Development of an Efficient Synthesis of (2-Aminopyrimidin-5-yl) Boronic Acid

Article abstract of DOI:10.1021/acs.oprd.5b00360

A practical and cost-effective synthesis of (2-aminopyrimidin-5-yl) boronic acid 1b has been developed. Key features of the synthesis include the inexpensive in situ protection of the amine via bis-silylation using TMSCl followed by metal-halogen exchange using n-BuLi and trapping with B(Oi-Pr)₃. The water-soluble boronic acid is isolated by a well-designed acid-base sequence providing the target in 80% yield and high purity for the two-step process. The large-scale (15 kg) implementation of a Suzuki-Miyaura borylation to form the pinacol boronic ester is also described.

Full text of DOI:10.1021/acs.oprd.5b00360

Communication
pubs.acs.org/OPRD
Development of an Efficient Synthesis of (2-Aminopyrimidin-5-yl)
Boronic Acid
Nitinchandra D. Patel,* Yongda Zhang, Joe Gao, Kanwar Sidhu, Jon C. Lorenz, Keith R. Fandrick,
Jason A. Mulder, Melissa A. Herbage, Zhibin Li, Shengli Ma, Heewon Lee, Nelu Grinberg, Jinhua J. Song,
Carl A. Busacca, Nathan K. Yee, and Chris H. Senanayake
Chemical Development US, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, P.O. Box 368, Ridgefield, Connecticut
06877-0368, United States
*
S Supporting Information
a metal−halogen exchange (n-BuLi in THF/toluene) in the
ABSTRACT: A practical and cost-effective synthesis of
2-aminopyrimidin-5-yl) boronic acid 1b has been
presence of triisopropylborate B(Oi-Pr) to provide the target
3
(
in moderate yields after purification. An alternative Suzuki−
Miyaura borylation of the corresponding bromide 2 by the
same investigators employing bis(pinacolato)diboron (KOAc/
developed. Key features of the synthesis include the
inexpensive in situ protection of the amine via bis-silylation
using TMSCl followed by metal−halogen exchange using
1
,4-dioxane, 80 °C) afforded compound 1a, which was used
n-BuLi and trapping with B(Oi-Pr) . The water-soluble
3
directly in cross-coupling reactions without any further
purification. Herein, we describe our efforts to develop an
efficient, cost-effective and scalable approach to pyrimidine
boronate 1.
boronic acid is isolated by a well-designed acid−base
sequence providing the target in 80% yield and high purity
for the two-step process. The large-scale (15 kg)
implementation of a Suzuki−Miyaura borylation to form
the pinacol boronic ester is also described.
RESULTS AND DISCUSSION
■
A metal catalyzed Suzuki−Miyaura borylation of compound 2
using bis(pinacolato)diboron (B pin ) provides rapid access to
2
2
INTRODUCTION
■
5,6b,f
the desired compound 1a.
A screening of solvents and
1
Aryl boronic acids and esters have become ubiquitous in
synthetic chemistry in both industrial and academic settings
due to their straightforward use in a wide range of transition
catalysts for the metal catalyzed borylation reaction was first
conducted (Table 1). It was found that PdCl (dppf)-DCM
2
adduct at 0.5 mol % catalyst loading in 1,4-dioxane at reflux
(∼100 °C) gave complete conversion in 4−6 h. The reaction
mixture was filtered through a Celite 545 pad and then rinsed
the pad with ethyl acetate. The filtrates were washed with 10 wt
% brine solution, and the resulting organic layer was
concentrated to obtain oil, which upon trituration from
2
,3
metal-catalyzed coupling reactions. However, heterocyclic
boronic acids and esters can be difficult to synthesize cost-
effectively on large scale. Difficulties with preparation and
isolation such as instability to workup conditions, high
solubility in water, and residual inorganic salts are often
encountered with the synthesis of nondistillable boronic esters
or acids. As part of a recent drug development program for a
heptane afforded solids in ∼76% yield (1−5 g scale) (Table
7
1
, entry 1). However, the use of the Class 2 solvent 1,4-
4
dioxane and high catalyst loading persuaded us to conduct a
further screening to render the process efficient for operation at
larger scale. In addition, pinacol boronate hydrolysis to the
corresponding boronic acid during the aqueous washes was
observed, leading to low recoveries (Table 1, entries 1, 2, 3).
