Synthesis of quinazolin-4(3H)-ones via Pd(II)-catalyzed intramolecular C(sp2)-H carboxamidation of N-arylamidines

Article abstract of DOI:10.1021/jo2007362

An efficient synthesis of quinazolin-4(3H)-ones from N-arylamidines, through palladium-catalyzed intramolecular C(sp²)-H carboxamidation, has been developed. The reaction, carried out in the presence of 1.0 equiv of CuO as oxidant under atmospheric pressure of CO, provides diversified 2-aryl(alkyl)quinazolin-4(3H)-ones in reasonable to good yields from N-arylamidines, which are readily derived from anilines and nitriles. Compared with existing approaches to quinazolin-4(3H)-ones, the current strategy features atom-economy and step-efficiency.

Full text of DOI:10.1021/jo2007362

NOTE
pubs.acs.org/joc
Synthesis of Quinazolin-4(3H)-ones via Pd(II)-Catalyzed Intramolecular
C(sp2)ÀH Carboxamidation of N-arylamidines
Bin Ma, Yong Wang, Jiangling Peng, and Qiang Zhu*
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences,
190 Kaiyuan Avenue, Guangzhou 510530, China
S Supporting Information
b
ABSTRACT: An efficient synthesis of quinazolin-4(3H)-ones
from N-arylamidines, through palladium-catalyzed intramolecular
C(sp2)ÀH carboxamidation, has been developed. The reaction,
carried out in the presence of 1.0 equiv of CuO as oxidant under
atmospheric pressure of CO, provides diversified 2-aryl(alkyl)-
quinazolin-4(3H)-ones in reasonable to good yields from N-aryla-
midines, which are readily derived from anilines and nitriles.
Compared with existing approaches to quinazolin-4(3H)-ones,
the current strategy features atom-economy and step-efficiency.
alladium-catalyzed carbonylation of alkenyl or aryl (pseudo)-
halides represents a straightforward approach to carboxylic
derived readily from anilines and nitriles.15 This strategy delivers
quinazolin-4(3H)-ones in only two steps from commercial
available chemicals, and no atoms except protons in substrates
are lost during the process (Scheme 1).
P
acids and their derivatives.1 However, the requisite of using
prefunctionalized (pseudo)halide substrates and the generation
of environmentally unfriendly waste make alternative approaches
highly desirable. Substantial achievements have been made in the
area of direct functionalization of CÀH bonds during the past
decade.2 Carbonylation of CÀH bonds, catalyzed by transition
metals under the aid of an appropriate directing group, has
however attracted much less attention until very recently.3,4
Compared with intermolecular CÀH carbonylation,3 the intra-
molecular fashion obviates the need for extra steps of introducing
and removing the directing group which acts as an intramolecular
nucleophile as well.4 Therefore, the intramolecular CÀH carbo-
nylation is an ideal and truly atom-economical approach to
lactones and lactams.4 Herein, we would like to report a
palladium-catalyzed intramolecular C(sp2)ÀH carboxamidation
of N-arylamidines, providing an efficient approach to diversified
quinazolin-4(3H)-one derivatives.
The reaction conditions were optimized with N-phenylben-
zamidine 1a as substrate,15,16 and the results are summarized in
Table 1. Yu’s conditions for the carboxylation of o-CÀH bonds in
anilides to form N-acylanthranilic acids, employing Pd(OAc)2
(10 mol %), benzoquinone (BQ, 1.0 equiv), p-TsOH (0.5 equiv),
HOAc/dioxane (2:1) as solvent, and atmospheric pressure of
CO, were applied first (entry 1, Table 1).3b Gratifyingly, the
desired product 2-phenylquinazolin-4(3H)-one 2a, contami-
nated with small amount of hydroquinone, was formed in 34%
yield (by NMR). To simplify the purification, inorganic oxidant
Cu(OAc)2 was used in place of BQ, and the yield of 2a was
improved from 52% to 59% in the absence of p-TsOH (entries
2À3, Table 1). Alteration of the palladium species to PdCl2 or
Pd(TFA)2 did not improve the results. Other oxidants including
CuCl2, PhI(OAc)2, AgOAc, CuSO4 5H2O, and CuO were then
3
Quinazolin-4(3H)-one is an important scaffold found in many
natural products and synthetic drugs or drug candidates exhibit-
ing a wide range of biological activities, including antibacterial,5
antiinflammatory,6 antifungal,7 anticancer,8 antimicrobial,9 and
antimalarial activities.10 As a result, numerous synthetic efforts
have been made for their synthesis.11 The most widely used
method is probably the condensation of 2-aminobenzoic acids or
their derivatives with carboxylic acid derivatives under acidic
or basic conditions (Scheme 1).11,12 Recently, Fu developed
novel cascade methods starting from 2-halobenzoic acids or
2-halobenzamides.13 Alper and co-authors reported alternative
approaches via tandem reactions involving palladium-catalyzed
cyclocarbonylation of 2-iodoanilines or their derivatives as the
key step.14 We speculated that the quinazolin-4(3H)-one motif
could also be constructed by palladium-catalyzed intramolecular
C(sp2)ÀH carboxamidation of simple N-arylamidines, which are
screened (entries 6À10, Table 1), with CuO being the most
effective. The selection of solvent was also crucial, identifying
acetic acid as the optimum solvent (entries 11À13, Table 1).
