Selective and Serial Suzuki-Miyaura Reactions of Polychlorinated Aromatics with Alkyl Pinacol Boronic Esters

Article abstract of DOI:10.1021/acs.orglett.6b02323

Among cross-coupling reactions, the Suzuki-Miyaura transformation stands out because of its practical advantages, including the commercial availability and low toxicity of the required reagents, mild reaction conditions, and functional group compatibility. Nevertheless, few conditions can be used to cross-couple alkyl boronic acids or esters with aryl halides, especially 2-pyridyl halides. Herein, we describe two novel Suzuki-Miyaura protocols that enable selective conversion of polychlorinated aromatics, with a focus on reactions to convert 2,6-dichloropyridines to 2-chloro-6-alkylpyridines or 2-aryl-6-alkylpyridines.

Full text of DOI:10.1021/acs.orglett.6b02323

Letter
pubs.acs.org/OrgLett
Selective and Serial Suzuki−Miyaura Reactions of Polychlorinated
Aromatics with Alkyl Pinacol Boronic Esters
Sebastien Laulhe,† J. Miles Blackburn, and Jennifer L. Roizen*
́
́
Duke University, Department of Chemistry, Box 90346, Durham, North Carolina 27708-0354, United States
S
* Supporting Information
ABSTRACT: Among cross-coupling reactions, the Suzuki−Miyaura transformation stands out because of its practical
advantages, including the commercial availability and low toxicity of the required reagents, mild reaction conditions, and
functional group compatibility. Nevertheless, few conditions can be used to cross-couple alkyl boronic acids or esters with aryl
halides, especially 2-pyridyl halides. Herein, we describe two novel Suzuki−Miyaura protocols that enable selective conversion of
polychlorinated aromatics, with a focus on reactions to convert 2,6-dichloropyridines to 2-chloro-6-alkylpyridines or 2-aryl-6-
alkylpyridines.
he 2-alkylpyridyl motif is critically important within
natural products, pharmaceutical agents, fragrances,
two new carbon−carbon bonds serially in a single reaction
vessel (eq 2).
T
ligands for catalysis, molecular electronic devices, and
biomimetic scaffolds (Figure 1).1 Several powerful strategies
Scheme 1. Selective and Serial Reactions
Owing to their relatively low cost and broad commercial
availability, heteroaryl chlorides offer practical value over
heteroaryl bromides and iodides as substrates in Suzuki−
Miyaura reactions. Nevertheless, this transformation is
challenging due to (1) the strength of aryl chloride bonds
relative to aryl iodide or bromide bonds13 and (2) the ability
of heteroatoms to coordinate to and inhibit the reactivity of
transition metal catalysts. Alkylboron reagents add to these
challenges as they can contribute to formation of undesired
byproducts through protodeboronation, protodehalogenation,
oxidation, and homocoupling.
To overcome these limitations, we chose to focus on the
reaction of 2,6-dichloropyridine (1a) with heptyl pinacol
boronic ester (2a). We sought conditions to generate 2-
chloro-6-alkylpyridine 3a selectively (Table 1). The optimal
conditions would not furnish exhaustively cross-coupled 2,6-
dialkylpyridine 4a.
Figure 1. Alkylpyridine motifs are critical. Glc = D-glucose.1
have been reported recently to form new C(sp2)−C(sp3)
bonds in order to access substituted pyrdines.2−5 In terms of
cross-coupling reactions, access to 2-pyridyl organometallic
reagents6,7 is imperfect,8 as most remain difficult to isolate or
have limited stability. Additionally, many of the associated
reactions require toxic reagents or prove ineffective with
primary alkyl electrophiles. By contrast, heteroaryl chlorides
are readily accessible, but have remained challenging
substrates9,10 particularly in Suzuki−Miyaura10,11 reactions.
