Noteworthy mechanistic precedence in the exclusive formation of one regioisomer in the Beckmann rearrangement of ketoximes of 4-piperidones annulated to pyrazolo-indole nucleus by organocatalyst derived from TCT and DMF

Article abstract of DOI:10.1080/00397911.2011.589558

Application of a very mild protocol to the Beckmann rearrangement of ketoximes of pyrazolo annulated oxocarbazole 5a and oxoazacarbazole 5b with the organocatalyst derived from 2,4,6-trichloro[1,3,5]triazine (TCT) and dimethylformamide (DMF) has been explored to provide a regioselective formation of the corresponding azepine 6a and 1,4-diazepine 6b respectively in good yield and purity. The mechanistic precedence for the exclusive formation of only one regioisomer has been discussed. Copyright Taylor & Francis Group, LLC.

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Noteworthy Mechanistic Precedence
in the Exclusive Formation of One
Regioisomer in the Beckmann
Rearrangement of Ketoximes of 4-
Piperidones Annulated to Pyrazolo-
indole Nucleus by Organocatalyst
Derived from TCT and DMF
Ruchi Tyagi a , Navjeet Kaur a , Bhawani Singh a & D. Kishore a
a Department of Chemistry, Banasthali University, Banasthali, India
Accepted author version posted online: 24 Jan 2012.Version of
record first published: 05 Sep 2012.
To cite this article: Ruchi Tyagi , Navjeet Kaur , Bhawani Singh & D. Kishore (2013): Noteworthy
Mechanistic Precedence in the Exclusive Formation of One Regioisomer in the Beckmann
Rearrangement of Ketoximes of 4-Piperidones Annulated to Pyrazolo-indole Nucleus by Organocatalyst
Derived from TCT and DMF, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 43:1, 16-25
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Synthetic Communications1, 43: 16–25, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2011.589558
NOTEWORTHY MECHANISTIC PRECEDENCE IN THE
EXCLUSIVE FORMATION OF ONE REGIOISOMER IN
THE BECKMANN REARRANGEMENT OF KETOXIMES
OF 4-PIPERIDONES ANNULATED TO
PYRAZOLO-INDOLE NUCLEUS BY ORGANOCATALYST
DERIVED FROM TCT AND DMF
Ruchi Tyagi, Navjeet Kaur, Bhawani Singh, and D. Kishore
Department of Chemistry, Banasthali University, Banasthali, India
GRAPHICAL ABSTRACT
Abstract Application of a very mild protocol to the Beckmann rearrangement of ketoximes
of pyrazolo annulated oxocarbazole 5a and oxoazacarbazole 5b with the organocatalyst
derived from 2,4,6-trichloro[1,3,5]triazine (TCT) and dimethylformamide (DMF) has
been explored to provide a regioselective formation of the corresponding azepine 6a and
1,4-diazepine 6b respectively in good yield and purity. The mechanistic precedence for
the exclusive formation of only one regioisomer has been discussed.
Keywords Beckmann rearrangement; Fischer indolization; Japp–Kilingemann reaction;
oxoazacarbazoles; oxocarbazoles; pyrazole; TCT-DMF complex
INTRODUCTION
1,4-Benzodiazepines represent an important class of privileged templates whose
numerous derivatives have been found to have selective activities against a diverse
array of biological targets.[1,2] Recent demonstrations that 1,4-benzodiazepine ana-
logs can be used as potential nonnucleoside reverse transcriptase inhibitors and
active anticancer agents have stimulated further interest in this nucleus from yet
another perspective.[3] Literature pertaining to the one-pot synthetic routes for
1,4-benzodiazepine nucleus from quinazoline,[4] indole,[5] isatin,[6] isatoic anhydride,
quinoline azide,[7] 4-quinolone,[8] and 4-isoquinolone[9] has revealed that
Received March 4, 2011.
Address correspondence to Bhawani Singh, Department of Chemistry, Banasthali University,
Banasthali 304022, India. E-mail: bsyadav2000@gmail.com
16

