Stereospecific Pd-catalyzed cross-coupling reactions of secondary alkylboron nucleophiles and aryl chlorides

Article abstract of DOI:10.1021/ja508815w

We report the development of a Pd-catalyzed process for the stereospecific cross-coupling of unactivated secondary alkylboron nucleophiles and aryl chlorides. This process tolerates the use of secondary alkylboronic acids and secondary alkyltrifluoroborates and occurs without significant isomerization of the alkyl nucelophile. Optically active secondary alkyltrifluoroborate reagents undergo cross-coupling reactions with stereospecific inversion of configuration using this method.

Full text of DOI:10.1021/ja508815w

Communication
pubs.acs.org/JACS
Stereospecific Pd-Catalyzed Cross-Coupling Reactions of Secondary
Alkylboron Nucleophiles and Aryl Chlorides
Ling Li,† Shibin Zhao,†,‡ Amruta Joshi-Pangu,†,‡ Mohamed Diane,† and Mark R. Biscoe*,†,‡
†Department of Chemistry, The City College of New York (CCNY), 160 Convent Avenue, New York, New York 10031, United
States,
‡The Graduate Center, The City University of New York (CUNY), 365 Fifth Avenue, New York, New York 10016, United States
S
* Supporting Information
reactions that broadly tolerate the use of secondary and tertiary
alkyl nucleophiles.3,4 In particular, we are interested in the use
ABSTRACT: We report the development of a Pd-
catalyzed process for the stereospecific cross-coupling of
unactivated secondary alkylboron nucleophiles and aryl
chlorides. This process tolerates the use of secondary
alkylboronic acids and secondary alkyltrifluoroborates and
occurs without significant isomerization of the alkyl
nucelophile. Optically active secondary alkyltrifluoroborate
reagents undergo cross-coupling reactions with stereo-
specific inversion of configuration using this method.
of optically active alkyl nucleophiles that are configurationally
stable and isolable. Such nucleophiles can, in principal, be
employed as building blocks for the rapid and reliable
construction of optically active drug libraries via stereospecific
cross-coupling reactions. Recently, we reported a Pd-catalyzed
Stille cross-coupling reaction that enabled the broad use of
unactivated secondary alkylstannatranes.4d This was the first
process that did not require the use of activated (containing a
C(sp2) α-carbon, heteroatomic α-carbon, or strongly coordi-
nating β-carbonyl group) alkylmetal nucleophiles to achieve
stereospecific cross-coupling reactions.5 Building upon this
work, we sought to extend the use of secondary alkyl
nucleophiles to alkylboron nucleophiles, which are more
configurationally stable and more easily prepared than their
alkylstannatrane analogues.6 Herein, we report the first
palladium-catalyzed process that permits the broad use of
unactivated secondary alkylboron nuclophiles in cross-coupling
reactions without concurrent isomerization. Secondary alkyl-
boronic acids and secondary alkyltrifluoroborates both undergo
cross-coupling reactions with aryl chlorides using this
procedure. Importantly, when enantioenriched alkyltrifluor-
oborates are employed, cross-coupling products are obtained
with highly enantiospecific inversion of absolute configuration.
The groups of Molander and Dreher7a and of van der
Hoogenband7b reported the first attempts to develop a Pd-
catalyzed process that enabled the broad use of secondary
alkylboron nucleophiles in cross-coupling reactions.8 Using
bulky, electron-rich, phosphine ligands, they reported processes
that permitted the cross-coupling of secondary carbocyclic
boron reagents and aryl electrophiles. However, noncyclic
secondary alkylboron nucleophiles underwent extensive isomer-
ization using these methods. Inspired by these studies, we set
fourth to develop a general process that could overcome these
limitations, while also enabling the development of a
stereospecific variant for the Suzuki coupling. While exploring
the use of alternative alkylboron reagents in Suzuki reactions,
we discovered that the isomerization of acyclic secondary
alkylboronic acids could be overcome through modification of
the conditions used by Molander and Dreher. In the cross-
coupling of 4-chloroanisole and s-BuB(OH)2, isomerization was
suppressed through use of a preformed Pt-Bu3 palladium
he development of transition metal-catalyzed carbon−
Tcarbon cross-coupling reactions has revolutionized the
manner by which we approach the synthesis of complex organic
molecules.1 Classical studies have focused mainly on the
creation of C(sp2)−C(sp2) bonds for the construction of planar
molecular topologies. More recently, C(sp3) nucleophiles and
electrophiles have been investigated in cross-coupling reactions,
which more readily allows the manipulation of the three-
dimensional space of a molecule.2 The use of C(sp3) coupling
partners in transition metal-catalyzed reactions is complicated
by slow transmetalation and the propensity of alkyl ligands to
undergo β-hydride elimination processes. These complications
increase for secondary and tertiary alkyl coupling partners,
which readily undergo isomerization and racemization via a β-
hydride elimination/reinsertion sequence following trans-
metalation (Figure 1).2,3 A major focus of the research in our
laboratory is the development of efficient metal-catalyzed
Figure 1. Catalytic cycle and possible side reactions in the Pd-
catalyzed cross-coupling reaction of optically active nucleophiles and
aryl electrophiles.
