Synthesis of 2-amino-4-(methoxycarbonyl)phenylboronic acid hydrochloride, a key intermediate for the synthesis of quinolines derivatives

Article abstract of DOI:10.3184/174751914X14175346572646

A practical and efficient process for the synthesis in good yield of 2-amino-4-(methoxycarbonyl)phenylboronic acid hydrochloride from p-bromo toluene has been developed via borylation, oxidation, nitration, esterification and hydrogenation.

Full text of DOI:10.3184/174751914X14175346572646

JOURNAL OF CHEMICAL RESEARCH 2014
VOL. 38 DECEMBER, 719–721
RESEARCH PAPER 719
Synthesis of 2‑amino‑4‑(methoxycarbonyl)phenylboronic acid
hydrochloride, a key intermediate for the synthesis of quinolines derivatives
Feng Xue*, Chang‑Gong Li, Yong Zhu and Tian‑Jun Lou
Key Laboratory of Functional Organic Molecules of Xinxiang City Henan Province, College of Chemistry and Chemical Engineering, Henan
Institute of Science and Technology, Xinxiang Henan, 453002, P.R. China
Apracticalandefficientprocessforthesynthesisingoodyieldof2‑amino‑4‑(methoxycarbonyl)phenylboronicacidhydrochloride
from p‑bromo toluene has been developed via borylation, oxidation, nitration, esterification and hydrogenation.
Keywords: 2‑amino‑4‑(methoxycarbonyl)phenylboronic acid hydrochloride, borylation, oxidation, nitration, esterification,
hydrogenation
In the search for biologically active compounds as potential
drug candidates, the efficient synthesis of both libraries and
individualheterocyclicsmallmoleculesisofmajorimportanceto
the pharmaceutical industry.1 Approaches involving a sequence
of regiocontrolled halogenation followed by palladium‑
catalysed coupling reaction based upon a heterocyclic scaffold
have been successfully developed.2 In particular, functionalised
arylboronic acids and arylboronates are highly valuable
because consecutive cross‑coupling is possible from these
compounds, which can rapidly lead to the complex structure
of target molecules.3 Among these compounds, 2‑amino‑4‑
(methoxycarbonyl)phenylboronic acid hydrochloride 1 is a
versatile synthetic intermediate used in cross‑coupling reaction
for the preparation of a wide variety of natural products and
biologically active compounds,4,5 such as pyrimidoquinolines,6
imidazoquinolines,7 thiazoquinolines and oxazoquinolines8
derivatives. These possess various types of significant
biological properties as vaccine adjuvants, such as antiHIV,
antituberculosis, anticancer, antimycobacterial (Scheme 1). For
example, imiquimod (a simple imidazoquinoline) is an FDA‑
approved immune response modifier administered as a cream
on the skin for the treatment of cutaneous tumours. Imiquimod
exerts its immunostimulatory effects through TLK 7 expression
on plasmacytoid dendritic cells and B cells in humans.9
Despite the recognised importance of 2‑amino‑4‑
(methoxycarbonyl)phenylboronic acid hydrochloride in
Scheme 1 Representative compounds based on 2‑amino‑4‑(methoxycarbonyl)phenylboronic acid hydrochloride 1.
* Correspondent. E‑mail: fxuehist@sina.com
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720 JOURNAL OF CHEMICAL RESEARCH 2014
COOH
HNO3/H2SO4
KMnO4, NaOH
Mg, THF
B(OMe)3
H+
Br
76%
75
70%
%
B(OH)2
14
B(OH)2
13
15
COOH
COOMe
COOMe
Pd/C, H2
HCl
SOCl2, MeOH
NH2HCl
NO2
NO2
B(OH)2
17
80%
68%
B(OH)2
B(OH)2
16
1
Scheme 2 Preparation of 2‑amino‑4‑(methoxycarbonyl)phenylboronic acid hydrochloride 1.
synthesis, to the best of our knowledge, there are no readily
boronic acid 14 was readily converted to 16 by oxidation
with potassium permanganate in an alkaline solution. After a
preliminary study of the nitration of boronic acid, a satisfactory
procedure was developed, whereby p‑carboxyphenylboronic
acid 15 was easily nitrated at room temperature by a mixture
of fuming nitric acid and sulfuric acids to yield a single product
2‑nitro‑carboxyphenylboronic acid 16. Note that if the boronic
acid 15 was first esterified, and the esterified product was then
nitrated, some byproducts were produced that were difficult
to separate. During the next esterification process (Table 1),
1.2 equiv. of SOCl2 was used in the refluxing methanol. A
simple aqueous workup afforded relatively pure product 17
in 80% yield (Table 1, entry 4), which was suitable for use in
the next hydrogenation step. In comparison with traditional
conc. sulfuric acid‑activated esterification reaction, the present
procedure both avoided the previously‑reported harsh reaction
conditions and improved the yield of product.
available published methods to prepare this compound in
the accessible chemical literature. Thus, we now describe a
practical and efficient process for the preparation of 2‑amino‑
4‑(methoxycarbonyl)phenylboronic acid hydrochloride. Using
smooth and simple reaction procedures from readily available
starting materials, this method of synthesis provides easy
access to the target compound (Scheme 2).
