A general method for Suzuki-Miyaura coupling reactions using lithium triisopropyl borates

Article abstract of DOI:10.1021/ol302063g

Conditions for the Suzuki-Miyaura coupling of lithium triisopropyl borates are reported, as well as a procedure for a one-pot lithiation, borylation, and subsequent Suzuki-Miyaura coupling of various heterocycles with aryl halides. These borate species are much more stable toward protodeboronation than the corresponding boronic acids and can conveniently be stored on benchtop at room temperature.

Full text of DOI:10.1021/ol302063g

ORGANIC
LETTERS
2012
Vol. 14, No. 17
4606–4609
A General Method for SuzukiꢀMiyaura
Coupling Reactions Using Lithium
Triisopropyl Borates
Matthias A. Oberli and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge,
Massachusetts 02139, United States
sbuchwal@mit.edu
Received July 25, 2012
ABSTRACT
Conditions for the SuzukiꢀMiyaura coupling of lithium triisopropyl borates are reported, as well as a procedure for a one-pot lithiation, borylation,
and subsequent SuzukiꢀMiyaura coupling of various heterocycles with aryl halides. These borate species are much more stable toward
protodeboronation than the corresponding boronic acids and can conveniently be stored on benchtop at room temperature.
The SuzukiꢀMiyaura cross-coupling (SMC) reaction
has become an indispensible tool for the preparation of a
wide variety of organic molecules and materials.1,2 Key to
the success of this reaction is the inherent compatibility of
organoboron compounds with many functional groups,3
their low toxicity, and the fact that many organoboronic
acids are commerciallyavailable. However, under the most
commonly used SMC conditions, many organoboronic
acids, especially five-membered heterocyclic boronic acids,
are prone to decomposition via protodeboronation and other
processes.4 To address these issues, both improved catalyst
systems5 and protected or masked boronate substrates6 have
been developed, allowing for the cross-coupling of inherently
unstable boronic acids such as five-membered heterocycles7
and polyfluorophenyl boronic acids.5a
Scheme 1. Preparation and Use of Lithium Triisopropyl Borates
3 as Nucleophiles for SuzukiꢀMiyaura Reactions
(1) (a) Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979,
866–867. (b) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett.
1979, 20, 3437–3440. (c) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth.
Commun. 1981, 11, 513–519.
(2) For selected reviews about the SuzukiꢀMiyaura cross-coupling,
see: (a) Fleckenstein, C. A.; Plenio, H. Chem. Soc. Rev. 2010, 39, 694–
711. (b) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461–
1473. (c) Blleina, F.; Carpita, A.; Rossi, R. Synthesis 2004, 2419–2440.
(d) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–2483.
(3) Molander, G. A.; Figueroa, R. Aldrichimica Acta 2005, 38, 49–56.
(4) (a) Kuivila, H. G.; Reuwer, J. F.; Mangravite, J. A. Can. J. Chem.
1963, 41, 3081–3090. (b) Kuivila, H. G.; Reuwer, J. F.; Mangravite, J. A.
J. Am. Chem. Soc. 1964, 86, 2666–2670.
(6) (a) Billingsley, K. L.; Buchwald, S. L. Angew. Chem., Int. Ed.
2008, 47, 4695–4698. (b) Yamamoto, Y.; Takizawa, M.; Yu, X.-Q.;
Miyaura, N. Angew. Chem., Int. Ed. 2008, 47, 928–931. (c) Noguchi, H.;
Shioda, T.; Chou, C.-M.; Suginome, M. Org. Lett. 2008, 10, 377–380.
(d) Hodgson, P. B.; Salingue, F. H. Tetrahedron Lett. 2004, 45, 685–687.
(5) (a) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010,
132, 14073–14075. (b) Yang, D. X.; Colleti, S. L.; Wu, K.; Song, M.; Li,
€
ꢀ
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G. Y.; Shen, H. C. Org. Lett. 2009, 11, 381–384. (c) Wuttke, E.; Nagele,
(e) Gravel, M.; Thomson, K. A.; Zak, M.; Berube, C.; Hall, D. G. J. Org.
