Unanticipated products from reductive and oxidative cleavages of 1-substituted 3,3-diphenyl-1′-methylspiro[azetidine-2,3′-indoline]- 2′,4-diones

Article abstract of DOI:10.1002/jhet.731

Titled spiroazetidinones 1a,b undergo reductive cleavage on treatment with excess lithium aluminum hydride forming 3-benzhydryl-1-methylindole as the main product together with a γ-amino alcohol depending upon the substituent present on the azetidin-2-one

Full text of DOI:10.1002/jhet.731

1312
Unanticipated Products from Reductive and Oxidative Cleavages
of 1-Substituted 3,3-diphenyl-10-methylspiro
[azetidine-2,30-indoline]-20,4-diones
Vol 48
Girija S. Singh* and Patrick M. Luntha
Chemistry Department, University of Botswana, Private Bag 0022, Gaborone, Botswana
*E-mail: singhgs@mopipi.ub.bw
Received September 14, 2010 accepted 28 November 2010
DOI 10.1002/jhet.731
Published online 18 August 2011 in Wiley Online Library (wileyonlinelibrary.com).
Titled spiroazetidinones 1a,b undergo reductive cleavage on treatment with excess lithium aluminum
hydride forming 3-benzhydryl-1-methylindole as the main product together with a c-amino alcohol
depending upon the substituent present on the azetidin-2-one ring. Treatment of 1a with Ce(IV) ammonium
nitrate affords 2-hydroxy-N-(4-methoxyphenyl)-2,2-diphenylacetamide besides the anticipated N-unsubsti-
tuted 2-azetidinone, whereas a similar treatment of 1-benzhydryl-3,3-diphenyl-2-azetidinone 1b affords the
ring expansion product 1,3-oxazolidin-4-one. The products have been characterized on the basis of satisfac-
tory analytical and spectral (IR, 1H and 13C-NMR, DEPT, HMBC) data and their formation is discussed.
J. Heterocyclic Chem., 48, 1312 (2011).
INTRODUCTION
borohydride [27]. Formation of azetidine is reported in
some cases using LAH, monochloroalane, and Raney
nickel [5,9]. However, 2-azetidinones having two phenyl
rings on C-3 are mostly stable and have been observed
inert to acids, bases, and some reducing agents as well
[28]. There is an example of hydrolytic cleavage of 3,3-
diphenylazetidin-2-one to an alkene and imine, but the
cleavage is attributed to the presence of a 2-pyrrolyl
group on C-4 position [29].
2-Azetidinone ring, commonly known as b-lactams, is
the key structural feature in the famous class of antibiot-
ics, b-lactam antibiotics [1]. Some b-lactams are also in
clinical use as b-lactamase inhibitors and cholesterol
absorption inhibitors [2–4]. The synthesis and biological
screening of 2-azetidinones have been the principal
focus of early researchers in the field. Recent years,
however, have witnessed an extensive research in appli-
cation of 2-azetidinones as synthons [5–10]. As a result,
such compounds have found application in synthesis of
diverse classes of compounds such as b-amino acid,
c-amino alcohols, aziridines, azetidines, pyrrole deriva-
tives, and many other heterocyclic compounds of poten-
tial biological interest [5].
The N-dearylation (4-methoxyphenyl group) and
N-dealkylation (bis-4-anisylmethyl group, 4-methoxy-
phenethyl group) of 2-azetidinones by oxidative cleav-
age on treatment with well known oxidizing agent
Ce(IV) ammonium nitrate (CAN) are well-known reac-
tions [30–34]. This reaction opens up room for a wide
variety of transformation on the 2-azetidinone ring.
We wish to report in this article the results obtained
from treatment of 1-(4-methoxyphenyl)- and 1-benz-
hydryl-3,3-diphenyl-10-methylspiro[azetidine-2,30-indoline]-
20,4-dione 1a,b with LAH and with CAN leading to
formation of products from reductive and oxidative clea-
vages, respectively. To the best of our knowledge, 2-aze-
tidinones having two phenyl groups on C-3 position of the
ring have not been subjected to such studies in the past.
