Synthesis of N1 -alkyl-1,4-diazepin-5-ones via Schmidt ring expansion chemistry

Article abstract of DOI:10.1515/HC.2011.002

Reaction of 4-piperidone with alkyl bromides gave the corresponding N-alkyl-4-piperidones, and treatment of these with hydrazoic acid resulted in the Schmidt reaction to give the corresponding N¹-alkyl-1,4-diazepin- 5-ones in good overall yield

Full text of DOI:10.1515/HC.2011.002

Heterocycl. Commun., Vol. 17(1-2), pp. 17–19, 2011 • Copyright © by Walter de Gruyter • Berlin • Boston. DOI 10.1515/HC.2011.002
Synthesis of N1-alkyl-1,4-diazepin-5-ones via Schmidt
ring expansion chemistry
with sulfuric acid (Groves et al., 1997). Although this method
did give the desired diazepinone 3, it was obtained in low
yield. The water solubility of 3 was once again a factor in the
poor isolated yield.
Morin Frick, Danielle McAtee, Jesse McAtee,
Christina Wysoczynski and Partha S. Ray*
Department of Chemistry, University of West Georgia,
Carrollton, GA 30118, USA
We reasoned that alkylating 4-piperidone first followed by
the ring expansion chemistry with hydrazoic acid may be a
better strategy since the N-alkyl diazepineone derivatives (2)
would be more hydrophobic than 3 and, consequently, they
should extract into organic solvents more easily than 3. With
this in mind, we treated 4-piperidone with the alkyl bromides
8a–c and potassium carbonate in N,N-dimethylformamide
(DMF) and obtained the corresponding N-alkylated 4-piper-
idones 9a–c in very good yields (Scheme 3). We were grati-
fied to find that ring expansion of these N-alkyl-4-piperidones
with hydrazoic acid did, indeed, give the corresponding diaz-
epinones 2a–c in very good isolated yields after purification
by column chromatography. We are currently investigating
the conversion of these intermediates to our targets.
*Corresponding author
e-mail: psray@westga.edu
Abstract
Reaction of 4-piperidone with alkyl bromides gave the corre-
sponding N-alkyl-4-piperidones, and treatment of these with
hydrazoic acid resulted in the Schmidt reaction to give the corre-
sponding N1-alkyl-1,4-diazepin-5-ones in good overall yields.
Keywords: N1-Alkyl-1,4-diazepin-5-ones; N-alkyl-4-
piperidones; ring expansion; Schmidt reaction.
Introduction
Experimental
We have previously reported (Parker et al., 2002; Huddleston
et al., 2004) on our rationale for the design of pyrimido[4,5-e]
[1,4]diazepine-based folates (1) as potential antitumor agents
via inhibition of the enzyme glycinamide ribonucleotide
formyltransferase (Baldwin et al., 1991; Taylor et al., 1997;
Read et al., 1999). One of our synthetic strategies to these tar-
gets relies on the preparation of the diazepinone derivatives
2 (Scheme 1). We had envisioned preparing these derivatives
via straightforward alkylation of tetrahydro-1,4-diazepin-5-
one (3) with appropriate alkyl halides.
MeltingpointsweredeterminedinopencapillarytubesusingaMELT-
1
TEMP apparatus and are uncorrected. All H and 13C NMR spectra
were recorded at 400 MHz and 100 MHz, respectively, on a Varian
400 spectrometer. Chemical shifts are expressed in parts per million
(ppm) downfield from internal tetramethylsilane. Column chroma-
tography was performed on Merck silica gel 60 (240–400) mesh,
and silica gel plates were used for TLC determinations. Elemental
analyses were determined by Atlantic Microlab Inc. (Norcross, GA,
USA) and were within 0.4% of the theoretical values.
