Chemoselective Synthesis of 1,1-Disubstituted Vinyl Triflates from Terminal Alkynes Using TfOH in the Presence of TMSN3

Article abstract of DOI:10.1021/acs.orglett.9b01576

1,1-Disubstituted vinyl triflates are synthesized by direct hydrotriflation of terminal alkynes employing a combination of TfOH and TMSN₃ in DCM at room temperature. Interestingly, under these conditions, only terminal alkynes were selectively

Full text of DOI:10.1021/acs.orglett.9b01576

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Chemoselective Synthesis of 1,1-Disubstituted Vinyl Triflates from
Terminal Alkynes Using TfOH in the Presence of TMSN3
Jumreang Tummatorn,*,‡,§ Kunlayanee Punjajom,§ Warabhorn Rodphon,§
Sureeporn Ruengsangtongkul,‡ Nattawadee Chaisan,§ Kanyapat Lumyong,‡
Charnsak Thongsornkleeb,†,§ Phongprapan Nimnual,§ and Somsak Ruchirawat‡,§
†Laboratory of Organic Synthesis, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand
‡Laboratory of Medicinal Chemistry, Chulabhorn Research Institute, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand
§Program on Chemical Biology, Chulabhorn Graduate Institute, Center of Excellence on Environmental Health and Toxicology
(EHT), Ministry of Education, 54 Kamphaeng Phet 6, Laksi, Bangkok 10210, Thailand
S
* Supporting Information
ABSTRACT: 1,1-Disubstituted vinyl triflates are synthesized
by direct hydrotriflation of terminal alkynes employing a
combination of TfOH and TMSN3 in DCM at room
temperature. Interestingly, under these conditions, only
terminal alkynes were selectively converted to the correspond-
ing vinyl triflates, while internal alkynes were not reacted. A
broad range of substrates were successfully converted to the
corresponding 1,1-disubstituted vinyl triflates in good to excellent yields even those with internal alkyne moieties present in the
molecules.
Scheme 1. Methods for the Synthesis of Vinyl Triflates
inyl triflate is an important functional group used in many
Vsynthetic transformations, especially for cross-coupling
reactions including C−C,1 C−O,2 C−N,3 and C−halogen4
bond formations. The most general method for preparing vinyl
triflate derivatives is the trifluoromethanesulfonylation or
triflation of enolates using various triflating agents.5 However,
only a few reported methods employed alkynes as starting
materials in spite of their ease of access (Scheme 1). In fact,
the conditions using trifluoromethanesulfonic or triflic acid
(TfOH) as the hydrotriflating agent has been reported.6,7,4b
However, most reactions needed to be carried out under low
temperatures8 to avoid solvolysis of the vinyl triflate product.9
In addition, this method has no particular chemoselectivity
toward the alkyne substrates; both internal and terminal
alkynes could be converted to vinyl triflates nonselectively. A
similar lack of selectivity was also observed when using
rhodium,10 ruthenium,11 copper,12 and zinc13 complexes as the
catalysts. Therefore, development of a new method for
controlling chemoselectivity of hydrotriflation of alkynes is a
challenging task. In this work, we discovered that combination
of TMSN3 and TfOH reagents could chemoselectively convert
only the terminal alkynes to 1,1-disubstituted vinyl triflates at
room temperature. This combination essentially lowered the
reactivity of TfOH in hydrotriflation on internal alkynes,
resulting in only trace amount of trisubstituted vinyl triflates
while terminal alkynes readily reacted to give 1,1-disubstituted
vinyl triflates in good conversion with no formation of the
corresponding vinyl azides. This novel mode of reactivity
observed in combination of TfOH and TMSN3 was envisioned
to be a potentially useful tool for chemical synthesis, especially
when the reaction is performed on compounds containing
both internal and terminal alkynes.
To elaborate on these findings, reactions were performed
with various internal alkynes as shown in Scheme 2. The
Received: May 5, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01576
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
TfOH in DCM at room temperature was the optimal
conditions for the chemoselective hydrotriflation of terminal
alkynes to give 1,1-disubstituted vinyl triflates.
