Cu-benzotriazole-catalyzed electrophilic cyclization of N-arylimines: A methodical tandem approach to O-protected-4hydroxyquinazolines-

Article abstract of DOI:10.1039/c4ra07377k

A remarkably efficient approach to O-protected-4-hydroxyquinazolines has been developed via the copper-benzotriazole (Cu-BtH)-catalyzed intramolecular electrophilic cyclization of N-arylimines, achieved through the reaction of 2-aminobenzonitriles and various aldehydes. the Partner Organisations 2014.

Full text of DOI:10.1039/c4ra07377k

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Journal Name
RSCPublishing
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Cu-Benzotriazole Catalyzed Electrophilic Cyclization
of N-Arylimines: A Methodical Tandem Approach to
O-Protected-4-hydroxyquinazolines.
Cite this: DOI: 10.1039/x0xx00000x
Satyanarayana Battula,a,b Ram A. Vishwakarma a,b* and Qazi Naveed Ahmed a,b*
Received 00th January 2012,
Accepted 00th January 2012
DOI: 10.1039/x0xx00000x
www.rsc.org/
An unprecedented efficient approach to O-protected-4- catalytic system had overcome the limitations of Cu promoted
hydroxyquinazolines has been developed via copper- reactions in the concern of yield, reaction time, temperature and the
benzotriazole
(Cu-BtH)
catalyzed
intramolecular use of Cu in stoichiometric amounts.12,13 The ability of Cu-BtH catalytic
electrophilic cyclization of N-arylimines, achieved through system was further extended in shape of our work towards generation
reaction of 2-aminobenzonitriles and various aldehydes.
of quinazolines in good yields.
Cl
N
N
NHNH2
Introduction
N
Quinazolines are one of the vital basic scaffolds of N-containing
hetero-arens, prevalently appears in nature as natural alkaloids.1 As
their features, quinazoline structural congeners are exhibiting a wide
range of biological and pharmacological activities in areas as diverse
as anti-cancer, anti-tubercular, anti-bacterial, anti-malarial and anti-
viral.2 Owing to their significant role in chemistry and biology,
development of novel and convenient methods has always been a
topic of research worldwide. Even though several methods are
available for synthesis of 2-substituted3 and 2,4-disubstituted4
quinazolines, 4-oxysubstituted quinazolines have recently gained
importance, on account of its biological properties in areas related to
anticancer (VEGFR2, EGFR and BRAF) and anti HIV.5,6 In past,
synthesis of O-protected-4-hydroxyquinazoline (PHQ) was achieved
by various groups through chemical transformation of different
starting materials as described in scheme 1.5-10 All these reported
N
O
NNH2
N
R1
OR
N
R1
NH
1a
1d
N
ref. 16, 17, 18
ref. 19, 20
N
R2
N
R2
3
1e
CuI-BtH
4Ao MS, 90o
C
(R : Me, CD3, Et) ROH, K2CO3
CN
O
+
R1
This work
R2
NH2
1
2
Scheme 1. Approaches for the Synthesis of 4-alkoxyquinazolines
Results and disscussions
Our studies are initiated with the reaction of 2-AN 1a with 4-
anisaldehyde 2a in presence of CuI (10 mol %) and K2CO3 (1.5 equiv) in
MeOH at room temperature where in, we observed a surprising
methods (1a-1d) involve synthesis from bicyclic-N-heterocycles with
limitations in terms of either using an expensive catalysts like BOP7/
HCCP8 or applying harsh conditions. In this context, we developed an
efficient copper-benzotriazole (Cu-BtH) catalyzed tandem method
product 3a (4-methoxyquinazoline) in 5 % yield (Table 1, entry 1).
Yield of 3a increased to 15%, when same reaction was conducted
under reflux conditions with CuI (entry 2). Reaction in presence of
CuCl resulted in poor yields (12%, entry 3). Later, few Cu (II) catalysts
were also screened under reflux conditions, but were found not to be
so effective (entry 4, 5 and 6). To improve the yields, we employed
CuI-BtH system to our reaction under different conditions (entry 7-17).
A paradigm shift in yield of product 3a (59 %, entry 7) was observed
when the reaction was performed with 10 mol% of catalytic system.
An investigation regarding optimization of metal to ligand optimal
concentration (entry 8-11) was also studied and the results clearly
(
1e) for synthesis of PHQ through intramolecular electrophilic
cyclization of N-arylimines obtained during the reaction of 2-
aminobenzonitriles (2-AN) with aldehydes.
