A robust three-step telescoped synthesis of electron-deficient amide substituted arylboronic acids

Article abstract of DOI:10.1021/op100267p

A robust three-step telescoped process for the preparation of electron-deficient amide-substituted arylboronic acids from readily available bromobenzoic acids has been developed. An EDC-HOBT-promoted amide formation of a bromobenzoic acid was followed by subjection of the product stream to a palladium-mediated cross-coupling with B₂(pin)₂. The resultant mixture of the arylboronate ester and arylboronic acid was directly treated with NaIO₄, followed by a heptane-MeTHF crystallization, to cleanly afford the corresponding arylboronic acid in good yield. This general procedure was used to synthesize electron-deficient amide-substituted arylboronic acids with a diverse array of electron-withdrawing substituents.

Full text of DOI:10.1021/op100267p

COMMUNICATION
pubs.acs.org/OPRD
A Robust Three-Step Telescoped Synthesis of Electron- Deficient
Amide Substituted Arylboronic Acids
Jason Zhu, Thomas M. Razler,* Zhongmin Xu, David A. Conlon, Eric W. Sortore, Alan W. Fritz,
Roman Demerzhan, and Jason T. Sweeney
Department of Process Research and Development, Bristol-Myers Squibb Co., One Squibb Drive, New Brunswick,
New Jersey 08903, United States
S Supporting Information
b
ABSTRACT: A robust three-step telescoped process for
the preparation of electron-deficient amide-substituted
arylboronic acids from readily available bromobenzoic
acids has been developed. An EDC-HOBT-promoted
amide formation of a bromobenzoic acid was followed
by subjection of the product stream to a palladium-
mediated cross-coupling with B2(pin)2. The resultant
mixture of the arylboronate ester and arylboronic acid
Figure 1. Three-step telescoped synthesis of electron-deficient amide-
substituted arylboronic acids.
was directly treated with NaIO4, followed by a heptane-
MeTHF crystallization, to cleanly afford the correspond-
ing arylboronic acid in good yield. This general procedure
was used to synthesize electron-deficient amide-substituted
arylboronic acids with a diverse array of electron-
acids (Figure 1). An inverse heptane-methyltetrahydrofuran
withdrawing substituents.
procedure to prepare electron-deficient, amide-substituted aryl-
boronic acids from readily available bromo-substituted benzoic
(MeTHF) crystallization was developed to circumvent the sub-
strate hygroscopicity and afford the isolated arylboronic acids in
good yields.10
’ INTRODUCTION
’ RESULTS AND DISCUSSION
Arylboronic acids are extremely useful building blocks
that have found utility in the synthesis of a broad range of mole-
We recently needed to prepare a variety of electron-deficient
amide-sustituted arylboronic acids. During the preparation of
these compounds a number of challenges were encountered that
are unique to this class of compounds. The details of the design,
challenges, and optimization of the three-step telescoped process
for the preparation of electron-deficient amide-substituted aryl-
cules including materials, agrochemicals, pharmaceuticals, and in
the synthesis of natural products.1,2 The preparation of many
aryl and heteroarylboronic acids,3 boronate esters,4 and potas-
sium trifluoroborate salts5 are described in the literature, and
many are commercially available. Amide-substituted arylboro-
boronic acids are discussed below.
nic acids represent a potentially important bidirectional linch-
Installation of the amide moiety was deemed the necessary
pin building block, readily elaborated at both the boronic acid
first step to minimize the number of transformations in
the presence of the sensitive boronic acid functionality. An
and carboxy functional sites (Figure 1).6 There are a limited
number of reports on the preparation of amide-substituted
arylboronic acids,7 and few are available commercially. More-
over, the amide-substituted arylboronic acids that are com-
mercially available are prohibitively expensive for use in large-
scale applications.
