Copper-catalyzed synthesis of quinazoline derivatives via ullmann-type coupling and aerobic oxidation

Article abstract of DOI:10.1021/jo101685d

A simple and efficient copper-catalyzed approach to quinazoline derivatives has been developed, and the protocol uses readily available substituted (2-bromophenyl)methylamines and amides as the starting materials, and the cascade reactions were performed

Full text of DOI:10.1021/jo101685d

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of them show remarkable activity as anticancer,4 antiviral,5
Copper-Catalyzed Synthesis of Quinazoline
Derivatives via Ullmann-Type Coupling and Aerobic
Oxidation
and antitubercular agents.6 Molecules containing the quina-
zoline unit have been popular drugs. For example, Erlotinib
is used in the treatment of several types of tumors,7 Prazosin
acts as an R-adrenergic blocker,8 and Iressa as an epidermal
growth factor receptor inhibitor was approved by the Food
and Drug Administration in USA for the treatment of lung
cancer9 (Figure 1). Wide demands of diverse quinazoline
derivatives in various fields promote people to develop
different synthetic methods. Many methods for syntheses
of quinazoline derivatives have been developed thus far.10
For example, reactions of 2-amino-N-arylbenzamidines and
formic acid provided 4-arylaminoquinazolines.11 Reactions
of 2-amino-N0-phenylbenzimidamides with aromatic alde-
hydes yielded 2-aryl-4-arylimino-2,3-dihydroquinazolines,
followed by oxidation with potassium permanganate to give
the corresponding quinazolines.12 Couplings of 2-aminoben-
zonitriles with carbon dioxide (1 atm) at 20 °C, assisted by
DBU (1,8-diazabicyclo[5.4.0]undec-7-ene), gave 2,4-dihy-
droxyquinazolines.13 6-Substituted quinazoline-2,4-diones
were converted to 2,4-dichloroquinazolines in excellent
yields by refluxing in phosphorus oxychloride.14 Although
the previous methods for synthesis of quinazoline derivatives
are efficient, the used starting materials often are not readily
available and difficult to prepare. It is highly desirable to
search for a more convenient and efficient approach. Re-
cently, there has been great progress in copper-catalyzed
N-arylations,15 and the N-arylation strategy has been used to
make N-heterocycles.16 We have also developed some effi-
cient methods for copper-catalyzed cross couplings17 and
synthesis of N-heterocycles.18 Copper-catalyzed synthesis of
quinazoline derivatives has also been developed by Truong’s
Chen Wang,† Shangfu Li,‡ Hongxia Liu,‡ Yuyang Jiang,‡
and Hua Fu*,†
†Key Laboratory of Bioorganic Phosphorus Chemistry and
Chemical Biology (Ministry of Education), Department of
Chemistry, Tsinghua University, Beijing 100084,
People’s Republic of China, and ‡Key Laboratory of Chemical
Biology (Guangdong Province), Graduate School of Shenzhen,
Tsinghua University, Shenzhen 518057,
People’s Republic of China
fuhua@mail.tsinghua.edu.cn
Received August 26, 2010
A simple and efficient copper-catalyzed approach to
quinazoline derivatives has been developed, and the pro-
tocol uses readily available substituted (2-bromophenyl)-
methylamines and amides as the starting materials, and
the cascade reactions were performed under air via se-
quential Ullmann-type coupling and aerobic oxidation
without addition of any ligand or additive. The present
method provides a convenient and practical strategy for
synthesis of quinazoline derivatives.
(6) (a) Waisser, K.; Gregor, J.; Dostal, H.; Kunes, J.; Kubicova, L.;
Klimesova, V.; Kaustova, J. Farmaco 2001, 56, 803. (b) Kunes, J.; Bazant, J.;
Pour, M.; Waisser, K.; Slosarek, M.; Janota, J. Farmaco 2000, 55, 725.
(7) Gundla, R.; Kazemi, R.; Sanam, R.; Muttineni, R.; Sarma, J. A. R. P.;
Dayam, R.; Neamati, N. J. Med. Chem. 2008, 51, 3367.
(8) Mendes da Silva, J. F.; Walters, M.; Al-Damluji, S.; Ganellin, C. R.
Bioorg. Med. Chem. 2008, 16, 7254.
(9) (a) Rewcastle, G. W.; Palmer, B. D.; Bridges, A. J.; Hollis Showalter,
H. D.; Sun, L.; Nelson, J.; McMichael, A.; Kraker, A. J.; Fry, D. W.; Denny,
W. A. J. Med. Chem. 1996, 39, 918. (b) Luth, A.; Lowe, W. Eur. J. Med.
Chem. 2008, 43, 1478.
