A regioselective synthesis of tetrahydrobenzodiazepin-5-ones via the Schmidt rearrangement of quinolones

Article abstract of DOI:10.1081/SCC-200026212

The regioselective synthesis of 2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-5- ones by the Schmidt rearrangement of 1,2,3,4-tetrahydro-4-quinolones with oxygen substituents at C-8 is described.

Full text of DOI:10.1081/SCC-200026212

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A Regioselective Synthesis of
Tetrahydrobenzodiazepin‐5‐ones
via the Schmidt
Rearrangement of Quinolones
Ricardo A. Tapia a & César Centella a
a Facultad de Química, Pontificia Universidad
Católica de Chile, Casilla 306, Santiago, 22, Chile
Published online: 10 Jan 2011.
To cite this article: Ricardo A. Tapia & César Centella (2004) A Regioselective
Synthesis of Tetrahydrobenzodiazepin‐5‐ones via the Schmidt Rearrangement
of Quinolones, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 34:15, 2757-2765, DOI: 10.1081/
SCC-200026212
To link to this article: http://dx.doi.org/10.1081/SCC-200026212
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SYNTHETIC COMMUNICATIONSw
Vol. 34, No. 15, pp. 2757–2765, 2004
A Regioselective Synthesis of
Tetrahydrobenzodiazepin-5-ones via the
Schmidt Rearrangement of Quinolones
*
Ricardo A. Tapia and Cesar Centella
´
´ ´
Facultad de Quımica, Pontificia Universidad Catolica de Chile, Casilla,
Santiago, Chile
ABSTRACT
The regioselective synthesis of 2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-
5-ones by the Schmidt rearrangement of 1,2,3,4-tetrahydro-4-quinolones
with oxygen substituents at C-8 is described.
Key Words: Benzodiazepines; Schmidt rearrangement; Quinolones;
Ketones; Hydrazoic acid.
INTRODUCTION
The wide range of biological activities displayed by benzodiazepines have
attracted attention in synthetic organic chemistry.[1–3] In the context of a
*
´
Correspondence: Ricardo A. Tapia, Facultad de Quımica, Pontificia Universidad
´
Catolica de Chile, Casilla 306, Santiago 22, Chile; E-mail: rtapia@puc.cl.
2757
DOI: 10.1081/SCC-200026212
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com
Copyright # 2004 by Marcel Dekker, Inc.

2758
Tapia and Centella
project to obtain heterocyclic quinones[4,5] with the quinone moiety fused to a
diazepine ring we became interested in the Schmidt rearrangement of
quinolones.
The Schmidt reaction on 1,2,3,4-tetrahydro-4-quinolones (I) was first
reported by Ittyerah and Mann[6] to give a mixture of 2,3,4,5-tetrahydro-1,5-ben-
zodiazepin-2-ones (II) and 2,3,4,5-tetrahydro-1,4-benzodiazepin-5-ones (III)
through migration of an aryl or an alkyl group, respectively. When the aromatic
ring of I has no substituent, the alkyl migration predominates, affording 1,4-
benzodiazepin-5-ones (III) as the major isomers. The presence, on the aromatic
system, of electron-donating or electron-withdrawing substituents seems to
have little influence on the ratio of regioisomers. On the other hand, a reversal
of regioselectivity is observed when the nitrogen atom bears an electron-with-
drawing substituent, such as an acetyl group. In this case, the aryl migration
prevails, leading mainly to 1,5-benzodiazepin-2-ones (II) (Table 1).[7]
The generally accepted mechanism for the Schmidt rearrangement
involves formation of syn- and anti-iminodiazonium ions, followed by
migration of the anti-substituent.[8] In addition, it has been suggested that
the lone pair electron of the heterocyclic nitrogen plays an important role in
the Schmidt rearrangement of tetrahydroquinolones. When the iminodi-
azonium ion is formed, delocalization of the nitrogen lone pair electron in
Sch. 1(a) would result in a partial double bond formation between C-4a and
C-4, inhibiting the aryl migration. Moreover, the lone pair electron delocalization
Table 1. Migratory tendencies in the Schmidt reaction of tetrahydroquinolones.[7]
Benzodiazepine isomer ratio
Tetrahydroquinolones
II (1,5-isomer)
III (1,4-isomer)
Ia R1 ¼ H, R2 ¼ H, R3 ¼ H
Ib R1 ¼ H, R2 ¼ H, R3 ¼ OMe
Ic R1 ¼ H, R2 ¼ Cl, R3 ¼ H
Id R1 ¼ Ac, R2 ¼ H, R3 ¼ H
Ie R1 ¼ Ac, R2 ¼ Cl, R3 ¼ H
If R1 ¼ Ac, R2 ¼ H, R3 ¼ OMe
20
30
35
95
90
90
80
70
65
5
10
10