With the optimized reaction conditions in hand, the scope of
the palladium-catalyzed intramolecular C(sp2)ÀH carboxamida-
tion forming quinazolin-4(3H)-ones was investigated. As shown
in Table 2, electron-donating groups on ortho-, meta-, and para-
positions of the N-aryl moiety of 1 favored the reaction, provid-
ing corresponding substituted 2-phenylquinazolin-4(3H)-ones
(2bÀg) in reasonable to good yields. Notably, when two
asymmetric C(sp2)ÀH bonds were present in meta-substituted
N-arylamidines 1e,f, only the less hindered CÀH bond was
carbonylated. Unfortunately, substrates with electron-withdrawing
Received: April 8, 2011
Published: June 15, 2011
r
2011 American Chemical Society
6362
dx.doi.org/10.1021/jo2007362 J. Org. Chem. 2011, 76, 6362–6366
|

The Journal of Organic Chemistry
NOTE
Scheme 1. Major Approaches to Quinazolin-4(3H)-ones
To gain insight into the reaction mechanism, monodeuter-
ated N-phenylbenzamidine 1a-D was subjected to the reaction
conditions (Scheme 2). The reaction was quenched at 4 h, and
the deuteration rates in both recovered starting material and the
product were tested. It was found that the deuterium was
partially lost in the recovered 1a-D from over 95% to about
75%, and only one-third of the product was deuterium incor-
porated. The results suggested that the CÀH bond activation
was reversible and deuteriumÀhydrogen exchange occurred
during the reaction.
Based on the results of substrate scope exploration and
deuteration study, a plausible reaction mechanism is proposed
in Scheme 3. Initial chelation of the amidine nitrogen with
palladium(II) forms intermediate A, followed by reversible
cyclopalladation. The coordinated CO inserts into the CÀPd
bond in B, generating a seven-membered palladocycle C. Re-
ductive elimination leads to the product 2 and releases Pd(0)
which is reoxidized by CuO under the aid of HOAc.
In summary, we have developed an efficient synthesis of
quinazolin-4(3H)-ones from N-arylamidines, through palladium-
catalyzed intramolecular C(sp2)ÀH carboxamidation. The reac-
tion is carried out in the presence of Pd(OAc)2 (10 mol %), and
CuO (1.0 equiv), under 1 atm of CO atmosphere in HOAc,
providing diversified 2-aryl(alkyl)quinazolin-4(3H)-ones in rea-
sonable to good yields. The reaction proceeds smoothly with
electron-rich N-arylamidines, which are readily derived from
anilines and nitriles. Compared with existing approaches to
quinazolin-4(3H)-ones, thecurrent accessfeatures atom-economy
and step-efficiency.
Table 1. Optimization of Reaction Conditionsa
entry catalyst (0.1 equiv) oxidant (1.0 equiv) solvent yield (%)b
1c
2c
3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl 2
BQ
Ad
A
34e
52
’ EXPERIMENTAL SECTION
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CuCl2
A
59
General Information. All reagents were purchased without further
purification. Reactions were monitored using thin-layer chromatography
(TLC) on commercial silica gel plates (GF254). Visualization of the
developed plates was performed under UV light (254 nm). Flash column
chromatography was performed on silica gel (200À300 mesh). 1H and
13C NMR spectra were recorded on a 400 or 500 MHz spectrometer.
Chemical shifts (δ) were reported in ppm referenced to an internal
tetramethylsilane standard or the DMSO-d6 residual peak (δ 2.50) for
1H NMR. Chemical shifts of 13C NMR were reported relative to CDCl3
(δ 77.0) or DMSO-d6 (δ 39.5). High resolution mass spectra (HRMS)
were obtained on an ESI-LC-MS/MS Spectrometer.
