Palladium-catalyzed borylation of aryl and heteroaryl halides utilizing tetrakis(dimethylamino)diboron: One step greener

Article abstract of DOI:10.1021/ol302124j

The palladium-catalyzed borylation of aryl and heteroaryl halides with a novel borylating agent, tetrakis(dimethylamino)diboron [(Me₂N) ₂B-B(NMe₂)₂], is reported. The method is complementary to the previously reported method utilizing bis-boronic acid (BBA) in that certain substrates perform better under one set of optimized reaction conditions than the other. Because tetrakis(dimethylamino)diboron is the synthetic precursor to both BBA and bis(pinacolato)diboron (B ₂Pin₂), the new method represents a more atom-economical and efficient approach to current borylation methods.

Full text of DOI:10.1021/ol302124j

ORGANIC
LETTERS
2012
Vol. 14, No. 18
4814–4817
Palladium-Catalyzed Borylation of Aryl
and Heteroaryl Halides Utilizing
Tetrakis(dimethylamino)diboron:
One Step Greener
Gary A. Molander,* Sarah L. J. Trice, and Steven M. Kennedy
Roy and Diana Vagelos Laboratories and Penn/Merck Laboratory for High Throughput
Experimentation, Department of Chemistry, University of Pennsylvania, Philadelphia,
Pennsylvania 19104-6323, United States
gmolandr@sas.upenn.edu
Received July 31, 2012
ABSTRACT
The palladium-catalyzed borylation of aryl and heteroaryl halides with a novel borylating agent, tetrakis(dimethylamino)diboron
[(Me2N)2BÀB(NMe2)2], is reported. The method is complementary to the previously reported method utilizing bis-boronic acid (BBA) in that
certain substrates perform better under one set of optimized reaction conditions than the other. Because tetrakis(dimethylamino)diboron is the
synthetic precursor to both BBA and bis(pinacolato)diboron (B2Pin2), the new method represents a more atom-economical and efficient approach
to current borylation methods.
The discovery of the palladium-catalyzed borylation of
aryl halides with bis(pinacolato)diboron (B2Pin2) by
Miyauraand co-workers in1995revolutionizedthe synthe-
sis of arylborons used for cross-coupling reactions.1 For
the first time, pinacol boronates could be prepared without
the use of harsh organometallic reagents, providing access
to numerous aryl- and heteroarylboron derivatives pos-
sessing sensitive functional groups. With greater access to
diverse borylated species, exploration of the SuzukiÀ
Miyaura reaction exploded. Since then, many groups have
focused on improving the scope of this important CÀC
bond-forming reaction. Surprisingly, few have worked to
develop new ways to access the requisite borylated species.
The methods that have emerged still rely largely on B2Pin2
or modified versions of this reagent.2À13
Recently, we reported a user-friendly, more environ-
mentally sound method that provides direct access to
boronic acids utilizing bis-boronic acid (BBA).14,15 With
the crude boronic acid provided after Celite filtration and
aqueous workup, one can isolate the boronic acid itself or
synthesize myriad boronate esters and trifluoroborates. It
is also possible to skip the workup and isolation altogether
(4) Chow, W. K.; So, C. M.; Lau, C. P.; Kwong, F. Y. Chem.;Eur. J.
2011, 17, 6913–6917.
€
(5) Furstner, A.; Seidel, G. Org. Lett. 2002, 4, 541–543.
(6) Ishiyama, T.; Ishida, K.; Miyaura, N. Tetrahedron 2001, 57,
9813–9816.
(1) Ishiyama, T.; Murata, M.; Miyaura, N. J. Org. Chem. 1995, 60,
(7) Kawamorita, S.; Ohmiya, H.; Iwai, T.; Sawamura, M. Angew.
Chem., Int. Ed. 2011, 50, 8363–8366.
(8) Lu, J.; Guan, Z.; Gao, J.; Zhang, Z. Appl. Organomet. Chem.
7508–7510.
(2) Billingsley, K.; Barder, T.; Buchwald, S. Angew. Chem Int. Ed.
2007, 46, 5359–5363.
2011, 25, 537–541.
(3) Billingsley, K. L.; Buchwald, S. L. J. Org. Chem. 2008, 73, 5589–
5591.
