Sequential Difunctionalization of 2-Iodobiphenyls by Exploiting the Reactivities of a Palladacycle and an Acyclic Arylpalladium Species

Article abstract of DOI:10.1021/acs.orglett.6b00753

A novel sequential difunctionalization reaction of 2-iodobiphenyl has been developed by exploiting the distinct reactivities of a palladacycle and an acyclic arylpalladium species. In this tandem reaction, an in situ formed dibenzopalladacyclopentadiene reacts selectively with an alkyl halide, after which the thus formed acyclic arylpalladium species selectively undergoes a Heck reaction with an alkene. This work demonstrates the strong relationship between the coordination mode of a transition metal complex and its reactivity, which could shed light on the mechanisms of other transition-metal-catalyzed reactions and offer the opportunity to develop other synthetically enabling organic transformations.

Full text of DOI:10.1021/acs.orglett.6b00753

Letter
pubs.acs.org/OrgLett
Sequential Difunctionalization of 2‑Iodobiphenyls by Exploiting the
Reactivities of a Palladacycle and an Acyclic Arylpalladium Species
Dushen Chen, Guangfa Shi, Hang Jiang, Yu Zhang, and Yanghui Zhang*
Department of Chemistry, and Shanghai Key Lab of Chemical Assessment and Sustainability, Tongji University, 1239 Siping Road,
Shanghai, 200092, P. R. China
S
* Supporting Information
ABSTRACT: A novel sequential difunctionalization reaction of
2-iodobiphenyl has been developed by exploiting the distinct
reactivities of a palladacycle and an acyclic arylpalladium species.
In this tandem reaction, an in situ formed dibenzopalladacyclo-
pentadiene reacts selectively with an alkyl halide, after which the
thus formed acyclic arylpalladium species selectively undergoes a
Heck reaction with an alkene. This work demonstrates the
strong relationship between the coordination mode of a
transition metal complex and its reactivity, which could shed
light on the mechanisms of other transition-metal-catalyzed reactions and offer the opportunity to develop other synthetically
enabling organic transformations.
Herein, we report our success in the sequential alkylation/
ransition metal catalysts are particularly versatile in
Torganic synthesis and allow for a wide range of organic alkenylation of dibenzopalladacyclopentadienes by exploiting
reactions to be developed.1 A pervasive theme in catalysis
the divergent reactivity of palladacycle and acyclic arylpalladium
intermediates with alkyl halides and alkenes. The dibenzopalla-
dacyclopentadienes were obtained from 2-iodobiphenyls via
C−H activation.7,8 This reaction conceptually represents how
new reactions can be developed through a detailed under-
standing of the relationship between a metal’s coordination
mode and its reactivity. The selectivity with which the
palladacycle reacts with alkyl halides suggests that metallacycles
could provide a generally useful mode of reactivity for
developing alkylation reactions with alkyl halides.
We commenced our study by investigating the reaction of 2-
iodobiphenyl with n-butyl chloride and styrene. After an
extensive survey of reaction conditions, the desired difunction-
alized biphenyl product was obtained in 10% yield in the
presence of Pd(OAc)2 and KOAc in DMF (Table 1, entry 1).
The yield increased to a lesser extent when 2 equiv K2CO3 and
5 equiv n-BuCl were added (entries 2 and 3). At this stage, we
envisioned that the catalytic cycle would start with the oxidative
addition of 1a to a Pd(0) species. If it was the case, we reasoned
that the addition of a reductant would improve the yield by
accelerating the reduction of Pd(II) to Pd(0). Notably, the
yield increased dramatically to 50% when 2 equiv methanol was
added (entry 4), and was further improved to 60% by using i-
PrOH as the reductant (entry 5). Gratifyingly, a yield of 82%
was observed in the presence of 5 equiv K2CO3 (entry 6). The
reaction gave lower yield or no product formation in other
solvents (entries 7−9). The product was not observed when
the reaction was carried out under an air atmosphere (entry
research is that the coordination environment and the redox
state of the metal have a dramatic impact on reactivity.2 Hence,
it is important to study the relationship between the
coordination mode of organometallic intermediates and their
reactivity in elementary steps along the reaction coordinate, so
as to better understand the overall underlying mechanism and
to develop new reactions.
