Negishi cross-coupling of secondary alkylzinc halides with aryl/heteroaryl halides using Pd-PEPPSI-IPent

Article abstract of DOI:10.1039/c0cc04835f

Pd-PEPPSI-IPent has proven to be an excellent catalyst for the Negishi cross-coupling reaction of secondary alkylzinc reagents with a wide variety of aryl/heteroaryl halides. Importantly, β-hydride elimination/migratory insertion of the organometallic leading to the production of isomeric coupling products has been significantly reduced using the highly-hindered Ipent ligand.

Full text of DOI:10.1039/c0cc04835f

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COMMUNICATION
Negishi cross-coupling of secondary alkylzinc halides with
aryl/heteroaryl halides using Pd–PEPPSI–IPentw
Selc¸ uk C¸ alimsiz and Michael G. Organ*
Received 7th November 2010, Accepted 14th January 2011
DOI: 10.1039/c0cc04835f
Pd–PEPPSI–IPent has proven to be an excellent catalyst for the
Negishi cross-coupling reaction of secondary alkylzinc reagents
with a wide variety of aryl/heteroaryl halides. Importantly,
b-hydride elimination/migratory insertion of the organometallic
leading to the production of isomeric coupling products has been
significantly reduced using the highly-hindered Ipent ligand.
Transition metal-catalyzed cross-coupling has seen significant
advances in the coupling of sp, sp2 and sp3-hybdridized carbon
nucleophiles with alkyl, aryl or alkenyl electrophiles.1 Among
these couplings, one of the most challenging remains those
between Csp2 and secondary Csp3 centres.2 During the last decade,
a number of groups have developed catalyst systems that are
uniquely suited for the coupling of secondary alkyl halides
with sp2 hybridized aryl/alkenyl nucleophiles.3,4 On the other
hand, only a handful of studies have been published relating to
the analogous cross-coupling of secondary Csp3-hybridized
organometallics with aryl halides. One of the major difficulties
in this transformation results from the undesired b-hydride
elimination/migratory insertion sequence that competes with
reductive elimination leading to isomerised coupling products
(Scheme 1). To suppress this isomerisation, the rate of reductive
elimination, relative to b-hydride elimination, should be enhanced
as much as possible. Several research groups have addressed
this issue by employing catalysts containing sterically-bulky
phosphine ligands. In 1972 and 1984, Kumada/Tamao and
Fig. 1 Previously employed ligands in metal-catalyzed cross-coupling
reactions of secondary Csp3 hybridized organometallics and Pd–PEPPSI
complexes.
Table
arylbromides
1
Negishi cross-coupling of isopropylzinc bromide with
Entry
a
Aryl bromide
Catalyst
Yielda
10 : 11
R = 4-CN
6
7
6
7
6
7
6
7
6
7
6
7
6
7
6
7
6
7
6
7
85
92
64
78
99
98
83
99
89
95
77
84
78
71
31
57
99
80
99
46
3 : 1
27 : 1
6 : 1
39 : 1
6 : 1
b
c
d
e
f
R = 4-CHO
R = 4-COCH3
R = 4-CO2CH3
R = 4-OCH3
R = 3-CN
30 : 1
5 : 1
40 : 1
2.5 : 1
33 : 1
1 : 1.4
11 : 1
1.6 : 1
22 : 1
3.5 : 1
34 : 1
1 : 8
g
h
i
R = 3-CHO
R = 3-OCH3
R = 2-CN
Scheme 1 Mechanism for the transition metal-catalyzed Negishi cross-
coupling of iso-propylzinc halide with an aryl halide.
2.4 : 1
1 : 9
2 : 1
j
R = 2-OCH3
Department of Chemistry, York University 4700 Keele Street,
Toronto, ON, M3J1P3, Canada. E-mail: organ@yorku.ca
w Electronic supplementary information (ESI) available: See DOI:
10.1039/c0cc04835f
a
Isolated yields of mixtures of i-Pr and n-Pr products; average of two runs.
c
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Hayashi, respectively, reported that NiCl2(dppp) (1, Fig. 1)
and PdCl2(dppf) (2, Fig. 1) can couple secondary alkyl
Grignards with a limited array of aryl and vinyl halides.5 In
2008, Molander and Hoogenband independently reported the
Suzuki–Miyaura coupling of secondary alkyltrifluoroborates
with aryl halides in the presence of n-BuPAd2 (3, Fig. 1) and
RuPhos (4, Fig. 1), respectively.6 These publications described
efficient coupling of cyclic alkyltrifluoroborates, although
when linear alkyltrifluoroborates were used the ratio of
desired- (non-isomerised) to isomerised-product was moderate
and functional group incompatibilities surfaced. Recently,
Han and Buchwald published a report detailing the Pd-catalysed
coupling of secondary alkylzinc halides with aryl bromides
and activated aryl chlorides using the bulky CPhos ligand
(5, Fig. 1).7 Under their optimal conditions good ratios of
secondary to primary alkyl couplings with several substrates
were observed although the b-hydride elimination pathway
could not be fully eliminated.
We have been systematically evaluating the steric and
electronic properties of Pd–N-heterocyclic carbene (NHC)
complexes (e.g., 6 and 7, Fig. 1) in an effort to enhance their
catalytic performance in various cross-coupling reactions.8
NMR studies that we have performed on these metal complexes
are suggestive that increases in bulk on the N-phenyl substi-
tuent lead to enhanced positive charge on the Pd metal.9 It is
generally true that electron-poor metal centers tend to undergo
reductive processes faster than electron-rich ones. Further,