Hence, a nonaqueous isolation for these reactions was pursued
FLAP inhibitor 8, an effective synthesis of the requisite 2-
aminopyrimidine boronic acid was required (Scheme 1). Bryce
5
a
et al. have reported a direct synthesis of the corresponding
boronic acid 1b from 2-amino-5-bromopyrimidine 2 employing
Scheme 1. Retrosynthetic Strategy for FLAP Inhibitor 8
(
Table 1, entries 4, 5, 6) by performing a hot filtration of the
reaction mixture to remove the inorganic salts, followed by
crystallization from ethanol. Replacing 1,4-dioxane with 2-
MeTHF allowed for a more efficient removal of the inorganics
with the hot filtration and provided 1a in high purity (>95 wt
%) after crystallization (Table 1, entry 6). However, when the
process was scaled to 1 kg, the reaction stalled with the lower
catalyst loading (0.5 mol %), and an additional charge of
catalyst was required to drive the reaction to completion. In
order to further align the Pd source for the subsequent cross-
Received: November 3, 2015
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.oprd.5b00360
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
Table 1. Optimization of Metal Catalyzed Suzuki−Miyaura Borylation of 2
entry
solvent
Pd−L source (mol %)
temp. (°C)
conversion (%)
isolated yield (%)
a
1
2
3
4
5
6
7
1,4-dioxane
DMF
PdCl (dppf)-DCM, 0.5 mol %
100 °C
105 °C
100 °C
100 °C
100 °C
80 °C
98%
97%
98%
98%
98%
98%
99.5%
75.6%
2
a
PdCl (dppf)-DCM, 0.1 mol %
62.0%
2
a
1,4-dioxane
1,4-dioxane
1,4-dioxane
2-MeTHF
2-MeTHF
PdCl (dppf)-DCM, 0.1 mol %
76.0%
2
b
,
,
d
PdCl (dppf)-DCM, 0.1 mol %
86.0%
87.0%
82% ,
2
b
c
,
e
f
PdCl (dppf)-DCM, 0.1 mol %
2
,
bcf
PdCl (dppf)-DCM, 0.5 mol %
2
Pd (dba) (0.1 mol %),
80 °C
80.1% , ,
bc
2
3
Fc(PtBu )-HBF (0.2 mol %)
2
4
a
b
c
d
e
Aqueous work up was performed. No aqueous work up was performed. 2 equiv of potassium acetate was used. 63 wt % by NMR assay. 73 wt %
f
by NMR assay. >95 wt % by NMR assay.
coupling step, the catalyst source was replaced with Pd (dba)3
as a compatible N-protecting group for the lithiation chemistry.
The desired N-protected substrate 3 was readily obtained by
treating the solution of 2-amino-5-bromopyrimidine 2 and
STABASE (1.0 equiv) in THF with 1 M LiHMDS/Toluene
at 0 °C (Scheme 3) in excellent yield (>96%). The N-protected
2
0
.1 mol % /Fc(PtBu )-HBF (0.2 mol %), which also afforded
2 4
complete conversion (Table 1, entry 7). The reaction mixture
was then diluted with THF and filtered hot (ca. 60 °C)
followed by a solvent switch to ethanol, CUNO (type 5)
carbon treatment, and crystallization. This optimized process
was successfully scaled to provide 15 kg of product 1a as an off-
white crystalline solid in 80% isolated yield and 98 wt % purity
8b,c
Scheme 3. Synthesis of 1b Using STABASE Group
(Scheme 2).
