An efficient synthesis of 1,4-oxazepines from β-formyl enamide using I2-NaHCO3 system

Article abstract of DOI:10.1081/SCC-100106037

A new and efficient method for synthesis of 1,4-oxazepine has been developed utilizing I₂-NaHCO₃ promoted intramolecular cyclisation of N-progargyl-β-hydroxylmethyl enamide. The method is mild and simple.

Full text of DOI:10.1081/SCC-100106037

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AN EFFICIENT SYNTHESIS OF 1,4-OXAZEPINES FROM
β-FORMYL ENAMIDE USING I2-NaHCO3 SYSTEM
Moanochet Longchar a , Apurba Chetia a , Shahadat Ahmed a , Romesh C. Boruah b
Jagir S. Sandhu a
&
a Organic Chemistry Division , Regional Research Laboratory , Jorhat, 785006, India
b Organic Chemistry Division , Regional Research Laboratory , Jorhat, 785006, India
Published online: 20 Aug 2006.
To cite this article: Moanochet Longchar , Apurba Chetia , Shahadat Ahmed , Romesh C. Boruah & Jagir S. Sandhu
(2001) AN EFFICIENT SYNTHESIS OF 1,4-OXAZEPINES FROM β-FORMYL ENAMIDE USING I2-NaHCO3 SYSTEM, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry, 31:21, 3281-3287,
DOI: 10.1081/SCC-100106037
To link to this article: http://dx.doi.org/10.1081/SCC-100106037
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SYNTHETIC COMMUNICATIONS, 31(21), 3281–3287 (2001)
AN EFFICIENT SYNTHESIS OF
1,4-OXAZEPINES FROM b-FORMYL
ENAMIDE USING I2-NaHCO3 SYSTEM
Moanochet Longchar, Apurba Chetia,
Shahadat Ahmed, Romesh C. Boruah,*
and Jagir S. Sandhu
Organic Chemistry Division, Regional Research
Laboratory, Jorhat, 785006, India
ABSTRACT
Anew and efficient method for synthesis of 1,4-oxazepine
has been developed utilizing I2-NaHCO3 promoted intramole-
cular cyclisation of N-progargyl-b-hydroxylmethyl enamide.
The method is mild and simple.
The 1,4-oxazepines constitute the parent core of many pharmaceutical
compounds such as loxapine, nitroxapine hydrochloride, linadryl-H and
related products.1 They find wide application in the asymmetric synthesis
of monoterpenoid alkaloids and secoiridoids.2 The construction of this
structural unit would be useful and indeed, several approaches have been
reported.3 However, these methods comprise certain disadvantages which
include harsh reaction conditions4 or use of highly reactive reagents5 and
therefore development of protocol using mild and readily available reagents
*Corresponding author.
3281
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

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LONGCHAR ET AL.
is needed. The reagent system I2-NaHCO3 has been considered as a
mild albeit powerful tool6 for iodolactonization of g-unsaturated acids,7
iodoetherification of g-unsaturated alcohol8 and iodolactamization of
N-substituted carbamates.9 This strategy has played a key role in the synthe-
sis of natural products including estrone-taloromycin10 and fungal metabo-
lites.11 However, the literature reports limit the applications of I2-NaHCO3
system within 1,5- or 1,6-cyclisations utilizing olefinic double bonds.6–10
Recently, we have documented the development of b-formyl enamide
as an organic synthon in Diels–Alder reaction12 and diyne formation.13 In
particular, b-formyl enamide has emerged as a valuable precursor for a
number of functionalised pyridines.14 The encouraging results prompted
us to explore its synthetic utility for other biologically potential heterocycles.
In continuation of our interests,15 we present here a mild and facile
approach for preparation of 1,4-oxazepines from N-propargyl-b-hydroxy-
methyl enamides using I2-NaHCO3 system.
In a representative experiment, to a solution of 3b-acetoxy-17-
(N,N-propargylacetamido)-16-formyl-androst-5,16-diene (1a, 10 mmol)13
in methanol (20 ml) was added NaBH4 (10 mmol) at room temperature
under nitrogen for 1 h. On completion of reaction, it was concentrated
under reduced pressure and purified by silica-gel column chromatography
to afford 3b-acetoxy-17-(N,N-propargylacetamido)-16-hydroxymethyl-
androst-5,16-diene (2a) in 90% yield. Stirring of 2a (1 mmole) with iodine
(5 mmole) and NaHCO3 (10 mmole) in a mixture of diethyl-ether (40 ml)
and water (10 ml) for 8 h at room temperature followed by treatment16
1
with aqueous Na2SO3 afforded 6a in 88% yield (Scheme 1). The H NMR
Scheme 1. Reagents i) NaBH4/MeOH/0–10ꢀC; ii) I2-NaHCO3/Et2O-H2O/r.t.;
iii) Na2SO3-H2O.