metal complexes containing more-sterically-hindered ligands
undergo reductive elimination faster than complexes with less-
hindered ancillary ligands.10 Thus, we reasoned that sterically-
bulky Pd–PEPPSI–IPent (7, Fig. 1)11 could perform well in the
coupling of secondary Csp3-hybridized organometallics with
aryl halides where the rate of reductive elimination would
have to be significantly faster than b-hydride elimination. We
have shown by experiment,8a–c supported and explained by
calculation,8d–f that Pd–PEPPSI–IPr does not readily undergo
Table 2 Negishi cross-coupling of secondary alkylzinc halides with aryl/heteroaryl halidesa
Entry Aryl halide
Product
Yield (%) Entry Aryl halide
Product
Yield (%)
1
80
70
7
8
92
2
3
94
61
82b
9
4
5
76b,c
10
11
95
82
40d
6
90
12
83
a
b
Isolated yields; average of two runs. 3.4 equivalents of the alkylzinc reagent was used. 16/1 branched/linear. 6/1 desired/isomerized.
c
d
c
5182 Chem. Commun., 2011, 47, 5181–5183
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b-hydride elimination, hence the reason for its great success in
11 alkyl–11 alkyl couplings. We have proposed that through-
space interactions between the electron-poor Pd centre (following
oxidative addition) and the electron-rich C–H bonds of the
isopropyl substituent keep the metal coordinatively saturated
and mitigate the necessity for agostic interactions that lead to
b-hydride elimination.8d,e Here in we set out to investigate the use
of Pd–PEPPSI–IPent in Negishi cross-coupling of secondary
alkylzinc halides with aryl/heteroaryl halides.
halides. Under the optimized conditions, the rate of reductive
elimination relative to b-hydride elimination was suitable to
almost eliminate the formation of isomerized projects, which is
a significant problem for this transformation.
We thank the NSERC (Canada) and the ORDCF (Ontario)
for funding.
Notes and references
In order to see the clear-cut connection between steric bulk
of the NHC ligand and catalytic performance of PEPPSI
complexes, we compared the reactivity of Pd–PEPPSI–IPr (6)
with Pd–PEPPSI–IPent (7). We first prepared isopropylzinc
bromide in THF using Knochel’s method12 and examined its
coupling with p-cyano-bromobenzene. After a short optimiza-
tion study, it was found that in the presence of 1 mol% of
either Pd–PEPPSI precatalyst (i.e., 6 or 7), coupling was
completed within 30 minutes at room temperature. We were
pleased that 7 gave rise to good yield, but more importantly it
exhibited excellent selectivity for the branched (non-isomerized)
product. Conversely, while conversion was also high with 6,
the ratio of branched to linear product was dramatically lower
(Table 1, 10 : 11). The same trend was observed when a variety
of ortho-, meta-, and para-substituted aryl bromides were
subjected to the optimized reaction conditions (Table 1).
Moreover, an interesting trend emerged between selectivity
for the branched product and the sterics of the oxidative
addition partner. Selectivity for the branched product decreased
in the following order: para- > meta- > ortho- (see Table 1,
entries a, f and i for –CN; entries b and g for –CHO; entries e,
h, and j for –OMe). Remarkably, while reduced, Ipent (7) still
showed a preference for the non-isomerized product with
ortho-substituted aryl chlorides, while Ipr (6) inverted selectivity
in favour of the linear, less sterically-crowded isomerised
product (entries i and j). Additionally, electronic properties of
the aryl group on the relative rate of reductive elimination was
not significant in our study, as was the case in the report by Han
and Buchwald.7 These results are in agreement with the report
of Culkin and Hartwig who studied the rate of reductive
elimination from DPPBz-ligated arylpalladium alkyl complexes
and reported that aryl group electronic properties had a minor
effect on the rate of reductive elimination.13
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9 Unpublished NMR studies.
Following these promising results, 7 was further evaluated
using a variety of cyclic and acylic alkylzinc reagents that were
effectively coupled with several aryl halides (Table 2), including
sterically-bulky mesityl (entry 1), nitrile (entries 2 and 10),
aniline (entries 3 and 4), aldehyde (entry 5) and pinacol
boronic acid (entry 9). It is noteworthy that the acidic aniline
moiety could be coupled with the secondary zinc reagent,
further illustrating the selectivity and utlility of the Negishi
cross-coupling reaction.14 Heteroaryl halides including pyridine
(entry 6), quinoline (entry 7), pyridazine (entry 8) and benzo-
thiazole (entry 11) were also coupled in high yields. Moreover,
when acyclic alkylzinc reagents were employed the ratio for
branched to isomerized products was good to excellent
(entries 4, 9 and 10).
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Sterically-bulky Pd–PEPPSI–IPent (7) has proven to be an
excellent precatalyst for the Negishi cross-coupling of secondary
alkylzinc reagents with a wide variety of aryl/heteroaryl
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 5181–5183 5183