Lewis acid-catalyzed 2-arylquinazoline formation from: N ′-arylbenzimidamides and paraformaldehyde

Article abstract of DOI:10.1039/c6gc02319c

An efficient procedure for the synthesis of 2-arylquinazolines from N′-arylbenzimidamides has been developed under transition-metal-free conditions. In this process, stable and low-toxicity paraformaldehyde was used as the carbon source. A broad range of

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Lewis acid-catalyzed 2-arylquinazoline formation from N’-
arylbenzimidamides and paraformaldehyde
Xiufang Cheng,a Huamin Wang,a Fuhong Xiao, a* and Guo-Jun Deng a*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/chemcomm
Cl
An efficient procedure for the synthesis of 2-arylquinazolines
from N’-arylbenzimidamides has been developed under
transition-metal-free conditions. In this process, stable and low
toxicity paraformaldehyde was used as the carbon source. A
broad range of functional groups were well tolerated in this
reaction system.
F
HN
O
HN
O
O
H
N
N
O
O
N
N
N
N
O
Tarceva (II)
Gefitinb (I)
NH
Quinazoline derivatives are important Nꢀheterocycles1 due to their
ubiquitous structure as well as biological and pharmacological
activity.2 They are core structures commonly existing in a variety of
drug molecules. For example, geftinib and tarceva3 have been
extensively utilized as inhibitors of cell growth in vitro for the
treatment of nonꢀsmall cell lung cancer (Figure1, I, II). Tykerb4 is
commonly prescribed for treating breast cancer (Figure1, III).
CCT2415335 blocked CHK2 (ckpoint kinase 2) activity in human
tumor cell lines in response to DNA damage (Figure1, IV). Because
of their importance as privileged scaffolds in drug candidates, a
variety of methods have been developed to synthesize substituted
quinazolines during the past several decades.6 The classic synthesis
of substituted quinazolines are the following two methods: (1)
oxidative/cyclization reaction of 2ꢀaminobenzylamines with
different coupling reagents;7 and (2) amination cyclization of amides
with 2ꢀhalobenzenes or 2ꢀhalobenzyl amines.8 Despite the merits of
these methods, some of them suffer from limitations such as preꢀ
functionalization of both the coupling partners and inevitable toxic
transitionꢀmetal catalysts as well as stoichiometric strong oxidants.9
It is therefore desirable to develop new methods for the synthesis of
quinazolines under transitionꢀmetalꢀfree conditions with regard to
green chemistry and synthetic practice, especially for the
pharmaceutical industry.
O
F
S
HN
O
O
O
O
O
O
Cl
N
OH
F
N
N
N
HO
CCT241533 (IV)
Tykerb (III)
Figure 1. Quinazolines as core structures in pharmaceuticals
complicated skeletons as oneꢀcarbon homologation reagents.11 In
recent years, various methods have been developed to use paraforꢀ
maldehyde installing
a
methylene,12 carbonyl13 and
hydroxymethyl14 group into various substrates. In our recent
study on the paraformaldehyde insertion to construct the
heterocycles, we reported a palladiumꢀcatalyzed phthalazinone
synthesis using paraformaldehyde as the carbon source via an
in situ ortho formylation of 2ꢀhalomethylbenzoates15 and an
efficient procedure for 2ꢀaroylbenzofuran preparation from 2ꢀ
bromophenols, phenacyl bromides and paraformaldehyde.16 In
2013 years, Zhang and coꢀworkers reported an efficient Cuꢀ
catalyzed synthesis of quinazolines from amidines and DMSO,
DMF, DMA, NMP or TMEDA through direct oxidative
amination of NꢀH bonds and methyl C(sp3)
–H bonds followed
by intramolecular CꢀC bond formation reactions (Scheme 1a).9a
Inspired by this elegant work as well as our recent success in
using oxygen as the sole oxidant to construct the heterocycles,17
herein, we developed a new and efficient approach for the
Paraformaldehyde has been receiving more and more attention
because of the advantages of lowꢀcost, stability and low toxicity.10
And it has been used for the synthesis of an incredible variety of
synthesis of 2ꢀarylquinazoline through
a boron Lewis
a.Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry
of Education, College of Chemistry, Xiangtan University, Xiangtan 411105, China.
