Divergent Synthesis of Imidazoles and Quinazolines via Pd(OAc)2-Catalyzed Annulation of N-Allylamidines

Article abstract of DOI:10.1021/acs.orglett.5b01435

A Pd(OAc)₂-catalyzed divergent synthesis of multisubstituted imidazoles and quinazolines from N-allylamidines has been developed. In the presence of oxidant O₂ from air and/or a ligand and Pd(OAc)₂, imidazoles were obtaine

Full text of DOI:10.1021/acs.orglett.5b01435

Letter
pubs.acs.org/OrgLett
Divergent Synthesis of Imidazoles and Quinazolines via
Pd(OAc)2‑Catalyzed Annulation of N‑Allylamidines
Li Xu,† Hongxian Li,† Ziyang Liao,† Kaiyan Lou,† Hexin Xie,† Hao Li,*,† and Wei Wang*,†,‡
†Shanghai Key Laboratory of New Drug Design, School of Pharmacy, and State Key Laboratory of Bioengineering Reactor, East
China University of Science and Technology, 130 Mei-long Road, Shanghai 200237, China
‡Department of Chemistry and Chemical Biology, University of New Mexico, Albuquerque, New Mexico 87131-0001, United States
S
* Supporting Information
ABSTRACT: A Pd(OAc)2-catalyzed divergent synthesis of
multisubstituted imidazoles and quinazolines from N-allylami-
dines has been developed. In the presence of oxidant O2 from
air and/or a ligand and Pd(OAc)2, imidazoles were obtained.
Nonetheless, under microwave (MW) irradiation in a sealed
system, quinazolines as major products were produced.
midazoles and quinazolines are important aromatic hetero-
cycles widely distributed in a large number of natural
other amines such as N-allylamidines, which can be easily
prepared by the reported procedures.13 The realization of this
reaction could afford an approach to synthetically and
biologically important imidazoles (Scheme 1, eq 2). However,
during the course of our investigation, unexpectedly, we found
that the reaction conditions were critical for the products
formed. In the presence of oxidant O2 from air and/or a ligand
and Pd(OAc)2, the expected imidazoles were obtained.
Nonetheless, under microwave (MW) irradiation in a sealed
system, quinazolines were produced as major products. Here
we wish to disclose the results of the investigation.
In the initial attempt, we carried out a model reaction of N-
allyl-N′-(4-methoxyphenyl)benzimidamide (1a) in the pres-
ence of Pd(OAc)2 (20 mol %) and open air in toluene at 80 °C
for 12 h, conditions similar to those used in our previous study
(Table 1).12 To our delight, the hydroamination reaction
worked smoothly to give the desired imidazole 2a in 55% yield
(entry 1). Encouraged by this result, we attempted to optimize
reaction conditions to improve the reaction yields. First,
different palladium(II) catalysts such as PdCl2 and Pd(TFA)2
were screened under the same reaction conditions. PdCl2
afforded the product with similar yield (45%, entry 2), while
Pd(TFA)2 gave poorer yield (10%, entry 3). We also found
oxidant (e.g., O2) was necessary for this reaction. No reaction
took place under N2 atmosphere at all (entry 4). Interestingly,
the reaction with oxygen balloon afforded a lower yield
compared with the yield obtained when air was used as oxidant
(43%, entry 5). Next, effects from different ligands including
phosphine and nitrogen-based ligands were tested. The results
revealed that most of ligands could not improve yields (entries
6−14), except the ligand L8, where the yield was increased to
70% (entry 15). In terms of the catalyst loading, 20 mol % was
necessary for this reaction. The reaction yield was decreased to
45% when the catalyst loading was lowered to 10 mol % (entry
I
products and bioactive compounds.1 They show a wide range
of attractive biological properties,2−6 such as anticancer
activities2 represented by drugs erotinib4 and gefitinib,6
cholinergic agonist (e.g., pilocarpine),3 and selective adrenergic
blocker prazosin.5 Because of their importance as privileged
scaffolds in drug discovery, in the past decade, significant efforts
have been made on the construction of imidazoles7 and
quinazolines,8 including annulation methods. In this context,
recently, transition-metal-catalyzed intermolecular annulation
of propargylamides with amines9 and intramolecular annulation
of propargylamidines10 to form imidazole rings have been
developed (Scheme 1, eq 1). Moreover, the oxidative
Scheme 1. Annulation of N-Allylamidines
annulation of N-arylmethanamidines reported by Long very
recently demonstrated the potential divergent synthesis of
substituted benzimidazoles and quinazolines under different
conditions.11 However, they display limited substrate scope.
