Interesting reaction of the indanone oximes under Beckmann rearrangement conditions

Article abstract of DOI:10.1016/S0960-894X(01)00754-5

Attempted Beckmann rearrangement of the 6-methoxyindanone oximes in conventional conditions resulted in the formation of the two kinds of unexpected products: 2-sulfonyloxyindanone and the dimeric product. Related rearrangement was also observed in the re

Full text of DOI:10.1016/S0960-894X(01)00754-5

Bioorganic & Medicinal Chemistry Letters 12 (2002) 387–390
Interesting Reaction of the Indanone Oximes Under Beckmann
Rearrangement Conditions
Yasuhiro Torisawa,* Takao Nishi and Jun-ichi Minamikawa
Process Research Laboratory, Second Tokushima Factory, Otsuka Pharmaceutical Co., Ltd,
Kawauchi-cho, Tokushima 771-0182, Japan
Received 20 September 2001;accepted 9 November 2001
Abstract—Attempted Beckmann rearrangement of the 6-methoxyindanone oximes in conventional conditions resulted in the for-
mation of the two kinds of unexpected products: 2-sulfonyloxyindanone and the dimeric product. Related rearrangement was also
observed in the reaction with RhCl–trifluoromethansulfonic acid system. # 2002 Elsevier Science Ltd. All rights reserved.
The Beckmann rearrangement has often been recom-
mended as an expedient procedure for the conversion of
cyclic ketoximes into the corresponding ring-expanded
lactams in a stereospecific manner.1 By the aid of various
acid catalysts, the reaction has found broad application
from the manufacturing process to a variety of labora-
tory scale synthesis. The subtle substituent effect in this
robust synthetic process should be noted, especially in
view of the practical application. For example, in the
reported example of unsubstituted indanone oximes, the
Beckmann products were obtained only in low yield
(ꢀ20% by PPA). On the other hand, in the substituted
indanone oximes, yields varied depending on the sub-
stituents, indicating substituents both in the benzene
ring and cyclopentane ring of indanone being
influencial.1
the unsubstituted indanone oxime with various catalysts
including Rh catalyst.
Reaction with Eaton Reagent
In order to obtain the ring-substituted carbostyrils (2),
our search has focused on the oxime bearing alkoxy
group (1) and adopted the mild catalyst: P2O5–MeSO3H
(Eaton reagent).
Conversion of some dimethoxyindanone oximes into
the isocarbostyril derivatives was reported by this
reagent.1 Thus, we carried out the reaction of 3 by
starting at room temperature and slowly heating to
100 ꢁC to observe the behavior of this oxime.2
Several years ago, we started a project aimed at ela-
boration of an optional synthetic pathway to the sub-
stituted carbostyril (3,4-dihydroquinolin-2-one) core (2)
via Beckmann rearrangement of the substituted oxime
(1). Disclosed herein is the results of our study on the
Beckmann rearrangement of methoxyindanone oximes
with some conventional acid catalysts (PPA, P2O5–
MsOH, TsCl, AlR3, etc.) and non-conventional pro-
moters [K-10 clay, Bi(OTf)3, transition metal catalysts].
Our study has now revealed the interesting reactivity of
6-methoxyindanone oxime (3), which has not been
described before. We have also extended our survey to
In contrast to our expectations, the major product iso-
lated was the a-sulfonyloxy derivative (4, 33%).3 None
of the normal Beckmann products (carbostyril or iso-
carbostyril) were isolated.
Along with 4, a polar product (5: 13%) was obtained,
which was formed after prolonged reaction time. The
1
structure of 4 was determined on the basis of H and
13C NMR as shown in Scheme 1.4
Further experimentation with the oxime tosylate (6)
also furnished the same products in a slightly higher
yield.3 Product 4 (50%) lost OTs group of the starting
material (6), which suggested that the transformation
might follow an intermolecular path rather than intra-
molecular way in the Eaton reagent.
*Corresponding author. Tel.:+81-88-665-2126;fax:+81-88-637-1144;
e-mail: torisawa@fact.otsuka.co.jp
0960-894X/02/$ - see front matter # 2002 Elsevier Science Ltd. All rights reserved.
PII: S0960-894X(01)00754-5

