Quinazolinone-directed C-H activation: A novel strategy for the acetoxylation-methoxylation of the arenes

Article abstract of DOI:10.1055/s-0031-1290962

2-Aryl-4-quinazolinones undergo smooth acetoxylation in the presence of 5 mol% Pd(OAc)and a stoichiometric amount of PhI(OAc)via C-H activation to produce the corresponding acetoxy-substituted 4(3H)-quinazolinone derivatives in good yields with high regioselectivity. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290962

1364▌
LETTER
letter
Quinazolinone-Directed C–H Activation: A Novel Strategy for the
Acetoxylation–Methoxylation of the Arenes
Quinazolinone-Directed C–H Activation
B. V. Subba Reddy,* G. Narasimhulu, N. Umadevi, J. S. Yadav
Natural Product Chemistry, Indian Institute of Chemical Technology, Hyderabad 500007, India
Fax +91(40)27160512; E-mail: basireddy@iict.res.in
Received: 29.02.2012; Accepted after revision: 15.03.2012
rect functionalization of unactivated C–H bonds.7,8 How-
ever, direct functionalization of substrates with similar C–
H bonds tends to require a directing group.9 The majority
of the directing groups are often difficult to attach or re-
move, thus limiting these protocols to particular types of
substrates.10 Consequently, substrate directed C–H bond
activation has received a considerable interest. However,
the oxidation of aromatic C–H bonds is a challenging task
in organic synthesis.11 Furthermore, there are no reports
on the oxidative functionalization of aryl-substituted
quinazolinones by means of a dual activation of both am-
ide and ortho-chelating imine group.
Abstract: 2-Aryl-4-quinazolinones undergo smooth acetoxylation
in the presence of 5 mol% Pd(OAc)2 and a stoichiometric amount of
PhI(OAc)2 via C–H activation to produce the corresponding ace-
toxy-substituted 4(3H)-quinazolinone derivatives in good yields
with high regioselectivity.
Key words: 2-aryl-4-quinazolinone, hypervalent iodine reagent,
acetoxylation, C–H activation
4(3H)-Quinazolinone derivatives have attracted much at-
tention in medicinal chemistry because of their wide spec-
trum of pharmacological activities1 including anticancer,2
anti-inflammatory,3 anticonvulsant,4a antimicrobial,4b,c
and antidiuretic activities.5 Some of the quinazolinone de-
rivatives were found to be potent non-nucleoside reverse
transcriptase inhibitors (NNRTIs) of human immunodefi-
ciency virus type-1 (HIV-1).6a Therefore, there is a great
demand for the generation of novel quinazolinone librar-
ies for biological evaluation (Figure 1).6b,c
Following our interest on direct functionalization of
arenes via C–H activation,12 we herein report a novel
strategy for the acetoxylation–methoxylation of arenes by
means of substrate-directed C–H activation using
Pd(OAc)2/PhI(OAc)2. The starting 2-aryl-4-quinazoli-
nones were prepared by a known procedure.13 According-
ly, we first attempted monoacetoxylation of 2-phenyl-
4(3H)-quinazolinone using 1.1 equivalents of PhI(OAc)2
and 1.1 equivalents of Ac2O in the presence of 5 mol%
Pd(OAc)2. The reaction proceeds smoothly in 1,2-dichlo-
roethane (DCE) at reflux temperature and provides the
monoacetoxylated product 3a in 83% yield (Scheme 1).
N
Cl
O
N
N
Similarly, various substituted 2-aryl-4(3H)-quinazoli-
nones such as 4-methyl, 4-bromo, 4-nitro, 3-tert-butyldi-
methylsilyloxy, and 3-phenoxy derivatives underwent
smooth acetoxylation under the above reaction conditions
(Table 1). In case of the substrates bearing 3-phenoxy-
and 3-tert-butyldimethylsilyloxy substituents, acetoxyl-
ation took place selectively at less sterically hindered or-
tho position (entries 5 and 6, Table 1). It is noteworthy to
mention that no dehalogenation was observed in case of
halogenated substrates (entries 3, Table 1 and Table 2).
