Direct synthesis of quinazolines through copper-catalyzed reaction of aniline-derived benzamidines

Article abstract of DOI:10.1021/ol1016756

A novel synthesis of 2-phenyl-4-[(triisopropylsilyl)methyl]quinazolines from monosubstituted arenes has been developed. Treatment of N-phenylbenzamidines with 5-nitro-1-[(triisopropylsilyl)ethynyl]-1,2- benziodoxol-3(1H)-one and K₂CO₃ in the presence of a catalytic amount of CuBr in benzene gives 2-phenyl-4-[(triisopropylsilyl)methyl] quinazolines in moderate to good yields.

Full text of DOI:10.1021/ol1016756

ORGANIC
LETTERS
2010
Vol. 12, No. 17
3963-3965
Direct Synthesis of Quinazolines
through Copper-Catalyzed Reaction of
Aniline-Derived Benzamidines
Yusuke Ohta, Yusuke Tokimizu, Shinya Oishi, Nobutaka Fujii,* and Hiroaki Ohno*
Graduate School of Pharmaceutical Sciences, Kyoto UniVersity, Sakyo-ku,
Kyoto 606-8501, Japan
hohno@pharm.kyoto-u.ac.jp; nfujii@pharm.kyoto-u.ac.jp
Received July 20, 2010
ABSTRACT
A novel synthesis of 2-phenyl-4-[(triisopropylsilyl)methyl]quinazolines from monosubstituted arenes has been developed. Treatment of
N-phenylbenzamidines with 5-nitro-1-[(triisopropylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one and K2CO3 in the presence of a catalytic amount of
CuBr in benzene gives 2-phenyl-4-[(triisopropylsilyl)methyl]quinazolines in moderate to good yields.
Many biologically active compounds contain the quinazoline
motif, including the potent anti-lung cancer agent, gefitinib,1
and the R-adrenergic blocker, prazosin.2 Most of the synthetic
routes to quinazolines depend on the use of anilines bearing
an ortho-functional group.3 This limitation prompted us to
develop a direct synthesis of these compounds from ortho-
unfunctionalized aniline derivatives.
pyrroles at the 3-position by use of alkynyliodoxolone
reagent.9 We postulated that the amidine group in N-
phenylbenzamidine 1a could function as both a directing
group for copper-catalyzed C-H alkynylation10 with an
appropriate alkyne 2 and a nucleophilic group for cyclization
of 3a to directly give substituted quinazoline 4 (Scheme 1).
Otherwise, nitrogen alkynylation11 might promote tautomer-
ization-electrocyclization cascade12 of 3b to give the same
quinazoline 4. The challenges of this strategy include
predominant alkyne introduction over benzimidazole forma-
Since the pioneering works on C-H alkynylation of
heteroarenes using a stoichiometric amount of metal by
Kalinin and Trofimov4 and using transition-metal catalyst
by Gevorgyan,5 significant advances have been made in the
field of aromatic C-H alkynylation.6-8 Recently, Waser
reported gold-catalyzed C-H alkynylation of indoles and
(5) (a) Seregin, I. V.; Ryabova, V.; Gevorgyan, V. J. Am. Chem. Soc.
2007, 129, 7742. For other reactions of a highly reactive C-H bond on a
heteroaryl ring, see: (b) Gu, Y.; Wang, X. Tetrahedron Lett. 2009, 50, 763.
(c) Matsuyama, N.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2009, 11,
4156. (d) Besselie´vre, F.; Piguel, S. Angew. Chem., Int. Ed. 2009, 48, 9553.
(e) Kitahara, M.; Hirano, K.; Tsurugi, H.; Satoh, T.; Miura, M. Chem.sEur.
J. 2010, 16, 1772.
(1) Gundla, R.; Kazemi, R.; Sanam, R.; Muttineni, R.; Sarma, J. A. R. P.;
Dayam, R.; Neamati, N. J. Med. Chem. 2008, 51, 3367.
(2) Mendes da Silva, J. F.; Walters, M.; Al-Damluji, S.; Ganellin, C. R.
Bioorg. Med. Chem. 2008, 16, 7254.
(6) (a) Kobayashi, K.; Arisawa, M.; Yamaguchi, M. J. Am. Chem. Soc.
2002, 124, 8528. (b) Amemiya, R.; Fujii, M.; Yamaguchi, M. Tetrahedron
Lett. 2004, 45, 4333. (c) Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009,
11, 3250.
