3-Pyrrolidinones: Michael addition and Schmidt rearrangement reactions

Article abstract of DOI:10.1080/00397910802378373

Various spiro-pyrano[3,2-b]pyrrolo-2-oxoindolines 3a-d and dicyano-pyrano[3,2-b]pyrroles 5a-e have been synthesized in the present study by Michael addition of 3-pyrrolidinones 1 to isatin-3-ylidenes 2 and arylidenemalononitrile 4. Hexahydro-4-oxo-1-aryl-

Full text of DOI:10.1080/00397910802378373

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3-Pyrrolidinones: Michael
Addition and Schmidt
Rearrangement Reactions
F. A. Amer a , M. Hammouda a , A. A. S. El-Ahl a & B.
F. Abdel-Wahab b
a Chemistry Department , Faculty of Science,
Mansoura University , Mansoura, Egypt
b Applied Organic Chemistry Department , National
Research Center , Dokki, Giza, Egypt
Published online: 08 Jan 2009.
To cite this article: F. A. Amer , M. Hammouda , A. A. S. El-Ahl & B. F. Abdel-Wahab
(2009) 3-Pyrrolidinones: Michael Addition and Schmidt Rearrangement Reactions,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 39:3, 416-425, DOI: 10.1080/00397910802378373
To link to this article: http://dx.doi.org/10.1080/00397910802378373
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Synthetic Communications1, 39: 416–425, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802378373
3-Pyrrolidinones: Michael Addition and Schmidt
Rearrangement Reactions
F. A. Amer,1 M. Hammouda,1 A. A. S. El-Ahl,1 and
B. F. Abdel-Wahab2
1Chemistry Department, Faculty of Science, Mansoura University,
Mansoura, Egypt
2Applied Organic Chemistry Department, National Research Center,
Dokki, Giza, Egypt
Abstract: Various spiro-pyrano[3,2-b]pyrrolo-2-oxoindolines 3a–d and dicyano-
pyrano[3,2-b]pyrroles 5a–e have been synthesized in the present study by Michael
addition of 3-pyrrolidinones 1 to isatin-3-ylidenes 2 and arylidenemalononitrile 4.
Hexahydro-4-oxo-1-aryl-pyrimidine-5-carboxylic acids 7a,b were synthesized
from 1 by Schmidt rearrangement.
Keywords: Arylidenemalononitriles, isatin-3-ylidines, Michael addition, 3-pyrro-
lidinones, Schmidt rearrangement
INTRODUCTION
3-Pyrrolidinones are the key starting materials for the synthesis of a
number of fused heterocycles, such as anticancer drugs (e.g., methotrex-
ate),[1,2] floroquinolone antibacterials (e.g., gemifloxacin, norfloxacin),[3–6]
and inhibitors of HIV-1 replication,[7] and DNA.[8,9] The medicinal
applications of spiro-2-oxoindolines as muscle relaxants and anti-
inflammatory agents is well known.[10,11] Several spiro-2-oxoindoline
derivatives were reported to exhibit analgesics,[12] platelet aggregation
inhibitory,[13] bactericidal, and central nervous system (CNS) depressant
Received January 2, 2008.
Address correspondence to Bakr F. Abdel-Wahab, Applied Organic Chemistry
Department, National Research Center, Dokki, Giza, Egypt. E-mail: Bakrfatehy@
yahoo.com
416