Benzotriazole (BtH) is an inexpensive, air and moisture stable
compound, showing an excellent ligandic properties and being used
as catalyst in many valuable transformations.11 Its tendency to form
complexes with copper has emphasized lot of importance in past few
years and has been utilized in diverse directions including C-X (hetero
atom like N & S) bond formation.12 Reactions catalyzed by Cu-BtH
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indicated that 10 mol% of CuI combines with 20 mol% of BtH Further a reaction when tested with hydroxylbenzotriazole (HOBt/ L2)
produces best condition for catalyzing such reactions (67%, entry 8).
resulted in low yields (68%, entry17). No reaction was observed in
absence of CuI (entry 18).
Table 1. Optimization of the reaction conditionsa
With the optimized procedure in hand, we synthesized a variety of O-
methoxy-protected quinazolines (3a
-
3v) as summarized in scheme 2.
could
All sorts of aldehydes 2 (aryl, alkyl and heteroaryl) and 2-AN
1
be converted to the corresponding quinazolines in good to excellent
yields (72-86%), however aryl (3a-3n) and heteroaryl aldehydes (3o-
3r) provided little improvement in yields than compare to aliphatic
entry
Copper
(mol%)
L
(mol%)
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
L1(10)
L1(20)
L1(25)
L1(20)
L1(20)
L1(20)
L1(20)
L1(20)
L1(20)
L1(20)
L2(20)
L1(20)
base
(equiv)
ta
yield[b]
(%)
5
(h)
24
24
24
24
24
24
24
24
24
24
24
12
24
24
24
24
24
24
CuI (10)
CuI (10)
CuCl (10)
Cu(OAc)2 (10)
Cu(OTf)2 (10)
Cu(acac)2 (10)
CuI (10)
CuI (10)
CuI (10)
CuI (5)
CuI (20)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
CuI (10)
ꢀ
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (1.5)
K2CO3 (2)
K2CO3 (2.5)
Cs2CO3 (2)
KOtBu (2)
Et3N (2)
1. *
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.¤
13.
14.
15.
16.
17.
18.
ones (3s
lead to desired product in good yields (3u
provided evidence in support of launching methoxy (-OMe) group
from solvent. Furthermore in few reactions compound was also
,
3t). Same reaction when conducted in deuterated methanol
15
12
8
5
8
59
67
66
58
63
78
76
68
71
59
68
NR
,
3v). This reaction itself
4
generated in 10-15% yield (Scheme 3). In order to overcome the
limitation, such reactions when performed in presence of O2 balloon
produced exclusively desired product 3.
K2CO3 (2)
K2CO3 (2)
a 2-AN 1a (0.854 mmol), 4-methoxybenz-aldehyde 2a (1.025 mmol), CuI (10 mol%),
[b]
BtH (20 mol%) and K2CO3 (2 equiv) with MeOH (2 ml). ta- time. Yield of isolated
products,* reaction at room temperature, ¤ observed same yield, when reaction was
carried out in nitrogen atmosphere (as in absence of N2), NR-no reaction.
Scheme 3. Aerobic assistance in the conversion of dihydro product 4 to 3
In order to obtain better results a series of reactions were conducted
in presence of different bases (entry 12-16). Maximum yields of 3a was
achieved by reaction of 1a with 2a in presence of Cu-BtH (10 mol%: 20
mol%) in methanol using 2 equiv of K2CO3 under reflux condition.
Later we observed no product (O-ethoxy protected quinazolines,
EPQ) when a reaction was tried between
1 and 2 under similar
conditions in ethanol. Taking hints from literature on reactions of
imine formation, we performed above reactions under dry conditions
in presence of molecular sieves. We could achieve desired product
(EPQ) in good yields in all reactions tested between
1 and 2 (scheme
4, 3w-3z). Compared with reactions for generation of MPQ, EPQ
synthesis was associated with lower yields, longer reaction times and
needed dry conditions.