(9) Moldoveanu, C.; Wilson, D.; Wilson, C.; Corcoran, P.; Rosen, B.;
Percec, V. Org. Lett. 2009, 11, 4974–4977.
r
10.1021/ol302124j
Published on Web 09/04/2012
2012 American Chemical Society

Scheme 1. Synthesis of Trifluoroborates, Boronate Esters, and
One-Pot Cross-Coupled Products from the Same Boronic Acid
Intermediate
Scheme 2. Synthesis of B2Pin2 and BBA from Shared Precursor
(Me2N)2BB(NMe2)2
and instead performa one-pot, two-step borylation/Suzuki
reaction, providing cross-coupled products from two aryl
halides (Scheme 1). This method represents a break-
through on the existing Miyaura borylation using B2Pin2.
Through the use of BBA, pinacol is eliminated from the
entireprocess, thusmaking access to the boronic acidmuch
easier and more efficient.
The use of BBA had appeared only infrequently in the
chemical literature at the start of our research, in part because
it was not commercially available, and thus, its synthesis was
required.16À18 The synthetic sequence for the production of
BBA is shared with that of B2Pin2 up to the precursor
tetrakis(dimethylamino)diborane [(Me2N)2BB(NMe2)2].19
However, instead of adding pinacol in the last step, (Me2N)2-
BB(NMe2)2 is hydrolyzed with aqueous acid at low tempera-
tures. The product BBA, a white solid, precipitates out of
solution and can be filtered off and dried (Scheme 2).20,21
(Me2N)2BB(NMe2)2 has appeared in the chemical lit-
erature as a precursor to other boronate esters,22À29 but
not as a high-yielding, general borylating agent.30,31 In this
paper, we report the first broadly successful borylation
of aryl- and heteroaryl halides and pseudohalides using
(Me2N)2BB(NMe2)2. Through the use of this method, the
necessity to convert (Me2N)2BB(NMe2)2 into BBA or
B2Pin2 is avoided, reducing both time and chemical waste.
These savings are especially noteworthy when one con-
siders the inefficiency of B2Pin2 in general. Pinacol makes
up >90% of the mass of B2Pin2. Once synthesized, many
pinacol boronates are converted to the corresponding
boronic acids or trifluoroborates with often harsh, ineffi-
cient, or tedious methods, while needlessly disposing of
pinacol.23,32À41 As with our first borylation method
with BBA, (Me2N)2BB(NMe2)2 virtually eliminates this
demasking step, providing more efficient and greener
access to desired compounds.
(10) Moldoveanu, C.; Wilson, D.; Wilson, C.; Leowananwat, P.;
Resmerita, A.; Lui, C.; Rosen, B.; Percec, V. J. Org. Chem. 2010, 75,
5438–5452.
(11) Rosen, B.; Huang, C.; Percec, V. Org. Lett. 2008, 10, 2597–2600.
(12) Tang, W.; Keshipeddy, S.; Zhang, Y.; Wei, X.; Savoie, J.; Patel,
N. D.; Yee, N. K.; Senanayake, C. H. Org. Lett. 2011, 13, 1366–1369.
(13) Wilson, D.;Wilson, C.;Moldoveanu, C.;Resmerita, A.;Corcoran,
P.; Hoang, L.; Rosen, B.; Percec, V. J. Am. Chem. Soc. 2010, 132,
1800–1801.
The new method utilizing (Me2N)2BB(NMe2)2 is per-
formed with only slight modifications to our recently
optimized method usingBBA and Buchwald’ssecond-gen-
eration palladium precatalyst (XPhos-Pd-G2, L = XPhos,
(27) Moezzi, A.; Olmstead, M.; Power, P. Organometallics 1992, 11,
2383–2388.
(14) Molander, G. A.; Trice, S. L. J.; Dreher, S. D. J. Am. Chem. Soc.
2010, 132, 17701–17703.
(28) Moezzi, A.; Olmstead, M.; Power, P. J. Chem. Soc., Dalton
Trans. 1992, 2429–2434.
(29) Lawlor, F.; Norman, N.; Pickett, N.; Robins, E. G.; Nguyen, P.;
Lesley, G.; Marder, T.; Ashmore, J.; Green, J. Inorg. Chem. 1998, 37,
5282–5288.