4
A
53
5
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
A
56
6
A
45
7
PhI(OAc)2
AgOAc
A
0
8
A
27
9
CuSO4 5H2O
A
54
3
10
11
12
13
CuO
CuO
CuO
CuO
A
Bf
61
23
69 (61)g
HOAc
TFA
trace
General Procedure for the Synthesis of Quinazolin-4(3H)-
ones. A 10 mL Schlenk-type tube (with a Teflon high pressure valve
and side arm) equipped with a magnetic stir bar was charged with
substrate 1 (0.2 mmol), followed by Pd(OAc)2 (4.5 mg, 0.02 mmol),
CuO (16 mg, 0.2 mmol), and acetic acid (1.5 mL) as solvent. The
reaction tube was evacuated and back-filled with CO (five times,
balloon) and heated to 110 °C for 23 h under vigorous stirring. Upon
completion, the reaction mixture was cooled to room temperature. The
reaction mixture was neutralized with saturated solution of NaHCO3
and then extracted with ethyl acetate. The aqueous layer was further
extracted with EtOAc (3 Â 20 mL). The combined organic layers were
dried over Na2SO4, filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography on silica gel.
Synthesis of N-(2-Deuteriophenyl)benzamidine 1a-D.16,20
A dried round-bottom flask (25 mL in volume) was charged with NaH
(60% in mineral oil) (180 mg, 4.5 mmol, 60%, 1.5 equiv). Under a
stream of argon, DMSO (3 mL) was added, and the resulting suspension
was cooled with an iceÀwater bath prior to the addition of 2-deuterioani-
line (280 mg, 3 mmol, 1.0 equiv) and benzonitrile (0.33 mL, 3.3 mmol,
1.1 equiv). The mixture was kept at 0 °C for 60 min and then stirred
a Reaction conditions: 1a (0.2 mmol), Pd(OAc)2 (10 mol %), oxidant
(1.0 equiv), CO balloon (1 atm), solvent (1.5 mL), 110 °C, 23 h.
c
b 1H NMR yield. 0.5 equiv of TsOH was added. d Solvent A: HOAc:
dioxane (2:1). e Hydroquinone was detected in the product. f Solvent B:
C2H5COOH:dioxane (2:1). g Isolated yield in parentheses.
groups, such as Cl and F, on any positions of the N-aryl ring were
intact under the standard reaction conditions, suggesting that an
electrophilic aromatic substitution (SEAr) pathway may be
involved in the CÀH bond activation. Substitution effect on
the benzamidine moiety was also examined. Electron-rich ben-
zamidines (1hÀk) provided much better results than electon-
deficient ones, indicating that the electron density on the
amidine nitrogen was crucial in chelation with the palladium
catalyst. In general, less sterically hindered alkyl amidines were
good substrates in the current CÀH carboxamidation, yielding
corresponding 2-alkylquinazolin-4(3H)-ones 2lÀq in up to
81% yield.
6363
dx.doi.org/10.1021/jo2007362 |J. Org. Chem. 2011, 76, 6362–6366

The Journal of Organic Chemistry
NOTE
Table 2. Scope of Pd(II)-Catalyzed Intramolecular C(sp2)ÀH Carboxamidationa
a Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (10 mol %), CuO (1.0 equiv), CO balloon (1 atm), HOAc (1.5 mL), 110 °C, 23 h. b Isolated yield of 2.
Scheme 2. Deuteration Study
at room temperature until the starting material was consumed as
monitored by TLC analysis. IceÀwater (10 mL) was added while
maintaining vigorous stirring. The aqueous layer was extracted with
EtOAc (3 Â 10 mL). The extracts were combined and washed with
water (2 Â 20 mL). The organic layer was dried over Na2SO4, filtered,
and concentrated under reduced pressure. The residue was purified by
silica gel chromatography to get 414 mg (70%) of N-(2-deuteriophenyl)-
benzamidine 1a-D. 1H NMR (400 MHz, CDCl3) δ 7.87 (d, J = 4.0 Hz,
6364
dx.doi.org/10.1021/jo2007362 |J. Org. Chem. 2011, 76, 6362–6366

The Journal of Organic Chemistry
NOTE
Scheme 3. Plausible Reaction Mechanism
7-Methoxy-2-phenylquinazolin-4(3H)-one (2f)11e. Eluent:
petroleum ether/ethyl acetate (4:1). Yield: 74% (39 mg). White solid.