Synthesis of Tetrahydrobenzodiazepin-5-ones
2759
Scheme 1. Heterocyclic nitrogen participating in (a) inhibiting the aryl migration and
(b) stabilizing the carbocation generated via the alkyl migration.
of nitrogen would stabilize the newly developing positive charge in Sch. 1(b),
enhancing the alkyl migration (Sch. 1). In contrast, the presence of an acetyl
group on the heterocyclic nitrogen, by reducing its resonance effect, favors the
aryl migration.[9]
RESULTS AND DISCUSSION
In view to obtain precursors of benzodiazepinequinones via the Schmidt
rearrangement, we synthesized 1,2,3,4-tetrahydro-4-quinolones 3 bearing an
oxygenated substituent at the C-8 position. Thus, reaction of 2-methoxyaniline
(1) with methyl acrylate (for a previous example of the reaction of anilines
with methyl, acrylate see Ref.[10]) followed by basic hydrolysis gave 3-(2-meth-
oxyphenylamino)propanoic acid (2) (for a previous report on the influence of
steric and electronic effect on the Schmidt rearrangement, see Ref.[11]). Then,
cyclization of 2 in polyphosphoric acid at 1508C gave tetrahydroquinolone 3a,
which on treatment with hydrobromic acid under reflux for 5 hr afforded
phenol 3b in good yield. Reaction of 3a with acetic anhydride and pyridine
yielded acetylquinolone 3c (Sch. 2).
Then, the Schmidt rearrangement of compound 3 was studied using
sodium azide and sulfuric acid. Thus, tetrahydroquinolone 3a gave a mixture
of 1,5-benzodiazepin-2-one 4a and 1,4-benzodiazepin-5-one 5a in the ratio of
20 : 80. The hydroxy derivative 3b afforded similarly 4b and 5b with a ratio of
31 : 69 (Table 2).
The structure of the 1,5-benzodiazepine isomers 4a and 4b was assigned
from their respective 1H-NMR spectral data. Thus, considering 4a, the
methylene protons adjacent to the carbonyl group (3-CH2) are shifted to
high field (d ¼ 2.77 ppm). On the other hand, for 1,4-benzodiazepinone 5a,
the same protons showed a multiplet at d ¼ 3.55 ppm due to their deshielding

