Lithiation of 3-(acylamino)-2-unsubstituted-, 3-(acylamino)-2-ethyl-, and 3-(acylamino)-2-propyl-4(3H)-quinazolinones: Convenient syntheses of more complex quinazolinones

Article abstract of DOI:10.1021/jo950988t

3-(Pivaloylamino)- and 3-(acetylamino)-4(3H)-quinazolinones react with alkyllithium reagents to give 1,2-addition products in very good yields. Lithiation takes place with LDA and is regioselective at position 2. The lithium reagents thus obtained react with a variety of electrophiles to give the corresponding substituted derivatives in very good yields. Reactions of the lithium reagents with iodine give oxidatively dimerized cyclic structures. 3-(Pivaloylamino)- and 3-(acetylamino)-2-ethyl-4(3H)-quinazolinones and 3-(pivaloylamino)- and 3-(acetylamino)-2-propyl-4(3H)-quinazolinones are lithiated at the benzylic position with LDA. The lithium reagents so produced also react with a variety of electrophiles to give the corresponding 2-substituted-4(3H)-quinazolinone derivatives in very good yields. However, lithiation of 3-(acylamino)-2-(1-methylethyl)-4(3H)-quinazolinones was unsuccessful, as were lithiations of compounds having a diacetylamino group at position 3. The amide groups have been cleaved in good yield under basic or acidic conditions from some of the products to provide access to the free amino compounds.

Full text of DOI:10.1021/jo950988t

J . Org. Chem. 1996, 61, 647-655
647
Lith ia tion of 3-(Acyla m in o)-2-u n su bstitu ted -,
3-(Acyla m in o)-2-eth yl-, a n d
3-(Acyla m in o)-2-p r op yl-4(3H)-qu in a zolin on es: Con ven ien t
Syn th eses of Mor e Com p lex Qu in a zolin on es1
Keith Smith,*,† Gamal A. El-Hiti,† Mohamed F. Abdel-Megeed,‡ and Mohamed A. Abdo‡
Department of Chemistry, University of Wales Swansea,§ Swansea, SA2 8PP, U.K., and Department of
Chemistry, Faculty of Science, Tanta University, Tanta, Egypt
Received May 31, 1995X
3-(Pivaloylamino)- and 3-(acetylamino)-4(3H)-quinazolinones react with alkyllithium reagents to
give 1,2-addition products in very good yields. Lithiation takes place with LDA and is regioselective
at position 2. The lithium reagents thus obtained react with a variety of electrophiles to give the
corresponding substituted derivatives in very good yields. Reactions of the lithium reagents with
iodine give oxidatively dimerized cyclic structures. 3-(Pivaloylamino)- and 3-(acetylamino)-2-ethyl-
4(3H)-quinazolinones and 3-(pivaloylamino)- and 3-(acetylamino)-2-propyl-4(3H)-quinazolinones are
lithiated at the benzylic position with LDA. The lithium reagents so produced also react with a
variety of electrophiles to give the corresponding 2-substituted-4(3H)-quinazolinone derivatives in
very good yields. However, lithiation of 3-(acylamino)-2-(1-methylethyl)-4(3H)-quinazolinones was
unsuccessful, as were lithiations of compounds having a diacetylamino group at position 3. The
amide groups have been cleaved in good yield under basic or acidic conditions from some of the
products to provide access to the free amino compounds.
In tr od u ction
quinazolinones.11,12 In a continuation of our own inter-
ests in heterocyclic chemistry,13 particularly in the use
of lithiation for heterocyclic synthesis,14 we have recently
shown that 3-(acylamino)-2-methyl-4(3H)-quinazolinones
also undergo lithiation at the methyl group with n-
butyllithium.1 We now report the synthesis of 2-substi-
tuted quinazolinone derivatives via lithiation of 3-(acy-
lamino)-2-unsubstituted-, 3-(acylamino)-2-ethyl-, and
3-(acylamino)-2-propyl-4(3H)-quinazolinones. Compounds
possessing this ring system show a variety of biological
activities.15
Metalation of aromatic substrates is an important
strategy for the synthesis of regiospecifically substituted
benzenes and heterocycles.2-5 However, the high reactiv-
ity of diazines toward nucleophilic addition renders the
metalation of these compounds more difficult than for
aromatic compounds which are less prone to such reac-
tions.5 Nevertheless, metalations of several pyrimidine
derivatives have been reported.6-10 Wolfe has shown that
double lithiation provides a useful method for side-chain
elaboration of 3-unsubstituted- or 3-aryl-2-methyl-4(3H)-
Resu lts a n d Discu ssion
† University of Wales Swansea.
3-(Pivaloylamino)-4(3H)-quinazolinone (4) and 3-(acety-
lamino)-4(3H)-quinazolinone (5) were synthesized ac-
cording to Scheme 1.16
It was hoped that ortho-lithiation would take place as
for (pivaloylamino)benzenes2 or various (pivaloylami-
‡ Tanta University.
§ Formerly known as the University College of Swansea.
X Abstract published in Advance ACS Abstracts, November 15, 1995.
(1) Part 38 in the series Novel Heterocyclic Systems. For part 37,
see: Smith, K.; El-Hiti, G. A.; Abdo, M. A.; Abdel-Megeed, M. F. J .
Chem. Soc., Perkin Trans. 1 1995, 1029.
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H. W.; Rodriquez, H. R. Org. React. 1980, 26, 1. Slocum, D. W.;
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Reitz, D. B. Chem. Rev. 1984, 84, 471. Snieckus, V. Ibid. 1990, 90,
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Forbes, I.; Pratt, R. A.; Raphael, R. A. Tetrahedron Lett. 1978, 3965.
Beak, P.; Brown, R. A. J . Org. Chem. 1979, 44, 4464. Smith, K.;
Lindsay, C. M.; Pritchard, G. J . J . Am. Chem. Soc. 1989, 111, 665.
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563. Gjos, N.; Gronowitz, S. Acta Chem. Scand. 1971, 25, 2596. Taylor,
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Chem. 1988, 66, 1135. Marsais, F.; Que´guiner, G. Tetrahedron 1983,
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Commun. 1986, 670. Marsais, F.; Bouley, E.; Que´guiner, G. J .
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1974, 15, 2373.
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Chem. 1974, 39, 595.
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Chem. 1980, 45, 2169.
(13) See, for example: Smith, K.; Matthews, I.; Hulme, N. M.;
Martin, G. E. J . Chem. Soc., Perkin Trans. 1 1986, 2075. Lindsay, C.
M.; Smith, K.; Martin, G. E. J . Heterocycl. Chem. 1987, 24, 1357.
Matthews, I.; Smith, K.; Martin, G. E. J . Chem. Soc., Perkin Trans. 1
1987, 2839. Smith, K.; Morris, I. K.; Owen, P. G.; Bass, R. J . Ibid.
1988, 77. Smith, K.; Hammond, M. E. W.; J ames, D. M.; Ellison, I. J .;
Hutchings, M. G. Chem. Lett. 1990, 351. Smith, K.; Small, A.;
Hutchings, M. G. Ibid. 1990, 347. Smith, K.; Small, A.; Hutchings, M.
G. Synlett 1991, 485. Smith, K.; J ames, D. M.; Mistry, A. G.; Bye, M.
R.; Faulkner, D. J . Tetrahedron 1992, 48, 7479.
(14) See, for example: Smith, K.; Pritchard, G. J . Angew. Chem.
1990, 102, 298. Angew. Chem., Int. Ed. Engl. 1990, 29, 282.
(15) See, for example: Harrison, E. F.; Larsen, A. A. U.S. Patent
3 560 619, 1971; Chem. Abstr. 1971, 75, 5929. Alaimo, R. J . U.S. Patent
3 997 538, 1976; Chem. Abstr. 1977, 86, 121366. Gupta, D. P.; Ahmad,
S.; Kumar, A.; Shanker, K. Indian J . Chem., Sect. B 1988, 27, 1060.
Shukla, J . S.; Fadayan, M. Asian J . Chem. 1989, 1, 208. Takasugi, J .
J .; et al. ACS Symp. Ser. 1995, 584 (Synthesis and Chemistry of
Agrochemicals IV), 384. U.S. Patent 5 354 755, 1995; Chem. Abstr.
1995, 122, 25858.
(8) Kress, T. J . J . Org. Chem. 1979, 44, 2081.
(9) Ple´, N.; Turck, A.; Heynderickx, A.; Que´guiner, G. J . Heterocycl.
Chem. 1994, 31, 1311.
(16) Dighe, V. S.; Somasekhara, S.; Bagavant, G.; Mukherjee, S. L.
Current Sci. (India) 1964, 33, 78.
(10) Radinov, R.; Haimova, M.; Simova, E. Synthesis 1986, 886.
0022-3263/96/1961-0647$12.00/0 © 1996 American Chemical Society

648 J . Org. Chem., Vol. 61, No. 2, 1996
Smith et al.
Sch em e 1
Sch em e 3
Ta ble 2. P r od u cts fr om Rea ction of Dilith io Com p ou n d s
13a a n d 13b w ith Electr op h iles
Sch em e 2
Ta ble 1. Syn th esis of
2-Alk yl-1,2-d ih yd r o-4(3H)-qu in a zolin on e Der iva tives 7-12
Accor d in g to Sch em e 2
a
Yields reported are for isolated and purified materials. b Over-
all yield obtained with MeI; see text for discussion. c 15 (67%); 16
(16%); 17 (6%). 23 (59%); 24 (28%); 25 (5%).
d
product
R
R′
yield, %a
7
8
9
10
11
12
t-Bu
t-Bu
t-Bu
Me
Me
Me
n-Bu
t-Bu
Me
n-Bu
t-Bu
Me
96
98
90
82
84
70
2. Two molar equivalents of LDA were used, the first to
remove the NH proton and the other one to remove the
hydrogen from position 2 to form the dilithio derivatives
13 (Scheme 3). It is interesting that no deprotonation of
the methyl group occurred for the case of compound 5 (R
) Me), in view of the acidic character of the R-protons.18
Such side reactions take place with simple acetanilides
and account for the preferred use of the pivaloylamino
group in directed lithiation reactions.2 However, we have
observed a similar phenomenon with the corresponding
2-methylquinazolinones.1
a
Yields reported are for isolated and purified materials.
no)pyridines,17 so that substitution of the hydrogen at
position 2 could be achieved. However, it was found that
lithiation of 4 and 5 did not take place with alkyllithiums.
Instead, nucleophilic attack occurred at the imine bond
to give 1,2-addition products (Scheme 2). The reactions
of 4 and 5 with 1 equiv of alkyllithiums were complete
within 5 min to give very good yields of 2-alkyl-1,2-
dihydro-3-(acylamino)-4(3H)-quinazolinones 7-12 (Table
1).
Reactions of the dilithio reagents 13a and 13b with a
range of electrophiles (benzophenone, methyl iodide, D2O,
cyclohexanone, acetophenone, phenyl isocyanate) resulted
in the production of the corresponding 2-substituted-
4(3H)-quinazolinone derivatives 14-29 in very good
yields (Table 2).
1
The compounds 7-12 are fluorescent. Their H NMR
spectra show a characteristic H-2 signal in the δ 4.4-
5.1 region, and their 13C NMR spectra show that C-2
appears in the δ 68-80 region.
Chemoselective lithiation of 3-(acylamino)-4(3H)-
quinazolinones 4 and 5 was achieved by use of LDA at
-78 °C, and the reaction was regioselective at position
As can be seen from Table 2, there is little difference
between the yields in the acetylamino series and those
in the pivaloylamino series. The reactions with excess
(4 equiv) methyl iodide resulted in almost quantitative
yields of alkylated products, but as mixtures of 2-methyl-,
2-ethyl-, and 2-(1-methylethyl)quinazolinone derivatives.