General procedure for alkylation of 4-piperidone (7)
with alkyl halides 8a–c
Results and discussion
To a mixture of 3.4 g (22 mmol) of 4-piperidone monohydrate hydro-
chloride, the alkyl bromide 8a, b or c (21 mmol), anhydrous DMF
(10 ml) and anhydrous potassium carbonate (22 mmol) were added.
The mixture was stirred for 24 h and water (100 ml) was added. The
mixture was extracted with ethyl acetate (3×50 ml) and organic lay-
ers were combined, washed with brine (50 ml), and dried over anhy-
drous sodium sulfate. The mixture was filtered and the solvent was
removed by rotary evaporation under reduced pressure. The residue
was purified by column chromatography on silica gel using 1%–2%
methanol in chloroform to give the desired product.
We attempted to prepare 3 following literature procedures as
outlined in Scheme 2. Thus, reaction of methyl acrylate with
ethylenediamine gave the 1,4-conjugate addition product 6
in quantitative crude yield (Plenio et al., 2001). However,
attempts to cyclize this material gave a mixture of products
from which it was difficult to isolate the desired cyclic prod-
uct 3 in good yield. The problem was that 3 is very water
soluble and even with continuous extraction procedures, it
was not possible to obtain better than 10% yield of pure prod-
uct after column chromatography. We therefore investigated
an alternative method to the synthesis of 3 which relied on
the Schmidt ring expansion reaction of 4-piperidone (7) with
hydrazoic acid, generated from the treatment of sodium azide
1-(4-Bromobenzyl)piperidin-4-one (9a, Rowbottom et al.,
2007) A colorless solid was obtained in 84% yield; mp 59–60°C;
1H NMR (CDCl3): δ 2.45 (t, J=6.1 Hz, 4H), 2.73 (t, J=6.1 Hz, 4H),
3.57 (s, 2H), 7.25 (d, J=8.3 Hz, 2H), 7.46 (d, J=8.3 Hz, 2H); 13C NMR
(CDCl3): δ 14.5, 53.1, 61.4, 121.5, 130.7, 131.7, 137.0, 209.2.
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18 M. Frick et al.
O
X
NH
CO2H
CO2H
O
N
n
N
n
NH
N
HN
H2N
O
N
H
O
N
H
N
H
3
2: n=0,1, or 2
X=Br or CO2Me
1a: n=0
1b: n=1
1c: n=2
Scheme 1 General strategy to pyrimido[4,5-e] [1,4]diazepine-based folates (1).
OMe
NH2
H
N
OMe
H2N
+
H2N
O
5
Plenio et al.
6
O
4
Plenio et al.
NaN3, H2SO4
AcOH
,
NH
NH
O
Groves et al.
N
H
O
7
3
Scheme 2 Synthesis of tetrahydro-1,4-diazepin-5-one (3).
X
X
K2CO3, DMF
NH
+
N
n
Br
O
n
O
7
9a: n=0; X=Br
9b: n=0; X=CO2Me
9c: n=1; X=Br
8a: n=0; X=Br
8b: n=0; X=CO2Me
8c: n=1; X=Br
X
NaN3, H2SO4,
AcOH
n
N
O
N
H
2a: n=0; X=Br
2b: n=0; X=CO2Me
2c: n=1; X=Br
Scheme 3 Synthesis of N1-alkyl-1,4-diazepin-5-ones via the Schmidt reaction.
Methyl 4-[(4-oxopiperidin-1-yl)methyl]benzoate (9b, Arniz et
al., 2007) A colorless solid was obtained in 88% yield; mp 63–
65°C; 1H NMR (CDCl3): δ 2.47 (t, J=5.9 Hz, 4H), 2.76 (t, J=5.9 Hz,
4H), 3.68 (s, 2H), 3.92 (s, 3H), 7.45 (d, J=8 Hz, 2H), 8.02 (d, J=8 Hz,
2H); 13C NMR (CDCl3): δ 41.4, 52.3, 53.2, 61.8, 128.9, 129.9, 143.8,
167.1, 209.1.