3-Pyrrolidinones
417
activities.[14] The starting material, 3-pyrrolidinones 1a,b, was prepared
from primary aromatic amines, acrylonitrile, and ethyl bromoacetate
according to the reported procedures.[15] In view of these observations
and in continuation of our work on 3-pyrrolidinone,[16] the synthesis of
novel spiro-pyrrolo[3,2-b]-4-pyranyl-2-oxoindoline, dicyanopyrrolo[3,2-
b]-4-pyrane, and hexahydropyrimidin-4-one derivatives starting from
N-aryl-3-pyrrolidinones by Michael addition and Schmidt rearrangement
was studied.
RESULTS AND DISCUSSION
Michael Addition Reactions
Base-catalyzed Michael addition of 1a,b to the exocyclic double bond of
the 3-ylidene derivative 2a,b afforded the regiospecifically Michael adduct
intermediate A, which underwent subsequent cyclization to give spiro-2-
oxoindoline derivatives 3a–d in good yield (Scheme 1). IR spectra of 3a
displayed an absorption band at 1708 cmꢀ1 attributable for the carbonyl
group of 2-oxoindoline part of the product, sharp absorption bands at
2235 and 2196 cmꢀ1 for two carbonitrile groups.
The IR spectra of 3c showed absorption bands at 1716 and
1678 cmꢀ1, which indicated the presence of two carbonyl groups, namely,
the 2-oxoindoline carbonyl group and the carbethoxy carbonyl group.
The IR spectra showed only one carbonitrile group at 2238 cmꢀ1. The
1H NMR of 3c showed four singlets at 9.7, 8.1, 7.51, and 3.76 ppm for
NH, NH2, pyrrole proton, and methoxy group, respectively, and also
showed a quartet at 3.64 and a triplet at 0.69 ppm for CH2 and CH3 of
carbethoxy group, respectively.
Treatment of 1a,b with arylidenemalononitrile 4a–e derivatives in
ethanol containing a catalytic amount of piperidine afforded the pyrano-
[3,2-b]pyrrole derivatives 5a–e in good yields, which are oxoisosters of the
corresponding indole derivatives and were expected to exhibit a wide
spectrum of biological activity (Scheme 1).
The structure of pyrano[3,2-b]pyrroles 5a–e is based on spectral and
analytical data. The mass spectrum of 5b showed the molecular ion peak at
m=z 403, which is assigned to Mþ þ 1. The 1H NMR of 5a revealed the pres-
ence of two protons as a broad singlet at 6.98 ppm, assigned for the amino
group, and a sharp singlet at 7.68 ppm, assigned for the pyrrole ring proton.
One-pot synthesis of compound 5c was investigated. Thus, when a
mixture of 1a, p-bromobenzaldehyde, and malononitrile in a molar ratio
of 1:1:1 was refluxed in ethanol containing a catalytic amount of piperi-
dine, the pyrano[3,2-b]pyrrole 5c was isolated in a low yield. The reaction

418
F. A. Amer et al.
Scheme 1. Michael addition reaction.
could proceed via two pathways. In pathway a, the p-bromobenzalde-
hyde reacted first with malononitrile to give p-bromobenzylidenemalono-
nitrile 2, which reacted with 3-pyrrolidinone 1a to give 5c. In pathway b,
the aldehyde reacted first with 3-pyrrolidinone to give p-bromobenzyli-
dene-3-pyrrolidinone 6, which underwent Michael addition reaction with
malononitrile to give 5c (Scheme 2).
To prove that the reaction could proceed through pathway a or b, we
tried to prepare compound 6 by reaction of p-bromobenzaldehyde with
1a in ethanol containing a catalytic amount of piperdine: the reaction
did not proceed to afford p-bromobenzylidene derivative 6.
Schmidt Rearrangement
3-Pyrrolidinones 1a,b undergo Schmidt rearrangement conditions to
afford hexahydropyrimidinones 7a,b or 6-oxo-4-p-(substitutedphenyl)-
piperazine-2-carboxylic acid 8a,b. The Schmidt rearrangement was

3-Pyrrolidinones
419
Scheme 2. One-pot synthesis of 5c.
accompanied by hydrolysis of the cyano group into the carboxylic group
(Scheme 3).
The structures of the hexahydropyrimidine derivatives 7a,b were
based on spectral and analytical data. The mass spectrum of 7b displayed
the molecular ion peak at m=z 248, which is assigned to Mþ ꢀ 2, and the
major fragmentations were in agreement with the assigned structure.
1H NMR confirmed the assigned structures of 7a,b and excluded the
1
structures 8a,b. The H NMR of 7b displayed a doublet of doublet at
3.74–3.65 ppm, assigned for the magnetically nonequivalent protons Ha
and Hb. The mechanism for the regiospecific rearrangement of 1a,b
shown in Scheme 4 was based upon the relative boat–chair confor-
mations of strain energy. Synchronous rearrangement of azidohydrine
with loss of nitrogen can lead directly to the lactam. Two possible

420
F. A. Amer et al.
Scheme 3. Schmidt rearrangement reaction.
azidohydrines are derivable from 3-pyrrolidinones 1a,b. If azide is prim-
arily on the less hindered convex face of the molecule as in A, it would be
stabilized by hydrogen bonding between the cyano and hydroxyl groups.
Migration occurs with an energetically favored chair conformation, in
which the azalactam 7a,b will result via methylene migration. Methine
migration of the same azidohydrine to afford 8a,b would occur via the
less favorable boat transition state.[17]
Scheme 4. Mechanism of Schmidt rearrangement.