Results and discussion
During the first‑step involving the preparation of p‑tolylboronic
acid 14 from bromotoluene 13, the methyl borate should be
completely free from methyl alcohol, since the latter caused a
marked diminution in the yield, apparently greater than could
be accounted for on the basis of the Grignard reagent being
destroyedbythealcohol. Sincemethylborateformsanazeotropic
mixture with methyl alcohol from which it is relatively difficult
to remove the last traces of methyl alcohol, washing with cold
concd sulfuric acid was used to obtain the purified methyl
borate. Preliminary tests showed that the reaction conditions
were improved by adding the p‑tolylmagnesium bromide to an
ether solution of methyl borate under noncryogenic conditions
(−12ꢀ°C),ꢀinsteadꢀofꢀtheꢀprocedureꢀusedꢀbyꢀChan,10 thus avoiding
cryogenicꢀ conditionsꢀ (−78ꢀ°C). Subsequently, the resulting
Finally, after careful exploration of other reducing
reagents such as hydrazine hydrate, Fe/HOAc and Zn/HOAc
(Table 2), the 2‑amino‑4‑(methoxycarbonyl)phenylboronic
acid hydrochloride 1 was smoothly obtained through Pd/C
hydrogenation under 1 atm H2 pressure in 68% yield (Table 2,
entry 4).
Table 2 Screening of reducing reagents in the hydrogenation reaction of 17a
Table 1 Screening of activating reagents in the esterification reaction of 16a
COOMe
COOMe
H
COO
COOMe
NH2HCl
NO2
NO2
NO2
B(OH)2
B(OH)2
B(OH)2
B(OH)2
1
17
16
17
Reaction
temperature/°C
Entry Reducing reagents
Product
Yield/%f
Entry
Activating reagent
Product
Yield/%
1b
2c
3c
4d
5d
Conc. H2SO4
DMAP
DCC
SOCl2
(COCl)2
17
17
17
17
17
65
70
72
80
77
1b
2c
3d
4e
Pd/C+N2H4H2O
Fe/HOAc
Zn/HOAc
65 °C
65 °C
65 °C
40 °C
1
1
1
1
40
50
43
68
Pd/C+H2
aThe reaction was carried out in methanol for 8 h.
bPd/C (10 g mol–1), N2H4H2O (1.6 equiv.) was used.
cFe (40 g mol–1) was used.
aThe reaction was carried out in refluxed methanol for 3 h.
bConc. H2SO4 (0.08 equiv.) was used. c DMAP (0.1 equiv.) or DCC (0.1 equiv.)
was used.
dZn (40 g mol–1) was used.
dSOCl2 (1.2 equiv.) or (COCl)2 (1.2 equiv.) was used.
eIsolated yield based on compound 16.
ePd/C (10 g mol–1), H2 (1 atm) was used.
fIsolated yield based on compound 17.
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JOURNAL OF CHEMICAL RESEARCH 2014 721
4-(Methoxycarbonyl)-2-nitrophenylboronic acid (17): SOCl2
(23 g, 0.19 mol) was slowly added to a solution of 2‑nitro‑4‑
carboxyphenylboronic acid 2 (35 g, 0.16 mol) in methanol (350 mL)
dropwise, After the reaction mixture had been refluxed for 3 h, it
was poured into cold ice water and then stirred for another 0.5 h.
The reaction mixture was filtered and then rinsed with EtOAc.
The resulting filtercake was dried to give the corresponding
4‑(methoxycarbonyl)‑2‑nitrophenylboronic acid 17 (28.9 g, 80% yield).
m.p.ꢀ158–161ꢀ°C.ꢀ1HNMR (d6-DMSO)ꢀδꢀ8.55–8.58ꢀ(d,ꢀ1H,ꢀJ=5.3 Hz),
8.39 (b, 2H), 8.26–8.28 (m, 1H), 7.73 (d, 1H, J=7.6 Hz), 3.92 (s, 3H).
HRMS calcd for C8H8BNO6 [M]+ 225.0445; found: 225.0439.
A practical and efficient process for the preparation
2‑amino‑4‑(methoxycarbonyl)phenylboronic acid
of
hydrochloride, a key compound in the formation of many
quinolines derivatives is described. To develop a process
for this important compound with overall efficiency, each
procedure was carefully surveyed to ensure the optimal
results. Eventually, a facile as well as cost‑effective process
has been developed through borylation, oxidation, nitration,
esterification, hydrogenation reaction to afford the target
compound in good yield and high quality.