1H NMR (400 MHz, DMSO-d6) δ 12.43 (br, 1H), 8.17 (d, J = 7.2 Hz,
2H), 8.05(d, J= 8.8 Hz, 1H), 7.56 (m, 3H), 7.19 (s, 1H), 7.10 (d, J=8.4Hz,
1H), 3.92 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 164.2, 161.7,
152.9, 151.0, 132.7, 131.4, 128.5, 127.7, 127.4, 116.2, 114.4, 108.5, 55.7;
Exact mass calcd for C15H13N2O2 [M + H]+ 253.0972, Found 253.0985.
5,7-Dimethyl-2-phenylquinazolin-4(3H)-one (2g)17. Eluent:
petroleum ether/ethyl acetate (4:1). Yield: 70% (35 mg). White solid. 1H
NMR (400 MHz, DMSO-d6) δ 12.21 (br, 1H), 8.16 (d, J = 7.2 Hz, 2H),
7.56 (m, 3H), 7.37 (s, 1H), 7.09 (s, 1H), 2.77 (s, 3H), 2.40 (s, 3H); 13C
NMR (125 MHz, DMSO-d6) δ 162.8, 151.9, 150.4, 143.8, 139.6, 132.5,
131.2, 130.3, 128.5, 127.6, 125.4, 116.9, 22.3, 21.0; Exact mass calcd for
C16H15N2O [M + H]+ 251.1179, Found 251.1152.
2-o-Tolylquinazolin-4(3H)-one (2h)18. Eluent: petroleum ether/
ethyl acetate (6:1). Yield: 74% (35 mg). White solid. 1H NMR (400 MHz,
DMSO-d6) δ 12.47 (br, 1H), 8.16 (d, J = 7.2 Hz, 1H), 7.83 (t, J = 7.2 Hz,
1H), 7.68 (d, J = 8.0 Hz, 1H), 7.54 (t, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz,
1H), 7.43 (t, J = 6.4 Hz, 1H), 7.35 (d, J = 4.8 Hz, 1H), 7.32 (t, J = 5.2 Hz,
1H), 2.37 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 161.8, 154.4,
148.7, 136.1, 134.4, 134.2, 130.5, 129.8, 129.1, 127.3, 126.6, 125.7, 125.6,
120.9, 19.5; Exact mass calcd for C15H13N2O [M + H]+ 237.1022, Found
237.0996.
2-m-Tolylquinazolin-4(3H)-one (2i)11e. Eluent: petroleum ether/
ethyl acetate (4:1). Yield: 53% (25 mg). White solid. 1H NMR (400 MHz,
DMSO-d6) δ 12.47 (br, 1H), 8.15 (d, J = 7.6 Hz, 1H), 8.03 (s, 1H), 7.97
(d, J = 7.2 Hz, 1H), 7.83 (t, J = 7.2 Hz, 1H), 7.74 (d, J = 8.0 Hz, 1H), 7.52
(t, J = 7.2 Hz, 1H), 7.43 (m, 2H); 13C NMR (125 MHz, DMSO-d6) δ
162.2, 152.3, 148.7, 137.9, 134.6, 132.6, 132.0, 128.5, 128.2, 127.4, 126.5,
125.8, 124.9, 121.0, 20.9; Exact mass calcd for C15H13N2O [M + H]+
237.1022, Found 237.1001.
2-p-Tolylquinazolin-4(3H)-one (2j)13a. Eluent: petroleum ether/
ethyl acetate (4:1). Yield: 70% (33 mg). White solid. 1H NMR (400 MHz,
DMSO-d6) δ 12.48 (br, 1H), 8.14 (d, J = 8 Hz, 1H), 8.10 (d, J = 8.4 Hz,
2H), 7.82 (t, J = 8 Hz, 1H), 7.73 (d, J = 8 Hz, 1H), 7.52 (t, J = 8 Hz, 1H),
7.34 (d, J = 8.0 Hz, 2H), 2.40 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ
162.2, 152.2, 148.8, 141.4, 129.9, 129.1, 127.6, 127.4, 126.3, 125.8, 120.9,
20.9; Exact mass calcd for C15H12N2NaO [M + Na]+ 259.0842, Found
259.0828.
2H), 7.46 (m, 3H), 7.36 (m, 2H), 7.07 (t, J = 7.2 Hz, 1H), 7.00 (d, J =
8.0 Hz, 1H), 4.85 (br, 2H).
Mechanistic Study. The reaction of N-(2-deuteriophenyl)benz-
amidine 1a-D (20 mg, 0.1 mmol) was run for 4 h following the general
procedure. The product was obtained in 5 mg (23%), and the starting
material was recovered in 12 mg (60%). The deuteration rates of both
product and recovered 1a-D were determined by 1H NMR integration
(2a:2a-D = 2:1, 1a:1a-D = 1: 3).