2760
Tapia and Centella
Scheme 2. Reagents and conditions: (a) methyl acrylate, acetic acid 1458C, 24 hr; (b)
KOH, EtOH, reflux, 2 hr; AcOH, 75%; (c) polyphosphoric acid, 1508C, 58%; (d) HBr,
reflux, 5 hr, 82%; (e) acetic anhydride, pyridine, room temperature, 24 hr, 87%.
by the adjacent nitrogen atom. The structures for 4b and 5b were determined
in a similar manner.
The above results agree with the previous work on the Schmidt reaction of
tetrahydroquinolones, confirming that a methoxy or a hydroxy group on the aro-
matic ring has a little influence on the regioisomeric ratio.[7] The predominant
regioisomer is the 1,4-benzodiazepinone (5a or 5b) produced via an alkyl migration.
Finally, considering the Schmidt rearrangement of N-acetylquinolone 3c
and following the literature data, the expected 1,5-benzodiazepinone 4c via an
aryl migration was not obtained. The reaction afforded only the 1,4-benzodia-
zepinone 5c (alkyl migration) in 90% yield. The unexpected regioselectivity
observed in the rearrangement of N-acetylquinolone 3c is probably due to a
steric interaction between the methoxy group at C-8 and the N-acetyl group
(for a previous report on the influence of steric and electronic effect on the
Schmidt rearrangement, see Ref.[11]).
Another useful difference that confirms the structure of each isomer is that
the 1H-NMR signal of the 6-H proton for the 1,4-isomers (5a, 5b, 5c) is highly
deshielded (d ¼ 7.30–7.61 ppm) by the peri-carbonyl group, while for the
1,5-isomers (4a, 4b) the 1H-NMR signal of the 9-H proton is shielded
(d ¼ 6.57–6.60 ppm), since the amide moiety is connected to the aromatic
ring by the nitrogen atom.
In conclusion, we have described a simple access to 1,4-benzodia-
zepinones 5 using the Schmidt reaction on 1,2,3,4-tetrahydro-4-quinolones
3 bearing oxygenated substituents at C-8.
EXPERIMENTAL
Melting points were determined with a Meltemp apparatus and are
not corrected. IR spectra were obtained on a Bruker Model Vector 22

Synthesis of Tetrahydrobenzodiazepin-5-ones
2761

2762
Tapia and Centella
spectrophotometer. NMR spectra (1H and 13C) were recorded on a Bruker
AM-200 spectrometer 200 (200 and 50 MHz), using TMS as internal
reference. Column chromatography was performed on silica gel Merck 60
(70–230 mesh). Elemental analyses were performed on a Fison EA 1108
CHNS-O analyzer.
2-(2-Methoxyphenyl)propanoic acid (2). A mixture of o-anisidine
(20 g, 0.162 mol), methyl acrylate (17.2 g, 0.2 mol), and acetic acid (6.0 mL)
was heated at 1458C for 24 hr. The reaction mixture was concentrated and
the residue was slowly treated with a solution of potassium hydroxide
(11.4 g, 0.2 mol) in ethanol (70 mL). After heating at reflux for 2 hr, the
solution was cooled, diluted with water (200 mL), and extracted with ethyl
ether (3 Â 100 mL). The aqueous solution was acidified with acetic acid
and extracted with chloroform (3 Â 100 mL). The combined organic phases
were washed with water (50 mL) and then dried (MgSO4) and concentrated.
The crude product was crystallized from benzene to give (75%) of acid 2,
m.p. 87–888C (87–888C).a
1,2,3,4-Tetrahydro-8-methoxyquinolin-4-one (3a). Obtained in 58%
yield from acid 2 (10 mmol) according to the general method of Atwal et al.[12]
1,2,3,4-Tetrahydro-8-hydroxyquinolin-4-one (3b). A solution of
1,2,3,4-tetrahydro-8-methoxyquinolin-4-one 3a (1.0 g, 5.65 mmol) in aqueous
hydrobromic acid (48%, 25 mL) was heated to reflux for 5 hr. The reaction
mixture was concentrated under reduced pressure, the residue was poured
into a solution of saturated sodium carbonate and extracted with ethyl
acetate (4 Â 25 mL). The extract was dried (MgSO4), the solvent evaporated
under vacuum, and the crude product was purified by column chromatography
using methylene chloride–ethyl acetate (1 : 1) to yield phenol 3b (0.75 g,
82%), m.p. 223–2248C. Anal. calcd for C9H9NO2(163.18): C, 66.25; H,
5.56; N, 8.58. Found: C, 65.95; H, 5.29; N, 8.54. IR (KBr): 3400,
1
1640 cm21; H-NMR (acetone-d6): 2.6–2.7 (1H, m, 3-H), 3.1–3.2 (2H, m,
2-H), 3.6–3.7 (1H, m, 3-H), 5.60 (1H, br s, NH), 6.55 (1H, t, J ¼ 8.0 Hz,
6-H), 6.94 (1H, dd, J ¼ 8.0 and 1.3 Hz, 7-H), 7.32 (1H, dd, J ¼ 8.0 and
1.3 Hz, 5-H), 8.98 (1H, br s, OH); 13C-NMR (acetone-d6): 39.1, 43.0, 117.0,
118.5, 118.8, 120.6, 144.4, 145.9, and 193.9.
1,2,3,4-Tetrahydro-8-methoxy-N-acetyl-4-quinolone (3c). Acetic anhy-
dride (5 mL) was added to a solution of quinolone 3a (0.5g, 2.8 mmol) in
pyridine (3 mL) and the mixture was left overnight at room temperature. The
reaction mixture was poured into ice-water and was extracted with methylene
aThis compound was obtained previously by reaction of o-anisidine with propiolactone,
see reference.[12]