Quinazoline derivatives have attracted much attention
for their various biological and medicinal properties. For
example, they act as the potent tyrosine kinase and cellular
phosphorylation inhibitors,1 and they are also used as
ligands for benzodiazepine and GABA receptors in the
central nervous system (CNS)2 or as DNA binders.3 Some
(10) For reviews, see: (a) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.;
Guiry, P. J. Tetrahedron 2005, 61, 10153. (b) Besson, T.; Chosson, E. Comb.
Chem. High Throughput Screening 2007, 10, 903. (c) Michael, J. P. Nat. Prod.
Rep. 2003, 20, 476. (d) Undheim, K.; Benneche, T. In Comprehensive
Heterocyclic Chemistry; Pergamon: Oxford, UK, 1998; Vol. 6. Selected
examples: (e) Shreder, K. R.; Wong, M. S.; Nomanbhoy, T.; Leventhal,
P. S.; Fuller, S. R. Org. Lett. 2004, 6, 3715. (f) Costa, M.; Ca, N. D.; Gabriele,
B.; Massera, C.; Salerno, G.; Soliani, M. J. Org. Chem. 2004, 69, 2469. (g)
Yoon, D. S.; Han, Y.; Stark, T. M.; Haber, J. C.; Gregg, B. T.; Stankovich,
S. B. Org. Lett. 2004, 6, 4775. (h) Wiedemann, S. H.; Ellman, J. A.; Bergman,
R. G. J. Org. Chem. 2006, 71, 1969. (i) Fekner, T.; Muller-Bunz, H.; Guiry,
P. J. Org. Lett. 2006, 8, 5109. (j) Kappe, C. O. Angew. Chem., Int. Ed. 2004,
43, 6250. (k) Bianchi, I.; Forlani, R.; Minetto, G.; Peretto, I.; Regalia, N.;
Taddei, M.; Raveglia, L. F. J. Comb. Chem. 2006, 8, 491. (l) Ferrini, S.;
Ponticelli, F.; Taddei, M. Org. Lett. 2007, 9, 69.
*To whom correspondence should be addressed. Fax: 86-10-62781695.
(1) Fry, D. W.; Kraker, A. J.; McMichael, A.; Ambroso, L. A.; Nelson,
J. M.; Leopold, W. R.; Connors, R. W.; Bridges, A. J. Science 1994, 265,
1093.
(2) (a) Colotta, V.; Catarzi, D.; Varano, F.; Lenzi, O.; Filacchioni, G.;
Costagli, C.; Galli, A.; Ghelardini, C.; Galeotti, N.; Gratteri, P.; Sgrignani,
J.; Deflorian, F.; Moro, S. J. Med. Chem. 2006, 49, 6015. (b) Lewerenz, A.;
Hentschel, S.; Vissiennon, Z.; Michael, S.; Nieber, K. Drug Dev. Res. 2003,
58, 420.
(3) Malecki, N.; Carato, P.; Rigo, G.; Goossens, J. F.; Houssin, R.; Bailly,
C.; Henichart, J. P. Bioorg. Med. Chem. 2004, 12, 641.
ꢀ
(11) Szczepankiewicz, W.; Suwinski, J. Tetrahedron Lett. 1998, 39, 1785.
ꢀ
(12) Szczepankiewicz, W.; Suwinski, J. J.; Bujok, R. Tetrahedron 2000,
(4) (a) Doyle, L. A.; Ross, D. D. Oncogene 2003, 22, 7340. (b) Henderson,
E. A.; Bavetsias, V.; Theti, D. S.; Wilson, S. C.; Clauss, R.; Jackman, A. L.
Bioorg. Med. Chem. 2006, 14, 5020. (c) Foster, A.; Coffrey, H. A.; Morin,
M. J.; Rastinejad, F. Science 1999, 286, 2507.
(5) (a) Chien, T.-C.; Chen, C.-S.; Yu, F.-H.; Chern, J.-W. Chem. Pharm.
Bull. 2004, 52, 1422. (b) Herget, T.; Freitag, M.; Morbitzer, M.; Kupfer, R.;
Stamminger, T.; Marschall, M. Antimicrob. Agents Chemother. 2004, 48,
4154.
56, 9343.
(13) Mizuno, T.; Okamoto, N.; Ito, T.; Miyata, Y. Tetrahedron Lett.
2000, 41, 1051.