EDC-HOBT coupling protocol with pyrrolidine in acetoni-
trile proved to be optimal and provided the corresponding
pyrrolidine amide 5 in high yield and greater than 98% HPLC
purity (Scheme 1). Alternative procedures, including a Schotten-
Baumann reaction, delivered a lower yield of the amide and up to
In addition to the amide functionality, other electron-with-
drawing substituents such as fluorine, trifluoromethyl, and nitrile
create a highly electron-deficient arene ring, making arylboronic
acid preparation through palladium-catalyzed or metal-halogen
exchange borylation protocols significantly more challenging.8
Also, the electron-deficient arene ring increases the Lewis acidity
of boron, leading to problems with arylboronic acid isolation.
The boronate ester form of boronic acids is stabilized in electron-
deficient arylboronic acids, and Lewis basic species, such as water,
coordinate to boron, making isolation of a crystalline compound
difficult.9 Herein, we report a convenient, three-step telescoped
Scheme 1. Pyrrolidine amide formation
Received: October 4, 2010
Published: January 14, 2011
r
2011 American Chemical Society
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Scheme 2. Unproductive o-amide metalation
25% recovery of the benzoic acid through hydrolysis of the
intermediate benzoyl chloride. After 2 h, the reaction mixture
was concentrated, solvent exchanged to MeTHF, and washed
with 1 N NaOH to remove HOBT and the EDC-urea. On the
basis of its high purity, bromo-aryl pyrrolidine amide 5 was
carried forward as a solution in MeTHF.
such as peroxides are known to oxidatively add to boron,16
however, electrophilic oxidants, such as NaIO4, are unable to
donate an electron pair to boron’s empty orbital, thus provid-
ing chemoselectivity for the pinacol while leaving the boronic
acid functionality intact.
Safety evaluation of the three-step telescoped procedure re-
vealed a significant 70 °C adiabatic temperature rise during the
NaIO4 oxidation (Table 1). Advanced Reactive Systems Screen-
ing Tool (ARSST) analysis indicated a reaction runaway at an
onset temperature of 120 °C with a self-heating rate of 60 °C/min
and a corresponding pressurization rate of 20-30 psig/min.
Interestingly, use of an inverse addition mode where the reaction
mixture was added to a suspension of NaIO4 in water resulted in
a delayed exotherm where the adiabatic temperature rise (36 °C)
occurred after a 20-min delay at 22 °C, compared to an addition-
controlled, instantaneous exothermic 12 °C temperature rise for
the normal mode of addition. In order to operate safely, we
avoided the potential hazard of the delayed exotherm at ambient
temperature by adding NaIO4 to the boronate ester-boronic
acid solution in MeTHF and maintained the reaction tempera-
ture between 20 and 25 °C, with active jacket cooling, well below
the 120 °C exothermic onset temperature.
With the amide prepared, our attention turned to installation
of the boronic acid moiety through the intermediacy of a
boronate ester. Initial development for this transformation fo-
cused on utilizing a metal-halogen exchange protocol with
bromo-aryl pyrrolidine amide 5, followed by quenching with
tri-isopropoxyborane.11 However, in addition to forming the
desired boronate ester 8 in 45% yield, a side product was
observed in 35% yield that was identified as the o-diisopro-
poxyboronate amide 9. The competitive o-amide-directed
deprotonation was a substantial side reaction that persisted
with all of the bases evaluated, e.g., n-BuLi, LDA, or i-PrMgCl.
An earlier report by Wang and Senanayake utilized i-PrMgCl
to effect the metal-halogen exchange of a similar amide-
substituted aryl halide (however, without substitution at the
3-position) and did not observe the ortho-deprotonation.3d
Presumably, the 3-fluoro substitution on the arene ring increases
the undesired o-metalated side product by increasing the
acidity of the o-amide proton (Scheme 2).12 Furthermore,
the mixture of arylboronate esters (8 and 9) was found to be in
an inconsistent equilibrium with the corresponding boronic
acids (10 and 11).
