Copper-catalyzed annulation of amidines for quinazoline synthesis

Article abstract of DOI:10.1039/c3cc43129k

An efficient Cu-catalyzed synthesis of quinazolines via the C-N bond formation reactions between N-H bonds of amidines and C(sp³)-H bonds adjacent to sulfur or nitrogen atoms in the commonly used solvents, such as DMSO, DMF, DMA, NMP or TMEDA,

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Copper-catalyzed annulation of amidines for
quinazoline synthesis†
Cite this: DOI: 10.1039/c3cc43129k
Yunhe Lv, Yan Li, Tao Xiong,* Weiya Pu, Hongwei Zhang, Kai Sun, Qun Liu and
Qian Zhang*
Received 27th April 2013,
Accepted 25th May 2013
DOI: 10.1039/c3cc43129k
www.rsc.org/chemcomm
An efficient Cu-catalyzed synthesis of quinazolines via the C–N bond
formation reactions between N–H bonds of amidines and C(sp3)–H bonds
adjacent to sulfur or nitrogen atoms in the commonly used solvents, such
as DMSO, DMF, DMA, NMP or TMEDA, followed by intramolecular C–C
bond formation reactions was developed for the first time.
Nitrogen functionality is prevalent in synthetic and natural small
molecules with a high level of biological activities,1 which motivates
the development of methodologies to introduce nitrogen atoms into
organic molecules. Among various C–N bond construction methods,
Scheme 1 Annulation reactions of amidines.
the direct C–N bond formation reaction between C–H and N–H reaction between benzylic methyl C(sp3)–H and aromatic C(sp2)–H
bonds is the most powerful methodology because of avoiding bonds, and subsequent intramolecular C–O bond formation reac-
prefunctionalization of the substrates, minimum environmental tion.7 As part of our continuing interest in the construction of C–N
impact and fewer synthetic steps.2 In the area of C–H bond direct bonds directly from C–H bonds,8 amidines were selected as nitrogen
amination reaction, a significant breakthrough was achieved arising sources and sp3 carbon in DMSO was used as a one carbon synthon
from the discovery of metal nitrenes.3 As a result, the substrates to perform the intermolecular annulation reactions. Initially, the
studied underwent efficient nitrene insertion into various C–H reaction of N-p-tolylbenzimidamide 1a with DMSO was tested. After
bonds, especially aliphatic C(sp3)–H bonds. Copper-nitrene inter- careful screening (see the ESI†), we were pleased to find that
mediates have long been proposed as reactive intermediates in a the annulation product 7-methyl-2-phenyl-3,4-dihydroquinazoline 2a
number of copper-catalyzed alkane amination and alkene aziridina- (CCDC 932059) could be obtained in 71% yield by employing
tion reactions.4 Recently, a very interesting work suggested that in 3.0 equivalents of Selectfluor as an oxidant and Cu(OTf)2 as the
the presence of a copper catalyst and O2, amidines (containing two catalyst (Table 1). Notably, under these conditions, the intramolecular
N–H bonds) might be directly used as nitrogen-centred radicals or cyclization product 7-methyl-2-phenyl-3,4-dihydroquinazoline was not
nitrene nitrogen sources,5 which suggested the potential application obtained in the works of Buchwald and Brasche6 and Shi et al.9
of amidines to be used as a copper-nitrene nitrogen source.6 In this (Scheme 1), in which DMSO or NMP was only used as solvent.
communication, we developed a novel copper-catalyzed synthesis of
Quinazoline derivatives, widely distributed in natural products and
quinazolines from amidines. Remarkably, the C–N bond formation synthetic pharmaceuticals, have been extensively studied for their
reactions between N–H bonds of amidines and methyl C(sp3)–H biological and therapeutic activities,10 which include protein tyrosine
bonds of DMSO, DMF, N,N-dimethylacetamide (DMA), N-methyl- kinase, cellular phosphorylation inhibitors,11 anticancer,10a,d,12 anti-
pyrrolidone (NMP) or N1,N1,N2,N2-tetramethylethane-1,2-diamine viral,13 and antitubercular agents.14 Therefore, numerous efforts have
(TMEDA) were realized for the first time (Scheme 1).
been devoted to develop methods for the synthesis of quinazolines.
Recently, with benzylic methyl sp3 carbon as the one carbon Most of the synthetic routes to quinazolines depend on the use of
synthon, starting from N-para-tolylamides, we realized the construc- anilines bearing an ortho-functional group.15 Alternatively, synthesis
tion of benzoxazine derivatives via dehydrogenative cross-coupling of quinazolines from available ortho-unfunctionalized aniline,16 such
as amidine 1a, is attractive. Amidines 1 were easily prepared by the
reaction of anilines with nitriles in the presence of AlCl3 or NaH.6,9
With the optimal conditions in hand, we examined the scope of
Department of Chemistry, Northeast Normal University, Changchun, 130024, China.
E-mail: xiongt626@nenu.edu.cn, zhangq651@nenu.edu.cn; Fax: +86-431-5099759
this novel annulation reaction. As described in Table 1, starting
† Electronic supplementary information (ESI) available. CCDC 932059. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c3cc43129k from substrates 1b–1e, the desired annulation products
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Table 1 Intermolecular annulation of amidines 1 with DMSOa,b
Scheme 2 Intermolecular annulation of amidine 1w with various one carbon
synthons.
an opportunity for further transformation. However, from the cyclic
amidine substrates 1ac and 1ad, no reactions occurred.
The efficient utilization of C(sp3)–H bonds of DMSO in the trans-
