Heck Reaction of Electronically Diverse Tertiary Alkyl Halides

Article abstract of DOI:10.1021/acs.orglett.7b03591

The efficient Pd-catalyzed Heck reaction of diverse tertiary alkyl halides with alkenes has been developed. Unactivated tertiary alkyl halides efficiently react at room temperature under visible light irradiation with no exogenous photosensitizers required. For activated tertiary alkyl halides, the same catalytic system works well without light. These methods offer a general access to electronically diverse alkenes possessing quaternary and functionalized tertiary allylic carbon centers. The substituents at these centers include alkyl-, carbalkoxy-, tosyl-, phosphonyl-, and boronate groups. It was also shown that the end-game mechanism of this transformation may vary depending on the type of the substrates used.

Full text of DOI:10.1021/acs.orglett.7b03591

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Heck Reaction of Electronically Diverse Tertiary Alkyl Halides
Daria Kurandina, Monica Rivas, Maxim Radzhabov, and Vladimir Gevorgyan*
́
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, United States
S
* Supporting Information
ABSTRACT: The efficient Pd-catalyzed Heck reaction of diverse tertiary alkyl halides
with alkenes has been developed. Unactivated tertiary alkyl halides efficiently react at
room temperature under visible light irradiation with no exogenous photosensitizers
required. For activated tertiary alkyl halides, the same catalytic system works well
without light. These methods offer a general access to electronically diverse alkenes
possessing quaternary and functionalized tertiary allylic carbon centers. The substituents
at these centers include alkyl-, carbalkoxy-, tosyl-, phosphonyl-, and boronate groups. It
was also shown that the end-game mechanism of this transformation may vary
depending on the type of the substrates used.
he Mizoroki−Heck reaction1 is a fundamental trans-
Scheme 1. Heck Reaction of Tertiary Alkyl Halides
Tformation in organic chemistry that is traditionally used
for coupling of aryl and vinyl halides/pseudohalides with
alkenes.2 Originally, employment of alkyl halides in this reaction
was not straightforward due to premature β-hydrogen
elimination3 and slow oxidative addition rates.4 Although there
were numerous reports on the Heck reaction of activated5 and
perfluorinated6 alkyl halides, employment of unactivated alkyl
halides became possible only after seminal works by Fu7 and
Alexanian.8 Due to the above-mentioned reasons, employment
of tertiary alkyl halides in Heck reactions is even more
problematic. For activated tertiary alkyl halides, the solution
was found by Lei,9 Thomas,10 and Nishikata11 employing Ni-,
Fe-, and Cu catalysts, respectively (Scheme 1a). Still, these
methods either require high temperatures or are limited in scope.
All these transformations were proposed to occur via generation
of alkyl radical species stabilized by adjacent electron-with-
drawing groups. This may be a reason for the underutilization of
unactivated tertiary alkyl halides in Heck-type reactions for a long
time. In 2002, Oshima reported the Co-catalyzed Heck-type
coupling of 1°, 2°, and 3° alkyl halides with styrenes promoted by
Me3SiCH2MgCl (Scheme 1b). Obviously, the requisite Grignard
reagent limits the scope of this method.12 Recently, Hashmi
reported a single example of coupling between tert-butyl bromide
and 1,1-diphenyl ethene under light-induced, Au-catalyzed
Heck-type reaction (Scheme 1c).13a A single report by deMeijere
disclosed a moderately efficient Pd-catalyzed Heck reaction of
room temperature, visible light-induced,17 exogenous photosensitizer-
free18 Pd-catalyzed Heck reaction of a wide range of tertiary alkyl
halides with alkenes to produce electronically neutral,19
electrophilic, and nucleophilic allylic systems possessing
quaternary and functionalized tertiary carbon center (Scheme
1f).
unactivated tertiary halides (Scheme 1d).14 However, it is limited
to employment of adamantyl bromide, a substrate not disposed
to β-hydrogen elimination.
