Catalytic anti-Markovnikov hydrobromination of alkynes

Article abstract of DOI:10.1021/ja503944n

We have developed the first catalytic method for anti-Markovnikov hydrobromination of alkynes. The reaction affords terminal E-alkenyl bromides in high yield and with excellent regio- and diastereoselectivity. Both aryl- and alkyl-substituted terminal alkynes can be used as substrates. Furthermore, the reaction conditions are compatible with a wide range of functional groups, including esters, nitriles, epoxides, aryl boronic esters, terminal alkenes, silyl ethers, aryl halides, and alkyl halides. A preliminary study of the reaction mechanism suggests that the hydrobromination reaction involves hydrocupration of an alkyne, followed by the bromination of the alkenyl copper intermediate. This study also suggests that 2-tert-butyl potassium phenoxide functions as a mild catalyst turnover reagent and provides a better understanding of the unique effectiveness of (BrCl₂C)₂ among brominating reagents.

Full text of DOI:10.1021/ja503944n

Article
pubs.acs.org/JACS
Catalytic Anti-Markovnikov Hydrobromination of Alkynes
Mycah R. Uehling,† Richard P. Rucker,† and Gojko Lalic*
Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
S
* Supporting Information
ABSTRACT: We have developed the first catalytic method
for anti-Markovnikov hydrobromination of alkynes. The
reaction affords terminal E-alkenyl bromides in high yield
and with excellent regio- and diastereoselectivity. Both aryl-
and alkyl-substituted terminal alkynes can be used as
substrates. Furthermore, the reaction conditions are compat-
ible with a wide range of functional groups, including esters, nitriles, epoxides, aryl boronic esters, terminal alkenes, silyl ethers,
aryl halides, and alkyl halides. A preliminary study of the reaction mechanism suggests that the hydrobromination reaction
involves hydrocupration of an alkyne, followed by the bromination of the alkenyl copper intermediate. This study also suggests
that 2-tert-butyl potassium phenoxide functions as a mild catalyst turnover reagent and provides a better understanding of the
unique effectiveness of (BrCl2C)2 among brominating reagents.
Unfortunately, the high reactivity of aluminum and
zirconium reagents limits the functional group compatibility
and the scope of these methods.12 In addition, zirconocene
hydrochloride is expensive and sensitive to light and
moisture,12,13 which has prompted the development of
numerous methods for its in situ preparation.14 Hydro-
stannylation offers excellent functional group compatibility
and is often used in the hydrobromination of complex
substrates;15 however, toxic byproducts are also formed. The
method based on hydroboration7 is rarely used, as it requires
multiple steps and is often low yielding.16 Finally, all of these
methods require stoichiometric hydrometalation of the substrate
prior to the halogenation step.
INTRODUCTION
■
Alkenyl halides are important intermediates in organic
synthesis. They are used as coupling partners in transition
metal catalyzed cross-coupling reactions1 and as precursors to a
wide range of organometallic reagents, including organozinc,
organolithium, and Grignard reagents.2 Despite the prominent
role of alkenyl halides in organic chemistry, the methods for
their synthesis have remained mostly unchanged over the last
40 years. Although various synthetic precursors have been used
in synthesis of alkenyl halides,3,4 one of the most common
methods is still the anti-Markovnikov hydrohalogenation of
alkynes. This transformation involves hydrometalation of an
alkyne using zirconium,5 tin,6 boron,7 or aluminum hydrides,8,9
followed by electrophilic halogenation of the stoichiometric
alkenyl metal intermediate (see Figure 1). In general, the
In this article we report the first catalytic anti-Markovnikov
hydrohalogenation of alkynes (Figure 1). We describe the
development of the reaction, the exploration of the reaction
scope, and the study of the reaction mechanism.
RESULTS AND DISCUSSION
■
Approach and Reaction Development. One of the
major difficulties in developing a catalytic version of the
hydrohalogenation reaction is the efficient formation of an
appropriate metal hydride reagent under catalytic conditions,
where hydrometalation is just one of the steps in the catalytic
cycle. Recently, we demonstrated an effective hydrometalation
under catalytic conditions in the context of the catalytic
semireduction of alkynes (eq 1).17 We showed that the
semireduction can be accomplished by hydrocupration,
followed by protonation of the alkenyl copper intermediate.
In this transformation, the key catalytic intermediate respon-
sible for the hydrometalation of alkyne is a copper hydride
complex formed by transmetalation of a copper alkoxide with a
silane.