Synthesis of Tetrahydrobenzodiazepin-5-ones
2763
chloride (2 Â 25mL). The organic extract was washed with 5% sodium carbon-
ate solution, then water, and dried (MgSO4). The solvent was removed and the
residue was purified by column chromatography using methylene chloride-ethyl
acetate (20 : 1) to give compound 3c (0.52 g, 87%) as an oil. Anal. calcd for
C12H13NO3(219.24): C, 65.74; H, 5.98; N, 6.39. Found: C, 65.81; H, 6.16; N,
1
6.30. IR (KBr): 1675, 1645cm21; H-NMR (CDCl3): 2.13 (s, 3H, CH3), 2.75
(2H, m, 3-H), 3.4 (1H, m, 2-H), 3.87 (3H, s, OCH3), 5.0 (1H, m, 2-H), 7.12
(1H, dd, J ¼ 8.2 and 1.4 Hz, 7-H), 7.22 (1H, t, J ¼ 8.2 Hz, 6-H), 7.56 (1H,
dd, J ¼ 8.2 and 1.4 Hz, 5-H); 13C-NMR (CDCl3): 21.9, 40.1, 44.1, 55.9,
117.2, 119.3, 127.0, 128.5, 134.1, 152.4, 171.1, and 194.9.
Schmidt Expansion on 1,2,3,4-Tetrahydroquinolin-4-ones. General
Procedure. Concentrated sulfuric acid (2.5 mL) was added slowly to a
stirred solution of quinolone 3 (500 mg) in chloroform (5 mL) at 08C, then
sodium azide (500 mg) was added gradually over 30 min. After 3 hr at room
temperature, the reaction mixture was cooled and then neutralized with 10%
aqueous solution of NaHCO3 and extracted with ethyl acetate. The extract
was dried with NaSO4 and filtered. The filtrate was chromatographed on a
silica gel column with ethyl acetate/methylene chloride.
6-Methoxy-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one (4a) and
9-methoxy-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-5-one (5a). From qui-
nolone 3a obtained in order of elution, 4a (18%), RF 0.50 (ethyl acetate),
m.p. 140–1418C. Anal. calcd for C10H12N2O2 (192.22): C, 62.49; H, 6.29;
N, 14.57. Found: C, 62.20; H, 6,10; N, 14.50. IR (KBr): 3365, 3310, 3170,
1
1669 cm21; H-NMR (CDCl3): 2.77 (2H, t, J ¼ 5.7 Hz, 3-CH2), 3.62 (2H, t,
J ¼ 5.7 Hz, 4-CH2), 3.85 (3H, s, OCH3), 4.4 (1H, br s, NH), 6.53 (1 H, dd,
J ¼ 8.0 and 1.5 Hz, 7-H), 6.57 (1H, dd, J ¼ 8.0 and 1.5 Hz, 9-H), 6.71 (1H,
t, J ¼ 8.0 Hz, 8-H), and 8.16 (1H, br s, HNC55O); 13C-NMR (CDCl3): 37.1,
45.0, 55.9, 106.0, 114.5, 118.5, 125.2, 128.9, 149.3, and 174.0; and 5a
(70%), RF 0.23 (ethyl acetate), m.p. 201–2028C. Anal. calcd for
C10H12N2O2 (192.22): C, 62.49; H, 6.29; N, 14.57. Found: C, 62.30; H,
1
6,15; N, 14.45; IR (KBr): 3195, 1655 cm21; H-NMR (CDCl3): 3.55 (4H,
m, 2-CH2 and 3-CH2), 3.83 (3H, s, OCH3), 4.3 (1H, br s, NH), 6.66 (1H, t,
J ¼ 8.0 Hz, 7-H), 6.82 (1H, dd, J ¼ 8.0 and 1.2 Hz, 8-H), 7.42 (1H, br s,
HNC55O), and 7.61 (1H, dd, J ¼ 8.0 and 1.2 Hz, 6-H); 13C-NMR (CDCl3):
42.3, 48.3, 56.0, 111.6, 115.8, 116.6, 124.7, 136.8, 147.3, and 172.0.
6-Hydroxy-2,3,4,5-tetrahydro-1H-1,5-benzodiazepin-2-one (4b) and
9-Hydroxy-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-5-one (5b). From qui-
nolone 3a obtained in order of elution, 4b (22%), RF 0.30 (ethyl acetate),
m.p. 219–2208C. Anal. calcd for C9H10N2O2(178.19): C, 60.67; H, 5.66; N,
15.72. Found: C, 60.40; H, 5.35; N, 15.50. IR (KBr): 3376, 3177,
;
1646 cm21 1H-NMR (DMSO-d6): 2.55 (2H, m, 3-CH2), 3.53 (2H, m,
4-CH2), 4.94 (1H, br s, NH), 6.6 (3H, m, ArH), 9.38 (1H, s, OH) and 9.63

