Rearrangement of 4-imino-4H-3,1-benzoxazines to 4-quinazolinones via amidine carboxamides

Full text of DOI:10.1021/jo9820465

J . Org. Chem. 1999, 64, 1397-1399
1397
Rea r r a n gem en t of
4-Im in o-4H-3,1-ben zoxa zin es to
4-Qu in a zolin on es via Am id in e
Ca r boxa m id es
Feng He and Barry B. Snider*
Department of Chemistry, Brandeis University,
Waltham, Massachusetts, 02454-9110
Received October 9, 1998
Ganesan recently reported a very short synthesis of
fumiquinazoline G, in which the key step is the cycliza-
tion of N-acylanthranilamide 1, R ) Fmoc, with PPh3,
I2, and EtN(i-Pr)2 in CH2Cl2 at 25 °C to give a cyclization
product that they reported to be 4-quinazolinone 2, R )
Fmoc, in 65% yield.1,2 Deprotection of the Fmoc group
with 20% piperidine in CH2Cl2 followed by preparative
TLC of the crude product gives 75% of fumiquinazoline
G (4) from the cyclization product.
fumiquinazoline G, and C-4 absorbs at δ 147.5 as opposed
to δ 160.9 in fumiquinazoline G.4 Furthermore, there are
no NOEs between the aliphatic protons of the two
different side chains, which is consistent with 4-imino-
4H-3,1-benzoxazine 3 but not with 4-quinazolinone 2.
Finally, the product hydrolyzes to regenerate 1, R )
Fmoc, on silica gel chromatography unless Et3N is
present in the eluent. 4-Imino-4H-3,1-benzoxazines are
expected to be hydrolytically unstable, while 4-quinazoli-
nones are known to be hydrolytically stable.5
We have previously prepared 4-imino-4H-3,1-benzox-
azines by the addition of primary amines to acid chlorides
such as 7, which provides 85% of 8 with spectral data
similar to those of 3.6 Of even greater significance,
Mazurkiewicz reported in 1989 that treatment of N-
acylanthranilamides 9a , 9b, 9d , and 9e with PPh3, Br2,
and Et3N in CH2Cl2 for 0.2-1 h at reflux (conditions very
similar to those of Ganesan) provides 84-95% of the
corresponding 4-imino-4H-3,1-benzoxazine 10.7,8 Mazurk-
iewicz reported that 4-imino-4H-3,1-benzoxazines 10a
and 10b isomerize to 4-quinazolinones 11a and 11b on
treatment with excess HCl in ClCH2CH2Cl for 120 h at
25 °C or 2-6 h at 70 °C.7
Despite this compelling evidence that the structure of
the cyclization product is 3, not 2, we are able to reproduce
Ganesan’s fumiquinazoline G synthesis. Treatment of 3,
R ) Fmoc, with piperidine to deprotect the Fmoc group
affords an intermediate that is converted to fumiquinazo-
line G (4) on preparative TLC. However, deprotection of
the Fmoc group with DMAP provides 3, R ) H, that does
not cyclize to fumiquinazoline G on preparative TLC.
Moreover, deprotection of 3, R ) allyloxycarbonyl, with
Pd(PPh3)4 also gives 3, R ) H, that does not cyclize to
fumiquinazoline G on preparative TLC. These results
suggest that piperidine plays a crucial role in the
conversion of 3 to 4 beyond that of deprotecting the Fmoc
group.
We recently reported the first synthesis of asperlicin
(5) which was based on a novel, efficient route to the
hydroxyimidazoindolone moiety.3 We reexamined Gane-
san’s fumiquinazoline G synthesis as part of a plan to
use his 4-quinazolinone synthesis and our route to
hydroxyimidazoindolones for the synthesis of fumiquinazo-
line B (6).
The spectral data and chemical reactivity of Ganesan’s
cyclization product suggested that it is not quinazolinone
2, R ) Fmoc, but rather 4-imino-4H-3,1-benzoxazine 3,
R ) Fmoc. The downfield aromatic proton absorbs at δ
8.20 rather than at δ 8.39 as in fumiquinazoline G (4).
The downfield 13C NMR absorptions, which were as-
signed by HMBC correlation, are even more problematic.
