Facile synthesis of 2-substituted-quinazolin-4-(3H)-ones promoted by SmI2

Article abstract of DOI:10.1081/SCC-100000519

Mediated by SmI₂,2-substituted-quinazolin-4-(3H)-ones are readily accessible in fair yields by reaction of N,N-diethyl-o-nitrobenzamide with appropriate aryl and benzyl nitriles.

Full text of DOI:10.1081/SCC-100000519

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FACILE SYNTHESIS OF 2-SUBSTITUTED-QUINAZOLIN-4-
(3H)-ONES PROMOTED BY SmI2
Xiaoliang Xu a , Ping Lu a & Yongmin Zhang b
a Department of Chemistry , Zhejiang University (Xixi Campus) , Hangzhou, 310028,
People's Republic of China
b Department of Chemistry , Zhejiang University (Xixi Campus) , Hangzhou, 310028,
People's Republic of China
Published online: 09 Nov 2006.
To cite this article: Xiaoliang Xu , Ping Lu & Yongmin Zhang (2001) FACILE SYNTHESIS OF 2-SUBSTITUTED-QUINAZOLIN-4-
(3H)-ONES PROMOTED BY SmI2 , Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 31:3, 323-327, DOI: 10.1081/SCC-100000519
To link to this article: http://dx.doi.org/10.1081/SCC-100000519
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SYNTHETIC COMMUNICATIONS, 31(3), 323–327 (2001)
FACILE SYNTHESIS OF 2-SUBSTITUTED-
QUINAZOLIN-4-(3H)-ONES PROMOTED
BY SmI2
Xiaoliang Xu, Ping Lu, and Yongmin Zhang∗
Department of Chemistry, Zhejiang University (Xixi
Campus), Hangzhou, 310028, People’s Republic of China
ABSTRACT
Mediated by SmI2, 2-substituted-quinazolin-4-(3H)-ones are
readily accessible in fair yields by reaction of N,N-diethyl-o-
nitrobenzamide with appropriate aryl and benzyl nitriles.
The chemistry of samarium (II) iodide (SmI2) is of current interest in or-
ganic synthesis (1–6). Since its introduction by Kagan and his group, SmI2 has
been extensively investigated as a mild, neutral, selective, versatile, and ether-
soluble one-electron transfer reductant in synthetic chemistry (7). Barbier reac-
tions (8,9), Reformatsky reactions (10,11), the homocoupling allylic or benzylic
halides (12,13), acid chlorides, (14), carbonyl compounds (15,16), the reduction of
organohalo compounds (17,18), etc., have been reported using SmI2 as a reagent.
The reactivity of SmI2 toward various nitrogen compounds including nitro cou-
pounds (19–21), azo coupounds (22), hydrazones (20,23), oximes (20), imines
(20), azides (24–26), and hydroxylamines (27) has been examined. The cyano
group, however, is more stable to samarium diiodide than is a nitro group and could
not be reduced by this reagent. Souppe and Kagan (20) reported that aromatic and
∗Corresponding author.
323
Copyright ꢀ 2001 by Marcel Dekker, Inc.
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C

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XU, LU, AND ZHANG
aliphatic nitriles are inert in the presence of SmI2, and m- or p-nitrobenzonitrile
could be selectively reduced to the corresponding cyanoanilines in almost quanti-
tative yields.
Quinazolin-4-(3H)-ones or the tautomeric hydroxyquinazolines, especially
their 2-aryl or alkyl derivatives, are a class of fused heterocycles of considerable
interest due to the remarkable diversity of their biological activities (28). Indeed,
some of these compounds possess soporofic, diuretic, and antiinflammatory prop-
erties, and may be further modified in the construction of new pharmaceutical
entities (29). Unfortunately, synthetic methods for the elaboration of this bicyclic
system of rather simple structure are not general in scope, and involve multistep,
and often low-yielding, reaction sequences. The main synthetic approaches to
such compounds consist of preliminary amidation of 2-aminobenzonitrile (30),
2-aminobenzoic acid (28), or ethyl 2-aminobenzoate (31). The oxidative ring clo-
sure of intermediates under acidic conditions affords the quinazolinones in vari-
ous yields (32). The compounds are also accessible by aza-Wittig reactions from
α-azido-substituted aromatic imides (33,34) or from aromatic iminophosphoranes
and isocyanates (35). Different one-step syntheses have been described, but the
condensation of 2-aminobenzoic acid with amides (36), thioamides (37), or ni-
triles requires either high temperatures or must be affected in a sealed tube at
200◦C (38).
Here we report a novel method for the synthesis of 2-aryl and 2-benzyl-
quinazolin-4-(3H)-ones (Sch. 1). Table 1 summarizes our results on the reaction
of N,N-diethyl-o-nitrobenzamide and appropriate aromatic and benzyl nitriles with
SmI2 to give 2-aryl and 2-benzyl-quinazolin-4-(3H)-ones in fair yields. However,
N,N-diethyl-o-nitrobenzamide failed to react with acetonitrile to give a similar
product under the same conditions. We found that the results were satisfactory
when two substrates were treated with SmI2 in dry THF under −20◦C at the
beginning of reactions.
In conclusion, we believe that the above work provides a useful method for
the preparation of 2-substituted-quinazolin-4-(3H)-ones. The remarkable advan-
tages of this reaction are neutral and mild reaction conditions and simple opera-
tion. Further studies to synthesize these types of compounds using SmI2 are now
in progress in our laboratory.
O
CONEt2
Sml2 / THF
NH
+ RCN
−20°C
R.T.
NO2
N
R
then reflux for one hour
Scheme 1.