(17) Smith, K.; Lindsay, C. M.; Morris, I. K.; Matthews, I.; Pritchard,
G. J . Sulfur Lett. 1994, 17, 197. Smith, K.; Lindsay, C. M.; Morris, I.
K. Chem. Ind. (London) 1988, 9302. Smith, K.; Anderson, D.; Mat-
thews, I. Sulfur Lett. 1995, 18, 79.
(18) Colwell, W. T.; Yamamoto, K.; Christie, P.; Henry, D. W. Synth.
Commun. 1972, 2, 109. Woodbury, R. P.; Rathke, M. W. J . Org. Chem.
1977, 42, 1688.

Lithiation of 3-(Acylamino)quinazolinones
J . Org. Chem., Vol. 61, No. 2, 1996 649
Sch em e 4
Sch em e 5
It appears, therefore, that the 2-methylquinazolinone
derivatives initially produced undergo lithiation by the
excess LDA present in the reaction mixture and then
methylate to give the 2-ethyl derivatives. These in turn
react further to give the 2-(1-methylethyl) derivatives.
The overall yields of products reflect the facts that
production of ethyl compounds requires 2 equiv of base,
that propyl derivatives require 3 equiv of base, and that
a total of ca. 1.2 equiv of base are available after 1 equiv
has been used for deprotonation of the acylamino deriva-
tive. We have not attempted to optimize the yield of any
individual product from these reactions, but it is likely
that control of the total amount of base and/or methyl
iodide would be helpful in this respect. For our own
purposes it was useful to have samples of compounds 16,
17, 24, and 25 available for further study.
Ta ble 3. 3-(Acyla m in o)-2-a lk yl-4(3H)-qu in a zolin on es 16,
17, 24, 25, 35, a n d 36 P r ep a r ed a Accor d in g to Sch em e 5
compd
R
R′
yield, %b
16
17
24
25
35
36
Et
i-Pr
Et
i-Pr
n-Pr
n-Pr
t-Bu
t-Bu
Me
Me
t-Bu
Me
90
90
81
89
91
87
1
The H NMR spectra of all of the products except 15,
18, 23, and 26 show interesting diastereotopic features
(see Experimental Section). For example, in the spectra
of compounds 14 and 22 the two phenyl groups appear
with separated signals, and for compounds 19 and 27 the
two sides of the cyclohexane ring appear with separated
signals. Similarly, for compounds 16 and 24, the two
hydrogen atoms of the CH2 group at position 2 occur as
independent, coupled signals, and for compounds 17 and
25, the two methyl groups of the isopropyl group occur
as two separate doublets. For compounds 20 and 28, the
extra complication of the presence of an asymmetric
carbon atom results in the appearance in the NMR of
two distereoisomers with unequal proportions. This
phenomenon results from the orthogonal arrangement
of the two ends of the hydrazine system and a high
barrier to rotation about the N-N bond, as was also seen
with products from 3-(acylamino)-2-methyl-4(3H)-quin-
azolinones.1
a
b
See Experimental Section for details. Yields reported are for
isolated and purified materials.
Sch em e 6
Reactions of the dilithio species 13 with iodine pro-
ceeded in an interesting manner. Instead of 2-io-
doquinazolinone derivatives being formed, oxidative dimer-
ization took place to give the pentacyclic compounds 30
and 31 (Scheme 4).
The 1H NMR spectra of compounds 30 and 31 are
characterized by the lack of NH protons. The FAB mass
spectra for these compounds show pseudomolecular ion
peaks (MH+) at 487 and 403, respectively, and base peaks
at 244 and 202, respectively.
Ethyl, n-propyl, and isopropyl groups were selected as
representative alkyl groups for incorporation at position
2 of the 4(3H)-quinazolinone system, in order that
lithiation of such compounds could be studied. Thus,
compounds 16, 17, 24, 25, 35, and 36 were prepared from
34 according to Scheme 5.19 The yields of all compounds
were excellent (Table 3).
yields. However, successful lithiation was achieved with
2.2 molar equiv of LDA in THF at -78 °C for 1 h. Initial
addition of LDA provided a yellow solution when ap-
proximately 1 equiv had been added and then gave a deep
red solution as the remaining LDA was added. Addition
of methyl iodide gave compound 17 from compound 16
and compound 25 from 24 in 92% and 84% isolated
yields, respectively (Scheme 6).
In order to test the versatility of the intermediate
dilithio compounds 37, they were reacted with several
electrophiles (Scheme 7, R ) Me). The results are shown
in Table 4.
Attempts to lithiate 3-(pivaloylamino)-2-ethyl-4(3H)-
quinazolinone (16) and 3-(acetylamino)-2-ethyl-4(3H)-
quinazolinone (24) with butyllithium gave only low
As can be seen from Table 4, the dianions 37 react with
a variety of electrophiles to form the corresponding
substituted products 38-49 in good yields. In the
reactions of the dianion of 24 (i.e., 37b) with benzophe-
(19) Klosa, J . J . Prakt. Chem. 1961, 31, 3.

650 J . Org. Chem., Vol. 61, No. 2, 1996
Smith et al.
Ta ble 5. P r od u cts fr om Rea ction s Accor d in g to
Sch em e 7
Sch em e 7 (R ) Et)a
Ta ble 4. P r od u cts fr om Rea ction s Accor d in g to
Sch em e 7 (R ) Me)a
a
b
See Experimental Section for details. Yields reported are for
isolated and purified products.
and 24, which would suggest that the process was
tolerant of a variety of primary alkyl groups at position
2. It was found that lithiation of 35 and 36 with LDA
did indeed take place smoothly and that the dilithio
reagents produced reacted with representative electro-
philes (methyl iodide, benzophenone, cyclohexanone) to
give the corresponding 2-substituted-4(3H)-quinazolino-
nes 52-57 (Scheme 7, R ) Et) in very good yields (Table
5).
A side product obtained (5% yield) in the reaction of
the dianion of 36 with cyclohexanone was identified as
2-[1-(1-hydroxycyclohexyl)propyl]-3-[[(1-hydroxycyclohexyl)-
acetyl]amino]-4(3H)-quinazolinone (58), evidently formed
again by further lithiation in the acetyl group. This side
product was eliminated when 2.0 equiv of lithiating agent
were used instead of 2.2 equiv.
In order to discover whether the reaction was ap-
plicable to cases in which there was a secondary alkyl
group at position 2 of the quinazolinone system, lithia-
tions of 3-(pivaloylamino)-2-(1-methylethyl)-4(3H)-quin-
azolinone (17) and 3-(acetylamino)-2-(1-methylethyl)-
4(3H)-quinazolinone (25) with LDA were attempted.
However, after attempted trapping with methyl iodide
17 and 25 were recovered unchanged. Similarly, at-
tempts to lithiate 2-alkyl-3-(diacetylamino)-4(3H)-quin-
azolinones and 2-unsubstituted-3-(diacetylamino)-4(3H)-
quinazolinone met with failure.
a
b
See Experimental Section for details. Yields reported are for
isolated and purified products.
We have previously shown that it is possible to
hydrolyze the acylamino group of 2-ethyl-3-(acylamino)-
4(3H)-quinazolinones under basic conditions to provide
access to the corresponding 3-amino compound.1 In order
to demonstrate whether the hydrolysis is possible in
acidic conditions too and also for other 2-substituents,
we have hydrolyzed 15, 17, 23, and 25 under acidic and/
or basic conditions. We found that addition of hydro-
chloric acid or aqueous sodium hydroxide to a methanolic
solution of these compounds, followed by a period of
reflux, removed the acyl group to give 3-amino-2-methyl-
4(3H)-quinazolinone (32)20 or 3-amino-2-(1-methylethyl)-
4(3H)-quinazolinone (34c)21 in good yield (Scheme 8).
none and cyclohexanone a small quantity (3-4% yield)
of a byproduct was isolated. This resulted in each case
from attack of a further equivalent of the electrophile on
the methyl group of the acetylamino unit, giving rise to
the products 50 and 51 respectively.
Apparently, the excess of LDA was giving rise to a
small quantity of trianion, which in turn led to 50 and
51. However, by use of 2.0 equiv of LDA instead of 2.2
equiv it was possible to eliminate the byproduct com-
pletely.
Attention was next turned to lithiation of 3-(acy-
lamino)-2-propyl-4(3H)-quinazolinones. It was hoped
that lithiation of 35 and 36 would take place as for 16
Con clu sion
Direct lithiation of 3-(acylamino)-4(3H)-quinazolinones
with LDA is a facile, practical, and regiospecific process
(20) Bogert, M. T.; Gortner, R. A. J . Am. Chem. Soc. 1909, 31, 943.
(21) Fahmy, A. F. M.; El-Hashash, M. A.; Habashy, M. A.; El-
Wannise, S. A. Rev. Roum. Chim. 1978, 23, 1567; Chem. Abstr. 1978,
91, 20422.

Lithiation of 3-(Acylamino)quinazolinones
J . Org. Chem., Vol. 61, No. 2, 1996 651
Gen er a l P r oced u r e for th e Syn th esis of 3-(Acyla m in o)-
2-a lk yl-1,2-d ih yd r o-4(3H)-qu in a zolin on es. To a cooled
(-78 °C), stirred solution of 4 or 5 (2.0 mmol) in THF (20 mL)
under N2 was added a solution of alkyllithium (2.7 mL of 1.6
M, 2.2 mmol). The yellow solution obtained was allowed to
stir at -78 °C for 5 min; then the temperature was raised to
0 °C. The mixture was quenched with aqueous saturated NH4-
Cl (20 mL) and diluted with Et2O (20 mL). The organic layer
was washed with H2O (2 × 20 mL), dried (MgSO4), and
evaporated. The products obtained were recrystallized from
EtOAc to give white crystals.
Sch em e 8
2-Bu tyl-3-(pivaloylam in o)-1,2-dih ydr o-4(3H)-qu in azoli-
n on e (7): mp 157-158 °C; H NMR (CDCl3) δ 8.54 (s, exch,
providing access to a broad variety of 2-substituted
derivatives. A similar metalation procedure allows re-
giospecific electrophilic substitution of 3-(acylamino)-2-
n-alkyl-4(3H)-quinazolinones at the benzylic position of
the n-alkyl group. These procedures provide efficient
syntheses of more complicated 3-(acylamino)-2-substituted-
4(3H)-quinazolinone derivatives, which are not easily
synthesized by other routes. The facility with which the
acylamino group can be cleaved, as exemplified by the
syntheses of 3-amino-2-alkyl-4(3H)-quinazolinones, makes
the process even more attractive for the elaboration of
structures with potential pharmacological significance.
1
1H), 7.80 (d, J ) 8.0 Hz, 1H), 7.23 (t, J ) 8.0 Hz, 1H), 6.75 (t,
J ) 8.0 Hz, 1H), 6.63 (d, J ) 8.0 Hz, 1H), 4.97 (m, 1H), 4.92
(s, exch, 1H), 1.64 (m, 2H), 1.32 (s, 9H), 1.27-1.16 (m, 4H),
0.81 (t, J ) 7.0 Hz, 3H); 13C NMR (CDCl3) δ 178.2, 163.5, 146.2,
133.9, 128.6, 118.9, 115.5, 115.0, 71.4, 38.5, 32.0, 26.5, 22.3,
27.4, 13.9; HRMS calcd for C17H26N3O2 304.2025, found
304.2025. Anal. Calcd for C17H25N3O2: C, 67.32; H, 8.25; N,
13.86. Found: C, 67.43; H, 8.48; N, 13.79.
2-(1,1-Dim et h ylet h yl)-3-(p iva loyla m in o)-1,2-d ih yd r o-
4(3H)-qu in a zolin on e (8): mp 200-202 °C; 1H NMR (CDCl3)
δ 8.58 (s, exch, 1H), 7.71 (d, J ) 7.8 Hz, 1H), 7.17 (t, J ) 7.8
Hz, 1H), 6.66 (t, J ) 7.8 Hz, 1H), 6.56 (d, J ) 7.8 Hz, 1H),
5.25 (d, J ) 4.5 Hz, exch, 1H), 4.70 (d, J ) 4.5 Hz, 1H), 1.32
(s, 9H), 0.89 (s, 9H); 13C NMR (CDCl3) δ 177.2, 162.5, 146.9,
137.1, 128.2, 117.8, 114.6, 114.2, 79.1, 40.8, 38.4, 27.3, 25.8;
HRMS calcd for C17H26N3O2 304.2025, found 304.2021. Anal.