2-Amino-4-(methoxycarbonyl)phenylboronic acid hydrochloride
(1): Concentrated hydrochloric acid (18 g) was added to a solution of
4‑(methoxycarbonyl)‑2‑nitrophenylboronic acid 3 (30 g, 0.13 mol) in
methanol (300 mL). After the reaction mixture had been hydrogenated
over 10% Pd/C (1.3 g, 10 g mol–1)ꢀunderꢀ1ꢀatmꢀpressureꢀatꢀ40ꢀ°Cꢀforꢀ8ꢀh,ꢀ
the catalyst was removed by filtration through Celite®, washed with
MeOH and concentrated under reduced pressure. The residue was
rinsed with acetone, then filtered. The resulting filtercake was dried
under vacuum to afford 2‑amino‑4‑(methoxycarbonyl)phenylboronic
acid hydrochloride 1ꢀ (21.0ꢀg,ꢀ 68%ꢀ yield).ꢀ m.p.ꢀ 178–180ꢀ°C,ꢀ whichꢀ
matched that observed for the corresponding product purchased
Experimental
Solvents and reagents were purchased from Sigma‑Aldrich and
used without further purification. Melting points were determined
on a Mettler FP5 apparatus and are uncorrected. NMR spectra were
recorded on Bruker DRX 400 MHz spectrometer using CDCl3 as
solvent, and TMS as internal standard. High resolution mass spectra
were recorded on Applied Biosystems Mariner System 5303.
p-Tolylboronic acid (14): Magnesium turnings (0.72 g, 30 mmol)
were placed in a round‑bottomed flask and then flame‑dried under
N2. bromotoluene (5.1 g, 30 mmol) dissolved in pure ether (20 mL)
was added slowly with an addition funnel to the flask. The reaction
mixture was gently refluxed for 3 to 4 h. After cooling, the Grignard
reagent was transferred to a solution of (3.1 g, 30 mmol) of (CH3O)3B
inꢀpureꢀetherꢀ(10ꢀmL)ꢀatꢀ–12ꢀ°Cꢀandꢀstirredꢀovernightꢀslowlyꢀwarmingꢀ
up to room temperature. After acidification with 10% HCI (10 mL),
the product was extracted into ether (3×100 mL) and dried (sodium
sulfate). The solvent was then removed under reduced pressure, and
the product was precipitated by hexane with further recrystallisation
from water. p‑Tolylboronic acid 14 (3.1 g) was obtained in 76% yield as
whiteꢀneedles.ꢀm.p.ꢀ244–245ꢀ°Cꢀ(lit.10ꢀ243–244ꢀ°C).
p-Carboxyphenylboronic acid (15): p‑Tolylboronic acid 14 (7.5 g,
55 mmol) was dissolved in water (350 mL) containing sodium
hydroxide (4.5 g). The stirred mixture was treated with a solution of
potassium permanganate (16.6 g, 105 mmol) in water (500 mL) as
follows. The permanganate solution was divided into eight portions,
each of which was added in turn every hour. After all portions of
the permanganate solution had been added, the mixture was stirred
overnight. Excess permanganate was destroyed by the addition of
Na2SO3, and the manganese dioxide was filtered off. The filtrate
wasꢀ concentratedꢀ toꢀ aboutꢀ 200ꢀmLꢀ belowꢀ 40ꢀ°C,ꢀ andꢀ thenꢀ acidifiedꢀ
carefully with hydrochloric acid. The crystals that were separated
were collected, washed with water, and recrystallised from water
to afford compound 15ꢀ (6.39ꢀg,ꢀ 70%ꢀ yield),ꢀ m.p.ꢀ 230–233ꢀ°Cꢀ (lit.11
232–234ꢀ°C).
1
from Combi‑Blocks Company. H NMR (d6-DMSO)ꢀδꢀ7.83–7.85ꢀ(d,ꢀ
1H, J=8.0 Hz), 7.59–7.63 (m, 2H), 3.86 (s, 3H). 13C NMR (d6‑DMSO)
δꢀ 165.9,ꢀ 138.5,ꢀ 136.9,ꢀ 132.6,ꢀ 127.2,ꢀ 123.3,ꢀ 53.0.ꢀ HRMSꢀ calcdꢀ forꢀ
C8H11BClNO4 [M]+ 231.0470; found: 231.0473.
This work was supported by the National Natural Science
Foundation of China (21072046).
Received 19 September 2014; accepted 7 November 2014
Paper 1402922 doi: 10.3184/174751914X14175346572646
Published online: 19 December 2014
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A stirred slurry
7
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