Furthermore, the reaction was successful even with N-
methyl-4-quinazolinone (entry 7, Table 1).
OMe
ghrelin receptor antagonist
HN
O
N
O
N
N
OMe
vasopressin V1b receptor antagonist
In this C–H activation, Pd(OAc)2 acts as a catalyst to ac-
tivate aromatic C–H bond via quinazolinone-directed ox-
idative insertion. PhI(OAc)2 acts as an oxidant to
reoxidize Pd(0) to Pd(II). Ac2O acts as an acetoxylating
agent. The acetoxylation of 2-phenyl-4(3H)-quinazoli-
none was highly ortho selective and provides the acetox-
ylated products in good yields. The efficiency of other co-
oxidants such as AgOAc, Cu(OAc)2, Mn(OAc)3, and ben-
zoquinone was tested for this reaction. To our surprise, the
yields were far from satisfactory when the reactions were
carried out with the above co-oxidants. Thus PhI(OAc)2
Figure 1 Representative examples of biologically active 2-aryl-4-
quinazolinones
In recent years, palladium-catalyzed ligand-directed C–H
bond activation has emerged as a powerful tool for the di-
SYNLETT 2012, 23, 1364–1370
Advanced online publication: 14.05.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0031-1290962; Art ID: ST-2012-D0180-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Quinazolinone-Directed C–H Activation
1365
O
O
N
O
NH
Pd(OAc)2 (5 mol%)
Ac2O, DCE, reflux
NH
O
PhI(OAc)2
+
N
3a
2
1
Scheme 1 Monoacetoxylation of 2-phenyl-4(3H)-quinazolinone
was found to be effective in terms of conversion. Acetox- we performed the acetoxylation at various temperatures in
ylation was also performed using various amounts of various solvents. The reaction proceeds well in refluxing
Pd(OAc)2. Under optimized conditions, the acetoxylation 1,2-dichloroethane. The reaction was found to be sluggish
typically requires 5 mol% Pd(OAc)2 and a stoichiometric either in toluene or in 1,4-dioxane. As solvent, DCE gave
amount of PhI(OAc)2 to achieve good conversions. Next the best results.
Table 1 Pd(OAc)2-Catalyzed Acetoxylation or Methoxylation of 2-Aryl-4(3H)-quinazolinone
Product 3a
Yield (%)b
83
Entry
1
Quinazolinone 1
Time (h)
8.0
O
O
NH
NH
NH
NH
N
OAc
OAc
OAc
N
1a
3a
O
O
2
3
4
7.6
89
80
75
NH
N
N
3b
1b
O
O
8.3
NH
N
N
Br
Br
1c
3c
O
O
10.0
NH
NH
N
OAc
N
NO2
NO2
3d
1d
O
O
5
9.0
82
NH
N
NH
OAc
N
OTBS
OTBS
1e
3e
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1364–1370

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B. V. S. Reddy et al.
LETTER
Table 1 Pd(OAc)2-Catalyzed Acetoxylation or Methoxylation of 2-Aryl-4(3H)-quinazolinone (continued)
Product 3a
Yield (%)b
80
Entry
6
Quinazolinone 1
Time (h)
9.4
O
O
NH
N
NH
OAc
OPh
N
OPh
1f
3f
O
O
7
8
5.3
6.2
83
Me
N
Me
N
N
N
AcO
1g
3g
3h
O
O
N
80c
NH
N
NH
OMe
1h
a All products were characterized by NMR, IR, and MS.
b Yield refers to pure products after chromatography.
c Methoxylation was performed using PhI(OAc)2 in MeOH.