Calcd for C17H25N3O2: C, 67.32; H, 8.25; N, 13.86. Found: C,
67.34; H, 8.30; N, 13.79.
2-Meth yl-3-(pivaloylam in o)-1,2-dih ydr o-4(3H)-qu in azoli-
n on e (9): mp 235 °C; 1H NMR (DMSO-d6) δ 9.70 (s, exch, 1H),
7.61 (d, J ) 7.9 Hz, 1H), 7.27 (t, J ) 7.9 Hz, 1H), 6.73 (s, exch,
1H), 6.71-6.69 (m, 2H), 5.64 (q, J ) 5.7 Hz, 1H), 1.32 (d, J )
5.7 Hz, 3H), 1.18 (s, 9H); 13C NMR (DMSO-d6) δ 176.6, 162.8,
148.0, 133.5, 128.0, 117.5, 114.5, 114.3, 67.4, 37.6, 27.2, 19.2;
HRMS calcd for C14H20N3O2 262.1556, found 262.1556. Anal.
Calcd for C14H19N3O2: C, 64.36; H, 7.28; N, 16.09. Found: C,
64.15; H, 7.36; N, 15.96.
Exp er im en ta l Section
Melting points are uncorrected. 1H and 13C NMR spectra
were recorded at 400 MHz for 1H and 100 MHz for 13C. Low-
resolution mass spectra were recorded at 70 ev (EI) or by the
use of ammonia as ionization gas (CI). Elemental analyses
were obtained from the Laboratories of the University of
Wales, Cardiff. Column chromatography was carried out using
Merck Kieselgel 60 (230-400 mesh). Alkyllithiums were
estimated prior to use by the method of Watson and East-
ham.22 THF was distilled from sodium benzophenone ketyl.
Other solvents were purified by standard procedures.23,24
Other chemicals were used without further purification. All
compounds gave microanalyses and accurately mass measured
molecular ions (or MH+ ions) which confirmed their elemental
composition. IR and mass spectra were in agreement with the
assigned structures.
3-(P iva loyla m in o)-4(3H)-qu in a zolin on e (4). A mixture
of 3 (5.00 g, 31.0 mmol), pivaloyl chloride (4.00 g, 32.0 mmol),
and Et3N (4 mL) in dry toluene (60 mL) was heated under
reflux for 30 min with stirring. The organic layer was washed
twice with a saturated NaHCO3 solution (20 mL) and H2O (25
mL), dried (MgSO4), and evaporated in vacuo. Crystallization
from EtOAc/Et2O gave cotton-like white crystals (6.46 g, 26.0
mmol; 85%): mp 136 °C; 1H NMR (CDCl3) δ 8.91 (s, exch, 1H),
8.19 (d, J ) 8.2 Hz, 1H), 7.91 (s, 1H), 7.74 (t, J ) 8.2 Hz, 1H),
7.67 (d, J ) 8.2 Hz, 1H), 7.47 (t, J ) 8.2 Hz, 1H), 1.34 (s, 9H);
13C NMR (CDCl3) δ 179.3, 159.4, 147.4, 147.1, 134.8, 127.8,
127.5, 126.7, 122.0, 38.9, 27.2; HRMS calcd for C13H16N3O2
246.1243, found 246.1243. Anal. Calcd for C13H15N3O2: C,
63.67; H, 6.12; N, 17.14. Found: C, 63.45; H, 6.28; N, 17.23.
3-(Acetyla m in o)-4(3H)-qu in a zolin on e (5). Compound 5
was prepared according to the literature method as white
crystals: mp 210-211 °C (lit. mp 168-170 °C, shrinks at 120-
125 °C);16 1H NMR (DMSO-d6) δ 11.26 (s, exch, 1H), 8.22 (s,
1H), 8.19 (d, J ) 8.1 Hz, 1H), 7.87 (t, J ) 8.1 Hz, 1H), 7.73 (d,
J ) 8.1 Hz, 1H), 7.59 (t, J ) 8.1 Hz, 1H), 2.11 (s, 3H); 13C
NMR (DMSO-d6) δ 169.4, 158.4, 148.8, 147.2, 134.7, 127.4,
127.3, 126.3, 122.0, 20.4; HRMS calcd for C10H9N3O2 203.0695,
found 203.0695. Anal. Calcd for C10H9N3O2: C, 59.11; H, 4.43;
N, 20.69. Found: C, 59.22; H, 4.16; N, 20.85
3-(Acetyla m in o)-2-bu tyl-1,2-d ih yd r o-4(3H)-qu in a zoli-
1
n on e (10): mp > 250 °C; H NMR (CDCl3) δ 9.08 (br s, exch,
1H), 7.82 (d, J ) 7.9 Hz, 1H), 7.32 (t, J ) 7.9 Hz, 1H), 6.82 (t,
J ) 7.9 Hz, 1H), 6.66 (d, J ) 7.9 Hz, 1H), 5.04 (m, 1H), 4.74
(br s, exch, 1H), 2.10 (s, 3H), 1.84-1.77 (m, 2H), 1.34-1.26
(m, 4H), 0.87 (t, J ) 6.8 Hz, 3H); 13C NMR (CDCl3) δ 169.8,
163.5, 146.0, 134.3, 128.7, 119.1, 115.6, 114.9, 71.9, 32.9, 26.6,
22.4, 20.9, 13.9; HRMS calcd for C14H20N3O2 262.1556, found
262.1556. Anal. Calcd for C14H19N3O2: C, 64.36; H, 7.28; N,
16.09. Found: C, 64.44; H, 7.38; N, 16.03.
3-(Acetylam in o)-2-(1,1-dim eth yleth yl)-1,2-dih ydr o-4(3H)-
qu in a zolin on e (11): mp > 250 °C; 1H NMR (DMSO-d6) δ
10.24 (s, exch, 1H), 7.50 (d, J ) 7.8 Hz, 1H), 7.18 (t, J ) 7.8
Hz, 1H), 7.01 (d, exch, J ) 3.1 Hz, 1H), 6.67 (d, J ) 7.8 Hz,
1H), 6.54 (t, J ) 7.8 Hz, 1H), 4.43 (d, J ) 3.1 Hz, 1H), 1.89 (s,
3H), 0.85 (s, 9H); 13C NMR (DMSO-d6) δ 167.7, 161.2, 147.6,
133.5, 127.5, 115.7, 113.4, 113.2, 79.0, 40.7, 25.2, 20.6; HRMS
calcd for C14H20N3O2 262.1556, found 262.1556. Anal. Calcd
for C14H19N3O2: C, 64.36; H, 7.28; N, 16.09. Found: C, 64.56;
H, 7.38; N, 16.02.
3-(Acetyla m in o)-2-m eth yl-1,2-d ih yd r o-4(3H)-qu in a zoli-
n on e (12): mp > 250 °C; 1H NMR (CDCl3) δ 9.30 (s, exch,
1H), 7.78 (d, J ) 7.9 Hz, 1H), 7.24 (t, J ) 7.9 Hz, 1H), 6.76 (t,
J ) 7.9 Hz, 1H), 6.62 (d, J ) 7.9 Hz, 1H), 5.21-5.17 (m, 1H),
5.03 (d, J ) 5.9 Hz, exch, 1H), 2.05 (s, 3H), 1.41 (d, J ) 5.9
Hz, 3H); 13C NMR (CDCl3) δ 170.3, 164.0, 146.6, 134.3, 128.7,
119.2, 115.4, 114.6, 68.2, 20.7, 19.2; HRMS calcd for C11H14N3O2
220.1086, found 220.1086. Anal. Calcd for C11H13N3O2: C,
60.27; H, 5.93; N, 19.18. Found: C, 60.43; H, 5.99; N, 19.09.
Gen er a l P r oced u r e for th e Syn th esis of 3-(Acyla m in o)-
2-su bstitu ted -4(3H)-qu in a zolin on es 14-31. A solution of
LDA in heptane (2.7 mL of 1.6 M, 4.4 mmol) was added in a
dropwise manner to a stirred solution of 4 or 5 (2.0 mmol) in
THF (20 mL, N2 atmosphere) maintained at -78 °C. Forma-
tion of the dianion was observed as a yellowish brown solution.
The mixture was stirred at -78 °C for an additional 1 h, after
(22) Watson, S. C.; Eastham, J . F. J . Organomet. Chem. 1967, 9,
165.
(23) Vogel’s Textbook of Practical Organic Chemistry, 4th ed.;
Wiley: New York, 1978.
(24) Perrin, D. D.; Armarego, W. L. F.; Perrin, D. R. Purification of
Laboratory Chemicals; Pergamon: Oxford, 1966.
(25) Zentmyer, D. T.; Wagner, E. C. J . Org. Chem. 1949, 14, 967.
Sammour, A.; Selim, M. I.; El-Kasaby, M.; Abdalla, M. Acta Chim.
1973, 78, 293; Chem. Abstr. 1973, 79, 137061.

652 J . Org. Chem., Vol. 61, No. 2, 1996
Smith et al.
which an electrophile (2.2 mmol) (in THF (8 mL) if solid,
otherwise neat) was added. The mixture was stirred for 4 h
and then removed from the cooling bath and allowed to warm
to room temperature, diluted with Et2O (15 mL), and quenched
with aqueous saturated NH4Cl (15 mL). The organic layer was
washed with H2O (2 × 20 mL), dried (MgSO4), and evaporated.
The products obtained were recrystallized from EtOAc to give
white crystals.
7.36-7.19 (m, 10H), 5.78 (s, exch, 1H), 1.37 (s, 3H); 13C NMR
(DMSO-d6) δ 166.6, 159.4, 158.4, 144.9, 143.1, 134.7, 128.2,
128.0, 127.8, 127.7, 127.6, 127.0, 126.7, 126.5, 126.3, 121.2,
81.5, 19.7; HRMS calcd for C23H20N3O3 386.1505, found
386.1505. Anal. Calcd for C23H19N3O3: C, 71.69; H, 4.93; N,
10.91. Found: C, 71.49; H, 5.06; N, 10.71.
3-(Acetylam in o)-2-m eth yl-4(3H)-qu in azolin on e (23): mp
175-176 °C (lit. mp 176.5 °C).20
2-(Hyd r oxyd ip h en ylm eth yl)-3-(p iva loyla m in o)-4(3H)-
qu in a zolin on e (14): mp 149-151 °C; 1H NMR (CDCl3) δ 8.25
(d, J ) 8.1 Hz, 1H), 7.82 (t, J ) 8.1 Hz, 1H), 7.75 (d, J ) 8.1
Hz, 1H), 7.55 (t, J ) 8.1 Hz, 1H), 7.47-7.31 (m, 10H), 6.86 (s,
exch, 1H), 6.21 (s, exch, 1H), 0.97 (s, 9H); 13C NMR (CDCl3) δ
176.6, 160.0, 158.4, 144.8, 142.4, 141.9, 135.0, 128.3, 128.2,
128.12, 128.07, 127.9, 127.83, 127.79, 127.7, 127.3, 121.1, 81.0,
38.6, 26.7; HRMS calcd for C26H26N3O3 428.1974, found
428.1974. Anal. Calcd for C26H25N3O3. H2O: C, 70.11; H,
6.06; N, 9.40. Found: C, 70.12; H, 6.18; N, 9.40.