Herein, we disclose systems for the reaction of bench stable
alkyl pinacol boronic esters with aryl chlorides, with a focus
on polyhalogenated 2-pyridyl chlorides. Polyhalogenated six-
membered heteroarenes12 react with predictable selectivity
(Scheme 1, eq 1) and undergo successive cross-coupling
reactions with distinct organoboron compounds to generate
Received: August 4, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02323
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Reaction Optimization
Table 2. Tolerated Functional Group Variations
a
b
c
d
e
1
Determined by H NMR. 5 mol % Pd. 80 °C. 110 °C. 1 mol %
a
f
1
General reaction conditions: 1.0 equiv of aryl chloride, 0.13 M
Pd. 2-Heptylpyridine (14% yield) was detected by H NMR.
dioxane/H2O (2:1), 2.3 equiv of R2(CH2)2Bpin, 1 mol % Pd2(dba)3, 6
mol % FcPPh2, 6.0 equiv of K3PO4, 18 h, 100 °C. Isolated yield. 48
b
c
The targeted bond-forming reaction proceeds with poor
efficiency using many of the cutting-edge protocols designed
to couple aryl halides with organoboron compounds (entries
1−4).14 We anticipated that use of sterically encumbered
bidentate phosphine ligands would promote the desired
reaction.15 Indeed, some bidentate ligands furnish 2-chloro-
6-heptylpyridine (3a, entries 5−7).
d
e
h. Isolated after reaction with trifluoroacetic acid. 1.5 equiv of
R2(CH2)2Bpin, 3.0 equiv of K3PO4.
Electronic perturbations influence reactivity: electron-rich 4-
chloroanisole does not react under these conditions (Table 3,
entry 3).
The denticity of these bidentate ligands is not critical to
reaction efficiency. When a monodentate analogue of
DPEPhos, (o-MeOC6H4)PPh2, is employed, high catalyst
turnover numbers are achieved, though reaction selectivity
erodes (entry 8). Under the optimal conditions, a
monodentate analogue of dppf, FcPPh2, is used as a ligand.
To the best of our knowledge FcPPh2 has been described
only once as a ligand for Suzuki−Miyaura reactions,16 though
more sterically encumbered analogues are in common use.17
Under the optimal conditions, 2,6-dichloropyridines react with
heptyl boronic pinacol ester in 2:1 dioxane/H2O at 100 °C
with K3PO4 as a base, 1 mol % Pd2(dba)3, and 6 mol %
FcPPh2 to afford desired 2-chloro-6-heptylpyridine (3a) in
excellent selectivity and 74% isolated yield (entry 9).18
FcPPh2 proves to be more effective in this reaction than
many standard ligands, including PPh3 (entry 10). Relative to
a phenyl group, the ferrocenyl group is more sterically
encumbering19 and better able to stabilize adjacent partial
positive charge.20 These features have great effect, as PPh3
These conditions face expected limitations in terms of
substrate scope. Aromatic compounds that are sensitive to the
combination of water and base, such as 2,4- and 2,5-
dichloropyrimidine, degrade under the reaction conditions.
The reaction proceeds selectively to generate the 2-chloro-
6-alkylpyridine rather than the 2,6-dialkylpyridine. In principle,
the selectivity of the reaction may arise from the 6-alkyl
substituent performing the following roles: (a) hindering
precoordination of the catalyst by sterically shielding the
pyridine nitrogen, (b) raising the transition state barrier for
oxidative addition based on sterically induced strain,21 (c)
disfavoring transmetalation by sterically encumbering the
reactive aryl−Pd species, or (d) increasing the barrier to
oxidative addition or transmetalation electronically. To
evaluate these possibilities, we probed the differences in
substrate reactivity (Table 3). If the steric size of the alkyl
substituent were the principal determinant of selectivity, we
would expect to see statistical mixtures of coupled products
for substrates with distal chlorides, yet these substrates couple
selectively (entries 4−6).
1
furnishes desired 3a in only 21% H NMR yield.
Under these selective conditions, chloropyridines react in
good yields with alkyl pinacol boronic esters that are
saturated, or incorporate distal functional groups including
an olefin, an acetal masked aldehyde, and a primary alkyl
chloride (Table 2). These conditions are tolerant of nitro and
ketone functional groups, transforming electron-deficient
chlorobenzene analogues efficiently (Table 3, entries 1, 2).