However, bisacetoxylation was observed by increasing tives participated well in bisacetoxylation. The results of
the amount of the oxidant and acetic anhydride because of the bisacetoxylation are summarized in Table 2.
dual activation of arene by amide and imine groups of
quinazolinone. For example, treatment of 2-phenyl-
4(3H)-quinazolinone with 2.2 equivalents Of PhI(OAc)2
Next, we extended this method to study the methoxylation
of 2-aryl-4(3H)-quinazolinone. Accordingly, treatment of
2-p-tolyl-4(3H)-quinazolinone with a stoichiometric
and 2.2 equivalents of Ac2O in the presence of 5 mol%
amount of PhI(OAc)2 and 5 mol% Pd(OAc)2 in refluxing
Pd(OAc)2 afforded the bisacetoxy product 4a in 80%
methanol gave the monomethoxy product 3h in 80%
yield (Scheme 2).
yield. Thus, methoxylation of arenes was achieved by
Similarly, various 2-aryl-4(3H)-quinazolinone such as 4- merely changing the solvent from DCE to methanol
methyl-, 4-chloro-, 4-methoxy-, and 3,5-dimethyl deriva- (Scheme 3).
O
N
O
O
O
N
NH
O
NH
Pd(OAc)2 (5 mol%)
Ac2O, DCE, reflux
PhI(OAc)2
+
O
1
2
4a
Scheme 2 Bisacetoxylation of 2-phenyl-4(3H)-quinazolinone
O
O
NH
Pd(OAc)2 (5 mol%)
MeOH, reflux
NH
OMe
PhI(OAc)2
+
N
N
2
1
3h
Scheme 3 Monomethoxylation of 2-p-tolyl-4(3H)-quinazolinone
Synlett 2012, 23, 1364–1370
© Georg Thieme Verlag Stuttgart · New York

LETTER
Quinazolinone-Directed C–H Activation
1367
Notably, bismethoxylation of phenyl-4(3H)-quinazoli- IR, and MS. The scope and generality of this process is il-
none was observed when the reaction was performed with lustrated with respect to various 2-aryl-4(3H)-quinazoli-
2.2 equivalents of PhI(OAc)2 and 5 mol% Pd(OAc)2 in nones bearing electron-rich as well as electron-deficient
methanol at reflux temperature (entry 6, Table 2). Similar- substituents on aromatic ring, and the results are presented
ly, various 2-aryl-4(3H)-quinazolinone derivatives bear- in Table 1 and 2.14 Finally, the cleavage of 2-aryl-4-quin-
ing substitutions at ortho, meta, and para positions azolinone was achieved using lithium in liquid ammo-
participated well in oxidative functionalization. No acet- nia.15 In this reductive cleavage, a mixture of 2-
oxylation was observed in the absence of either Pd(OAc)2 hydroxybenzamide and anthranilamide was obtained as
or PhI(OAc)2. The products were characterized by NMR,
Table 2 Pd(OAc)2-Catalyzed Bisacetoxylation or Bismethoxylation of 2-Aryl-4(3H)-quinazolinone
Product 4a
Yield (%)b
80
Entry
1
Quinazolinone 1
Time (h)
8.0
O
O
NH
NH
NH
NH
NH
OAc
OAc
OAc
OAc
OAc
NH
N
N
AcO
1a
4a
4b
4c
4d
O
O
2
3
4
5
7.8
8.5
7.2
8.5
87
80
86
83
NH
N
N
AcO
1b
O
O
NH
N
N
Cl
Cl
AcO
1c
O
O
NH
N
N
AcO
OMe
OMe
1d
O
O
NH
N
N
AcO
1e
4e
O
O
N
85c
6
6.0
NH
N
NH
OMe
MeO
1f
4f
a All products were characterized by NMR, IR, and MS.
b Yield refers to pure products after chromatography.
c Methoxylation was performed using PhI(OAc)2 in MeOH.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1364–1370

1368
B. V. S. Reddy et al.
LETTER
M. M.; Moawad, E. B.; el-Shafei, A. M. Boll. Chim. Farm.
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product.