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SYNTHESIS OF 2-SUBSTITUTED-QUINAZOLIN-4-(3H)-ONES
325
Table 1.
Entry
R
Yield (%)a
1a
1b
1c
1d
1e
1f
1g
1h
1i
Ph
PhCH2
m-CH3C6H4
p-ClC6H4
3,4-(OCH2O)C6H3
2,4-dichloroC6H3
p-MeOC6H4
p-CH3C6H4
CH3
68
61
63
75
58
55
64
63
0b
aN,N-diethyl-o-nitrobenzamide
1
mmol, nitriles
1.5 mmol, SmI2 6 mmol were used. Yields based
on N,N-diethyl-o-nitrobenzamide.
bthe reaction was studied under 0◦C, 20◦C, and re-
fluxing conditions.
EXPERIMENTAL
Tetrahydrofuran was distilled from sodium benzophenone immediately prior
to use. All reactions were conducted under a nitrogen atomsphere. Melting points
1
are uncorrected. H NMR spectra were recorded on a Bruker AC 80 instrument
as DMSO-d6 solutions using TMS as internal standard. IR spectra were deter-
mined on a PE-683 spectrometer. Mass spectra were obtained on a HP 5989A
mass spectrometer using electron-impact mode (70 eV). Elemental analyses were
performed on a Carlo Erba 1106 instrument. Metallic samarium and all solvents
were purchased from commercial sources, without further purification before use.
General Procedure for the Syntheses of 2-Substituted-Quinazolin-4-
(3H)-Ones. A solution of N,N-diethyl-o-nitrobenzamide (39) (1 mmol) and ni-
triles (1.5 mmol) in anhydrous THF (5 mL) was added dropwise to a solution of
SmI2 (6 mmol) in THF (40 mL) at −20◦C under a nitrogen atomsphere. The mix-
ture is allowed to reach r.t., then refluxed for 1 h. After cooling, THF was distilled
under reduced pressure. Water (10 mL) was added and the pH of the mixture was
then adjusted to 5–6 by addition of HCL (0.1 N). the mixture was extracted with
EtOAc (3 × 30 mL), washed with diluted brine, filtered, and evaporated under
reduced pressure. The crude product was washed with EtOH, then H2O, to give
the product.
1a:m.p. 234–236◦C(lit. (31)236◦C;υmax (KBr)/cm−1 1660;δH (DMSO-d6),
12.5 (1H, s), 7.5–8.3 (9H, m).

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XU, LU, AND ZHANG
1b:m.p. 257–258◦C. (lit. (31)256◦C);υmax (KBr)/cm−1 1655;δH (DMSO-d6)
12.4 (1H, s), 7.5–8.2 (9H, m), 4.0 (2H, s).
1c:m.p. 210–212◦C(lit. (29)212◦C);υmax (KBr)/cm−1 1660;δH (DMSO-d6)
12.5 (1H, s), 7.4–8.2 (8H, m), 2.4 (1H,s).
1d:m.p. 305–306◦C(lit. (40)306◦C);υmax (KBr)/cm−1 1670;δH (DMSO-d6)
12.8 (1H, s), 7.7–8.4 (8H, m).
1e:m.p. 245–247◦C(lit. (29)246◦C);υmax (KBr)/cm−1 1650;δH (DMSO-d6)
12.4 (1H, s), 7.2–8.2 (8H, m), 6.0 (1H, s).
1f: m.p. 248–250◦C; υmax (KBr)/ cm−1 1680; δH (DMSO-d6) 12.6 (1H, s),
7.7–8.4 (7H, m) m/z 292 (M+ + 2, 26), 290 (M+, 41), 119 (100%); Anal. for
C14H8N2OCl2: Cal. (found) C, 57.76 (57.78); H, 2.77 (2.65); N, 9.62 (9.53)%.
1g:m.p. 247–248◦C(lit. (31)247◦C);υmax (KBr)/cm−1 1660;δH (DMSO-d6)
12.4 (1H, s), 7.1–8.2 (8H, m), 3.8 (3H, s).
1h: m.p. 241◦C (lit. (31) 241◦C); υmax (KBr)cm/−1 1670; δH (DMSO-d6)
12.5 (1H, s), 7.4–8.2 (8H, m), 2.3 (1H, s).
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Received in the UK November 24, 1999

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