N -Tosyl-3-azacyclohexyne. Synthesis and chemistry of a strained cyclic ynamide

Article abstract of DOI:10.1021/ja509055r

The first synthesis of a strained six-membered cyclic ynamide is described. N-Tosyl-3-azacyclohexyne is generated via fluoride-promoted 1,2 elimination under conditions that allow trapping of the strained heterocyclic alkyne in a variety of addition, insertion, and [2 + 2], [3 + 2], and [4 + 2] cycloaddition reactions.

Full text of DOI:10.1021/ja509055r

Communication
pubs.acs.org/JACS
N‑Tosyl-3-Azacyclohexyne. Synthesis and Chemistry of a Strained
Cyclic Ynamide
Sami F. Tlais and Rick L. Danheiser*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States
S
* Supporting Information
ABSTRACT: The first synthesis of a strained six-
membered cyclic ynamide is described. N-Tosyl-3-
azacyclohexyne is generated via fluoride-promoted 1,2
elimination under conditions that allow trapping of the
strained heterocyclic alkyne in a variety of addition,
insertion, and [2 + 2], [3 + 2], and [4 + 2] cycloaddition
reactions.
For our initial studies on the chemistry of azacyclohexynes,
we focused our attention on the N-tosyl derivative 1 and
targeted the cyclic enamide 5 as a potential intermediate for its
synthesis (Scheme 1).10 Several considerations motivated our
he role of o-benzyne as the key intermediate in the
Scheme 1. Strategy for the Generation of N-Tosyl-3-
azacyclohexyne
T
reaction of chlorobenzene with KNH2 was established
through a series of groundbreaking experiments reported by J.
D. Roberts et al. in 1953.1 Today arynes 2 and hetarynes3 rank
among the most extensively studied reactive intermediates in
organic chemistry. The electronic structure of these highly
strained alkynes continues to attract great interest, and these
remarkable species also have found an important place as
4
building blocks in organic synthesis. Cyclohexynes, on the
other hand, are considerably less stable than benzynes, and to
date these more exotic species have found very limited use in
synthesis.5,6 Even less attention has been focused on heterocyclic
variants of cyclohexyne, and the application of these species in
synthesis has not previously been explored. Our interest in the
application of ynamides as synthetic building blocks7,8 led us to
consider whether the preparation of strained cyclic ynamides
such as 1 might be feasible and whether such species might
engage in transformations with utility for the construction of
complex molecules. Herein we report the first synthesis of N-
tosyl-3-azacyclohexyne (1) as well as its participation in highly
regioselective transformations leading to a diverse range of
heterocyclic compounds.
choice of 5 as an attractive precursor to the strained cyclic
alkyne. First, several alternate routes could be envisioned for
the preparation of 5 beginning with readily available derivatives
of δ-valerolactam. Exposure of 5 to the action of fluoride ion
was then expected to provide access to the azacyclohexyne
under mild conditions that would be compatible with the
presence of a wide range of interesting reaction partners
capable of trapping the strained alkyne. Note that the
elimination process proposed for the generation of 1 from 5
(Scheme 1, pathway a) constitutes a variant of the well
established Kobayashi method for the preparation of arynes
from o-(trialkylsilyl)aryl triflates.11 It is relevant to note that
1,2-eliminations of this type have previously been employed for
the generation of cyclohexyne6c,f as well as 1,2,3-cyclo-
hexatriene.12
To our knowledge, only a single report of the generation of
an azacyclohexyne has appeared previously. In 1988, Wentrup
et al. reported that flash vacuum pyrolysis of isoxazolone 2
provides access to azacyclohexyne 4 which was identified
through the use of low-temperature IR spectroscopy.9
Decomposition of the unstable heterocyclic alkyne was
observed to take place upon warming above −150 °C. The
formation of azacyclohexyne in this reaction is believed to
proceed via the rearrangement of the intermediate carbene 3
(eq 1).
As depicted in Scheme 1, the formation of azacyclohexyne 1
via pathway a would involve a syn mode of elimination with
triflate as leaving group. It did not escape our notice that the
Received: September 9, 2014
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
Communication
potential exists in this reaction for an alternative mode of
fragmentation leading to alkynyl triflate 6 (pathway b). While it
was our expectation that elimination of triflate would take
precedence over anti elimination of the less electrofugal
sulfonamide nitrogen, it occurred to us that 6 could itself
undergo further reaction to afford the desired azacyclohexyne.
Specifically, cyclization of 6 and α-elimination could produce
the alkylidene carbene 7, which could rearrange to
azacyclohexyne as shown in Scheme 1. Note that the formation
of alkylidene carbenes of type 7 via a closely related reaction of
sulfonamide anions with alkynyliodonium salts has previously
been reported by Feldman,13 and the rearrangement of 7 to 1
finds precedent in the work of Wentrup depicted in eq 1.
Scheme 2 outlines the synthesis of azacyclohexyne precursor
5 beginning with the readily available lactam 8.14 Direct C-
With an expeditious route to 5 in hand, we turned our
attention to investigating the feasibility of employing this
compound as a precursor to N-tosyl-3-azacyclohexyne. 2,5-
Dimethylfuran was selected as a potential trap for the strained
alkyne, and experiments were carried out by exposing the silyl
triflate to the action of various fluoride reagents in the presence
of 2 equiv of the furan. Tetrabutylammonium fluoride served as