Table 1. Safety comparison of the NaIO4 order of addition
and reaction profile
NaIO4 order
of addition
ΔTadiabatic
(22 °C)
ΔH
ΔTadiabatic self heat rate
(120 °C)
(kJ/mol) (120 °C)
A palladium-mediated protocol with bis(pinacolato)diboron
[B2(pin)2] avoided the formation of the o-amide side product,
but gave rise to a similar mixture of the boronate ester 12 and the
targeted boronic acid 10. PdCl2(dppf) (1 mol %), B2(pin)2,
KOAc, and MeTHF at 80 °C proved to be the optimal reaction
conditions and delivered a high yield (85-90%) of the arylboro-
nate ester 12 and arylboronic acid 10 as a 1:1 mixture after
10-15 h (Scheme 3).13 Upon reaction workup, pinacol exchange
from boron resulted in a fluctuating boronate ester-boronic
acid ratio with each workup step.14 To circumvent the pinacol
exchange, treatment of the arylboronate ester and arylboronic
acid mixture in MeTHF with sodium periodate (NaIO4) in-
duced an oxidative cleavage of the free pinacol 13 in solution.15 The
conversion of pinacol 13 to 2 equiv of acetone eliminated the
potential to regenerate the boronate ester 12 and drove the
equilibrium to the arylboronic acid 10. Nucleophilic oxidants
normal NaIO4
addn to rxn
mixture
þ12 °C
-167.3
-305.1
þ70 °C þ 60 °C/min
inverse rxn
mixture addn
to NaIO4
þ36 °C
(20 min delay)
þ 80 °C þ 61 °C/min
Isolation of the amide-substituted arylboronic acid 10 from
the MeTHF reaction stream proved to be problematic. Crystal-
lization from MeTHF and nonpolar antisolvents either directly
afforded oils or crystals that transformed into oils upon standing.
Repeated azeotropic drying of the arylboronic acid solution from
either MeTHF or toluene was unable to achieve a solution with a
water content below 0.8 wt % (measured by Karl Fischer titration).
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Scheme 3. Arylboronate ester-arylboronic acid equilibrium
In an effort to address these issues, we focused on the develop-
ment of an inverse crystallization protocol, wherein the polar
MeTHF-arylboronic acid solution would be added slowly to
a nonpolar solvent. The impetus for this potential solution was
our hypothesis that water associated with the arylboronic acid
would be insoluble in the nonpolar antisolvent, n-heptane
(which has 0.01 wt % solubility in heptane), and would partition
out as a separate aqueous phase.17 In effect, this would create
an anhydrous local environment for crystallization to occur
and allow for arylboronic acid isolation. Experimentally, a
solution of the arylboronic acid 10 in MeTHF (KF = 0.86%)
was added simultaneously with heptane over 2 h to a stirred
solution of heptane at ambient temperature. We were pleased
that no oiling was observed and a thick, white crystalline
suspension was obtained to afford arylboronic acid 10 as a
white, crystalline solid after filtration and drying.18
With a robust procedure in hand, we explored the substrate
scope of the three-step procedure by evaluating the aryl ring electro-
nics, substitution pattern, and amide functionality (Table 2). A
variety of electron-deficient functionalities were well tolerated.
3-Fluoro, 2,6-difluoro, 2- and 3-chloro, 3-trifluoromethyl, and 3-nitro
functionalized aryl rings all afforded the desired products in good
yields. While both 4-bromo- and 3-bromo-substituted benzoic acids
produced the corresponding pyrrolidine amide phenylboronic acids
in good yields (entries 1-7), the 2-bromo-substituted example did
not. Presumably, a stable five-membered palladacycle was formed
with the amide in step 2, precluding transmetalation with B2(pin)2.
In addition to pyrrolidine amides, cyclic morpholine amide (entry
8) and monosubstituted p-chlorophenyl amide (entry 10) both
afforded the corresponding arylboronic acid products in good yield.