C-2 absorbs at δ 159.1, as opposed to δ 151.4 in
We prepared simpler systems that were more ame-
nable to detailed study to determine the function of
piperidine. Cyclization of 9a -c with PPh3, I2, and EtN-
(4) Takahashi, C.; Matsushita, T.; Doi, M.; Minoura, K.; Shingu, T.;
Kumeda, Y.; Numata, A. J . Chem. Soc., Perkin Trans. 1 1995, 2345-
2353.
(5) (a) Brown, D. J . Quinazolines, Supplement 1; Wiley: New York,
1996; Chapter 4. (b) Sinha, S.; Srivastava, M. In Progress in Drug
Research; J ucker, E., Ed.; Birkha¨user: Basel, 1994; Vol. 43, pp 143-
238.
(6) He, F., Snider, B. B. Unpublished results.
(1) Wang, H.; Ganesan, A. J . Org. Chem. 1998, 63, 2432-2433.
(2) For the first synthesis of fumiquinazoline G see: He, F.; Snider,
B. B. Synlett 1997, 483-484.
(3) He, F.; Foxman, B. M.; Snider, B. B. J . Am. Chem. Soc. 1998,
120, 6417-6418.
(7) Mazurkiewicz, R. Monatsh. Chem. 1989, 120, 973-980.
(8) For other reports of 4-imino-4H-3,1-benzoxazines see: (a) Molina,
P.; Alajarin, M.; Vidal, A.; De la Concepcion Foces-Foces, M.; Hernan-
dez Cano, F. Tetrahedron 1989, 45, 4263-4286. (b) Colonna, M.; Poloni,
M. Ann. Chim. (Rome) 1973, 63, 287-290.
10.1021/jo9820465 CCC: $18.00 © 1999 American Chemical Society
Published on Web 02/04/1999

1398 J . Org. Chem., Vol. 64, No. 4, 1999
Notes
with CH2Cl2.10 Dissolution of 10a in neat piperidine for
1 h or in 20% piperidine in EtOAc overnight, followed
by concentration, affords 82% of amidine carboxamide 12.
The 1H NMR spectrum shows a characteristic absorption
at δ 6.55 which fits well with that reported for the parent
amidine lacking the N-methylcarboxamide,11 and the
absorption at δ 8.19 is shifted downfield from δ 8.01 in
10a . The configuration of the amidine carbon-nitrogen
double bond was established by the strong NOE between
the hydrogen at δ 6.55 and the methyl group at δ 1.92.
An NOE between the NH proton at δ 8.97 and the
piperidine hydrogens at δ 3.60 suggests that 12 exists
primarily in the conformation shown, possibly because
of intramolecular hydrogen bonding between the amide
hydrogen and the amidine nitrogen. The 13C NMR
spectrum also fits well with that reported for the parent
amidine lacking the N-methylcarboxamide.12 Amidine
carboxamide 12 cyclizes quantitatively to 4-quinazolinone
11a on stirring with silica gel in EtOAc for overnight.
Cyclization also occurs slowly in CDCl3 solution which
presumably contains traces of DCl.
The conversion of 4-imino-4H-3,1-benzoxazine 3, R )
Fmoc, to fumiquinazoline G (4) proceeds through amidine
carboxamide 14, which is formed quantitatively on dis-
solution in 20% piperidine in EtOAc for 1 h at 25 °C.
Flash chromatography gives 93% of 14 containing only
5-10% of 4 if 2% Et3N is present in the eluent to prevent
1
cyclization. The H NMR spectrum of 14 shows absorp-
tions at δ 8.20 and 6.49 indicating that an amidine
carboxamide is present. Amidine carboxamide 14 cyclizes
to 4-quinazolinone 15, which spontaneously cyclizes with
loss of methanol to give 82% of fumiquinazoline G on
stirring overnight in 2:1 EtOAc/MeOH containing silica
gel.