Scheme 2. Pilot Plant Synthesis of 1a
The cost and low atom economy associated with B pin2
2
provided us the impetus to develop a more mature process for
the target compound. Initial efforts on the formation of the
target boronic acid following a literature procedure, using 2-
5a
compound 3 was then treated with n-BuLi (2.5 M in hexanes,
amino-5-bromopyrimidine and B(Oi-Pr) with n-BuLi/THF/−
1.2 equiv) in the presence of B(Oi-Pr) (1.5 equiv) at −78 °C
3
3
7
8 °C gave inconsistent or poor yields (11−40%). It is known
to afford the tetrahedral borate intermediate which upon HCl
treatment and pH neutralization provided the desired boronic
acid 1b as a white solid in 81% isolated yield and yet with a low
assay (62 wt %). The low assay was determined to be caused by
trapped inorganic salts in the boronic acid 1b solids. Therefore,
the crude solids were slurried in hot 4:2 mixture (v/v) of
MeOH-water at 70 °C for 2 h followed by cooling and filtration
to obtain target 1b in 96% yield (77% overall yield from 2) with
an improved assay purity of 85 wt %, with the remainder being
that boronic acid 1b can be prepared from 2-amino-5-
bromopyrimidine via an amine protection/metal−halogen
6
exchange process, followed by trapping with trialkylborate.
The amine protecting groups that were utilized in the literature
6a,d,e,h,i
methods included the BOC group,
imines derived from
6
e,j
6g
benzophenone, and a benzyl protecting group; however,
those methods suffered from modest yields and required two or
three isolation steps as well as a deprotection step. We sought a
procedure where the amine protection group could be installed
in situ and also removed without having to perform an
additional chemical operation. Our attention thus turned to the
potential use of tetramethyldisilylazacyclopentane (STABA-
9
simply water.
While the STABASE process was suitable for the preparation
of kilogram quantities of 1b, it became apparent that the
STABASE reagent was not readily available at low cost on large
scale, and thus a final round of process optimization was
8
a
SE), a protecting group originally developed by Magnus et al.
B
DOI: 10.1021/acs.oprd.5b00360
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
Communication
undertaken. TMSCl was thus explored as a potential alternative
area %), and starting material 2 (∼7 area %) at 220 nm. By
10a
to STABASE. It was previously demonstrated by Asher that
increasing the equivalents of both reagents (B(Oi-Pr) and n-
3
10b
it could be utilized as aniline protecting group
utilizing
BuLi) to 1.5 and 1.45 equiv, respectively, 94 area % conversion
was observed to boronic acid 1b with <2 area % of starting
material 2 (entry 2). Complete consumption was observed with
additional charge of the reagents (entry 3).
lithium-halogen exchange chemistry. When compound 2 was
treated with TMSCl (2 equiv) in THF at 0 °C with 1 M
LiHMDS/Toluene as the base (Table 2, entry 1), or MeLi
With the optimized reaction conditions in place, we began to
streamline the processing procedure. Upon completion of the
borylation, the batch was cooled to 0 °C, and the pH was
adjusted to ∼9 with conc. HCl. Extraction of the boronic acid
Table 2. Optimization of Bis-TMS Adduct 4 Formation
1b with EtOAc failed to provide high recovery due to the high
solubility of 1b in water under basic conditions. A practical
purification was found by first removing THF by distillation
and then adjusting the pH to 1−1.5 using HCl. Water dilution
and organic washes (heptane and ethyl acetate) removed
unreacted 2 and nonpolar impurities. Finally, the pH of the
aqueous layer was adjusted to 5.5−6 using aq. NaOH, which
provided boronic acid 1b as a precipitate. After filtration, a
reslurry in water at 85 °C followed by filtration and drying
furnished 1b in 80% overall yield (from 2) with 99% (HPLC)
and 90 wt % purity. The remaining mass was principally
a
entry solvent temp. (°C)
base (2.2 equiv)
conversion (%)
1
2
3
4
THF
THF
THF
THF
0 °C
0 °C
0 °C
22−40 °C
1 M LiHMDS/Tol
>97%
>97%
0%
1.6 M MeLi/Et O
2
NaH
NaH (i-PrOH 7 mol %)
>95%
a
Conversion confirmed by HNMR analysis.
