Intramolecular cyclization with nitrenium ions generated by treatment of N-acylaminophthalimides with hypervalent iodine compounds: Formation of lactams and spiro-fused lactams

Article abstract of DOI:10.1021/jo0347009

N-Phthalimido-N-acylnitrenium ions are generated from N-acylaminophthalimides, a new class of precursors, by treatment with hypervalent iodine compounds (PIFA and HTIB). In HFIP, the nitrenium ions undergo intramolecular electrophilic substitution reactio

Full text of DOI:10.1021/jo0347009

In tr a m olecu la r Cycliza tion w ith Nitr en iu m Ion s Gen er a ted by
Tr ea tm en t of N-Acyla m in op h th a lim id es w ith Hyp er va len t Iod in e
Com p ou n d s: F or m a tion of La cta m s a n d Sp ir o-F u sed La cta m s
Yasuo Kikugawa,* Akira Nagashima, Takeshi Sakamoto, Etsuko Miyazawa, and
Megumi Shiiya
Faculty of Pharmaceutical Sciences, J osai University, 1-1 Keyakidai, Sakado, Saitama 350-0295, J apan
kikugawa@josai.ac.jp
Received May 23, 2003
N-Phthalimido-N-acylnitrenium ions are generated from N-acylaminophthalimides, a new class of
precursors, by treatment with hypervalent iodine compounds (PIFA and HTIB). In HFIP, the
nitrenium ions undergo intramolecular electrophilic substitution reactions to afford N-aminonitrogen
heterocycles in high yields. In TFEA, spirodienones bearing the 1-azaspiro[4.5]decane skeleton are
obtained by treatment of N-phthalimido-3-(4-halogenophenyl)propanamides with HTIB as a result
of ipso attack of the intermediate nitrenium ion. Similarly, using PIFA in TFEA, ipso cyclization
of unactivated benzenoid compounds occurs to afford spirodiene derivatives. This involves loss of
aromaticity despite the absence of other activating substituents on the phenyl group.
In tr od u ction
an electron-donating methoxy group attached to the
nitrogen and are able to undergo inter- and intramolecu-
lar substitution reactions with a range of aromatic
compounds. Since this report, several applications of
these intermediates in the synthesis of biologically active
compounds have been published.7
Nitrenium ions are reactive intermediates that con-
tinue to attract attention from synthetic, theoretical, and
biological perspectives.1 However, despite much effort,
synthetic applications of nitrenium ions remain limited,
primarily because their existence as reaction intermedi-
ates is quite fleeting. Exceptions to this include synthetic
applications of certain stabilized nitrenium ions. For
example, arylnitrenium ions2 and N-methoxy-N-acylni-
trenium ions (I)3 are stabilized by the neighboring aryl
group and lone pair on oxygen, respectively, as shown
by MNDO molecular orbital calculations and by reactions
that involve them. In addition, the stabilization of
nitrenium ions by other heteroatoms, such as nitrogen
and sulfur, is also predicted.4 These stabilized nitrenium
ions are proving to be useful synthetic intermediates.
From our previous observations, we expected that
replacing an oxygen atom by nitrogen in the precursor
would also have an additional stabilizing influence on a
generated nitrenium ion. We detail herein electrophilic
reactions of N-phthalimodo-N-acylnitrenium ions (II), a
new class of positive nitrogen ions, generated from 1.
In our initial attempt, we studied the intramolecular
cyclization of N-chloro-N-(3-phenylpropionyl)amino-
phthalimide synthesized from the corresponding amide
(1b) by reaction with t-BuOCl. Cyclization with Zn(OAc)2
following the literature procedure6 produced N-phthal-
imido-3,4-dihydrocarbostyril (2b) in 85% yield. However,
use of t-BuOCl is not recommended because of com-
mercial inaccessibily in bulk quantities8 and environ-
mental problems related to disposal. Therefore, we have
examined the reaction of II generated from 1 by the
action of PIFA and [hydroxy(tosyloxy)iodo]benzene (HTIB),
both of which reagents have low toxicity, are readily
available, are easy to handle, and are environmentally
Previously, we have reported that I can be generated
from the corresponding N-chloro-N-methoxyamides by
the action of silver5a-c or zinc6 ions or by direct oxidation
of N-methoxyamides with phenyliodine(III) bis(trifluoro-
acetate)5d (PIFA). These nitrenium ions are stabilized by
(5) (a) Kikugawa, Y.; Kawase, M. J . Am. Chem. Soc. 1984, 106, 5728.
(b) Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad, J . L. J .
Chem. Soc., Perkin Trans. 1 1984, 2255. (c) Kawase, M.; Kitamura,
T.; Kikugawa, Y. J . Org. Chem. 1989, 54, 3394. (d) Kikugawa, Y.;
Kawase, M. Chem. Lett. 1990, 581.
(6) Kikugawa, Y.; Shimada, M.; Matsumoto, K. Heterocycles 1994,
37, 293.
(7) (a) Herrero, M. T.; Tellitu, I.; Dom´ınguez, E.; Herna´ndez, S.;
Moreno, I.; SanMart´ın, R. Tetrahedron 2002, 58, 8581. (b) Wardrop,
D. J .; Zhang, W. Org. Lett. 2001, 3, 2353. (c) Wardrop, D. J .; Basak, A.
Org. Lett. 2001, 3, 1053 and references therein.
(8) Tilstam, U.; Harre, M.; Heckrodt, T.; Weinmann, H. Tetrahedron
Lett. 2001, 42, 5385.
(1) (a) Bogdal, D. Heterocycles 2000, 53, 2679. (b) Abramovitch, R.
A.; J eyaraman, R. In Azides and Nitrenes: Reactivity and Utility;
Scriven, E. F. V., Ed.; Academic Press: New York, 1984; pp 297-357.
(2) Ford, G. P.; Scribner, J . D. J . Am. Chem. Soc. 1981, 103, 4281.
Ohwada, A.; Nara, S.; Sakamoto, T.; Kikugawa, Y. J . Chem. Soc.,
Perkin Trans. 1 2001, 3064 and references therein.
(3) Glover, S. A.; Goosen, A.; McCleland, C. W.; Schoonraad, J . L.
Tetrahedron 1987, 43, 2577.
(4) Glover, S. A.; Scott, A. P. Tetrahedron 1989, 45, 1763.
10.1021/jo0347009 CCC: $25.00 © 2003 American Chemical Society
Published on Web 07/26/2003
J . Org. Chem. 2003, 68, 6739-6744
6739