2-Phenylquinazolin-4(3H)-one (2a)13c. Eluent: petroleum ether/
ethyl acetate (4:1). Yield: 61% (27 mg). White solid. 1H NMR (400 MHz,
DMSO-d6) δ 12.53 (br, 1H), 8.17 (t, J = 7.2 Hz, 3H), 7.84 (m, 1H), 7.74
(d, J = 8.0 Hz, 1H), 7.50À7.60 (m, 4H); 13C NMR (125 MHz, DMSO-d6)
δ 162.3, 152.4, 148.7, 134.6, 132.7, 131.4, 128.6, 127.8, 127.4, 126.6, 125.8,
121.0; Exact mass calcd for C14H11N2O [M + H]+ 223.0866, Found
223.0875.
6-Methyl-2-phenylquinazolin-4(3H)-one (2b)11d. Eluent:
petroleum ether/ethyl acetate (4:1). Yield: 68% (32 mg). White solid.
1H NMR (400 MHz, DMSO-d6) δ 12.47 (br, 1H), 8.16 (d, J = 6.4 Hz,
2H), 7.95 (s, 1H), 7.65 (s, 2H), 7.55 (m, 3H), 2.46 (s, 3H); 13C NMR
(125 MHz, DMSO-d6) δ 162.1, 151.4, 146.7, 136.3, 135.8, 132.7,
131.2, 128.5, 127.6, 127.3, 125.2, 120.7, 20.8; Exact mass calcd for
C15H12N2NaO [M + Na]+ 259.0842, Found 259.0834.
2-(3,4-Dimethylphenyl)quinazolin-4(3H)-one (2k). Eluent:
petroleum ether/ethyl acetate (4:1). Yield: 62% (31 mg). White solid.
1H NMR (500 MHz, DMSO-d6) δ 12.40 (br, 1H), 8.14 (d, J = 8 Hz,
1H), 8.01 (s, 1H), 7.92 (d, J = 7.5 Hz, 1H), 7.81 (t, J = 7.5, 1H), 7.73 (d,
J = 8 Hz, 1H), 7.50 (d, J = 7.5 Hz, 1H), 7.29 (d, J = 8 Hz, 1 H), 2.32
(s, 3H), 2.31 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 162.2, 152.3,
148.8, 140.2, 136.5, 134.5, 130.1, 129.6, 128.6, 127.4, 126.3, 125.8, 125.1,
120.9, 19.4, 19.3; Exact mass calcd for C16H15N2O [M + H]+ 251.1179,
Found 251.1151.
6-Methoxy-2-phenylquinazolin-4(3H)-one (2c)13a. Eluent:
petroleum ether/ethyl acetate (4:1). Yield: 54% (27 mg). White solid.
1H NMR (400 MHz, DMSO-d6) δ 12.52 (br, 1H), 8.16 (d, J = 6.0 Hz,
2H), 7.70 (d, J = 8.8 Hz, 1 H), 7.55 (s, 4H), 7.45 (d, J = 8.4 Hz, 1H), 3.89
(s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 162.0, 157.7, 150.1, 143.2,
132.8, 131.0, 129.2, 128.5, 127.5, 124.1, 121.8, 105.9, 55.6; Exact mass
calcd for C15H13N2O2 [M + H]+ 253.0972, Found 253.0984.
8-Methyl-2-phenylquinazolin-4(3H)-one (2d)11d. Eluent:
petroleum ether/ethyl acetate (4:1). Yield: 53% (25 mg). White solid.
1H NMR (400 MHz, DMSO-d6) δ 12.53 (br, 1H), 8.22 (d, J = 6.8 Hz,
2H), 8.00 (d, J = 7.6 Hz, 1H), 7.68 (d, J = 6.8 Hz, 1H), 7.56 (m, 3H),
7.38 (t, J = 7.6 Hz, 1H), 2.62 (s, 3H); 13C NMR (125 MHz, DMSO-d6)
δ 162.5, 151.0, 147.1, 135.6, 134.9, 132.9, 131.3, 128.6, 127.7, 126.1,
123.5, 120.9, 17.1; Exact mass calcd for C15H13N2O [M + H]+ 237.1022,
Found 237.1018.
