Copper-catalyzed aerobic oxidative amination of sp3C-H bonds: Efficient synthesis of 2-hetarylquinazolin-4(3 H)-ones

Article abstract of DOI:10.1021/ol501454j

An efficient synthesis of 2-hetarylquinazolin-4(3H)-ones via copper-catalyzed direct aerobic oxidative amination of sp³C-H bonds has been developed. This tandem oxidation-amination-cyclization transformation represents a straightforward protocol to prepare 2-hetaryl-substituted quinazolinones from easily available 2-aminobenzamides and (2-azaaryl)methanes.

Full text of DOI:10.1021/ol501454j

Letter
pubs.acs.org/OrgLett
Copper-Catalyzed Aerobic Oxidative Amination of sp3C−H Bonds:
Efficient Synthesis of 2‑Hetarylquinazolin-4(3H)‑ones
Qiang Li,† Yao Huang,† Tieqiao Chen,† Yongbo Zhou,*,† Qing Xu,‡ Shuang-Feng Yin,*,†
and Li-Biao Han†
†State Key Laboratory of Chemo/Biosensing and Chemo metrics, College of Chemistry and Chemical Engineering, Hunan
University, Changsha 410082, China
‡College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou 325035, China
S
* Supporting Information
ABSTRACT: An efficient synthesis of 2-hetarylquinazolin-
4(3H)-ones via copper-catalyzed direct aerobic oxidative
amination of sp3C−H bonds has been developed. This tandem
oxidation−amination−cyclization transformation represents a
straightforward protocol to prepare 2-hetaryl-substituted
quinazolinones from easily available 2-aminobenzamides and
(2-azaaryl)methanes.
uinazolin-4(3H)-one compounds, especially 2-hetero-
synthesis.9 However, examples of such reactions applied in the
construction of N-heterocycles remain scarce.10,11 Herein, we
disclose an efficient synthesis of 2-hetarylquinazolin-4(3H)-ones
1 using the readily available 2-aminobenzamides 2 and (2-
azaaryl)methanes 3 (eq 1). This transformation proceeds via Cu-
Q cycle-substituted quinazolin-4(3H)-ones, constitute the
key core units of many synthetic drugs and natural products.1−3
For example, luotonin A3a,b has cytotoxicity toward human
cancer lines, while bouchardatine3c occurs in the natural product
Bouchardatia neurococca (Figure 1). Traditionally, quinazolin-
catalyzed direct aerobic oxidative amination of sp3C−H bonds.12
Compared to conventional methods, this procedure is
distinguished by using clean O2 as an oxidant, avoiding the use
of the dangerous hyperoxides and hypervalent iodine(III)
reagents.9d,11,13 To the best of our knowledge, no similar
examples have been reported for such a one-pot synthesis of 2-
hetarylquinazolin-4(3H)-one directly from (2-azaaryl)methane
3, which is cheap and readily available. This new method
provides a totally convenient and environmentally friendly access
to heterocyclic compounds 1 via a novel efficient oxidation−
amination−cyclization tandem process.
As a model reaction, the reaction of 2-aminobenzamide 2a
with 2-methylpyridine 3a under oxygen atmosphere (1 atm) was
investigated first (Table 1), disclosing that a catalytic amount of
copper and Ph2PO2H could promote the reaction efficiently. An
extensive screening of the reaction conditions revealed that 1aa
was generated in 80% yield in the presence of a catalytic amount
of CuCl and Ph2PO2H (run 5). All of the copper catalyst, acid
and oxygen are essential for this reaction. The absence of any of
them led to failure of the formation of the desired product 1aa
(runs 1−4). When less amount of catalyst CuCl/Ph2PO2H was
Figure 1. Examples of quinazolin-4(3H)-one fused natural product and
synthetic drug.