Received: September 2, 2014
© XXXX American Chemical Society
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Journal of the American Chemical Society
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precatalyst9 (1) and K2CO3 in a 2:1 mixture of toluene and
water (Table 1). When Pd(dba)2 and P(t-Bu)3·HBF4 were used
Table 2. Pd-Catalyzed Cross-Coupling Reactions of
Secondary Alkylboronic Acids and Aryl Chlorides
a
Table 1. Optimization of Reaction Conditions for the Pd-
Catalyzed Cross-Coupling of s-BuB(OH)2 and 4-
Chloroanisole
a
a
entry
variations from above
yield (%)
2:3
1
2
none
98
98
70
<5
94
89
94
89
<5
<5
97
>200:1
36:1
36:1
−
2 mol % P(t-Bu)3 precatalyst
3
2 mol % Pd(dba)2, 2 mol % P(t-Bu)3·HBF4
Cs2CO3 (3 equiv) instead of K2CO3
K3PO4-H2O (3 equiv) instead of K2CO3
5 mol % n-BuP(Ad)2 precatalyst
5 mol % PhP(t-Bu)2 precatalyst
toluene/H2O(1:2)
4
5
69:1
6
4:1
7
32:1
70:1
−
−
>200:1
8
9
THF instead of toluene
10
11
dioxane instead of toluene
methylcylcohexane instead of toluene
a
Yields and selectivities determined by GC.
a
ArCl (0.5 mmol), RB(OH)2 (0.75 mmol), 100 °C, 24 h; average
b
isolated yield of 2 runs; >50:1 ratio of retention to isomerization. 60%
yield using 4-bromoanisole.
in place of the preformed palladium catalyst (entry 3), the
reaction did not reach full conversion. The use of other
trialkylphosphine ligands resulted in increased isomerization.
When K2CO3 was replaced with Cs2CO3, the reaction failed
completely (entry 4). By increasing the catalyst loading from 2
to 5 mol %, we observed enhanced selectivity for the branched
product 2.
Because of the greater stability of alkyltrifluoroboronate
reagents in comparison to alkylboronic acids, we investigated
the extension of the nucleophilic coupling partner using
secondary alkyltrifluoroborates (Table 3). The cross-coupling
reactions proceeded efficiently using hydrocarbon nucleophiles,
though lower reaction temperatures and extended reaction
times were required to prevent background protodeboronation.
Incorporation of a heterocyclic group into the skeleton of the
nucleophile resulted in incomplete conversion. Not surpris-
ingly, reactions involving symmetric, carbocyclic, secondary
alkyltrifluoroborates provided cross-coupling products in high
yield.11 While toluene can be employed successfully in all of
these reactions, in some instances, we observed that
protodeboronation was minimized (ca. 5−10% less proto-
deboronation) using benzene as the organic solvent compo-
nent.
To evaluate the stereochemical course of this reaction, we
prepared enantioenriched (R)-7 and (R)-8 using Brown’s12 and
Matteson’s13 chiral auxiliary-based protocols. These stereo-
chemical assignments were further confirmed through
oxidation10b of (R)-7 and (R)-8 and comparison of the
products to the corresponding commercially available, optically
active alcohols (see Supporting Information). Derivatization of
commercially available (S)-3-phenylbutyric acid (9) enabled
access to (S)-10 and (S)-11 (Figure 2a,c). When (R)-7 was
employed in a cross-coupling reaction with chlorobenzene, (S)-
10 was obtained with inversion of absolute stereochemistry
(Figure 2b). The stereochemical assignment was made through
comparison with synthesized (S)-10. A similar stereochemical
analysis was performed for the cross-coupling reaction of (S)-8
and chlorobenzene, which also showed stereoinversion in the
formation of (S)-11 (Figure 2d). Both (S)-10 and (S)-11 were
generated with high enatiospecificity (% es)14 using this
process.