3-Pyrrolidinones
421
EXPERIMENTAL
All melting points were taken on an Electrothermal IA 9000 series digital
melting-point apparatus. Elemental analytical data (in accordance with
the calculated values) were obtained from the Microanalytical Unit, Cairo
University, Cairo, Egypt. The IR spectra (KBr) were recorded on a
Shimadzu CVT-04 spectrophotometer. The 1H NMR spectra were recor-
ded at 270 MHz on a Varian EM-360 spectrometer using TMS as an
internal standard. The mass spectra were performed using a Varian
MAT CH-5 spectrometer (70 eV). All reactions were followed by thin-
layer chromatography (TLC, silica gel, aluminum sheets 60 F254, Merck).
Physical data are given in Table 1.
Table 1. Physical data, yields, and elemental analysis for compounds 3, 5, and 7
Found, (%) [calculated (%)]
Cpd.
no.
Molecular
formula
Yield
Mp (ꢁC) (%) Color
C
H
N
3a
3b
3c
3d
5a
5b
5c
5d
5e
7a
7b
C23H15N5O3
C23H15N5O2
C25H20N4O5
C25H20N4O4
C23H18N4O2
C22H15ClN4O2
C22H15BrN4O2
C23H18N4O
67.52
[67.47]
70.32
[70.22]
65.68
[65.78]
68.08
[68.17]
72.32
[72.24]
65.44
[65.59]
59.16
[59.07]
75.02
[75.39]
61.18
3.62
[3.69]
3.77
[3.84]
4.33
[4.42]
4.56
[4.58]
4.81
[4.74]
3.85
[3.75]
3.32
[3.38]
4.71
[4.95]
3.6
16.97
[17.11]
17.65
[17.8]
12.38
[12.27]
12.66
[12.72]
14.55
[14.65]
13.94
[13.91]
12.62
[12.53]
15.18
[15.29]
12.86
271–272 62 Pale
yellow
258–259 62 Pale
yellow
273–274 81 White
282–283 83 White
255–256 86 Pale
yellow
260–262 77 Pale
yellow
257–258 82 Pale
yellow
198–200 69 Pale
yellow
209–210 81 Pale
yellow
C22H15BrN4O
C12H12N2O3
C12H12N2O4
[61.26]
62.06
[62.12]
58.06
[58.11]
[3.51]
5.21
[5.26]
4.87
[4.89]
[12.99]
12.06
[12.11]
11.29
[11.32]
186–187 82 Colorless
177–178 84 Colorless