EXCLUSIVE FORMATION OF ONE REGIOISOMER
17
acid-catalyzed Beckmann rearrangement of 4-quinolone oxime provides a very con-
venient synthetic entry to the benzodiazepine nucleus.[10] It has been demonstrated
that the acid-catalyzed Beckmann rearrangement of the ketoximes of N-substituted
4-quinolones resulted in the formation of both the regioisomers, viz, 1,4- and
1,5-benzodiazepines, the ratio of which depended upon the nature of the substituent
present on the nitrogen atom.[11] This imposed a very serious limitation on the use of
this procedure when exclusively only one regioisomer (the 1,4-benzodiazepine) was
sought in synthesis.
The discovery of cytotoxic properties in pyridocarbazole derivatives[12] (for
example, ellipticene, olivacine, carbazole, and azacarbazole) was hailed as a major
step forward in the battle against cancer. Seemingly limitless structural features that
their analogs provide, coupled with the impressive biological properties they show,
have made them mainstays in cancer chemotherapy.[13] Recently, some azacarbazole
derivatives have been reported to be potent and selective cytotoxic agents.[14]
As a part of an ongoing study on the synthesis of biologically active carbazole
analogs, this investigation was undertaken to explore the accessibility of some novel
carbazole and azacarbazole derivatives, which contained on its one side the biologically
active pyrazole nucleus and on the other side the potentially useful anti-HIV-prone 1,4-
diazepine class of privileged template, on this premise that their presence in tandem in a
single molecular framework of carbazoles and azacarbazoles could produce an interest-
ing series of the biologically active materials typically represented by 6a, b structures.
RESULTS AND DISCUSSION
The synthetic plan conceived for the preparation of the materials 6a and 6b
(Scheme 1) required it to be accomplished in three stages. The first stage of this strat-
egy involved the conversion of 5-indazolyldiazonium chloride to the pyrazolo-fused
oxocarbazole 4a, 10, and oxoazacarbazole 4b derivatives respectively. These were
realized by the interaction of indazolyldiazonium chloride with 2-hydroxymethyli-
dene cyclohexanone 2a or 2-hydroxymethylidene cyclopentanone 8 and N-benzyl-
3-hydroxymethylidene-4-piperidone 2b respectively under the conditions of
Japp–Klingemann reaction[15] followed by the Fischer indolization[16] of the resulting
hydrazones with Kent’s acid (HCl=AcOH; 1:4 v=v). The compounds 3a, b, and 9
were in turn obtained following the reported procedure,[17] which consisted of treat-
ing cyclohexanone, N-benzyl-4-piperidone, and cyclopentanone respectively with
ethyl formate in the presence of sodium ethoxide. The second stage of the strategy
required the conversion of 4a, b, and 10 to the corresponding ketoximes derivatives
5a, b, and 11 through their reaction with hydroxylamine hydrochloride in the pres-
ence of a base. Though the acid-catalyzed reaction has been most often employed for
the rearrangement of ketoximes, but we intended to search for an alternate reagent
because of the obvious reasons stated earlier. A search for this revealed that a quan-
titative conversion of ketoximes into the corresponding lactams under mild
conditions with an organocatalyst has been reported.[17,18] This procedure consisted
of the reaction of ketoximes with a complex formed by 2,4,6-trichloro[1,3,5]triazine
(TCT, cyanuric chloride) and dimethylformamide (DMF). This strategy, when
applied to the conversion of ketoximes 5a, b to the corresponding diazepine deriva-
tives (Scheme 1), yielded exclusively one regioisomer 6a and 6b respectively in good