3-(Acetyla m in o)-2-eth yl-4(3H)-qu in a zolin on e (24): mp
135-136 °C (lit. mp 136-138 °C).19
3-(Ace t yla m in o)-2-(1-m e t h yle t h yl)-4(3H )-q u in a zoli-
1
n on e (25): mp 122 °C; H NMR (CDCl3) δ 9.32 (s, exch, 1H),
8.12 (d, J ) 8.0 Hz, 1H), 7.72 (t, J ) 8.0 Hz, 1H), 7.66 (d, J )
8.0 Hz, 1H), 7.40 (t, J ) 8.0 Hz, 1H), 3.18 (hept, J ) 6.8 Hz,
1H), 2.27 (s, 3H), 1.32, 1.27 (2 d, J ) 6.8 Hz, 6H); 13C NMR
(CDCl3) δ 170.9, 161.9, 147.3, 134.9, 127.7, 126.59, 126.58,
120.4, 31.0, 21.3, 21.0, 20.1; HRMS calcd for C13H15N3O2
245.1164, found 245.1164. Anal. Calcd for C13H15N3O2.
H2O: C, 59.31; H, 6.44; N, 15.97. Found: C, 59.04; H, 6.63;
N, 15.96.
2-Meth yl-3-(P iva loyla m in o)-4(3H)-qu in a zolin on e (15):
mp 161-163 °C (lit. mp 161-163 °C).1
2-Eth yl-3-(pivaloylam in o)-4(3H)-qu in azolin on e (16): mp
194-195 °C (lit. mp 194-195 °C).1
3-(Acetyla m in o)-2-d eu ter io-4(3H)-qu in a zolin on e (26):
mp 211 °C; 1H NMR (DMSO-d6) δ 11.45 (s, exch, 1H), 8.32 (d,
J ) 8.0 Hz, 1H), 7.99 (t, J ) 8.0 Hz, 1H), 7.84 (d, J ) 8.0 Hz,
1H), 7.70 (t, J ) 8.0 Hz, 1H), 2.25 (s, 3H); 13C NMR (DMSO-
d6) δ 169.2, 158.3, 158.0, 147.3, 134.5, 127.4, 127.1, 126.3,
122.1, 20.4; HRMS calcd for C10H8N3O2D 204.0758, found
204.0758.
3-(Ac e t y la m i n o )-2-(1-h y d r o x y c y c lo h e x y l)-4(3H )-
qu in a zolin on e (27): mp 170 °C; 1H NMR (DMSO-d6) δ 11.62
(s, exch, 1H), 8.09 (d, J ) 8.0 Hz, 1H), 7.84 (t, J ) 8.0 Hz,
1H), 7.67 (d, J ) 8.0 Hz, 1H), 7.53 (t, J ) 8.0 Hz, 1H), 5.12 (s,
exch, 1H), 2.07 (s, 3H), 2.00-1.25 (m, 10H); 13C NMR (DMSO-
d6) δ 169.3, 160.9, 159.7, 145.5, 134.8, 127.5, 127.1, 126.4,
120.7, 73.7, 35.4, 34.8, 25.2, 21.6, 21.5, 21.0; HRMS calcd for
C16H20N3O3 302.1505, found 302.1505. Anal. Calcd for
C16H19N3O3‚H2O: C, 60.18; H, 6.58; N, 13.16. Found: C, 60.02;
H, 6.39; N, 13.04.
3-(Acet yla m in o)-2-(1-h yd r oxy-1-p h en ylet h yl)-4(3H )-
qu in a zolin on e (28): mp 189-190 °C. Compound 28 appears
in its NMR spectra as a mixture of two isomers a and b with
a ratio of 1:3. 1H NMR (DMSO-d6): 28a , δ 9.85 (s, exch, 1H),
8.09 (d, J ) 8.0 Hz, 1H), 7.87 (t, J ) 8.0 Hz, 1H), 7.78 (d, J )
8.0 Hz, 1H), 7.56 (t, J ) 8.0 Hz, 1H), 7.32-7.12 (m, 5H), 6.09
(s, exch, 1H), 1.69 (s, 3H), 1.37 (s, 3H); 28b, δ 10.23 (s, exch,
1H), 8.09 (d, J ) 8.0 Hz, 1H), 7.87 (t, J ) 8.0 Hz, 1H), 7.78 (d,
J ) 8.0 Hz, 1H), 7.57 (t, J ) 8.0 Hz, 1H), 7.32-7.12 (m, 5H),
6.41 (s, exch, 1H), 1.81 (s, 3H), 1.37 (s, 3H). 13C NMR (DMSO-
d6): 28a , δ 168.4, 159.7, 159.2, 145.4, 144.7, 135.0, 127.9, 127.7,
127.3, 126.6, 126.2, 124.7, 121.0, 75.3, 29.9, 20.4; 28b, δ 166.0,
160.0, 159.2, 145.5, 144.7, 134.8, 127.8, 127.7, 127.4, 126.6,
126.5, 123.9, 121.3, 76.4, 32.6, 19.7. HRMS: calcd for
C18H18N3O3 324.1548, found 324.1548. Anal. Calcd for
C18H17N3O3: C, 66.87; H, 5.26; N, 13.00. Found: C, 66.61; H,
5.43; N, 12.88.
3-(Ace t yla m in o)-2-[(p h e n yla m in o)ca r b on yl]-4(3H )-
qu in a zolin on e (29): mp 251-252 °C; 1H NMR (DMSO-d6) δ
11.19 (s, exch, 1H), 10.72 (s, exch, 1H), 8.23 (d, J ) 8.0 Hz,
1H), 7.90 (t, J ) 8.0 Hz, 1H), 7.83 (d, J ) 8.0 Hz, 1H), 7.72 (d,
J ) 8.0 Hz, 2H), 7.58 (t, J ) 8.0 Hz, 1H), 7.32 (t, J ) 8.0 Hz,
2H), 7.10 (t, J ) 8.0 Hz, 1H), 2.05 (s, 3H); 13C NMR (DMSO-
d6) δ 169.0, 158.7, 158.3, 150.5, 145.9, 138.0, 134.8, 128.6,
128.4, 127.8, 127.7, 126.8, 124.3, 124.2, 122.1, 120.1, 20.5;
HRMS calcd for C17H14N4O3 322.1066, found 322.1066. Anal.
Calcd for C17H14N4O3: C, 63.35; H, 4.34; N, 17.39. Found: C,
63.26; H, 4.58; N, 17.45.
2-(1-Met h ylet h yl)-3-(p iva loyla m in o)-4(3H )-q u in a zoli-
1
n on e (17): mp 174-175 °C; H NMR (CDCl3) δ 8.45 (s, exch,
1H), 8.12 (d, J ) 8.0 Hz, 1H), 7.70 (t, J ) 8.0 Hz, 1H), 7.63 (d,
J ) 8.0 Hz, 1H), 7.38 (t, J ) 8.0 Hz, 1H), 3.04 (hept, J ) 6.7
Hz, 1H), 1.36 (s, 9H), 1.27, 1.19 (2 d, J ) 6.7 Hz, 6H); 13C NMR
(CDCl3) δ 179.2, 161.83, 160.6, 147.1, 134.6, 127.6, 126.5, 126.4,
120.5, 38.9, 31.0, 27.2, 21.0, 20.1; HRMS calcd for C16H21N3O2
287.1634, found 287.1634. Anal. Calcd for C16H21N3O2: C,
66.90; H, 7.32; N, 14.63. Found: C, 66.68; H, 7.51; N, 14.48.
2-Deu ter io-3-(pivaloylam in o)-4(3H)-qu in azolin on e (18):
mp 136 °C; 1H NMR (CDCl3) δ 8.85 (s, exch, 1H), 8.19 (d, J )
8.0 Hz, 1H), 7.75 (t, J ) 8.0 Hz, 1H), 7.68 (d, J ) 8.0 Hz, 1H),
7.47 (t, J ) 8.0 Hz, 1H), 1.34 (s, 9H); 13C NMR (CDCl3) δ 179.3,
159.41, 159.38, 147.1, 134.8, 127.8, 127.5, 127.0, 122.0, 38.9,
27.2; HRMS calcd for C13H14N3O2D 246.1227, found 246.1227.
2-(1-H yd r oxycycloh e xyl)-3-(p iva loyla m in o)-4(3H )-
1
qu in a zolin on e (19): mp 208 °C; H NMR (CDCl3) δ 8.40 (s,
exch, 1H), 8.13 (d, J ) 8.0 Hz, 1H), 7.70 (t, J ) 8.0 Hz, 1H),
7.58 (d, J ) 8.0 Hz, 1H), 7.42 (t, J ) 8.0 Hz, 1H), 4.79 (s, exch,
1H), 2.15-1.18 (m, 10H), 1.35 (s, 9H); 13C NMR (CDCl3) δ
178.7, 160.5, 159.9, 145.3, 134.9, 127.7, 127.2, 127.0, 120.5,
73.9, 39.0, 35.0, 34.7, 25.4, 21.7, 21.6, 21.1; HRMS calcd for
C19H26N3O3, 344.1974, found 344.1974. Anal. Calcd for
C19H25N3O3: C, 66.47; H, 7.29; N, 12.24. Found: C, 66.51; H,
7.30; N, 12.21.
2-(1-Hyd r oxy-1-p h en yleth yl)-3-(p iva loyla m in o)-4(3H)-
qu in a zolin on e (20): mp 175-176 °C. Compound 20 appears
in its NMR spectra as a mixture of two isomers, a and b, with
a ratio of 3:5. 1H NMR (CDCl3): 20a , δ 8.19 (d, J ) 8.0 Hz,
1H), 7.77 (t, J ) 8.0 Hz, 1H), 7.55 (d, J ) 8.0 Hz, 1H), 7.35-
7.24 (m, 7H), 4.78 (s, exch, 1H), 1.93 (s, 3H), 1.04 (s, 9H); 20b,
δ 8.19 (d, J ) 8.0 Hz, 1H), 7.77 (t, J ) 8.0 Hz, 1H), 7.55 (d, J
) 8.0 Hz, 1H), 7.35-7.24 (m, 7H), 5.73 (s, exch, 1H), 1.88 (s,
3H), 1.07 (s, 9H). 13C NMR (CDCl3): 20a , δ 177.9, 160.6, 158.5,
145.3, 143.9, 134.9, 128.4, 127.9, 127.5, 127.3, 127.1, 124.8,
121.1, 75.1, 38.7, 29.7, 26.8; 20b, δ 176.9, 160.0, 159.5, 145.0,
143.1, 134.9, 128.7, 127.9, 127.8, 127.3, 127.1, 125.5, 121.1,
75.9, 38.6, 29.7, 26.8. HRMS: calcd for C21H24N3O3 366.1818,
found 366.1818. Anal. Calcd for C21H23N3O3: C, 69.04; H,
6.30; N, 11.50. Found: C, 69.09; H, 6.38; N, 11.40.
2-[(P h en yla m in o)ca r b on yl]-3-(p iva loyla m in o)-4(3H )-
qu in a zolin on e (21): mp 266-268 °C; 1H NMR (DMSO-d6) δ
11.02 (s, exch, 1H), 10.87 (s, exch, 1H), 8.21 (d, J ) 8.0 Hz,
1H), 7.95 (t, J ) 8.0 Hz, 1H), 7.84 (d, J ) 8.0 Hz, 1H), 7.70-
7.67 (m, 3H), 7.36 (t, J ) 8.1 Hz, 2H), 7.13 (t, J ) 8.1 Hz, 1H),
1.14 (s, 9H); 13C NMR (DMSO-d6) δ 176.9, 158.6, 158.4, 151.1,
146.0, 137.9, 137.8, 135.4, 128.9, 128.4, 127.9, 126.6, 124.5,
121.9, 119.9, 37.9, 26.8; HRMS calcd for C20H21N4O3 365.1614,
found 365.1614. Anal. Calcd for C20H20N4O3: C, 65.93; H,
5.49; N, 15.38. Found: C, 65.77; H, 5.68; N, 15.38.