Mechanistically, the reaction was assumed to proceed via
the formation of five-membered transition state by an ox-
idative insertion of Pd(II) into the aromatic C–H bond as
depicted in Scheme 4. Thus formed palladacyle might be
stabilized with an amide group to induce the ortho acetox-
ylation. The resulting Pd(0) could be reoxidized to Pd(II)
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PhI(OAc)2
Pd(0)
Pd(II)
O
N
NH
O
N
NH
C–H activation
O
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AcO
NH
N
Pd
AcO
Scheme 4 A plausible reaction pathway
In summary, we have developed a novel protocol for the
oxidative functionalization of 2-aryl-4(3H)-quinazoli-
nones via C–H activation. The method is very useful not
only for acetoxylation but also for methoxylation of aro-
matic systems. By using this method, both electron-rich as
well as electron-deficient 2-aryl-4-quinazolinones could
be successfully derivatized by C–H activation.
Acknowledgment
G.N.L. thanks CSIR, N.U. thanks UGC, New Delhi for the award of
fellowships. J.S.Y. acknowledges the partial support by King Saud
University for Global Research Network for Organic Synthesis
(GRNOS).
References and Notes
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Trivedi, B. K.; Webdale, L. J. Med. Chem. 1998, 41, 1042.
(2) Xia, Y.; Yang, Z. Y.; Hour, M. J.; Kuo, S. C.; Xia, P.;
Bastow, K. F.; Nakanishi, Y.; Nampoothiri, P.; Hackl, T.;
Hamel, E.; Lee, K. H. Bioorg. Med. Chem. Lett. 2001, 11,
1193.
(3) Kenichi, O.; Yoshihisa, Y.; Toyonari, O.; Toru, I.; Yoshio, I.
J. Med. Chem. 1985, 28, 568.
(4) (a) Buchanan, J. G.; Sable, H. Z. In Selective Organic
Transformations, Vol. 2; Thyagarajan, B. S., Ed.; Wiley:
New York, 1972, 1–95. (b) Khalil, M. A.; Habib, N. S.
Farmaco, Ed. Sci. 1987, 42, 973. (c) Habib, O. M.; Girges,
(10) (a) Wasa, M.; Worrell, B. T.; Yu, J.-Q. Angew. Chem. Int.
Ed. 2010, 49, 1275. (b) Chernyak, N.; Dudnik, A. S.;
Huang, C.; Gevorgyan, V. J. Am. Chem. Soc. 2010, 132,
8270.
(11) (a) Desai, L. V.; Ren, D. T.; Rosner, T. Org. Lett. 2010, 12,
1032. (b) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am.
Synlett 2012, 23, 1364–1370
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chem. Soc. 2004, 126, 2300. (c) Wang, G.-W.; Yuan, T.-T.;
Quinazolinone-Directed C–H Activation
1369
m/z = 281 [M + H], 303 [M + Na].
Wu, X.-L. J. Org. Chem. 2008, 73, 4717. (d) Wang, G.-W.;
Yuan, T.-T. J. Org. Chem. 2010, 75, 476. (e) Stowers, K. J.;
Sanford, M. S. Org. Lett. 2009, 11, 4584. (f) Desai, L. V.;
Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141.
(g) Kalyani, D.; Sanford, M. S. Org. Lett. 2005, 7, 4149.
(12) (a) Reddy, B. V. S.; Reddy, L. R.; Corey, E. J. Org. Lett.
2006, 8, 3391. (b) Reddy, B. V. S.; Ramesh, K.; Yadav, J. S.