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Chem. 2002, 67, 3–15.
r
10.1021/ol302063g
Published on Web 08/15/2012
2012 American Chemical Society

Lithium triisopropyl borates (LTB) are often accessed
as intermediates in the syntheses of commonly used masked
boronates such as the organotrifluoroborates8 and
N-methyliminodiacetic acid (MIDA) boronates (Scheme 1).9
Specifically lithium triisopropyl 2-pyridinylborates have
been employed directly as nucleophiles for SCM reac-
tions.6a However, the coupling of other LTB nucleophiles,
particularly those derived from heterocycles that form
unstable boronic acids, has been largely unexplored. Herein,
we report the use of lithium triisopropyl borates as nucleo-
philes in SCM reactions for a wide range of heterocycles.
Lithium triisopropyl borates (LTB) 3 are readily pre-
pared via a one-pot procedure.6d For the borates depicted
in Scheme 2, lithiation at ꢀ78 °C was followed by the
addition of triisopropyl borate, after which the solution
was gradually warmed to room temperature. The solvent
was then removed, and the resulting LTB was dried under
vacuum at 80 °C. The crude borate salt, still containing
lithium bromide, was directly used in SMC reactions
without any further purification based on a 100% yield.10
Using this procedure, lithium triisopropyl borates 5ꢀ12
were synthesized and subsequently used as nucleophiles in
SMC reactions with various aryl and heteroaryl electro-
philes. We began by evaluating the use of LTBs under
conditions previously reported for the SMC using a diphe-
nyl phosphine oxide ligand.6a While these couplings were
successful, we found that by using XPhos precatalyst 13 we
could obtain higher yields of coupled products under
milder reaction conditions and in shorter reaction times
(Scheme 3). The use of precatalyst 13 was crucial in that it
rapidly generates the catalytically active Pd(0)L1 catalyst
at the low reaction temperature (40 °C) required for the
efficient coupling of these sensitive borates. The reactions
were run with a 3 mol % catalyst loading in a 1:2 THF/
aqueous 0.5 M K3PO4 solution. Decreasing the loading of
13 from 3 to 1 mol % resulted in a slightly lower yield (14b,
96% vs 14c, 84%).
Scheme 2. Synthesis of Lithium Triisopropyl Boratesa
a These were isolated and used in coupling reactions without purifica-
tion. Reaction conditions: ArBr (3.16 mmol), THF (3 mL), toluene (12 mL),
n-BuLi (1.4 mL, 2.5 M in hexanes, 3.48 mmol, 1.1 equiv), B(OiPr)3 (0.75 mL,
3.48 mmol, 1.1 equiv), ꢀ78 °C to rt, 8 h.
immediately for an SMC and found that borates 5ꢀ12
were remarkably robust. When used in an SMC reaction,
these borates reacted to provide products in comparable
yields even after being stored at room temperature for a
month in a closed vial under air. In fact, the use of aryl
borates 5, 7, and 10 gave comparable yields in SCM
reactions after storage under air for up to 4 months. In
comparison, 2-furanyl boronic acid loses 90% of its activ-
ity following storage under air for just 15 days.9a
We hypothesize that the bulky isopropyl groups in the
LTB protect the borate against protodeboronation. Since
no reaction was observed with LTB under anhydrous
SMC reaction conditions, we also presume that hydro-
lysis of the LTBs to their corresponding boronic acids is
required for fast and efficient transmetalation. However,
an advantage of using the boronate complex as a nucleo-
phile is that the reaction occurs in a THF/water mixture as
solvent with no additional base added, as upon hydrolysis,
basic isopropylate is released. The pH value of a typical
reaction mixture in THF with water as cosolvent is be-
tween 12 and 13. Thus, the use of LTB nucleophiles allows
for SMC reaction with base-sensitive substrates such as
nitro aromatics, methyl esters, or oxazoles (Scheme 4).11
We next sought to combine the lithiation, borylation,
and SMC reaction into a one-pot procedure. Previously,
we showed that an analogous one-pot sequence could be
successfully applied to flow conditions.12 To this end, the
aqueous base was directly added to the crude solution of
LTB at ꢀ78 °C, followed by the aryl halide, precatalyst 13,
Aryl bromides, chlorides, and triflates were all compe-
tent electrophiles and could be coupled with good to
excellent yields. Significantly, the mild reaction conditions
allowed for the coupling of (L)-4-bromophenylalanine
without any erosion in enantioselectivity 24.