Scheme 2. Initial Reaction Evaluations
Having the optimal conditions for the synthesis of vinyl
triflates in hands, our attention was turned to study the scope
of the reaction (Scheme 4). The utility of this method was
Scheme 4. Substrate Scope for the Synthesis of Vinyl
a
Triflates from Terminal Alkynes
reaction of methylphenylacetylene (2a) with 1.0 equiv each of
TMSN3 and TfOH offered vinyl triflate in only trace amount
whereas using TfOH alone could provide the corresponding
products (4a) as an isomeric mixture in good combined yields
(69−81%).7 When using diphenylacetylene (2b) as the
starting material, no reaction was observed with 1.0 equiv
each of TfOH and TMSN3 even after stirring overnight,
whereas the reaction between 2b with 1.0 equiv of TfOH alone
resulted in the decomposition within 20 min. These results
highlighted the essential role of TMSN3 in lowering the
reactivity of TfOH in the current protocol. To optimize the
conditions, phenylacetylene (1a) was used as the screening
substrate.14 Using 1.0 equiv each of TMSN3 and TfOH, the
reaction provided the desired product (3a) in 64% yield. After
further optimization, product 3a could be obtained in
quantitative yield when 2.0 equiv each of TMSN3 and TfOH
were employed in DCM at room temperature for 10 min. To
probe the chemoselectivity of this protocol, a 1:1 mixture of
compounds 1a and 2a was subjected to the optimal conditions
employing TMSN3 (2.0 equiv) and TfOH (2.0 equiv) in DCM
at room temperature for overnight. This reaction provided
vinyl triflate 3a as the major product in 74% yield, while
product 4a (from 2a) was obtained in only 13% yield even
after an overnight stirring. In addition, several additives were
also screened for this transformation. Apparently, the
combination of TfOH and TMSCl could smoothly provide
the desired product at room temperature. However, no
chemoselectivity was observed when using this combination.
The results showed that the selectivity of hydrotriflation
dropped to almost 1:1 ratio of 3a and 4a as shown in Scheme
3. Therefore, a combination of 2.0 equiv each of TMSN3 and
Scheme 3. Crossover Experiments of Internal and External
Alkynes
a
b
Isolated yields. Yield was determined by 1H NMR of an inseparable
mixture of product and starting material.
probed with substrates containing terminal alkynes. The
reaction of phenylacetylene (1a) produced product 3a in
quantitative yield. With electronically neutral substrates as in p-
and m-tolylacetylene (1b and 1c), the reactions furnished the
corresponding vinyl triflates 3b and 3c in excellent yields.
However, o-tolylacetylene (1d) proved incompatible under
B
DOI: 10.1021/acs.orglett.9b01576
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
these conditions; the reaction resulted in decomposition of 1d
and only trace amount of product 3d was observed. Then,
halogen substituted phenylacetylene derivatives, including
fluorine, chlorine, and bromine substituents, were examined.
The reactions of p-, m-, and o-fluorophenylacetylenes provided
the desired products (3e−g) in moderate to excellent yields
(62−92%). The reactions also proceeded excellently for p-, m-
and o-chlorophenylacetylenes (1h−j), furnishing the desired
products all in excellent yields (3h−j). Similar results were also
observed in the bromine analogues; substrates 1k−m were
transformed to the corresponding vinyl triflates 3k−m in
excellent efficiencies. Unfortunately, p- and o-methoxy-
substituted substrates (3n and 3p) decomposed under the
reaction conditions. However, the reaction of m-methoxy
substrate (1o) was uneventful; the substrate was transformed
to the corresponding vinyl triflate (3o) in 69% yield. For this
substrate, we also employed conditions previously reported by
others using only TfOH in DCM for comparison to observe
only decomposition of the substrate.7 This result clearly
showed the superiority of our method over the previously
reported procedure. It also further highlighted the essential
role of TMSN3 for the success of the reaction. The methoxy
group located at the meta-position in 1o could not delocalize
electrons to the vinyl carbocation; therefore, the reactive
quinone methide-type species could not be generated, hence
the successful reaction. Next, substrates with electron-with-
drawing substituents were evaluated. The reaction of p-nitro-
substituted substrate (1q) was incomplete and gave the desired
vinyl triflate (3q) in low yield, probably due to the generation
of the unstable vinyl cation intermediate. With methyl ester
substituents, both at the p- and m-positions (1r and 1s), the
reactions provided the vinyl triflate products in 86% and 72%
yields, respectively. For p-nitrile-substituted substrate (1t), the
reaction could not go to completion, probably due to the
nitrile functional group became protonated by TfOH resulting
in only 26% yield of the desired product (3t). The latter effect
was also observed in pyridine-containing substrate (1u), the
reaction of which only led to decomposition. Furthermore, we
found that alkynylnaphthalene 1v and alkynylcyclohexene 1w
were incompatible in this reaction and could not be converted
to the corresponding vinyl triflates; only decomposition was
observed for these compounds. The reaction was next
attempted with alkylalkynes. Gratifyingly, the reactions
proceeded efficiently to afford the corresponding products
(3x−z) in good to excellent yields (80 to ≥99%).
Furthermore, a range of substrates containing both internal
and terminal alkynes within the same molecules (1) was
examined as shown in Scheme 5. For compound 1a′
containing only the parent phenyl ring, the reaction proceeded
smoothly to give the corresponding product 3a′ in 69% yield.