General procedure for the ring expansion of N-alkyl-4-
piperidones 9a–c with hydrazoic acid
The N-alkyl 4-piperidone 9a, b or c (5 mmol) was added to a mixture
of glacial acetic acid (3 ml) and concentrated sulfuric acid (1.5 ml)
and the mixture was cooled in an ice-water bath. Sodium azide
(5 mmol) was added in small portions over a 20 min period to the
stirred mixture. The mixture was left stirring for 12 h. The mixture
was cooled in an ice-water bath, and a saturated solution of sodium
hydroxide was added dropwise until the pH was 7–8. The mixture
was extracted with dichloromethane (3×50 ml) and the combined
organic layers were washed with water (50 ml) and dried over anhy-
drous sodium sulfate. The mixture was filtered and the solvent was
1-(4-Bromophenethyl)piperidin-4-one (9c, Schnatterer et al.,
2009) A colorless solid was obtained in 85% yield; mp 67–68°C;
1H NMR (CDCl3): δ 2.47 (t, J=6.3 Hz, 4H), 2.67–2.72 (m, 2H),
2.78–2.83 (m, 6H), 7.1 (d, J=8.1 Hz, 2H), 7.42 (d, J=8.1 Hz, 2H);
13C NMR (CDCl3): δ 33.5, 41.2, 53.1, 58.9, 120.0, 130.4, 131.5,
138.9, 208.9.
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Synthesis of N1-alkyl-1,4-diazepin-5-ones via Schmidt ring expansion chemistry 19
removed by rotary evaporation under reduced pressure. The residue
was purified by column chromatography on silica gel using 2%–3%
methanol in chloroform to give the ring expanded product.
the treatment of inflammatory disorders. U.S. Pat. Appl. 2007,
20070155726 A1 20070705.
Baldwin, S. W.; Tse, A.; Gossett, L. S.; Taylor, E. C.; Rosowsky, A.;
Shih, C.; Moran, R. G. Structural features of 5,10-dideaza-5,
6,7,8-tetrahydrofolate that determine inhibition of mammalian
glycinamide ribonucleotide formyltransferase. Biochemistry
1991, 30, 1997–2006, and references cited therein.
Groves, J. T.; Nemo, T. E.; Myers, R. S. Rapid amide hydrolysis
mediated by copper and zinc. J. Am. Chem. Soc. 1997, 101,
1033–1035.
Huddleston, N. E.; Harris, J. L.; Nguyen, H. L.; Ray, P. S. Synthesis
of 2-amino-4-chloro-6,9-bis-(2,4-dimethoxybenzyl)-6,7,8,9-tet-
rahydro-5H-pyrimido[4,5-e]diazepine: a potentially useful inter-
mediate to pyrimido[4,5-e]diazepine-based folates. Heterocycl.
Commum. 2004, 10, 405–406.
Parker, D. P.; Hughes, S. A.; Parker, D. L.; Ray, P. S. An unexpected
dimer formation from a (2-aminoethylamino)-5-formylpyrimi-
dine intermediate. Heterocycl. Commum. 2002, 8, 419–422.
Plenio, H.; Aberle, C.; Shihadeh, Y. A.; Lloris, J. M.; Martinez-
Manez, R.; Pardo, T.; Soto, J. Ferrocene-cyclam: a redox-active
macrocycle for the complexation of transition metal ions and a
study on the influence of the relative permittivity on the cou-
lombic interaction between metal cations. Chem. Eur. J. 2001,
7, 2848–2861.
1-(4-Bromobenzyl)-1,4-diazepin-5-one (2a) A colorless solid
1
was obtained in 83% yield; mp 170°C; H NMR (CDCl3): δ 2.57–
2.61 (m, 6H), 3.28–3.29 (m, 2H), 3.54 (s, 2H), 6.51 (br s, exchange-
able with D2O, 1H), 7.21 (d, J=8.1 Hz, 2H), 7.45 (d, J=8.1 Hz, 2H);
13C NMR (CDCl3): δ 38.2, 42.0, 50.8, 57.2, 62.6, 121.2, 130.7, 131.7,
137.5, 178.1. Analysis: calcd. for C12H15BrN2O: C, 50.90; H, 5.34;
N, 9.89, Br, 28.22. Found: C, 50.98; H, 5.29; N, 9.80; Br, 27.99.