18
R. TYAGI ET AL.
Scheme 1. Synthesis of 1,4-azepinones.
yield and purity. The structures of compounds 4a, b and 6a, b were established on the
1
basis of their microanalysis, infrared (IR), H NMR, and mass (MS) spectral data.
The data presented in the experimental section were found to be in good agreement
with the assigned structures. The IR spectra of 4a, b showed the presence of a strong
absorption band near 1700 cmꢀ1 for the CO group, whose conversion to the corre-
sponding ketoximes 5a, b was evident by the disappearance of the peak for CO
group. The presence of diazepine ring in 6a, b was ascertained by the appearance
of the CO absorption band at a low frequency at 1660 cmꢀ1 and NH str. at
1
3300 cmꢀ1. The H NMR spectrum displayed the peak for NH proton of azepine
ring at d 8.00–8.09 ppm. The most diagnostic evidence that established the formation
of the compounds 5a, b and 6a, b was the appearance of the proton of indole NH in
the region of d 10.1 in all the compounds. (The NH proton of indazole nucleus
appeared at a much downfield region at d 12.4 ppm). The appearance of the Mþ
peaks corresponding to their molecular formula in MS spectra substantiated further
the formation of the compounds and unequivocally established their structures.
The mechanistic pathway shown in Scheme 2 rationalizes the formation of 6a,
b from 5a, b. It is assumed that the reaction proceeded through the formation of a
complex formed from 2,4,6-trichloro[1,3,5]triazine (TCT, cyanuric chloride, an inex-
pensive reagent) and DMF, which allowed the Beckmann rearrangement to take

EXCLUSIVE FORMATION OF ONE REGIOISOMER
19
Scheme 2. Mechanistic pathway of TCT-DMF-catalyzed Beckmann rearrangement.
place on 5a, b to generate 6a, b respectively. The mechanistic scheme for this
rearrangement shown in Scheme 2 is based on the earlier precedence for this reaction
in the literature.[17,18]
A plausible mechanistic scheme for the exclusive formation of 6a (95%) and 6b
(98%) from the rearrangement of the corresponding ketoximes 5a and 5b respectively
with TCT and DMF is shown in Scheme 3. The reaction is believed to proceed by a
pathway similar to that outlined in Scheme 2. It is suggested that the species G gen-
erated in Scheme 2 presumably facilitates the departure of its chlorine atom by the
indole nitrogen, which initiates an intramolecular nucleophilic attack on the
carbon-bearing the chlorine atom to generate a relatively more stable species K
via the intermediacy of J (Scheme 3). The indicated orientation that the species G
acquires facilitates on one hand the rearrangement to occur only through path a
and on the other hand precludes its reaction in proceeding through path b to form
the other regioisomers 7a and 7b. It is apparent that the rearrangement through path
a would allow 6a and 6b to be exclusively formed in the reaction.
In view of establishing the generality of this reaction, the Beckmann rearrange-
ment of the corresponding cyclopentanone oxime 11 was also examined. The
required oxime 11 was realized in a straightforward manner in three steps from 9
(Scheme 4), on allowing the same strategy to operate on 9 that had resulted the for-
mation of 5a from 3a (Scheme 1). The rearrangement of 11 with TCT-DMF pro-
duced exclusively 12 in 82% yield. The minor amounts of other products formed
were not examined. The same mechanism (Scheme 2) that allowed the formation
of 6a and 6b from 5a and 5b was presumed to operate also in the formation of

20
R. TYAGI ET AL.
Scheme 3. Mechanism for the exclusive formation of one-regioisomer 6a and 6b only.
12 from 11. We believe that in both the reactions the indole nitrogen has played a
determining role in allowing the formation of the one regioisomer only. In the
1H NMR spectrum of 12, the occurrence of two downfield triplets for the protons
of two CH2 groups at d 3.40 and 2.83 clearly indicated these to be present in close
proximity to nitrogen atom. Had 13 been formed, the two CH2 groups would have
been present close to CO group and the protons of the CH2 group would have
1
appeared in an upfield region. In the H NMR spectrum of 6b (containing the
N-benzyl group), the two CH2 groups were found to be flanked in between the
two nitrogen atoms, and this caused the two triplets of the CH2 protons to appear
much downfield in the region of d 3.25 and 3.15. Had the 7b been formed, it would
have caused the CH2 protons lying close to CO group to appear in the upfield region.
As this was not observed, it clearly ruled out the possibility of the formation of 7b.