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Y. Torisawa et al. / Bioorg. Med. Chem. Lett. 12 (2002) 387–390
In order to gain a further insight into the reaction, we
next struggled to clarify the structure of the minor pro-
duct (5). The unexpected dimeric structure of 5 (30%
from 6)5 was deduced on the basis of spectroscopic
analysis (as shown in Scheme 2). Two sets of C¼O and
OMe are present in one molecule. We have as yet been
unable to find another example of such dimerizartion
during Beckmann rearrangement. Noteworthy is that
the product isolated was an indenone derivative as
The same reaction of the oxime tosylate (6) with PPA
was, on the contrary, very sluggish even under heating
to ꢀ120 ꢁC. Although we could not detect or isolate
any intermediate in the reaction with PPA, an inter-
mediacy of a-oxy-intermediate similar to 4 was specu-
lated.
We further searched for various acid catalysts for 6 and
found that K-10 clay in xylene converted 6 into a clea-
ner mixture than in the reaction with PPA or Al2O3.
The unstable compound (8)9 was isolated from the
mixture only in low yield (5–10%).
1
shown in Scheme 2. Both H and 13C NMR indicated
the indenone skeleton (an olefinic proton at 5.80s which
correlates with a carbon at 125.2).
We were then interested in the effect of the mild acid
Bi(OTf)3 (BIT)10 on this reaction. Fortunately, an
improved result was attained by the reaction of 6 with
the combined solid acids [BIT/K-10 clay] in xylene at
<100 ꢁC for 1 h to give 8 in 22% isolated yield along
with the indanone recovered (28%).11
Reaction with Lewis Acid Catalysts
In other reactions with mild promoters (Al2O3, SiO2,
AcOK–aq EtOH, K-10 clay, aqueous sulfuric acid), 6
only returned to 3 via simple hydrolysis. Attempted reac-
tions of 3 with Lewis acid in solvent-free system (ZrCl4,
BiCl3, AlCl3, InCl3)6 resulted in partial demethylation to
the phenol and decomposition to base-line products.
Indanone oxime
Having observed some unprecedented transformation
with the 6-methoxyindanone oximes (3, 6), we also sur-
veyed the same reaction with other substrates including
other oxime derivatives. The reaction of the indanone
oxime (9) with PPA was reported to give the carbostyrils
(10 and 11) in ca. 20% combined yield.1 We thus treated
indanone oxime in our PPA-BIT conditions and found
that carbostyril (10) was the major component along
with the isomeric isocarbostyril (11) in 45% combined
Aluminum reagents have also found some utility in the
Beckmann rearrangement.1b,7 However, simple hydro-
lysis was observed again in the reaction of 3 with excess
triisobutylaluminum (TIBAL) at room temperature.
DIBAL-H did furnish the rearranged and reduced
compound (7: 85% from 3) as a sole product (1,2,3,4-
8
tetrahydroquinoline: 7;Scheme 2).
Reaction in PPA System
6-Methoxyindanone oxime
We reinvestigated the reaction with PPA, which is the
most frequently used reagent for various indanone
derivatives.1 A careful treatment of the oxime (3) with
PPA (30 wt) at around 100 ꢁC for 1 h produced the
dimer (5) along with a small amount of recovered start-
ing material (Scheme 2).
Scheme 1.
Scheme 2.