Evidently, the development of a method that would feature
mild reaction conditions and broad substrate scope, including
both activated and unactivated tertiary alkyl halides, is highly
warranted. Very recently, our group introduced the first visible
light-induced15 Pd-catalyzed Heck reaction, which allows
activated and unactivated primary and secondary alkyl electro-
philes to react with vinylarenes in a highly efficient and
stereoselective manner (Scheme 1e).16 Herein, we report general
Aiming at the elaboration of the Heck reaction with
unactivated tertiary alkyl halides, we commenced our studies
Received: November 19, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03591
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
with tert-butyl iodide 1a. First, the reaction of 1a with styrene 2a
was tested under the reported palladium-based thermal
conditions;8b,20 however, only decomposition of the starting
materials was observed (Table 1, entries 1 and 2). Switching to our
efficiency for 1h (entry 13). Remarkably, the control experiments
for both activated substrates (1d and 1h) indicated that these
reactions proceed efficiently without light to produce 3da and
3ha at room temperature and at 40 °C, respectively (entries 12
and 16).
With the optimized conditions in hand, the generality of
visible-light-induced reaction of unactivated tertiary alkyl halides
was investigated first (Scheme 2). Reaction of tert-butyl iodide 1a
a
Table 1. Optimization
Scheme 2. Scope of Unactivated Tertiary Alkyl Iodides
a
Conditions I: 1a 1.0 mmol, 2 0.5 mmol, Pd(OAc)2 0.05 mmol,
Xantphos 0.1 mmol, Cs2CO3 1 mmol, PhH 0.5 M, 34 W blue LED, rt,
b
12 h. Pd(OAc)2 (2 mol %) and Xantphos (4 mol %) was added to
the reaction mixture after 12 h, and the reaction was stirred for an
c
d
additional 6 h. Yield for a 1 mmol scale reaction. 1 (0.25 mmol) and
2 (0.5 mmol) were used.
with both electron-rich and electron-deficient para-substituted
styrenes21 proceeded very efficiently, leading to alkene products
in excellent yields (3aa−af). Reactions with meta-and ortho-
substituted styrenes proceeded uneventfully, as well (3ag−aj).
Importantly, sensitive functional groups such as primary alcohol
(3ah) and aldehyde (3ai) were tolerated under these reaction
conditions. Moreover, vinyl heteroarenes were found to be
competent substrates in this reaction to produce heterocyclic
derivatives 3ak−am in good to excellent yields. Other
unactivated tertiary iodides reacted well with styrene and
acrylonitrile to produce alkenes possessing quaternary allylic
carbon centers (3ba, 3ca, 3cn).
a
Conditions: 1a 0.1 mmol scale, catalyst (10 mol %), ligand (20 mol
b
%), base (2 equiv), benzene (0.5 M), 34 W blue LED. GC−MS yield.
Next, the scope of activated tertiary alkyl halides under the
newly developed thermal Heck reaction conditions was
examined (Scheme 3). It was found that a variety of electron-
deficient alkyl halides underwent smooth Heck reaction to
produce electrophilic alkenes, possessing carbethoxydimethyl-
(3da), phosphonyldimethyl- (3ea), tosyldimethyl- (3fa), and
dicarbethoxymethyl- (3gb−gp) moieties in good to nearly
quantitative yields. Motivated by the great synthetic usefulness of
allylboronates,22,23 we attempted approaching this important
motif via Heck reaction of pinacolboronyldimethyl methyl iodide
(1h). Gratifyingly, it was found that a wide range of electronically
different styrenes, as well as vinyl heteroarenes, underwent a
smooth reaction with 1h, resulting in useful22 tertiary allylic
boronates (3ha−hl) in excellent yields.
previously found conditions for visible-light-induced Heck reaction of
primary and secondary alkyl halides16 led to formation of 3aa in
87% yield (entry 3)! Other catalyst/ligand combinations, such as
Pd(PPh3)4, and Pd(OAc)2 with DPEphos, t-Bu-Xantphos, L,18b,c
or DPPE were much less efficient (entries 4−7). Control
experiments indicated that both light and the Pd catalyst are
essential for this transformation (entries 8 and 9). Naturally, we
were eager to verify if this method could also be used for
reactions of activated tertiary alkyl halides. It was found that
activated tertiary alkyl halides of different electronic nature, such
as 1d and 1h, were incompatible with the standard thermal
palladium-based conditions, reported for alkyl Heck reaction8b
(entries 10 and 13). However, under the developed blue light
conditions, satisfactory yields of the corresponding products
were obtained (entries 11 and 14). Further optimization under
blue light led to significant improvement of the reaction
Upon investigating the scope of this transformation, it was
found that the reaction of tertiary alkyl bromide 1g with phenyl
vinyl ether (2s) did not produce the expected Heck product.