EXCLUSIVE FORMATION OF ONE REGIOISOMER
21
Scheme 4. Synthesis of 3,4-dihydropyazolo[4,3-b]azacarbazole-1(2H)-one.
EXPERIMENTAL
Melting points were determined in an open capillary and are uncorrected. The IR
spectra were recorded on a Schimadzu FTIR-8400S. 1H NMR spectra were recorded
using CDCl3 on Bruker DRX-300 spectrometer using tetramethylsilane (TMS) as
internal reference, and values are expressed in d ppm. Mass spectra were taken on a
Jeol SX-102 mass spectrometer at 70 eV. 5-Aminoindazole required in synthesis was
prepared from the reduction[19] of commercially available 5-nitroindazole.
Preparation Using Japp–Klingemann Reaction
A solution of 5-indazolyl amine 1 (1.0 g, 0.050 mol) in aqueous HCl (2 ml con-
centrated HCl in 4 ml water) was treated with a cold saturated solution of sodium
nitrite (0.7 g in 2 ml water) while the temperature was kept at 0 to 5 ꢁC. The solution
was kept aside for 10 min. It was then added portionwise to an ice-cooled mixture
containing
0.050 mol) or 2-hydroxymethylene cyclopentanone 9 and sodium acetate trihydrate
(E)-1-benzyl-3-(hydroxymethylidine)-piperidin-4-one
3b
(1.30 g,
(1.80 g) in methanol (10 ml) and water (6 ml) over a period of 0.5 h with stirring.