422
F. A. Amer et al.
Synthesis of Spiro-pyrano[3,2-b]pyrrole-2-oxoindoline Derivatives (3a–d)
A mixture of 1a or 1b (2 mmol) in ethanol (20 ml), compound 2 (0.4 g,
2 mmol in the case 3a,b or 0.5 g, 2 mmol in the case 3c,d), and two drops
of piperidine were refluxed for 4 h, and left to cool overnight. The result-
ing solid product was filtered off and recrystallized from ethanol.
5-Amino-2-oxo-1-(40-methoxyphenyl)-1,10,20,3a,7,7a0-
hexahydrospiro[indole-30,7-pyrano[3,2-b]pyrrole]-3,60-dicarbonitrile (3a)
1H NMR (DMSO-d6): 3.68 (s, 3H, OCH3), 6.30–6.91 (m, 8H, Ar-H), 7.31
(s, 1H, pyrrole-H), 7.64 (s, 2H, NH2), 10.08 (s, 1H, NH). IR: 1708 cmꢀ1
,
2196 cmꢀ1, 2235 cmꢀ1, 3381 cmꢀ1, 3319 cmꢀ1. Mass spectra: m=z 409
[M]þ.
5-Amino-2-oxo-1-(40-methylphenyl)-1,10,20,3a,7,7a0-hexahydrospiro[indole-
30,7-pyrano[3,2-b]pyrrole]-3,60-dicarbonitrile (3b)
1H NMR (DMSO-d6): 2.32 (s, 3H, CH3), 6.24–6.88 (m, 8H, Ar-H), 7.36
(s, 1H, pyrrole-H), 7.98 (s, 2H, NH2), 10.03 (s, 1H, NH). IR: 1706 cmꢀ1
,
2196 cmꢀ1; 2234 cmꢀ1, 3301 cmꢀ1, 3278 cmꢀ1. Mass spectra: m=z 393
[M]þ.
Ethyl 5-Amino-3-cyano-2-oxo-1-(40-methoxyphenyl)-1,10,20,3a,7,7a0-
hexahydrospiro[indole-30,7-pyrano[3,2-b]pyrrole]-60-carboxylate (3c)
1H NMR (DMSO-d6): 0.69 (t, 3H, O-CH2CH3), 3.64 (q, 2H, OCH2CH3),
3.76 (s, 3H, OCH3), 6.16–6.86 (m, 8H, Ar-H), 7.51 (s, 1H, pyrrole-H), 8.1
(s, 2H, NH2), 9.7 (s, 1H, NH). IR: 1680 cmꢀ1, 1706 cmꢀ1, 2231 cmꢀ1
3393 cmꢀ1, 3287 cmꢀ1. Mass spectra: m=z 456 [M]þ.
,
Ethyl 5-Amino-3-cyano-2-oxo-1-(40-methylphenyl)-1,10,20,3a,7,7a0-
hexahydrospiro[indole-30,7-pyrano[3,2-b]pyrrole]-60-carboxylate (3d)
1H NMR (DMSO-d6): 0.71 (t, 3H, O-CH2CH3), 2.29 (s, 3H, CH3), 3.58
(q, 2H, OCH2CH3), 6.22–6.87 (m, 8H, Ar-H), 7.49 (s, 1H, pyrrole-H),
8.08 (s, 2H, NH2), 9.6 (s, 1H, NH). IR: 1678 cmꢀ1, 1716 cmꢀ1, 2238cmꢀ1
,
3349, 3269 cmꢀ1. Mass spectra: m=z 440 [M]þ.

3-Pyrrolidinones
423
3.3.5-Amino-1,7-dihydro-1-(aryl)-7-(aryl)pyrano[3,2-b]pyrrole-
3,6-dicarbonitrile (5a–e)
A mixture of 1a or 1b (2 mmol) in ethanol (20 ml), appropriate arylidene
malononitrile 4 (2 mmol), and a few drops of piperidine were refluxed for
4 h and Left to cool. The resulting solid product was filtered off, dried,
and recrystallized from ethanol.
5-Amino-1,7-dihydro-1-(4-methoxyphenyl)-7-p-tolylpyrano[3,2-b]pyrrole-
3,6-dicarbonitrile (5a)
1H NMR (CDCl3): 2.2 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 4.8 (s, 1H, C4-
H), 6.59 (d, 4H, Ar-H), 6.98 (s, 2H, NH2), 7.10–7.08 (d, 4H, Ar-H), 7.68
(s, 1H, C6-H). IR: 2195 cmꢀ1, 2234 cmꢀ1, 3424 cmꢀ1, 3325 cmꢀ1. Mass
spectra: m=z 382 [M]þ.
5-Amino-7-(4-chlorophenyl)-1,7-dihydro-1-(4-methoxyphenyl)pyrano[3,2-
b]pyrrole-3,6-dicarbonitrile (5b)
1H NMR (CDCl3): 3.74 (s, 3H, OCH3), 4.91 (s, 1H, C4-H); 6.74 (d, 2H,
J ¼ 8.38, Ar-H), 6.86 (d, 2H; J ¼ 8.97, Ar-H), 7.06–7.16 (m, 6H, 4Ar-H &
NH2), 7.71 (s, 1H, C6-H). IR: 2195 cmꢀ1, 2235 cmꢀ1, 3418 cmꢀ1
3324 cmꢀ1. Mass spectra: m=z 403 [M þ 1]þ, 402 [M]þ.
,
5-Amino-7-(4-bromophenyl)-1,7-dihydro-1-(4-methoxyphenyl)pyrano[3,2-
b]pyrrole-3,6-dicarbonitrile (5c)
1H NMR (CDCl3): 3.68 (s, 3H, OCH3), 4.91 (s, 1H, C4-H), 6.72 (d, 2H,
J ¼ 8.28, Ar-H), 6.88 (d, 2H; J ¼ 8.97, Ar-H), 7.17–7.09 (m, 6H, 4Ar-H &
NH2), 7.73 (s, 1H, C6-H). IR: 2195 cmꢀ1, 2234 cmꢀ1, 3410 cmꢀ1
3321 cmꢀ1. Mass spectra: m=z 448 [M þ 2]þ, 447 [M þ 1]þ, 446 [M]þ.
,
5-Amino-1,7-dihydro-1,7-dip-tolylpyrano[3,2-b]pyrrole-
3,6-dicarbonitrile (5d)
1H NMR (CDCl3): 2.19 (s, 3H, CH3), 2.24 (s, 3H, CH3), 4.78 (s, 1H, C4-
H), 6.49 (d, 2H, Ar-H), 6.96 (s, 2H, NH2), 7.07–7.18 (d, 2H, Ar-H), 7.69
(s, 1H, C6-H). IR: 2195 cmꢀ1; 2238 cmꢀ1; 3369 cmꢀ1, 3319 cmꢀ1. Mass
spectra: m=z 366 [M]þ.