Synlett 2011, 169. (c) Reddy, B. V. S.; Revathi, G.; Reddy,
A. S.; Yadav, J. S. Synlett 2011, 2374.
Compound 3b (Table 1): solid, mp 198–200 °C. IR (neat):
max = 3446, 2923, 2853, 1773, 1743, 1671, 1605, 1462,
ν
1371, 1258, 1191, 1077, 1021, 965, 773 cm–1. 1H NMR (300
MHz, CDCl3): δ = 2.08 (s, 3 H), 2.33 (s, 3 H), 7.07 (s, 1 H),
7.20–7.28 (m, 1 H), 7.44–7.57 (m, 1 H), 7.75–7.83 (m, 2 H),
7.91 (d, 1 H, J = 7.9 Hz), 8.28 (d, 1 H, J = 8.3Hz). 13C NMR
(75 MHz, CDCl3): δ = 21.1, 21.4, 114.2, 122.5, 124.2, 126.4,
126.9, 127.4, 127.8, 128.1, 130.1, 134.8, 143.3, 148.3,
149.7, 162.9, 168.9. ESI-MS: m/z = 295 [M + H], 317 [M +
Na].
(13) Abdel-Jalil, R. J.; Voelter, W.; Saeed, M. Tetrahedron Lett.
2004, 45, 3475.
Compound 3c (Table 1): solid, mp 159–160 °C. IR (neat):
νmax = 3353, 3222, 2923, 2854, 1689, 1592, 1478, 1396,
1211, 1164, 1052, 936, 759, 682 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 2.06 (s, 3 H), 7.36–7.60 (m, 3 H), 7.62–7.81 (m,
3 H), 8.23 (d, 1 H, J = 7.9 Hz). ESI-MS: m/z = 359 [M + H],
381 [M + Na].
Compound 3d (Table 1): solid, mp 272–274 °C. IR (KBr):
νmax = 2923, 2853, 1782, 1687, 1609, 1467, 1348, 1296,
1178, 1053, 941, 889, 771 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 2.58 (s, 3 H), 7.48–7.58 (m, 2 H), 7.77–7.85 (m,
2 H), 8.23–8.31 (m, 2 H), 8.34 (d, 1 H, J = 8.9 Hz), 8.50 (d,
1 H, J = 7.9 Hz). ESI-MS: m/z = 326 [M + H], 348 [M + Na].
HRMS: m/z calcd for C16H12N3O5: 326.0771; found:
326.0784.
(14) Preparation of 2-Aryl-4(3H)-quinazolinone (1)
To a mixture of anthranilimide (544 mg, 4.0 mmol) and
benzaldehyde (470 mg, 4.4 mmol) in EtOH (20 mL) was
added CuCl2 (804 mg, 6 mmol) at 25 °C. The resulting
mixture was stirred under reflux for 3 h as required to
complete the reaction. After complete conversion, as
indicated by TLC, the solvent was removed in vacuo, and the
mixture was diluted with H2O and extracted with EtOAc
(3 × 15 mL). The combined organic layers were dried over
anhyd Na2SO4, concentrated in vacuo, and purified by
column chromatography on silica gel (Merck, 60–120 mesh,
EtOAc–hexane = 4:6) to afford the pure quinazolinone (1,
Scheme 5).
Compound 3e (Table 1): solid, mp 118–119 °C. IR (KBr):
ν
max = 3424, 3137, 3063, 2928, 2856, 1760, 1671, 1574,
O
O
1508, 1471, 1364, 1256, 1199, 992, 926, 838, 777 cm–1. 1H
NMR (300 MHz, CDCl3): δ = 0.26 (s, 6 H), 1.02 (s, 9 H),
2.30 (s, 3 H), 6.97 (d, 1 H, J = 8.9 Hz), 7.09 (d, 1 H, J = 8.9
Hz), 7.43–7.56 (m, 2 H), 7.72–7.83 (m, 2 H), 8.27 (d, 1 H,
J = 6.9 Hz), 10.53 (br s, 1 H). 13C NMR (75 MHz, CDCl3):
δ = –4.4, 18.1, 21.0, 25.5, 121.2, 120.9, 123.3, 124.5, 126.5,
127, 127.8, 134.7, 142.3, 149, 149.6, 153.7, 162.6, 169.2.
ESI-MS: m/z = 411 [M + H], 433 [M + Na]. HRMS: m/z
calcd for C22H27N2O4Si: 411.1740; found: 411.1722.