Furthermore, they are not applicable to the less active N-
allylamidines.
Previously, we uncovered palladium-catalyzed the annulation
of simple alkenylamines.12 As part of our continuous efforts in
this area, we wish to extend the useful annulation process to
Received: May 15, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01435
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of Reaction Conditions
Table 2. Substrate Scope of the Reaction
b
entry
Ar′, Ar″
yield (%)
1
4-MeOC6H4, Ph
3-MeOC6H4, Ph
2-MeOC6H4, Ph
4-MeC6H4, Ph
70 (2a)
72 (2b)
78 (2c)
61 (2d)
54 (2e)
45 (2f)
51 (2g)
49 (2h)
36 (2i)
45 (2j)
77 (2k)
2
3
4
5
2-MeC6H4, Ph
6
3,4,5-(MeO)3C6H2, Ph
Ph, Ph
7
b
entry
cat.
ligand
yield (%)
8
2-naphthyl, Ph
9
4-CF3C6H4, Ph
1
2
3
Pd(OAc)2
PdCl2
50
45
10
10
11
4-MeOC6H4, 4-CF3C6H4
4-MeOC6H4, 4-MeOC6H4
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
a
c
4
Unless specified, a solution of the catalyst (0.02 mmol) with ligand
L8 (0.02 mmol) in toluene (1 mL) was stirred for 30 min at rt, 1 (0.1
mmol) was added, and the solution was stirred for 12 h at 80 °C.
Isolated yield.
d
5
43
31
53
44
23
35
30
30
34
38
70
45
6
PPh3
BINAP
L1
b
7
8
with alkyl substituents did not work under these reaction
conditions.
In our exploratory studies, we found that when amidine 1g
with 20 mol % of Pd(OAc)2 in 1 mL of xylenes was heated to
170 °C under microwave (MW) conditions (150 W) for 2 h
unexpected quinazoline 3g was separated as the major product
in 65% yield and imidazole 2g as the minor product (Table 3,
9
L2
10
11
12
13
14
15
L3
L4
L5
L6
L7
L8
e
16
L8
a
a
Table 3. Searching Optimal Reaction Conditions
Unless specified, a solution of the catalyst with ligand (1:1) in toluene
(1 mL) was stirred at rt for 30 min, 1a (0.1 mmol) was added, and the
b
c
solution was stirred for 12 h at 80 °C. Isolated yield. The solution
was filled with N2. 1 atm of O2 was used as oxidant. 10 mol % of
d
e
catalyst and ligand was used.
b
entry
cat
solvent
xylenes
yield (%)
16). Moreover, solvent screening showed that toluene was the
best for this process.14 Finally, it was found that the
temperature was also important for this reaction. Heating the
reaction mixture generally improved the reaction yield.
1
2
3
4
5
6
Pd(OAc)2
PdCl2
65
48
63
35
23
60
xylenes
Pd(TFA)2
PdCl2(PPh3)2
PdCl2(dppf)
Pd(OAc)2
xylenes
xylenes
We have found the optimal reaction conditions to form
imidazoles: N-allylamidines 1 with 20 mol % of Pd(OAc)2 and
ligand L8 in toluene at 80 °C for 12 h. Next, we probed the
substrate scope of this annulation process (Table 2). The
reactions proceeded smoothly for a range of N-allylamidines
(Table 2). Apparently, the reaction yields were affected by the
electronic nature of the substituents on the aromatic rings.
Generally, the aromatic group on nitrogen with strong electron-
donating methoxy groups afforded higher yields (70−78%,
entries 1−3). The amidines with less electron-donating methyl
groups on phenyl ring gave lower yields (54−61%, entries 4
and 5). Steric hindrance also affected yield, as more hindered
trimethoxy-substituted amidine 1f gave lower yield (entry 6).
The phenyl- and 2-naphthylamidines afforded the products
with acceptable yields (entries 7 and 8). The amidine with an
electron-withdrawing moiety gave a lower reaction yield (36%,
entry 9). Furthermore, the electron-withdrawing moiety on the
second phenyl group also affected the yield (entry 10). The
amidine with both phenyl rings bearing electron-donating
group gave much higher yield (77%, entry 11). However, a
limitation of this process is also recognized in that amidines
xylenes
chlorobenzene
a
Unless specified, a solution of 1g (0.1 mmol) with the catalyst (0.02
mmol) in solvent (1 mL) was heated in the microwave at 170 °C for 2
h. Isolated yield.
b
entry 1). Encouraged by this result, we then performed catalyst
and solvent screening for this interesting reaction. Among a
number of palladium catalysts in xylene screened for this
reaction, Pd(OAc)2 gave the highest yield under these
conditions (entries 1−5). Chlorobenzene was tested as solvent
for this reaction with no improved yield (entry 6).