(15) Molander, G. A.; Trice, S. L. J.; Kennedy, S. M.; Dreher, S. D.;
Tudge, M. T. J. Am. Chem. Soc. 2012, 134, 11667–11673.
(16) (a) Pilarski, L. T.; Szabo, K. Angew. Chem., Int. Ed. 2011, 50,
8230–8232. (b) Sebelius, S.; Olsson, V.; Szabo, K. J. Am. Chem. Soc.
2005, 127, 10478–10479.
(30) Ishiyama, T.; Matsuda, N.; Murata, M.; Ozawa, F.; Suzuki, A.;
Miyaura, N. Organometallics 1996, 15, 713–720.
(31) Ishiyama, T.; Itoh, Y.; Kitano, T.; Miyaura, N. Tetrahedron
Lett. 1997, 38, 3447–3450.
(32) Nakamura, H.; Fujiwara, M.; Yamamoto, Y. J. Org. Chem.
1998, 63, 7529–7530.
(17) Selander, N.; Kipke, A.; Sebelius, S.; Szabo, K. J. Am. Chem.
Soc. 2007, 129, 13723–12731.
(18) Selander, N.; Szabo, K. Chem. Commun. 2008, 3420–3422.
(19) Ishiyama, T.; Murata, M.; Ahiko, T.; Miyaura, N. Org. Synth.
2004, 10, 115–119.
(20) McCloskey, A. L.; Brotherton, R. J.; Boone, J. L. J. Am. Chem.
Soc. 1961, 83, 4750–4754.
(21) BBA is now commercially available. CAS 13675-18-8.
(22) Clegg, W.; Lawlor, F.; Lesley, G.; Marder, T.; Norman, N.;
Orpen, G.; Quayle, M.; Rice, C.; Scott, A.; Souza, F. J. Organomet.
Chem. 1997, 550, 183–192.
(33) Falck, J. R.; Bondlela, M.; Venkataraman, S. K. J. Org. Chem.
2001, 66, 7148–7150.
(34) Deng, H.; Jung, J. K.; Liu, T.; Kuntz, K. W.; Snapper, M. L.;
Hoveyda, A. H. J. Am. Chem. Soc. 2003, 125, 9032–9034.
(35) Song, Y. L.; Morin, C. Synlett 2001, 266–268.
(36) Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1999, 64, 2976–2977.
(37) Ma, D.; Wu, Q. Tetrahedron Lett. 2001, 42, 5279–5281.
(38) Yang, W.; He, H.; Drueckhammer, D. G. Angew. Chem., Int. Ed.
2001, 40, 1714–1718.
(23) Zaidlewicz, M.; Wolan, A. J. Organomet. Chem. 2002, 657, 129–
135.
(24) Nguyen, P.; Lesley, G.; Taylor, N.; T., M. Inorg. Chem. 1994, 33,
4623–4624.
(39) Pennington, T.; Kardiman, C.; Hutton, C. Tetrahedron Lett.
2004, 45, 6657–6660.
(40) Yuen, A.; Hutton, C. Tetrahedron Lett. 2005, 46, 7899–7903.
(41) Bagutski, V.; Ros, A.; Aggarwal, V. K. Tetrahedron 2009, 65,
9956–9960.
(25) Boller, T. M.; Murphy, J. M.; Hapke, M.; Ishiyama, T.;
Miyuaura, N.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 14263–14278.
(26) Clegg, W.; Johann, T.; Marder, T.; Norman, N.; Orpen, G.;
Peakman, T.; Quayle, M.; Rice, C.; Scott, A. J. Chem. Soc., Dalton
Trans. 1998, 1431–1438.