Figure 1. Anti-Markovnikov Hydrohalogenation of Alkynes.
hydrometalations are highly syn selective,10 ensuring the
formation of the (E)-alkenyl metal intermediate. In addition,
anti-Markovnikov selectivity is commonly observed, although
high Markovnikov selectivity11,9 has been observed in transition
metal catalyzed hydrometalation reactions. Overall, the hydro-
metalation−halogenation sequence is effective in providing
terminal E-alkenyl halides with high regio- and diastereose-
lectivity.
Received: April 20, 2014
© XXXX American Chemical Society
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promoting the reaction. Even closely related NHC (N-
heterocyclic carbene) copper complexes were completely
ineffective as catalysts. Other silanes provided significantly
lower yields of the desired product.
Reactions performed in dichloromethane and chlorobenzene
provided significant amounts of the desired products, while the
results obtained in THF are representative of the results
obtained in a number of other organic solvents.
Phenoxide 1 provided significantly better results than several
other closely related phenoxides, or potassium tert-butoxide,
which is commonly used as a turnover reagent in reactions
mediated by copper hydride complexes. Other common
brominating reagents, such as 1,2-dibromoethane or NBS,
were completely ineffective in the reaction. The underlying
causes for some of the findings shown in Table 1 will be
discussed in the context of the reaction mechanism at the end
of this section.
Hydrobromination of Alkyl-Substituted Alkynes. The
reaction conditions described in Table 1 proved to be effective
in the hydrobromination of a number of alkyl-substituted
alkynes (see Table 2). The reaction was compatible with several
Our strategy for the development of the catalytic hydro-
bromination (eq 2) is based on the approach we used in the
semireduction of alkynes. However, the development of the
hydrobromination reaction presents two new challenges. In the
semireduction, the protonation of the alkenyl copper
intermediate by an alcohol (see eq 1) leads directly to the
catalyst turnover, as the resulting copper alkoxide can
subsequently form the copper hydride intermediate by
transmetalation with a silane. In the hydrobromination reaction,
a new approach to catalyst turnover is needed. The second
challenge is to identify the brominating reagent compatible with
our approach.
Despite these challenges, we have developed an efficient
method for catalytic hydrobromination of alkynes shown in
Table 1. The best results are obtained using (BrCl2C)2 as a
Table 2. Catalytic Hydrobromination of Alkyl-Substituted
Alkynes
Table 1. Development of Catalytic Hydrobromination of
Alkynes
a
Alkyne (1.0 equiv, 0.5 mmol), Ph2SiH2 (1.5 equiv), (BrCl2C)2 (1.3
brominating reagent, with IPrCuCl as a catalyst and Ph2SiH2 as
a hydride source. Phenoxide 1 is a necessary additive
responsible for the catalyst turnover.18 The reaction is
performed at room temperature and is completed within an
hour. Furthermore, (BrCl2C)2, while not often used as a
brominating reagent, is a cheap, readily available, and stable
crystalline solid.
We made several observations, summarized in Table 1,
during the process of reaction optimization. We found that
IPrCuCl catalyst was necessary and uniquely effective in
equiv), and 1 (1.6 equiv). (BrCl2C)2 added over 1 h.
functional groups that are often reduced using other methods
for alkyne hydrobromination, such as esters, nitriles, epoxides,
and alkyl halides. The hydrobromination can also be
accomplished in the presence of alkenes, aryl halides, aryl
ethers, and silyl ethers. Heterocycles, such as indole, are also
compatible with the reaction. Finally, alkynes with branched
alkyl substituents are also tolerated (14). In all cases, we
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observed only the formation of a single regio- and
diastereoisomer of the alkenyl bromide.
Scheme 1. Proposed Catalytic Cycle
To demonstrate the utility of the new procedure, we
performed the hydrobromination reaction on a preparative
scale. Under the standard reaction conditions described in
Table 2, we were able to prepare 1 g of alkenyl bromide 16 in
excellent yield (eq 3).
Hydrobromination of Aryl-Substituted Alkynes. We
also explored the reactivity of aryl-substituted alkynes, and we
found that styrenyl bromides with both electron-donating and
electron-withdrawing substituents could be successfully pre-
pared (see Table 3). Additionally, we were surprised to find
product and copper bromide 29. Catalyst turnover (step 4) is
accomplished by ligand substitution in the presence of
phenoxide 1. Considering that the hydrocupration of alkynes
(step 3) has been well-documented in the literature,21 our focus
in the process of the reaction development was on the other
three steps of the proposed catalytic cycle.