12
water. The optimized process to boronic acid 1b is shown in
Scheme 4. The boronic acid 1b obtained from this process was
successfully utilized for the Suzuki coupling reaction to
(
entry 2) a quantitative formation of the bis-TMS adduct 4 was
1
11
observed by H NMR. When sodium hydride (NaH) was
used as the base for silylation no desired bis-TMS adduct 4 was
observed (entry 3). However, when bromide 2 was treated with
NaH (1.2 equiv) (entry 4) in THF along with catalytic amount
of i-PrOH (7 mol %) as an additive, the deprotonation reaction
4b
synthesize compound 7 for our FLAP Inhibitor program.
Scheme 5. Suzuki Coupling of Boronic Acid 1b to 7
initiated with a mild exotherm and concurrent H gas evolution.
2
A process was thus developed whereby sequential addition of
NaH and TMSCl (2×) furnished >95% conversion to the
desired bis-TMS adduct 4.
After obtaining the bis-TMS adduct 4 in THF, n-BuLi (1.2
equiv of 2.5 M in hexanes) was charged at −78 °C to promote
the lithium−bromine exchange in the presence of B(Oi-Pr)
3
(
1.3 equiv) (Table 3, entry 1). The reaction mixture was
CONCLUSION
■
In conclusion, we have developed a practical process for the
synthesis of (2-aminopyrimidin-5-yl) boronic acid (1b) in high
yield (80%) and purity (>99% HPLC) from 2-amino-5-
bromopyrimidine 2. Applying inexpensive in situ silyl
protection and metal−halogen exchange followed by trapping
Table 3. Optimization of Boronic Acid Formation
with borate (B(Oi-Pr) led to an effective process suitable for
3
multikilogram scale production of this heterocyclic boronic
acid. Moreover, we have successfully demonstrated the Pd
catalyzed Suzuki−Miyaura borylation using bis(pinacolato)-
diboron on 15 kg scale.
B(Oi-Pr)3
(equiv)
n-BuLi
(equiv)
1b (A
%)
2 (A
%)
entry solvent
5 (A%)
1
2
3
THF
THF
THF
1.3
1.2
81%
94%
95%
12%
7%
EXPERIMENTAL SECTION
1.5
1.45
1.48
<0.5%
<0.3%
<2%
■
1.55
General Methods. Reaction progress and chemical purity
1
were evaluated by HPLC or HNMR analysis (please refer to
1
warmed to 0 °C at which point HPLC analysis indicated the
presence of desired boronic acid 1b (81 area %), ArH 5 (12
Supporting Information for H NMR information). HPLC
conditions were as follows; Agilent Poroshell 120 (EC-C18, 4.6
Scheme 4. Optimized Route to Boronic Acid 1b
C
DOI: 10.1021/acs.oprd.5b00360
Org. Process Res. Dev. XXXX, XXX, XXX−XXX

Organic Process Research & Development
100 mm) with mobile phases A (0.2% H PO and 40 mM
Communication
×
NMR (CD Cl , 500 MHz) δ: 8.24 (s, 2H), 0.77 (s, 4H), 0.24
3
4
2
2
NH PF in water) and B (acetonitrile). Detection was at 220
(s, 12H).
4
6
nm, flow was set at 1.0 mL/min, and the temperature was 20
C (Run time: 8.5 min). Gradient: 0 min, A = 98%, B = 2%; 2.5
min, A = 98%, B = 2%; 5.5 min, A = 5%, B = 95%; 8.5 min, A =
%, B = 95%.