4(3H)-ones are prepared by the oxidative condensation of o-
aminobenzamide with aldehydes or carboxylic acid derivatives
under acidic or basic conditions.4−6 However, the corresponding
aldehydes are usually expensive and chemically unstable for
preparation and storage, while the acid derivatives only show low
reactivity due to severe decarboxylation side reactions.7 To
overcome these drawbacks, alternative methods, such as
intramolecular cyclization of o-haloanilides and oxidative
condensation of o-aminobenzamide with alcohols, haloalkane,
and amines, etc., have been developed.8 Although these synthetic
protocols serve well, these transformations require prefunction-
alized substrates and usually suffer from poor atom economy.
Thus, more straightforward methods for the preparation of
quinazolin-4(3H)-one compounds from easily available sub-
strates still remain highly desirable.
Recently, the direct transformations of methylarenes and
methylhetarenes have attracted increasing attention due to their
recognized importance in biology, pharmacology, and organic
Received: May 20, 2014
© XXXX American Chemical Society
A
dx.doi.org/10.1021/ol501454j | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Table 2. Synthesis of 2-Hetarylquinazolin-4(3H)-ones 1
b
run
[Cu]
CuCl
acid
solvent
yield (%)
1
2
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
C6H5Cl
MeCN
THF
none
none
none
none
80
c
3
Ph2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
PhCO2H
PhCH2CO2H
CF3CO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
Ph2PO2H
d
4
CuCl
CuCl
CuCl
CuCl
CuCl
CuBr
CuI
5
e
6
55(76)
35
f
7
g
8
40
9
32
10
11
12
13
14
15
16
17
18
19
20
21
22
CuCl2
CuBr2
Cu(OAc)2
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
CuCl
68
31
27
47
60
35
27
21
DCE
11
toluene
dioxane
C6H5Cl
57
65
h
22
43
a
Reaction conditions: 2a (0.2 mmol), 3a (0.4 mmol), copper catalyst
(15 mol %), an acid (50 mol %), and solvent (1 mL) in a 25 mL sealed
b
glass tube, O2 (1 atm), 130 °C, 8 h. GC yields using n-dodecane as an
c
d
internal standard. 1 equiv of Ph2PO2H was used. Conducted under
e
nitrogen. 10 mol % of CuCl was used. Yield in parentheses refers to
reaction performed for 24 h. 5 mol % of CuCl was used. 20 mol % of
Ph2PO2H was used. Under air.
f
g
h
loaded, the yield of 1aa decreased (runs 6−8). Among the copper
catalysts investigated, CuCl showed the highest catalytic
efficiency (Table 1, runs 9−13). As to the acid, although inferior
to Ph2PO2H, carboxylic acids such as PhCO2H, PhCH2CO2H,
and CF3CO2H also catalyzed the reaction to give moderate yields
of 1aa (runs 14−16). As for the solvents (runs 17−21), the
reaction also took place in toluene and dioxane to give good
yields of the product but afforded low yields in acetonitrile, THF,
and ClCH2CH2Cl (DCE). Finally, the reaction could be carried
out under air to give the product in a moderate yield (run 22).
As shown in Table 2, this aerobic oxidative amination can be
applied to a variety of substrates to produce the corresponding 2-
hetaryl-quinazolin-4(3H)-one 1 in good yields. In addition to
this monosubstituted 2-methylpyridine 3a, disubstituted 5-ethyl-
2-methylpyridine 3b and 2,6-dimethylpyridine 3c also gave high
yields of the corresponding products (runs 2 and 3). Noteworthy
was that only the methyl group at the 2-position of 3b was
oxidatively aminated in this reaction. Very interestingly, a
substrate with the methyl group at the 3-position (3d) did not
react at all under the present reaction conditions (run 4).
