A clean and expedient synthesis of pyrido[1,4]oxazepino spiropyrrolidines through one-pot, three-component [3+2] cycloaddition reaction

Article abstract of DOI:10.1080/00397910903531730

One-pot three component synthesis of novel pyrido[1,4]-oxazepine fused spiropyrrolidines has been accomplished in good yields by 1,3-dipolar cycloaddition reaction of azomethine ylide, derived from paraformaldehyde and sarcosine with (E)-4-benzylidene-hexahydro-1H-pyrido[2,1-c][1,4]-oxazepine-3(7H) -one as dipolarophiles derived from Baylis-Hillman adducts. The effect of solvent on the [3+2]-cycloaddition reaction is also studied. Copyright

Full text of DOI:10.1080/00397910903531730

Synthetic Communications1, 40: 3721–3727, 2010
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910903531730
A CLEAN AND EXPEDIENT SYNTHESIS OF
PYRIDO[1,4]OXAZEPINO SPIROPYRROLIDINES
THROUGH ONE-POT, THREE-COMPONENT [3 þ 2]
CYCLOADDITION REACTION
S. Kathiravan, A. R. Suresh Babu, and R. Raghunathan
Department of Organic Chemistry, University of Madras, Chennai, India
One-pot three component synthesis of novel pyrido[1,4]-oxazepine fused spiropyrrolidines
has been accomplished in good yields by 1,3-dipolar cycloaddition reaction of azomethine
ylide, derived from paraformaldehyde and sarcosine with (E)-4-benzylidene-hexahydro-
1H-pyrido[2,1-c][1,4]-oxazepine-3(7H)-one as dipolarophiles derived from Baylis-Hillman
adducts. The effect of solvent on the [3 þ 2]-cycloaddition reaction is also studied.
Keywords: Azomethine ylide; Baylis–Hillman adducts; cycloaddition; pyrido[1,4]-oxazepine;
spiropyrrolidine
INTRODUCTION
Azepines are known to be biologically active compounds. The seven membered
azepine and oxepine ring systems are important core units in a variety of biologically
interesting natural products such as balanol a potent protein kinase C inhibitor
and isolaurepinnacin.[1] Seven membered heterocycles with two heteroatoms in 1,
4-positions, are known to possess manifold biological activities. In particular aryl
annulated [1,4]-diazepine and [1,4]-oxazepine[2] units are crucial moieties in several
psychoactive pharmaceuticals eg, oxazepam 1 (transquilizer). Moreover 6-benzylidene
oxazepine-5,7-dione[3,4] 2 is a valuable chiral template for stereoselective synthesis.
The synthesis of alkaloids such as calvine (3a) and 2-epicalvine (3b) containing a
1,7- tetramethylene-1,4-oxazepine-5-one was recently reported.[5]
[3 þ 2]-Cycloaddition reaction is one of the most useful methods for the
construction of five membered heterocyclic rings. Because of their high regio- and
stereoselectivity, it has led to a number of heterocycle syntheses which utilize such reac-
tion as the key step.[6] The pyrrolidine moiety is one of the significant core structures
among the natural and unnatural heterocyclic compounds[7] with remarkable med-
icinal activities.[8] In particular, pyrrolidines have played a unique role in the design
and synthesis of novel biologically active compounds serving as anti-inflammatory,
Received September 15, 2009.
Address correspondence to Professor R. Raghunathan, Department of Organic Chemistry,
University of Madras, Chennai 600 025, India. E-mail: ragharaghunathan@yahoo.com
3721

3722
S. KATHIRAVAN, A. R. SURESH BABU, AND R. RAGHUNATHAN
Figure 1. Biologically active [1,4]-oxazepine alkaloids.
antiasthmatic, antituberclosis, antibacterial, antihypertensive, antitumor, and most
notably, antimalarial agents.[9] Moreover oxazepine substituents are biologically
active and exist in the structures of the various antimalarial and antitumor agents.[10]
Consequently, the integeration of pyrrolidine moiety with oxazepine derivative may
increase their biological activities or create new medicinal properties.
In continuation of our research in the area of 1,3-dipolar cycloadditions[11] we
herein report for the first time, a three component, one-pot synthesis of novel oxa-
zepine based spiropyrrolidines through cycloaddition reaction of the azomethine
ylides with (E)-4-benzylidene-hexahydro-1H-pyrido[2,1-c][1,4]-oxazepine-3(7H)-one
(4 a–e).
The synthetic strategy for the construction of the cycloadducts is shown
in Figure 2. Pyrido[1,4]-oxazepine-7-ones[12] were prepared by the condensation of
Baylis–Hillman adducts[13] (8) with amino alcohol.
Figure 2. Disconnection approach to pyrido[1,4]oxazepinopyrrolidine.