-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-
Bis-silylation Using TMSCl (5-Bromo-N,N-bis-
(trimethylsilyl)pyrimidin-2-amine) (4). To a clean, dry,
nitrogen-interted 2 L multineck jacketed reactor equipped with
a reflux condenser and gas bubbler was charged 2-amino-5-
bromopyrimidine 2 (50.0 g, 100 wt %, 287.35 mmol). The
reactor was evacuated and purged with nitrogen. THF (500
mL) was charged to get beige color suspension followed by i-
PrOH (1.6 mL, 20.11 mmol, 7 mol %) at 20−23 °C. Sodium
hydride (60% dispersed in mineral oil, 13.79 g, 344.83 mmol,
1.2 equiv) was charged to above mixture at once (Caution!!
exotherm to 35−40 °C with gas evolution!). The resulting
suspension was stirred for additional 1 h at 40 °C. Then the
slurry was cooled to 20 °C, and TMSCl (37.46 g, 344.83 mmol,
1.2 equiv) was charged slowly over 15 min keeping the internal
temperature under 30 °C. The resulting mixture was stirred for
additional 1 h after which the batch was cooled to 20 °C.
Second portion of sodium hydride (60% dispersed in mineral
oil, 12.64 g, 316.09 mmol, 1.1 equiv) was charged to the above
mixture at 20 °C (Caution!! Slow exotherm to 30−35 °C with
gas evolution!) and held at 40 °C for additional 1h before it was
recooled back to 20 °C. TMSCl (34.34 g, 316.09 mmol, 1.1
equiv) was charged slowly over 15 min keeping the internal
temperature under 30 °C. The final slurry was stirred at 20 °C
for additional 2 h after which an aliquot was tested for bis-
silylation (0.1 mL aliquot was concentrated using Rotovap,
°
5
5
pyrimidin-2-amine (1a). To a clean, dry, nitrogen-inerted
suitable reactor were charged 2-amino-5-bromopyrimidine 2
(15.0 kg, 100 wt %, 86.2 mol), bis(pinacolato)diboron (24.2 kg,
9
5.3 mol), di-tert-butylphosphinoferrocene tetrafluoroborate
(
(
0.072 kg, 0.2 mol %), tris(dibenzylidineacetone)palladium
0.080 kg, 0.1 mol %), and potassium acetate (16.92 kg, 172.4
mol). The reactor was evacuated and purged with nitrogen
three times. In a separate vessel, 2-MeTHF (60 kg) was sparged
with nitrogen and then transferred to the main reactor. The
mixture was heated to 82 °C over 0.5 h and held at 82 °C for
4.5 h (slurry forms). The mixture was cooled to 55 °C, and
THF (200 kg) was added and then reheated back to 60 °C.
The solution was filtered at 60 °C to remove solids, ensuring
both filter and the receiver were heated to 60 °C. THF (67 kg)
heated to 60 °C was used to rinse the reactor and filtered solids.
The combined filtrates were distilled at ∼55 °C under vacuum
(274 Torr) to the minimum stirrable volume. Ethanol (90 kg)
was added, and the mixture was again concentrated to
minimum volume. Ethanol (240 kg) was added, and the
mixture was heated to 65 °C and held for 1 h. The ethanol
solution was then filtered through a heated (65 °C) filter
containing CUNO type 5 carbon. The reactor and filter were
rinsed with preheated (60 °C) ethanol (24 kg). The combined
filtrates were placed in a clean reactor and were concentrated at
1
diluted in CD Cl , and filtered to remove inorganics. H NMR
2
2
analysis of the filtrate indicated >95% bis-silylation inter-
1
mediate). H NMR (CD Cl , 400 MHz) δ: 8.23 (s, 2H), 0.15
2
2
(s, 18H). The crude reaction mixture of bis-silylated adduct 4
was directly used in next borylation step.
(2-Aminopyrimidin-5-yl)boronic Acid (1b). Borylation.