6,13-Dipivaloyl-1,2,4,5-tetr azin o[3,2-b:6,5-b′]bisqu in azo-
1
lin e-7,14(6a H,13a H)-d ion e (30): mp 155-157 °C; H NMR
(CDCl3) δ 8.40 (d, J ) 8.0 Hz, 2H), 7.78 (t, J ) 8.0 Hz, 2H),
7.70 (d, J ) 8.0 Hz, 2H), 7.47 (t, J ) 8.0 Hz, 2H), 1.52 (s, 18H);
13C NMR (CDCl3) δ 168.3, 155.7, 151.7, 147.1, 135.0, 127.5,
126.7, 125.4, 118.9, 33.2, 27.3; HRMS calcd for C26H27N6O4
487.2093, found 487.2098. Anal. Calcd for C26H26N6O4: C,
64.19; H, 5.35; N, 17.28. Found: C, 64.38; H, 5.71; N, 17.31.
6,13-Dia cetyl-1,2,4,5-tetr a zin o[3,2-b:6,5-b′]bisqu in a zo-
3-(Acet yla m in o)-2-(h yd r oxyd ip h en ylm et h yl)-4(3H )-
qu in a zolin on e (22): mp 197-198 °C; 1H NMR (DMSO-d6) δ
10.22 (s, exch, 1H), 8.11 (d, J ) 8.0 Hz, 1H), 7.99 (t, J ) 8.0
Hz, 1H), 7.55 (t, J ) 8.0 Hz, 1H), 7.47 (d, J ) 8.0 Hz, 1H),
1
lin e-7,14(6a H,13a H)-d ion e (31): mp 255-257 °C; H NMR
(DMSO-d6) δ 8.25 (d, J ) 8.0 Hz, 2H), 7.84 (t, J ) 8.0 Hz, 2H),

Lithiation of 3-(Acylamino)quinazolinones
J . Org. Chem., Vol. 61, No. 2, 1996 653
7.65 (d, J ) 8.0 Hz, 2H), 7.50 (t, J ) 8.0 Hz, 2H), 2.58 (s, 6H);
13C NMR (DMSO-d6) δ 160.0, 155.3, 152.1, 147.1, 135.1, 126.8,
126.5, 125.3, 118.7, 11.6; HRMS calcd for C20H15N6O4 403.1155,
found 403.1155. Anal. Calcd for C20H14N6O4: C, 59.70; H,
3.48; N, 20.89. Found: C, 59.54; H, 3.50; N, 20.68.
Gen er a l P r oced u r e for th e Syn th esis of 2-Alk yl-3-
(p iva loyla m in o)-4(3H)-qu in a zolin on es. A mixture of the
appropriate compound 3421,25 (36.6 mmol), pivaloyl chloride
(4.80 g, 39.4 mmol), and Et3N (8 mL) in dry toluene (80 mL)
was heated under reflux for 30 min, with stirring. The organic
layer was washed with saturated NaHCO3 (2 × 20 mL) and
H2O (25 mL), dried (MgSO4), and evaporated. Crystallization
from EtOAc gave white crystals. In the cases of compounds
16 and 17 the products were identical in all respects to the
compounds obtained according to Scheme 3.
3-(P iva loyla m in o)-2-p r op yl-4(3H)-qu in a zolin on e (35):
mp 152 °C; 1H NMR (CDCl3) δ 8.41 (s, exch, 1H, NH), 8.12 (d,
J ) 8.0 Hz, 1H), 7.71 (t, J ) 8.0 Hz, 1H), 7.60 (d, J ) 8.0 Hz,
1H), 7.39 (t, J ) 8.0 Hz, 1H), 2.59-2.62 (m, 2H), 1.72 (sextet,
J ) 7.5 Hz, 2H), 1.37 (s, 9H), 0.97 (t, J ) 7.5 Hz, 3H); 13C
NMR (CDCl3) δ 179.0, 160.4, 157.8, 147.0, 134.8, 127.4, 126.54,
126.48, 120.5, 38.9, 35.5, 27.2, 19.9, 13.8; HRMS calcd for
C16H22N3O2 288.1712, found 288.1712. Anal. Calcd for
C16H21N3O2: C, 66.90; H, 7.32; N, 14.63. Found: C, 67.08; H,
7.47; N, 14.83.
26.6, 26.4, 26.2, 10.4; HRMS calcd for C15H19N3O2D 275.1618,
found 275.1618.
2-[1-(1-H yd r oxycycloh exyl)et h yl]-3-(p iva loyla m in o)-
4(3H)-qu in a zolin on e (40): mp 174-175 °C. Compound 40
appears in its NMR spectra as a mixture of two isomers, a
and b, in a ratio of 5:6. 1H NMR (CDCl3): 40a , δ 8.24 (s, exch,
1H), 8.19 (d, J ) 8.0 Hz, 1H), 7.75 (t, J ) 8.0 Hz, 1H), 7.63 (d,
J ) 8.0 Hz, 1H), 7.44 (t, J ) 8.0 Hz, 1H), 5.79 (s, exch, 1H),
2.87 (q, J ) 7.0 Hz, 1H), 1.40 (s, 9H), 1.30 (d, J ) 7.0 Hz, 3H),
1.84-1.19 (m, 10H); 40b, δ 8.29 (s, exch, 1H), 8.18 (d, J ) 8.0
Hz, 1H), 7.75 (t, J ) 8.0 Hz, 1H), 7.65 (d, J ) 8.0Hz, 1H), 7.44
(t, J ) 8.0 Hz, 1H), 5.02 (s, exch, 1H), 3.14 (q, J ) 7.0 Hz,
1H), 1.41 (s, 9H), 1.34 (d, J ) 7.0 Hz, 3H), 1.84-1.19 (m, 10H).
13C NMR (CDCl3): 40a , δ 179.1, 162.4, 160.0, 145.5, 135.0,
127.1, 126.95, 126.9, 120.5, 72.2, 42.5, 39.0, 37.7, 35.4, 27.2,
25.7, 22.1, 21.9, 13.6; 40b, δ 179.1, 161.8, 160.0, 145.9, 135.0,
127.3, 126.9, 126.8, 120.4, 72.7, 42.3, 39.0, 39.0, 34.8, 25.7, 21.8,
21.8, 27.2, 13.4. HRMS: calcd for C21H30N3O3 372.2287, found
372.2287. Anal. Calcd for C21H29N3O3: C, 67.92; H, 7.81; N,
11.32. Found: C, 67.98; H, 7.94; N, 11.17.
2-[1-(1-Hyd r oxycyclop en tyl)eth yl]-3-(p iva loyla m in o)-
4(3H)-qu in a zolin on e (41): mp 122-124 °C. Compound 41
appears as a mixture of two isomers, a and b, in a ratio of 5:8
in its NMR spectra. 1H NMR (CDCl3): 41a , δ 8.32 (s, exch,
1H), 8.18 (d, J ) 8.0 Hz, 1H), 7.74 (t, J ) 8.0 Hz, 1H), 7.62 (d,
J ) 8.0 Hz, 1H), 7.44 (t, J ) 8.0 Hz, 1H), 5.27 (s, exch, 1H),
3.10 (q, J ) 7.0 Hz, 1H), 1.93-1.46 (m, 8H), 1.40 (s, 9H), 1.36
(d, J ) 7.0 Hz, 3H); 41b, δ 8.38 (s, exch, 1H), 8.16 (d, J ) 8.0
Hz, 1H), 7.74 (t, J ) 8.0 Hz, 1H), 7.60 (d, J ) 8.0 Hz, 1H),
7.44 (t, J ) 8.0 Hz, 1H), 5.64 (s, exch, 1H), 2.76 (q, J ) 7.0 Hz,
1H), 1.93-1.46 (m, 8H), 1.39 (s, 9H), 1.38 (d, J ) 7.0 Hz, 3H).
13C NMR (CDCl3): 41a , δ 179.3, 162.2, 159.9, 145.8, 135.0,
127.1, 126.9, 126.8, 120.6, 83.4, 43.6, 40.1, 39.0, 38.2, 27.2, 24.1,
23.9, 15.0; 41b, δ 179.3, 162.4, 159.9, 145.6, 135.0, 127.2, 126.9,
126.8, 120.6, 83.1, 44.0, 39.07, 38.8, 38.2, 27.2, 23.89, 23.86,
15.3. HRMS: calcd for C20H28N3O3 358.2131, found 358.2131.
Anal. Calcd for C20H27N3O3: C, 67.22; H, 7.56; N, 11.67.
Found: C, 67.00; H, 7.60; N, 11.57.
2-(2-Hydr oxy-1-m eth yl-2-ph en ylpr opyl)-3-(pivaloylam i-
n o)-4(3H)-qu in a zolin on e (42): mp 120-121 °C. Compound
42 appears in its NMR spectra as a mixture of two isomers, a
and b, in a ratio of 3:4. 1H NMR (CDCl3): 42a , δ 8.42 (s, exch,
1H), 8.20 (d, J ) 8.0 Hz, 1H), 7.77 (t, J ) 8.0 Hz, 1H), 7.68 (d,
J ) 8.0 Hz, 1H), 7.49-7.30 (m, 6H), 5.87 (s, exch, 1H), 3.47
(q, J ) 7.0 Hz, 1H), 1.36 (s, 3H), 1.40 (s, 9H), 1.07 (d, J ) 7.0
Hz, 3H); 42b, δ 8.49 (s, exch, 1H), 8.18 (d, J ) 8.0 Hz, 1H),
7.77 (t, J ) 8.0 Hz, 1H), 7.68 (d, J ) 8.0 Hz, 1H), 7.49-7.30
(m, 6H), 6.51 (s, exch, 1H), 3.20 (q, J ) 7.0 Hz, 1H), 1.37 (s,
3H), 1.45 (s, 9H), 0.98 (d, J )8.0 Hz, 3H). 13C NMR (CDCl3):
42a , δ 179.4, 162.3, 159.9, 146.0, 145.5, 135.2, 128.2, 128.0,
127.1, 126.9, 126.5, 124.8, 120.6, 75.6, 44.6, 39.1, 29.8, 27.2,
14.7; 42b, 179.3, 162.3, 159.9, 146.5, 145.8, 135.2, 128.3, 128.2,
127.2, 127.0, 126.7, 124.7, 120.5, 75.6, 44.4, 39.1, 30.0, 27.2,
15.1. HRMS: calcd for C23H28N3O3 394.2131, found 394.2131.
Anal. Calcd for C23H27N3O3: C, 70.23; H, 6.87; N, 10.68.
Found: C, 70.29; H, 7.09; N, 10.44.
Gen er a l P r oced u r e for t h e Syn t h esis of 3-(Acet yl-
a m in o)-2-a lk yl-4(3H)-qu in a zolin on es. Compounds 24 and
25 were prepared according to a literature procedure.19
Compound 36 was prepared in similar manner.