Recently, spiro-fused 2-azetidinones have drawn con-
siderable interest because of some biological activities
associated with such 2-azetidinone [11–24]. Efforts are
on to explore their synthetic applications, which
prompted us to study the synthesis, biological activity,
and chemistry (reduction and oxidation) of 2-azetidi-
nones spiro-fused to another biologically important
structural motif, 2-indolinone. The product(s) of reduc-
tion of 2-azetidinones depends on the reducing agent
used and the substituent present on the 2-azetidinone
ring. For example, the reduction of N-Boc substituted
2-azetidinone with lithium aluminum hydride (LAH)
results into formation of c-amino alcohols quantitatively
[25,26]. The N(1)-C(4) cleavage is reported in case of
C(4)-formyloxy substituted 2-aztidinones using sodium
RESULTS AND DISCUSSION
Reactions with LAH. Treatment of the 1-(4-methox-
yphenyl)-3,3-diphenyl-10-methylspiro[azetidine-2,30-indo-
line]-20,4-dione 1a [20] with 6.0 molar equivalents of
LAH led to the formation of 3-benzhydryl-1-
C
V
2011 HeteroCorporation

November 2011 Unanticipated Products from Reductive and Oxidative Cleavages of 1-Substituted
3,3-diphenyl-10-methylspiro[azetidine-2,30-indoline]-20,4-diones
1313
Scheme 1
methylindole 2 which was identified by comparison of
its NMR spectral data with the one reported earlier, and
a c-amino alcohol, 3-(2-hydroxy-1,1-diphenylethyl)-3-(4-
methoxyphenylamino)-1-methylindolin-2-ol 3 (Scheme
1). It is noteworthy to mention that the indoles are com-
pounds of biological significance, and their transforma-
tion is an area of current interest [35,36]. The synthesis
of 2 has been reported recently by the reaction of benz-
hydrol with 1-methylindole using indium trichloride as a
catalysts in toluene at 80ꢀC for 15 h [37]. The formation
of c-amino alcohols as a sole product by reductive
cleavage of 2-azetidinones and their application in the
synthesis of oxazinanes have been reported recently
[38]. However, partial reduction of the indolinone ring
in this case was surprising. Thus, the presence of meth-
ylene carbon (CH2), two quaternary carbons (spiro-car-
bon and C-Ph2), and methine carbon (C20) (see experi-
mental) was confirmed by DEPT NMR spectroscopy.
The N-methyl proton showed correlation with methine
carbon at d98 ppm in the HMBC NMR spectra.
used for the synthesis of 2-azetidinones, are reported to
give aniline derivatives as a result of complete reduction
of the azomethine linkage and cleavage of the indoline
ring in the presence of sodium borohydride [40], none
of the two 2-azetidinones under study was found reac-
tive to either sodium borohydride or monochloroalane.
Reaction
with
cerium(IV)
ammonium
nitrate. Treatment of the spiro-fused 2-azetidinone 1a
with CAN according to the method described in the lit-
erature [30,31] afforded the compound 4, formed from
the cleavage of N1-C4 and C3-C4 bonds of the 2-azeti-
dinone ring, in reasonable yield besides the anticipated
spiro-fused 2-azetidinone having unsubstituted nitrogen
5 (Scheme 2). A similar treatment of the 2-azetidinone
1b with CAN afforded an unanticipated solid product 6
in 53% yield. This product has been characterized as 3-
benzhydryl-5,5-diphenyl-10-methylspiro[oxazolidin-2,30-
indolin]-4,20-dione 6 on the basis of analytical and spec-
tral data discussed briefly in the succeeding paragraph.
The 1,3-oxazolidin-4-ones constitute a biologically im-
portant class and have been synthesized in the recent
past either by treatment of O-allylacetamides with
TBSOTf or by cyclocondensation of imines with a-
hydroxy acids [41,42]. To the best of our knowledge, no
any other product is reported from the oxidative cleav-
age of 2-azetidinones in the presence of CAN except the
N-deprotected 2-azetidinones and product derived from
the leaving group.