(14) Lee, S. J.; Konoshi, Y.; Yu, D. T.; Miskowski, T. A.; Riviello, C. M.;
Macina, O. T.; Frierson, M. R.; Kondo, K.; Sugitani, M.; Sircar, J. C.;
Blazejewski, K. M. J. Med. Chem. 1995, 38, 3547.
7936 J. Org. Chem. 2010, 75, 7936–7938
Published on Web 10/22/2010
DOI: 10.1021/jo101685d
r
2010 American Chemical Society

Wang et al.
JOCNote
TABLE 1. Copper-Catalyzed Cascade Synthesis of 2-Phenylquinazo-
line (3a) via Reaction of (2-Bromophenyl)methylamine (1a) with Benz-
amide (2a): Optimization of Conditionsa
entry
cat.
CuI
CuI
CuI
base
solvent
temp (°C)
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
Cs2CO3
K2CO3
Na2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
2-propanol
2-propanol
2-propanol
2-propanol
2-propanol
2-propanol
2-propanol
2-propanol
DMF
DMSO
dioxane
2-propanol
2-propanol
2-propanol
2-propanol
110
110
110
110
110
110
110
110
110
110
110
60
8
87
46
43
45
29
64
CuI
FIGURE 1. Quinazoline and popular drugs containing the quina-
zoline unit.
CuBr
Cu2O
CuCl2
group16g and us18b via couplings of 2-halobenzaldehydes
with amidine hydrochlorides. Considering more ready avail-
ability of amides than amidines, herein, we report a simple
and efficient copper-catalyzed synthesis of quinazoline deri-
vatives using inexpensive and readily available substituted
(2-bromophenyl)methylamines and amides as the starting
materials without addition of any ligand or additive under air.
During optimization of reaction conditions including the
catalysts, bases and solvents, (2-bromophenyl)methylamine
(1a) with benzamide (2a), were used as the model substrates.
As shown in Table 1, four bases were investigated at 110 °C
with 0.1 equiv of CuI as the catalyst (relative to amount of 1a)
in 2-propanol in a sealed vessel under air (entries 1-4), and
K2CO3 showed the highest efficiency (entry 2). Several
copper salts were tested, and CuI exhibited the best activity
(compare entries 2 and 5-7). Only a trace amount of target
product was observed in the absence of copper catalyst (entry 8).
We attempted different solvents (entries 9-11), and 2-propanol
gave the highest yield (compare entries 2 and 9-11). The yields
decreased when reaction temperature was lowered (compare
tracec
25
33
20
25
CuI
CuI
CuI
CuI
CuI
CuI
CuI
90
110
83
56
20d
32e
aReaction condition: (2-bromophenyl)methylamine (1a) (0.3 mmol),
benzamide (2a) (0.45 mmol), catalyst (0.03 mmol), base (0.6 mmol),
solvent (1.0 mL) in a sealed vessel under air. bIsolated yield. cIn the absence
of copper catalyst. dUnder nitrogen atmosphere. eIn a flask linked with an
opened condenser under air.
SCHEME 1. Possible Mechanism for Synthesis of Quinazoline
Derivatives
(15) For recent reviews on copper-catalyzed cross couplings, see: (a)
Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc.
2001, 123, 7727. (b) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450. (c) Kunz,
K.; Scholz, U.; Ganzer, D. Synlett 2003, 2428. (d) Ley, S. V.; Thomas, A. W.
Angew. Chem., Int. Ed. 2003, 42, 5400. (e) Beletskaya, I. P.; Cheprakov, A. V.
Coord. Chem. Rev. 2004, 248, 2337. (f) Evano, G.; Blanchard, N.; Toumi, M.
Chem. Rev. 2008, 108, 3054. (g) Monnier, F.; Taillefer, M. Angew. Chem.,
Int. Ed. 2009, 48, 6954 and references cited therein.
(16) For recent studies on the synthesis of N-heterocycles through
Ullmann-type couplings, see: (a) Martin, R.; Rivero, M. R.; Buchwald,
S. L. Angew. Chem., Int. Ed. 2006, 45, 7079. (b) Evindar, G.; Batey, R. A.
J. Org. Chem. 2006, 71, 1802. (c) Bonnaterre, F.; Bois-Choussy, M.; Zhu, J.
Org. Lett. 2006, 8, 4351. (d) Zou, B.; Yuan, Q.; Ma, D. Angew. Chem., Int. Ed.
2007, 46, 2598. (e) Chen, Y.; Xie, X.; Ma, D. J. Org. Chem. 2007, 72, 9329.
