Stereoselective Synthesis of (Z)-β-Enamido Triflates and Fluorosulfonates from N-Fluoroalkylated Triazoles

Article abstract of DOI:10.1002/chem.201901632

N-Fluoroalkylated 1,2,3-triazoles in the presence of triflic acid or fluorosulfonic acid underwent a cascade reaction consisting of triazole protonation, ring opening, nitrogen elimination, sulfonate addition, HF elimination, and hydrolysis to furnish novel trifluoromethanesulfonyloxy- or fluorosulfonyloxy-substituted enamides, respectively, in a highly stereoselective fashion. The vinyl triflates underwent cross-coupling reactions to a variety of substituted enamides and serve as sources of the aminovinyl cations. In reactions with triflic acid, electron-rich triazoles afforded 2-fluoroalkylated oxazoles.

Full text of DOI:10.1002/chem.201901632

A Journal of
Accepted Article
Title: Stereoselective Synthesis of (Z)-β-Enamido Triflates and
Fluorosulfonates from N-Fluoroalkylated Triazoles
Authors: Athanasios Markos, Svatava Voltrová, Vladimir Motornov,
David Tichy, Blanka Klepetářová, and Petr Beier
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To be cited as: Chem. Eur. J. 10.1002/chem.201901632
Link to VoR: http://dx.doi.org/10.1002/chem.201901632
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Stereoselective Synthesis of (Z)--Enamido Triflates and
Fluorosulfonates from N-Fluoroalkylated Triazoles
Athanasios Markos,[a,b] Svatava Voltrová,[a] Vladimir Motornov,[a,c] David Tichý,[a] Blanka Klepetářová[a]
and Petr Beier*[a]
Abstract: N-Fluoroalkylated 1,2,3-triazoles in the presence of triflic
acid or fluorosulfonic acid underwent a cascade reaction consisting
of triazole protonation, ring opening, nitrogen elimination, sulfonate
addition, HF elimination, and hydrolysis to furnish novel
trifluoromethanesulfonyl- or fluorosulfonyl-substituted enamides,
respectively, in a highly stereoselective fashion. The vinyl triflates
underwent cross-coupling reactions to a variety of substituted
enamides and serve as sources of the aminovinyl cations. In
reactions with triflic acid, electron-rich triazoles afforded 2-
fluoroalkylated oxazoles.
carbenoids.[37,38] However, the reactivity profiles of N-fluoroalkyl
triazoles and N-sulfonyl triazoles are markedly different.
Herein, we report a conceptually unprecedented, stereoselective
and metal-free transformation of N-fluoroalkyl-substituted 1,2,3-
triazoles to -fluorosulfonyl or -trifluoromethanesulfonyl
enamides in presence of fluorosulfonic or triflic acids. These
enamido triflates and fluorosulfonates are a new class of
compounds. Enamido triflates cannot be prepared by triflatation
of
-aminoketones
due
to
their
self-condensation.
Mechanistically, the reaction proceeds through the formation of
relatively stable triazolium salts via aminovinyl cation
intermediate (Figure 1C). Unlike other vinyl triflates, (Z)--
enamido triflates and fluorosulfonates are stable solids.
Since
the
first
report
in
the
late
1960’s,[1],[2]
trifluoromethanesulfonates (triflates) have become the subject of
numerous studies not only as precursors of vinyl cations[3–6] but
also as substrates in transition metal-catalyzed C-C bond-
forming reactions.[7–11] Recently, the synthetic community has
been witnessing a renewed interest in tranformations involving
vinyl cations.[12,13] Despite valuable synthetic applications of vinyl
triflates, they possess some drawbacks which limit their
industrial application. For instance, they are commonly liquids,
sensitive to hydrolysis and their preparation requires expensive
reagents.[14] Vinyl triflates are usually prepared from carbonyl
compounds either by trapping the respective enolate with a
triflating agent[15,16] or by treating the carbonyl compound with
triflic anhydride in the presence of a bulky base.[11],[17–20] Other
synthetic approaches are based on the introduction of triflate
moiety into alkynes.[21–23] Recently, Gaunt and Studer described
regio- and stereoselective electrophile-induced triflation of
alkynes via hypervalent iodine reagents. This methodology
enabled the introduction of highly functionalized alkenes,[24]
acrylonitriles,[25] and vinyl perfluoroalkanes[26] into organic
molecules (Figure 1A).