Treatment of the 1-(diphenylmethyl)-3,3-diphenyl-10-
methylspiro[azetidine-2,30-indoline]-20,4-dione 1b [21]
with LAH in a similar manner as described for 1a
showed three spots on the TLC. Purification using silica
gel column and n-hexane-ethyl acetate as eluent
afforded the 3-benzhydryl-1-methylindole 2 as the main
product. The other two products present in trace
amounts could not be characterized due to low yields.
The product 2 may be formed by aromatization of an
alkene obtained from the reduction of c-lactam carbonyl
to CH2 and reductive cleavage of azetidin-2-one. The
formation of an alkene by reductive cleavage of the
2-azetidinone ring is reported earlier [39]. The product
3 results from partial reduction of the C¼¼O group of
the indolinone ring and cleavage of the N-C(2) bond of
the 2-azetidinone. No cleavage of the 2-indolinone ring
occurred on treatment with LAH. Although some 3-
alkylimino-1-methylindolin-2-ones, similar to the ones
The IR spectrum of this compound showed a slightly
broad but strong absorption band at 1732 cmꢁ1 instead
of 1760 and 1728 cmꢁ1 as observed in the substrate 1b
indicating the presence of more than one carbonyl group
in the product 6 which was further confirmed as two
carbonyl carbons by 13C-NMR spectra. The 1H-NMR
spectrum showed the same number of protons as in the
substrate, but the splitting pattern of the aromatic pro-
tons and the chemical shift of the only methine proton
were different from that in the substrate. As shown in
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

1314
G. S. Singh and P. M. Luntha
Vol 48
Scheme 2
Figure 1, the methine proton at d 5.88 ppm in the sub-
strate 1b shifted upfield to d 5.61 ppm in product 6. The
13C-NMR spectrum showed two carbonyl carbons closer
to each other (d 171.5 and 170.5 ppm) than in the sub-
strate (d174.0, 169.5 ppm). Two quaternary carbons
(established by DEPT) observed at d 75.3 and 71.4 ppm
in the 13C-NMR spectrum of the substrate shifted down-
field to d 91.7 and 85.8 ppm indicating the presence of
electronegative atom adjacent to them. The mass spec-
trum of the compound 6 showed the molecular ion peak
at 536 that was 16 more than the mass of the substrate
indicating addition of an oxygen atom or water molecule
onto the substrate.
two carbon signals have been assigned to spiro carbon
(C2,30) and carbonyl carbon of the oxazolidinone ring,
respectively. The N-methyl proton correlated to the
other low field carbon signal at d 171.5, and hence, this
later signal has been assigned to the indolinone ring car-
bonyl carbon.
It seems from the formation of products 4 and 6 that
after loss of electron from substrates to CAN water
attaches itself on C-3 position of the 2-azetidinone ring
and cleaves the ring besides N-dearylation. The cleavage
of C3-C4 bond occurs in both the substrates, but the
cleavage of N1-C4 bond depends upon the substituent
present. In substrate 1a having an N-C6H4-OMe-4
group, the cleavage of N1-C4 bond takes place affording
the product 4. In substrate 1b having an N-CHPh2
group, the N1-C4 bond does not cleave and the ring
opened intermediate formed by cleavage of C3-C4 bond
possibly undergoes oxidative cyclization to yield the
ring expansion product 1,3-oxazolidin-4-one 6.
After establishing from the spectral data, elemental
analysis, mixed mp with substrate 1b and different Rf
value on the TLC plate that the substance was different
from the substrate, various possibilities with regard to
structure were closely looked at. As we already had
results from cleavage of N1-C4 and C3-C4 bonds in
compound 1a, we investigated the structures possible
from cleavage of these bonds. The spectral data dis-
cussed above in combination with DEPT, HMQC, and
HMBC of 1H and 13NMR signals suggested the com-
pound as spiro-1,3-oxazolidin-4-one 6. Because the
methine proton signal at d 5.60 ppm showed correlation
with quaternary carbon signal at d 91.7 and carbonyl
carbon signal at d170.5 ppm in the HMBC spectra, these
CONCLUSIONS
In conclusion, the article reports hitherto unknown
cleavage of spiro-fused 2-azetidionones ring and novel
entry into 3-benzhydryl-1-methylindole and spiro-
fused oxazolidine ring systems from spiro-fused 2-
azetidinones.