Methyl 4-[(5-oxo-1,4-diazepin-1-yl)methyl]benzoate (2b)
A
colorless solid was obtained in 85% yield; mp 148–149°C; 1H NMR
(CDCl3): δ 2.59–2.64 (m, 6H), 3.19–3.40 (m, 2H), 3.65 (s, 2H), 3.92
(s, 3H), 6.52 (br s, exchangeable with D2O, IH), 7.41 (d, J=8.5 Hz,
2H), 8.0 (d, J=8.5 Hz, 2H); 13C NMR (CDCl3): δ 38.2, 43.0, 50.9,
52.3, 57.3, 62.9, 128.9, 129.4, 129.9, 143.9, 167.1, 178.1. Analysis:
calcd. for C14H18N2O3: C, 64.10; H, 6.92; N, 10.68. Found: C, 64.10;
H, 6.95; N, 10.61.
1-(4-Bromophenethyl)-1,4-diazepin-5-one (2c)
A colorless
solid was obtained in 82% yield; mp 147–148°C; 1H NMR (CDCl3): δ
2.62–2.73 (m, 10H), 3.29–3.32 (m, 2H), 6.38 (br s, exchangeable with
D2O, 1H), 7.07 (d, J=8.3 Hz, 2H), 7.40 (d, J=8.3 Hz, 2H); 13C NMR
(CDCl3): δ 32.9, 37.9, 42.8, 50.5, 57.1, 50.2, 119.9, 130.4, 131.4,
139.0, 177.8. Analysis: calcd. for C13H17BrN2O: C, 52.54; H, 5.77; N,
9.43; Br, 26.89. Found: C, 52.66; H, 5.80; N, 9.34; Br, 26.75.
Read, M. W.; Miller, M. L.; Ray, P. S. Synthesis of N-{[4-(2-amino-
4(3H)-oxo-5,6,7,8-tetrahydro-(9H)-pyrimido[4,5-b]azepin-6-yl)
benzoyl}-L-glutamic acid and two of its conformationally-re-
stricted analogs. Tetrahedron 1999, 55, 373–392.
Rowbottom, M. W.; Vickers, T. D.; Tamiya, J.; Zhang, M.; Dyck, B.;
Grey, J.; Schwarz, D.; Heise, C. E.; Hedrick, M.; Wen, J.; et al.
Synthesis and structure-activity relationships of spirohydantoin
derived small-molecule antagonists of the melanin-concentrating
hormone receptor-1 (MCH-R1). Bioorg. Med. Chem. Letters
2007, 17, 2171–2178.
Schnatterer, S.; Maier, M.; Petry, F.; Kanuf, W.; Seeger, K. Pesticidal
substituted piperidines and their preparation. U.S. Pat. Appl.
2009, US 20090082389 A1 20090326.
Acknowledgements
We are grateful to the faculty research grant and student assistant
research programs at the University of West Georgia for financial
support.
References
Taylor, E. C.; Dowling, J. E. Synthesis of a pyrimido[4,5-b]azepin
analog of 5,10-dideaza-5,6,7,8-tetrahydrofolic acid (DDATHF).
Bioorg. Med. Chem. Letters 1997, 7, 453–456.
Arniz, D.; Brown, G.; Claret, E.; Cleve, A.; Davey, D.; Guilford,
W.; Khim, S. K.; Kirkland, T.; Kochanny, M. J.; Liang, A.
Diamine derivatives as inhibitors of leukotriene A4 hydrolase
and their preparation, pharmaceutical compositions and use in
Received March 31, 2011; accepted April 20, 2011
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