N-Sulfonyl triazoles, precursors of azavinyl carbenes, are known
to undergo a variety of rhodium-catalyzed reactions. They have
been used for the preparation of different types of heterocycles,
N-sulfonyl-containing compounds,[27] and for stereoselective
synthesis of 2,2-diaryl or 2-alkyl-2-aryl- substituted N-sulfonyl
enamides (Figure 1B).[28–33] We have recently shown that N-
fluoroalkyl triazoles prepared by a [3+2] cycloaddition of stable
and safe azido(per)fluoroalkanes and alkynes[34–36] are efficiently
transformed to new N-fluoroalkyl heterocycles via rhodium
Figure 1. Recent synthetic approaches from alkynes to vinyl triflates or
substituted alkenes. A - Alkyne functionalizations using hypervalent iodine
compounds, B - Rh(II)-catalyzed reactions of N-sulfonyl triazoles and C -
superacid-mediated approach to (Z)--enamido triflates and fluorosulfonates.
Furthermore, the triflate group can be substituted for a variety of
carbon functions in cross-coupling reactions to provide
medicinally and synthetically attractive enamides,[39–41] which are
difficult to prepare using other methods. Triazoles with electron-
rich groups attached on the aryl ring in position 4 behaved
differently and they provided 2-fluoroalkyl oxazoles.
Considering the high stability of carbon-nitrogen bond of N-
fluoroalkyl triazoles in comparison with sulfur-nitrogen bond of
N-sulfonyl triazoles[42] and good hydrolytic stability of 1,2,3-
triazoles and their salts,[43–46] we assumed that the addition of a
strong Brønsted acid would yield a triazolium salt that might lead
to ring opening, nitrogen elimination and ultimately afford an
enamine (Scheme 1A).
[a]
A. Markos, Dr. S. Voltrová, V. Motornov, Dr. B. Klepetářová, Dr. P.
Beier.
The Institute of Organic Chemistry and Biochemistry of the Czech
Academy of Sciences
Flemingovo nam. 2, 16610 Prague 6 (Czech Republic)
E-mail: beier@uochb.cas.cz
A. Markos
Department of Organic Chemistry, Faculty of Science, Charles
University
Hlavova 2030/8, CZ-128 43 Prague 2 (Czech Republic)
V. Motornov
[b]
[c]
Higher Chemical College, D. I. Mendeleev University of the
Chemical Technology of Russia
Miusskaya sq. 9, Moscow 125047 (Russia)
Supporting information for this article is given via a link at the end of
the document.((Please delete this text if not appropriate))
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Table 1. Reaction scope to (Z)-vinylsulfonates.[a]
Scheme 1. Initial hypothesis and findings.
To test this hypothesis, we treated triazole 1a with triflic acid. A
precipitate quickly formed from the 1,2-dichloroethane (DCE)
solution at ambient temperature, which was followed by a slow
dissolution accompanied by gas evolution and the formation of
vinyl triflate 2a. NMR spectroscopy revealed a high efficiency of
the reaction without side-products and the presence of only (Z)-
stereoisomer of the product. However, aqueous workup resulted
in decomposition due to hydrolytic instability of the NHCF3
moiety.[47] This outcome led us to use
a longer chain
perfluoroalkyl group and to stabilize the product in the form of
enamide. Thus, triazole 3a with triflic acid provided enamine 4a
which upon HF elimination and hydrolysis, afforded enamide 6a
(Scheme 1B). Optimization experiments revealed that if the
substrate 3 containined an electron-rich aryl group, the reactions
proceeded at ambient temperature, whereas for electron-poor
aryl groups, the temperature needed to be increased to 40-60 °C.