EXPERIMENTAL
Melting points have been recorded on a Stuart Scientific
melting point apparatus and are uncorrected. The IR spectra
were recorded on a Perkin-Elmer-781 IR spectrophotometer
using KBr disc of the sample. The 1H and 13C-NMR spectra
were recorded in a CDCl3 solution at 300 MHz and 75.4
MHz, respectively, on a BrukerTM 300 MHz spectrometer. The
mass spectra were recorded on Finnignan LC QDECA mass
spectrometer.
The 2-azetidinones 1a,b were synthesized by the reaction of
2-diazo-1,2-diphenylethanone with imines according to
reported methods [20,21].
Figure 1. Significant 1H- and 13C-NMR signals and HMBC
correlationship.
Journal of Heterocyclic Chemistry
DOI 10.1002/jhet

November 2011 Unanticipated Products from Reductive and Oxidative Cleavages of 1-Substituted
3,3-diphenyl-10-methylspiro[azetidine-2,30-indoline]-20,4-diones
1315
General procedure for the reaction of spiroazetidinones
with LAH. LAH (0.05 g, 1.2 mmol) was added to a solution
of an appropriate substrate 1 (0.2 mmol) in THF (4 mL). The
mixture was stirred at room temperature until TLC showed
complete disappearance of the substrate (6 h). The reaction
mixture, after addition of a few drops of water, was filtered
through celite. The filtrate was dried on anhydrous magnesium
sulfate before removing the solvent on rotary evaporator. The
residue was purified by thin layer chromatography on silica
gel using n-hexane and ethyl acetate as eluent.
3-Benzhydryl-1-methylindole (2). Mp: 131–133ꢀC (lit.
132ꢀC); IR (KBr, cmꢁ1): 2927, 1600, 1469, 740; 1H-NMR
(CDCl3, d d ppm): 7.22–6.86 (14H, arom.), 6.32 (s, 1H, C(2)-
H), 5.58 (s, 1H, C-H), 3.61 (s, 3H, N-CH3); 13C-NMR
(CDCl3, d ppm): 144.12, 137.45, 129.01, 128.73, 128.26,
127.38, 126.17, 121.62, 119.99, 118.82, 118.28, 109.11, 48.80,
32.68; Mass (m/z, r. i.): 298 (20), 297 (60), 296 (17), 220
(100), 167 (30). Anal. Calcd. for C22H19N: C, 88.85; H, 6.44;
N, 4.71. Found: C, 88.63; H, 6.65; N, 4.70.
3-(2-Hydroxy-1,1-diphenylethyl)-4-(methoxyphenylamino)-
1-methylindolin-2-ol (3). IR (KBr, cmꢁ1): 3325–3280, 2900,
1590; 1H-NMR (CDCl3, d ppm): 7.38–7.16 (m, 12H, arom),
6.97 (t, 1H, arom), 6.49 (dd, 2H, arom), 6.32 (d, 1H, arom),
6.15 (dd, 2H, arom), 5.80 (bs, 1H), 5.70 (s, 1H, CH), 5.65 (bs,
1H), 4.09 (bs, 1H), 3.67 (s, 2H, CH2), 3.57 (s, 3H, OMe), 2.94
(s, 3H, N-Me); 13C-NMR (CDCl3, d ppm): 153.2, 151.7,
143.8, 140.1, 139.0, 129.7, 128.2, 127.9, 127.6, 127.0, 117.4,
117.0, 114.5, 104.9, 98.0 (C20-H, DEPT), 78.6 (quaternary car-
bon, DEPT), 69.4 (CH2, DEPT), 68.1 (quaternary carbon,
DEPT), 55.6 (O-Me), 30.6 (N-Me); Mass (m/z, r. i.): 464 (Mþ-
2, 2), 446 (10), 428 (100), 296 (20), 268 (65), 252 (25), 237
(20), 223 (5), 196 (25), 167 (88), 146 (50), 122 (78), 77 (22).