22
R. TYAGI ET AL.
The contents were allowed to stand for a further 0.5 h and the resulting solid mass
was filtered, washed with water, dried, and recrystallized from ethanol. Similarly
the cyclohexan-1-one-2-[5-indazolyl]hydrazone was prepared. These were employed
in the next step for Fischer indolization without further purification to give 4a, 4b,
and 10 respectively.
General Method for the Preparation of 4a, 4b, and 10
A solution of hydrazone (0.01 mol) suspended in a mixture of acetic acid and HCl
(3:1 ml) was refluxed on a preheated oil bath to 125–130ꢁC for 0.5 h. The contents were
then cooled and poured into ice-cold water with stirring and basified with ammonia. The
separated brown solid was purified by passing through a column of silica gel using 50%
benzene in petroleum ether as eluant to give 4a, 4b, and 10 respectively.
8,9-Dihydropyrazolo[4,3-b]carbazol-6(1H,5H,7H)-one 4a. This was pre-
pared following the general procedure mentioned above. Yield: 65%; mp
1
238–240 ꢁC; IR (KBr) cmꢀ1: 3290, 2920, 1720, 1510, 1020; H NMR (300 MHz,
CDCl3þDMSO-d6) d ppm: 12.4 (1H, s, NH), 10.1 (1H, s, NH), 8.20 (1H, s, CH),
7.60 (1H, s, ArCH), 7.44 (1H, s, ArCH), 2.43 (2H, t, CH2), 2.10 (2H, m, CH2),
1.89 (2H, t, CH2); MS m=z (percent abundance): 225 [Mþ] (25%), 109 (38%), 165
(50%), 136 (56%), 91 (88%); Analytical data calcd.=found for C13H11N3O: N,
18.52=18.69; C, 69.32=69.54; H, 4.92=5.08.
9-Benzyl-7,8-dihydropyrazolo[4,3-b]carbazol-6(1H,5H,7H)-one (4b). This
was prepared following the general procedure mentioned above. Yield: 70%; mp
1
277–279 ꢁC; IR (KBr) cmꢀ1: 3220, 2910, 1735, 1520, 1040; H NMR (300 MHz,
CDCl3 þ DMSO-d6) d ppm: 11.9 (1H, s, NH), 10.8 (1H, s, NH), 8.15 (1H, s, CH),
7.79–7.57 (2H, m, ArH), 7.14–7.06 (5H, m, ArH), 4.32 (2H, t, CH2), 3.39 (2H, t,
CH2), 2.63 (2H, s, CH2); MS m=z (percent abundance): 316 [Mþ](18%), 288
(26%), 221 (40%), 147 (52%), 91 (81%). Analytical data calcd.=found for
C19H16N4O: N, 17.71=17.94; C, 72.13=72.31; H, 5.10=5.29.
Pyrazolo[4,3-b]-1,2-dihydrocyclopentan[b]indol-3(4H)-one 10. The gen-
eral method mentioned above was applied to the synthesis of 10. Yield: 71%; mp
1
210–212 ꢁC; IR(KBr) cmꢀ1: 3250, 29350, 1710, 1540, 1040; H NMR (300 MHz,
CDCl3 þ DMSO-d6) d ppm: 12.1 (1H, s, NH), 10.3 (1H, s, NH), 8.15 (1H, s, CH),
7.63 (1H, s, ArH), 7.57 (1H, s, ArH), 2.67 (2H, t, CH2), 2.71 (2H, t, CH2); MS:
m=z 211 [Mþ]. Analytical data calcd.=found for C13H11N3O: N, 19.89=20.09; C,
68.24=68.44; H, 4.29=4.38.
Preparation of Ketoxime 5a, 5b, and 11
To a mixture of 0.137 mol of 4a/b or 10, hydroxylamine hydrochloride (0.216 g,
0.06 M), 0.1 g of sodium hydroxide (pellet form) in 0.2 ml of rectified spirit, and
0.1 ml water were added in portions with shaking. As the reaction became too
vigorous, the flask was cooled in running tap water. When all the sodium hydroxide
was added, a reflux condenser was attached to the flask, and the mixture was refluxed
for 20 min, cooled, and poured into 5 ml of water. The precipitate (oxime) was