Next, the scope of this new microwave-assisted annulation
process for the synthesis of quinazolines was probed under the
best reaction conditions (Table 3, entry 1). Studies revealed
that the process serves as a general approach to structurally
diverse quinazoline 3 and imidazole 2 (Table 4). It should be
noted that quinazoline 3 and imidazole 2 can be separated by
column directly. N-Allyl-N′-phenylbenzimidamide 1g gave a
87% total yield of quinazoline 3g and imidazole 2g in 3:1 ratio
B
DOI: 10.1021/acs.orglett.5b01435
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
gives imidazoles 2 and Pd(0), which is oxidized by O2 to
regenerate catalyst Pd(II). While under the microwave
irradiation conditions at 170 °C, the reaction probably
undergoes isomerization of palladium−alkene complex inter-
mediate I15and C−H activation16 via presumed intermediates
IV and V and leads to quinazoline product 3. However, part of
amidine 1 can follow the Wacker-type mechanism to give
imidazoles 2, observed in the process.
In summary, we have developed new palladium-catalyzed
annulation processes for multisubstituted imidazoles and
quinazolines from N-allylamidines under different conditions
for the first time. Palladium-catalyzed Wacker-type reaction
affords imidazoles in moderate to good yields, while palladium-
catalyzed C−H activation under microwave irradiation leads to
quinazolines as the major product. Further exploration of the
interesting chemistry for synthesis of other heterocyclics is
under investigation, and the results will be reported in due
course.
Table 4. Substrate Scope for C−H Activation
b
c
entry
X
Ar
C6H5
yield (%)
3:2
1
H
87
90
87
77
80
92
88
94
86
73
87
3.0:1 (3g:2g)
3.7:1 (3a:2a)
2.0:1 (3c:2c)
2.9:1 (3d:2d)
3.2:1 (3e:2e)
1.2:1 (3f:2f)
7.8:1 (3l:2l)
1.4:1 (3h:2h)
2.8:1 (3j:2j)
1.2:1 (3m:2m)
0.8:1 (3i:2i)
2
4-OMe
2-OMe
4-Me
C6H5
3
C6H5
4
C6H5
5
2-Me
C6H5
6
3,4,5-OMe
3,5-OMe
o-benzeno
4-OMe
4-OMe
4-CF3
C6H5
7
C6H5
8
C6H5
9
4-CF3C6H4
4-FC6H4
C6H5
10
11
a
Unless specified, a solution of 1 (0.1 mmol) with the catalyst (0.02
ASSOCIATED CONTENT
■
mmol) in xylenes (1 mL) was heated in the microwave at 170 °C for 2
h. Isolated yield. The ratio of separated yields.
S
b
c
* Supporting Information
1
Experimental procedures, H and 13C NMR and HRMS data
(entry 1). The substitution with a single electron-donating
group on the phenyl ring of the N′ position gave similar results
(entries 2−5). More hindered trimethoxy-substituted amidine
1f gave excellent yield but with reduced selectivity (1.2:1, entry
6). To our surprise, N-allyl-N′-(3,5-dimethoxyphenyl)-
benzimidamide 1l afforded a high yield with good selectivity
(88%, 7.8:1 of 3l:2l, entry 7). N-Allyl-N′-(naphthalen-1-
yl)benzimidamide 1h had a similar result as 1f (entry 8). The
amidines with electron-withdrawing groups on the phenyl ring
of benzimidamide afforded much higher total yields compared
with the previous conditions to form imadazoles alone (entries
9 and 10). Finally, the amidine with electron-withdrawing
moiety at the N′-position gave a high reaction yield but with
reverse chemoselectivity, in which the imidazole product 2i was
the major product (entry 11).
for experimental procedures, and characterization of the
products 2 and 3. The Supporting Information is available
free of charge on the ACS Publications website at DOI:
10.1021/acs.orglett.5b01435.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: hli77@ecust.edu.cn.
*E-mail: wwang@unm.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support of this research from the Eastern Scholar
program at Shanghai Institutions of Higher Learning (No.
201226, H.L.), the National Science Foundation of China (No.
21372073, W.W.), and the Fundamental Research Funds for
the Central Universities and the China 111 Project (Grant
B07023, H.L. and W.W.) is gratefully acknowledged.
The proposed catalytic cycle for the two divergent annulation
reactions is described in Scheme 2. A similar pathway to pyrrole
Scheme 2. Proposed Catalytic Cycle for Annulation
Reactions
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