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Table. I2-NaHCO3 Mediated Cyclisation of N-Propargyl-b-hydroxy-
methylenamide
of 6a showed loss of N-acetyl group and appearance of two triplet signals at
d 5.20 and 4.94 for geminal olefinic protons (J ¼ 1.4 Hz) and a singlet signal
at 7.42 for conjugated imine proton of 1,4-oxazepine ring. Similarly steroi-
dal N-propargyl-b-hydroxymethylenamide (2b–c) afforded products 6b–c in
excellent yields.
In an effort to generalize the cyclisation reaction, the b-hydroxymethy-
lenamides of cycloalkanes (4a–b) were prepared from corresponding
b-formyl enamides by reduction with NaBH4 in excellent yields (92–94%).
Similarly, cyclisation reactions of 4a–b promoted by I2-NaHCO3 afforded
1,4-oxazepines (7a–b) in 68–79% yields.
The product obtained indicated a mechanism of sequential process
involving 1,7-cyclisation, deacetylation and reductive dehalogenation reac-
tions. As a first step, the propargyl group undergoes an electrophilic attack
by iodine7 to the intermediate iodonium ion (A) which would undergo
a nucleophilic attack of an alkoxide anion,10 generated in situ, to afford
iodomethylene-1,4-oxazepine intermediate (B). Subsequent attack of base
HCOÀ3 on methylene proton linked to oxygen atom led to loss of acetalde-
hyde to form iodoalkene 5 followed by dehalogenation with sodium sulfite
to afford 1,4-benzoxazepine 6. The isolation of acetaldehyde render further
support to our proposed mechanistic pathway.

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LONGCHAR ET AL.
In conclusion, an efficient application of b-formyl enamide is described
for convenient preparation of 1,4-oxazepines involving a 1,7-cyclisation
reaction. The use of I2-NaHCO3 provides a mild and simple strategy for
high yield preparation of 1,4-oxazepines.
EXPERIMENTAL
Melting points were determined on a Buchi melting point apparatus
and are uncorrected. IR spectra were recorded by using a Perkin Elmer 237
and 580B spectrometers in KBr discs. 1H NMR spectra were recorded
in Varian T-60 and Bruker 300 MHz spectrometer. Mass spectra were
recorded on a Incos 50 mass spectra machine. Elemental analysis were
obtained from a Perkin Elmer Series II 2400 machine. N-Propargyl-b-
formyl enamides were prepared according to a reported procedure.15a
General Procedure for Reduction of 3b-Acetoxy-16-formyl-
17-(N,N-propargylacetamido)-androst-5,16-diene (1a)
To a solution of N-propargyl-b-formyl enamide (1a, 438 mg, 1 mmol)
in methanol (20 ml) was added NaBH4 (380 mg, 10 mmol) in small portions
at 0ꢀC and the reaction mixture was stirred at same temperature for 1 h.
On completion of reaction it was poured into ice–cold water (200 ml) and
extracted with CH2Cl2 (3 Â 25 ml). The organic portion was separated,
washed with water and dried over Na2SO4. Removal of solvent gave
a white solid which was purified by column chromatography using
CHCl3/MeOH: 95/5 as eluant to afford 3b-acetoxy-16-(hydroxymethyl)-
17-(N-propargylacetamido)-androst-5,16-diene (2a) as white crystals
(CHCl3), yield 418 mg (95%), mp 198–199ꢀC, Rf ¼ 0.15 in CHCl3. IR
(KBr) n 3410, 3235, 2915, 2150, 1725, 1630, 1250 cmÀ1
;
1H NMR
(CDCl3): d 5.48 (1H, bs), 4.50 (1H, bs), 4.20 (2H, t), 4.0 (1H, m), 3.80
(1H, m), 1.89 (3H, s), 1.58 (3H, s), 1.02 (3H, s), 0.88 (3H, s), 2.20–1.30
(22H, m); MS: m/z 439 (Mþ þ H), 438 (M+), 408, 366. Anal. Calcd. for
C27H37NO4: C, 73.77; H, 8.48; N, 3.19. Found: C, 73.89; H, 8.69; N, 3.70.
Cyclisation of 3b-Acetoxy-16-(hydroxymethyl)-17-
(N,N-propargylacetamido)-androst-5,16-diene (2a)
Amixture of 2a (440 mg, 1 mmol), NaHCO3 (840 mg, 10 mmol) and
iodine (1.27 g, 5 mmol) were taken in ether (40 ml) and water (10 ml) and