formation of 1 to 2 leads us to broaden this new type of reaction by
testing the annulation of amidines 1 with similar C(sp3)–H bonds
adjacent to heteroatoms in some other solvents. After many inves-
tigations, satisfyingly, in the presence of Cu(OTf)2 (0.1 equiv.) and
1-fluoropyridinium tetrafluoroborate (3.0 equiv.) instead of Select-
fluor, the reaction of 1w with DMF (2 mL) was performed at 130 1C
for 14 h, and the desired product 2w was afforded in 68% yield
(Scheme 2). To our delight, other one carbon synthons, such as
N,N-dimethylacetamide (DMA), N-methyl-2-pyrrolidone (NMP) and
N1,N1,N2,N2-tetramethylethane-1,2-diamine (TMEDA) (3.0 equiv. of
TMEDA was used with 2 mL of CH3CN), were also effective in
performing the annulation reaction to provide 2w in 51%, 42% and
57% yield, respectively (Scheme 2). However, no reaction occurred
with N,N-diethylformamide (DEF) and N,N-diethylacetamide (DEA)
as the corresponding one carbon synthon.
The kinetic deuterium isotope effect (DMSO and DMSO-d6 reacted
with substrate 1c/1r, both kH/kD E 1.8; Scheme 3) of the reaction was
investigated under the optimal conditions, which indicated that the
first C(sp3)–H bond cleavage in DMSO might be involved in the rate-
limiting step. In the work of Chiba and co-workers,5a the possible
nitrene species starting from 1c was trapped by DMSO to provide a
sulfoxyimine product. Under the same conditions, when the reaction
of 1c was performed at 130 1C for 6 h, 2c0 was generated in 12% yield,
along with sulfoxyimine 3 in 47% yield [eqn (1)]. This result showed
that the in situ generated nitrene species could react with DMSO to
form quinazoline 2c0.
a
Reaction conditions: 1 (0.3 mmol), Cu(OTf)2 (0.03 mmol) and Select-
b
fluor (0.9 mmol) in 2 mL DMSO at 130 1C. Yield of the isolated product.
dihydroquinazolines 2b/2b0, 2d/2d0 and 2e/2e0 were obtained in
74–82% yields with poor regio-selectivity. From 4-methylphenyl sub-
stituted amidine 1f, the annulated product 2f was afforded as a single
regioisomer. However, no desired annulation products were obtained
from ortho-substituted aniline moiety or ortho-substituted nitrile
moiety containing substrates 1g–1j. It should be noted that substrates
1k–1r underwent the annulation/aromatization reaction smoothly to
give quinazolines 2k–2r in moderate to excellent yields. In addition,
when dihydroquinazoline 2a was treated under the optimal condi-
tions for 3 h, 77% yield of aromatization quinazoline could also be
(1)
Although the mechanistic details of this transformation are not
obtained. The scope of the intermolecular annulation reaction was very clear at the moment, based on the experimental results and
further examined with respect to various nitrile derivatives. Starting some related research,5,6 a possible mechanism was proposed in
from nitrile derivatives containing both electron-withdrawing and Scheme 4. Initially, the oxidation of CuX with the F+ oxidant (such as
electron-donating groups on the aromatic ring of nitrile moieties, Selectfluor) provides the Cu(III) complex A,7,8b,17 which reacts with
quinazolines 2s–2ab were obtained in good to excellent yields. 1ab amidine 1 via the elimination of HF and HBF4 to provide a four-
underwent annulation at the sterically more hindered 1-position of membered Cu(III) intermediate B. Then, a copper-nitrene inter-
the naphthalene ring to give 2ab, which can be attributed to the mediate C might be generated and at the same time stabilized by
dominating electronic effect. The ability to incorporate C–Br and C–Cl its equilibrium structure B.18 The subsequent coordination of inter-
bonds (2p, 2w and 2x) makes this method appealing, since it offers mediate C with DMSO provides a copper–nitrene complex D, which
c
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Scheme 4 Possible mechanism for the synthesis of quinazolines 2.
undergoes a C–N bond formation reaction via nitrene insertion into
the C(sp3)–H bond of DMSO to give intermediate E. Finally, in the
presence of H+, the cleavage of the C–S bond19 gives an iminium
species G, which undergoes an electrophilic addition reaction or
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quinazolines 2a–2f and in the presence of an oxidant, the following
aromatization reaction gives the quinazoline products 2k–2ab. Since
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brium intermediate B) is sterically hindered, the steric effect might
play an important role in the annulation reaction (no reaction occurs
starting from 1g–1j (Table 1) and DEF and DEA (Scheme 2)).
In summary, we have succeeded in developing an efficient
Cu-catalyzed synthesis of quinazolines from amidines and DMSO,
DMF, DMA, NMP or TMEDA through direct oxidative amination of
N–H bonds and methyl C(sp3)–H bonds followed by intramolecular
C–C bond formation reactions. The generality and high selectivity of
the annulation reaction towards various C(sp3)–H bonds together
with employing readily available amidines as the substrates made
this method very attractive. Further studies utilizing this strategy for
the construction of various C–N bonds are ongoing in our lab.
Financial support of this research by the SRFDP (20110043110002),
the NNSFC (21172033, 21202014), the Fundamental Research
Funds for the Central Universities (11GJHZ001, 11QNJJ015) and
NENU-10SSXT139 is greatly acknowledged.
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c
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