3-(Acetyla m in o)-2-p r op yl-4(3H)-qu in a zolin on e (36): mp
1
135-136 °C; H NMR (CDCl3) δ 9.38 (s, exch, 1H), 8.13 (d, J
) 8.0 Hz, 1H), 7.73 (t, J ) 8.0 Hz, 1H), 7.69 (d, J ) 8.0 Hz,
1H), 7.39 (t, J ) 8.0 Hz, 1H), 2.79-2.64 (m, 2H), 2.24 (s, 3H),
1.79 (sextet, J ) 7.3 Hz, 2H), 1.02 (t, J ) 7.3 Hz, 3H); 13C
NMR (CDCl3) δ 170.7, 160.9, 157.8, 147.1, 135.0, 127.5, 126.63,
126.62, 120.5, 35.4, 20.9, 19.9, 13.8; HRMS calcd for C13H16N3O2
246.1243, found 246.1243. Anal. Calcd for C13H15N3O2: C,
63.67; H, 6.12; N, 17.14. Found: C, 63.82; H, 6.17; N, 17.43.
Gen er a l P r oced u r e for th e Syn th esis of 3-(Acyla m in o)-
2-su bstitu ted -4(3H)-qu in a zolin on es 38 -58. A solution of
LDA in pentane (2.7 mL of 1.6 M, 4.4 mmol) was added
dropwise under nitrogen to a stirred solution of the appropriate
3-(acylamino)-2-alkyl-4(3H)-quinazolinone (16, 24, 35, or 36)
(2.0 mmol) in THF (20 mL) at -78 °C. Formation of the
dianion was observed as a very deep red solution. The mixture
was stirred at -78 °C for 30 min, after which an electrophile
(2.2 mmol) (as a solution in THF for solids) was added. The
mixture was stirred for 2 h, then allowed to warm to room
temperature, diluted with Et2O (20 mL), and quenched with
aqueous saturated NH4Cl (20 mL). The organic layer was
washed with H2O (2 × 20 mL), dried (MgSO4), and evaporated.
The products were purified by column chromatography (Et2O)
and then crystallized, usually from EtOAc, to give white
crystals.
2-(2-H yd r oxy-2,2-d ip h en yl-1-m et h ylet h yl)-3-(p iva lo-
yla m in o)-4(3H)-qu in a zolin on e (38): mp 196-197 °C. Com-
pound 38 appeared as a mixture of two isomers, a and b, in a
ratio of 1:2 in its NMR spectra. 1H NMR (CDCl3): 38a , δ 8.15
(d, J ) 8.0 Hz, 1H), 7.78 (t, J ) 8.0 Hz, 1H), 7.61-7.09 (m,
14H), 4.00 (q, J ) 6.8 Hz, 1H), 1.46 (s, 9H), 1.22 (d, J ) 6.8
Hz, 3H); 38b, δ 8.06 (d, J ) 8.0 Hz, 1H), 7.69 (t, J ) 8.0 Hz,
1H), 7.61-7.01 (m, 14H), 4.33 (q, J ) 6.8 Hz, 1H), 1.44 (s, 9H),
1.35 (d, J ) 6.8 Hz, 3H). 13C NMR (CDCl3): 38a , δ 179.4,
161.5, 159.8, 147.8, 145.8, 145.1, 134.9, 128.3, 128.1, 127.0,
126.7, 126.3, 126.0, 125.5, 120.2, 79.3, 42.4, 39.2, 27.3, 14.6;
38b, δ 179.4, 161.5, 159.6, 147.8, 145.4, 144.7, 135.0, 128.2,
128.0, 126.9, 126.8, 126.2, 126.0, 125.2, 120.3, 79.5, 42.1, 39.2,
27.3, 14.9. HRMS: calcd for C28H30N3O3 456.2287, found
456.2287. Anal. Calcd for C28H29N3O3: C, 73.84; H, 6.37; N,
9.23. Found: C, 73.73; H, 6.49; N, 9.14.
2-(1-Iod oe t h yl)-3-(p iva loyla m in o)-4(3H )-q u in a zoli-
1
n on e (43): mp 167-168 °C; H NMR (CDCl3) δ 8.22 (d, J )
8.0 Hz, 1H), 8.09 (s, exch, 1H), 7.77-7.72 (m, 2H), 7.48 (t, J )
8.0 Hz, 1H), 4.93 (q, J ) 6.9 Hz, 1H), 2.27 (d, J ) 6.9 Hz, 3H),
1.43 (s, 9H); 13C NMR (CDCl3) δ 178.8, 160.0, 156.8, 146.6,
134.9, 128.2, 127.4, 127.0, 121.1, 39.1, 27.1, 24.3, 16.4; HRMS
calcd for C15H19N3O2I 400.0522, found 400.0522. Anal. Calcd
for C15H18N3O2I: C, 45.11; H, 4.51; N, 10.52. Found: C, 45.29;
H, 4.63; N, 10.29.
3-(Acet yla m in o)-2-(2-h yd r oxy-2,2-d ip h en yl-1-m et h yl-
eth yl)-4(3H)-qu in a zolin on e (44): mp 139-140 °C. Com-
pound 44 appears in its NMR spectra as a mixture of two
isomers, a and b, in a ratio of 1:2. 1H NMR (CDCl3): 44a , δ
8.74 (s, exch, 1H), 8.11 (d, J ) 8.0 Hz, 1H), 7.73-6.89 (m, 14H),
4.10 (q, J ) 6.9 Hz, 1H), 3.32 (s, 3H), 1.34 (d, J ) 6.9 Hz, 3H);
44b, δ 8.76 (s, exch, 1H), 8.11 (d, J ) 8.0 Hz, 1H), 7.73-6.89
(m, 14H), 4.42 (q, J ) 6.9 Hz, 1H), 2.25 (s, 3H), 1.24 (d, J )
6.9 Hz, 3H). 13C NMR (CDCl3): 44a , δ 171.5, 161.8, 160.4,
147.9, 145.4, 144.7, 135.2, 128.1, 127.0, 126.6, 126.3, 125.6,
125.1, 120.1, 79.4, 42.5, 21.3, 14.7; 44b, δ 171.5, 161.9, 160.3,
2-(1-Deu ter ioeth yl)-3-(p iva loyla m in o)-4(3H)-qu in a zoli-
1
n on e (39): mp 194-195 °C; H NMR (CDCl3) δ 8.44 (s, exch,
1H), 8.10 (d, J ) 8.0 Hz, 1H), 7.71 (t, J ) 8.0 Hz, 1H), 7.58 (d,
J ) 8.0 Hz, 1H), 7.40 (t, J ) 8.0 Hz, 1H), 2.64-2.62 (m), 1.36,
1.20 (m, J ) 7.2 Hz, 3H); 13C NMR (CDCl3) δ 180.0, 160.4,
158.5, 147.0, 134.7, 127.5, 126.5, 126.5, 120.453, 38.951, 27.2,

654 J . Org. Chem., Vol. 61, No. 2, 1996
Smith et al.
147.9, 145.53, 144.7, 135.4, 128.2, 127.2, 126.7, 126.4, 126.0,
125.5, 120.1, 79.7, 42.3, 21.2, 15.3. HRMS: calcd for C25H24N3O3
414.1818, found 414.1818. Anal. Calcd for C25H23N3O3: C,
72.64; H, 5.57; N, 10.17. Found: C, 72.51; H, 5.70; N, 10.39.
3-(Acet yla m in o)-2-(1-d eu t er ioet h yl)-4(3H )-q u in a zoli-
n on e (45): mp 135-136 °C; 1H NMR (CDCl3) δ 9.12 (s, exch,
1H), 8.15 (d, J ) 8.0 Hz, 1H), 7.74 (t, J ) 8.0 Hz, 1H), 7.67 (d,
J ) 8.0 Hz, 1H, H-8), 7.42 (t, J ) 8.0 Hz, 1H, H-6), 2.84-2.78
(m, 1H, CH), 2.26 (s, 3H), 1.32 (m, J ) 7.3 Hz, 3H); 13C NMR
(CDCl3) δ 170.2, 160.9, 158.6, 147.2, 135.0, 127.5, 126.71,
126.66, 120.5, 26.9, 26.6, 26.4, 21.0, 10.6; HRMS calcd for
C12H13N3O2D 233.1149, found 233.1149.
25.1, 20.9, 14.2; 49b, δ 170.8, 159.5, 157.6, 146.2, 134.5, 127.5,
126.9, 126.5, 120.8, 24.2, 20.5, 15.6. HRMS: calcd for
C12H12N3O2I 356.9974, found 356.9974. Anal. Calcd for
C12H11N3O2I: C, 40.33; H, 3.36. N, 11.76. Found: C, 40.47;
H, 3.26; N, 11.71.
2-(2-Hyd r oxy-2,2-d ip h en yl-1-m eth yleth yl)-3-[[(h yd r ox-
ydiph en ylm eth yl)acetyl]am in o]-4(3H)-qu in azolin on e (50):
mp 202 °C. Compound 50 appears in its NMR spectra as a
mixture of two isomers, a and b, in a ratio of 3:5. 1H NMR
(DMSO-d6): 50a , δ 10.99 (s, exch, 1H), 8.06 (d, J ) 8.0 Hz,
1H), 7.74-6.88 (m, 24H), 6.29 (s, exch, 1H), 4.19 (q, J ) 6.8
Hz, 1H), 3.73, 3.51 (2 d, J ) 15.0 Hz, 2H), 1.15 (d, J ) 6.8 Hz,
3H); 50b, δ 11.33 (s, exch, 1H), 8.05 (d, J ) 8.0 Hz, 1H), 7.74-
6.88 (m, 24H), 6.01 (s, exch, 1H), 4.26 (q, J ) 6.8 Hz, 1H),
3.79, 3.38 (2 d, J ) 15.0 Hz, 2H), 0.70 (d, J ) 6.8 Hz, 3H). 13C
NMR (DMSO-d6): 50a , 171.1, 162.6, 158.4 148.2, 147.5, 146.3,
145.1, 144.8, 134.8, 128.1, 128.0, 126.8, 126.5, 126.4, 125.8,
125.7, 125.3, 125.2, 120.0, 79.2, 76.2, 44.9, 41.4, 14.5; 50b, δ
171.9, 162.7, 158.4, 148.4, 146.9, 146.1, 145.6, 144.9, 134.9,
128.1, 128.0, 127.8, 127.7, 126.8, 126.0, 125.6, 125.5, 125.4,
120.1, 78.9, 76.2, 44.7, 41.6, 14.0. HRMS: calcd for C38H34N3O4
596.2549, found 596.2546. Anal. Calcd for C38H33N3O4: C,
76.64; H, 5.54; N, 7.06. Found: C, 76.40; H, 5.74; N, 6.99.
2-[1-(1-Hyd r oxycycloh exyl)eth yl]-3-[[(1-h yd r oxycyclo-
h exyl)a cetyl]a m in o]-4(3H)-qu in a zolin on e (51): mp 102-
104 °C. Compound 51 appears in its NMR spectra as a
mixture of two isomers, a and b, in a ratio of 5:6. 1H NMR
(CDCl3): 51a , δ 9.35 (s, exch, 1H), 7.82 (d, J ) 8.0 Hz, 1H),
7.61 (t, J ) 8.0 Hz, 1H), 7.51 (d, J ) 8.0 Hz, 1H), 7.18 (t, J )
8.0 Hz, 1H), 5.14 (s, exch, 1H), 4.46 (s, exch, 1H), 2.97 (q, J )
7.0 Hz, 1H), 1.96-1.25 (m, 20H), 1.36 (d, J ) 7.0 Hz, 3H); 51b,
δ 9.30 (s, exch, 1H), 7.79 (d, J ) 8.0 Hz, 1H), 7.57 (t, J ) 8.0
Hz, 1H), 7.53 (d, J ) 8.0 Hz, 1H), 7.20 (t, J ) 8.0 Hz, 1H),
5.68 (s, exch, 1H), 4.28 (s, exch, 1H), 3.23 (q, J ) 7.0 Hz, 1H),
1.96-1.25 (m, 20H), 1.28 (d, J ) 7.0 Hz, 3H). HRMS: calcd
for C24H34N3O4 428.2549, found, 428.2549.