(f) Yuan, X.; Xu, X.; Zhou, X.; Yuan, J.; Mai, L.; Li, Y. J. Org. Chem. 2007,
72, 1510. (g) Wang, B.; Lu, B.; Jiang, Y.; Zhang, Y.; Ma, D. Org. Lett. 2008,
10, 2761. (h) Altenhoff, G.; Glorius, F. Adv. Synth. Catal. 2004, 346, 1661.
(i) Truong, V. L.; Morrow, M. Tetrahedron Lett. 2010, 51, 758.
(17) (a) Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2005, 70, 8107.
(b) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem.—Eur. J. 2006, 12,
3636. (c) Jiang, D.; Fu, H.; Jiang, Y.; Zhao, Y. J. Org. Chem. 2007, 72, 672.
(d) Jiang, Q.; Jiang, D.; Jiang, Y.; Fu, H.; Zhao, Y. Synlett 2007, 72, 1836. (e)
Guo, X.; Rao, H.; Fu, H.; Jiang, Y.; Zhao, Y. Adv. Synth. Catal. 2006, 348,
2197. (f) Zeng, L.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. Adv. Synth. Catal.
2009, 351, 1671. (g) Gao, X.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. J. Org.
Chem. 2008, 73, 6864. (h) Yang, D.; Fu, H. Chem.—Eur. J. 2010, 16, 2366.
(i) Li, X.; Yang, D.; Jiang, Y.; Fu, H. Green Chem. 2010, 12, 1097. (j) Rao, H.;
Fu, H.; Jiang, Y.; Zhao, Y. Adv. Synth. Catal. 2010, 352, 458.
(18) (a) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed. 2009,
48, 348. (b) Huang, C.; Fu, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Commun.
2008, 6333. (c) Yang, D.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y. J. Org. Chem.
2008, 73, 7841. (d) Yang, D.; Liu, H.; Yang, H.; Fu, H.; Hu, L.; Jiang, Y.;
Zhao, Y. Adv. Synth. Catal. 2009, 351, 1999. (e) Wang, F.; Liu, H.; Fu, H.;
Jiang, Y.; Zhao, Y. Org. Lett. 2009, 11, 2469. (f) Lu, J.; Gong, X.; Yang, H.;
Fu, H. Chem. Commun. 2010, 46, 4172. (g) Zhao, H.; Fu, H.; Qiao, R. J. Org.
Chem. 2010, 75, 3311. (h) Yang, X.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. Adv.
Synth. Catal. 2010, 352, 1033. (i) Gong, X.; Yang, H.; Liu, H.; Jiang, Y.;
Zhao, Y.; Fu, H. Org. Lett. 2010, 12, 3128.
entries 2, 12, and 13). The cascade reaction afforded the target
product in 20% yield under nitrogen atmosphere (extrusion of
air), which showed oxygen in air involved in the oxidative
process during the formation of the quinazoline derivative.
However, only 32% yield was afforded when the reaction was
performed in a flask linked with an opened condenser under air
at the refluxing temperature of 2-propanol (83 °C) (entry 15).
The result showed that lower temperature and more oxygen was
not favorable for the Ullmann-type N-arylation (see the reaction
mechanism in Scheme 1).
The scope of copper-catalyzed cascade reactions of substi-
tuted (2-bromophenyl)methylamines and aromatic amides
was investigated under the optimized conditions (10 mmol %
CuI as the catalyst, 2 equiv of K2CO3 as the base, 2-propanol
as the solvent under air). As shown in Table 2, all the substrates
examined provided moderate to good yields at 110 °C. The
substituted (2-bromophenyl)methylamines containing electron-
donating groups showed slightly lower reactivity. For amides,
the substrates containing electron-withdrawing groups usually
provided higher yields than ones containing electron-donating
groups. Unfortunately, couplings of the substituted (2-bromo-
phenyl)methylamines with aliphatic amides did not work by
J. Org. Chem. Vol. 75, No. 22, 2010 7937

Wang et al.
JOCNote
TABLE 2. Copper-Catalyzed Cascade Synthesis of Quinazoline Deri-
vativesa
A possible mechanism for synthesis of quinazoline deri-
vatives was proposed in Scheme 1 according to the results
above and the ortho-substituent effects.18a,d,19 Coordination
of substituted (2-bromophenyl)methylamine (1) with Cu(I)
ion give I, and oxidative addition of I leads to II. Treatment
of II with amide (2) provides III in the presence of base
(K2CO3), and reductive elimination of III affords N-aryla-
tion product (IV) leaving copper catalyst. Intramolecular
dehydrative cyclization in IV followed by air-promoted
aromatization can be performed to provide the desired target
product (3). The copper-catalyzed cascade reactions did
not need a ligand because of the ortho-substituent effect of
amino in substituted (2-bromophenyl)methylamine.
