Nickel-Catalyzed Denitrogenative ortho-Arylation of Benzotriazinones with Organic Boronic Acids: an Efficient Route to Losartan and Irbesartan Drug Molecules

Article abstract of DOI:10.1002/adsc.201800923

Denitrogenative ortho-arylation, vinylation and methylation of 1,2,3-benzotriazin-4-(3H)-ones with organic boronic acids catalyzed by nickel complexes to give a wide range of o-substituted benzamides were demonstrated. Further, the catalytic reaction is successfully applied to the synthesis of the popular hypertensive drugs losartan and irbesartan in high yields. (Figure presented.).

Full text of DOI:10.1002/adsc.201800923

Title: Nickel-Catalyzed Denitrogenative ortho-Arylation of
Benzotriazinones with Organic Boronic Acids: an Efficient Route
to Losartan and Irbesartan Drug Molecules
Authors: Vijaykumar H. Thorat, Nitinkumar Satyadev Upadhyay, and
Chien-Hong Cheng
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800923
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10.1002/adsc.201800923
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Nickel-Catalyzed
Denitrogenative
ortho-Arylation
of
Benzotriazinones with Organic Boronic Acids: an Efficient
Route to Losartan and Irbesartan Drug Molecules
Vijaykumar H.Thorat,a Nitinkumar Satyadev Upadhyay,a and Chien-Hong Cheng*a
a
Department of Chemistry, National Tsing Hua University, Hsinchu 30013, Taiwan.
e-mail: chcheng@mx.nthu.edu.tw; Fax: +886-3-5724698; Tel: +886-3-5721454
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Denitrogenative ortho-arylation, vinylation and
methylation of 1,2,3-benzotriazin-4-(3H)-ones with organic
boronic acids catalyzed by nickel complexes to give a wide
range of o-substituted benzamides were demonstrated.
Further, the catalytic reaction is successfully applied to the
synthesis of the popular hypertensive drugs losartan and
irbesartan in high yields.
Keywords: nickel-catalyzed; arylation; boronic acid;
nickelacycle; losartan
Transition metal-catalyzed ortho-arylation is
considered to be the most elegant approach to achieve
biaryl motifs. A variety of arylating reagents like aryl
halide, pseudo-halide, and organometallics with
suitable directing groups have been successfully
utilized as reaction partners to obtain these biaryl
motifs.[3-9] Among the known organometallic reagents,
the organoboron reagent has been found to be the
most effective, air stable and low toxic reagent used
to attain the biary target motif. Several research
groups focused their efforts on developing efficient
approaches to synthesize the biaryl motifs which play
a crucial role in the biological activity profiles of
several drug molecules. Firstly, in 1998 Oi et al.
reported a rhodium-catalyzed arylation of 2-aryl
pyridines using arylstannanes as the arylating
reagent.[4a] Shi and co-workers showed a palladium-
catalyzed ortho-arylation of acetanilides with
arylsilanes.[5a] Kakiuchi’s group used ruthenium-
catalyzed reaction of aromatic ketones with
arylboronates to obtain arylated products.[6a] Recently,
Tang and co-workers demonstrated a Pd-catalyzed
denitrogenative Suzuki and carbonylative Suzuki
coupling of benzotriazole and boronic acids to give
various ortho-aminosubstituted biaryls and biaryl
ketone analogs.[5d] Jaganmohan’s group disclosed
Introduction
Hypertension is a common persisting medical
condition leading to high risks like heart failure,
stroke, coronary artery disease and atrial fibrillation
observed in almost all countries nowadays. In this
context, angiotensin II receptor blockers (ARBs) have
been successfully developed as the promising drug
candidates. These ARBs have drawn tremendous
attention due to their efficiency and bioavailability.
As a result, several new ARBs analogs are emerging
for clinical trials every year.[1,2] Currently, ARBs such
as valsartan, losartan, candesartan, and irbesartan are
widely available as drugs for the treatment of
hypertension in the market. These drugs are
nonpeptidic and mainly comprised of a basic biaryl
tetrazole moiety, which is necessary for binding to
the receptor and improving the oral availability of
these drugs.
ruthenium-catalyzed
arylation
of
N-methyl
Figure 1. Blockbuster ARB drug molecules.