2-Isobutylquinazolin-4(3H)-one (2l)13e. Eluent: petroleum ether/
ethyl acetate (6:1). Yield: 80% (32 mg). White solid. 1H NMR (400 MHz,
DMSO-d6) δ 12.15 (br, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.76 (t, J = 7.6 Hz,
1H), 7.59 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 2.47 (d, J = 7.2 Hz,
2H), 2.18 (m, 1H), 0.92 (d, J = 6.8 Hz, 6H); 13C NMR(125 MHz, DMSO-
d6) δ 161.8, 156.7, 148.9, 134.2, 126.8, 125.9, 125.6, 120.7, 43.3, 27.0, 22.1;
Exact mass calcd for C12H15N2O [M + H]+ 203.1179, Found 203.1195.
2-Isobutyl-7-methylquinazolin-4(3H)-one (2m)13e. Eluent:
petroleum ether/ethyl acetate (6:1). Yield: 74% (32 mg). White solid.
1H NMR (400 MHz, DMSO-d6) δ 12.05 (br, 1H), 7.87 (s, 1H), 7.58
(d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.4 Hz, 1H), 2.45 (d, J = 7.2 Hz, 2H), 2.42
(s, 3H), 2.18 (m, 1H), 0.92 (d, J = 6.8 Hz, 6H); 13C NMR (125 MHz,
DMSO-d6) δ 161.7, 155.8, 146.9, 135.5, 135.4, 126.7, 125.0, 120.5, 43.2,
27.0, 22.1, 20.7; Exact mass calcd for C13H17N2O [M + H]+ 217.1335,
Found 217.1332.
7-Methyl-2-phenylquinazolin-4(3H)-one (2e)13a. Eluent:
petroleum ether/ethyl acetate (4:1). Yield: 72% (34 mg). White solid.
1H NMR (400 MHz, DMSO-d6) δ 12.45 (br, 1H), 8.16 (d, J = 6.8 Hz,
2H), 8.03 (d, J = 8.0 Hz, 1 H), 7.56 (m, 4H), 7.33 (d, J = 8.0 Hz, 1H), 2.46
(s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 162.1, 152.3, 148.8, 145.0,
132.8, 131.3, 128.6, 128.0, 127.7, 127.1, 125.7, 118.6, 21.3; Exact mass
calcd for C15H13N2O [M + H]+ 237.1022, Found 237.1008.
6365
dx.doi.org/10.1021/jo2007362 |J. Org. Chem. 2011, 76, 6362–6366

The Journal of Organic Chemistry
NOTE
2-tert-Butylquinazolin-4(3H)-one (2n)11d. Eluent: petroleum
ether/ethyl acetate (6:1). Yield: 60% (24 mg). White solid. H NMR
Bailey, C. D.; Ford, J. G.; Tyler, S. N. G.; Gagne, M. R.; Lloyd-Jones, G. C.;
Booker-Milburn, K. I. Angew. Chem., Int. Ed. 2009, 48, 1830.
(4) For examples of intramolecular CÀH carbonylation, see:
(a) Haffemayer, B.; Gulias, M.; Gaunt., M. J. Chem. Sci. 2011, 2, 312.
(b) Yoo, E.-J.; Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 17378.
(c) Orito, K.; Horibata, A.; Nakamura, T.; Ushito, H.; Nagasaki, H.;
Yuguchi, M.; Yamashita, S.; Tokuda, M. J. Am. Chem. Soc. 2004,
126, 14342. (d) Lu, Y.; Leow, D.; Wang, X.; Engle, K. M.; Yu, J.-Q.
Chem. Sci. 2011, 2, 967.
1
(400 MHz, DMSO-d6) δ 11.88 (br, 1H), 8.08 (d, J = 7.6 Hz, 1H), 7.77
(t, J = 7.6 Hz, 1H), 7.61 (d, J = 8.0 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H), 1.34
(s, 9H); 13C NMR (125 MHz, DMSO-d6) δ 162.6, 162.3, 148.3, 134.3,
127.3, 126.2, 125.6, 120.6, 37.2, 27.8; Exact mass calcd for C12H15N2O
[M + H]+ 203.1179, Found 203.1185.
2-Benzylquinazolin-4(3H)-one (2o)19. Eluent: petroleum ether/
1
ethyl acetate (7:1). Yield: 60% (28 mg). Yellow solid. H NMR (400
(5) Kung, P. P.; Casper, M. D.; Cook, K. L.; Wilson-Lingard, L.;
Risen, L. M.; Vickers, T. A.; Ranken, R.; Blyn, L. B.; Wyatt, R.; Cook,
P. D.; Ecker, D. J. J. Med. Chem. 1999, 42, 4705.
MHz, DMSO-d6) δ 12.43 (br, 1H), 8.07 (d, J = 7.6 Hz, 1H), 7.77 (t, J =
8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.38 (d, J =
7.8 Hz, 2H), 7.32 (t, J = 7.8 Hz, 2H), 7.24 (t, J = 7.6 Hz, 1H), 3.93 (s, 2H);
13C NMR (125 MHz, DMSO-d6) δ 161.8, 155.9, 148.9, 136.5, 134.4,
128.8, 128.5, 126.9, 126.8, 126.2, 125.7, 120.7, 40.7; Exact mass calcd for
C15H13N2O [M + H]+ 237.1022, Found 237.1017.