The generality of the cross-coupling reaction was evaluated
using i-PrB(OH)2 (4) (no α-branching) and s-BuB(OH)2 (5)
(containing α-branching) as nucleophiles alongside a variety of
aryl chloride electrophiles (Table 2). Electron-rich and
electron-deficient aryl chlorides provided the corresponding
cross-coupling products in high yields. The presence of an
ortho substitutent on the electrophile was well-tolerated in the
reaction. Additionally, heterocyclic aryl chlorides could be
employed in these reactions with moderate generality. For all
substrates, a >50:1 ratio of retention to isomerization products
was achieved. When heteroarenes with the chloride leaving
group located directly on the heteroaryl ring (e.g., 3-
chloropyridine) were employed, the reaction uniformly gave
poor results. In our eyes, this constitutes the major scope
limitation of the aryl chloride component. We were pleased to
observe that the identical conditions employed for secondary
alkylboronic acids could be used for i-PrBF3K (6) and s-
BuBF3K (7). A similar substrate scope was also achieved using
secondary alkyltrifluoroborates (Table 2). Since secondary
alkyltrifluoroborates are significantly more stable than their
secondary alkylboronic acid analogues,10 the ability to employ
alkyltrifluoroborate reagents in this reaction greatly increases
the overall utility of this process. When 4-bromoanisole was
employed in a cross-coupling reaction with 6 using these
conditions, the desired product was obtained in 60% yield.
However, the use of aryl sulfonates resulted in the formation of
<10% desired product. For all substrates, a >50:1 ratio of
retention to isomerization products was again achieved.
B
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Journal of the American Chemical Society
Communication
reported by the Molander5r and Suginome5s groups in Suzuki
reactions using activated secondary alkylboron nucleophiles
containing β-coordinating groups. Additionally, the groups of
Hall5v and Morken5y have demonstrated that the Pd-catalyzed
monoarylation of geminal bis(boranates) occurs with inversion
of configuration. Our work constitutes the first demonstration
of an enantiospecific secondary alkyl Suzuki reaction employing
an unactivated nucleophile. This process enables the use of (R)-
sBuBF3K, the simplest optically active secondary alkylboron
nucleophile possible. Therefore, transmetalation to Pd(II) in
this process is not biased by electronic perturbations and
should most closely represent the fundamental mechanism of
transmetalation for secondary alkylboron nucleophiles. Our
observation that unactivated secondary alkyltrifluoroborates
undergo transmetalation to Pd(II) with inversion is also
consistent with previous reports from Kalbalka16 and
Aggarwal17 in which unactivated secondary alkylboron reagents
undergo electrophilic substitution with clean inversion.
Table 3. Pd-Catalyzed Cross-Coupling Reactions of
Secondary Alkyltrifluoroborates and Aryl Chlorides
a
Six cross-coupling reactions from Tables 2 and 3 were
repeated using (R)-7 and (R)-8. Because heterocyclic electro-
philes are of particular importance in medicinal chemistry,
while also typically the most difficult substrates to employ in
metal-catalyzed processes, we focused on stereospecific cross-
coupling reactions involving heteroaromatic electrophiles.
These reactions resulted in the formation of the corresponding
(S) products with low erosion of enantiomeric excess (Figure
3). The high enantiospecificity (% es) of this process using
a
ArCl (0.5 mmol), RBF3K (0.75−1.0 mmol); average isolated yield of
b
two runs; >50:1 ratio of retention to isomerization. Using
benzene:H2O (1:1) as solvent, 10 mol % 1, 60 °C, 48 h. Using
c
toluene:H2O (2:1) as solvent, 5 mol % 1, 100 °C, 24 h.
Figure 3. Use of (R)-7 and (R)-8 in stereospecific cross-coupling
reactions with aryl and heteroaryl chlorides.
heteroaromatic electophiles should enable the use of this
process in the generation of diverse libraries of optically active
drug candidates. Thus, alkylboron reagents such as (R)-7 and
(R)-8 can be viewed as general building blocks for use in the
rapid preparation of libraries of nonracemic molecules during
the drug discovery process.