Similarly, 2-methylquinoline 3e and 6-methoxy-2-methylquino-
line 3f also gave the expected condensation products 1ae and 1af
in 86% and 56% yield, respectively (runs 5 and 6). In addition to
these simple heterocycles, heterocycles fused multiple heter-
oatoms were also suitable substrates for this transformation. For
a
Reaction conditions: 2 (0.2 mmol), 3 (0.4 mmol), CuCl (0.03 mmol,
15 mol %), Ph2PO2H (0.1 mmol), C6H5Cl (1 mL), 130 °C, 8 h.
b
c
Isolated yields (GC yields in parentheses) based on 2. 20 mol % of
d
CuCl, 4-nitrobenzoic acid (0.2 mmol), 150 °C, 18 h. 30 mol % of
CuCl, 4-nitrobenzoic acid (0.2 mmol), 150 °C, 18 h. 63% of 3f was
recovered, whereas substrate 2a was fully consumed.
e
example, both 2-methylpyrazine 3g and 2-methylquinoxaline 3h
produced the corresponding condensation products 1ag and 1ah
(runs 7 and 8). The reaction was further successfully applied to
sulfur-containing 2-methylthiazole 3i and 2-methylbenzothiazole
3j, and the oxidative condensation products 1ai and 1aj were
obtained in good yields under similar reaction conditions (runs 9
and 10). As for 2-aminobenzamides 2, in addition to the simplest
2a, the chloro-substituted 2b and methyl-substituted 2c also
served as good substrates to produce the oxidative condensation
products efficiently (runs 11−13 and 14−16). Importantly, the
substituted N-methylbenzamide 2d could also be employed in
B
dx.doi.org/10.1021/ol501454j | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
this reaction to give the corresponding condensation products in
good yields (runs 17−19). It should be noted that these oxidative
condensation products 1 are valuable synthetic intermediates for
the synthesis of biologically active compounds.1b For example,
luotonin A (Figure 1) can be easily prepared by using the product
1ae.14
Scheme 2. Proposed Mechanism
In order to obtain insight into the reaction mechanism, several
control experiments were carried out (Scheme 1). First, by
Scheme 1. Control Experiments
In summary, we have disclosed an efficient copper-catalyzed
aerobic oxidative sp3C−H amination of (2-azaaryl)methanes
leading to 2-hetarylquinazolin-4(3H)-ones using oxygen as the
sole oxidant under mild conditions. Three sp3C−H and three
N−H bonds are removed in this novel chemistry to produce the
highly valuable N-heterocycles from readily available materials.
Further extension and synthetic applications of this Cu-catalyzed
oxidative C−H amination method are ongoing in our laboratory.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, product characterization, mechanistic
studies, and H and 13C NMR spectra of the products. This
material is available free of charge via the Internet at http://pubs.
acs.org.
1
replacing 2a with 2-ethyl-6-methylaniline 4 in the reaction with
3a, an imine 5 was obtained in 22% yield,15 indicating that an
imine intermediate was involved in the above catalytic oxidative
condensation process (Scheme 1, a). It was initially assumed that
3a was oxidized to picolinic acid 6a, which then reacted with 2a
to give 1aa.16 However, this possibility was readily ruled out
because it was confirmed that a mixture of 2a with picolinic acid
6a under the standard conditions did not afford the product 1aa
(Scheme 1, b). When picolinaldehyde 6b was allowed to react
with 2a, 1aa was obtained in 42% yield (Scheme 1, c). This result
indicated that aldehydes perhaps served as the efficient
intermediate. Finally, the reaction was strongly retarded in the
presence of a radical scavenger. For example, by addition of
2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) or 2,6-di-tert-
butyl-4-methylphenol (BHT), only a trace of 1aa was obtained,
showing that radical intermediates were involved in this
transformation (Scheme 1, d).
