesized using 1a as limiting reagent (51.0 mg, 0.22
mmol): pale yellow oil, 85.4 mg, 90%; IR νmax (film)/cm−1 2929, 2853,
(7) Shirakawa, E.; Itoh, K.-I.; Higashino, T.; Hayashi, T. J. Am. Chem.
Soc. 2010, 132, 15537−15539.
(8) Gray, V. J.; Slater, B.; Wilden, J. D. Chem.Eur. J. 2012, 18,
1
1446, 1321, 1201, 1139, 1017, 943; H NMR (600 MHz, CDCl3) δH
15582−15585.
8.03 (s, 1 H), 7.96−7.94 (m, 2 H), 7.41−7.38 (m, 3 H), 3.45−3.40 (m, 1
H), 3.37 (q, J = 7.2 Hz, 4 H), 1.92−1.90 (m, 2 H), 1.67−1.63 (m, 2 H),
1.54−1.52 (m, 1 H), 1.31−1.14 (m, 11 H); 13C NMR (150 MHz,
CDCl3) δC 145.0, 133.8, 133.6, 131.0, 130.3, 128.5, 48.5, 43.2, 33.3, 26.0,
25.7, 14.9; LRMS (CI) 353 (32), 217 (100), 134 (17); HRMS (CI)
calcd for C18H27NO2S2 (M+) 353.1478, found 353.1479.
General Procedure for the Conversion 6a and 6b to Alkynyl
Sulfides 7a and 7b. To a flame-dried flask under argon were added α-
addition products 6a or 6b (1.0 equiv) and anhydrous THF (2.0 mL).
The resulting solution was cooled to −78 °C. To the solution was added
dropwise lithium diisopropylamide solution (1.8 M in THF/heptanes/
ethylbenzene, 2.0 equiv). The resulting yellow solution was stirred at
−78 °C for 30 min before being allowed to warm to rt. The reaction was
diluted with CH2Cl2 (20 mL) and washed with water (10 mL) and brine
(10 mL). The organic fractions were dried over MgSO4, filtered, and
concentrated in vacuo and then purified via column chromatography
(EtOAc/PE) to yield alkynyl sulfides 7a-7b.
(9) Zhou, H.; Anderson, G. M.; Mondal, B.; Doni, E.; Ironmonger, V.;
Kranz, M.; Tuttle, T.; Murphy, J. A. Chem. Sci. 2014, 5, 476−482.
(10) Cuthbertson, J.; Gray, V. J.; Wilden, J. D. Chem. Commun. 2014,
50, 2575−2578.
(11) (a) Miyachi, N.; Shibasaki, M. J. Org. Chem. 1990, 55, 1975−1976.
(b) Kabanyane, S. T.; MaGee, D. I. Can. J. Chem. 1992, 70, 2758−2763.
(c) Braga, A. L.; Reckziegel, A.; Menezes, P. H.; Stefani, H. A.
Tetrahedron Lett. 1993, 34, 393−394. (d) Takeda, H.; Shimada, S.;
Ohnishi, S.; Nakanishi, F.; Matsuda, H. Tetrahedron Lett. 1998, 39,
3701−3704. (e) Back, T. G. Tetrahedron 2001, 57, 5263−5301.
(12) Marzo, L.; Parra, A.; Frias, M.; Aleman, J.; Garcia Ruano, J. L. Eur.
J. Org. Chem. 2013, 4405−4409.
(13) Tanaka, R.; Rodgers, M.; Simonaitis, R.; Miller, S. I. Tetrahedron
1971, 27, 2651−2669.
(14) Minehan, T. G.; Sosa, J. R.; Tudjarian, A. A. Org. Lett. 2008, 10,
5091−5094.
(15) Voets, M.; Smet, M.; Dehaen, W. J. Chem. Soc., Perkin Trans. 1
1999, 1473−1475.
( )-Isopropyl(phenylethynyl)sulfane (7a). Synthesized using 6a as
limiting reagent (30.0 mg, 0.06 mmol): pale yellow oil, 13.0 mg, 77%; IR
νmax (film)/cm−1 2958, 2924, 2854, 2165, 1596, 1487, 1455, 1380, 1238,
(16) Riddell, N.; Tam, W. J. Org. Chem. 2006, 71, 1934−1937.
1
1155, 1069; H NMR (600 MHz, CDCl3) δH 7.43−7.41 (m, 2 H),
7.30−7.28 (m, 3 H), 3.26 (sept, J = 6.8 Hz, 1 H), 1.44 (d, J = 6.8 Hz, 6
H); 13C NMR (150 MHz, CDCl3) δC 131.5, 128.4, 128.0, 123.7, 94.9,
78.7, 40.0, 23.1; LRMS (EI) 176 (37), 134 (100); HRMS (EI) calcd for
C11H12S (M+) 176.0654, found 176.0654.
( )-Cyclohexyl(phenylethynyl)sulfane (7b). Synthesized using 6b as
limiting reagent (55.0 mg, 0.16 mmol): colorless oil, 23.6 mg, 71%; IR
νmax (film)/cm−1 2928, 2853, 2164, 1486, 1447, 1262, 1201; 1H NMR
(600 MHz, CDCl3) δH 7.42−7.41 (m, 2 H), 7.31−7.27 (m, 3 H), 3.00
5874
dx.doi.org/10.1021/jo500814y | J. Org. Chem. 2014, 79, 5869−5874