Development of the direct Suzuki-Miyaura cross-coupling of primary B-alkyl MIDA-boronates and aryl bromides

Article abstract of DOI:10.1021/ol500057a

The development of a palladium-catalyzed sp³-sp² Suzuki-Miyaura cross-coupling of B-alkyl-N-methyliminodiacetyl (B-alkyl MIDA) boronates and (hetero)aryl bromides is reported. This transformation is tolerant of a variety of functional groups (F, NO₂, CN, Cl, COCH₃, and CHO). B-Alkyl MIDA boronates allow an efficient cross-coupling reaction directed toward the synthesis of unsymmetrical methylene diaryls as well as alkylated arenes in good to excellent yields.

Full text of DOI:10.1021/ol500057a

Letter
pubs.acs.org/OrgLett
Development of the Direct Suzuki−Miyaura Cross-Coupling of
Primary B‑Alkyl MIDA-boronates and Aryl Bromides
Jeffrey D. St. Denis, Conor C. G. Scully, C. Frank Lee, and Andrei K. Yudin*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, Ontario, Canada
M5S 3H6
S
* Supporting Information
ABSTRACT: The development of a palladium-catalyzed sp3−
sp2 Suzuki−Miyaura cross-coupling of B-alkyl-N-methylimino-
diacetyl (B-alkyl MIDA) boronates and (hetero)aryl bromides
is reported. This transformation is tolerant of a variety of
functional groups (F, NO2, CN, Cl, COCH3, and CHO). B-
Alkyl MIDA boronates allow an efficient cross-coupling reaction directed toward the synthesis of unsymmetrical methylene
diaryls as well as alkylated arenes in good to excellent yields.
he high functional group tolerance,1 stability,2 and
In contrast to the challenges associated with manipulation of
3,4
Taccessibility of boronic acids
B-alkyl-9-BBN reagents, most B-alkyl boronic acids are stable
under ambient conditions and can be isolated through
crystallization or chromatography.10 However, boronic acids
give rise to side reactions (e.g., protodeborylation and β-
hydride elimination) under Suzuki−Miyaura conditions, which
is why superstoichiometric loadings are often required.4,9,11
Tetrahedral boronates inhibit the undesired deborylation by
coordinative saturation of the normally vacant p-orbital of
boron. The most effective tetrahedral boronates that inhibit the
undesired decomposition pathways are the potassium trifluor-
oborates (RBF3K) and N-methyliminodiacetyl boronates (RB-
[MIDA]).12
have made the Suzuki−
Table 1. Optimization of Reaction Conditions
ligand
%
%
yield
%
a
a
b
entry
[Pd] (mol %)
(mol %) conversion
selectivity
1
2
Pd(OAc)2 (10)
Pd(OAc)2 (10)
PPh3 (20)
73
81
42
24
58
30
S-Phos
(20)
Primary and secondary sp3-RBF3K species have been
successfully applied in the Suzuki−Miyaura reaction with
various electrophilic partners,13 whereas sp3-MIDA boronates
have remained underdeveloped with pinene-derived iminodi-
acetic acid (PIDA) boronates as notable exceptions.14 Herein,
we demonstrate that primary sp3-MIDA boronates successfully
participate in the Suzuki−Miyaura cross-coupling forming
unsymmetrical methylene diaryls and alkylated arenes which
are important structural units found in a number of
pharmaceutically relevant compounds.15
B-Benzyl MIDA boronate 1 and bromobenzene served as
prototypical coupling partners. A variety of palladium catalysts
and ligands were screened, and their cross-coupling perfomance
was measured via internally calibrated gas chromatography
(Table 1).
3
4
5
Pd(PPh3)4 (10)
PdCl2 (10)
none
99
71
0
49
25
0
50
35
0
dppf (20)
c
6
PdCl(dppf)·
CH2Cl2 (10)
63
39
62
d
7
PdCl(dppf)·
CH2Cl2 (10)
60
99
60
55
89
30
92
89
50
8
PdCl(dppf)·
CH2Cl2 (10)
e
9
PdCl(dppf)·
CH2Cl2 (10)
a
Yields obtained by GC vs calibrated internal standard (naphthalene).
% selectivity = (% yield/% conversion) × 100. 3.0 equiv of K2CO3
was used. Reagent-grade THF and distilled H2O used. Toluene was
used in place of THF.
b
c
d
e
Moderate to excellent conversion ratios were observed in