Y. Torisawa et al. / Bioorg. Med. Chem. Lett. 12 (2002) 387–390
389
yield. We could not isolate any dimeric product from
the mixtures. The rest of the products were recovered, 9
and 13. Also surveyed was the reactivity of other inda-
none derivatives (12) towards Beckmann and Schmidt
reactions in PPA. In agreement with the old report,12
the Schmidt reaction of 13 gave the desired carbostyril
as the sole product in reasonable isolated yield as shown
in Scheme 2.
isolated yield) containing the OTs group migrated to the
2-position of indanone. The structure is confirmed by the
comparison of the previously obtained compounds (4,
8), which clearly distinguished 17 from the OTf deriva-
tive (18). We further attempted similar transformation
with methoxy-substituted indanone oxime tosylates
from 3 and 14 and found that the 1,3-rearrangement is a
general reaction pathway independent of the position of
a methoxy group.13
4-Methoxyindanone oxime
In the recent report by Yamaguchi, the Rh catalyst system
has been successfully employed for the catalytic Beck-
mann rearrangement of acyclic oximes.14 It is also pro-
posed that oxidative addition of Rh(I) species to N–OH
bond could be most probable.
As shown in Scheme 2, reaction of 14 in conventional
PPA conditions afforded a black mixture, from which
none of the carbostyril structure was isolated. Instead,
isomeric isocarbostyril (15) was obtained in 5ꢀ10%
yields. We could not isolate any dimeric structure cor-
responding to 5 in this reaction.
Although we could neither propose a plausible reaction
mechanism nor isolate any pivotal intermediates in our
studies, we are speculating that the interaction between
the oxime C¼N bond and metal (or acid) catalyst pro-
motes isomerization of the C¼N bond (from exo to
endo) for the anomalous reaction pathway as described
above.
Further attempts to improve Beckmann reaction of 14
by the use of PPA-BIT afforded the isocarbostyril (15,
30% isolated yields). Isocarbostyrils were obtained pre-
dominantly from the reaction by Eaton reagent in the
literature. Successful transformation to carbostyril was
only possible provided that the 2-position of the inda-
none oxime was substituted by alkyl groups.1
In conclusion, we have surveyed the behaviors of inda-
none oximes under various Beckmann conditions. The
oximes (3, 6, 9, 12, 14) were all sluggish towards con-
ventional Beckmann conditions. Some of them (3, 6)
were presumably prone to isomerize, by the action of an
acid, and the unexpected dimer 5 was formed through
the intermediacy of 4 or 8. For the intramolecular
migration of the oxime sulfonate 6 to 8, a mild catalyst
Bi(OTf)3 played a crucial role.
Mechanistic Speculations
The interesting reactivity of indanone oximes under
Beckmann rearrangement conditions described above is
particularly intriguing from the mechanistic point of
view. We thus focused our attention on the interaction
of the oxime double bond with catalytic H-metal species
(H-M-X) generated in acidic (protic) media. As shown
in Scheme 3, indanone oxime (9) itself remained intact
with such catalysts as Pd(OAc)2, RhCl(PPh3)3,
NiCl2(PPh3)2, in AcOH or MeSO3H as well as with
typical Lewis acids such as AlCl3 and ZrCl4. The only
observable phenomena were the E,Z isomerization of
oxime OH and hydrolysis to indanone, as experienced
in the previous reaction with Lewis acids.
The dimer formation was characteristic to 6-methoxy-
indanone oximes (3, 6), and similar dimerization was
not observed in other indanone series such as indanone
itself and 4-methoxyindanone. We, however, disclosed
here a related rearrangement of the oxime tosylate 16
with Rh catalyst in the presence of TfOH. One impor-
tant conclusion from our survey is that conventional
Beckmann protocols are not suitable for practical car-
bostyril synthesis.
We, however, observed that the reaction of the inda-
none oxime sulfonate (16) with RhCl(PPh3)3–TfOH in
EDC at reflux gave a single polar product (17, 30%
Acknowledgements
We thank Mr. I. Miura in our laboratory for his helpful
assistance in NMR assignment. We also thank Professor
T. Ishikawa (Chiba University) for the helpful discussion
in manuscript preparation and encouragement.
References and Notes
1. (a) For recent reviews, see: Gawley, R. E. Organic Reaction
1988, 35, 1, and references cited therein. (b) Maruoka, K.;
Yamamoto, H. Comp. Org. Synth.;Trost, B. M., Fleming, I.,
Eds.;Pergamon: Oxford, 1991;Vol. 6, p 763.
Scheme 3.