(3) For recent reviews, see: (a) Connolly, D. J.; Cusack, D.; O’Sullivan,
T. P.; Guiry, P. J. Tetrahedron 2005, 61, 10153. (b) Michael, J. P. Nat.
Prod. Rep. 2007, 24, 223.
(7) For dehydrogenative C-H alkynylation of activated arenes, see: (a)
de Haro, T.; Nevado, C. J. Am. Chem. Soc. 2010, 132, 1512. (b) Wei, Y.;
Zhao, H.; Kan, J.; Su, W.; Hong, M. J. Am. Chem. Soc. 2010, 132, 2522.
(c) Yang, L.; Zhao, L.; Li, C.-J. Chem. Commun. 2010, 4184.
(8) For a recent review, see: Dudnik, A. S.; Gevorgyan, V. Angew.
Chem., Int. Ed. 2010, 49, 2096.
(4) For C-H alkynylation of heteroarenes in the presence of a
stoichiometric amount of metal, see: (a) Kalinin, V. K.; Pashchenko, D. N.;
She, F. M. MendeleeV Commun. 1992, 2, 60. (b) Trofimov, B. A.; Stepanova,
Z. V.; Sobenina, L. N.; Mikhaleva, A. I.; Ushakov, I. A. Tetrahedron Lett.
2004, 45, 6513. (c) Trofimov, B. A.; Sobenina, L. N.; Stepanova, Z. V.;
Vakul’skaya, T. I.; Kazheva, O. N.; Aleksandrov, G. G.; Dyachenko, O. A.;
Mikhaleva, A. I. Tetrahedron 2008, 64, 5541. For a related radical reaction,
see: (d) Martelli, G.; Spagnolo, P.; Tiecco, M. J. Chem. Soc. B 1970, 1413.
(9) Brand, J. P.; Charpentier, J.; Waser, J. Angew. Chem., Int. Ed. 2009,
48, 9346.
(10) For related C-H alkynylation of anilines, see refs 6b and 6c.
10.1021/ol1016756  2010 American Chemical Society
Published on Web 08/12/2010

Scheme 1
.
Direct Synthesis of Quinazoline through
Table 1. Optimization of Reaction Conditionsa
Copper-Catalyzed Alkynylation and Cyclization
tion13 and regioselective cyclization14 or alkynylation in the
presence of two nitrogen atoms.
We initially explored appropriate alkyne sources for the
reaction. After considerable experimentation using various
terminal and internal alkynes in combination with series of
copper(I and II) salts and solvents (see the Supporting
Information),15 we obtained promising results by use of
alkynyl halides or related reagents and CuBr in benzene
(Table 1). When N-phenylbenzamidine 1a was reacted with
2-(triisopropylsilyl)ethynyl bromide 2a in the presence of
CuBr (20 mol %) and K2CO3 (1 equiv) in benzene, 1H NMR
indicated formation of the desired quinazoline 4a as an
inseparable mixture with an unidentified compound (entry
1). The use of alkynyl iodonium salt 2b led to the
decomposition of the amidine 1a (entry 2). Iodoxolone
derivatives 2c-f were tested as alkyne sources based on
Waser’s reports on C-H alkynylation of indoles with 2c.9,16
As expected, 2c bearing a TIPS group was a favorable alkyne
a All reactions were conducted with 1a (0.13 mmol) and 2 (1.5 equiv)
in the presence of CuBr (20 mol %) in benzene at 80 °C for 1 h. b Isolated
yields. c ND ) not determined. d MS4Å (300 mg) was added.
source and provided the desired quinazoline 4a in 20% yield
(entry 3). Addition of 4 Å molecular sieves (MS4Å) slightly
improved the yield to 31% (entry 4). The reaction of
N-phenylbenzamidine 1a with 2d bearing a TMS group did
not produce the desired quinazoline 4b (entry 5). The same
result was obtained when 2e (phenyl group) and 2f (t-butyl
group) were used (entries 6 and 7, respectively). These results
prompted our investigation of an appropriate substituent on
the aryl ring of 2c. Both 5-methyl- and 5-fluorobenziodoxo-
lones (2g and 2h) increased the yield of 4a to ca. 61% with
some impurities (entries 8 and 9). 5-Nitrobenziodoxolone
2i showed a clear conversion to 4a in 44-61% yield (entry
10). With the addition of MS4Å, this direct synthesis of
quinazoline was a reproducible reaction (entry 11).