424
F. A. Amer et al.
5-Amino-7-(4-chlorophenyl)-1,7-dihydro-1-p-tolylpyrano-
[3,2-b]pyrrole-3,6-dicarbonitrile (5e)
1H NMR (CDCl3): 2.14 (s, 3H, CH3), 4.87 (s, 1H, C4-H), 6.72 (d, 2H,
J ¼ 8.35, Ar-H), 6.87 (d, 2H; J ¼ 8.65, Ar-H), 7.07–7.18 (m, 6H, 4Ar-H
& NH2), 7.68 (s, 1H, C6-H). IR: 2206 cmꢀ1; 2238 cmꢀ1; 3330 cmꢀ1
3280 cmꢀ1. Mass spectra: m=z 387 [M þ 1]þ; 386 [M]þ.
,
Synthesis of 1-Aryl-5-carboxy-hexahydropyrimidin-4-ones 7a,b
To a stirred mixture of 1a or 1b (5 mmol) in chloroform (20 ml) and conc.
sulfuric acid (4–5 ml) in an ice bath, sodium azide (0.325 g, 5 mmol) was
added over a period of 1 h. The reaction mixture was stirred at room tem-
perature for 4 h, then heated at 50–60 ꢁC for 30 min. The reaction mixture
was poured into ice-cold water and neutralized with ammonium hydr-
oxide. The resulting solid product was filtered off, dried, and recrystal-
lized from ethyl acetate to give 7a,b as colorless crystals.
Hexahydro-4-oxo-1-p-tolylpyrimidine-5-carboxylic Acid (7a)
1H NMR (CDCl3): 2.29 (s, 3H, CH3), 3.74–3.65 (dd, 2H, J ¼ 10 and
18 Hz, Ha & Hb at C2), 4.08–3.92 (m, 3H, C5-H & C6-H2), 5.66 (s, 1H,
NH), 6.65 (d, 2H, J ¼ 8 Hz, Ar-H), 6.85 (s, 1H, COOH), 7.12 (d, 2H,
J ¼ 8 Hz, Ar-H). IR: 1669 cmꢀ1, 1763 cmꢀ1 , 3203 cmꢀ1, 3405 cmꢀ1. Mass
spectra: m=z 332 [M ꢀ 2]þ.
Hexahydro-1-(4-methoxyphenyl)-4-oxopyrimidine-5-carboxylic Acid (7b)
1H NMR (CDCl3): 3.51 (s, 3H, OCH3), 3.74–3.65 (dd, 2H, J ¼ 10 and
18 Hz, Ha & Hb at C2), 4.07–3.90 (m, 3H, C5-H & C6-H2), 5.67 (s, 1H,
NH), 6.61 (d, 2H, J ¼ 8 Hz, Ar-H), 6.87 (s, 1H, COOH), 7.10 (d, 2H,
J ¼ 8 Hz, Ar-H). IR: 1669 cmꢀ1, 1763 cmꢀ1, 3200 cmꢀ1, 3406 cmꢀ1. Mass
spectra: m=z 248 [M ꢀ 2]þ.
REFERENCES
1. Taylor, E. C.; Fletcher, S. T.; Cody, V.; Kempton, R. J. Synthesis of acylpyr-
roles via a-(dimethy1amino)-a-pyrrolylacetonitriles. J. Org. Chem. 1988, 53,
6118.
2. Taylor, E. C.; Ahmed, Z.; Robke, D. J.; Kempton, R. J. Alternative syntheses
of N-[40-(alkoxycarbonylphenyl)]-3-pyrrolidinones. J. Org. Chem. 1991, 56,
5443.