Commercially available, 4-(N,N-dimethylcarbamoyl)-3-fluorophe-
nylboronic acid (entry 10) was produced in 0.5 kg and 74% yield
over the three steps, thus demonstrating the feasibility of our
protocol on a multihundred gram scale.
’ EXPERIMENTAL SECTION
General. The following experimentals are representative ex-
amples and illustrate the general method for the execution of
each synthetic step.
Preparation of 4-Bromo-3-fluoro-pyrrolidinylbenzamide
(5). Pyrrolidine (20.3 g, 0.28 mol) was added to a solution of
1-bromo-2-fluorobenzoic acid (25.0 g, 0.11 mol), 1-hydroxyben-
zotriazole hydrate (43.7 g, 0.28 mol) and 1-(3-dimethylamino-
propyl)-3-ethylcarbodiimide hydrochloride (54.7 g, 0.28 mol) in
acetonitrile (8 mL/g) at ambient temperature. The reaction
mixture was heated to 70 °C for 2 h and concentrated to approx-
imately 2 mL/g. The reaction mixture was cooled to 20 °C,
diluted with MeTHF (20 mL/g), washed with 1 N NaOH
(2ꢀ, 5 mL/g), and 12 wt % aqueous NaCl (5 mL/g). The
solution was passed through Darco and azeotropically dried to an
end point of <0.05% water by weight (KF measurement) to
afford 4-bromo-3-fluoro-pyrrolidinylbenzamide 5 (28.0 g, 90.5%
solution yield) as a solution in MeTHF (∼10 mL/g).
Preparation of 2-Fluoro-4-(pyrrolidinylcarbamoyl)phenyl-
boronic Acid, Pinacol Ester (12). Bis(pinacolato)diboron
[B2(pin)2, 28.0 g, 0.11 mol], potassium acetate (27.1 g, 0.28 mol),
and [1,10-bis(diphenylphosphino)ferrocene]dichloridepalladium-
(II) (PdCl2dppf, 0.75 g, 0.0009 mol) were charged to the solution
prepared above. The reaction mixture was sparged (subsurface)
with nitrogen for 5 min, and the reaction mixture was heated to
80 °C for 15 h. After cooling to 20 °C, the reaction mixture was
diluted with water (10 mL/g) and filtered through Celite. The phases
were separated, and the organic stream was washed with water
(10 mL/g). The organic stream was filtered through Darco, washed
with 1 N NaOH (10 mL/g) and discarded. The aqueous layer was
then diluted with fresh MeTHF (10 mL/g), cooled to 0 °C, and
acidified to pH 1.5 with 3 N HCl. The MeTHF stream was filtered
through Celite and used directly in the next step as a 1:1 mixture of the
2-fluoro-4-(pyrrolidinylcarbamoyl)phenylboronic acid, pinacol ester,
and 2-fluoro-4-(pyrrolidinylcarbamoyl)phenylboronic acid (28.9 g,
79.7% solution yield over two steps) in MeTHF (10 mL/g).
Preparation of 2-Fluoro-4-(pyrrolidinylcarbamoyl)phenyl-
boronic Acid (10). Water (10 mL/g) was charged to the
1:1 mixture of the boronate ester and boronic acid in MeTHF,
followed by sodium periodate (NaIO4, 28.2 g, 0.13 mol). The
jacketed reaction vessel was maintained at 10 °C by a com-
bination of cooling and addition rates. After 1.5 h, 1 N HCl
(7 mL/g) was added, the temperature was warmed to 20 °C,
and the reaction stirred for an additional 15 h. Upon reaction
completion (nondetectable boronate ester), the phases were
separated, and the organic stream was washed with 20 wt %
’ CONCLUSION
A robust three-step telescoped procedure has been developed
for the scalable synthesis of synthetically useful, electron-
deficient amide-substituted arylboronic acids. Benefits include
the use of readily available benzoic acid starting materials,
inexpensive reagents, operational convenience, and generality for
a variety of functional groups. A safe operating procedure was
developed for the conversion of arylboronate esters to arylboro-
nic acids using NaIO4. The large-scale preparation of these
synthetically useful bidirectional linchpins may aid in the dis-
covery of new medicines to address unmet medical needs.