2764
Tapia and Centella
(1H, br s, HNC55O); 13C-NMR (DMSO-d6): 36.8, 44.1, 109.3, 112.9, 117.4,
126.2, 128.1, 146.6, and 172.8; and 5b (48%), RF 0.13 (ethyl acetate), m.p.
146–1478C. Anal. calcd for C9H10N2O2 (178.19): C, 60.67; H, 5.66; N,
15.72. Found: C, 60.35; H, 5.40; N, 15.45. IR (KBr): 3423, 3267, 3188,
1641 cm21 1H-NMR (DMSO-d6): 3.27 (2H, m, 3-CH2), 3.46 (2H, m,
;
2-CH2), 5.80 (1H, s, NH), 6.47 (1H, t, J ¼ 8.0 Hz, 7-H), 6.80 (1H, dd,
J ¼ 8.0 and 1.5 Hz, 8-H), 7.32 (1H, dd, J ¼ 8.0 and 1.5 Hz, 6-H), 8.00 (1H,
br s, HNC55O), and 9.74 (1H, br s, OH); 13C-NMR (DMSO-d6): 41.4, 47.9,
114.42, 114.47, 116.7, 122.8, 136.2, 144.7, and 170.1.
1-Acetyl-9-methoxy-2,3,4,5-tetrahydro-1H-1,4-benzodiazepin-5-one
(5c). From quinolone 3a was obtained compound 5c (90%), m.p. 150–1518C.
Anal. calcd for C12H14N2O3 (234.26): C, 61.53; H, 6.02; N, 11.96: Found: C,
;
61.60; H, 6.30; N, 12.15. IR (KBr): 3190, 1675, 1650 cm21 1H-NMR
(CDCl3): 2.9 (2H, m, 3-CH2), 3.2 (1H, m, 2-CH2), 3.86 (3H, s, CH3), 4.4
(1H, dt, J ¼ 5.7 and 12.7 Hz, 2-H), 7.15 (2H, dd, J ¼ 1.1 and 8.0 Hz, 8-H),
7.30 (2H, dd, J ¼ 1.1 and 8.0 Hz, 6-H), 7.48 (1H, t, J ¼ 8.0 Hz, 7-H), and
8.20 (1H, br s, HNC55O); 13C-NMR (CDCl3): 21.1, 38.1, 47.8, 55.9, 114.6,
120.1, 125.7, 129.7, 135.1, 154.6, 169.4, and 170.2.
ACKNOWLEDGMENT
The authors are grateful to FONDECYT for the financial support of this
work.
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Received in the USA March 31, 2004