Fax: (+86)0731-5829-2251; Tel:(+86)0731-5829-8280; E-mail: gjdeng@xtu.edu.cn;
fhxiao@xtu.edu.cn.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
acid/oxygen catalytic system (Scheme 1b). This method offers
new access to various substituted quinazolines in good yields
using paraformaldehyde as the carbon source. The mild and
transitionꢀmetal free reaction conditions are attractive features
of this method.
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other solvents were tested (entries 11ꢀ14). No desired product
was observed when the reaction was carried out in the absence
of paraformaldehyde (entry 15). This result suggested that
paraformaldehyde is the oneꢀcarbon homologation reagent,
while the DMSO is not. We found that a modest 66% yield still
could be obtained when the reaction temperature was decreased
to 120 °C (entry 16). Furthermore, the yield was improved to
94% when the reaction was carried out under O2 atmosphere
(entry 17).
The substrate scope toward this novel annulation reaction
was then investigated, and the results were listed in Table 2.
First, the effect of the substituent attached on the aniline ring
Scheme 1 New strategy for the synthesis of quinazolines
Table 1 Optimization of the reaction conditionsa
(
i.e., R1) was examined. Anilines with electronꢀdonating groups
at the para position reacted with paraformaldehyde smoothly
and gave the corresponding quinazolines (2b-2f) in good yields.
Chlorineꢀsubstituted substrate 1g and 1j afforded the
corresponding 2g and 2j in 80% and 68% yields, respectively.
However, bromo group (1h and 1i) significantly decreased the
reaction yields (2h and 2i). Notably, carbon−halogen bonds of
the substrates remained intact during all the reactions,
providing an additional handle for further derivatization. To our
surprise, the methyl substituted product 2k was obtained in
91% isolated yield. Anilines with multiꢀgroups did not
influence on the reaction at all, producing the corresponding
compounds 2l-2m in good yields. (Z)ꢀN'ꢀ(naphthalenꢀ1ꢀ
yl)benzimidamide (1n) successfully provided the functionalized
quinazoline 2n in 94% yield. The metaꢀmethyl substrate (1o
)
produced two regioisomers 2o and 2o’in moderate yields (58%
and 20%, respectively).
Table 2 Intermolecular annulation of imidamides
1
with
paraformaldehydea
H
C
N
NH2
R1
R1
BF3 Et2O, K2CO3
N
N
(CH2O)n
140 oC, O2
2
1
H3C
iPr
tBu
N
N
N
N
N
Ph
N
Ph
N
Ph
N
N
Ph
2a, 92%
H3CO
2b, 90%
2c, 84%
2d, 90%
a Reaction conditions: 1a (0.2 mmol), paraformaldehyde (0.6 mmol),
catalyst (10 mol %), additive (1 equiv.), solvent (0.8 mL), 24 h, 140
oC. b GC yield. c without paraformaldehyde. d At 120 oC. e Under O2.
F3CO
Ph
Cl
Ph
Br
Ph
N
N
N
N
N
N
N
Ph
2e, 75%
2f, 84%
2g, 80%
2h, 65%
To initiate our study, we began by testing the Lewis acid
catalyzed annulation of (Z)ꢀN'ꢀphenylbenzimidamide 1a with
paraformaldehyde (Table 1). When the reaction was conducted
in the presence of 10 mol % of Cu(OTf)2 and 1 equiv. K2CO3 at
H3C
N
N
N
N
N
N
Ph
N
Ph
Ph
N
CH3
Ph
Br
Cl
CH3
2k, 91%
CH3
o
140 C in DMSO, the desired product 2ꢀphenylquinazoline 2a
2i, 65%
2j, 68%
2l, 89%
was obtained in 35% yield (entry 1). This result prompted us to
further test several Lewis acids (entries 2ꢀ5). To our delight, the
formation of 2a was observed in 80% yield when the catalyst
was replaced by BF3·Et2O (entry 5). Unfortunately, the reaction
did not proceed smoothly under Bronsted acid conditions or in
the absence of base (entries 6ꢀ7). Compared with K2CO3, some
other bases such as Cs2CO3, NaOH and NaHCO3 provided
lower yields (entries 8ꢀ10). The reaction was less efficient when
Br
N
N
N
N
N
Ph
N
Ph
H3C
N
Ph
N
Ph
CH3
2m, 76%
2n, 94%
2o, 58%
2o', 20%
a
Reaction conditions:
mmol), catalyst (10 mol %), K2CO3 (1 equiv.), DMSO (0.8 mL),
24 h, 140 oC. Isolated yields based on
1 (0.2 mmol), paraformaldehyde (0.6
1.