benzamides with boronic acids to offer ortho-
arylation products.[6c] Also, Ni(II)-catalyzed ortho-
arylation of aromatic amides with arylsilanes using
PIP (2-pyridinylisopropyl) bidentate auxiliary as the
1
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10.1002/adsc.201800923
Advanced Synthesis & Catalysis
directing group was reported.[7a] In 2018, Mannathan
group described a nickel-catalyzed denitrogentaive
cross- coupling reaction of 1,2,3-benzotriazin-4-(3H)-
ones with boronic acids to prepare ortho-arylated
benzamides.[7e]
Over the years, transition metal-catalyzed
denitrogenative reactions have received enormous
attention and employed by several research groups to
achieve biaryl motifs.[10-14] In this line, 1,2,3 triazole
derivatives such as 1,2,3-benzotriazin-4-(3H)-one, N-
sulfonyl-1,2,3-triazole, pyridotriazole and N-
aroylbenzotriazoles can serve as the synthons or
substrates and are widely used in the denitrogenative
reactions. These triazole moieties, in the presence of
nickel catalysts, readily react with suitable π-
components like alkyne, alkene, allene, aryne,
isocyanide, and CO2 to yield several heterocyclic
compounds possessing biological applications. In
continuation of our previous results,[10a] here we
report a Ni-catalyzed denitrogenative ortho-arylation
of benzotriazinones with arylboronic acids and the
application of this catalytic reaction.
3a
Yield[b]
(%)
Catalyst
Entry
Ligand
Base
Solvent
(10 mol %)
1
2
3
4
5
6
7
8
9
[Ni(cod)2] dppm (20)
[Ni(cod)2] dppe (10)
[Ni(cod)2] dppp (20)
[Ni(cod)2] PPh3 (20)
[Ni(cod)2] PPh3 (10)
CsF
CsF
CsF
CsF
CsF
toluene
toluene
toluene
toluene
toluene
-
-
-
89
38
79
86
81
85
77
86
82
82
65
51
45
-
[Ni(cod)2] PPh3 (20) KF/18-crown-6 toluene
[Ni(cod)2] PPh3 (20)
[Ni(cod)2] PPh3 (20)
[Ni(cod)2] PPh3 (20)
Cs2CO3
CsF
CsF
toluene
ACN
THF
THF
dioxane
DME
10 [Ni(cod)2] PPh3 (20) KF/18-crown-6
11 [Ni(cod)2] PPh3 (20)
12 [Ni(cod)2] PPh3 (20)
13 [Ni(cod)2] PPh3 (20)
14 [Ni(cod)2] PPh3 (20)
15 [Ni(cod)2] PPh3 (20)
16 [Ni(cod)2] PPh3 (20)
CsF
CsF
CsF
CsF
CsF
CsF
-
CsF
-
CsF
DCE
DMF
DMSO
DMA
toluene
toluene
toluene
toluene
Results and Discussion
17 [Ni(cod)2]
18 [Ni(cod)2]
PPh3 (20)
-
-
-
-
-
-
Initially, we focused our attention on the
activation of triazole core by using suitable nickel
complexes and ligands. Later, we screened the
reaction conditions by choosing 1,2,3-benzotriazin-4-
(3H)-one as the model substrate.[15] Thus, treatment
of 1a (0.10 mmol) with phenylboronic acid 2a (0.15
mmol) using CsF (0.30 mmol) as the base under
catalyst system Ni(cod)2 (0.010 mmol) and dppm
(0.020 mmol) in toluene at 80°C for 8 h, no desired
denitrogenative ortho-arylated product was observed
(Table 1, entry 1). Other bidentate ligands dppe and
dppp also did not offer the arylated product.
However, when 1a was treated with 2a in the
presence of CsF (0.30 mmol), PPh3 (20 mol %) and
Ni(cod)2 (0.010 mmol) in toluene at 80°C, the ortho-
arylated product 3a was obtained in 89% isolated
yield (Table 1 entry 4). The decrease in the amount of
PPh3 ligand gave a lower yield of product 3a (entry
5). Other bases like KF with 18-crown-6, and Cs2CO3
also yielded the desired product in moderate to good
yield (entries 6, 7). Different solvents like ACN, THF,
dioxane, DME, DCE, DMF, DMSO, and DMA also
furnished the desired products, but in lower (45-86%)
yields (entries 8-16). No reaction occurred in the
absence of a nickel catalyst (entry 19). Upon
switching to P(p-MeOC6H5)3, P(p-MeC6H5)3 and P(o-
MeOC6H5)3 ligands, product 3a was obtained in 87%,
85%, and 70%, respectively (See Supporting
Information for details). However other ligands like
19
-
20 [Ni(PPh3)4]
[a] Reaction conditions: Unless otherwise mentioned, all reactions
were carried out using 1a (0.10 mmol), 2a (0.15 mmol),
[Ni(cod)2] (10 mol %), ligand (20 mol %), CsF (0.30 mmol),
solvent (2.0 mL), 80 °C, 8 h under N2 in a sealed tube (25 mL).[b]
isolated yield. Dppm = bis(diphenylphosphino)methane, dppe =
bis(diphenylphosphino)ethane,
dppp
=
bis(diphenylphosphino)propane. Safety consideration: we had
never faced problem during the reaction and workup. The
generation of nitrogen gas during the reaction is expected to raise
the pressure in the reaction tube from 1 atm to ~1.2 atm; when the
reaction is completed, the sealed tube is cooled to room
temperature and the cap should be opened carefully.