For substrates containing p-haloarylalkyne substituents (1b′
and 1c′), the reactions also proceeded successfully to give the
desired products in 61% and 69% yields, respectively. The
reaction of p-methoxy-substituted substrate 1d′ was more
problematic as it provided the corresponding product (3d′) in
trace amount. Under strong acidic conditions, the p-methoxy
substituent could delocalize electrons into the para-cationic
species, resulting in the formation of quinone methide-type
intermediates that could undergo other side reactions; this thus
contributed to the lower yield. The decomposition observed in
these substrates was similar to that observed for compound 1n
and 1p in Scheme 4. However, in substrates containing an
electron-withdrawing p-methyl ester group (1e′), the reaction
Scheme 5. Scope of Substrates for the Reaction of
Compounds Containing Both Internal and Terminal
Alkynes
a,b
a
b
Isolated yields. Reaction time is in parentheses.
occurred smoothly to produce the corresponding vinyl triflate
3e′ in 75% yield. We next turned our attention to study aryl
1,3-diyne substrates. With m-phenylalkynyl phenylacetylene
(1f′), the reaction underwent a smooth conversion at the
terminal alkyne to afford the desired product (3f′) in 76%
yield. Other substituents on the m-arylalkynyl group were next
examined. As shown with the chlorine and fluorine substituents
in substrates 1g′−h′, the reactions proceeded excellently to
furnish vinyl triflates 3g′ and 3h′ in 94% and 83% yields,
respectively. As a representative of electron-withdrawing group,
compound 1i′ with methyl ester group was next employed as
the substrate. Under the optimal conditions, the desired
product 3i′ was afforded in 58% yield. Besides the arylalkynyl
substituents, the reaction was also tested with the substrate
containing alkylalkynyl substituent (1j′). This compound
could be converted successfully to the desired vinyl triflate
3j′ in 77% yield. Surprisingly, the reaction of dialkynyl
substrate 1k′ did not proceed under the optimal conditions,
resulting in no reaction, while the reaction of compound 3l′
underwent decomposition.
The mechanism of the reaction is proposed as a working
mechanism in Scheme 6. We hypothesized that the reaction of
2.0 equiv each of TMSN3 and TfOH quickly set up an
equilibrium with the predominant direction to the right to
form TMSOTf and HN3. An experimental study was
performed using 19F NMR for monitoring the reaction
between TMSN3 and TfOH. The result showed that TMSOTf
was rapidly generated in situ corroborating well with the
C
DOI: 10.1021/acs.orglett.9b01576
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Postgraduate Education and Research Development Office
(PERDO), Ministry of Education, and Thailand Research
Fund through the Royal Golden Jubilee (RGJ) Ph.D. Program
(Grant No. PHD/0217/2558) and Thailand Research Fund
(RSA6080085).
Scheme 6. Proposed Working Reaction Mechanism
REFERENCES
(1) (a) Vila, C.; Hornillos, V.; Giannerini, M.; Fan
Feringa, B. L. Chem. Eur. J. 2014, 20, 13078−13083. (b) Scott, W. J.;
Pena, M. R.; Sward, K.; Stoessel, S. J.; Stille, J. J. Org. Chem. 1985, 50,
2302−2308. (c) Occhiato, E. G.; Trabocchi, A.; Guarna, A. J. Org.
Chem. 2001, 66, 2459−2465. (d) Ackerman, L. K.; Lovell, M. M.;
Weix, D. J. Nature 2015, 524, 454. (e) Garcia Martinez, A.; Osío
■
́
̃
anas-Mastral, M.;
́
Barcina, J.; Colorado Heras, M. d. R.; de Fresno Cerezo, A.
Organometallics 2001, 20, 1020−1023. (f) Ciattini, P. G.; Morera, E.;
Ortar, G. Tetrahedron Lett. 1992, 33, 4815−4818.
(2) (a) Andersson, C. M.; Hallberg, A. J. Org. Chem. 1989, 54,
1502−1505. (b) Kwon, H. B.; McKee, B. H.; Stille, J. J. Org. Chem.
1990, 55, 3114−3118. (c) Vallin, K. S.; Larhed, M.; Johansson, K.;
Hallberg, A. J. Org. Chem. 2000, 65, 4537−4542. (d) Willis, M. C.;
Taylor, D.; Gillmore, A. T. Chem. Commun. 2003, 2222−2223.
(3) (a) Vallin, K. S.; Zhang, Q.; Larhed, M.; Curran, D. P.; Hallberg,
A. J. Org. Chem. 2003, 68, 6639−6645. (b) Ikawa, T.; Nishiyama, T.;
Shigeta, T.; Mohri, S.; Morita, S.; Takayanagi, S. I.; Terauchi, Y.;
Morikawa, Y.; Takagi, A.; Ishikawa, Y. Angew. Chem. 2011, 123,
5792−5795. (c) Stolley, R. M.; Guo, W.; Louie, J. Org. Lett. 2012, 14,
322−325.
hypothesis.15 In this equilibrium TfOH was generated slowly
in the reverse direction. TfOH present in the reaction then
readily added to the terminal alkyne moiety in the starting
material to give the desired product. At this point, the
remaining ratio of TMSN3 and TfOH was 2:1 which forced the
equilibrium to lie even further to the right, effectively reducing
the concentration of TfOH in the reaction mixture, resulting in
low effective concentration of TfOH and became insufficient
to promote the second hydrotriflation. As a result, only
terminal alkyne reacted under these conditions.