(6) (a) Lowe, J. A.; Archer, R. L.; Chapin, D. S.; Cheng, J. B.; Helweg,
D.; Johnson, J. L.; Koe, B. K.; Lebel, L. A.; Moore, P. F.; Nielsen, J. A.;
Russo, L. L.; Shirley, J. T. J. Med. Chem. 1991, 34, 624. (b) de Laszlo,
S. E.; Quagliato, C. S.; Greenlee, W. J.; Patchett, A. A.; Chang, R. S. L.;
Lotti, V. J.; Chen, T.-B.; Scheck, S. A.; Faust, K. A.; Kivlighn, S. S.;
Schorn, T. S.; Zingaro, G. J.; Siegl, P. K. S. J. Med. Chem. 1993, 36, 3207.
(7) Liverton, N. J.; Armstrong, D. J.; Claremon, D. A.; Remy, D. C.;
Baldwin, J. J.; Lynch, R. J.; Zhang, G.; Gould, R. J. Bioorg. Med. Chem.
Lett. 1998, 8, 483.
(8) (a) Jiang, J. B.; Hesson, D. P.; Dusak, B. A.; Dexter, D. L.; Kang,
G. J.; Hamel, E. J. Med. Chem. 1990, 33, 1721. (b) Cao, S. L.; Feng, Y. P.;
Jiang, Y. Y.; Liu, S. Y.; Ding, G. Y.; Li, R. T. Bioorg. Med. Chem. Lett. 2005,
15, 1915.
(9) (a) Habib, O. M.; Moawad, E. B.; Girges, M. M.; El-Shafei, A. M.
Boll. Chim. Farm. 1995, 134, 503. (b) Ibrahim, S. S.; Abdel-Halim, A. M.;
Gabr, Y.; El-Edfawy, S.; Abdel-Rahman, R. J. Chem. Res., Synop. 1997, 154.
(10) Kobayashi, S.; Ueno, M.; Suzuki, R.; Ishitani, H. Tetrahedron
Lett. 1999, 40, 2175.
(11) (a) Eguchi, S. Heterocyl. Chem. 2006, 6, 113. (b) Connolly, D, J.;
Cusack, D.; O’Sullivan, T. P.; Guiry, P. J. Tetrahedron 2005, 61, 10153.
(c) Witt, A.; Bergman, J. Curr. Org. Chem. 2003, 7, 659. (d) Zhang, X. D.;
Ye, D. J.; Sun, H. F.; Guo, D. L.; Wang, J.; Huang, H.; Zhang, X.; Jiang,
H. L.; Liu, H. Green Chem. 2009, 11, 1881. (e) Gupta, S.; Agarwal, P. K.;
Kundu, K. B. Tetrahedron Lett. 2010, 51, 1887.
2-Cyclohexylquinazolin-4(3H)-one (2p)12d. Eluent: petroleum
1
ether/ethyl acetate (6:1). Yield: 77% (35 mg). White solid. H NMR
(400 MHz, DMSO-d6) δ 12.10 (br, 1H), 8.07 (d, J = 7.8 Hz, 1H), 7.76
(t, J = 7.8 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.45 (t, J = 8.0 Hz, 1H), 2.57
(m, 1H), 1.90 (m, 2H), 1.79 (m, 2H), 1.68 (m, 1H), 1.58 (m, 2H), 1.28
(m, 3H); 13C NMR (125 MHz, DMSO-d6) δ 161.9, 160.7, 148.9, 134.2,
126.9, 125.8, 125.6, 120.9, 42.8, 30.2, 25.5, 25.3; Exact mass calcd for
C14H17N2O [M + H]+ 229.1335, Found 229.1338.
2-Methylquinazolin-4(3H)-one(2q)13c. Eluent: petroleum ether/
ethyl acetate (6:1). Yield: 81% (26 mg). White solid. 1H NMR (400 MHz,
DMSO-d6) δ 12.19 (br, 1H), 8.07 (d, J = 6.4 Hz, 1H), 7.76 (t, J = 6.0 Hz,
1H), 7.56 (d, J = 6.4 Hz, 1H), 7.45 (t, J = 6.0 Hz, 1H), 2.34 (s, 3H); 13C
NMR (125 MHz, DMSO-d6) δ 161.7, 154.2, 148.9, 134.2, 126.5, 125.8,
125.6, 120.6, 21.4; Exact mass calcd for C9H9N2O [M + H]+ 161.0709,
Found 161.0725.