SYNTHESIS OF PIPERIDO-OXAZEPINO SPIROPYRROLIDINES
3723
Scheme 1. Mechanism for the generation of azomethine ylide from paraformaldehyde and sarcosine.
RESULTS AND DISCUSSION
Of all the routes available for the generation of azomethine ylide decarboxylation
method is favourable and convenient for the synthesis of heterocyclic compounds.[14]
In this method, an aldehyde and a primary=secondary amino acid are condensed to
generate the reactive intermediate, which is then trapped by dipolarophiles. The mech-
anism for the generation of azomethine ylide is shown in Scheme 1.
Pyrido[1,4]-oxazepine-7-ones (4a–e, 1.0 equiv,) were reacted with the azomethine
ylide derived from paraformaldehyde (9, 6.0 equiv,) and sarcosine (10, 1,5 equiv,) in
refluxing toluene for 12 hours under Dean–Stark conditions to give the cycloadducts
11–15 in good yields (Scheme 2).
The products were characterized on the basis of their elemental analysis as well
as 1H NMR, 13C NMR, and mass spectral analysis. Thus the 1H NMR spectrum of 12
exhibited a singlet at d 2.09 due to the ꢀNCH3 protons of the pyrrolidine moiety. The
-NCH2 protons of the pyrrolidine ring occurred as two doublets at d 3.37 (J ¼12.9 Hz)
and 4.03 (J ¼ 12.9 Hz). The ꢀNCH2 protons of the pyrrolidine ring adjacent to
benzylic proton appeared as two doublet of doublets at d 2.85 (J ¼ 11.4, 7.4 Hz)
and 3.01 (J ¼ 13.2, 7.4 Hz). The benzylic proton appeared as a multiplet in the range
d 4.15–4.31. The –NCH2 protons of the oxazepine ring appeared as two doublets at d
2.13 and 2.17 (J ¼ 6.0 Hz). A singlet at d 1.18 (1H) and a multiplet in the range d
1.21–1.173 (9H) corresponding to rest of the other methylene protons of the oxazepine
ring. The bridge head proton of the oxazepine ring showed a broad singlet at d 2.24.
The aromatic protons resonated as a multiplet in the range d 7.14–7.35.
The off resonance proton decoupled 13CNMR spectrum of 12 exhibited peaks at
d 55.75 ppm due to the ꢀNCH3 carbons. The pyrrolidine methylene carbons reso-
nated at d 60.44 and d 63.19 ppm. The spiro carbon showed a peak at d 72.46 ppm.
The carbonyl group presented in the oxazepine ring exhibited a peak at d
171.42 ppm. Moreover, the presence of a molecular ion peak at m=z 393.4 (Mþ) in
Scheme 2. Reaction of azomethine ylide generated from paraformaldehyde and sarcosine with pyrido[1,4]-
oxazepine-7-one.

3724
S. KATHIRAVAN, A. R. SURESH BABU, AND R. RAGHUNATHAN
Table 1. [3 þ 2]-Cycloaddition reaction of pyrido [1,4]-oxazepine derived dipolaropiles
4 (a–f) with sarcosine 10 and paraformaldehyde 9
the mass spectrum of 12 confirmed the structure of the cycloadduct, and it showed
satisfactory elemental analysis. The results are summarized in Table 1.
CONCLUSION
In conclusion we have synthesized a series of hitherto unknown pyrido[1,4]-
oxazepine fused spiropyrrolidines through one-pot three component intermolecular
1,3-dipolar cycloaddition reaction of azomethine ylide with benzylidene oxazepine
derived from Baylis–Hillman adducts.