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Table 2. Electron-deficient amide-substituted arylboronic acid substrate scopea
a All reactions were conducted with 25 g of the starting bromo-substituted benzoic acid except entry 9. b All bromo-subsituted benzoic acids were
commercially available. c Isolated yields. d 0.70 kg of 4-bromo-2-fluorobenzoic acid afforded 0.50 kg of 4-(N,N-dimethylcarbamoyl)-3-fluorophenyl-
boronic acid in 74% yield over the three steps.
sodium thiosulfate (5 mL/g), 12 wt % aqueous NaCl (5 mL/g),
filtered through Celite, and concentrated to 4 mL/g. Heptane
(4 mL/g) was added simultaneously with the reaction stream
over 2 h to a lightly stirred flask of heptane (4 mL/g) at rt. The
resultant white slurry was stirred for 1 h, filtered, washed with
heptane (2ꢀ, 3 mL/g), and dried on the filter for 1 h. The
white cake was dried in a vacuum oven at 20 °C with 23 mmHg
for 24 h to afford 2-fluoro-4-(pyrrolidinylcarbamoyl)phenylboronic
acid as a white solid (15.9 g, 59.1% over three steps). 1H NMR
(400 MHz, DMSO-d6) δ 7.75 (d, J = 7.6 Hz, 1 H), 7.30 (d, J =
7.4 Hz, 1 H), 7.23 (d, J = 9.6, 1 H), 3.45 (t, J = 6.6 Hz, 2 H),
3.36 (t, J = 5.8 Hz, 2 H), 1.85-1.80, (m, 4 H); 13C NMR (100
MHz, DMSO-d6) δ 166.8, 166.0, 163.6, 140.4, 135.3, 122.2,
113.5, 48.7, 45.9, 25.9, 23.8; Exact mass calcd for C11H13BFNO3
238.1051, found 238.1052.
Subkilogram-Scale Preparation of 4-(N,N-Dimethyl-
carbamoyl)-3-fluorophenylboronic Acid (21). Preparation
of 4-Bromo-2-fluoro-N,N-dimethylbenzamide. N,N-Dimethyl-
amine hydrochloride (0.655 kg, 8.03 mol) was added to a solution
of 1-bromo-3-fluorobenzoic acid (0.704 kg, 3.21 mol), 1-hydro-
xybenzotriazole hydrate (0.992 kg, 6.48 mol), 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide hydrochloride) (1.25 kg,
6.53 mol), and diisopropylethylamine (1.04 kg, 8.06 mol) in
acetonitrile (4.42 kg, 8 L/kg) at ambient temperature. The
reaction mixture was heated to 70 °C for 2 h and concentrated
by vacuum distillation (30 °C internal batch temp, 60 mmHg)
to 2 L/kg. The reaction mixture was cooled to 20-25 °C,
diluted with MeTHF (20 L/kg), and washed with 1 N NaOH
(2ꢀ, 5 L/kg) and 12 wt % aqueous NaCl (5 L/kg). The
solution was passed through a carbon pad (R53SP pad, 1.75”
diameter) and azeotropically dried (35 °C batch temp, 60
mmHg) to a KF end point of <0.02 wt % water (KF
measurement) to afford 4-bromo-2-fluoro-N,N-dimethylben-
zamide (0.776 kg, 98.1% solution yield) as a solution in
MeTHF (10 L/kg).