Org. Lett., Vol. 14, No. 18, 2012
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Table 1. Trifluoroborate Synthesis from Aryl Chlorides and
Bromides*
Scheme 3. Comparison of (Me2N)2BB(NMe2)2 and BBA
Methods
Scheme 3).15,42 The same low catalyst load of 0.5 mol %
with 1.0 mol % of XPhos (3:1 ligand/catalyst) is used as
well as 3 equiv of KOAc. Although the BBA method is
performed in EtOH, the current method produces higher
yields when run in MeOH. Aside from the fact that BBA is
a solid and (Me2N)2BB(NMe2)2 is a liquid, operationally
speaking, the setup of the reactions is identical. As all
reagents used are air stable, the solids are first weighed on a
benchtop balance. The vessel is then sealed and placed
under an atmosphere of argon. Degassed MeOH is added
to the reaction via syringe, followed by (Me2N)2BB(NMe2)2
in a similar manner. The reaction is then heated for the
time required. When BBA was used in our previous
method, a very distinct color change occurred, indicating
the completion of the reaction. Although a color change is
observed with (Me2N)2BB(NMe2)2, it is slightly less dis-
tinct with some substrates, and therefore, a GC analysis is
performed to confirm consumption of starting material.
In our first disclosure of the borylation of aryl chlorides
with BBA, we demonstrated the isolation of the boronic
acid product but found it difficult to obtain the pure
crystalline form without some loss in yield. The same was
found with the current method. Although the trifluorobo-
rate of 4-fluorobenzene was obtained in an excellent yield
of 97% (Table 1, entry 8), isolation of the corresponding
boronic acid afforded the crystalline solid in 85% yield
(∼95% pure, Table 1, entry 8f). As we seek to demonstrate
the efficiency of the present method, crude boronic acids
were conveniently converted to the corresponding trifluoro-
borates. This transformation also preserves the CÀB bond
more effectively if the compounds are to be stored on the
benchtop for prolonged periods of time.
* General conditions: 0.5 mol % of 1, 1.0 mol % 2, 3.0 equiv of
KOAc, 3.0 equiv of B2(NMe2)4, MeOH (0.2 M), 60 °C for time indicated.
a 0.5 M MeOH. b Yield from previous method with B2(OH)4 as boron
source (ref 15). c Reaction run in a round-bottom flask with reflux
condenser under argon. d 10 mmol reaction run under general reaction
conditions. e (1) 5.0 mol % of Pd(OAc)2, 10 mol % of 2, 3.0 equiv of
KOAc, 60 °C in 2 mL MeOH for 20 min. (2) 3.0 equiv of B2(NMe2)4
dissolved in 5.5 mL of MeOH, 1-chloro-4-fluorobenzene, 60 °C for time
indicated. f Yield of isolated boronic acid. g From the acetonide.
vessel affected the reaction. There was no apparent differ-
ence in carrying out the reaction under these conditions
(Table 1, entry 2c). The reaction can also be efficiently
scaled to 10 mmol with no loss in yield (Table 1, entry 5d).
Although not as operationally simple, the less expensive
Pd(OAc)2 can be used in place of the preformed precatalyst 1,
providing the 4-fluorophenyltrifluoroborate in 87% yield
(Table 1, entry 8e). (Me2N)2BB(NMe2)2 appears in our
hands to be more stable to the borylation reaction condi-
tions than BBA, but preconversion of Pd(OAc)2 to Pd(0)
or the use of the preformed Pd-XPhos-G2 still provide
far superior conversion to product than reactions using
Pd(OAc)2 directly. Preformation to Pd(0) is adequately
achieved by heating Pd(OAc)2 with XPhos and KOAc in
MeOH for 30 min at 60 °C before addition of (Me2N)2-
BB(NMe2)2 and the aryl halide.
The scope of the borylation of aryl chlorides and
bromides is outlined in Table 1. The method tolerates a
wide range of functional groups, providing most trifluoro-
borates in good to excellent yield. It should also be noted
that increasing the solvent concentration from 0.2 M
MeOH to 0.5 M did not appear to affect the yield in the
substrates attempted (Table 1, entries 1a and 8a). A reac-
tion was performed in a round-bottom flask fitted with a
reflux condenser to determine whether a sealed reaction
For comparison, yields of trifluoroborates obtained
through the use of BBA are also included in the tables
throughout.15 In general, yields are comparable across both
synthetic platforms (Table 1, entries 1, 6À9, 13, and 15).
In a few instances, BBA provides yields 10% or above that
(42) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010,
132, 14073–14075.