SYNTHESIS OF PIPERIDO-OXAZEPINO SPIROPYRROLIDINES
3725
EXPERIMENTAL
General
All melting points are uncorrected. IR spectra were recorded on a Shimadzu
FT-IR 8300 instrument. Mass spectra were recorded on a Jeol DX 303 HF spec-
trometer with Maspec System (msw=9629). 1H and 13C NMR were recorded in CDCl3
using TMS as internal standard on a Bruker spectrometer at 300 and 75 MHz, respect-
ively. Elemental analyses were carried out on a Perkin-Elmer 2400 B instrument.
Representative Experimental Procedure for the Synthesis of
Cycloadducts (11–15)
A mixture of sarcosine (1.5 equiv), paraformaldehyde (6.0 equiv) and the corre-
sponding [1,4]-Oxazepine-7-one (1.0 equiv) was heated under reflux in toluene in a
Dean-Starck apparatus (10 ml for 1 mmol of dipolarophile). After the completion
of the reaction as evidenced by TLC the reaction mixture was filtered through a
pad of celite and the solvent was removed under reduced pressure. The crude product
was subjected to column chromatography using petroleum ether: ethyl acetate (3:2) as
eluent to get pure product.
1-N-Methyl-3-phenylhexahydro-1H-pyrido[2,3-c][1,4]oxazepin-3-(7H)-
one pyrrolidine 11. Time 12 h, 0.24 g, Rf- 0.8, (Hexane-Ethylacetate 3:1) white
1
powder, Yield 83%. mp 94–96 ꢁC. H NMR (300 MHz, CDCl3); d 1.28 (s, 1H);
1.29–1.36 (m, 2H); 1.56–1.81 (m, 10H), 2.18 (d, J ¼ 3.9 Hz, 1H); 2.23 (d, J ¼ 4.8 Hz,
1H), 2.32 (brs, 1H); 2.93 (dd, J ¼ 11.1, 7.2 Hz, 1H); 3.09 (dd, J ¼ 12.0, 7.2 Hz,
1H); 3.46 (d, J ¼ 13.2 Hz, 1H); 4.20 (d, J ¼ 13.2 Hz, 1H); 4.25–4.31 (m, 1H);
7.23–7.47 (m, 5H); 13C NMR (75 MHz); d 23.8; 25.2; 29.2; 31.7; 40.0; 42.4; 44.8;
48.2; 55.7; 60.6; 63.2; 73.0; 128.4; 128.5; 134.2; 161.3; 172.2; m=z 314 (Mþ).
Elemental anal. Calcd. for C19H26N2O2: C, 72.58; H, 8.32; N, 8.91; Found: C,
72.66; H, 8.43; N, 8.87.
1-N-Methyl-3-(p-bromophenyl)hexahydro-1H-pyrido[2,3-c][1,4]oxazepin-
3-(7H)-one pyrrolidine 12. Time 12 h, 0.24 g, Rf- 0.6, (Hexane-Ethylacetate 3:2)
1
light yellow powder, Yield 85%. mp 146–148 ꢁC. H NMR (300 MHz, CDCl3); d
1.18 (s,1H); 1.21–1.73 (m, 9H); 2.09 (s, 3H); 2.13 (d, J ¼ 6.0 Hz, 1H); 2.17 (d,
J ¼ 6.0 Hz, 1H); 2.24 (brs, 1H); 2.85 (dd, J ¼ 11.4, 7.4 Hz, 1H); 3.01 (dd, J ¼ 13.2,
7.4 Hz, 1H); 3.37 (d, J ¼ 13.2 Hz, 1H); 4.03 (d, J ¼ 6.9 Hz, 1H); 4.15–4.31 (m, 1H);
7.14–7.35 (m, 4H); 13C NMR (75 MHz CDCl3); d 23.8; 25.2; 29.1; 29.6; 30.8; 40.0;
46.2; 55.75; 60.4; 63.1; 72.4; 123.0; 130.0; 131.7; 133.18; 134.9; 171.4; m=z 392.3
(Mþ). Elemental anal. Calcd. for C19H25N2O2Br: C, 58.00; H, 6.39; N, 7.12; Found:
C, 58.20; H, 6.43; N, 7.03.
1-N-Methyl-3-(p-methylphenyl)hexahydro-1H-pyrido[2,3-c][1,4]oxazepin-
3-(7H)-one pyrrolidine 13. Time 12 h, 0.22 g, Rf- 0.6, (Hexane-Ethylacetate 3:2) Pale
1
yellow solid, Yield 81%. mp 222–224 ꢁC. H NMR (300 MHz, CDCl3); d 1.25–1.67
(m, 11H); 1.68 (s, 3H); 2.25 (d, J ¼ 9.3 Hz, 1H); 2.37 (s, 3H); 2.96 (d, J ¼ 11.4 Hz,
1H); 3.23 (d, J ¼ 12.3 Hz, 1H); 4.13 (dd, J ¼ 12.3, 12.3 Hz, 2H); 4.45 (d, J ¼ 12 Hz,
1H); 7.17–7.27 (m, 4H); 7.55 (s, 1H); 13C NMR (75 MHz CDCl3); d 22.6; 23.6; 27.2;