Having established the reaction conditions (Table 1, entry
11),17 we next examined the substrate scope of this reaction
using substituted N-phenylbenzamidines 1b-m (Table 2).
These can be readily prepared by Lewis acid mediated
addition of anilines to benzonitrile. The reactions using
amidines 1b-e, which were derived from anilines containing
a halogen atom at the 4-position, gave the corresponding
6-fluoro-, chloro-, bromo-, and iodoquinazolines 4e-h in
moderate yields (entries 1-4). Amidines substituted with an
electron-donating methyl, methoxy, or t-butyl group at the
4-position of the aryl ring were found to be good reaction
components and provided the quinazolines 4i-k in 60-67%
yields (entries 5-7). Substitution at the meta position was
investigated using amidine 1i prepared from 3-bromoaniline.
In the reaction, this gave a mixture of 5-bromo- and
7-bromoquinazoline derivatives 4l, which shows that the
(11) For selected examples of nitrogen alkynylation using alkynyliodo-
nium salts, see: (a) Murch, P.; Williamson, B. L.; Stang, P. J. Synthesis
1994, 1255. (b) Feldman, K. S.; Bruendl, M. M.; Schildknegt, K.; Bohnstedt,
A. C. J. Org. Chem. 1996, 61, 5440. (c) Witulski, B.; Stengel, T. Angew.
Chem., Int. Ed. 1999, 38, 2426. For a reaction including 1,2-silyl migration,
see: (d) Witulski, B.; Stengel, T. Angew. Chem., Int. Ed 1998, 37, 489. For
reviews, see: (e) Zhdankin, V. V.; Stang, P. J. Tetrahedron 1998, 54, 10927.
(f) DeKorver, K. A.; Li, H.; Lohse, A. G.; Hayashi, R.; Lu, Z.; Zhang, Y.;
Hsung, R. P. Chem. ReV 2010, DOI: 10.1021/cr100003s.
(12) For a related arene-ynamide cyclization, see: (a) Zhang, Y.; Hsung,
R. P.; Zhang, X.; Huang, J.; Slafer, B. W.; Davis, A. Org. Lett. 2005, 7,
1047. See also: (b) Shi, Z.; Zhang, C.; Li, S.; Pan, D.; Ding, S.; Cui, Y.;
Jiao, N. Angew. Chem., Int. Ed. 2009, 48, 4572.
(13) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47,
1932.
(14) (a) Palladium-catalyzed quinazolin-2-one formation by rearrange-
ment of benzo[d][1,3]oxazinamine derivatives: Costa, M.; Della Ca´, N.;
Gabriele, B.; Massera, C.; Salerno, G.; Soliani, M. J. Org. Chem. 2004,
69, 2469. (b) Platinum-catalyzed quinazolin-2-one formation from alkoxy-
substituted urea derivatives: Nakamura, I.; Sato, Y.; Terada, M. J. Am. Chem.
Soc. 2009, 131, 4198. (c) TfOH-mediated quinazolin-2-one formation:
Wang, H.; Liu, L.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. Tetrahedron
Lett. 2009, 50, 6841. (d) Gold-catalyzed selective synthesis of quinazolin-
2-ones over indoles: Gimeno, A.; Medio-Simo´n, M.; Ram´ırez de Arellano,
C.; Asensio, G.; Cuenca, A. B. Org. Lett. 2010, 12, 1900.
(15) In this study, we focused on the reaction using copper salts
(especially halides), generally cheaper than many other transition-metal salts/
complexes including those of palladium, nickel, and gallium.
(16) For synthesis of related 1-alkynylbenziodoxoles, see: (a) Ochiai,
M.; Masaki, Y.; Shiro, M. J. Org. Chem. 1991, 56, 5511. (b) Zhdankin,
V. V.; Kuehl, C. J.; Krasutsky, A. P.; Bolz, J. T.; Simonsen, A. J. J. Org.
Chem. 1996, 61, 6547. For a related reaction, see: (c) Nicolai, S.; Erard,
S.; Ferna´ndez Gonza´lez, D.; Waser, J. Org. Lett. 2010, 12, 384. (d)
Ferna´ndez Gonza´lez, D.; Brand, J. P.; Waser, J. Chem.sEur. J. 2010, DOI:
(17) The reaction conditions including solvent, base, and catalyst loading
were not optimized with 2i.
chem.201001539
.