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3285
stirred under N2 atmosphere at room temperature for 8 h. The reaction
was monitored vide silica gel TLC. On completion of reaction, it was
extracted with CH2Cl2 (3 Â 50 ml) and the combined organic portion was
washed with a saturated solution of Na2SO3. Removal of the solvent gave a
brownish product which was purified by column chromatography over
neutral alumina eluting with hexane/EtOAC: 95/5 system to afford 1,4-oxa-
zepine (6a) as white crystals, yield 348 mg (88%), Rf ¼ 0.6 (10% EtOAC/
hexane): mp 162–163ꢀC; IR (KBr) n 2990, 1735, 1645, 1375, 1250 cmÀ1
;
1H NMR (CDCl3): d 7.68 (1H, s), 5.40 (1H, bs), 5.20 (1H, t, J ¼ 1.4 Hz),
4.94 (1H, t, J ¼ 1.4 Hz), 4.62 (1H, m), 2.60–1.09 (19H, m), 2.03 (3H, s),
1.06 (3H, s), 0.92 (3H, s); MS: m/z 395 (Mþ), 335 (Mþ-CH3COOH).
Anal. Calcd. for C25H33NO3: C, 74.91; H, 8.40; N, 3.54. Found: C, 74.42;
H, 8.70; N, 3.94.
6b, yield 388 mg (85%), Rf ¼ 0.6 (10% EtOAC/hexane): mp 170–
172ꢀC; IR (KBr) n 2990, 1720, 1640, 1250 cmÀ1 1H NMR (CDCl3): d
;
7.90–7.10 (6H, m), 5.60 (1H, t, 1.50 Hz), 5.40 (1H, bs), 5.10 (1H, t,
J ¼ 1.5 Hz), 4.50 (1H, m), 2.20–0.90 (19H, m), 1.00 (3H, s), 0.80 (3H, s);
MS: m/z 457 (Mþ), 335 (Mþ-PhCOOH). Anal. Calcd. For C30H35NO3: C,
78.74; H, 7.71; N, 3.06. Found: C, 78.54; H, 7.58; N, 3.24.
6c, yield 301 mg (82%), Rf ¼ 0.55 (10% EtOAC/hexane): mp
165–167ꢀC; IR (KBr) n 2980, 1725, 1635, 1280 cmÀ1; H NMR (CDCl3): d
1
7.40 (1H, m), 5.50 (1H, t, 1.50 Hz), 5.30 (1H, bs), 5.10 (1H, t, J ¼ 1.5 Hz),
4.55 (1H, m), 3.20 (3H, s), 2.20–0.95 (19H, m), 1.00 (3H, s), 0.80 (3H, s);
MS: m/z 367 (Mþ). Anal. Calcd. For C24H33NO2: C, 78.43; H, 9.05; N, 3.81.
Found: C, 78.64; H, 8.88; N, 3.98.
7a, 129 mg (79%), Rf ¼ 0.5 (10% EtOAC/hexane): mp 102–103ꢀC; IR
(KBr) n 2980, 1640, 1255 cmÀ1; 1H NMR (300 MHz, CDCl3): d 7.51 (1H, t,
J ¼ 1.4 Hz), 5.22 (1H, t, J ¼ 1.4 Hz), 4.92 (1H, t, J ¼ 1.4 Hz), 2.54–0.85 (10H,
m); MS: m/z 163 (Mþ), 162. Anal. Calcd. For C10H13NO: C, 73.59; H, 8.03;
N, 8.58. Found: C, 73.42; H, 7.80; N, 8.44.
7b, 120 mg (68%), Rf ¼ 0.5 (10% EtOAC/hexane) mp 100–101ꢀC; IR
(KBr) n 2980, 1640, 1250 cmÀ1; 1H NMR (300 MHz, CDCl3): d 7.55 (1H, t,
J ¼ 1.4 Hz), 5.35 (1H, t, J ¼ 1.4 Hz), 4.85 (1H, t, J ¼ 1.4 Hz), 2.64–0.75 (12H,
m); MS m/z 177 (Mþ), 176. Anal. Calcd. for C11H15NO: C, 74.54; H, 8.53;
N, 7.90. Found: C, 74.61; H, 8.37; N, 8.02.
ACKNOWLEDGMENT
We thank the Department of Science and Technology, New Delhi for
financial support of this work.