’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra of all
the synthesized compounds. This material is available free of
S
b
(12) (a) Wu, H.; Xie, X.; Liu, G. J. Comb. Chem. 2010, 12, 346.
(b) Feng, E.; Zhou, Y.; Zhang, D.; Zhang, L.; Sun, H.; Jiang, H.; Liu, H.
J. Org. Chem. 2010, 75, 3274. (c) Dabiri, M.; Baghbanzadeh, M.; Delbari,
A. S. J. Comb. Chem. 2008, 10, 700. (d) Connolly, D. J.; Guiry, P. J.
Synlett. 2001, 11, 1707.
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(13) (a) Xu, W.; Jin, Y.; Liu, H.; Jiang, H.; Fu, H. Org. Lett. 2011,
13, 1274. (b) Yang, D.; Fu, H.; Hu, L.; Jiang, Y.; Zhao, Y. J. Comb. Chem.
2009, 11, 653. (c) Liu, X.; Fu, H.; Jiang, Y.; Zhao, Y. Angew. Chem., Int. Ed.
2009, 48, 348. (d) Huang, C.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Commun.
2008, 47, 6333. (e) Xu, W.; Fu, H. J. Org. Chem. 2011, 76, 3846.
(14) (a) Zeng, F.; Alper, H. Org. Lett. 2010, 12, 3642. (b) Zeng, F.;
Alper, H. Org. Lett. 2010, 12, 1188. (c) Zheng, Z.; Alper, H. Org. Lett.
2008, 10, 829.
(15) (a) Singh, B.; Collins, J. C. Chem. Commun. 1971, 498.
(b) Ogonor, J. I. Tetrahedron 1981, 37, 2909.
(16) (a) Brasche, G.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008,
47, 1932. (b) Xiao, Q.; Wang, W.-H.; Liu, G.; Meng, F.-K.; Chen, J.-H.;
Yang, Z.; Shi, Z.-J. Chem.—Eur. J. 2009, 15, 7292.
Corresponding Author
*E-mail: zhu_qiang@gibh.ac.cn.
’ ACKNOWLEDGMENT
We are grateful to the National Science Foundation of China
(21072190) and National Basic Research Program of China (973
Program 2011CB504004 and 2010CB945500) for financial
support of this work.
’ REFERENCES
(17) Ried, W.; Valentin., J. Liebigs Ann. 1967, 707, 250.
(18) Potewar, T. M.; Nadaf, R. N.; Daniel, T.; Lahoti, R. J.;
Srinivasan, K. V. Synth. Commun. 2005, 35, 231.
(19) Adib, M.; Ansari, S.; Mohammadi, A.; Bijanzadeh, H. R.
Tetrahedron Lett. 2010, 51, 32.
(1) (a) Skoda-Foldes, R.; Kollar, L. Curr. Org. Chem. 2002, 6, 1097.
(b) Colquhoun, H. M., Thompson, D. J., Twigg, M. V. Carbonylation,
Direct Synthesis of Carbonyl Compounds; Plenum Press: New York, 1991.
(2) For selected recent reviews on transition metal-catalyzed CÀH
functionalization, see: (a) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Rev. 2011,
111, 1293. (b) Lyons, T. W.; Sanford, M. S. Chem. Rev. 2010, 110, 1147.
(c) Ashenhurst, J. A. Chem. Soc. Rev. 2010, 39, 540. (d) Colby, D. A.;
Bergman, R. G.; Ellman, J. A. Chem. Rev. 2010, 110, 624. (e) Ackermann,
L.; Vincente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009, 48, 9792.
(f) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed.
2009, 48, 5094.
(20) Wang, H.; Wang, Y.; Peng, C.; Zhang, J.; Zhu, Q. J. Am. Chem.
Soc. 2010, 132, 13217.
(3) For examples of intermolecular CÀH carbonylation, see: (a) Giri,
R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14082. (b)Giri, R.; Lam, J. K.; Yu,
J.-Q. J. Am. Chem. Soc. 2010, 132, 686. (c) Houlden, C. E.; Hutchby, M.;
6366
dx.doi.org/10.1021/jo2007362 |J. Org. Chem. 2011, 76, 6362–6366