Compound 3f (Table 1): solid, mp 256–258 °C. IR (KBr):
νmax = 2924, 2855, 1766, 1670, 1602, 1467, 1369, 1302,
1190, 1070, 1012, 902, 746 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 2.31 (s, 3 H), 7.03–7.21 (m, 3 H), 7.28–7.60 (m,
5 H), 7.67–7.73 (m, 2 H), 7.81–7.86 (m, 1 H), 8.15 (d, 1 H,
J = 7.5 Hz), 10.79–10.93 (br s, 1 H). 13C NMR (75 MHz,
CDCl3): δ = 21, 96.1, 111.8, 114.2, 119, 120.3, 122, 122.9,
123.8, 124.9, 126.5, 127.1, 127.8, 128.2, 129.9, 134.7,
143.8, 148.9, 155.1, 156.6, 162.9, 168.8; ESI-MS: m/z = 373
[M + H], 395 [M + Na]. HRMS: m/z calcd for C22H17N2O4:
373.1183; found: 373.1198.
Compound 3g (Table 1): solid, mp 176–178 °C. IR (neat):
νmax = 3445, 2925, 2854, 1770, 1744, 1677, 1597, 1467,
1422, 1363, 1255, 1196, 1125, 1037, 894, 829, 774, 698 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.08 (s, 3 H), 2.45 (s, 3 H),
3.44 (s, 3 H), 7.12 (s, 1 H), 7.20 (d, 1 H, J = 7.5 Hz), 7.37 (d,
1 H, J = 8.3 Hz), 7.44–7.57 (m, 2 H), 7.72–7.79 (m, 1 H),
8.34 (d, 1 H, J = 7.5 Hz). 13C NMR (75 MHz, CDCl3): δ =
21.4, 24.8, 33.3, 114.2, 123.6, 126.6, 127, 127.1, 127.5, 129,
129.6, 131.9, 134.2, 141.9, 144.1, 147.6, 162.5, 168.7. ESI-
MS: m/z = 309 [M + H], 331 [M + Na].
H
CuCl2
NH
NH2
O
+
EtOH, reflux
N
NH2
1
Scheme 5
(15) Typical Procedures
(i) Monoacetoxylation
A mixture of 2-aryl-4(3H)-quinazolinone (1 mmol),
iodobenzenediacetate (1.1 mmol), Ac2O (1.1 mmol), and
Pd(OAc)2 (5 mol%) in DCE (5 mL) was stirred under reflux
for a specified time (Table 1). After complete conversion, as
indicated by TLC, the reaction mixture was diluted with H2O
(10 mL) and extracted with CH2Cl2 (3 × 10 mL). The
combined organic layers were dried over anhyd Na2SO4,
concentrated in vacuo, and purified by column chroma-
tography on silica gel (Merck, 60–20 mesh, EtOAc–hexane
= 4:6) to afford pure monoacetoxy quinazolinone derivative.
(ii) Bisacetoxylation
A mixture of 2-aryl-4(3H)-quinazolinone (1 mmol),
iodobenzenediacetate (2.2 mmol), Ac2O (2.2 mmol), and
Pd(OAc)2 (5 mol%) in DCE (5 mL) was stirred at reflux
temperature for a specified time (Table 2). After complete
conversion, as indicated by TLC, the reaction mixture was
diluted with H2O (10 mL) and extracted with CH2Cl2 (3 × 10
mL). The combined organic layers were dried over anhyd
Na2SO4, concentrated in vacuo, and purified by column
chromatography on silica gel (Merck, 60–20 mesh, EtOAc–
hexane = 4:6) to afford pure bisacetoxy quinazolinone
derivative. The products thus obtained were characterized by
IR, NMR, and MS and also by physical constants.