Having optimized the reaction conditions, we studied
the scope of the ortho-arylation reaction with
different 1,2,3-benzotriazin-4-(3H)-one substrates (1).
First, we examined the effect of substituents attached
to the N-aryl ring on the ortho-arylation. Various p-
substituted substrates 1a-1f were found to react
smoothly with phenylboronic acid 2a to give the
corresponding arylation products 3a-3f in excellent
yields (Table 2). We then turned to m-substituted
substrates, 1g-1j, which also underwent the expected
arylation to give the corresponding arylated products
3g-3j in good yields (80-87%). The sterically more
congested o-substituted substrates 1k-1n also reacted
well with 2a to provide the desired arylation products,
3k-3n, in 70-77% yields. Furthermore, various N-
alkyl, N-benzyl as well as N-naphthyl substrates 1p-
1t reacted efficiently under the optimized conditions
to afford arylation products 3p-3t in 81-89% yields.
N-dichlorophenyl substrate 1u also furnish 3u in 84%
yield. Notably, heterocyclic substrate 1v also
underwent arylation and furnished 3v in 82% yield.
P(o-MeC6H5)3,
ineffective.
P(p-FC6H5)3,
P(C6F5)3
were
Table 1. Optimization studies.[a]
2
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10.1002/adsc.201800923
Advanced Synthesis & Catalysis
The catalytic reaction exhibited good tolerance of the
functional groups like fluoro, methoxy and ester on
the aromatic ring of 1 and offered the expected
products 3w-3aa in good yields (79-84%). The
structures of arylation products 3o, 3z and 3aa were
unambiguously determined by X-ray crystallography
(Table 2).[16]
yields (67-82%). 2-Naphthyl and 1-naphthyl boronic
acids also gave the expected products, 4ap and 4aq,
in 81-82% yields, but the sterically hindered o-
tolylboronic acid 2r underwent o-arylation to give
4ar in only moderate yield. Unfortunately, the highly
electron-deficient pentafluorophenyl boronic acid, 2s,
and the heterocyclic boronic acids 2s-2u are not
active under the optimized reaction conditions. The
catalytic system is also well suited for the styryl and
methylboronic acids too to afford 4av and 4aw in
70% and 64% yields, respectively. However, alkyl
boronic acids like 1-hexylboronic acid and
cyclopropylboronic acid do not react under the
optimized reaction conditions.
Table 2. The scope of 1,2,3-benzotriazin-4(3H)-one
substrates in the o-arylation reaction.[a,b]
Table 3. The scope of boronic acid in the o-arylation
reaction of 1.[a,b]
a]Reaction conditions: 1a (0.10 mmol), 2a (0.15 mmol),
[
[Ni(cod)2] (10 mol %, 0.010 mmol), PPh3 (20 mol %, 0.020
mmol), CsF (0.30 mmol) in toluene (2.0 mL) at 80 °C for 8 h
under N2. [b]isolated yield.
The ortho-arylation reaction was further examined by
using various boronic acids (Table 3). Thus, when 1a
was allowed to react with electron-rich boronic acids
2b and 2c, arylation products 4ab and 4ac were
obtained in 84%, and 83% yields, respectively, The
boronic acids possessing electron-withdrawing
groups like para CHO, COCH3, CN and COOMe on
the phenyl ring also underwent the expected arylation,
but gave products 4ae-4ah in slightly lower 62-70%
yields. However, the electron-withdrawing fluoro-
containing groups, 4-CF3 and 4-F on phenylboronic
acid still afforded high product yields (4ad and 4ai).
The coupling of 3-substituted-phenyl boronic acids,
2j and 2k, with 1a furnished products 4aj and 4ak in
76% and 77% yields, respectively. Besides, 3,5-
disubstituted boronic acids underwent o-arylation
effectively affording 4al-4ao in moderate to good
3
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10.1002/adsc.201800923
Advanced Synthesis & Catalysis
Scheme 1. Competition experiments
However, the competition of electron-rich and -
deficient boronic acids, 2b and 2e, respectively, for
1a clearly showed a high reaction rate for 2b with 1a.