Metallacycles are important organometallic compounds and
are often intermediates in transition-metal catalysis. They have
been extensively studied over the years and have found diverse
applications in organic synthesis.3 Because of their unique cyclic
structure, metallacycles may exhibit reactivity patterns that are
different from those of common acyclic organometallic
complexes. In this context, dibenzometallacyclopentadienes
are particularly intriguing to our research group,4 because they
contain two aryl-metal bonds. There exists an opportunity to
difunctionalize these species, providing biphenyls with newly
installed functional groups at the 2- and 2′-positions. Therefore,
we sought to dibenzometallacyclopentadienes as a model to
probe the relationship between the coordination mode of
palladium and the resultant reactivity with different coupling
partners.
The reactions of transition-metal complexes with organic
halides and alkenes represent two of the most fundamental
classes of elementary reactions in catalysis.5 More significantly,
these two types of reactions proceed via distinct pathways.6
Therefore, we envisioned that organic halides and alkenes could
possess differentiated reactivities toward metallacycles and
acyclic organometallic species, and that this reactivity pattern
could be exploited in a productive catalytic cycle.
Received: March 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00753
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Organic Letters
Letter
high yields (4aab and 4aac). Both chloro and fluoro groups,
either at para or meta position, were well-tolerated (4aad−
4aag). Styrenes containing other common functional groups,
including phenyl, acetoxy, methoxy, and ester groups, were also
reactive, affording the difunctionalized products in moderate to
excellent yields (4aah−4aak). The reaction with 2-vinyl-
naphthalene was also high-yielding (4aal). Notably, the
protocol was compatible with heteroaryl olefins, including 2-
vinylpyridine and 2-vinylthiophene (4aam and 4aan). Next, the
compatibility of other alkenes was examined. Alkenes
containing an electron-withdrawing substituent, such as an
ester, amide, or sulfonyl group, underwent the difunctionaliza-
tion reaction successfully in moderate yields (4aao−4aaq).
Subsequently, we investigated the substrate scope with
respect to the alkyl chloride coupling partner. As shown in
Figure 2, linear primary alkyl chlorides containing a variety of
Table 1. Survey of the Reaction Conditions
n-BuCl KOAc K2CO3
entry (equiv) (equiv) (equiv)
reductant
(equiv)
a
solvent
yield (%)
1
3
3
5
5
5
5
5
5
5
5
5
5
4
4
4
4
4
4
4
4
4
4
4
4
DMF
DMF
DMF
DMF
DMF
DMF
DMA
THF
10
15
20
50
60
2
2
2
2
2
5
5
5
5
5
5
5
3
4
MeOH (2)
IPA (2)
IPA (2)
IPA (2)
IPA (2)
IPA (2)
IPA (2)
IPA (2)
IPA (2)
5
b
6
82 (80)
24
7
8
9
CH3CN
DMF
DMF
DMF
10
11
12
c
d
54
e
8
a
The yields were determined by 1H NMR analysis of the crude
reaction mixture using CHCl2CHCl2 as the internal standard.
Isolated yield. Under air atmosphere. 5 equiv n-BuBr. 5 equiv n-
b
c
d
e
BuI. IPA = isopropyl alcohol.
10). This could be due to unwanted oxidation of the
catalytically active Pd(0) species by O2, which would suppress
the reaction. n-Butyl bromide was also a competent coupling
partner, albeit in a lower yield (entry 11), and n-butyl iodide
was almost completely unreactive (entry12).
The substrate scope was next examined. We first investigated
the performance of a range of alkenes under the optimized
reaction conditions. Thus, a variety of styrene derivatives were
tested. As shown in Figure 1, reactions employing styrenes with
alkyl substituents on the arene gave the desired products in
Figure 2. Alkyl chloride scope. Isolated yield. (b) 100 °C. (c) A
mixture of two diastereomers.
functional groups effectively underwent the difunctionalization
reaction under the standard conditions to yield the alkylated
products (4aba−4afa). The more branched substrate, isobutyl
chloride, was also suitable (4aga). Notably, 2-(chloromethyl)-
oxirane was compatible with the protocol, forming two
diastereomers in a 1:1 ratio in an overall yield of 70%
(4aha). α-Chloroacetamide was also reactive, albeit in a low
yield (4aia). Unfortunately, the secondary alkyl chloride, 2-
chloroalkane, was not suitable, and no alkylated products were
observed.