2-(1-Meth ylp r op yl)-3-(p iva loyla m in o)-4(3H)-qu in a zoli-
n on e (52): mp 126-128 °C. Compound 52 appears in its NMR
spectra as a mixture of two isomers, a and b, in a ratio of 1:1.
1H NMR (CDCl3): 52a , δ 8.30 (s, exch, 1H), 8.15 (d, J ) 8.0
Hz, 1H), 7.72 (t, J ) 8.0 Hz, 1H), 7.65 (d, J ) 8.0 Hz, 1H),
7.40 (t, J ) 8.0 Hz, 1H), 2.80 (sextet, J ) 6.8 Hz, 1H), 1.94 (d
quintet, J ) ca. 7 and 15 Hz, 1H), 1.58-1.45 (m, 1H), 1.39 (s,
9H), 1.19 (d, J ) 6.8 Hz, 3H), 0.92 (t, J ) 6.8 Hz, 3H); 52b, δ
8.30 (s, exch, 1H), 8.15 (d, J ) 8.0 Hz, 1H), 7.72 (t, J ) 8.0 Hz,
1H), 7.65 (d, J ) 8.0 Hz, 1H), 7.40 (t, J ) 8.0 Hz, 1H), 2.89
(sextet, J ) 6.6 Hz, 1H), 1.73 (d quintet, J ) ca. 7 and 15 Hz,
1H), 1.58-1.45 (m, 1H), 1.40 (s, 9H), 1.29 (d, J ) 6.6 Hz, 3H),
0.86 (t, J ) 6.8 Hz, 3H). 13C NMR (CDCl3): 52a , δ 179.1,
161.4, 160.7, 147.2, 134.6, 127.3, 126.6, 126.4, 120.4, 40.0, 37.9,
27.2, 27.1, 18.7, 11.9; 52b, δ 179.2, 161.4, 160.7, 147.2, 134.7,
127.6, 126.6, 126.4, 120.5, 39.0, 37.6, 28.7, 27.2, 17.6, 12.0.
HRMS: calcd for C17H24N3O2 302.1869, found 302.1869. Anal.
Calcd for C17H23N3O2: C, 67.77; H, 7.64; N, 13.95. Found: C,
67.55; H, 7.75; N, 13.99.
2-[1-(Hyd r oxyd ip h en ylm eth yl)p r op yl]-3-(p iva loyla m i-
n o)-4(3H)-qu in a zolin on e (53): mp 175 °C. Compound 53
appears in its NMR spectra as a mixture of two isomers, a
and b, in a ratio of 1:6. 1H NMR (CDCl3): 53a δ 8.13 (d, J )
8.0 Hz, 1H), 7.83-7.08 (m, 13H), 6.79 (s, exch, 1H), 6.38 (s,
exch, 1H), 4.11 (br, 1H), 1.98, 1.80 (two m, 2H), 1.33 (s, 9H),
0.74 (br, 3H); 53b, δ 8.13 (d, J ) 8.0 Hz, 1H), 7.83-7.08 (m,
13H), 4.17 (dd, J ) 3 and 10 Hz, 1H), 2.18 (ddq, J ) 10, 15
and 7 Hz, 1H), 1.92 (ddq, J ) 3, 15 and 10 Hz, 1H), 1.43 (s,
9H). 13C NMR (CDCl3): δ 177.9, 160.3, 159.0, 147.1, 145.5,
144.2, 135.1, 128.4, 127.9, 127.2, 127.1, 125.8, 125.1, 120.5,
79.6, 50.4, 38.9, 27.36, 23.4, 12.8. HMRS: calcd for C29H32N3O3
470.2444, found 470.2444. Anal. Calcd for C29H31N3O3: C,
74.20; H, 6.61; N, 8.95. Found: C, 73.97; H, 6.71; N, 8.98.
2-[1-(1-Hyd r oxycycloh exyl)p r op yl]-3-(p iva loyla m in o)-
4(3H)-qu in a zolin on e (54): mp 80 °C. Compound 54 appears
in its NMR spectra as a mixture of two isomers, a and b, in a
ratio of 10:11. 1H NMR (CDCl3): 54a , δ 8.16 (d, J ) 8.0 Hz,
1H), 8.04 (s, exch, 1H), 7.74 (t, J ) 8.0 Hz, 1H), 7.66 (d, J )
8.0 Hz, 1H), 7.42 (t, J ) 8.0 Hz, 1H), 4.16 (s, exch, 1H), 2.91
(dd, J ) 4.4 and 9.6 Hz, 1H), 2.16-1.16 (complex overlapping
3-(Acetylam in o)-2-[1-(1-h ydr oxycycloh exyl)eth yl]-4(3H)-
qu in a zolin on e (46): mp 139-140 °C. Compound 46 appears
in its NMR spectra as a mixture of two isomers, a and b, in a
ratio of 9:10. 1H NMR (CDCl3): 46a , δ 9.50 (s, exch, 1H), 8.11
(d, J ) 8.0 Hz, 1H), 7.74 (t, J ) 8.0 Hz, 1H), 7.64 (d, J ) 8.0
Hz, 1H), 7.41 (t, J ) 8.0 Hz, 1H), 5.89 (s, exch, 1H), 2.96 (q, J
) 7.0 Hz, 1H), 2.29 (s, 3H), 1.92-1.35 (m, 10H), 1.28 (d, J )
7.0 Hz, 3H); 46b, δ 9.50 (s, exch, 1H), 8.11 (d, J ) 8.0 Hz,
1H), 7.74 (t, J ) 8.0 Hz, 1H), 7.62 (d, J ) 8.0 Hz, 1H), 7.41 (t,
J ) 8.0 Hz, 1H), 5.18 (s, exch, 1H), 3.21 (q, J ) 7.0 Hz, 1H),
2.30 (s, 3H), 1.92-1.35 (m, 10H), 1.32 (d, J ) 7.0 Hz, 3H). 13
C
NMR (CDCl3): 46a , δ 170.9, 162.1, 160.3, 145.5, 135.2, 127.3,
127.0, 126.7, 120.3, 72.3, 42.8, 36.9, 35.2, 25.6, 21.9, 21.7, 21.0,
13.5; 46b, δ 171.0, 162.5, 160.3, 145.9, 135.2, 127.1, 127.0,
126.7, 120.4, 72.7, 42.8, 37.4, 34.8, 25.6, 21.9, 21.7, 21.0, 13.7.
HRMS: calcd for C18H24N3O3 330.1818, found 330.1818. Anal.
Calcd for C18H23N3O3: C, 65.65; H, 6.99; N, 12.76. Found: C,
65.78; H, 7.02; N, 12.79.
3-(Ace t yla m in o)-2-[1-(1-h yd r oxycyclop e n t yl)e t h yl]-
4(3H)-qu in a zolin on e (47): mp 133-135 °C. Compound 47
appears in its NMR spectra as a mixture of two isomers, a
and b, in a ratio of 9:11. 1H NMR (DMSO-d6): 47a , δ 10.87
(s, exch, 1H), 8.17 (d, J ) 8.0 Hz, 1H), 7.76 (t, J ) 8.0 Hz,
1H), 7.62 (d, J ) 8.0 Hz, 1H), 7.46 (t, J ) 8.0 Hz, 1H), 5.26 (s,
exch, 1H), 3.26 (q, J ) 7.0 Hz, 1H), 2.19 (s, 3H), 2.01-1.46
(m, 8H), 1.33 (d, J ) 7.0 Hz, 3H); 47b, δ 10.87 (s, exch, 1H).
8.17 (d, J ) 8.0 Hz, 1H), 7.78 (t, J ) 8.0 Hz, 1H), 7.64 (d, J )
8.0 Hz, 1H), 7.46 (t, J ) 8.0 Hz, 1H), 5.59 (s, exch, 1H), 2.90
(q, J ) 7.0 Hz, 1H), 2.20 (s, 3H), 2.01-1.46 (m, 8H), 1.39 (d, J
) 7.0 Hz, 3H). 13C NMR (DMSO-d6): 47a , δ 175.1, 167.8,
164.0, 150.4, 139.7, 131.8, 131.7, 131.5, 125.6, 87.9, 48.0, 44.8,
42.7, 28.9, 28.7, 25.7, 20.0; 47b, δ 175.0, 167.8, 164.0, 150.6,
139.7, 131.8, 131.7, 131.5, 125.7, 87.6, 48.6, 44.9, 43.3, 28.7,
28.9, 25.7, 20.2. HRMS: calcd for C17H22N3O3 316.1661, found
316.1661. Anal. Calcd for C17H21N3O3: C, 61.26; H, 6.91; N,
12.61. Found: C, 61.12; H, 6.91; N, 12.63.
3-(Acetylam in o)-2-(2-h ydr oxy-1-m eth yl-2-ph en ylpr opyl)-
4(3H)-qu in a zolin on e (48): mp 130-131 °C. Compound 48
appears in its NMR spectra as a mixture of two isomers, a
and b, in a ratio of 2:3. 1H NMR (CDCl3): 48a , δ 9.21 (s, exch,
1H), 8.13 (d, J ) 8.0 Hz, 1H), 7.76 (t, J ) 8.0 Hz, 1H), 7.68 (d,
J ) 8.0 Hz, 1H), 7.50-7.24 (m, 6H), 6.03 (s, exch, 1H), 3.57
(q, J ) 7.0 Hz, 1H), 2.29 (s, 3H), 1.39 (s, 3H); 48b, δ 9.24 (s,
exch, 1H) 8.13 (d, J ) 8.0 Hz, 1H), 7.76 (t, J ) 8.0 Hz, 1H),
7.68 (d, J ) 8.0 Hz, 1H), 7.50-7.24 (m, 6H), 6.59 (s, exch, 1H),
3.30 (q, J ) 7.0 Hz, 1H), 2.33 (s, 3H), 1.63 (s, 3H), 1.00 (d, J
) 7.0 Hz, 3H). 13C NMR (CDCl3): 48a , δ 171.1, 161.8, 160.3,
146.2, 145.5, 135.4, 128.2, 127.3, 127.2, 126.9, 126.6, 124.9,
120.4, 75.6, 44.5, 29.9, 21.0; 14.9; 48b, d 171.0, 162.3, 160.3,
146.2, 145.8, 128.3, 127.1, 126.8, 126.6, 124.8, 120.5, 75.6, 44.6,
29.9, 21.1, 15.3. HRMS: calcd for C20H22N3O3 352.1661, found
352.1661. Anal. Calcd for C20H21N3O3: C, 68.37; H, 5.98; N,
11.92. Found: C, 68.16; H, 6.23; N, 11.62.
3-(Acet yla m in o)-2-(1-iod oet h yl)-4(3H )-q u in a zolin on e
(49): mp 145-146 °C. Compound 49 appears in its NMR
spectra as a mixture of two isomers, a and b, in a ratio of 2:9.
1H NMR (DMSO-d6): 49a , δ 10.59 (s, exch, 1H), 8.10 (d, J )
8.0 Hz, 1H), 7.80 (t, J ) 8.0 Hz, 1H), 7.63 (d, J ) 8.0 Hz, 1H),
7.33 (t, J ) 8.0 Hz, 1H), 5.40 (q, J ) 6.8 Hz, 1H), 3.44 (s, 3H),
2.23 (d, J ) 6.8 Hz, 3H); 49b, δ 10.98 (s, exch, 1H), 8.18 (d, J
) 8.0 Hz, 1H), 7.80 (t, J ) 8.0 Hz, 1H), 7.72 (d, J ) 8.0 Hz,
1H), 7.51 (d, J ) 8.0 Hz, 1H), 5.10 (q, J ) 6.8 Hz, 1H), 3.44 (s,
3H), 2.25 (d, J ) 6.8 Hz, 3H). 13C NMR (DMSO-d6): 49a , δ
168.8, 158.8, 157.3, 146.2, 134.4, 127.4, 126.1, 125.9, 119.5,

Lithiation of 3-(Acylamino)quinazolinones
J . Org. Chem., Vol. 61, No. 2, 1996 655
signals, 12H), 1.42 (s, 9H), 0.87 (t, J ) 7.5 Hz, 3H); 54b, δ
8.26 (s, exch, 1H), 8.18 (d, J ) 8.0 Hz, 1H), 7.76 (t, J ) 8.0 Hz,
1H), 7.66 (d, J ) 8.0 Hz, 1H), 7.46 (t, J ) 8.0 Hz, 1H), 5.58 (s,
exch, 1H), 3.01 (dd, J ) 3.3 and 9.7 Hz, 1H), 2.16-1.16
(complex overlapping signals, 12H), 0.83 (t, J ) 7.3 Hz, 3H).
