Efficient cross-coupling of secondary alkyltrifluoroborates with aryl chlorides-reaction discovery using parallel microscale experimentation

Article abstract of DOI:10.1021/ja8031423

Microscale parallel experimentation was used to discover three catalyst systems capable of coupling secondary organotrifluoroborates with sterically and electronically demanding aryl chlorides and bromides. The ensuing results represent the first comprehensive study of alkylboron coupling to aryl chlorides and, in particular, using secondary alkylboron partners. A ligand-dependent β-hydride elimination/reinsertion mechanism was implicated in the cross-coupling of more hindered substrates, leading to isomeric mixtures of coupled products in some cases. Copyright

Full text of DOI:10.1021/ja8031423

Published on Web 06/27/2008
Efficient Cross-Coupling of Secondary Alkyltrifluoroborates with Aryl
ChloridessReaction Discovery Using Parallel Microscale Experimentation
Spencer D. Dreher,*,† Peter G. Dormer,† Deidre L. Sandrock,‡ and Gary A. Molander*,‡
Department of Process Research and the Catalytic Reactions DiscoVery and DeVelopment Laboratory, Merck and
Co. Inc., 126 East Lincoln AVenue, Rahway, New Jersey 07065, and Department of Chemistry, UniVersity of
PennsylVania, 231 South 34th Street, Philadelphia, PennsylVania 19104-6323
Received May 5, 2008; E-mail: spencer_dreher@merck.com; gmolandr@sas.upenn.edu
Scheme 1
Cross-coupling reactions and, in particular, the Suzuki-Miyaura
reaction1 are among the most important reactions in modern
organic synthesis. Although there are many effective protocols
for the cross-coupling of secondary alkyl halides with aryl-
metallics,2 the complementary cross-coupling of secondary
(and potentially enantiomerically enriched) organometallics with
aryl halides is a notable and significant unsolved problem.3 There
have been at least two isolated examples of secondary boronic
acids being cross-coupled. In the earliest example, cyclopen-
tylboronic acid was cross-coupled in good yield with an aryl
chloride (eq 1).3e The second partners sec-butylboronic acid with
an aryl bromide generating a mixture of the desired sec-
electrophilic models, while potassium cyclopentyltrifluoroborate
3 was selected as the nucleophilic partner (Scheme 1). In
butylarene along with the undesired isomerized n-butylated
derivative (eq 2).3f However, in neither study was there
attempting to develop conditions that would perform well
development toward identifying a general solution to the
simultaneously for these two electrophilic substrates, we hoped
challenge of cross-coupling secondary organometallics.
that a common solution might evolve for a wide range of
coupling partners.
The parallel experimentation used in this study was accomplished
using a 96-well-plate reactor with 1 mL reaction vials [10 µmol of
substrate per reaction, 100 µL of solvent, 10 mol % of Pd(OAc)2,
and 20 mol % of ligand]. For each substrate, 12 ligands were
employed that have been shown in the literature to be effective in
oxidative addition with aryl chlorides, in conjunction with three
solvents [toluene, THF, cyclopentyl methyl ether (CPME)] and
Cs2CO3 base, conditions previously shown to be useful for primary
alkyltrifluoroborate coupling.7 From these experiments, the com-
bination of n-butyldiadamantylphosphine (n-BuPAd2, Catacxium
The difficulty in this transformation derives from two key steps
A) with Cs2CO3 in toluene was by far the most reactive combination
of the mechanistic cycle: the transmetalation step, which is more
for both substrates.
difficult for secondary alkyl groups than other organic moieties,3d
and the reductive elimination process, which competes with facile
The generality of these conditions was then evaluated using
a range of aryl electrophiles (Table 1). A variety of electron-
ꢀ-hydride elimination. To address the former issue, we have
employed organotrifluoroborates,4 which have a demonstrated
rich and electron-poor aryl chlorides and bromides performed
very well with these conditions. An aryl iodide (Table 1, entry
1) was also found to serve as a suitable electrophile, but required
a longer reaction time to go to completion.
ability to undergo transmetalation with limited interference from
competitive protodeboronation.5 To overcome the second ob-
stacle and find suitable conditions for the cross-coupling of
challenging aryl chlorides to secondary alkyltrifluoroborates, we
used parallel microscale experimentation. During the course of
our investigations, a similar approach with more highly reactive
aryl bromide electrophiles was reported by van den Hoogenband
et al.6
Interestingly, under these conditions, halobenzonitriles (entry
8) were unsuitable electrophiles, recovering starting material
almost quantitatively. Additionally, the yields of 4-chloro- and
4-bromoacetophenone (entry 3) were lower than the other
electron-poor substrates. This reaction does not appear to be
sensitive to steric hindrance, as 2-chloro- and 2-bromo-5-
methoxy-1,3-dimethylbenzene performed well (entry 6). Of
additional interest is the fact that the nitro group is not reduced
under these conditions (entry 7), whereas this can be a significant
side reaction using other alkylboron coupling partners.8
The electron-rich and sterically hindered 2-chloroanisole
1 and the heterocyclic 3-chloropyridine 2 were chosen as
† Merck and Co. Inc.
‡ University of Pennsylvania.
9
10.1021/ja8031423 CCC: $40.75
2008 American Chemical Society
J. AM. CHEM. SOC. 2008, 130, 9257–9259 9257