(i-Pr)2 yields 62-65% of 4-imino-4H-3,1-benzoxazines
1
10a -c. The H NMR spectral data for 10a and 10b are
identical to those reported by Mazurkiewicz.7 The 13C
NMR spectral data as assigned by HMBC correlation are
analogous to those of 3 and 8. C-2 of 10a absorbs at δ
158.2 and C-4 absorbs at δ 147.7, while C-2 of 4-quinazoli-
none 11a absorbs at δ 154.0 and C-4 absorbs at δ 161.7.9
The rearrangement of 4-imino-4H-3,1-benzoxazines to
4-quinazolinones via amidine carboxamides provides a
Treatment of 10a with 20% piperidine in CH2Cl2 for
30 min at 25 °C provides a complex mixture of amidine
carboxamide 12 and 1,1′-methylenebis(piperidine) (13),
which results from the well-known reaction of piperidine
(10) (a) Mills, J . E.; Maryanoff, C. A.; McComsey, D. F.; Stanzione,
R. C.; Scott, L. J . Org. Chem. 1987, 52, 1857-1859. (b) Matsumoto,
K.; Hashimoto, S.; Ikemi, Y.; Otani, S.; Heterocycles 1984, 22, 1417-
1420.
(9) (a) Al-Talib, M.; J ochims, J . C.; Hamed, A.; Wang, Q.; Ismail, A.
E. Synthesis 1992, 697-701. (b) Akazome, M.; Kondo, T.; Watanabe,
Y. J . Org. Chem. 1993, 58, 310-312. (c) Fuks, R. Tetrahedron 1973,
29, 2153-2156.
(11) Oszczapowicz, J .; Krawczyk, W.; Osek, J .; Raczynska, E. J .
Chem. Res. S 1985, 384-385.
(12) Oszczapowicz, J .; Raczynska, E.; Osek, J . Magn. Reson. Chem.
1986, 24, 9-14.

Notes
J . Org. Chem., Vol. 64, No. 4, 1999 1399
(dd, 1, J ) 1.2, 8.0), 7.72 (ddd, 1, J ) 1.2, 7.2, 8.0), 7.61 (br d, 1,
J ) 8.0), 7.44 (ddd, 1, J ) 1.2, 7.2, 8.0), 3.63 (s, 3), 2.63 (s, 3);
13C NMR 162.3, 154.4, 147.2, 134.1, 126.8, 126.6, 126.4, 120.2,
31.0, 23.6; IR (KBr) 1670, 1601. The data are consistent with
those previously reported.9
4-Im in o-4H-3,1-ben zoxa zin e 3, R ) F m oc, was prepared
as described by Ganesan:1 the 1H NMR and IR spectra are
identical to those reported; 13C NMR (CDCl3) 172.8, 159.1, 155.4,
147.5, 143.9, 143.8, 141.3 (2 C), 141.0, 135.9, 133.3, 128.3, 127.7
(2 C), 127.4, 127.1 (2 C), 126.4, 126.1, 125.1, 125.0, 122.8, 122.0,
120.0 (2 C), 119.4, 119.3, 118.9, 112.2, 111.1, 66.7, 59.8, 52.2,
49.0, 47.2, 29.5, 18.8.
valuable route to quinazolinones, since the 4-imino-4H-
3,1-benzoxazines are readily available by treatment of
N-acylanthranilamides with PPh3, Br2, or I2, and a
tertiary amine. We are currently exploring the scope of
the two-step rearrangement with respect to substituents
on the 4-imino-4H-3,1-benzoxazine, primary and second-
ary amine for amidine formation, and conditions for
isomerization ofthe amidine carboxamide tothe 4-quinazoli-
none.
Exp er im en ta l Section
4-Im in o-4H-3,1-ben zoxa zin e 3, R ) H. To a solution of 3,
R ) Fmoc, (3 mg, 0.005 mmol) in MeCN (0.2 mL) was added
DMAP (20 mg). The mixture was stirred at 75 °C for 4 h and
evaporated under reduced pressure to give a residue. Flash
chromatography of this residue on silica gel (5:1 EtOAc/MeOH
with 2% Et3N) afforded 1.5 mg (77%) of 3, R ) H: 1H NMR 8.21
(dd, 1, J ) 1.6, 8.0), 8.04 (br s, 1, NH), 7.73 (d, 1, J ) 7.6), 7.54
(ddd, 1, J ) 1.6, 8.0, 8.0), 7.36 (ddd, 1, J ) 1.2, 7.6, 7.6), 7.32 (d,
1, J ) 7.6), 7.31 (d, 1, J ) 7.6), 7.17 (ddd, 1, J ) 1.2, 8.0, 8.0),
7.10 (ddd, 1, J ) 1.2, 7.2, 8.4), 7.05 (d, 1, J ) 2.4), 4.93 (dd, 1, J
) 4.4, 8.4), 3.72 (s, 3), 3.51 (ddd, 1, J ) 0.4, 4.4, 14.0), 3.47 (q,
1, J ) 6.8), 3.26 (ddd, 1, J ) 0.4, 8.4, 14.0), 1.17 (d, 3, J ) 6.8).