Preparation of 4-(N,N-Dimethylcarbamoyl)-3-fluoro-
phenylboronic Acid, Pinacol Ester. Bis(pinacolato)diboron
[B2(pin)2, 0.996 kg, 3.92 mol], potassium acetate (0.948 kg,
9.66 mol), and [1,10-bis(diphenylphosphino)ferrocene]dichlo-
ridepalladium(II) (PdCl2dppf, 0.026 kg, 0.031 mol) were
charged to a solution of 4-bromo-2-fluoro-N,N-dimethylbenza-
mide (0.776 kg, 3.15 mol) in MeTHF (10 L/kg). The reaction
mixture was sparged (subsurface) with nitrogen for 15 min and
heated to 80 °C for 15 h. The reaction mixture was cooled to
20-25 °C, diluted with water (10 L/kg), and filtered through
Celite. The phases were separated, and the organic stream was
filtered through a carbon pad (R53SP, 1.75” diameter), washed
with 1 N NaOH (10 L/kg), and discarded. MeTHF (10 L/kg)
was added to the aqueous solution, the mixture was cooled to
0 °C and acidified to pH 1.5 with 3 N HCl. The aqueous phase
was removed, and the MeTHF stream was filtered through
Celite and used directly in the next step as a 1:1 mixture of
the 4-(N,N-dimethylcarbamoyl)-3-fluorophenylboronic acid,
pinacol ester and 4-(N,N-dimethylcarbamoyl)-3-fluorophenyl-
boronic acid (0.806 kg, 85.6% solution yield over two steps) in
MeTHF (10 L/kg).
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Preparation of 4-(N,N-Dimethylcarbamoyl)-3-fluoro-
phenylboronic Acid (21). Sodium periodate (NaIO4, 1.03 kg,
4.84 mol) was charged to the 1:1 mixture of 4-(N,N-dimethyl-
carbamoyl)-3-fluorophenylboronic acid, pinacol ester, and 4-(N,N-
dimethylcarbamoyl)-3-fluorophenylboronic acid (0.806 kg, 2.75
mol) in MeTHF (10 L/kg) and water (10 L/kg). The jacketed
reaction vessel was maintained at 10 °C (internal temperature).
After 1.5 h, 1 N HCl (7 L/kg) was added, the jacket temperature
was adjusted to 20 °C, and the reaction stirred for an additional 15
h. Uponreaction completion (boronate ester nondetectable by
HPLC analysis), the phases were separated, and the organic stream
was washed with 20 wt % sodium thiosulfate (5 L/kg), 12 wt %
aqueous NaCl (5 L/kg), filtered through Celite, and concentrated
to 4 L/kg. This solution was added simultaneously with heptane
(4 L/kg) over 2 h to a stirred flask of heptane (4 L/kg) at ambient
temperature. The resultant white slurry was stirred for 1 h, filtered,
washed with heptane (2ꢀ, 3 L/kg), and dried on the filter for 1 h.
The white cake was dried further in a vacuum oven at 20 °C and
23 mmHg for 24 h to afford 4-(N,N-dimethylcarbamoyl)-3-
fluorophenylboronic acid as a white solid (0.502 kg, 74.1% over
three steps). 1H NMR (400 MHz, DMSO-d6) δ 8.34 (br s, 2 H),
7.65 (d, J = 7.5 Hz, 1 H), 7.57 (d, J = 10.7 Hz, 1 H), 7.33 (t, J = 7.1
Hz, 1 H), 3.08 (s, 3 H), 2.82 (s, 3 H); 13C NMR (100 MHz,
DMSO-d6) δ 165.9, 158.7, 156.3, 130.6, 128.2, 126.5, 120.8, 38.1,
34.5; Exact mass calcd for C9H11BFNO3 211.0812, found 211.0810.
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’ ASSOCIATED CONTENT
S
Supporting Information. This material is available free
b
of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
Corresponding Author
*Telephone: (732)-227-5513. E-mail: thomas.razler@bms.com.
’ ACKNOWLEDGMENT
We thank Drs. Prashant Deshpande, David Kronenthal,
Rodney Parsons, Jaan Pesti, and Robert Waltermire for help-
ful discussions and comments during the preparation of this
manuscript.
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