The hydrolysis of unstable intermediates 4 to final enamides 6
was accomplished by elevating the temperature in moisture-
containing DCE or by hydrolysis on silica gel.
The scope of this new transformation was then studied on 4-
substituted-N-fluoroalkyl triazoles (Table 1). 4-Aryl-substituted
triazoles with the pentafluoroethyl, ArOCF2CF2, or difluoromethyl
groups were found to be relevant substrates and afforded
products 6 in good to high yields even on a multigram scale in
the case of 6b. A high functional group tolerance on the aryl ring
was found (6a-i) where alkyl, CF3, nitro, halogen and even
hydroxy group-containing triazoles furnish vinyl triflates 6 in
good yields and Z selectivities. In RhII-catalyzed transformations
of 1,2,3-triazoles the presence of a free OH group interfered with
rhodium-carbenoids.[48,49] With alkene or nitrile additives (MeCN
or 2-methyl-2-butene, 10 equiv.) our reaction was not affected,
while in Rh-catalyzed reactions transannulations took place.
Additionally, N-sulfonyl 1,2,3-triazoles did not react with triflic
acid in an analogous way to N-perfluoroalkyl triazoles but the
main observed reaction in the former case was desulfonylation.
The stereochemistry of products 6 as determined by 2D NMR
and X-ray analyses was excellent (>20:1, Z:E) in all cases
except for 6g and 6n where lower Z:E ratios were observed. N-
Difluoromethyl triazoles 3k and 3l showed lower reactivity
compared to other N-fluoroalkyl triazoles; nevertheless,
formamides 6k and 6l were isolated in good yields. On the other
hand, 4-alkyl-substituted triazole 3j afforded the product 6j in
rather low yield, indicating a limitation which is related to the
relatively lower stability of the vinyl cation intermediate as
discussed later. In some cases (6a-e), small amounts (<10%) of
[a] Isolated yields. [b] 2D ROESY NMR was measured. [c] After heating at
50 °C for 16 h, additional TfOH (0.45 equiv.) was added and the reaction
continued at 50 °C for 2 h. [d] NMR yield, product was not isolated. [e] (Z)-
isomer isolated in 70% yield. See Supporting Information for experimental
details.
the addition of various alcohols in the presence of a base led to
the formation of new carbamates 7a-c.
Keeping in mind the attractivity of fluorosulfonates in sulfur(VI)
fluoride exchange (SuFEx) chemistry,[50] we focused on the
preparation of vinyl fluorosulfonates (Table 1). The reaction of
triazoles 3 with fluorosulfonic acid (DCE, 40 °C) afforded vinyl
fluorosulfonates 8 in moderate to good yields and with the
exclusive formation of (Z)-isomers. This time, the amount of
side-products 9 increased (up to 20%). The fluoro-enamides 9
resulted from fluorodesulfonylation of 6 and 8. The formation of
9 is in line with the recent Sandford’s reports of nucleophilic
deoxyfluorination of aryl triflates and fluorosulfonates where the
latter underwent
a
more facile deoxofluorination than
triflates.[51,52] Triazoles 1 and 3 were unreactive in reactions with
other strong acids such as nitric or chlorosulfonic acids.
Concerning the mechanism of triazole ring opening and
formation of 2, we propose the formation of a protonated triazole
in the presence of triflic acid (triazolium triflate 10 was isolated
and fully characterized), followed by ring opening to the
diazonium compound, nitrogen elimination to the vinyl cation,
side-products
9 were observed. Although the starting N-
trifluoromethyl triazole 1a afforded hydrolytically unstable
enamine 2a, which prevented the isolation of a stable product,
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and reaction with the triflate anion tethered through a hydrogen
bonding with the oxygen of the triflate delivering the triflate in a Z
configuration (Pathway A). Alternatively, a carbocation which
reacts with the triflate anion can be formed, followed by a C-H
bond cleavage, ring opening and nitrogen elimination to afford
product 2 (Pathway B). The pathway B was ruled out based on
an isotope labelling experiment which showed that there was no
C-H/D bond cleavage during the course of the reaction (Scheme
2).