3964
Org. Lett., Vol. 12, No. 17, 2010

Table 2. Reaction of Various N-Phenylbenzamidinesa
Scheme 2. Removal of the TIPS Group
identically prepared through Sonogashira reaction of iodoa-
niline, did not produce the quinazoline 4a under standard
reaction conditions. Accordingly, C-H alkynylation of 1a
is not promoted in this system. At present, we can only say
that other reaction pathways, including nitrogen alkynylation
to produce 3b,19 would be more likely than the C-H
alkynylation pathway.
In summary, we have developed a novel synthesis of
quinazolines through copper-catalyzed alkynylation and
cyclization of N-phenylbenzamidines. This reaction is syn-
thetically useful since functionalized quinazolines can be
directly constructed from ortho-unsubstituted amidines,
readily prepared from commercially available anilines.
Further studies that include an investigation of the exact
reaction mechanism and elaboration of 4-(silylmethyl)quinazo-
lines including carbon-carbon bond formation are now in
progress.
a All reactions were conducted with 1 (0.13 mmol) and 2i (1.5 equiv)
in the presence of MS4Å (300 mg) and CuBr (20 mol %) in benzene at 80
°C for 1 h. b Isolated yields. c A 3.7:1 mixture of 5- and 7-bromoquinazolines.
d A 1.25:1 mixture of 5- and 7-methoxyquinazolines.
Acknowledgment. This work was supported by a Grant-
in-Aid for Scientific Research on Innovative Areas “Organic
Synthesis Based on Reaction Integration” (H.O.) and Tar-
geted Proteins Research Program from the Ministry of
Education, Culture, Sports, Science and Technology of Japan,
as well as the Program for Promotion of Fundamental Studies
in Health Sciences of the National Institute of Biomedical
Innovation (NIBIO). Y.O. is grateful for Research Fellow-
ships from the Japan Society for the Promotion of Science
(JSPS) for Young Scientists.
reaction proceeds with moderate regioselectivity (48%, 3.7:
1, entry 8). The use of N-(3-methoxyphenyl)benzamidine 1j
resulted in the highest yield of the desired 5-methoxy- and
7-methoxyquinazolines 4m without regioselectivity (77%,
1.25:1, entry 9). Quinazolines 4n and 4o with a substituted
arene at the 2-position were produced in 50 and 61% yield,
respectively, from amidines prepared using p-trifluoromethyl-
or p-methoxybenzonitrile (entries 10 and 11). This reaction
is applicable to the synthesis of 2-(heteroaryl)quinazolines.
For example, amidine 1m was allowed to react with 2i in
the presence of CuBr to give 2-(thiophen-2-yl)quinazoline
4p in 46% yield. In all cases, benzimidazole formation was
not observed. The moderate yields of the reaction are due
to formation of highly polar byproducts (unidentified).
Finally, desilylation of the resulting 2-phenyl-4-(triiso-
propylsilyl)methylquinazoline 4a was investigated (Scheme
2). The reaction of 4a with TBAF in THF-AcOH (20:1) at
room temperature led to efficient cleavage of the TIPS group
to give known quinazoline 518 in 76% yield.
Supporting Information Available: A general experi-
mental procedure, details of the reaction optimization, and
1H and 13C NMR spectra for all new compounds (1h, 1i,
1k, 2g-i, 4a, 4e-p) and 5. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL1016756
(19) For related electrophilic reactions with iodoxolane reagents, see:
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(b) Kieltsch, I.; Eisenberger, P.; Togni, A. Angew. Chem., Int. Ed. 2007,
46, 754. (c) Eisenberger, P.; Kieltsch, I.; Armanino, N.; Togni, A. Chem.
Commun. 2008, 1575. (d) Stanek, K.; Koller, R.; Togni, A. J. Org. Chem.
2008, 73, 7678. (e) Koller, R.; Stanek, K.; Stolz, D.; Aardoom, R.;
Niedermann, K.; Togni, A. Angew. Chem., Int. Ed. 2009, 48, 4332. (f)
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V. V.; Kuehl, C. J.; Krasutsky, A. P.; Bolz, J. T.; Mismash, B.; Woodward,
J. K.; Simonsen, A. J. Tetrahedron Lett. 1995, 36, 7975.
It should be noted that the amidine 3a bearing a (TIPS)-
ethynyl group at the ortho-position (Scheme 1, R ) TIPS),
(18) Anderson, R. K.; Carter, S. D.; Cheeseman, G. W. H. Tetrahedron
1979, 35, 2463.
Org. Lett., Vol. 12, No. 17, 2010
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