CuI-Mediated Bromoalkynylation and Hydroalkynylation Reactions of Unsymmetrical Benzynes: Complementary Modes of Addition

Article abstract of DOI:10.1002/anie.201811783

Benzynes formed by heating a suitable triyne (or tetrayne) substrate are shown to react with in situ generated alkynyl copper species. The latter are compatible with the polyyne substrates and two types of chemistries have been achieved: (i) 1-bromo-1-alkynes efficiently undergo net bromoalkynylation of the (unsymmetrical) benzynes and (ii) in situ generated alkynylcopper species give rise to hydroalkynylation products. The regiochemical preferences of these two modes of reaction are complementary to one another with respect to the position of alkynyl substituent in the final products.

Full text of DOI:10.1002/anie.201811783

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Accepted Article
Title: Cu(I)-Mediated Bromoalkynylation and Hydroalkynylation
Reactions of Unsymmetrical Benzynes: Complementary Modes
of Addition
Authors: Xiao Xiao, Tao Wang, Feng Xu, and Thomas R. Hoye
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10.1002/anie.201811783
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COMMUNICATION
Cu(I)-Mediated Bromoalkynylation and Hydroalkynylation
Reactions of Unsymmetrical Benzynes: Complementary Modes of
Addition
Xiao Xiao,[a] Tao Wang,[a] Feng Xu,[a] and Thomas R. Hoye*[a]
Abstract: Benzynes formed by heating a suitable triyne (or tetrayne)
substrate are shown to react with in situ-generated alkynyl copper
species. The latter are compatible with the polyyne substrates and
two types of chemistries have been achieved: (i) 1-bromo-1-alkynes
efficiently undergo net bromoalkynylation of the (unsymmetrical)
benzynes and (ii) in situ-generated alkynylcopper species give rise
to hydroalkynylation products. The regiochemical preferences of
these two modes of reaction are complementary to one another with
respect to the position of alkynyl substituent in the final products.
have found that bromoalkynylation occurs smoothly in the
presence of CuBr in MeCN solvent. For example (Figure 2a), the
tetrayne benzyne precursor 10, is trapped by 1-bromo-2-
phenylethyne (5a) in excellent yield when heated (80 °C) in the
presence of 10 mol% of CuBr (structural assignment discussed
below). Benzyne 11 is known to preferentially undergo
nucleophilic attack at C6, which is consistent with both the
easier steric access of the nucleophilic atom to C6 vs. C7 as
well as with the larger internal bond angle[7] at C6 computed for
(the
N-methanesulfonyl
analog
of)[8]
the
N-
toluenesulfonylbenzyne 11.
1,2-Haloalkynylation of arynes is a potentially valuable way to
install a considerable degree of complexity into the aryne family
of reactive intermediates. We are aware of only one report
describing such a transformation (Figure 1a). In 2010 Yoshida[1]
and coworkers showed that (symmetrical) benzynes generated
by the Kobayashi protocol[2] from 2-trimethylsilylaryl triflates (1)
could engage bromoalkynes in the presence substoichiometric
amounts of CuBr2. The major products 2 arose from the
(presumably sequential) introduction of two molecules[3] of
benzyne; these were sometimes accompanied by lesser
amounts of the 1:1 adducts 3, depending upon reaction
conditions. We report here that benzynes 7, generated by the
hexadehydro-Diels-Alder (HDDA) cycloisomerization reaction,[4]
efficiently undergo bromo- and hydro-alkynylation in the
presence of copper (I) catalysts (Figure 1b). A hallmark of the
HDDA reaction is that the reactive benzyne intermediates are
generated in the absence of any external reagent, rendering a
pristine
environment
for
the
trapping
event.