3a (78%), R1, R2: H, 4ꢀOMe
3g (86%), R: 4ꢀOMe
3b (75%), R1, R2: H, 3ꢀCl
3h (78%), R: 3ꢀCl
3c (79%), R1, R2: H, 4ꢀCl,
3d (83%), R1, R2: H, 3ꢀBr
3j (79%), R: 4ꢀF
3e (76%), R1, R2: H, 4ꢀF
3i (84%), R: 3ꢀBr
3f (78%), R1, R2: 3ꢀBr,4ꢀOMe
(3x, 71%)
(3y, 73%)
(3w, 69%)
(3z, 74%)
Scheme 4. Scope of the electrophilic cyclization of N-arylimines with EtOH as
solvent
3o (77%), x: O
3p (85%), x: S
3m (79%), R: 4ꢀCl
3n (80%), R: 3ꢀNO2
3k (78%), R: 7ꢀCl
3l (80%), R: 6ꢀBr
To gain insight in to the mechanism of reaction, a few reactions
(scheme 5) were keenly studied. In order to decipher the role of imine
transformation to
route, we performed a test reaction between imine
conditions. As expected, we observed 3d in 83% yield. In another
experiment a reaction was performed between and with equal
3
through intramolecular electrophilic cyclization
5
under similar
3q (81%), R1, R2: 6,7ꢀdi OMe 3s (80%), R: H
3r (78%), R1: H, R2: 6ꢀCl 3t (72%), R: iꢀbutyl
3u (75%), R1: H, R2: 4ꢀ OMe
3v (72%), R1: 6ꢀCl, R2: 4ꢀ Br
1
2
Scheme 2. Substrate scope of the electrophilic cyclization.
volumes of EtOH and MeOH as per procedure discussed in table 1. In
2 | J. Name., 2012, 00, 1-3
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this case we retrieved only MPQ, however reaction when carried out
in dry condition generated MPQ and EPQ in the yields of 72%, 11%
respectively and obviously justified role of nucleophilicity of alcohol
towards bringing the reaction. On that reason, reaction with ethanol
needed dry conditions and more reaction time. Moreover reactions
with week nucleophiles like isopropanol, n-propanol produced trace
Aknowledgement
S.B. thanks CSIR for the award of senior reaserch fellowship, we thank
to analytical department of IIIM. Authors also acknowledge to BSC-
0108 for funding to this work.
Notes and references
amount of product 3 under dry conditions.
a Medicinal Chemistry Division, Indian Institute of Integrative Medicine
(IIIM), Jammu, India,180001.
b Academy of Scientific and Innovative Research (AcSIR), Central Road
Research Institute, New Delhi – 110 025.
*ram@iiim.ac.in, naqazi@iiim.ac.in (IIIM/1679/2014)
Supplementary information: all compounds H1 and C13 spectra are
available.
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Scheme 5. Mechanistic studies of the reaction
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,
541.
On the basis of experimental results and related literature,12 we
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aminobenzonitrile initially forms N-arylimine with aldehyde, that
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A.
Instantaneously both the processes of intramolecular electrophilic
cyclization and oxidative addition of alcohols eventuates in a tandem
mode resulting in complex
predominantly converts to complex
process. Subsequent reductive elimination of complex
desired product . In order to justify presence of compound
presume an additional path where in complex
in H+ environment
generates dihydroquinazoline that undergoes oxidation to desired
product in oxygen atmosphere.
B
. In presence of base and air, it
through oxidative addition
, leads to the
, we
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alcohol
Conclusions
In summary, we developed a simple and efficient strategy for
constructing O-protected-4-hydroxyquinazolines in good yields. This
6
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3 through monocyclic
7
8
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intermediate followed by nucleophilic attack of alkoxy group.
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Cu-Benzotriazole Catalyzed Electrophilic Cyclization of N-Arylimines: A
Methodical Tandem Approach to O-Protected-4-hydroxyquinazolines.
Satyanarayana Battula,a,b Ram A. Vishwakarma a,b* and Qazi Naveed Ahmed a,b*
Medicinal Chemistry Division, Academy of Scientific and Innovative Research (AcSIR), Indian Institute of Integrative
Medicine (IIIM), Jammu, Jammu and Kashmir 1800o1, India.
E-mail: naqazi@iiim.ac.in, ram@iiim.ac.in.
ABSTRACT: An unprecedented approach for the synthesis of O-protected-4-hydroxyquinazoline has been
developed via copper-benzotriazole (Cu-BtH) catalyzed intramolecular electrophilic cyclization of N-arylimines,
achieved through reaction of 2-aminobenzonitriles and various aldehydes. This oxidative coupling of N-arylimines
is probably accomplished by the driving force of Cu-BtH catalytic system promoting cyclization to a bicyclic reactive
species followed by nucleophilic attack of alcohol. The reaction proceeds efficiently with a diverse set of
commercially available 2-aminobenzonitriles and benzaldehydes.