Am id in e Ca r boxa m id e 14. To a suspension of 3, R ) Fmoc
(24.5 mg, 0.04 mmol), in EtOAc (0.4 mL) was added piperidine
(distilled from CaH2, 0.1 mL). The mixture was stirred at room
temperature for 1 h. TLC (4:1 EtOAc/MeOH) indicated that the
deprotection was complete in 10 min and the conversion of the
resulting amine 3, R ) H, to amidine carboxamide 14 was
complete in 45 min. The mixture was evaporated under reduced
pressure to give a residue which was purified by flash chroma-
tography on silica gel (2:1 CH2Cl2/EtOAc with 2% of Et3N, then
2:1 EtOAc/MeOH with 2% of Et3N) to afford 17.2 mg (93%) of
amidine carboxamide 14 as a colorless oil containing 5-10% of
fumiquinazoline G (4): 1H NMR 9.37 (br d, 1, J ) 8.0, NH), 8.46
(br s, 1, NH), 8.20 (d, 1, J ) 7.2), 7.50 (d, 1, J ) 8.0), 7.29 (d, 1,
J ) 8.8), 7.27 (ddd, 1, J ) 1.6, 7.6, 8.0), 7.12 (ddd, 1, J ) 1.2,
8.0, 8.0), 7.05-6.97 (m, 3), 6.49 (d, 1, J ) 7.2), 5.26 (td, 1, J )
5.6, 8.0), 3.83 (br q, 1, J ) 6.8), 3.67 (s, 3), 3.38 (dd, 1, J ) 5.6,
15.2), 3.33 (dd, 1, J ) 5.6, 15.2), 3.28-3.20 (m, 2), 3.18-3.10
(m, 2), 1.68 (br s, 2, NH2), 1.51-1.44 (m, 2), 1.44-1.34 (m, 4),
1.06 (d, 3, J ) 6.8); 13C NMR 173.0, 166.6, 163.0, 150.2, 136.1,
131.7, 131.1, 127.6, 122.6, 121.9 (2 C), 121.3, 119.4, 118.7, 111.1,
110.6, 53.1, 52.2, 47.5, 47.2 (2 C), 28.3, 25.8 (2 C), 24.3, 21.5
(one quaternary carbon was not observed); IR (neat) 3252, 1739,
1634, 1591, 1520.
Gen er a l. NMR spectra were recorded in CDCl3 at 400 MHz.
Chemical shifts are reported in δ, coupling constants are
reported in hertz, and IR data are reported in cm-1
.
2-Meth yl-4-(m eth ylim in o)-4H-3,1-ben zoxa zin e (10a ). To
a solution of amide 9a (48 mg, 0.25 mmol) in CH2Cl2 (15 mL)
were added Ph3P (327.5 mg, 1.25 mmol), N,N-diisopropylethyl-
amine (404 mg, 545 µL, 3.13 mmol), and I2 (310.9 mg, 1.23
mmol). The reaction mixture was stirred at room temperature
for 5 h, quenched with aqueous Na2CO3 solution, dried (Na2-
SO4), and concentrated. The dark residue was purified by flash
chromatography on silica gel (5:1 hexane/EtOAc with 2% Et3N)
to give 28.3 mg (65%) of 10a as a white solid: mp 77-80 °C
(lit.7 mp 82-83 °C); 1H NMR 8.01 (dd, 1, J ) 1.5, 8.0), 7.51 (ddd,
1, J ) 1.5, 7.2, 8.0), 7.34-7.16 (m, 2), 3.19 (s, 3), 2.34 (s, 3); 13
C
NMR 158.2, 147.7, 141.5, 132.7, 127.7, 125.6, 125.2, 119.4, 33.2,
21.0; IR (KBr) 1680, 1654, 1603. The 1H NMR and IR spectra
are consistent with those previously reported.7
2-Meth yl-4-(p h en ylim in o)-4H-3,1-ben zoxa zin e (10b) was
produced following the procedure for 10a in 68% yield as an oil:
1H NMR 8.24 (dd, 1, J ) 1.2, 8.0), 7.59 (ddd, 1, J ) 1.2, 7.6,
8.8), 7.43-7.33 (m, 4), 7.20-7.10 (m, 3), 2.26 (s, 3); 13C NMR
158.0, 145.8, 145.3, 142.4, 133.6, 128.7 (2 C), 128.0, 126.4, 125.8,