We were next interested in evaluating the stability of
these unpurified heteroaryl triisopropyl borates if not used
(7) (a) Kabri, Y.; Gellis, A.; Vanelle, P. Eur. J. Org. Chem. 2009, 24,
4059–4066. (b) Gill, G. S.; Grobelny, D. W.; Chaplin, J. H.; Flynn, B. L.
J. Org. Chem. 2008, 73, 1131–1134. (c) Billingsley, K. L.; Buchwald, S. L.
J. Am. Chem. Soc. 2007, 129, 3358–3366. (d) Billingsley, K. L.; Anderson,
K. W.; Buchwald, S. L. Angew. Chem., Int. Ed. 2006, 45, 3484–3488.
(e) Tyrell, E.; Brookes, P. Synthesis 2004, 469–483. (f) Fleckenstein,
C. A.; Plenio, H. J. Org. Chem. 2008, 73, 3236–3244. (g) Li, J.-H.; Zhu,
Q.-M.; Xie, Y.-X. Tetrahedron 2006, 62, 10888–10895.
(8) (a) Molander, G. A.; Ellis, N. M. Acc. Chem. Res. 2007, 40, 275–
286. (b) Molander, G. A.; Canturk, B. Angew. Chem., Int. Ed. 2009, 48,
9240–9261. (c) Stefani, H.; Cella, R.; Vieira, A. Tetrahedron 2007, 63,
3623–3658.
(9) (a) Knapp, D. M.; Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc.
2009, 131, 6961–6963. (b) Gillis, E. P.; Burke, M. D. J. Am. Chem. Soc.
2007, 129, 6716–6717.
(10) It should be noted that, while 6-bromo-2-methylquinoline
was effectively transformed into 8, during attempts to transform 4-
bromoquinoline and N-methylbenzimidazole into their corresponding
LTBs, the addition of an n-butyl group to the 2-position was observed.
(11) The SuzukiꢀMiyaura reactions described in this paper worked,
in general, in THF with water as cosolvent. For some heterocyclic
substrate combinations, however, the use of THF combined with
aqueous potassium phosphate solution afforded higher yields.
(12) Shu, W.; Pellegatti, L.; Oberli, M. A.; Buchwald, S. L. Angew.
Chem., Int. Ed. 2011, 50, 10665–10669.
Org. Lett., Vol. 14, No. 17, 2012
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lithiation/borylation sequence to provide products 37
(Scheme 5) and 45 (Scheme 6) in good yields.
Scheme 3. Heteroaryl Triisopropyl Borates as Nucleophile in
SMC Reactions
Scheme 4. SMC Reaction in THF/Water Enables the Coupling
of Base Sensitive Substratesa
a Reaction conditions: 3 (0.375 mmol, 1.5 equiv), Ar0X0 (0.25 mmol,
1.0 equiv), 13 (3 mol %), THF (0.5 mL), water (1.0 mL). Isolated yields
based on two runs.
Scheme 5. One Pot LithiumꢀHalogen Exchange, Borylation,
and SCM Reaction
a 1% precatalyst 13 was used. b 87% yield after storing lithium
triisopropyl 2-furanyl borate for 4 months in a closed vial on a benchtop.
c 6% Z-isomer was obtained that corresponds to the same E/Z ratio as in
the starting material. d 4-Bromopyridine was used as HCl salt. e Without
racemization. f Reaction conditions: ArX (0.25 mmol, 1.0 equiv), 3
(0.375 to 0.75 mmol, 1.5 to 3.0 equiv), 13 (3 mol %), THF (0.5 mL),
and K3PO4 aq (0.5 M, 1.0 mL), 2 h, 40 °C. Isolated yields are the average
of two runs. g 3 equiv of 3 were used.
and stirring the SMC at 40 °C for 2 h. We found that
product formation occurred in yields similar to those of
SMC reactions conducted with isolated LTB (Scheme 5).