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Org. Lett., Vol. 14, No. 18, 2012

Table 2. Trifluoroborate Synthesis from Heteroaryl Chlorides
and Bromides*
Table 3. Scope of Electrophiles in the Borylation Reaction with
(Me2N)2BB(NMe2)2
a
a General conditions: 0.5 mol % of 1, 1.0 mol % of 2, 3.0 equiv of
KOAc, 3.0 equiv of B2(NMe2)4, MeOH (0.2 M), 60 °C for time indicated.
b Yield from previous method with B2(OH)4 as boron source (ref 15).
anisoles for direct comparison. The bromo-, chloro-, and
triflate-substituted anisole all performed well with either
borylation method. Iodides, however, provide the best
results with BBA as the borylating agent.
In summary, the first palladium-catalyzed direct boryla-
tion of aryl and heteroaryl halides utilizing (Me2N)2BB-
(NMe2)2 as a general borylating agent has been demon-
strated. The method tolerates a wide range of functional
groups, providing the corresponding trifluoroborates in
good to excellent yields.
As (Me2N)2BB(NMe2)2 is the common precursor to both
BBA and B2Pin2, the novel method represents an even more
atom-economical and efficient approach to previously re-
ported methods utilizing BBA or other derivatives (Table 3).
However, the methods are complementary, and in some
cases superior results can be obtained when one borylating
agent [BBA or (Me2N)2BB(NMe2)2] is used instead of the
other. In addition, because BBA is a solid and (Me2N)2-
BB(NMe2)2 is a liquid, there is now a choice of dosing if
desired. All reagents in the method are easily handled outside
of a glovebox, and degassed MeOH is used. Low catalyst
loads, low temperatures, and high solvent concentrations
provide an efficient and easy to use method for borylation.
* General conditions: 0.5 mol % of 1, 1.0 mol % 2, 3.0 equiv of KOAc,
3.0 equiv of B2(NMe2)4, MeOH (0.2 M), 60 °C for time indicated. a Yield
from previous method with B2(OH)4 as boron source (ref 15).
of (Me2N)2BB(NMe2)2 (Table 1, entries 3, 4, 10, and 12).
Noteworthy are the cases where (Me2N)2BB(NMe2)2 sig-
nificantly outperforms BBA (Table 1, entries 2 and 11),
with the 2,6-dimethyl phenyltrifluoroborate (Table 1, en-
try 16) providing the most impressive example of reactivity
differences. Even the 2,6-diethylphenyltrifluoroborate was
obtained in a reasonable yield of 43% (Table 1, entry 17).
The complementary nature of the two methods now
provides more synthetic options for the borylation of aryl
halides.
The method was also extended to heteroaryl halides,
further demonstrating that certain substrates provide
superior results employing one method over the other.
For example, both the isoxazole- and benzoxazole-
substituted phenyltrifluoroborates are obtained in superior
yield when BBA is used as the borylating source (Table 2,
entries 4 and 7).15 However, (Me2N)2BB(NMe2)2 can be
utilized to afford 3-thienyltrifluoroborate, a material that
could not be accessed in the previously developed BBA
method. With respect to the indoles synthesized, the use of
a Boc protecting group provides significantly higher yields
than when it is not used (Table 2, entries 5 and 6), with
(Me2N)2BB(NMe2)2 providing good to excellent results
for both. Most noteworthy when comparing methods is
the significant difference in catalyst load when borylating
heteroaryl compounds (Table 2, entries 3 and 8). When
using BBA, 5 mol % palladium was required.15 With
(Me2N)2BB(NMe2)2, a 10-fold decrease in catalyst loading
could be achieved (0.5 mol %).
Acknowledgment. We thank the National Institutes of
Health (NIGMS R01 GM081376) for its generous support
of this research. S.L.J.T. is funded through a Merck
Doctoral Fellowship. S.L.J.T. thanks Merck West Point
Medicinal Chemistry for their generous financial support
and encouragement during her doctoral program. Simon
Berritt (University of Pennsylvania) is acknowledged
for his dedication to the UPenn/Merck HTE Laboratory.
We thank BASF for a generous donation of (Me2N)2-
BB(NMe2)2.
Supporting Information Available. General procedures
and NMR spectra. This material is available free of
charge via the Internet at http://pubs.acs.org.
Finally, we explored the scope of electrophilic partners
that could be utilized in the reaction, using 4-substituted
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 18, 2012
4817