However, in the presence of O-nucleophiles, the carboxyalkox-
B
DOI: 10.1021/acs.orglett.7b03591
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a,b
generated Pd(0) species undergoes visible-light excitation to
produce the active Pd(0) complex A. Next, it undergoes an SET
with alkyl halide 1 to produce the putative alkyl Pd−hybrid
radical species B.25 Addition of the latter to alkene 2 produces a
new alkyl radical intermediate C. A subsequent β-H-elimination
delivers Heck product 3 and closes the catalytic cycle (D → A).
Alternatively, in the reaction with electron-rich aryl vinyl ether
(2s, Scheme 4), the Pd(I) species oxidizes intermediate C26 into
the stabilized cation E, which is then trapped by a nucleophile to
give the double-addition product, acetal 4.
Scheme 3. Scope of Activated Tertiary Alkyl Halides
In conclusion, we developed the first general, efficient, and
mild Heck reaction of tertiary alkyl halides. This visible light-
induced Pd-catalyzed method, which works well with unactivated
tertiary alkyl halides, operates at room temperature and does not
require employment of exogenous photosensitizers. For
activated tertiary alkyl halides, the same catalytic system does
not require light for a successful Heck coupling. Employment of
an array of alkyl halides allows synthesis of valuable electronically
diverse allylic products, including neutral alkenes possessing
quaternary carbon centers, electron-deficient alkenes having
carbalkoxy- and tosyl groups, as well as nucleophilic
allylboronates. Importantly, for the reactions of electronically
different alkenes, a mechanistic dichotomy was discovered. Thus,
in contrast to the reactions with electron-neutral and electron-
deficient alkenes, operating via hybrid Pd-radical mechanism, the
reactions with electron-rich alkenes proceed through a hybrid
radical/cationic pathway leading to mixed acetals, the products of
the double-addition process.
a
Conditions II: 1 (0.25 mmol), 2 (5 mmol), Pd(OAc)2 (0.025 mmol),
Xantphos (0.05 mmol), Cs2CO3 (0.5 mmol), PhH (0.5 mL), rt, 12 h.
b
Conditions III: 1a (0.375 mmol), 2 (0.25 mmol), Xantphos Pd G3
c
(0.025 mmol), iPr2NEt (0.5 mmol), PhH (0.5 mL), 40 °C, 12 h. 1
(0.25 mmol) and 2 (0.5 mmol) were used. 5 mol % of Xantphos Pd
G3 was used. Alkyl bromide was used. Reaction required 45 °C and
24 h for completion. Yield for a 1 mmol scale reaction.
d
e
f
g
ylation and alkoxyalkylation adducts, mixed acetals 4a and 4b,
were selectively obtained (Scheme 4). It is apparent that in
Scheme 4. Carboxyloxy- and Alkoxyalkylation of Aryl Vinyl
Ether
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03591.
Experimental details, characterization data for the
products, and NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: vlad@uic.edu.
ORCID
contrast to the previously reported reactions involving aryl-
16,18,19
(18b) and alkyl Pd-radical hybrid species,
this trans-
formation proceeds through cationic intermediates (vide infra).
On the basis of the observations above (Scheme 4) and our
initial mechanistic studies, including radical clock experiments,
radical trapping, and Stern−Volmer quenching experiments,24 as
well as literature precedents for Heck reactions of alkyl
halides,8,16,19 the following hybrid-Pd radical mechanism is
proposed for this transformation (Scheme 5). First, the in situ
Vladimir Gevorgyan: 0000-0002-7836-7596
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Institutes of Health (GM120281) for
financial support of this work. We also thank Ms. Yana McAuliff
(University of Illinois at Chicago) for technical help, Dr. Yang
Wang (Northwestern University) for initial experiments, and Dr.
Marvin Parasram (Princeton University) for helpful discussions.
Scheme 5. Proposed Reaction Mechanism
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