The results could be attributed to the fast
transmetalation step for electron-rich boronic acid 2b.
The synthetic utility of this reaction was tested by the
synthesis of popular drug molecules losartan and
irbesartan which are used for the treatment of high
blood pressure. First, the biaryl starting species 4a for
losartan was prepared by reacting 1s with 2b under
the optimized reaction conditions in 88% yield. Upon
treatment with PCl5 and TMSN3, 4a was converted to
tetrazole derivative 5a in 86 % yield. Bromination of
5a
by
DBDMH
(1,3-dibromo-5,5-dimethyl
hydantoin) using AIBN as initiator, followed by
nucleophilic displacement using 2-butyl-4-chloro-1H-
imidazole-5-carbaldehyde and K2CO3 in N,N-
dimethyl acetamide furnished 6a in 78% yield. One-
pot deprotection of the benzyl group and reduction of
formyl moiety in 6a was achieved with H2/Pd-C in
acetic acid to provide losartan in excellent yield.[17a]
Scheme 2. Synthesis of losartan and irbesartan
In addition to losartan, we also synthesize irbesartan
by employing a similar approach (Scheme 2). The
overall yields of losartan and irbesartan are 55% and
51%, respectively, comparable to the results reported
for the synthesis of losartan and irbesartan using
transition-metal catalysis.[17b-e,18]
[
a]Reaction conditions: 1a (0.10 mmol), 2a (0.15 mmol),
[Ni(cod)2] (10 mol %), PPh3 (20 mol %), and CsF (0.30 mmol) in
toluene (2.0 mL) at 80 °C for 8 h under N2. [b]isolated yield.
To understand the electronic nature of the present
catalytic reaction, we performed the competition
reaction between electron-rich and -deficient
substrates 1y and 1z with boronic acid 2a. The results
show that 1y reacted slightly faster than 1z indicating
that the reaction efficiency was not much affected by
the electronic factors of substrate 1.
Based on the previous literature reports and our
studies of the ring opening of 1,2,3-benzotriazin-4-
(3H)-one[10,19], a possible mechanism for the nickel-
catalyzed o-arylation reaction using 1a and 2a as
substrates are shown in Scheme 3. Initially, 1a reacts
with Ni(0) to form a five-membered azanickelacycle
intermediate A by the extrusion of an N2 molecule.
The transmetallation of phenylboronic acid 2a in the
presence of CsF provides intermediate B.
Subsequently protonation followed by reductive
elimination affords product 3a and the active nickel
species for the next catalytic cycle.
4
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10.1002/adsc.201800923
Advanced Synthesis & Catalysis
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Conclusion
In summary, we reported
denitrogenative o-arylation of 1,2,3-benzotriazin-4-
(3H)-one derivatives with organic boronic acids to
a
nickel-catalyzed
give biaryl compounds via
a
5-membered
azanickelacycle intermediate. The present catalytic
system tolerates a wide range of functionalities, and
show facile accessibility to bioactive drug molecules
like losartan and irbesartan. Further investigations on
the application of 1,2,3-benzotriazin-4-(3H)-one and
its related analogs are underway.
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General procedure for Ni-catalyzed ortho-
arylation
4(3H)-one (1a) with phenylboronic acid (2a): A 25-
mL sealed tube containing 3-(p-
of
3-(p-tolyl)benzo[d][1,2,3]triazin-
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tolyl)benzo[d][1,2,3]triazin-4(3H)-one 1a (0.10 mmol),
phenylboronic acid 2a (0.15 mmol), Ni(cod)2 (0.010
mmol), PPh3 (0.020 mmol), CsF (0.30 mmol) was
evacuated and purged with nitrogen gas three times. Then,
freshly distilled toluene (2 mL) was added under nitrogen
atmosphere, and the reaction mixture was stirred at 80 °C
for 8 h. The reaction mixture was cooled to room
temperature and was diluted with CH2Cl2 (10 mL). The
mixture was then filtered through a Celite pad and washed
sufficiently with CH2Cl2 (3 × 10 mL). The filtrate was
concentrated under reduced pressure and then purified by
column chromatography using hexane/diethyl ether as
eluents to afford the desired pure product 3a (25.5 mg;
89%).
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Acknowledgements
We thank the Ministry of Science and Technology of the Republic
of China (MOST 105-2633-M-007-003) for supporting this
research. V.T thanks the Ministry of Education, Taiwan for the
Taiwan Government scholarship.
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10.1002/adsc.201800923
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