Anal. Calcd. for C30H30N2O3: C, 77.23; H, 6.48; N, 6.00.
Found: C, 76.90; H, 6.70; N, 5.70.
General procedure for the reaction of spirozetidinones
with cerium ammonium nitrate. A cold solution (0ꢀC) of
CAN (0.6 mmol) in 3 mL of distilled water was added drop
wise to a solution of the appropriate 2-azetidinone (0.2 mmol)
in acetonitrile (5.0 mL) maintained at 0ꢀC. The reaction mix-
ture was stirred at 0ꢀC until TLC showed complete disappear-
ance of the substrate (6 h). Distilled water (3 mL) was then
added to the reaction mixture before extracting the mixture
with ethyl acetate (10 mL ꢂ 2). The ethyl acetate extract was
washed with saturated sodium hydrogen carbonate (5 mL).
The aqueous layer was extracted again with ethyl acetate (5
mL). The combined organic extract was washed in turn with
sodium hydrogen sulphite, sodium hydrogen carbonate, and so-
dium chloride. After drying over anhydrous magnesium sul-
phate and evaporation of ethyl acetate on a rotary evaporator,
the residue was purified by column chromatography using n-
hexane-ethyl acetate mixture. The characterization data of
products are given below.
3,3-Diphenyl-10-methylspiro[azetidine-2,30-indoline]-20,4-
dione (5). Mp: 198–200ꢀC, IR (KBr, cmꢁ1): 3248, 1767,
1
1705, 1612, 1477, 1362; H-NMR (CDCl3, d ppm): 7.50–6.72
(13H, arom.), 6.53 (s, 1H, N-H), 6.27 (dd, J ¼ 7.5, 0.6 Hz,
1H, arom), 3.24 (s, 3H, N-CH3), 13C-NMR (CDCl3, d ppm):
175.48, 169.70, 143.76, 138.51, 138.08, 130.36, 128.31,
128.29, 127.98, 127.60, 127.38, 126.53, 126.39, 124.67,
122.31, 108.34, 78.62, 67.21, 26.77. Mass (m/z, r. i.): 354
(Mþ, 100), 326 (50), 325 (88), 311 (67), 310 (75), 249 (29),
194 (68), 165 (86). Anal. Calcd. for C23H18N2O2 C, 77.95; H,
5.12; N, 7.90. Found: C, 77.55; H, 5.43; N, 7.70.
3-Benzhydryl-5,5-diphenyl-10-methylspiro[1,3-oxazolidin-2,30-
indolin]-4,20-dione (6). Mp: 202–204ꢀC; IR (KBr, cmꢁ1):
2928, 1732, 1616, 1469, 1327; 1H-NMR (CDCl3, d ppm):
7.69–7.64 (m, 4H), 7.39–7.02 (m 17H), 6.80 (t, 1H), 6.60 (d,
2H), 5.61 (s, 1H, methine), 2.94 (s, 3H, methyl); 13C-NMR
(CDCl3, d ppm): 171.5, 170.5, 144.0, 141.4, 140.9, 137.5,
137.1, 131.6, 129.6, 128.5, 128.2, 128.1, 128.0, 127.9, 127.87,
127.7, 127.5, 127.4, 126.6, 126.2, 124.6, 123.0, 108.7, 91.7,
85.9, 62.1, 26.3; Mass (m/z, r. i.): 536 (Mþ, 5), 375 (68. Mþ-
1-methylindolinone-O), 341 (24), 314 (12), 237 (34), 167
(100), 152 (22), 105 (24), 77 (15). Anal. Calcd. for
C36H28N2O3: reqd. C, 80.58; H, 5.26; N, 5.22. Found: C,
80.20; H, 5.52; N, 5.00.
Acknowledgments. Authors are thankful to the Chemistry
Department, University of Botswana, for providing the facilities
and to the Govt. of the Republic of Malawi for providing financial
assistance to PL.
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Journal of Heterocyclic Chemistry
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