On the basis of the experiments described above and literature
examples,17 a possible mechanism for this aerobic oxidation
cyclization reaction is outlined in Scheme 2. Since in the absence
of an acid18 or copper the reaction does not proceed, and the
methyl group of 3 must be located at the 2-position (a similar
reaction did not take place with 3-picoline 3i), it is assumed that
3a can be isomerized to a nonaromatic enamine intermediate
3a′.19,20 Moreover, it is confirmed that toluene does not react
under the present conditions, indicating that the nitrogen atom
of 3a is crucial for the formation of a metal enamide intermediate
7.9j−m Subsequent oxidation of 7 with O2 generates intermediate
8,21a which then reacts with 2a to give 9.21b Brønsted acid
catalyzed dehydration of 9 affords the imine intermediate 10,
which is cyclized to give 11. Finally, aerobic oxidation of 11
produces the product 1aa.22
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: zhouyb@hnu.edu.cn.
*E-mail: sf_yin@hnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSFC (Nos. 21172062, 21273067, 21373080) and
Fundamental Research Funds for the Central Universities
(Hunan University).
REFERENCES
■
(1) (a) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893. (b) Mhaske, S. B.; Argade, N. P. Tetrahedron 2006, 62, 9787
and references cited therein.
(2) (a) Jang, C. S.; Fu, F. Y.; Wang, C. Y.; Huang, K. C.; Lu, G.; Thou,
T. C. Science 1946, 103, 59. (b) D’yakonor, A. L.; Telezhenetskaya, M. V.
Chem. Nat. Compd. 1997, 33, 221. (c) Michael, J. P. Nat. Prod. Rep. 2004,
21, 650.
(3) (a) Ma, Z.-Z.; Hano, Y.; Nomura, T.; Chen, Y.-J. Heterocycles 1997,
46, 541. (b) Liang, J. L.; Cha, H. Y.; Jahng, Y. D. Molecules 2011, 16,
4861. (c) Wattanapiromsakul, C.; Forster, P. I.; Waterman, P. G.
Phytochemistry 2003, 64, 609.
(4) (a) Segarra, V.; Isabel Crespo, M.; Pujol, F.; Beleta, J.; Domenech,
T.; Miralpeix, M.; Palacios, J. M.; Castro, A.; Martinez, A. Bioorg. Med.
Chem. Lett. 1998, 8, 505. (b) Connolly, D. J.; Guiry, P. J. Synlett 2001,
1707. (c) Hattori, K.; Kido, Y.; Yamamoto, H.; Ishida, J.; Kamijo, K.;
Murano, K.; Ohkubo, M.; Kinoshita, T.; Iwashita, A.; Mihara, K.;
C
dx.doi.org/10.1021/ol501454j | Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Yamazaki, S.; Matsuoka, N.; Teramura, Y.; Miyake, H. J. Med. Chem.
2004, 47, 4151. (d) Liu, J. F.; Ye, P.; Zhang, B.; Bi, G.; Sargent, K.; Yu, L.;
Yohannes, D.; Baldino, C. M. J. Org. Chem. 2005, 70, 6339. (e) Liu, J. F.;
Kaselj, M.; Isome, Y.; Ye, P.; Sargent, K.; Sprague, K.; Cherrak, D.;
Wilson, C. J.; Si, Y.; Yohannes, D. J. Comb. Chem. 2006, 8, 7. (f) Adib,
M.; Ansari, S.; Mohammadi, A.; Bijanzadeh, H. R. Tetrahedron Lett.
2010, 51, 30. (g) Kshirsagar, U. A.; Argade, N. P. Org. Lett. 2010, 12,
3716.
(5) (a) Kotsuki, H.; Sakai, H.; Morimoto, H.; Suenaga, H. Synlett 1999,
1993. (b) Witt, A.; Bergman, J. Tetrahedron 2000, 56, 7245. (c) Yoo, C.
L.; Fettinger, J. C.; Kurth, M. J. J. Org. Chem. 2005, 70, 6941. (d) Roy, A.
D.; Subramanian, A.; Roy, R. J. Org. Chem. 2006, 71, 382. (e) Zhou, J.;
Fang, J. J. Org. Chem. 2011, 76, 7730.