EXCLUSIVE FORMATION OF ONE REGIOISOMER
23
filtered at the pump, washed, and recrystallized from methanol to give ketoxime 5a:
yield 70%, mp 245–46 ꢁC; 5b: yield 76%, mp 224–226 ꢁC; 11: yield 66%, mp 170 ꢁC.
Preparation of 1,4,5,6,8-Pentahydroimidazolo[7,8-b]indolo-
7(5H)-[6,5-f]azepine (3H)-2-one 6a
2,4,6-Trichloro[1,3,5]triazine (1.83 g, 10.0 mmol) was added to DMF (2 ml)
and maintained at 25 ꢁC. After formation of white solid, the reaction was monitored
(by TLC) until complete disappearance of TCT, and then ketoxime of
7,8,9-trihydropyrazolo[4,5-b] carbazol-6(3H)-one 5a (1.10 g, 10.0 mmol) in DMF
(15 ml) was added. After the addition, the mixture was stirred at room temperature
and monitored (by TLC) until the completion of the reaction (20 h). Water (20 ml)
was added, and then the organic phase was washed with 15 ml of a saturated solution
of Na2CO3 followed by brine solution. The organic layer was dried over the sodium
sulfate. Evaporation of solvent gave 6a. Yield: 1.27 g (95%), mp 155–156 ꢁC. IR
1
(KBr) cmꢀ1: 3340, 2930, 1660, 1600, 1490, 1090, 800; H NMR (300 MHz, CDCl3)
d ppm: 12.53 (1H, s, NH), 10.55 (1H, s, NH), 8.19 (1H, s, CH pyrazole ring), 8.09
(1H, t, NH), 7.88–7.76 (2H, s, ArH), 2.58 (2H, t, CH2), 2.13 (2H, t, CH2), 1.66
(2H, m, CH2). MS m=z (percent abundance): 240 [Mþ] (21%), 212 (28%), 165
(50%), 91 (78%); Analytical data calcd.=found for C13H12N4O: N, 23.22=23.41: C,
64.99=65.17: H, 5.03=5.26.
Preparation of 6-Benzyl-1,4,5,8-tetrahydroimidazolo[7,8-b]indolo-
7(5H)-[6,5-f]-azepine (3H)-2-one 6b
Compound 6b was prepared by the method used for preparation of 6a. Yield:
1
98%, mp 164–165 ꢁC. IR (KBr) cmꢀ1: 3300, 2900, 1665, 1580, 1490, 1025, 825; H
NMR (300 MHz, CDCl3 þ DMSO-d6) d ppm: 12.3 (1H, s, NH), 10.6 (1H, s, NH),
8.14 (1H, s, CH pyrazole ring), 8.09 (1H, t, NH), 7.82–7.10 (7H, m, ArH), 4.37
(2H, s, CH2), 3.25 (2H, t, CH2), 3.15 (2H, t, CH2). MS m=z (percent abundance):
331 [Mþ] (17%), 303 (22%), 286 (43%), 191 (51%), 109 (58%), 91 (81%). Analytical
data calcd.=found for C19H17N5O: N, 21.73=21.94; C, 68.87=69.08; H, 5.17=5.36.
Preparation of 3,4-Dihydro-pyrazolo-2H-pyrido[3,4-b]indol-
(6H,10H)-one 12
Compound 12 was prepared by the method used for preparation of 6a and 6b.
Yield 1.10 g (82%), mp 190 ꢁC. IR (KBr) cmꢀ1: 3310, 2920, 1710, 1650, 1090, 830; 1H
NMR (300 MHz, CDCl3) d ppm: 12.72 (1H, s, NH), 10.05 (1H, s, NH), 8.21 (1H, s,
CH pyrazole ring), 8.10 (1H, t, NH), 7.71 (1H, s, ArH), 7.74 (1H, s, ArH), 3.40 (2H,
t, CH2), 2.83 (2H, t, CH2); MS: m=z 226 [Mþ]. Analytical data: calcd.=found for
C13H12N4O: N, 23.22=23.41; C, 63.71=63.88; H, 4.46=4.61.
CONCLUSION
In conclusion, two noteworthy features from the strategy employed in synthesis
of the reported compounds are apparent from our study. First, it established that the

24
R. TYAGI ET AL.
Fischer indolization of 2-(2-indazolylhydrazono)cyclohexan-1-one and 1-benzyl-
3-(2-indazolylhydrazono)piperidin-4-ones provided a very convenient, one-pot
synthetic entry to the corresponding pyrazolo fused oxocarbazole 4a and oxoazacar-
bazole 4b derivatives. The study further established the versatility of the Japp–
Klingemann reaction to provide a one-step synthetic approach to the preparation
of hetero aryl hydrazones (on to the adjacent methylene carbon of a cyclic carbonyl
species), which are not normally accessible by conventional procedures. Second, it
established that the Beckmann rearrangement of the ketoximes of the indole ring
incorporated 4-piperidones by the organocatalyst derived from TCT þ DMF pro-
vided an elegant one-step approach to the regioselective formation of one regioi-
somer only, in high purity and good yield. The versatility of this process pathway
on other substrates is under study.
ACKNOWLEDGMENTS
The authors are thankful to CDRI, Lucknow, for providing the spectral data of
the compounds, and are grateful for the financial support provided by the Department
of Science and Technology (DST), New Delhi, to Banasthali Center for Education and
Research in Basic Sciences under the CURIE (Consolidation of University Research
for Innovation and Excellence in Women Universities) program.
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