One of the challenges in developing the catalytic hydro-
bromination reaction is achieving the turnover of the catalyst
(Scheme 1, step 4). We were intrigued by our initial finding
that alkoxide-based turnover reagents commonly used in
catalytic reactions of copper hydrides, such as potassium tert-
butoxide, performed poorly in the catalytic hydrobromination
(Table 1, entry 11). To provide an explanation for this
observation, we did a more detailed analysis of the hydro-
bromination reaction performed with potassium tert-butoxide
as an additive. We found that alkynyl bromide was the major
byproduct formed in this reaction.
Table 3. Catalytic Hydrobromination of Aryl-Substituted
Alkynes
Stoichiometric experiments shown in eq 4 (Scheme 2)
demonstrate that alkynyl bromide 30 can be formed from the
Scheme 2
a
Alkyne (1.0 equiv, 0.5 mmol), Ph2SiH2 (1.5 equiv), (BrCl2C)2 (1.3
b
equiv), and 1 (1.6 equiv). (BrCl2C)2 added over 0.5 h. 1-Phenyl-1-
propyne used as starting material. Reaction performed at 45 °C over 1
h.
that aryl boronic esters are compatible with the hydro-
bromination reaction, as these compounds are known to
participate in several copper-catalyzed transformations under
closely related conditions.19 As demonstrated by the synthesis
of 22 and 23, meta substitution is well tolerated, while the ortho
substitution leads to a lower yield of the desired product. The
synthesis of 24 suggests that some heteroaryl acetylenes can
also be used as substrates.20 Finally, the synthesis of 25
demonstrates that regioselective hydrobromination of disub-
stituted aryl acetylenes can also be accomplished. In all
reactions presented in Table 3, the formation of only one
regio- and diastereoisomer of the product was observed.
Mechanism. We propose that the reaction proceeds
according to the mechanism shown in Scheme 1. The proposed
catalytic cycle involves transmetalation of copper phenoxide 26
with the silane to form copper hydride 27 (step 1), which, after
hydrocupration of the alkyne (step 2), provides alkenyl copper
intermediate 28. Subsequent electrophilic bromination of the
alkenyl copper intermediate (step 3) provides the desired
alkyne in the presence of either copper or potassium tert-
butoxide. In contrast, we found that neither copper phenoxide
nor potassium phenoxide promotes the formation of the
alkynyl bromide (eq 5). These results suggest that the low
basicity of the turnover reagent is essential for the success of
the catalytic hydrobromination, and they explain the effective-
ness of the phenoxide additives.
While the transmetalation of copper alkoxides with silanes is
well-precedented in the literature,21 the transmetalation
involving copper phenoxide and a silane has not been
previously described (step 1). To explore the feasibility of
this transmetalation, we prepared 26 from IPrCuCl and
potassium phenoxide 1 (eq 6; Scheme 3). In a reaction with
Ph2SiH2, IPrCuH was formed within minutes at room
temperature (eq 7). Significantly slower transmetalation was
observed with other silanes, such as PMHS and (EtO)3SiH,
while no transmetalation was observed with less reactive
C
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syn selective. As a result, terminal E-alkenyl bromides are
obtained with excellent regio- and diastereoselectivity. A
preliminary study of the reaction mechanism provides support
for the proposed mechanism involving hydrocupration of an
alkyne followed by the electrophilic bromination of the alkenyl
copper intermediate. This study also provides insight into the
key properties of the brominating and turnover reagents used in
the hydrobromination reaction. Finally, the discovery of
phenoxides as mild turnover reagents is likely to enable the
development of new catalytic reactions with copper hydrides as
key catalytic intermediates.
Scheme 3. Catalyst Turnover and Transmetalation
Et3SiH. The results of experiments shown in eqs 6 and 7 clearly
demonstrated the feasibility of the proposed transmetalation
(step 1) and the proposed catalyst turnover (step 4) steps.
In an effort to identify a brominating reagent suitable for the
hydrobromination reaction, and at the same time learn more
about the electrophilic bromination of the alkenyl copper
intermediate (step 3), we prepared complex 31 and explored its
reactivity with a range of brominating reagents (Scheme 4). In a
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
lalic@chem.washington.edu
■
Scheme 4. Electrophilic Bromination
Author Contributions
†M.R.U. and R.P.R. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Professor Forrest Michael is gratefully acknowledged for helpful
discussions and suggestions. We thank the University of
Washington and the NSF (CAREER award #1254636) for
funding.
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■
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including esters, nitriles, epoxides, aryl boronic esters, alkyl
halides, and aryl halides. The key step in the reaction is a
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