We investigated conducting the SMC at a lower catalyst
loading (1 mol %) and found that, particularly for aryl
bromide electrophiles, the products were obtained in
slightlylower yields (14e to14g). Inthe caseofarylchloride
electrophiles, however, 1 mol % of precatalyst 13 was
sufficient (14h). Under the optimized conditions, a broad
scope of heterocyclic aryl halides were successful SMC
substrates. For the electrophilic coupling partner, pyri-
dines (32, 34, and 36), pyrimidines (33 and 37), 1H-indoles
(35), aromatic aldehydes (42), 3-chloro-1,2-benzisothia-
zole (39), and pyrazines (40) were all good substrates.
Notably, aryl bromides could also be selectively coupled
in the presence of chlorides (41). Nucleophiles bearing
acidic protons were incompatible and required the use of
protecting groups. In particular, a TIPS-protected pyrrole
and an SEM-protected pyrazole worked well in the
a 2% precatalyst 13 was used. b 1% precatalyst 13 was used. c Reac-
tion conditions: ArX (0.375 mmol, 1.5 equiv), THF (0.5 mL), n-BuLi
(2.5 M in hexanes, 0.41 mmol, 1.7 equiv), B(OiPr)3 (0.41 mmol, 1.7
equiv), ꢀ78 °C, 1 h, K3PO4 aq (0.5 M, 1.0 mL), ArX (0.25 mmol, 1.0
equiv), 13 (3 mol %), 2 h, 40 °C. Isolated yields are the average of two
runs. d 3 equiv of ArX were used.
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Org. Lett., Vol. 14, No. 17, 2012

Subsequently, we evaluated the lithiation/borylation/
SMC reaction sequence using nonhalogenated hetero-
cycles as LTB precursors via initial ortho-lithiation. In
this sequence, thiophene (46 and 47), benzothiophene (43
and 44), SEM-pyrazole (45), benzofuran (48 and 50), and
1,5-difluorobenzene(49) performed well(Scheme 6). How-
ever, furan, in contrast to bromofuran, did not yield the
desired product. To achieve full conversion, 3 equiv of the
heteroarene were required.
Scheme 6. One Pot LithiumꢀHalogen Exchange, Borylation,
and SCM Reaction of Heteroarenesa
In conclusion, we have demonstrated that lithium trii-
sopropyl borate salts are convenient and efficient coupling
partners for SuzukiꢀMiyaura reactions, particularly when
a sensitive heterocyle is required as the boronate compo-
nent. In addition to providing a general procedure for the
synthesis of LTBs and mild conditions for their coupling,
we have developed conditions for a one-pot lithiation/
borylation/SMC coupling sequence which provides a vari-
ety of heterocyclic bioaryl products in good yields. We
expect that these triisopropyl boronate salts, which are
stable at room temperature under an atmosphere of air,
will find widespread use.
Acknowledgment. We thank the Novartis Foundation,
formerly Ciba-Geigy Jubilee Foundation, for a postdoc-
toral fellowship to M.A.O. We thank Dr. Meredeth A.
McGowan (Massachusetts Institute of Technology) and
€
Dr. Marcel Alexander Dufert (Massachusetts Institute of
Technology) for help with this manuscript.
a Reaction conditions: ArX (0.75 mmol, 3.0 equiv), THF (1.0 mL),
n-BuLi (2.5 M in hexanes, 0.83 mmol, 3.3 equiv), B(OiPr)3 (0.83 mmol,
3.3 equiv), ꢀ78 °C, 1 h, K3PO4 aq (0.5 M, 2.0 mL), ArX (0.25 mmol, 1.0
equiv), 13 (3 mol %), 2 h, 40 °C. Isolated yields are the average of two
runs. b The reaction was run for 5 h instead of 2 h.
The use of Boc or benzyl protection groups, however,
resulted in decomposition and/or protecting-group cleav-
age. While methyl-imidazole only gave a trace amount of
coupling product, a trityl-protected imidazole electrophile
resulted in good yields of 50; the use of an N-methyl-1H-
imidazole as the LTB resulted in low yields of coupled
product 42.
Supporting Information Available. Experimental pro-
cedures along with experimental and spectroscopic data
for new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
The authors declare the following competing financial interest(s):
MIT has patents on XPhos from which S.L.B. receives royalty payments.
Org. Lett., Vol. 14, No. 17, 2012
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