In conclusion, a chemoselective hydrotriflation protocol of
terminal alkynes has been developed. Conversion of only
terminal alkynes, in the presence of internal counterparts, to
give 1,1-disubstituted vinyl triflates can be achieved with this
protocol based on the slow generation of TfOH. The current
protocol allowed access to 1,1-disubstituted vinyl triflates from
terminal alkynes even in the presence of internal alkynes. The
protocol is simple and convenient to conduct and allows access
to 1,1-disubstituted vinyl triflates selectively in excellent
efficiencies. This method complements well with other existing
strategies and methods for the generation of vinyl triflates,
especially for generation of the 1,1-disubstituted vinyl triflates.
(4) (a) Shen, X.; Hyde, A. M.; Buchwald, S. L. J. Am. Chem. Soc.
2010, 132, 14076−14078. (b) Shirakawa, E.; Imazaki, Y.; Hayashi, T.
Chem. Commun. 2009, 5088−5090.
(5) (a) Maity, P.; Lepore, S. D. J. Org. Chem. 2009, 74, 158−162.
(b) Ritter, K. Synthesis 1993, 1993, 735−762. (c) Specklin, S.; Bertus,
P.; Weibel, J.-M.; Pale, P. J. Org. Chem. 2008, 73, 7845−7848.
(d) Hargrove, R. J.; Stang, P. J. J. Org. Chem. 1974, 39, 581−582.
(e) Stang, P. J.; Anderson, A. G. J. Am. Chem. Soc. 1978, 100, 1520−
1525. (f) Stang, P. J. Acc. Chem. Res. 1978, 11, 107−114.
́
(6) (a) Dhakal, B.; Bohe, L.; Crich, D. J. Org. Chem. 2017, 82,
9263−9269. (b) Howells, R.; Mc Cown, J. Chem. Rev. 1977, 77, 69−
92.
(7) Lee, P. H.; Park, S. J.; Kim, J. S.; Lee, G. Y. Method for
preparation of alkenyl triflates. Repub. Korean Kongkae Taeho
Kongbo, KR 2014098468, Aug 8, 2014.
(8) Wu, J.-J.; Xu, J.; Zhao, X. Chem. Eur. J. 2016, 22, 15265−15269.
(9) (a) Summerville, R. H.; Senkler, C. A.; Schleyer, P. V. R. J. Am.
Chem. Soc. 1974, 96, 1100−1110. (b) Stang, P. J.; Summerville, R. J.
Am. Chem. Soc. 1969, 91, 4600−4601.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01576.
■
S
(10) (a) Yang, Y.; Moschetta, E. G.; Rioux, R. M. ChemCatChem
2013, 5, 3005−3013. (b) Yang, Y.; Chang, J.-W.; Rioux, R. M. J.
Catal. 2018, 365, 43−54.
(11) Ouyang, Y.; Xu, X.-H.; Qing, F.-L. Angew. Chem. 2018, 130,
7042−7045.
Optimization, experimental procedures, spectroscopic
data, and NMR spectra of compounds (PDF)
(12) (a) Wang, X.; Studer, A. Org. Lett. 2017, 19, 2977−2980.
(b) Suero, M. G.; Bayle, E. D.; Collins, B. S.; Gaunt, M. J. J. Am.
Chem. Soc. 2013, 135, 5332−5335.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jumreang@cri.or.th.
ORCID
(13) Al-huniti, M. H.; Lepore, S. D. Org. Lett. 2014, 16, 4154−4157.
(14) See the Supporting Information for additional optimization
studies.
(15) Nimnual, P.; Tummatorn, J.; Boekfa, B.; Thongsornkleeb, C.;
Ruchirawat, S.; Piyachat, P.; Punjajom, K. J. Org. Chem. 2019, 84,
5603−5613. Also see the Supporting Information for 19F NMR
experimental study in the formation of TMSOTf in situ.
Jumreang Tummatorn: 0000-0002-1662-151X
Charnsak Thongsornkleeb: 0000-0003-2653-5137
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research work was supported by Chulabhorn Research
Institute, Mahidol University, and the Center of Excellence on
Environmental Health and Toxicology, Science & Technology
D
DOI: 10.1021/acs.orglett.9b01576
Org. Lett. XXXX, XXX, XXX−XXX