In summary, we have developed a simple and efficient
method for synthesis of quinazoline derivatives. The proto-
col uses inexpensive and readily available substituted
(2-bromophenyl)methylamines and amides as the starting
materials without addition of any ligand or additive under air,
the corresponding target products were obtained in moderate
to good yields, and the cascade reactions underwent sequential
Ullmann-type coupling and aerobic oxidation. The quinazoline
derivatives are biologically and pharmaceutically active mole-
cules; therefore, the present method will be of wide application
in organic chemistry and medicinal chemistry.
Experimental Section
General Procedure for Synthesis of Compounds 3a-q. An
oven-dried Schlenk tube was charged with CuI (6 mg, 0.03
mmol), potassium carbonate (83 mg, 0.6 mmol), amide (0.45
mmol), substituted (2-bromophenyl)methylamine (0.3 mmol),
and i-PrOH (1.0 mL). The tube was sealed, and the mixture was
stirred at 110 °C for 24-32 h. After the resulting solution was
cooled to room temperature, the solvent was removed, and the
residue was purified by silica gel column chromatography to
give the desired product. Two examples are shown as follows:
2-(Thiophen-2-yl)quinazoline (3f). Eluent: petroleum ether/
ethyl acetate (10:1). Yield: 46 mg (73%). White solid, mp 132-
134 °C. 1H NMR (300 MHz, CDCl3, ppm): δ 9.33 (s, 1H),
8.15-8.14 (m, 1H), 7.99 (d, J = 6.9 Hz, 1H), 7.86-7.84 (m, 2H),
7.54-7.49 (m, 2H), 7.18 (m, 1H). 13C NMR (75 MHz, CDCl3,
ppm): δ 160.7, 158.1, 150.8, 144.1, 134.6, 130.2, 129.5, 128.6,
128.4, 127.5, 127.2, 123.6. HR-MS [M þ H]þ m/z calcd for
C12H8N2S 213.0486, found 213.0487.
6-(4-Fluorophenyl)-[1,3]dioxolo[4,5-g]quinazoline (3p). Eluent:
petroleum ether/ethyl acetate (10:1). Yield 70 mg (87%). White
solid, mp 216-218 °C. 1H NMR (300 MHz, CDCl3, ppm): δ 9.13
(s, br, 1H), 8.56-8.51 (t, 2H), 7.29 (s, 1H), 7.20-7.17 (m, 2H),
7.09 (s, 1H), 6.14 (s, 2H). 13C NMR (75 MHz, CDCl3, ppm):
δ165.5, 163.9, 157.6, 154.5, 148.6, 134.6, 130.6, 130.5, 130.4, 120.9,
115.9, 115.7, 115.6, 105.1, 102.5, 102.2, 102.0. HR-MS [M þ H]þ
m/z calcd for C15H9FN2O2 269.0726, found 269.0728.
Acknowledgment. Financial support was provided by the
National Natural Science Foundation of China (Grant No.
20972083), Chinese 863 Project (Grant No. 2007AA02Z160),
and the Key Subject Foundation from Beijing Department of
Education (XK100030514).
aReaction condition: substituted (2-bromophenyl)methylamine (1)
(0.3 mmol), amide (2) (0.45 mmol), CuI (0.03 mmol), K2CO3 (0.6 mmol),
2-propanol (1.0 mL) under air, reaction temperature 110 °C, reaction
time 24 h, in a sealed vessel. bIsolated yield. cReaction time (32 h).
Supporting Information Available: General experimental
procedures, characterization data, and 1H, 13C NMR spectra of
the synthesized compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
using a similar procedure. The cascade reactions could tolerate
functional groups including the ether bond in the substituted
(2-bromophenyl)methylamines (1), the C-F bond, nitro, ether
bond and heterocycle in the aromatic amides (2).
(19) (a) Nicolaou, K. C.; Boddy, C. N. C.; Natarajar, S.; Yue, T.-Y.; Li,
€
H.; Brase, S.; Ramanjulu, J. M. J. Am. Chem. Soc. 1997, 119, 3421. (b) Cai,
Q.; Zou, B.; Ma, D. Angew. Chem., Int. Ed. 2006, 45, 1276.
7938 J. Org. Chem. Vol. 75, No. 22, 2010