The
hydroalkynylation of benzynes has been studied more
extensively and, again, the (mostly symmetric) benzynes have
been generated by the Kobayashi protocol of fluoride treatment
of o-trimethylsilylaryl triflates.[5] Here, we not only show the
generality of this reaction under essentially neutral conditions,
but also provide mechanistic insights that can be inferred from
the products arising from the, necessarily, unsymmetrical HDDA-
benzynes. In addition, the regiochemical preferences for the
hydroalkynylation and the bromoalkynylation are complementary
to one another (cf. 8/8’ vs. 9/9’)—C–C bond formation occurs
preferentially at different carbon atoms of the benzynes 7.
Figure 1. [a] Previous reports by Yoshida et al. [b] This work.
The scope of the bromoalkynylation reaction is quite broad
(Figure 2a). Aliphatic and aromatic bromoalkynes with a variety
of functionalities are tolerated (cf. 12a–12k). We have also
examined several polyyne substrates that incorporate different
tethers; these led to the bromoalkynylation products 13–17. It is
noteworthy that we have never observed a product indicating
premature reaction of the HDDA polyyne precursor with any of
the active organometallic species involved in this chemistry.[9]
Moreover, we observed no desired product formation in the
absence of the copper catalyst.[10]
More generally,[6] metal-catalyzed functionalization of an
aryne is inherently challenging because the steady state
concentration of both the aryne and the active organometallic
must be sufficiently high to allow for their mutual capture. We
We envision the reaction proceeding through a mechanism
such as that depicted in Figure 2b. The initial thermal
cycloisomerization is the rate-determining step in the overall
cycle, because the reaction rate is similar for triyne 10
regardless of the trapping agent used.[11] We propose that
benzyne 11 initially undergoes nucleophilic addition with CuBr to
produce the aryl copper(I) species 18, which then reacts with a
molecule of the bromoalkyne to generate the Cu(III) adduct 19.
[a]
X. Xiao, T. Wang, F. Xu, T. R. Hoye*
Department of Chemistry
University of Minnesota
207 Pleasant St. SE
Minneapolis, Minnesota 55455 USA
E-mail: hoye@umn.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201811783
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arene ligands from the ArCuI2 species (analogous to 19)
became the dominate pathway (for more details, see Supporting
Information, page S19).[12] Purposely adding water into the
reaction mixture at the outset led to decreased overall yield of 12
with concomitant formation of the net hydrobromination adduct.
The structure of 12 was confirmed by its conversion to the
reductively debrominated derivative 20. The site of the aromatic
proton was definitively identified based on the indicated nOe and
HMBC analyses. This mode of regioselectivity supported the
above mechanistic view—namely, that the initial bromination by
CuBr had occurred at the more electrophilic site in benzyne 11.
We briefly explored several potential synthetic applications
of the bromoalkynylation products (Figure 3). One-pot halogen
exchange and global deprotections of, for example,
bromocarbazole 14 gave rise to alkynylcarbazole 21, whereas
heating compound 14 with sodium sulfide efficiently provided the
deprotected thienocarbazole 22.[13] Palladium-catalyzed cross-
couplings of the bromobenzene moiety were also tested.[14] For
example, Sonogashira and Suzuki reactions of the bromoalkyne
15 efficiently afforded the trialkynylbenzene 23 and the biaryl 24,
respectively.
Figure 3. Potential synthetic applications [see Supporting Information (SI) for
more experimental details].
Many alkyne cross-coupling reactions rely on the robustness
of copper acetylides.[15] We envisioned that when formed in situ,
these could serve as nucleophiles to arynes and that a net
hydroalkynylation process could ensue. This had the potential to
be complementary to the bromoalkynylation reaction with
respect to the point of attachment of the alkyne in the product
arene. However, an organic amine is often required to promote
Cu-acetylide formation, but (even tertiary) amines are excellent
nucleophilic trapping agents for benzynes.[16] Cu-acetylides can
be formed and trapped in situ by the action of a fluoride base
under conditions where arynes are being co-produced.[5] We
were pleased to see that in the absence of any added base,
Figure 2. [a] Scope of the bromoalkynylation reaction. [b] Proposed catalytic
cycle and basis for assignment of the constitution of 12a (cf. 20).