3-Pyrrolidinones
425
3. Kim, B. C.; Kim, Y. D.; Choi, H.; Kim, W. S. A process for the preparation
of pyrrolidino-quinoline-carboxylic acid derivatives (e.g., gemifloxacin with
improved filtration). Patent PCT Int. Appl. WO 01 68,649, 2001; Chem.
Abstr. 135, 242153a (2001).
4. Hong, C. Y.; Kim, Y. K.; Chang, J. H.; Kim, S. H.; Choi, H.; Nam, D. H.;
Kim, Y. Z.; Kwak, J. H. Novel fluoroquinolone antibacterial agents contain-
ing oxime-substituted(aminoethyl)pyrrolidines: Synthesis and antibacterial
activity of 7-(4-aminoethyl)-3-(methoxyimino)pyrrolidin-1-yl)-1-cyclopropyl-
6-fluro-4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic acid. J. Med.
Chem. 1997, 40, 3584.
5. Halazy, S.; Schwarz, M.; Quattropani, A.; Thomas, R.; Baxter, A.; Scheer, A.
Synthesis of substituted N-acyl=sulfonyl pyrrolidine as bax inhibitors. Patent
PCT Int. Appl. WO 01 72,705, 2001; Chem. Abstr. 135, 288686e (2001).
6. Lee, D. C.; Kwon, Y.; Kim, Y.; Rhee, C. High-yield process for preparing
3-aminomethyl-4-Z-methoxyiminopyrrolidine. Patent PCT Int. Appl. WO
02 18, 336, 2002; Chem. Abstr. 136, 216642k (2002).
7. Bouygues, M.; Medou. M.; Chermann, J. C.; Camplo, M.; Kraus, J. L. Short
and unexpectedly potent 3-pyrrolidinone type inhibitors of HIV-1 repli-
cation. Eur. J. Med. Chem. 1998, 33, 445.
8. Kumar, R.; Lown, W. J. Design and synthesis of novel DNA interstrand
cross-linking agents: C2-linked pyrrolo[2,1-c][1,4]benzodiazepine polyamide
conjugates. Heterocycl. Commun. 2002, 8, 115.
9. Kamal, A.; Srinivas, O.; Ramulu, P.; Ramesh, G.; Kumar, P. P.; Kumar,
M. S. Synthesis and DNA binding affinity of novel A-C8=C-C2-exo unsatu-
rated alkoxyamido-linked pyrrolo[2,1-c][1,4]benzodiazepine dimers. Bioorg.
Med. Chem. 2004, 12, 4337.
10. Ninomyia, K. Spirolactone compounds. Japan Patent 80 164,683, 1980;
Chem. Abstr. 95, 25036r (1982).
11. Kobayashi, G.; Matsuda, Y. Indole derivatives having spiro ring. Japan
Patent 70 25,894, 1970; Chem. Abstr. 74, 3529t (1972).
12. Kobayashi, G.; Matsuda, Y. Pyrazoline derivatives as analgesics. Japan
Patent, 68 03,385, 1968; Chem. Abstr. 69, 96716m (1969).
13. Kikugawa, K.; Ichino, M. Platelet aggregation inhibitors V: Pyrimidine
derivatives, indole derivatives, benzothiophenes, and benzoquinolizine,
derivatives. Chem. Pharm. Bull. 1973, 21, 1151.
14. Diebold, J. L.; Wolf, M. Spiro[2H, 3,1-1-benzooxazine]derivatives. U.S.
Patent 3,711,476, 1973; Chem. Abstr. 78, 97672s (1974).
15. Su, T. L.; Watanabe, K. A. Chemistry of the pyrrolo[3,4-c]pyrido[2,3-
d]pyrimidine system: Synthesis of 6,7-dihdropyrrolo[3,4-c]pyrido[2,3-d]
pyrimidines, a novel ring system with potential biological interest. J. Org.
Chem. 1989, 54, 220.
16. Amer, F. A.; Hammouda, M.; El-Ahl, A. A. S.; Abdel-Wahab, B. F. Synthesis
of important new pyrrolo[3,4-c]pyrazoles and pyrazololyl-pyrrolines from
heterocyclic b-ketonitriles. J. Chin. Chem. Soc. 2007, 54, 1543.
17. Krow, G. R. Nitrogen insertion reactions of bridged bicyclic ketones:
Regioselective lactam formation. Tetrahedron 1981, 37, 1283.