THF (150 mL) was charged to crude adduct 4 solution, and
6
0 °C under vacuum removing 260 L of distillate. The resulting
slurry was cooled to 20 °C over 2 h and then held at 20 °C for
h. The solids were collected by filtration and were rinsed with
2
ethanol (36 kg). The solids were dried on the filter for 1 h and
then in a vacuum oven at 45 °C for 8 h yielding 15 kg of 1a as a
the batch was cooled to −78 °C. B(Oi-Pr) (81.08 g, 431.12
3
mmol, 1.5 equiv) was charged to above mixture over 15 min
and cooled the mixture to −78 °C. n-BuLi (2.5 M in hexanes,
167 mL, 416.74 mmol, 1.45 equiv) was charged to above
mixture over 75 min keeping the internal temperature below
−65 °C and held at this temperature for additional 1 h after
which by HPLC the starting material was consumed (>99%
conversion). The batch was warmed up to 0 °C over 1 h and
quenched with 12 N HCl solution (20 mL, 240 mmol, 0.84
equiv) to adjust the pH ∼ 9 followed by water (500 mL). The
resulting biphasic layers were concentrated under vacuum
(temp. 45−50 °C) to distill approximately 700 mL of distillate.
Then 12 N HCl solution (45 mL, 540 mmol, 1.88 equiv) was
charged to adjust pH ∼ 1−1.5 at 20 °C. Water (600 mL),
heptane (175 mL), and ethyl acetate (175 mL) were charged to
above cloudy suspension and stirred vigorously for 30 min at 25
°C. The bottom aqueous layer containing product was
separated from the top organic layer (Note: The top organic
layer contained all nonpolar impurities and remaining bromide
2). The bottom aqueous layer containing boronic acid was
transferred into a clean reactor (Note: Same previous reactor
could be utilized after the rinse using ethyl acetate and water).
To the aqueous layer was charged 30 wt % aqueous NaOH
solution (60 mL) slowly over 90 min to adjust the pH 5.5−6 to
afford white slurry. The resulting slurry was stirred at 20 °C for
additional 1h after which the solids were collected by suction
filtration and rinsed with water (100 mL). The solids were
dried on funnel for 1h and then in a vacuum oven at 25 °C for
≥12 h yielding 40.2 g of 1b (82% yield, 81.6 wt %). Reslurry:
white crystalline solid (80% yield, 98 wt %, Pd 2 ppm). MP 212
1
°
C. H NMR (CDCl , 500 MHz) δ: 8.59 (s, 1H), 5.69 (s, 2H),
3
13
1
8
2
.33 (s, 12H). C NMR (CDCl , 125 MHz) δ: 164.87, 164.36,
4.08, 24.99. HRMS: [C H BN O + H ]: calculated
3
+
1
0
16
3
2
22.1408, found 222.1399.
-Bromo-2-(2,2,5,5-tetramethyl-1,2,5-azadisilolidin-1-
5
yl)pyrimidine (3). To a clean, dry, nitrogen-interted 250 mL
three-neck round-bottom flask were charged 2-amino-5-
bromopyrimidine 2 (10.0 g, 100 wt %, 57.47 mmol) and 1,2-
bis(chlorodimethylsilyl)ethane (12.37 g, 57.47 mmol). The
flask was evacuated and purged with nitrogen. THF (50 mL)
was charged to the flask, and the resulting mixture was cooled
to −10 °C using ice/brine bath. 1 M LiHMDS/toluene (126.44
mL, 126.44 mmol, 2.2 equiv) was charged to above mixture
while keeping the internal temperature below 0 °C and stirred
the resulting mixture for additional 1 h at 0 °C (0.1 mL reaction
aliquot was concentrated using Rotovap, diluted in CD Cl and
2
2
1
filtered to remove inorganics. H-NMR analysis of the filtrate
indicated >98% STABASE adduct (3). The reaction was
quenched with 10 wt % aqueous ammonium chloride (70 mL)
while keeping the internal temperature below 15 °C. The top
organic layer was washed with water (50 mL), and the resulting