the fluoride source in our initial studies. Reaction of silyl triflate
5 (0.1 M in THF) with 2 equiv of Bu4NF in the presence of
dimethylfuran at 25 °C for 2 h led to the isolation in 60% yield
of a white solid with spectroscopic data consistent with that
expected for the product of Diels−Alder addition of the
azacyclohexyne to dimethylfuran. Identification of the cyclo-
adduct as 13 was established unequivocally by X-ray crystallo-
graphic analysis (Scheme 4).
Scheme 2. Synthesis of Azacyclohexyne Precursor 5
Scheme 4. Generation and Trapping of N-Tosyl-3-
azacyclohexyne
silylation of 8 to afford 10 could not be achieved in good yield,
so an alternative route was devised based on the sequence
shown in Scheme 3. α-Bromination of lactam 8 followed by O-
Further studies of this transformation revealed that 13 could
be obtained in improved yield using 2 equiv of either cesium
fluoride or KF/18-crown-6 as the fluoride source. Best results
were obtained in reactions employing dilute solutions of 5
(0.05 M) in acetonitrile; for example, with KF/18-crown-6 the
yield decreased from 80 to 68% when the concentration was
increased from 0.05 to 0.15 M. No reaction took place with KF
in the absence of 18-crown-6, and with CsF the yield was only
55% when 1.2 equiv rather than 2 equiv of the reagent was
employed for the reaction.
Scheme 3. Strategy for α-Silylation of Lactam 8
The generation of N-tosyl-3-azacyclohexyne in the presence
of various nucleophiles, electrophiles, and cycloaddition
partners was examined next. Table 1 summarizes our results.
[4 + 2] Cycloaddition of the strained heterocyclic alkyne with
2,3,4,5- tetraphenylcyclopentadienone (“tetracyclone”) pro-
ceeded smoothly with spontaneous loss of CO by cyclo-
reversion to afford the expected tetrahydroquinoline 14 in good
yield.
The results of dipolar cycloadditions of the azacyclohexyne
proved particularly interesting. Interception of 1 with benzyl
azide17 and with ethyl diazoacetate18 took place with high
regioselectivity to furnish a single cycloadduct in each case. Also
completely regioselective was the reaction of the azacyclohex-
yne with 1,1,-diethoxyethylene19 which gave 17 after brief
exposure of the initial [2 + 2] cycloadduct to aqueous HCl.
Nucleophiles typically combine with arynes2,20 and hetar-
ynes3 in good yield, and generation of the cyclic ynamide 1 in
the presence of thiophenol afforded a single addition product
silylation of the α-bromo enolate was expected to provide 11,
and bromine−lithium exchange would then produce the
vinyllithium intermediate 12 that was expected to undergo a
1,3 O to C silyl shift15 to furnish 10 after aqueous workup.
Alternatively, direct silylation of intermediate 12 at carbon
followed by hydrolysis could also afford the desired α-silyl
lactam.
In the event, monobromination of 8 could not be achieved
cleanly, but the dibromide 9 could be obtained reproducibly
and in good yield as a nicely crystalline solid after trituration.
Conversion to α-silyl lactam 10 was then accomplished by
addition of 1 equiv of BuLi to a solution of 9 and 2 equiv of
Me3SiCl in THF at −78 °C followed after 1 h by addition of a
second equivalent of BuLi.16 Deprotonation of 10 with 1 equiv
of KHMDS and reaction of the resulting enolate with triflic
anhydride then furnished the desired azacyclohexyne precursor
5 in good yield.
B
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Journal of the American Chemical Society
Communication
interaction/distortion model introduced by Houk.25 Computa-
tional studies are planned to provide a rigorous basis for
understanding the chemistry of this fascinating heterocyclic
alkyne.
Table 1. Generation and Reactions of N-Tosyl-3-
azacyclohexyne
In summary, the generation of N-tosyl-3-azacyclohexyne can
be effected under mild conditions, and this strained heterocyclic
alkyne engages in highly regioselective transformations with a
variety of reaction partners providing access to nitrogen
heterocyclic compounds that in many cases would not be
easily obtained by alternative routes.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, characterization data (including X-ray
crystallographic data for 13), and 1H and 13C NMR spectra for
all new compounds. This material is available free of charge via
the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
danheisr@mit.edu
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Science Foundation (CHE-1111567)
and Pfizer, Inc. for generous financial support. X-ray crystallo-
graphic measurements were carried out with instrumentation
purchased with the aid of NSF grant CHE-0946721. The X-ray
crystal structure of 13 was obtained with the assistance of Dr.
Michael K. Takase.
18 in excellent yield.21 A single product was also obtained when
the azacyclohexyne was generated in the presence of tributyltin
hydride.22 In contrast to the efficient transformations presented
in Table 1, several other reaction partners failed to afford
trapping products in good yield. Complex mixtures were
obtained when 1 was generated in the presence of 1,3-
cyclohexadiene, the enolate derivatives of several 1,3-dicarbonyl
compounds, 1-heptyne, and ethyl phenyl ketene.
Concerning the mechanism of the conversion of 5 to 1, our
observations to date are most consistent with the direct
elimination pathway a shown in Scheme 1. Attempts to
intercept an alkylidene carbene intermediate (7) by carrying
out the reaction in cyclohexene or ethyl vinyl ether as solvent
have not been successful, and no products have been detected
from insertion of such a carbene on the aromatic ring of the
tosyl group.23
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D
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