Compound 3h (Table 1): solid, mp 156–58 °C. IR (neat):
ν
max = 3425, 3316, 2923, 2853, 1681, 1590, 1555, 1463,
1317, 1253, 1168, 1026, 951, 745 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 2.43 (s, 3 H), 4.07 (s, 3 H), 6.82 (s, 1 H), 6.94
(d, 1 H, J = 8.1 Hz), 7.37–7.47 (m, 1 H), 7.67–7.79 (m, 2 H),
8.24 (d, 1 H, J = 7.9 Hz), 8.44 (d, 1 H, J = 7.9 Hz), 10.81–
11.00 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 21.7, 55.9,
102.4, 112.3, 122.5, 126, 126.2, 127.5, 131.2, 134.2, 134.4,
144.1, 149.3, 150.7, 157.5, 161.8. ESI-MS: m/z = 267 [M +
H], 289 [M + Na]. HRMS: m/z calcd for C16H15N2O2:
Compound 3a (Table 1): solid, mp 188–190 °C. IR (neat):
ν
max = 3081, 2926, 1675, 1598, 1546, 1496, 1446, 1336,
1220, 1173, 1063, 939, 826, 767 cm–1. 1H NMR (500 MHz,
CDCl3): δ = 2.33 (s, 3 H), 7.26 (d, 1 H, J = 7.6 Hz), 7.42 (t,
1 H, J = 7.6 Hz), 7.49 (t, 1 H, J = 6.6 Hz), 7.55 (t, 1 H,
J = 6.6 Hz), 7.73–7.82 (m, 2 H), 8.08 (d, 1 H, J = 7.6 Hz),
8.26 (d, 1 H, J = 7.6 Hz), 10.54–10.65 (br s, 1 H). ESI-MS:
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 1364–1370

1370
B. V. S. Reddy et al.
LETTER
267.1128; found: 267.1160.
Compound 4a (Table 2): solid, mp 183–184 °C. IR (KBr):
7.44–7.56 (m, 1 H), 7.68–7.80 (m, 2 H), 8.28 (d, 1 H, J = 7.9
Hz), 9.43 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 15.8,
20.2, 121.1, 121.3, 126.4, 127.2, 127.7, 129.3, 134.6, 145.3,
147.1, 148.6, 161.3, 168.7. ESI-MS: m/z = 367 [M + H], 389
[M + Na].
Compound 4f (Table 2): solid, mp 199–201 °C. IR (KBr):
νmax = 3452, 3159, 2923, 2855, 1659, 1596, 1467, 1295,
1250, 1111, 1022, 939, 893, 757 cm–1. 1H NMR (300 MHz,
CDCl3): δ = 3.76 (s, 6 H), 6.60 (d, 2 H, J = 8.3 Hz), 7.36 (t,
1 H, J = 8.3 Hz), 7.46 (t, 1 H, J = 7.3 Hz), 7.76 (d, 2 H,
J = 6.4 Hz), 8.15–8.30 (m, 1 H), 10.21 (br s, 1 H). 13C NMR
(75 MHz, CDCl3): δ = 29.6, 55.9, 104.0, 112.3, 126.3, 126.7,
127.8, 132.0, 134.4, 149.1, 149.4, 158.4, 162.7. ESI-MS: m/z
= 283 [M + H]. HRMS: m/z calcd for C16H15N2O3: 283.1082;
found: 283.1075.
ν
max = 3429, 3187, 3074, 2923, 2854, 1770, 1657, 1606,
1463, 1364, 1281, 1189, 1032, 937, 854, 781 cm–1. 1H NMR
(300 MHz, CDCl3): δ = 2.15 (s, 6 H), 7.20 (d, 2 H, J = 8.1
Hz), 7.49–7.60 (m, 2 H), 7.80 (d, 2 H, J = 3.6 Hz), 8.30 (d, 1
H, J = 7.7 Hz). 13C NMR (75 MHz, CDCl3): δ = 20.7, 120.6,
120.9, 126.5, 127.5, 131.5, 134.8, 146.7, 148.4, 149.1,
161.9, 168.6. ESI-MS: m/z = 339 [M + H], 361 [M + Na].
HRMS: m/z cald for C18H14N2O5Na: 361.0800; found:
361.0788.
