Sulfonamide-Trapping Reactions of Thermally Generated Benzynes

Article abstract of DOI:10.1021/acs.orglett.8b03085

Reactions of tethered, tertiary sulfonamides with thermally generated benzynes are reported. Typically, the N-S bonds in the substrates cleave, and saturated heterocycles [tetrahydroquinolines (n = 2) and indolines (n = 1)] are formed. The process is accompanied by either sulfonyl transfer or desulfonylation from a zwitterionic intermediate, with the favored pathway being largely dependent upon the size (5- vs 6-membered) of the N-containing ring in the zwitterion.

Full text of DOI:10.1021/acs.orglett.8b03085

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Sulfonamide-Trapping Reactions of Thermally Generated Benzynes
Yuanxian Wang,† Lianyou Zheng,†,‡ and Thomas R. Hoye*
Department of Chemistry, University of Minnesota, 207 Pleasant Street SE, Minneapolis, Minnesota 55455, United States
S
* Supporting Information
ABSTRACT: Reactions of tethered, tertiary sulfonamides with
thermally generated benzynes are reported. Typically, the N−S
bonds in the substrates cleave, and saturated heterocycles
[tetrahydroquinolines (n = 2) and indolines (n = 1)] are
formed. The process is accompanied by either sulfonyl transfer
or desulfonylation from a zwitterionic intermediate, with the
favored pathway being largely dependent upon the size (5- vs 6-
membered) of the N-containing ring in the zwitterion.
ulfonamides are known to react, in situ, with benzyne
1b). The evidence in hand suggests that (the intramolecular)
reaction of various tertiary sulfonamides with HDDA-benzynes
gives zwitterions II, from which different products are obtained
via distinct reaction pathways. These mostly involve either
sulfonyl transfer or desulfonylation. In these reactions, the
sulfonyl group from the sulfonamide substrates are replaced by
aryl groups, which, to our knowledge, is a unique feature of the
reaction outcomes reported here.4 The products contain either
a tetrahydroquinoline (THQ) or indoline core structure
depending on whether the diyne terminus of the triyne
substrate and the sulfonamide nitrogen are connected by three
or two atoms, respectively. (Throughout this manuscript, we
have used Roman numerals I−X to label structures of
intermediate species that were not isolated and Arabic
numerals to designate the structures of isolated (and newly
characterized) compounds.)
S
intermediates1 made by the Kobayashi protocol2 (fluoride
ion + o-silylaryltriflate). Under these basic conditions, primary
or secondary sulfonamides trap the benzyne intermediates
(Figure 1a). Aryl-substituted sulfonamides are produced by
Shown in Table 1 are a series of reactions of hexadehydro-
Diels−Alder (HDDA) substrates that serve as precursors to
products having a newly fused piperidine ring. That is, the
amide (always a p-toluenesulfonamide) and alkyne are
connected by a trimethylene linker. When each of the triynes
1a−f was heated in a relatively inert5 solvent, the
corresponding THQs 2a−f were isolated in excellent yield.
We infer that within a THQ zwitterion such as II (n = 2) there
is ample orbital overlap to permit 1,3-migration of the sulfonyl
moiety (see further discussion below). It is worth mentioning
that none of the product arising from a potential aza-Claisen
rearrangement of the intermediate zwitterion arising from 1c
and leading to 2c was observed.
Figure 1. (a) Known modes of reaction of arynes with sulfonamides.
(b) Studies reported here show complementary reactions in which
sulfonyl migration or desulfonylation occurs.
We studied several related substrates that also contained a
trimethylene linker between the terminal alkyne and trapping
sulfonamide. The results are summarized in Table 2. Each
this formal insertion reaction of the aryne triple bond into an
N−H bond of the sulfonamide; the N−S bonds in the
substrates remain intact in the product. We now disclose an
alternative mode of reaction that emerges when benzynes (cf.
I) derived from thermal cyclization of triyne precursors3 are
trapped by fully substituted (i.e., tertiary) sulfonamides (Figure
Received: September 26, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03085
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Reactions of Ts-amide-Containing Triynes 1a−f
Having Various Linkers (ABC) Give Sulfonyl-Transfer
Product Tetrahydroquinolines 2a−f via Benzyne
Intermediates I
Table 2. Reactions of Triynes 1g−j Having Various
Sulfonamide Groups (R2) Give Tetrahydroquinoline
Derivatives 2g−j via Benzyne Intermediates I
a
Percent yield is of chromatographically purified material.
substrate showed behavior different from those in Table 1.
Substrate 1g (entry 1) is an N-aryl sulfonamide; it gave rise to
1
a complicated product array (TLC and H NMR) with no
clear evidence for the presence of any of 2g. Triynes 1h and 1i
(entries 2 and 3) are both methane- rather than toluenesulfo-
namides. They provided products (2h and 2i, respectively) in
which the sulfonyl group was absent. Elimination of sulfene
a
Percent yield is of chromatographically purified material.
B
DOI: 10.1021/acs.orglett.8b03085
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(IV) from within the zwitterion III would account for these
outcomes (see “mechanistic rationales,” at the bottom of Table
2). Finally, the nosylamide 1j gave two products. Sulfone 2j
arises by the same path as that to the tosylamide products
(Table 1), but its formation was accompanied by that of the p-
nitrophenyl-substituted biaryl compound 2j′ in which SO2 has
been ejected. This variant of the Truce−Smiles rearrangement6
can be viewed as proceeding by ipso-attack para to the nitro
substituent in V. Loss of SO2 from the delocalized zwitterion
VI would lead to 2j′. Similar transformations of classic
benzynes have been demonstrated.1c