Furthermore, these conditions affect the chemoselective
reaction of 1,3-dichloroisoquinoline at the more sterically
encumbered C(1) position (entry 7). The observed selectivity
complements known reactions to install an aryl group at
C(1).22 Moreover, this selectivity has been predicted21,23,24
and rationalized by comparing the expected bond dissociation
energies of 1,3-dichloroisoquinoline at C(1) and C(3).21 This
B
DOI: 10.1021/acs.orglett.6b02323
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Organic Letters
Letter
We sought to merge the selective method with a
compatible reaction, which would obviate the need to isolate
the 2-chloro-6-alkylpyridine intermediate. The resultant one-
pot serial reaction relies on the rapid rate of transmetalation
of arylboron compounds relative to alkylboron reagents
(Table 4). These conditions transform a wide range of
Table 3. Selectivity Based on Electronic Bias
Table 4. Iterative Cross-Coupling Reactions
a
General reaction conditions: 1.0 equiv of aryl chloride, 0.13 M
dioxane/H2O (2:1), 2.3 equiv of R2(CH2)2Bpin, 1 mol % Pd2(dba)3, 6
b
mol % FcPPh2, 6.0 equiv of K3PO4, 18−20 h, 100 °C. Isolated yield.
c
d
1.5 equiv of R2(CH2)2Bpin, 3.0 equiv of K3PO4. Not detected by 1H
e
NMR. Exhaustively coupled product (6% yield) was detected by
f
g
crude 1H NMR. 48 h. Isolated after reaction with trifluoroacetic acid.
h
2 mol % Pd2(dba)3, 12 mol % FcPPh2.
same logic predicts that 2,8-dichloroquinoline will undergo
cross-coupling at C(2), as is observed (entry 8).
a
As selectivity is not principally steric in origin, electron
donation by the new alkyl substituent must increase the
barrier either to oxidative addition or to transmetalation. This
hypothesis is consistent with the remarkably efficient
transformation of 2-chloro-6-tert-butoxypyridine, which incor-
porates an inductively withdrawing group meta- to the
activated C−Cl bond (entry 9), and the diminished reactivity
of 5-chloro-2-methoxypyridine, which includes a resonance
donating group para- to the targeted C−Cl bond (entry 10).
General reaction conditions: 1.0 equiv of aryl chloride, 0.13 M
dioxane/H2O (2:1), 2.3 equiv of R2(CH2)2Bpin, 1 mol % Pd2(dba)3, 6
mol % FcPPh2, 6.0 equiv of K3PO4, 18 h, 100 °C then 2.0 equiv of
b
c
organoboron reagent, 18−20 h unless noted. Isolated yield. 5 h.
arylboron compounds, including arylboronic acids and esters,
trifluoroborate salts,26 and N-methyl-iminodiacetic acid
(MIDA) boronate esters27 (entries 1−4). The reaction can
convert furyl, thiophenyl, and pyridyl boron compounds, as
well as an estrone derivative (entries 6−9) to furnish high
value differently substituted pyridines efficiently.
Scheme 2. Serial Cross-Coupling Transformations
The disclosed methods couple inexpensive and readily
available chloroaryl subunits with bench and air stable pinacol
boronic esters. A chemoselective transformation mediated by
FcPPh2/Pd2(dba)3 predictably and selectively converts poly-
chlorinated pyridine or benzene starting materials to
monoalkylated products. These conditions allow efficient
access to an antimycoplasmal agent. Additionally, a one-pot
sequential Suzuki−Miyaura reaction of alkyl- and then
arylboron compounds has been developed to access differ-
entially substituted pharmacologically relevant motifs.
The power of this cross-coupling method can be
demonstrated through the combination of our method with
Burke’s conditions6d to transform 2,6-dichloropyridine to an
antimycoplasmal agent25 (Scheme 2) via 2-chloro-6-butylpyr-
idine (Table 2, entry 4).
C
DOI: 10.1021/acs.orglett.6b02323
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02323.
■
S
Full experimental details, copies of NMR spectra (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: j.roizen@duke.edu.
Present Address
†Department of Chemistry and Chemical Biology, IUPUI,
Indianapolis, IN 46202.
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This project was funded by the American Chemical Society
Petroleum Research Fund Doctoral New Investigator Program
(PRF# 54824-DNI1) and by Duke University. J.M.B. was
supported by the National Institute of General Medical
Sciences (T32GM007105-41). Characterization data were
obtained on instrumentation secured by funding from the
NSF (CHE-0923097, ESI-MS, George Dubay, the Duke Dept.
of Chemistry Instrument Center), or the NSF, the NIH,
HHMI, the North Carolina Biotechnology Center and Duke
(Duke Magnetic Resonance Spectroscopy Center). EI-MS
data were obtained by M. Walla at the Univ. of South
Carolina Chemistry and Biochemistry Mass Spectrometry
Center. Jacob Timmerman, Prof. S. Malcolmson and Prof. R.
Widenhoefer of Duke University are thanked for their
insights.
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DOI: 10.1021/acs.orglett.6b02323
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