13C NMR (CDCl3): 54a , δ 178.8, 162.1, 160.0, 145.6, 134.8,
127.2, 126.9, 126.8, 120.6, 72.9, 49.7, 39.0, 37.6, 35.8, 28.3, 27.2,
25.8, 22.7, 20.6, 12.5; 54b, δ 177.9, 160.4, 159.8, 146.1, 135.1,
127.4, 127.0, 126.7, 120.4, 73.8, 51.5, 38.9, 37.6, 34.4, 27.3, 27.0,
25.6, 21.9, 21.6, 13.2. HRMS: calcd for C22H32N3O3 386.2444,
found 386.2444. Anal. Calcdfor C22H31N3O3: C, 68.57; H, 8.05;
N, 10.91. Found: C, 68.65; H, 8.17; N, 10.73.
3-(Acet yla m in o)-2-(1-m et h ylp r op yl)-4(3H )-q u in a zoli-
n on e (55): mp 102-104 °C. Compound 55 appears in its NMR
spectra as a mixture of two isomers, a and b, in a ratio of 1:1.
1H NMR (CDCl3): 55a , δ 9.47 (s, exch, 1H), 8.17 (d, J ) 8.0
Hz, 1H), 7.73 (t, J ) 8.0 Hz, 1H), 7.67 (d, J ) 8.0 Hz, 1H),
7.38 (t, J ) 8.0 Hz, 1H), 2.92 (sextet, J ) 7.0 Hz, 1H), 2.26 (s,
3H), 1.99 (d quintet, J ) ca. 7 and 15 Hz, 1H), 1.62-1.51 (m,
1H), 1.23 (d, J ) 7.0 Hz, 3H), 0.93 (t, J ) 7.5 Hz, 3H); 55b, δ
9.47 (s, exch, 1H), 8.17 (d, J ) 8.0 Hz, 1H), 7.73 (t, J ) 8.0 Hz,
1H), 7.67 (d, J ) 8.0 Hz, 1H), 7.38 (t, J ) 8.0 Hz, 1H), 3.04
(sextet, J ) 7.0 Hz, 1H), 2.27 (s, 3H), 1.81 (d quintet, J ) ca.
7 and 15 Hz, 1H), 1.62-1.51 (m, 1H), 1.30 (d, J ) 7.0 Hz, 3H),
0.87 (t, J ) 7.5 Hz, 3H). 13C NMR (CDCl3): 55a , δ 170.7,
161.6, 161.2, 147.3, 134.9, 127.6, 126.6, 126.5, 120.3, 37.9, 28.8,
21.0, 18.0, 12.0; 55b, δ 170.8, 161.5, 161.1, 147.3, 134.9, 127.6,
126.6, 126.5, 120.4, 37.5, 27.1, 19.2, 17.9, 11.8. HRMS: calcd
for C14H17N3O2 259.1321, found 259.1321. Anal. Calcd for
C H17N3O2 H2O: C, 60.66; H, 6.86; N, 15.16. Found: C, 60.71;
H1,4 7.58; N, 15.15.
3-(Acetylam in o)-2-[1-(h ydr oxydiph en ylm eth yl)pr opyl]-
4(3H)-qu in a zolin on e (56): mp 177-178 °C. Compound 56
appears in its NMR spectra as a mixture of two isomers, a
and b, in a ratio of 1:2. 1H NMR (DMSO-d6): 56a , δ 10.88 (s,
exch, 1H), 8.05 (d, J ) 8.0 Hz, 1H), 7.78-6.99 (m, 14H), 4.15
(t, J ) 5.5 Hz, 1H), 2.28 (s, 3H), 1.93-1.78 (overlapping m,
1H), 1.74-1.63 (overlapping m, 1H), 0.64 (t, J ) 7.6 Hz, 3H);
56b, δ 11.20 (s, exch, 1H), 8.01 (d, J ) 8.0 Hz, 1H), 7.79-6.99
(m, 14H), 4.28 (t, J ) 5.5 Hz, 1H), 2.23 (s, 3H), 1.93-1.78
(overlapping m, 1H), 1.74-1.63 (overlapping m, 1H), 0.51 (t,
J ) 7.6 Hz, 3H). 13C NMR (DMSO-d6): 56a , 170.3, 161.8,
158.2, 148.4, 145.8, 144.4, 135.0, 127.9, 127.8, 127.0, 126.3,
125.8, 125.5, 120.0, 79.1, 47.3, 22.9, 20.8, 12.4; 56b, δ 170.0,
162.1, 158.1, 148.3, 145.3, 144.6, 135.0, 128.1, 127.7, 126.5,
126.3, 125.6, 125.2, 119.9, 79.5, 48.1, 25.5, 20.7, 12.7. HRMS:
calcd for C26H26N3O3 428.1974, found 428.1974. Anal. Calcd
for C26H25N3O3: C, 73.07; H, 5.85; N, 9.84. Found: C, 73.16;
H, 5.99; N, 9.59.
3-(Acet yla m in o)-2-[1-(1-h yd r oxycycloh exyl)p r op yl]-
4(3H)-qu in a zolin on e (57): mp 78-80 °C. Compound 57
appears in its NMR spectra as a mixture of two isomers, a
and b, in a ratio of 1:1. 1H NMR (CDCl3): 57a , δ 8.99 (s, exch,
1H), 8.17 (d, J ) 8.0 Hz, 1H), 7.76 (t, J ) 8.0 Hz, 1H), 7.67 (d,
J ) 8.0 Hz, 1H), 7.43 (t, J ) 8.0 Hz, 1H), 4.49 (s, exch, 1H),
3.04 (dd, J ) 4.4 and 10.0 Hz, 1H), 2.30 (s, 3H), 2.07-1.11
(complex overlapping signals, 12H), 0.81 (t, J ) 7.5 Hz, 3H);
57b, δ 8.93 (s, exch, 1H), 8.17 (d, J ) 8.0 Hz, 1H), 7.77 (t, J )
8.0 Hz, 1H), 7.78 (d, J ) 8.0 Hz, 1H), 7.45 (t, J ) 8.0 Hz, 1H),
5.52 (s, exch, 1H), 3.10 (dd, J ) 3.9 and 9.9 Hz, 1H), 2.31 (s,
3H), 2.07-2.11 (complex overlapping signals, 12H), 0.83 (t, J
) 7.5 Hz, 3H). 13C NMR (CDCl3): 57a , δ 170.7, 162.0, 160.4,
145.7, 135.3, 127.3, 127.1, 126.9, 120.4, 72.9, 50.1, 37.5, 34.8,
25.8, 22.6, 21.8, 21.5, 21.1, 13.0; 57b, δ 170.2, 160.8, 160.3,
146.1, 135.1, 127.5, 126.94, 126.90, 120.2, 63.5, 51.6, 37.7, 35.7,
25.7, 22.0, 21.9, 21.5, 21.0, 12.2. HRMS: calcd for C19H26N3O3
344.1974, found 344.1974. Anal. Calcd for C19H25N3O3: C,
66.47; H, 7.29; N, 12.24. Found: C, 66.29; H, 7.51; N, 12.19.
2-[1-(1-H yd r oxycycloh exyl)p r op yl]-3-[[(1-h yd r oxycy-
cloh exyl)a cetyl]a m in o]-4(3H)-qu in a zolin on e (58): mp 72-
73 °C. Compound 58 appears in its NMR spectra as a mixture
of two isomers, a and b, in a ratio of 10:11. 1H NMR (CDCl3):
58a , δ 9.02 (s, exch, 1H), 7.91 (d, J ) 8.0 Hz, 1H), 7.73-7.61
(m, 2H), 7.26 (t, J ) 8.0 Hz, 1H), 5.44 (s, exch, 1H), 4.25 (s,
exch, 1H), 2.16 (dd, J ) 4.0 and 10.0 Hz, 1H), 2.63-1.05
(complex overlapping signals, 22H), 0.84 (t, J ) 7.5 Hz, 3H);
58b, δ 8.90 (s, exch, 1H), 7.91 (d, J ) 8.0 Hz, 1H), 7.73-7.61
(m, 2H), 7.26 (t, J ) 8.0 Hz, 1H), 5.44 (s, exch, 1H), 4.25 (s,
exch, 1H), 3.07 (dd, J ) 4.4 and 9.6 Hz, 1H), 2.63-1.05
(complex overlapping signals, 22H), 0.98 (t, J ) 7.5 Hz, 3H).
13C NMR (CDCl3): 58a , δ 171.6, 162.06, 160.5, 146.0, 135.0,
127.3, 126.9, 126.8, 120.0, 73.5, 71.0, 50.2, 47.2, 42.0, 37.5, 36.1,
34.8, 25.49, 25.47, 25.4, 22.6, 22.1, 21.7, 21.6, 12.3; 58b, δ
171.1, 160.8, 160.4, 145.6, 135.2, 127.0, 126.9, 126.8, 120.2,
73.0, 71.0, 51.6, 46.9, 38.6, 37.6, 36.7, 35.7, 25.8, 25.47, 25.46,
22.6, 22.0, 21.8, 21.6, 12.9. HRMS: calcd for C25H35N3O4
441.2628, found 441.2628. Anal. Calcd for C25H35N3O4: C,
68.03; H, 7.94; N, 9.52. Found: C, 67.92; H, 8.06; N, 9.36.
Hyd r olysis Rea ction s. 3-Am in o-2-m eth yl-4(3H)-qu in -
a zolin on e (32). A mixture of compound 15 or 23 (0.80 mmol),
MeOH (10 mL), and aqueous NaOH (20%, 7 mL) was heated
under reflux for 1 h. The solvent was removed in vacuo, and
the residue was extracted with EtOAc (15 mL). The extract
was washed with H2O (2 × 10 mL), dried (MgSO4), and
evaporated to give 32 (0.11 g, 0.6 mmol): mp 152 °C (lit. mp
152 °C).20
3-Am in o -2-(1-m e t h y le t h y l)-4(3H )-q u in a zo lin o n e -
(34c). A mixture of compound 17 or 25 (0.70 mmol), MeOH
(10 mL), and aqueous NaOH (20%, 5 mL) or hydrochloric acid
(1 M, 5 mL) was heated under reflux for 1 h. In the acidic
reaction the mixture was then neutralized with aqueous
NaOH. The solvent was removed in vacuo, and the residue
was extracted with EtOAc (15 mL). The extract was washed
with H2O (2 × 10 mL), dried (MgSO4), and evaporated to give
34c (ca. 0.011 g, 0.52 mmol; 75%), which was recrystallized
from light petroleum ether (bp 100-120 °C): mp 81 °C (lit.
mp 80).21
Ack n ow led gm en t. We thank the Egyptian Govern-
ment for a studentship to G. A. El-Hiti, the EPSRC and
the University of Wales for research grants for purchase
of the NMR equipment used in this work, and the
EPSRC Mass Spectrometry Centre in Swansea for mass
spectra.
Su p p or tin g In for m a tion Ava ila ble: Compound charac-
terization data, complete with NMR peak assignments (21
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
J O950988T