Finally, the compatibility of various substituted 2-iodobi-
phenyl derivatives was examined using 2a and 3a as the
reactants. A range of symmetrically substituted 2-iodobiphenyls
were subjected to the standard conditions. As shown in Figure
3, dimethylated substrates were reactive (4baa and 4caa), and
both fluoro and chloro groups were tolerated in the reaction
(4daa−4faa). Substrates containing two trifluoro- methyl or
two phenyl groups underwent the reaction in high yields (4gaa
and 4haa), and even a tetraalkoxy 2-iodobiphenyl was found to
be suitable (4iaa). The ortho-subsituted substrate, 2-iodo-2′-
methylbiphenyl, was not reactive.
2,2′-Disubstitued biphenyls can be found in a number of
natural and synthetic products. In particular, they are essential
structural motifs in many pharmaceutically active compounds.9
The reaction we developed may provide convenient access to
2,2′-disubstitued biphenyls for drug discovery and biological
studies.
To gain insight into the mechanism of the difunctionalization
reaction, we designed the experiment shown in Scheme 1. Two
Figure 1. Alkene scope. Isolated yield.
B
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Organic Letters
Letter
mentioned that the Heck products were the major byproducts
in the difunctionalization reactions. Moreover, no direct
butylated products were observed. This indicates that the
alkyl chloride does not react with the acyclic arylpalladium
species under the reaction conditions.
Furthermore, the coupling of 2-iodobiphenyl with n-BuCl in
the absence of an alkene was also invesitgated. Surprisingly, the
reaction provided three products: monobutylated biphenyl 6aa
and two dibutylated products (6aa-A and 6aa-B) in a ratio of
1:1 (Scheme 2). To gain insight into the operative mechanism
a
Scheme 2. Alkylation of 2-Iodobiphenyl
a
Isolated yield. The ratio of 6aa-A and 6aa-B was determined by GC−
1
MS and H NMR
in this butylation reaction, additional experiments were
designed and performed.10 First, the alkylation reaction was
carried out under deuterated conditions. All of the products
were fully deuterated at the 2 or 2′ positions. Furthermore,
when simple iodobenzene was used, no alkylated products were
observed. All of these experimental results are consistent with a
dibenzopalladacyclopentadiene intermediate, rather than a
simple open-chain arylpalladium species as the reactive
intermediate in the alkylation of 2-iodobiphenyl, even for the
monobutylated product 6aa. To the best of our knowledge, this
reaction is the first example of alkylation of diarylmetallacycle-
pentadienes. For transition-metal-catalyzed transformations,
reactions involving alkyl halides are often challenging.11,12
The dibenzometallacycles have a reactivity profile that is
distinct from those of common arylpalladium species and
exhibit unique reactivity toward alkyl halides. This strategy may
be extended to other metallacycles and offer further
opportunities for developing novel alkylation reactions.
Figure 3. 2-Iodobiphenyl scope. Isolated yield. (b) 100 °C.
a
Scheme 1. Mechanistic Studies
In principle, the difunctionalized products could arise from
Heck alkenylation followed by olefin-directed C−H alkylation
with alkyl chloride. To examine this possibility, we subjected
premade 5jo-A to the standard reaction conditions with n-
BuCl. The alkylated product was not observed, which rules out
this possibility.
a
Isolated yield.
reactions were performed, one with substrate 1j and the other
with substrate 1k. Each was allowed to react with ethyl acrylate
and n-BuCl under the standard conditions. The reaction with 1j
led to two isomeric difunctionalized products (4jao-A and
4jao-B) in a ratio of 1:0.9. The reaction with 1k also provided
both products in a 1:0.9 ratio. This outcome is consistent with
the two reactions proceeding via a common dibenzopallada-
cyclopentadiene intermediate. Furthermore, in these two
reactions, a direct alkenylated product (5jo-A for 1j; 5jo-B
for 1k) was formed. Direct Heck alkenylation took place at only
the carbon originally bearing an iodo group; the other isomer
with acrylate on the distal phenyl ring opposite to the iodo
group was not observed. On the basis of these results, we can
conclude that the Heck alkenylated products result from the
direct reaction of ethyl acrylate with an acyclic arylpalladium
species that is formed from the oxidative addition of 2-
iodobiphenyl to Pd(0) and a palladacycle is not involved in this
pathway to form the Heck alkenylated byproduct. It should be
A mechanism that is consistent with these findings is shown
in Scheme 3. The catalytic cycle starts with the oxidative
addition of 2-iodobiphenyl to a Pd(0) species to afford
arylpalladium(II) complex A. Subsequent C−H activation
forms the key intermediate dibenzopalladacyclopentadiene B.