This view is consistent with the fact that trace amounts of chloro-
or iodo-alkynylation products were observed (GC-MS) when
CuCl or CuI was used as the catalyst instead of CuBr. Reductive
elimination of the alkyne and arene ligands produces product 12.
Two minor byproducts often detected were those corresponding
to net hydrobromination and/or dibromination of the benzyne.
These can be accounted for by hydrolytic capture of the ArCu
species 18 by adventitious water or competitive (and, fortunately, copper chloride alone (5 mol%), in acetonitrile solution, induces
less facile) reductive elimination of bromo and arene ligands
from 19. It is noteworthy that when iodoalkynes was used,
efficient diiodination rather than iodoalkynylation of the benzyne
was observed. Presumably, the reductive elimination of iodo and
the addition of terminal alkynes (e.g., 6a) to HDDA benzyne
intermediates (e.g., 11 from 10) to give net hydroalkynylation
products (e.g., 25a; see SI for the reaction optimization studies
leading to the choice of conditions shown in the top of Figure 4a).
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10.1002/anie.201811783
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(Figure 2b) and is consistent with the proposal that Cu-acetylide
addition is involved in this transformation. Namely, the distorted
nature of the HDDA-benzyne 11 (Figure 2a) is consistent with an
initial alkynyl-cupration of the benzyne.
Given the quite good isolated yield, mild reaction conditions,
and the easy experimental setup, we were encouraged to
explore the generality of this hydroalkynylation reaction.
Products of both aromatic (25a–25g) and aliphatic (25h–25k)
alkyne addition are readily formed. For aromatic alkynes, the
impact of electronic effects from substituents was minimal and
ortho-substitution (25g) was tolerated.[17] As with the
bromoalkynylation, we also tested the behavior of several
HDDA-benzyne precursors containing different tethers in the
hydroalkynylation. These gave products 26–30 in high overall
yield. The level of regioselectivity was uniformly lower for the
hydroalkynylation. The reaction leading to 29 was performed on
a relatively large scale and showed no erosion in efficiency (88%
yield). The flanking aryl substituent in the intermediate benzyne
substantially inhibits approach of the nucleophile to the proximal
sp-carbon, leading to a reversal in the location of the alkyne in
29 vs. 30 (cf., also, 16).
Figure 5. Proposed initiation event(s) and catalytic cycle for the
hydroalkynylation reaction.
Figure 4. [a] Scope of the hydroalkynylation reaction revealed by outcomes
with various alkynes and benzyne precursors. [b] Cu-catalyzed
hydroalkynylation occurs faster than other potential aryne trapping reactions;
in the absence of catalyst, aryl ether 31 is the major product.
Orthogonal chemoselectivity can be achieved simply by
performing the reaction in the presence or absence of the Cu
catalyst. For example (Figure 4b), the hydroxy group in alkynol
6n traps benzyne 11 (from 10) to give the ether 31 when no
CuCl is used.[18] In contrast, under the copper catalysis
conditions described here, the complementary alkyne 25l was
formed highly selectively, indicating that the copper acetylide
trapping event of benzynes is much faster than that by OH. In
neither reaction was any of the product of the alternative
constitution observed by NMR analysis of the crude product
mixture. Additional selectivity was seen when natural product
derivatives were used as trapping agents.[19] Namely, the
hydroalkynylation products 25m and 25n were efficiently
Notably, only a slight excess (1.1 equiv) of alkyne needs to be
used because its oxidative dimerization can be mitigated either
by careful deoxygenation of the reaction solution or, more
conveniently, using sodium ascorbate, even under an ambient
atmosphere, to prevent formation of Cu(II) species. Presumably
these conditions allow for the Cu-acetylide to be relatively long-
lived; the use of just 5 mol% of copper loading gave high enough
steady-state concentration to effectively trap the reactive
benzyne. The structure of 25a is the complement to that of 20
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Lee, Org. Lett. 2013, 15, 1938; f) O. J. Diamond, T. B. Marder, Org.