Table 3. Reactions of Triynes 1k−n Having Tosyl or Mesyl
Sulfonamide Groups (R2) Give Desulfonylated Indoline
Derivatives 2k−n
We also studied several lower homologue substrates (1k−n,
Table 3) containing a dimethylene link between the diyne
terminus and sulfonamide nitrogen atom. These led to the
indoline derivatives 2k−n (entries 1−4), each containing a
newly formed 5-membered heterocycle. In this series, we did
not observe products of 1,3-sulfonyl migration analogous to
those in reactions of the tosylsulfonamide leading to THQs (cf.
Table 1). Rather, the isolated products were all devoid of the
sulfonyl group. We attribute this (bottom of Table 3) to the
higher activation energy (more strained transition state
structure) that would be required for the conversion of the
5-membered zwitterion VII, which contains a retracted
sulfonyl moiety, to the nonobserved product VIII. Desulfony-
lation within VII could proceed by the sulfene ejection (cf. III
to IV) for the Ms substrates (entries 3 and 4) or by
intervention of trace levels of a protic species such as water (IX
to X, Table 3, bottom). Protonation of the carbon and
desulfonylation by the resulting hydroxide would account for
product formation. Given the relatively low concentration at
which these experiments were performed (initial substrate
concentration of 0.01 M), we cannot confidently judge which
is the more likely scenario. The N-arylated, one methylene-
lower homologue 1n gave an interesting result in contrast to
the behavior of substrate 1g (Table 2, entry 1). The
methanesulfonamide 1n smoothly provided the N-phenylindo-
line 2n, again by loss of sulfene.
Finally, we observed that each of these indoline products
was susceptible to air autoxidation7 to the corresponding
indole. Performing the HDDA reaction under a nitrogen
atmosphere substantially improved the cleanliness of the
product mixture. In the case of 1m, we heated the reaction
mixture for an extended period of time (90 °C, 72 h) under a
headspace of air and isolated the indole 3 as the main product;
no indoline remained in the crude reaction mixture.
In conclusion, we have demonstrated that the nitrogen in
tertiary sulfonamide groups can react with HDDA-generated
benzynes to produce zwitterion intermediates. Various reaction
pathways ensue from these species, depending on the size of
the newly formed nitrogen heterocycle and the nature of the
substituent (alkyl vs aryl) present on the zwitterionic nitrogen
atom. The processes include sulfonyl transfer to the vicinal,
benzyne-derived carbon atom or desulfonylation events. Each
results in the formation of a new, saturated, benzo-fused
piperidine (i.e., a tetrahydroquinoline) or pyrrolidine (i.e., an
indoline) ring. Among other things, each of these trans-
formations results in the replacement of a robust N−SO2R
bond8 by a N−C bond, potentiated by the high energy of the
reactive benzyne intermediate.
a
Percent yield is of chromatographically purified material.
C
DOI: 10.1021/acs.orglett.8b03085
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Organic Letters
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(2) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Fluoride-induced 1,2-
Elimination of o-Trimethylsilylphenyl Triflate to Benzyne under Mild
Conditions. Chem. Lett. 1983, 12, 1211−1214.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b03085.
■
S
(3) (a) Miyawaki, K.; Suzuki, R.; Kawano, T.; Ueda, I. Cyclo-
aromatization of a Non-Conjugated Polyenyne System. Tetrahedron
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Experimental details for the preparation of new
compounds and spectroscopic data (including copies
1
of H and 13C NMR spectra) for their characterization
(PDF)
Accession Codes
CCDC 1857242 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
(4) Searles, S.; Nukina, S. Cleavage and Rearrangement of
Sulfonamides. Chem. Rev. 1959, 59, 1077−1103.
(5) Although solvents like toluene have been observed to trap
benzynes in Diels−Alder and or ene-type reactions, those processes
are sufficiently slow that they do not interfere with the more facile
trapping by the nucleophilic (and internally linked) nitrogen atom of
the sulfonamide.
(6) Henderson, A. R. P.; Kosowan, J. R.; Wood, T. E. The Truce−
Smiles Rearrangement and Related Reactions: A Review. Can. J.
Chem. 2017, 95, 483−504.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: hoye@umn.edu.
ORCID
(7) Padwa, A.; Kappe, C. O.; Cochran, J. E.; Snyder, J. P. Studies
Dealing with the Cycloaddition/Ring Opening/Elimination Sequence
of 2-Amino-Substituted Isobenzofurans. J. Org. Chem. 1997, 62,
2786−2797.
(8) For a discussion that reflects an early appreciation of the
robustness of sulfonamides and their stability, see: Searles, S.; Nukina,
S. Cleavage and Rearrangement of Sulfonamides. Chem. Rev. 1959,
59, 1077−1103.
Thomas R. Hoye: 0000-0001-9318-1477
Present Address
‡(L.Z.) The Center for Combinatorial Chemistry and Drug
Discovery, and School of Pharmaceutical Sciences, Jilin
University, 1266 Fujin Lu, Changchun, Jilin 130021, PR China.
Author Contributions
†Y.W. and L.Z. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support for this research was provided by the National
Institutes of General Medical Sciences of the U.S. Department
of Health and Human Services (R01 GM65597, then R35
GM127097). L.Z. received support from the China Scholar-
ship Council Program (201706175084). A portion of the
NMR spectral data were acquired with an instrument
purchased with funds provided by the NIH Shared
Instrumentation Grant program (S10OD011952). The X-ray
diffraction analysis was performed by Dr. Victor G. Young
(University of Minnesota).
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DOI: 10.1021/acs.orglett.8b03085
Org. Lett. XXXX, XXX, XXX−XXX