In summary, we have developed the first general process for
the Pd-catalyzed cross coupling of unactivated, secondary
alkylboron nucleophiles and aryl electrophiles. One set of
conditions enables the use of secondary alkylboronic acids and
secondary alkyltrifluoroborates in these reactions. In all cases,
only nominal isomerization of the nucleophile is observed
during the reaction. When an optically active alkyltrifluor-
oborate nucleophile is employed, cross coupling occurs with
inversion of absolute configuration. This process should
facilitate the use of optically active alkylboron compounds as
building blocks in the construction of optically active drug
Figure 2. (a) Synthesis of (S)-10 from (S)-3-phenylbutyric acid (S)-
(9). (b) Suzuki coupling of (R)-7 and PhCl. (c) Synthesis of (S)-11
from (S)-9. (d) Suzuki coupling of (R)-8 and PhCl.
In Suzuki reactions, both inversion and retention of absolute
configuration have been demonstrated for activated secondary
alkylboron nucleophiles. Retention of configuration has been
demonstrated by Crudden5q using benzylic alkylboron
nucleophiles and by Molander5w using α-OBn alkylboron
nucleophiles. Inversion of configuration has been previously
C
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Journal of the American Chemical Society
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libraries via enantiospecific cross-coupling reactions. We are
currently investigating extensions of this chemistry to more
diverse heterocyclic systems as well as the factors responsible
for the observed stereoselectivity.
ASSOCIATED CONTENT
■
S
* Supporting Information
Procedural, spectral, and crystallographic data. This material is
available free of charge via the Internet at http://pubs.acs.org
(6) Boudier, A.; Bromm, L. O.; Lotz, M.; Knochel, P. Angew. Chem.,
Int. Ed. 2000, 39, 4414.
AUTHOR INFORMATION
Corresponding Author
mbiscoe@ccny.cuny.edu
Notes
■
(7) (a) Dreher, S. D.; Dormer, P. G.; Sandrock, D. L.; Molander, G.
A. J. Am. Chem. Soc. 2008, 130, 9257. (b) van der Hoogenband, A.;
Lange, J. H. M.; Terpstra, J. W.; Koch, M.; Visser, G. M.; Visser, M.;
Korstanje, T. J.; Jastrzebski, J. T. B. H. Tetrahedron Lett. 2008, 49,
4122.
The authors declare no competing financial interest.
(8) For early, singular examples of cross-couplings using a secondary
alkylboron reagent, see: (a) Littke, A. F.; Dai, C.; Fu, G. C. J. Am.
Chem. Soc. 2000, 122, 4020. (b) Kataoka, N.; Shelby, Q.; Stambuli, J.
P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553.
(9) (a) Biscoe, M. R.; Fors, B. P.; Buchwald, S. L. J. Am. Chem. Soc.
2008, 130, 6686. (b) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am.
Chem. Soc. 2010, 132, 14073. (c) Bruno, N. C.; Tudge, M. T.;
Buchwald, S. L. Chem. Sci. 2013, 4, 916.
ACKNOWLEDGMENTS
■
We thank Xinghua Ma for performing initial investigations. We
thank the National Institutes of Health (5SC2GM096932 and
1SC1GM110010), the City College of New York (CCNY), the
Alfred P. Sloan Foundation, and PSC-CUNY for financial
support. We gratefully acknowledge the National Science
Foundation for an instrumentation grant (CHE-0840498). We
thank Jintao Chen for conducting the ArBr study.
(10) (a) Molander, G. A.; Sandrock, D. L. Curr. Opin. Drug Discovery
Devel. 2009, 12, 811. (b) Molander, G. A.; Cavalcanti, L. N. J. Org.
Chem. 2011, 76, 623.
(11) Potassium trans-2-methylcyclohexyltrifluoroborate underwent
significant isomerization (at least 5 products by GC/MS) in reactions
with chlorobenzene. Similar isomerization was observed in ref 7a.
(12) (a) Joshi, N. N.; Pyun, C.; Mahindroo, V.; Singaram, B.; Brown,
H. C. J. Org. Chem. 1992, 57, 504. (b) Lennox, A. J. J.; Lloyd-Jones, G.
C. Angew. Chem., Int. Ed. 2012, 51, 9385.
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