Chem. Front. 2017, 4, 891.
produced in the presence of CuCl when terminal alkynes derived
from estradiol and cinchonidine (see SI for details) were used as
the trapping agents. This is especially notable because these
molecules contain additional potentially competing reactive
moieties that include phenol,[8] alcohol,[18] tertiary amine,[19]
[5]
a) C. S. Xie, L. F. Liu, Y. H. Zhang, P. X. Xu, Org. Lett. 2008, 10, 2393;
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ether,[20] alkene,[21] cyclic alkane,[22] and quinoline sites[23] [24]
.
A mechanistic proposal for the hydroalkynylation reaction is
shown in Figure 5. At the top are possible ways by which an
initial copy of the requisite Cu-acetylide (34) could be formed.
Sacrificial reaction of one benzyne with CuCl would give the
arylcopper species 32, which could then engage in proton
exchange with the terminal alkyne 6.; indeed, we have detected
low levels of the benzyne + HCl adduct 33 by GCMS analysis of
a crude reaction mixture. Alternatively, acetonitrile could function
as a base to deprotonate a CuCl•6 complex, leading to the HCl
adduct 35[25] or its iminium hydrochloride salt 35•HCl.[26] Indeed,
we have observed that the choice of acetonitrile as solvent is
critical for success of the hydroalkynylation reaction. Once
produced, 34 could then enter the cycle highlighted by the gray
box. Alkynyl-cupration of benzyne 11 would give 36 and proton
exchange with 6 would lead to 25 and close the cycle.
[6]
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exchange (direct or indirect, the latter through the catalytic cycle)
between a preformed Cu-acetylide (from 6a) and a second, terminal
alkyne (6b) was occurring.
In conclusion, we have developed an efficient copper-
catalyzed protocol for installation of an alkynyl substituent onto a
HDDA-generated benzyne. 1-Bromoalkynes lead to products of
bromoalkynylation in which the bromide has preferentially
engaged the more electrophilic carbon of the (necessarily)
unsymmetrical benzyne (Figure 2a). The hydroalkynylation
reaction of terminal alkynes occurs in complementary fashion;
namely, the alkyne carbon is now attached to the more
electrophilic carbon (Figure 4). Catalytic cycles for each of these
two reaction processes are proposed (Figures 2b and 5). The
potential utility of the ortho-alkynylbromobenzene products as
substrates in further transformations of interest is also
demonstrated (Figure 3).
Acknowledgements
[18] P. H. Willoughby, D. W. Niu, T. Wang, M. K. Haj, C. J. Cramer, T. R.
Hoye, J. Am. Chem. Soc. 2014, 136, 13657.
This study was supported by the U.S. Dept. of Health and
Human Services [National Institute of General Medical Sciences
(R01 GM65597 then R35 GM127097)] and the National Science
Foundation (CHE-1665389). A portion of the NMR data were
obtained with an instrument funded by the NIH Shared
Instrumentation Grant program (S10OD011952).
[19] S. P. Ross, T. R. Hoye, Nat. Chem. 2017, 9, 523.
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[23] A. Bhunia, T. Roy, P. Pachfule, P. R. Rajamohanan, A. T. Biju, Angew.
Chem. Int. Ed. 2013, 52, 10040.
Keywords: metal-catalyzed aryne trapping • copper catalysis •
alkynylations
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COMMUNICATION
Xiao Xiao, Tao Wang, Feng Xu, Thomas R. Hoye*
Page No. – Page No.
Cu(I)-Mediated Bromoalkynylation and
Hydroalkynylation Reactions of Unsymmetrical
Benzynes: Complementary Modes of Addition
Cu-catalyzed bromo- and hydro-alkynylations of unsymmetrical arynes was described. These two mechanistically distinct modes of
reaction are efficient, broad in scope, and giving complementary alkynylation products. Mechanisms are proposed and potential for
synthetic elaboration is demonstrated.
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