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Furthermore, we investigated the scope by using a series of followed by elimination of BF3·H2O to furnish the intermediate
Nꢀphenyl aromatic amidines (Table 3).The substrates with and regenerate the catalyst BF3. Subsequent protonation of
either electronꢀdonating (CH3 or OCH3) or electronꢀ forms a cation species , which undergoes an intramolecular
withdrawing (Cl, Br, CF3 or CN) groups at the para position of Friedel−Craft reaction to afford the intermediate . Finally, the
C
C
D
F
the aromatic ring successfully engaged in this reaction and gave intermediate
F
is oxidized by O2 to give the product
the desired quinazoline products in 61ꢀ90% yields (2p-2u). The quinazoline 2a
reaction was sensitive to substitution on the ortho position of
the aromatic ring, delivering lower yield than paraꢀsubstituted
variant (2v and 2w). When the phenyl ring was replaced by a
naphthyl group, the reaction afforded the target molecule 2x in
75% yield. Notably, heterocyclic substituted substrates 1y and
2z performed very well, affording the respective quinazolines
in 92% and 62% yield (2y and 2z). When 1aa, which contained
two possible leaving groups, namely, iodine and chlorine, was
submitted to the reaction conditions, the annulation occurred
successfully and gave the desired product 2aa in 80% yield.
.
Ph
BF3 Et2O (10%)
DMSO (0.8 mL)
O2, 140 oC
O
a)
b)
+
N
1a
Ph
H
N
Ph
62% yield
2ab
O
N
H2O2 (2 equiv)
HOAc (0.5 mL)
O2, 55 oC
N
NH
N
Ph
Ph
95% yield
2a
3a
Table 3 Intermolecular annulation of imidamides
paraformaldehydea
1 with
Scheme 2 Synthesis of 2ꢀphenylquinazolinꢀ4(3H)ꢀone and
2,4ꢀdiphenylquinazoline.
a
Reaction conditions: 1 (0.2 mmoL), paraformaldehyde (0.6 mmol),
catalyst (10 mol%), K2CO3 (1 equiv.), DMSO (0.8 mL), 24 h, 140
oC. Isolated yields based on 1.
Scheme 3 Possible mechanism for the synthesis of quinazolines.
We delightedly found that 1a
,
when treated with
o
benzaldehyde in the presence of BF3·Et2O in DMSO at 140 C
for 24 h under O2 atmosphere, could also afford the desired 2,4ꢀ
diphenylquinazoline (2ab), albeit in moderate yield (Scheme
2a). We further evaluated the transformations of 2a, which was
treated with H2O2 in HOAc under O2 atmosphere to give 2ꢀ
phenylquinazolinꢀ4(3H)ꢀone (3a) in 95% yield (Scheme 2b).
Based on the aforementioned results and some related
research,9a,14b,18 a proposed mechanistic pathway for the lewis
In conclusion, we have developed a straightforward and
efficient access to 2ꢀarylquinazolines under transitionꢀmetalꢀ
free conditions. The stable and low toxicity paraformaldehyde
is used as the atomꢀeconomic oneꢀcarbon source to construct
heterocycles. Functional groups such as halogen and
heterocycles were well tolerated under the optimized reaction
conditions. This novel method provides a complementary,
environmentꢀfriendly, and easily handling approach to 2ꢀ
arylquinazolines. The detailed reaction mechanism and
synthetic application of this reaction are under investigation.
acidꢀcatalyzed
CꢀH
annulation
of
amidines
with
paraformaldehyde is depicted in Scheme 3. The reaction begins
with formaldehyde releasing from paraformaldehyde in the
presence of K2CO3.19, 20 Then formaldehyde is activated by the
oxophile Lewis acid BF3 to generate complex
A. The
nucleophilic attack of 1a to forms ionpair intermediate
A
B,
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Acknowledgements
c
d
This work was supported by the National Natural Science Foun
dation of China (21372187, 21502160, 21572194), and the Hun
an Provincial Innovative Foundation for Postgraduate (CX201
6B260).
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(
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4 | Green Chem., 2016, 00, 1-3
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An efficient procedure for the synthesis of 2-arylquinazolines from
N’-arylbenzimidamides has been developed under transition-metal-free conditions.