Alternatively, arylpalladium(II) species A can undergo a Heck
reaction with the alkene, yielding the observed olefinated
biphenyl byproduct. Intermediate B selectively reacts with the
alkyl chloride to give alkylated complex D, via either an
oxidative addition (C) or metathesis pathway (C′). Complex D
is an acyclic arylpalladium(II) species, so it reacts selectively
with the alkene to generate difunctionalized biphenyl as the
final product, releasing Pd(0) to close the catalytic cycle.
In conclusion, we have demonstrated that dibenzopallada-
cyclopentadienes have unique reactivity that is distinct from
that of common acyclic organometallic complexes. While
dibenzopalladacyclopentadienes selectively react with alkyl
C
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Letter
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halides, acyclic arylpalladium(II) species selectively undergo
Heck reactions with alkenes. By exploiting these two distinct
reactivity modes, we successfully developed a novel sequential
difunctionalization reaction of dibenzopalladacyclopentadienes
derived from C−H activation of 2-iodobiphenyls. This tandem
reaction provides convenient access to a variety of 2,2′-
disubstituted biphenyls. Efforts to study the reactivity of
dibenzopalladacyclopentadienes in other reactions and to
apply this strategy in investigating the reactivity of other
metallacycles are underway in our laboratory.
(9) Baudoin, O.; Guen
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ASSOCIATED CONTENT
* Supporting Information
■
(10) For the detailed mechanistic studies, see the Supporting
Information, Scheme S1. A detailed mechanism was proposed, see the
Supporting Information, Scheme S2.
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3, 1411. (b) Kambe, N.; Iwasaki, T.; Terao, J. Chem. Soc. Rev. 2011, 40,
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M. R.; Fu, G. C. Top. Organomet. Chem. 2005, 14, 85. (f) Frisch, A. C.;
Beller, M. Angew. Chem., Int. Ed. 2005, 44, 674.
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b00753.
Detailed experimental procedures, spectroscopic data
and characterization of products (PDF)
AUTHOR INFORMATION
Corresponding Author
(12) For selected examples of Pd-catalyzed C−H alkylations with
alkyl halides, see: (a) Shen, P.-X.; Wang, X.-C.; Wang, P.; Zhu, R.-Y.;
Yu, J.-Q. J. Am. Chem. Soc. 2015, 137, 11574. (b) Zhang, S.-Y.; Li, Q.;
He, G.; Nack, W. A.; Chen, G. J. Am. Chem. Soc. 2015, 137, 531.
(c) Zhu, R.; He, J.; Wang, X.-C.; Yu, J.-Q. J. Am. Chem. Soc. 2014, 136,
13194. (d) Chen, K.; Shi, B.-F. Angew. Chem., Int. Ed. 2014, 53, 11950.
(e) Zhang, S.-Y.; Li, Q.; He, G.; Nack, W. A.; Chen, G. J. Am. Chem.
Soc. 2013, 135, 12135. (f) Zhang, S.-Y.; He, G.; Nack, W. A.; Zhao, Y.-
S.; Li, Q.; Chen, G. J. Am. Chem. Soc. 2013, 135, 2124. (g) Chen, K.;
Hu, F.; Zhang, S.-Q.; Shi, B.-F. Chem. Sci. 2013, 4, 3906.
(h) Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2010, 132, 3965.
■
*E-mail: zhangyanghui@tongji.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The work was supported by the National Natural Science
Foundation of China (No. 21372176), the Program for
Professor of Special Appointment (Eastern Scholar) at
Shanghai Institutions of Higher Learning, and Shanghai Science
and Technology Commission (14DZ2261100).
REFERENCES
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