organic layer was filtered through a Frit funnel and rinsed with
toluene (20 mL). The filtrate was concentrated under vacuum
using Rotovap to dryness to afford STABASE adduct 3 as off-
1
white to tan solids (26.0 g, 69.5 wt % purity by HNMR assay,
1
quantitative yield), which was used directly in the next step. H
D
DOI: 10.1021/acs.oprd.5b00360
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Organic Process Research & Development
Communication
Solids of 1b (40.2) were charged into a suitable 250 mL three-
neck RBF equipped with a stir bar, heating mantle, condenser
and a temperature probe. Water (100 mL) was charged to RBF
and the resulting slurry was heated to 85 °C and stirred for
additional 1h. The slurry was cooled to 20 °C and stirred for
additional 1−2h before the solids were collected by suction
filtration. The solid cake was rinsed with water (80 mL) and
then with heptane (100 mL). The air-dried solids were placed
in a vacuum oven at 25 °C for ∼12 h yielding 35.51 g of 1b as
an off-white powder (80% overall yield, 90.0 wt %, remaining
Antimicrobials. Int. Pat. Appl. WO2006/038100A1, 2006. (h) Meudt,
A.; Lehnemann, B.; Scherer, S.; Kalinin, A.; Snieckus, V. Process for
the Preparation of Aniline Boronic Acids and their Derivatives.
EP2004/1479686A1, 2004. (i) Tian, Q.; et al. Org. Process Res. Dev.
2
015, 19, 416−426. (j) Busch, T.; Nonnenmacher, M. Process for the
Preparation of Boronic Acid Intermediates. US Pat. Appl. US2014/
330008A1, 2014.
7) ICH Q3C(R5): Impurities: Guideline for Residual Solvents,
011.
(8) (a) Magnus, P.; Djuric, S.; Venit, J. Tetrahedron Lett. 1981, 22
0
(
2
(19), 1787−1790. (b) Rizzo, C. J.; Wang, Z. Org. Lett. 2001, 3, 565−
568. (c) Rizzo, C. J.; Elmquist, C. E.; Stover, J. S.; Wang, Z. J. J. Am.
Chem. Soc. 2004, 126, 11189−11201.
(9) The boronic acid 1b was obtained in 85.22 wt % purity with
residual water after overnight vacuum drying at ambient temperature
to avoid forming boroxine derivatives.
mass is principally water). MP 200 °C (with decomposition
1
event). H NMR (DMSO-d , 500 MHz) δ: 8.52 (s, 2H), 7.99
6
1
3
(
s, 2H), 6.76 (s, 2H). C NMR (DMSO-d , 100 MHz) δ:
64.1, 163.9. HRMS: [C H BN O + H ]: calculated
4 6 3 2
40.06258, found 140.0639.
6
+
1
1
(10) (a) Asher, S. A.; Das, S.; Alexeev, V. L.; Sharma, A. C.; Geib, S. J.
Tetrahedron Lett. 2003, 44, 7719−7722. (b) Chikhalia, H. K.; Patel, A.
B.; Patel, R. V.; Kumari, P.; Rajani, D. P. Med. Chem. Res. 2013, 22,
367−381.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.oprd.5b00360.
1H and 13C NMR spectra of all new compounds (PDF)
■
*
S
1
(11) H NMR sample was prepared by taking an aliquot (0.1 mL)
from the reaction mixture followed by concentration using Rotovap
and then dilution with CD Cl (1.5 mL).
2
2
(12) ICP-MS data of the boronic acid 1b (see in Supporting
Information) indicates no presence of inorganic salts.
AUTHOR INFORMATION
Corresponding Author
E-mail: nitinchandra.patel@boehringer-ingelheim.com.
■
*
Notes
The authors declare no competing financial interest.
REFERENCES
■
(
1) For leading references see: Hall, D. G. Boronic Acids: Preparation
and Applications in Organic Synthesis. Medicine and Materials; Wiley:
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(
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DOI: 10.1021/acs.oprd.5b00360
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