(6) For traditional methods for the preparation of quinazolin-4(3H)-
ones derivatives, see: (a) Bergman, J.; Witt, A. Curr. Org. Chem. 2003, 7,
659. (b) Horton, D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003,
103, 893. (c) Connolly, D. J.; Cusack, D.; O’Sullivan, T. P.; Guiry, P. J.
Tetrahedron 2005, 61, 10153. (d) Patil, A.; Patil, O.; Patil, B.; Surana, J.
Mini-Rev. Med. Chem. 2011, 11, 633.
(7) Hammick reaction: (a) Dyson, P.; Hammick, D. Ll. J. Chem. Soc.
1937, 1724. (b) Ashworth, M. R. F.; Daffern, R. P.; Hammick, D. Ll. J.
Chem. Soc. 1939, 809. (c) Brown, E. V.; Shambhu, M. B. J. Org. Chem.
1971, 36, 2002.
(15) A trace of the picolinaldehyde 6b resulted from the 2-
methylpyridine was detected by GC and GC−MS.
(16) Lee, E. S.; Son, J. K.; Na, Y. H.; Jahng, Y. D. J. Heterocycl. Comm.
2004, 10, 325.
(17) (a) Tian, J. S.; Loh, T. P. Angew. Chem., Int. Ed. 2010, 49, 8417.
(b) Zhang, C.; Zong, X. L.; Zhang, L. R.; Jiao, N. Org. Lett. 2012, 14,
3280. (c) Xia, X. F.; Zhang, L. L.; Song, X. R.; Liu, X. Y.; Liang, Y. M. Org.
Lett. 2012, 14, 2480.
(18) For activation of pyridines and quinolines by Lewis acids:
(a) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc. 2008, 130,
2448. (b) Deng, G.; Li, C.-J. Org. Lett. 2009, 11, 1171.
(19) For examples: (a) Hamana, H.; Sugasawa, T. Chem. Lett. 1983,
333. (b) Hamana, H.; Sugasawa, T. Chem. Lett. 1984, 1591.
(20) Full incorporation of deuterium on the methyl group could be
obtained by refluxing 2-methylpyridine in D2O; see ref 9l.
(21) (a) Zhang, G.-W.; Miao, J.-M.; Zhao, Y.; Ge, H.-B. Angew. Chem.,
Int. Ed. 2012, 51, 8318. (b) Cai, Z. J.; Wang, S. Y.; Ji, S. J. Org. Lett. 2012,
14, 6068.
(22) (a) Abdel-Jalil, R. J.; Voelter, W.; Saeed, M. Tetrahedron Lett.
2004, 45, 3475. (b) Layeva, A. A.; Nosova, E. V.; Lipunova, G. N.;
Trashakhova, T. V.; Charushin, V. N. Russ. Chem. Bull. 2007, 56, 1821.
(8) For selected examples, see: (a) Zhou, J.; Fang, J. J. Org. Chem. 2011,
76, 7730. (b) Hikawa, H.; Ino, Y.; Suzuki, H.; Yokoyama, Y. J. Org. Chem.
2012, 77, 7046. (c) Watson, A. J. A.; Maxwell, A. C.; Williams, J. M. J.
Org. Biomol. Chem. 2012, 10, 240. (d) Sharif, M.; Opalach, J.; Langer, P.;
Beller, M.; Wu, X.-F. RSC Adv. 2014, 4, 8. (e) Zhao, D.; Zhou, Y.-R.;
Shen, Q.; Li, J.-X. RSC Adv. 2014, 4, 6486. (f) Ge, W.; Zhu, X.; Wei, Y.
RSC Adv. 2013, 3, 10817. (g) Thanh Binh, N.; Ermolenko, L.; Al-
Mourabit, A. Green Chem. 2013, 15, 2713. (h) Wei, H.; Li, T.; Zhou, Y.;
Zhou, L.; Zeng, Q. Synthesis 2013, 45, 3349.