Table 3. Cross-coupling reactions of (Z)--enamido triflates.[a]
[a] Isolated yields. [b] Prepared by one-pot two-steps procedure from 3f. [c]
2D ROESY NMR was measured. See Supporting Information for
experimental details.
can be performed in a one-pot two-step modification starting
from N-fluoroalkyl triazole 3: the dinaphthyl derivative 12d was
obtained in good yield from electron-rich triazole 3f via
metastable 6f.
Scheme 2. Proposed mechanisms: Pathway A via vinyl cation, Pathway B via
carbocation: The D/H ratio was determined by 1H NMR (for 1aD, 2aD R = p-
Tol, RF = CF3).
In conclusion, a practical, metal-free method for the synthesis of
novel β-enamido-sulfonates starting from N-fluoroalkyl-1,2,3-
triazoles is presented. The method has a high functional group
tolerance and uses readily available triflic or fluorosulfonic acids.
A mechanism involving the formation of a triazolium salt and
aminovinyl cation intermediate was proposed. Synthetic
transformations of vinyl triflates in cross-coupling reactions
afforded functionalized enamides. 2-Fluoroalkyl oxazoles were
prepared by a one-pot procedure from electron-rich triazoles by
the cyclization of vinyl triflate intermediates.
Unexpected results were observed in the case of triazoles with
electron-rich aromatic rings (such as p-methoxyphenyl or
naphthyl). Although vinyl triflates 6 were observed by NMR and
in the case of naphthyl-substituted vinyl triflate 6f fully
characterized, they were found to be highly reactive and 2-
fluoroalkyl oxazoles were isolated as final products in moderate
(11a) or good (11b-d) yields (Table 2).
Table 2. Transformation to 2-fluoroalkyl oxazoles.[a]
Acknowledgements
This work was financially supported by the Czech Academy of
Sciences (RVO: 61388963) and by the Ministry of Education,
Youth and Sports in the program INTER-EXCELLENCE
(LTAUSA18037). We would like to thank Prof. Ilan Marek
(Technion, Haifa, Israel) for discussing the mechanistic aspects
of the reaction, Prof. Huw Davies (Emory University, Atlanta,
USA) for discussing the stability of triazoles and Dr. Radek Pohl
(IOCB, Prague, Czech Republic) for the advanced NMR
measurements and spectra interpretation.
[a] Isolated yields.
This reactivity may be explained by the formation of vinyl cation
stabilized by electron-rich aryl groups. SN1-like cyclization with
amide oxygen followed by deprotonation afforded oxazoles 11.
Therefore, the superacid-mediated approach provides a route to
the rare C-2-fluorinated oxazoles directly from electron-rich N-
fluoroalkyltriazoles. In contrast to p-methoxyphenyl and
naphthyl-substituted triflates, the phenyl derivative 6b was stable,
even after prolonged heating in DCE.
To demonstrate the synthetic value of the method, we
investigated futher transformations of vinyl sulfonates to
synthetically versatile enamides (Table 3). Pd-Catalyzed cross-
coupling reactions including Suzuki (12a-e), Sonogashira
(13a,b) and Pd-catalyzed alkylation with diethyl zinc (14a)
proceeded with good to excellent yields and full retention of
configuration on the double bond. The cross-coupling reactions
Keywords: 1,2,3-triazoles • triazolium salt • vinyl cation •
enamide • vinyl triflate
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Athanasios Markos, Svatava Voltrová,
Vladimir Motornov, David Tichý, Blanka
Klepetářová and Petr Beier*
Page No. – Page No.
Stereoselective Synthesis of
(Z)--Enamido Triflates and
Fluorosulfonates from
N-Fluoroalkylated Triazoles
A new transformation of N-fluoroalkylated 1,2,3-triazoles is presented. In the presence of triflic or fluorosulfonic acids they are
converted to novel trifluoromethanesulfonyl- or fluorosulfonyl-substituted enamides, respectively, in a highly stereoselective fashion.
The trifluoromethanesulfonyl enamides are competent partners for cross-coupling reactions to stereodefined enamides.
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