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REFERENCES
1. a) Negwer, M. Organic Chemical Drugs and their Synonyms, 7th Edn,
Akademic Verlag, GmbH, Berlin, vol. II, 1994, p. 6305, 6388, 7851 and
5002. b) Elks, J. Dictionary of Drugs, C.R. Ganellin, Ed.; Chapman
and Hall, London, 1st Edn., 1990, p. L-00106.
2. a) Brown, R.T.; Ford, M.J. Tetrahedron Lett. 1990, 31, 2029.
b) Brown, R.T.; Ford, M.J. Tetrahedron Lett. 1990, 31, 2033.
c) Trost, B.M.; Greenspan, P.D.; Yang, B.V.; Sauluier, M.G. J. Am.
Chem. Soc. 1990, 112, 9022.
3. a) Comprehensive Heterocyclic Chemistry, II, Katritzky, A.R. Rees,
C.W., Scriven, E.F.V.; Eds.; Pergamon, Oxford, 1st Edn., 1996, vol.
9, p. 217 and references cited therein. b) Buriks, R.S.; Lovett, E.G. J.
Org. Chem. 1987, 52, 5247. c) Orlek, B.S.; Sammes, P.G.; Weller, D.J.
Chem. Commun. 1993, 607. d) Trost, B.M.; Yang, B.; Miller, M.L. J.
Am. Chem. Soc. 1989, 111, 6482. e) Tietze, L.F.; Brand, S.; Pfeiffer, T.;
Antel, J.; Harms, K.; Sheldrick, G.M. J. Am. Chem. Soc. 1987,
109, 921.
4. a) Cale, Jr., A.D.; Gero, T.W.; Walker, K.R.; Lo, Y.S.; Welstad, Jr.,
W.J.; Jaques, L.W.; Johnson, A.F.; Leonard, C.A.; Nolan, J.C.;
Johnson, D.N. J. Med. Chem. 1989, 32, 2178. b) Effland, R.C.;
Helsley, G.C.; Tegalar, J.J. J. Het. Chem. 1982, 19, 537.
5. Monkovic, I.; Willner, D.; Adam, M.A.; Brown, M.; Crenshaw, R.R.;
Fuller, C.E.; Jubby, P.F.; Luke, G.M.; Matiskella, J.A.; Montzka,
T.A. J. Med. Chem. 1988, 31, 1548.
6. a) Encyclopedia of Reagents for Organic Synthesis, Paquette, L.A., ed.
John Wiley and Sons, New York, 1995, vol. 4, p. 2797. b) Cardillo, G.;
Orena, M. Tetrahedron 1990, 46, 3321. c) Bartlett, P.A. Tetrahedron
1980, 36, 2.
7. a) Kurth, M.J.; Brown, E.G.; Lewis, E.J.; Mckew, J.C. Tetrahedron
Lett. 1988, 29, 1517. b) Bartlett, P.A.; Richardson, D.P.; Myerson, J.
Tetrahedron 1984, 40, 2317.
8. a) Tamaru, Y.; Kawamura, S.-C.; Yoshida, Z.-C. Tetrahedron Lett.
1985, 26, 2885. b) Tamura, Y.; Hojo, M.; Kawamura, S.-C.; Sawada,
S.; Yoshida, Z.-C. J. Org. Chem. 1987, 52, 4062.
9. a) Kurth, M.J.; Bloom, S.H. J. Org. Chem. 1989, 54, 411. b) Hirama,
M.; Iwashita, M.; Yamazaki, Y.; Ito, S. Tetrahedron Lett. 1984,
25, 4963.
10. Tietze, L.F.; Schneider, G.; Wolfling, J.; Nobel, T.; Wulff, C.;
Schubert, I.; Rubeling, A. Angew. Chem. Int. Ed. Engl. 1998, 37, 2469.
11. Williams, D.R.; White, F.H. J. Org. Chem. 1987, 52, 5067.

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3287
12. Boruah, R.C.; Ahmed, S.; Sharma, U.; Sandhu, J.S. J. Org. Chem.
2000, 65, 922.
13. Ahmed, S.; Boruah, R.C. Tetrahedron Lett. 1997, 38, 6747.
14. a) Sharma, U.; Ahmed, S.; Boruah, R.C. Tetrahedron Lett. 2000, 41,
3493. b) Ahmed, S.; Boruah, R.C. Tetrahedron Lett. 1996, 37, 8251.
c) Boruah, R.C.; Ahmed, S.; Sharma, U.; Sandhu, J.S. Ind. J. Chem.
1999, 38B, 274.
15. a) Ahmed, S.; Boruah, R.C. Ind. J. Chem. 1998, 37B, 838. b) Ahmed,
S.; Boruah, R.C. Tetrahedron Lett. 1997, 38, 1845. c) Ahmed, S.;
Sharma, U.; Longchar, M.; Boruah, R.C.; Sandhu, J.S. Synth.
Commun. 2000, 30, 771.
16. Compound 5 was found to be an unstable product, which decomposes
under aerobic condition. Reduction with Na2SO3 provided a compara-
tively stable product 6.
Received in the USADecember 15, 2000

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