C O M M U N I C A T I O N S
Table 1. Cross-Coupling of Secondary Potassium
find a ligand that was more selective for the branched to linear
isomer in the coupling of i-PrBF3K and 1. Using parallel
microscale experimentation, 60 structurally diverse ligands were
quickly screened with the toluene/water/Cs2CO3 system, and this
screen identified tri-tert-butylphosphine (t-Bu3P) and di-tert-
butylphenylphosphine (t-Bu2PPh) as superior (although slightly
less reactive) ligands to suppress ꢀ-hydride elimination and
subsequent isomerization.
Alkyltrifluoroborates with Aryl Halidesa
To achieve a better understanding of the isomerization
process, cross-coupling was examined with a series of ortho-
and para-substituted, electronically diverse substrates (Figure
1).
Product analysis by 1H NMR and GCMS was utilized to
determine that there is a strong steric influence on the interplay
between reductive elimination and ꢀ-hydride elimination, and
that the electron-rich methoxy- and electron-poor benzoate
substrates gave lower branched to linear ratios than did the
electron-neutral tolyl substrates. Both t-Bu3P and t-Bu2PPh
ligands generally gave better selectivity for branched to
linear isomers across the spectrum of substrates depicted in
Figure 1.
Conditions favoring the secondary alkylated aromatics were
then applied to both o-chloroanisole and p-chloroanisole (eqs 3
and 4). Although under conditions optimized to inhibit isomer-
ization the reactions were somewhat slower, reasonable isolated
yields of the products could be obtained. These experiments
served to highlight further the effects of steric encumbrance in
the electrophile on both the yield of the products and the isomeric
ratios found therein.
a General conditions: Pd(OAc)2 (2 mol %), n-BuPAd2 (3 mol %),
RBF3K (1.1 equiv), Cs2CO3 (3 equiv), and 10:1 toluene/H2O (0.20 M),
100 °C, 24 h. b Pd(OAc)2 (5 mol %), n-BuPAd2 (7.5 mol %), RBF3K
(1.3 equiv), 100 °C, 72 h. c General conditions, 72 h. d Ratio of ∼1:6
i-Pr to n-Pr. e Ratio of 3.5:1 i-Pr to n-Pr.
As predicted by the screening results with 3-chloropyridine,
a number of heterocyclic substrates gave good yields, as
well (entries 11-15). Using cyclohexyltrifluoroborate with the
present system, aryl chlorides 1 and 2 reacted in good yield
(entries 1 and 11), although under slightly more forcing
conditions. Specifically, the reaction necessitated the use of a
higher catalyst/ligand loading, longer reaction time, and a slight
excess of the trifluoroborate reagent. To the best of our
knowledge, a single example of cyclohexyl cross-coupling using
boron reagents can be found in the literature. It involved reaction
of tricyclohexylborane with an aryl iodide, but the yield was
moderate and only a single alkyl group transferred in the
process.2b Importantly, the results outlined in Table 1 represent
one of the few extensive cross-couplings of alkylborons of any
kind to aryl chlorides.9
Next, an even more challenging chiral (diastereomerically but
not enantiomerically pure) substrate was examined under several
conditions (Table 2). When potassium trans-2-methylcyclohexyl-
trifluoroborate 5 was reacted with 4-chlorobiphenyl 6 with
n-BuPAd2, t-Bu3P, and t-Bu2PPh, a mixture of product isomers
7, 8, 9, and 10 was obtained in each case.
As predicted in our study with i-PrBF3K, the n-BuPAd2 ligand
was more reactive but less selective than t-Bu3P and t-Bu2PPh.
Interestingly, as predicted in the elegant work by Keay,10 it
appears that the Pd remains coordinated to the same face of the
cyclohexyl ring throughout the elimination/reinsertion process,
as no traces of the cis-isomers were found by 1H NMR analysis.
An obvious consequence associated with this ring migration
mechanism is that as the Pd migrates it eventually symmetrizes
the molecule and subsequently generates enantiomeric organo-
palladiums. Thus both the regio- and stereocontrol of the
To probe the scope of the reaction further with respect to the
nucleophilic partner, these conditions were also applied to
i-PrBF3K in the coupling with aryl chloride 1. The cross-
coupling of i-PrBF3K with 1 gave a 78% yield of the propylated
product as a ∼1:6 ratio of the desired i-Pr to the undesired
n-Pr isomer (entry 1), while 4-chloroanisole (entry 2) gave a
3.5:1 ratio of i-Pr:n-Pr isomers. Attempts were then made to
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C O M M U N I C A T I O N S
Figure 1. Relative reactivity and selectivity (i-Pr vs n-Pr) of various electrophiles using n-BuPAd2, t-Bu3P, and t-Bu2PPh. All reactions used Cs2CO3
(3 equiv), 10:1 toluene/H2O, Pd(OAc)2 (2 mol %), ligand (3 mol %), i-PrBF3K (1.1 equiv), 18 h, 100 °C.
Table 2. Cross-Coupling of Potassium
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100 °C, 24 h. b Pd(OAc)2 (5 mol %), n-BuPAd2 (7.5 mol %), RBF3K
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elimination/reinsertion mechanism was implicated in the cross-
coupling process, leading to isomeric mixtures of coupled
products in some cases. Further work to suppress this Pd
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Acknowledgment. G.A.M. thanks the NIH General Medical
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Supporting Information Available: Experimental details and
spectral data of all compounds synthesized. This material is available
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