124.1, 122.5 (2 C), 119.2, 20.9; IR (neat) 1674, 1654, 1594. The
1H NMR and IR spectra are consistent with those previously
reported.7
2-Met h yl-4-((1-m et h ylet h yl)im in o)-4H -3,1-b en zoxa zin e
(10c) was produced following the procedure for 10a in 62% yield
as an oil: 1H NMR 8.06 (dd, 1, J ) 1.6, 8.4), 7.49 (ddd, 1, J )
1.6, 7.6, 8.8), 7.32-7.26 (m, 2), 4.16 (hept, 1, J ) 6.4), 2.32 (s,
3), 1.21 (d, 6, J ) 6.4); 13C NMR 158.4, 144.6, 141.7, 132.5, 127.5,
125.7, 125.5, 119.6, 46.1, 23.5 (2 C), 21.1; IR (neat) 1679, 1654,
1606.
Am id in e Ca r boxa m id e 12. A solution of 10a (10.2 mg,
0.0586 mmol) in piperidine (distilled from CaH2, 0.25 mL) was
stirred at room temperature for 1 h. The resulting mixture was
evaporated under reduced pressure to give crude 12. Flash
chromatography on silica gel (1:1 CH2Cl2/EtOAc with 2% Et3N)
afforded 12.4 mg (82%) of pure 12 as a colorless oil: 1H NMR
8.97 (br s, 1, NH), 8.19 (dd, 1, J ) 1.2, 8.0), 7.29 (ddd, 1, J )
1.2, 7.2, 8.0), 7.05 (ddd, 1, J ) 1.2, 7.2, 8.0), 6.55 (dd, 1, J ) 1.2,
8.0), 3.60 (br t, 4, J ) 4.8), 2.94 (d, 3, J ) 4.8), 1.92 (s, 3), 1.77-
1.69 (m, 2), 1.67-1.59 (m, 4); 13C NMR 167.8, 157.0, 149.4, 131.1,
130.8, 125.3, 123.1, 121.9, 45.9 (br, 2 C), 26.1, 26.0 (2 C), 24.7,
15.3; IR (neat) 3462 (br), 3207 (br), 1652, 1589, 1538. The 1H
and 13C NMR spectra correspond to those of closely related
amidines.11, 12
2,3-Dim eth yl-4(3H)-qu in a zolin on e (11a ). To a solution of
12 (6.2 mg, 0.024 mmol) in EtOAc (0.25 mL) was added silica
gel (EM 9385, silica gel 60, 230-400 mesh, 60 mg). The mixture
was stirred at room-temperature overnight. The silica gel was
filtered off, and the filtrate was evaporated under reduced
pressure to give 4.2 mg (100%) of 11a as a white solid: mp 107-
109 °C (needles, hexane) (lit.7 mp 109-109.5 °C); 1H NMR 8.26
Con ver sion of 14 to F u m iqu in a zolin e G (4). To a solution
of amidine carboxamide 14 (6.6 mg, 0.014 mmol) in a 2:1 mixture
of EtOAc and MeOH (0.3 mL) was added silica gel (EM 9385,
silica gel 60, 230-400 mesh, 66 mg). The suspension was stirred
at room-temperature overnight. The silica gel was filtered off,
and the filtrate was evaporated under reduced pressure to give
a residue, which was purified by flash chromatography on silica
1
gel (EtOAc) to give 4.2 mg (82%) of 4 with H NMR and 13C NMR
spectra identical to those previously reported.1,2,4
Ack n ow led gm en t. We are grateful to the National
Institutes of Health (GM50151) for generous financial
support.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectral data for 3, R ) Fmoc, 10a -c, 11a , 12, and 14, and
HMBC spectra for 3, R ) Fmoc, and 10a . This material is
available free of charge via the Internet at http://pubs.acs.org.
J O9820465