3726
S. KATHIRAVAN, A. R. SURESH BABU, AND R. RAGHUNATHAN
45.1; 47.6; 50.4; 55.8; 59.9; 63.4; 72.3; 93.5; 127.4; 131.1; 136.5; 138.0; 143.8; 158.3;
168.5; m=z 328.2 (Mþ). Elemental anal. Calcd. for C20H28N2O2: C, 93.14; H, 8.58;
N, 8.52; Found: C, 93.27; H, 8.63; N, 8.43.
1-N-Methyl-3-(p-nitrophenyl)hexahydro-1H-pyrido[2,3-c][1,4]oxazepin-
3-(7H)-one pyrrolidine 14. Time 12 h, 0.24 g, Rf- 0.6, (Hexane-Ethylacetate 3:1)
1
dark yellow powder, Yield 88%. mp 121–123 ꢁC. H NMR (300 MHz, CDCl3); d
0.1.25–1.83 (m, 11H); 2.22 (d, J ¼ 3.0 Hz, 1H); 2.59 (d, J ¼ 3.9 Hz, 1H); 2.29–2.36
(m, 2H); 2.93–2.97 (m, 1H); 3.18 (d, J ¼ 13.5 Hz, 1H); 3.52 (d, 13.5 Hz, 1H); 4.22
(s, 2H); 6.84 (s, 1H); 7.53 (d, J ¼ 7.2 Hz, 2H); 8.14 (d, J ¼ 8.7 Hz, 2H); 13C NMR
(75 MHz CDCl3); d 21.5; 22.9; 26.8; 27.3; 29.1; 29.6; 34.1; 43.7; 53.4; 57.6; 60.6;
69.9; 121.5; 126.9; 138.4; 145.1; 168.3; m=z 343.7 (Mþ). Elemental anal. Calcd. for
C19H25N3O4: C, 66.45; H, 7.33; N, 12.23; Found: C, 66.60; H, 7.42; N, 12.09.
1-N-Methyl-3-(o-chlorophenyl)hexahydro-1H-pyrido[2,3-c][1,4]oxazepin-
3-(7H)-one pyrrolidine 15. Time 12 h, 0.24 g, Rf- 0.6, (Hexane-Ethylacetate 3:1)
1
dark yellow powder, Yield 84%. mp 133–135 ꢁC. H NMR (300 MHz, CDCl3); d
1.17–1.48 (m, 11H); 2.21(s, 3H); 2.56 brs, 1H), 2.92 (d, J ¼ 11.7 Hz, 1H); 3.63
(d, J ¼ 15.6 Hz, 1H), 3.92 (d, J ¼ 12.3 Hz, 1H), 4.27 (dd, J ¼ 11.7, 9.0 Hz, 2H),
6.84–7.33 (m, 4H), 7.81(s, 1H); 13C NMR (75 MHz CDCl3); d 19.9; 22.7; 26.1;
28.6; 30.1; 40.23; 42.19; 44.86; 49.9; 53.7; 60.0; 63.2; 124.8; 125.6; 132.7; 137.3;
167.2; m= 347.6 (Mþ). Elemental anal. calcd. for C19H25N2O2: C, 65.52; H, 7.24;
N, 8.01; Found: C, 65.68; H, 7.31; N, 8.12.
ACKNOWLEDGMENTS
S.K. thanks Counsil of Scientific Industrial and Research (CSIR) for Senior
Research Fellowship (SRF). R.R. thanks DST-FIST for NMR facility and financial
assistance.
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