(9) For selected examples, see: (a) Powell, D. A.; Fan, H. J. Org. Chem.
2010, 75, 2726. (b) Xia, Q.; Chen, W.; Qiu, H. J. Org. Chem. 2011, 76,
7577. (c) Xue, Q.; Xie, J.; Li, H.; Cheng, Y.; Zhu, C. Chem. Commun.
2013, 49, 37. (d) Kim, H. J.; Kim, J.; Cho, S. H.; Chang, S. J. Am. Chem.
Soc. 2011, 133, 16382. (e) Samanta, R.; Lategahn, J.; Antonchick, A. P.
Chem. Commun. 2012, 48, 3194. (f) Ni, Z.; Zhang, Q.; Xiong, T.; Zheng,
Y.; Li, Y.; Zhang, H.; Zhang, J.; Liu, Q. Angew. Chem., Int. Ed. 2012, 51,
1244. (g) Amaoka, Y.; Kamijo, S.; Hoshikawa, T.; Inoue, M. J. Org.
Chem. 2012, 77, 9959. (h) Xiao, W.; Wei, J.; Zhou, C.-Y.; Che, C.-M.
Chem. Commun. 2013, 49, 4619. (i) Gephart, R. T.; Huang, D. L.; Aguila,
M. J. B.; Schmidt, G.; Shahu, A.; Warren, T. H. Angew. Chem., Int. Ed.
2012, 51, 6488. (j) Qian, B.; Guo, S.; Shao, J.; Zhu, Q.; Yang, L.; Xia, C.;
Huang, H. J. Am. Chem. Soc. 2010, 132, 3650. (k) Qian, B.; Guo, S.; Xia,
C.; Huang, H. Adv. Synth. Catal. 2010, 352, 3195. (l) Rueping, M.;
Tolstoluzhsky, N. Org. Lett. 2011, 13, 1095. (m) Komai, H.; Yoshino, T.;
Matsunaga, S.; Kanai, M. Org. Lett. 2011, 13, 1706.
(10) (a) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A. J. Am. Chem.
Soc. 2013, 135, 118. (b) Nguyen, T. B.; Ermolenko, L.; Al-Mourabit, A.
Org. Lett. 2013, 15, 4218.
(11) Very recently, two papers reported that toluene can be used for
direct oxidative amination for the construction of N-heterocycles,
however, toluene is required as solvent and the dangerous hyperoxides
are used as oxidant. In particular, these reactions suffer severe
homocoupling of toluene. (a) Gu, L. J.; Jin, C.; Guo, J. M.; Zhang, L.
Z.; Wang, W. Chem. Commun. 2013, 49, 10968. (b) Zhao, D.; Wang, T.;
Li, J. X. Chem. Commun. 2014, 50, 6471.
(12) For recent reviews on copper−dioxygene systems, see:
(a) Wendlandt, A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed.
2011, 50, 11062. (b) Zhang, C.; Tang, C.; Jiao, N. Chem. Soc. Rev. 2012,
41, 3464. (c) Allen, S. E.; Walvoord, R. R.; Padilla-Salinas, R.; Kozlowski,
M. C. Chem. Rev. 2013, 113, 6234.
(13) For selected examples of oxidative amination of C(sp3)−H bonds
using hyperoxides or hypervalent iodine (III) reagents as oxidants:
(a) Souto, J. A.; Zian, D.; Muniz, K. J. Am. Chem. Soc. 2012, 134, 7242.
̃
(b) Yan, Y. Z.; Zhang, Y. H.; Feng, C. G.; Zha, Z. G.; Wang, Z. Y. Angew.
Chem., Int. Ed. 2012, 51, 8077.
(14) Mhaske, S. B.; Argade, N. P. J. Org. Chem. 2004, 69, 4563.
D
dx.doi.org/10.1021/ol501454j | Org. Lett. XXXX, XXX, XXX−XXX