Compound 4b (Table 2): solid, mp 323–325 °C. IR (KBr):
νmax = 3178, 3068, 2923, 2855, 1779, 1660, 1620, 1467,
1366, 1283, 1190, 1057, 936, 878, 776 cm–1. 1H NMR (300
MHz, CDCl3): δ = 2.16 (s, 6 H), 2.46 (s, 3 H), 6.96 (s, 2 H),
7.46–7.56 (m, 1 H), 7.64–7.83 (m, 2 H), 8.28 (d, 2 H, J = 8.3
Hz), 9.58 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 20.7,
29.6, 121.6, 126.6, 127.4, 127.7, 134.8, 142.9, 146.7, 148.7,
148.9, 161.6, 168.9. ESI-MS: m/z = 353 [M + H], 375 [M +
Na].
(16) Reductive Cleavage of 2-Aryl-4(3H)-quinazolinone
A solution of 3a (400 mg, 1.43 mmol) in anhyd THF (8 mL)
and liquid NH3 (20 mL) was treated with lithium metal (60
mg, 8.5 mmol) at –78 °C (Scheme 6). After stirring for 20
min, the mixture was quenched with solid NH4Cl (1.5 g).
The color of the mixture was turned from blue to colorless.
Excess NH3 was allowed to evaporate, and the residual
mixture was quenched with H2O (5 mL) and Et2O (5 mL).
The organic layers were separated, and the aqueous layer
was extracted with Et2O (3 × 5 mL). The combined organic
layers were dried over anhyd Na2SO4 and concentrated
under reduced pressure. The resulting crude product was
purified by column chromatography on silica gel to give
ortho-hydroxybenzamide as yellow color oil. Rf = 0.5 (SiO2,
30% EtOAc in hexane).
Compound 4c (Table 2): solid, mp 197–199 °C. IR (KBr):
ν
max = 3182, 3071, 2923, 2853, 1784, 1762, 1656, 1600,
1468, 1364, 1272, 1180, 1145, 1048, 938, 875, 780, 690 cm–1.
1H NMR (300 MHz, CDCl3): δ = 2.13 (s, 6 H), 7.29 (s, 2 H),
7.43–7.56 (m, 2 H), 7.65–7.81 (m, 2 H), 8.26 (d, 1 H, J = 7.7
Hz). ESI-MS: m/z = 373 [M + H]. HRMS: m/z calcd for
C18H13N2O5NaCl: 395.0410; found: 395.0395.
Compound 4d (Table 2): solid, mp 178–180 °C. IR (neat):
νmax = 2923, 2853, 1785, 1664, 1603, 1466, 1369, 1296,
1181, 1047, 833, 774 cm–1. 1H NMR (300 MHz, CDCl3):
δ = 2.17 (s, 6 H), 3.86 (s, 3 H), 6.71 (s, 2 H), 7.48–7.57 (m,
1 H), 7.78 (d, 2 H, J = 3.6 Hz), 8.29 (d, 1 H, J = 7.9 Hz). 13
C
O
O
NMR (75 MHz, CDCl3): δ = 20.8, 55.9, 107.1, 126.6, 127.4,
134.9, 138.4, 139.2, 146.8, 150.2, 161.6, 163.9, 168.7. ESI-
MS: m/z = 369 [M + H]. HRMS: m/z calcd for C19H17N2O6:
369.1081; found: 369.1083.
Compound 4e (Table 2): solid, mp 165–166 °C. IR (KBr):
νmax = 3331, 2924, 2855, 1761, 1681, 1602, 1465, 1368,
1310, 1190, 1081, 971, 937, 887, 771 cm–1. 1H NMR (300
MHz, CDCl3): δ = 2.14 (s, 6 H), 2.18 (s, 6 H), 7.23 (s, 1 H),
OH
O
NH OAc
Li, liquid NH3
THF, 80%
NH2
NH2
+
N
NH2
3a
Scheme 6
Synlett 2012, 23, 1364–1370
© Georg Thieme Verlag Stuttgart · New York

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