390
Y. Torisawa et al. / Bioorg. Med. Chem. Lett. 12 (2002) 387–390
2. Eaton, P. E.;Carlson, G. R.;Lee, J. T. J. Org. Chem. 1973,
38, 4071.
3.31 (s, 3H), 3.21 (dd, 1H, J=16.7, 4.5 Hz);MS m/e 256
(M+), 160 (base).
3. General Procedure: Method A (Eaton system): To the
Eaton reagent (ca. 70 wt to substrate) was added a CH2Cl2
solution of the oxime (3;250–500 mg) or the oxime tosylate ( 6;
250–500 mg) at room temperature. Resulting mixture was kept
at this temperature for 0.5 h before being heated at 100 ꢁC for
2 h. TLC analysis indicated the complete consumption of the
starting material. After cooling to room temperature, the
mixture was poured into AcOEt–H2O (1:1), extracted several
times with AcOEt and worked up as usual. The crude pro-
ducts were purified by SiO2 column chromatography to afford
the products shown in Scheme 1. Method B (PPA system): The
oxime (3) or the tosylate (6) was added to PPA (70 wt) under
warming (60 ꢁC) to form homogeneous mixture with adequate
stirring. The whole mixture was carefully kept at around 100–
110 ꢁC (bath temperature) for less than 1 h. The mixture
turned to black and TLC indicated the consumption of the
oxime (3). Then the mixture was cooled to room temperature
and diluted with AcOEt and H2O. Crude product obtained
after evaporation of the dried organic solvent was purified by
chromatography to afford the dimer (5) along with a small
amount of the recovered oxime (3). Method C (PPA–BIT):
PPA and Bi(OTf)3 was first suspended in CH2Cl2, to which the
oxime was added at room temperature. Solvent was removed
by heating to leave an oil, which was gently heated at 100 ꢁC
for 1 h. TLC indicated the formation of the polar products.
The mixture was worked up as above and purified by column
chromatography to afford the products shown. Method D (BIT/
K-10): A mixture of the oxime tosylate (6), K-10 powder
(Aldrich, preheated), and Bi(OTf)3 powder in xylene was
hated at 90–100 ꢁC (bath temperature) for less than 1 h. TLC
indicated the formation of new products. The black mixture
was diluted with AcOEt–H2O (1:1), extracted several times
and worked up as usual. The crude products obtained were
purified by column chromatography to afford the products
shown in Scheme 2.
5. Selected data for 5: 13C NMR (CDCl3) d 204.8 (C¼O);
197.0 (C¼O);160.5;157.8;155.9;147.2;137.5;135.1;132.5;
127.8;125.2;121.2;119.0;117.8;115.8;109.7;56.4 (OMe);
55.5 (OMe);37.1;24.5;
1H NMR (CDCl3) d 7.49 (d, 1H,
J=8.4 Hz), 7.25 (d, 1H, J=8.4 Hz), 7.07 (d, 1H, J=2.4 Hz),
6.65 (dd, 1H, J=8.0, 2.4 Hz), 6.50 (d, 1H, J=7.9 Hz), 5.80 (s,
1H), 3.80 (s, 3H), 3.77 (s, 3H), 3.08 (m, 2H), 2.67 (m, 2H);MS
m/e 320 (M+), 162, 84 (base).
6. Thakur, A. J.;Boruah, A.;Prajapati, D.;Sandhu, J. S.
Synth. Commun. 2000, 30, 2105.
7. Maruoka, K.;Miyazaki, T.;Ando, M.;Matsumura, Y.;
Sakane, S.;Hattori, K.;Yamamoto, H. J. Am. Chem. Soc.
1983, 105, 2831.
8. Cho, H.;Murakami, K.;Nakanishi, H.;Isoshima, H.;
Hayakawa, K.;Uchida, I. Heterocycles 1998, 48, 919.
9. Selected spectral data for 8: 13C NMR (CDCl3) d 197.3
(C¼O);159.7 (O–C);144.9;142.5;134.4;133.0;129.6;128.0;
127.2;125.5;105.5;78.5 (O–C);55.4 (OMe);33.0, 21.5;
1H
NMR (CDCl3) d 7.91 (d, 2H, J=8.2 Hz), 7.37 (d, 2H, J=8.2
Hz), 7.31 (d, 1H, J=8.5 Hz), 7.22 (dd, 1H, J=8.5, 2.3 Hz),
7.13 (d, 1H, J=2.3 Hz), 5.12 (dd, 1H, J=8.0, 4.5 Hz), 3.80, (s,
3H), 3.55 (dd, 1H, J=16.8, 8.0 Hz), 3.12 (dd, 1H, J=16.7, 4.5
Hz), 2.45 (3H, s);MS m/e 332 (M+), 160 (base).
10. Torisawa, Y.;Nishi, T.;Minamikawa, J.
Res. Dev. 2001, 5, 84.
Org. Process
11. The mixed catalyst system (PPA–BIT) was prepared and
used as follows;PPA and Bi(OTf) was first suspended in
3
CH2Cl2, to which the oxime was added at room temperature.
Solvent was removed to leave an oil, which was gently heated
at 100 ꢁC for 1 h and worked up as usual.
12. The Schmidt reaction of unsubstituted indanone in, PPA–
NaN3 gave carbostyril as a sole product (60%). See also:
Briggs, L. H.;De Ath, G. C. J. Chem. Soc. 1937, 456.
13. Preliminary experiments showed the 1,3-rearrangement
reaction was faster in the methoxy-substituted oxime tosylates.
Further investigation revealed that other metal chlorides such
as PdCl2, CoCl2 were also effective for this transformation.
The scope and limitation of this rearrangement will be repor-
ted in due course.
4. Selected data for 4: 13C NMR (CDCl3) d 198.8 (C¼O);
160.0 (O–C);142.8;134.5;127.5;125.9;105.6;79.4 (O–C);55.6
(OMe);39.5;33.0; 1H NMR (CDCl3) d 7.38 (d, 1H, J=5.7
Hz), 7.25 (m, 1H), 7.17 (d, 1H, J=0.9 Hz), 5.34 (dd, 1H,
J=8.0, 4.5 Hz), 3.83, (s, 3H), 3.63 (dd, 1H, J=16.8, 8.0 Hz),
14. Arisawa, M.;Yamaguchi, M. Org. Lett. 2001, 3, 311.