every example. However, the selectivity of the reaction was
found to vary. The dialkylbiarylphosphine ligand S-Phos,16 in
combination with Pd(OAc)2, performed poorly in the coupling
reaction, providing only 24% yield and 36% selectivity17 for the
desired cross-coupling product (entry 2).18 Pd(PPh3)4 afforded
Miyaura reaction a potent tool in the synthesis of a wide range
of challenging targets.5 There has been comprehensive work on
the development of an efficient sp2−sp2 Suzuki−Miyaura cross-
coupling reaction;6 however, there have been far fewer reports
on sp3−sp2 or sp3−sp3 variants.3,7 B-Alkyl-9-BBN derivatives
are the most commonly employed reagents for sp3−sp2
Suzuki−Miyaura cross-couplings.2,3 However, difficulties with
isolation and functional group incompatibility of B-alkyl-9-BBN
reagents limit their widespread use.3a,8,9
Received: January 7, 2014
Published: February 14, 2014
© 2014 American Chemical Society
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Letter
a
Table 2. Suzuki−Miyaura Cross-Coupling of 1
Table 3. Cross-Coupling of Unfunctionalized Primary MIDA
Boronates
a
a
All reactions performed with 1.1 equiv of 1 and 1.0 equiv of arylBr.
48 h. No cross-coupled product was observed. 1.3 equiv of 1 was
b
c
d
used.
high conversion but afforded only 50% selectivity for
diphenylmethane 2 (entry 3). The facile oxidative addition of
Pd(OAc)2/S-Phos and Pd(PPh3)4 to the C−Br bond of
bromobenzene resulted in more deleterious side reactions,
including protodehalogenation, that afforded a reduced assay
yield. Commercially available PdCl2(dppf)·CH2Cl2 (3, entry 8)
proved to be the optimal catalyst, delivering excellent
conversion and yield after 21 h (entry 8).19 High selectivity
for the desired product could be due to the slower rate of
oxidative addition as compared to Pd(PPh3)4 and Pd(OAc)2/S-
Phos.20 The efficiency of 3 in the presence of other bases was
also tested to uncover the optimal set of reaction conditions.1,20
A screen of inorganic bases confirmed K2CO3 to be optimal for
this method (see the Supporting Information).21−23
a
All reactions performed with 1.1 equiv of MIDA boronate and 1.0
b
c
d
equiv of arylBr. 90 h. 90% conversion. 1.5 equiv of 15.
good yields. The electronic nature of the aryl bromides had an
impact on the overall performance of the cross-coupling
reaction. Electron-poor aryl bromides afforded higher yields
after 24 h, whereas electron-rich bromides required 48 h to
proceed to completion (entries 6 and 7). In addition,
bromopyridines (entries 10−12) required extended reaction
We then sought to expand the scope of aryl halide partners.
As illustrated in Table 2, the cross-coupling of 1 with a number
of aryl bromides resulted in the desired benzylated arenes in
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Letter
development has allowed the efficient synthesis of unsym-
metrical methylene diaryls and alkylated arenes.
Table 4. Cross-Coupling of Functionalized Primary MIDA
Boronates
a
ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental details and physical properties of compounds
(1H, 11B, 13C, HRMS). This material is available free of charge
via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ayudin@chem.utoronto.ca.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Funding for this work was provided by the Natural Science and
Engineering Research Council (NSERC) and the University of
Toronto. J.S.D. thanks NSERC for PGS-D funding and OGS
for the Queen Elizabeth II graduate scholarship. We thank Dr.
Matthew Forbes at the AIMS Laboratory (University of
Toronto) for assistance and discussion on elucidation of
reaction intermediates.
a
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All reactions performed with 1.1 equiv of MIDA boronate and 1.0
■
equiv of arylBr.
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