Kikugawa et al.
TABLE 1. Syn th esis of Ben za n n u la ted Com p ou n d s
fr om N-Acyla m in op h th a lim id es
SCHEME 1
rich arenes bearing such substitutents as a methoxy or
dimethoxy function. This limitation is consistent with the
reported behavior of an intermolecular version of a
similar reaction, in which highly electron-rich arenes
alone can react with azodicarboxylates.10
The phthalimido group of N-phthalimido-3,4-dihydro-
carbostyril (2b) was deprotected by the action of hydra-
zine hydrate as usual to give N-amino-3,4-dihydrocar-
bostyril in 95% yield. If desired, the N-amino group can
be removed with Raney Ni (W-2) to give 3,4-dihydrocar-
bostyril in 91% yield or by the literature method (NaNO2-
HOAc).9
These N-amino compounds should be useful starting
compounds for the synthesis of N,N′-linked bisazahet-
erocycles.11 The oxidative rearrangement of N-amino-2-
indolinone with lead tetraacetate and t-BuOCl gave
3(2H)-cinnoline.12 N-Amino-2-indolinone also can be con-
verted to the corresponding amino-nitrene by lead tet-
raacetate oxidation.13
Syn th esis of 3H-Ben zoxazol-2-on es an d 4H-Ben zo-
[1,4]oxa zin -3-on e. A valuable extension of this proce-
dure would be its application to the synthesis of systems
incorporating two heteroatoms in a ring. With this end
in view, we have undertaken the synthesis of benzox-
azolone derivatives (2e-h ) using aryl N-phthaloylcar-
bamates (1e-h ).
Treatment of 1e with PIFA (1.1 molar equiv) in TFEA
for 3 h at room temperature gave 2e and the p-iodophen-
ylated compound (3e) in 30% and in 20% yields, respec-
tively (Scheme 1). It is evident that the oxygen function
directly attached to the phenyl group unfavorably af-
fected the cyclization reaction and the p-iodophenyl group
of PIFA migrated to the amide nitrogen to afford 3e.14
As a strategy to retard this rearrangement, 4-chlorophen-
yliodine(III) bis(trifluoroacetate) (p-ClPIFA) was synthe-
sized.15 Reactions using p-ClPIFA were examined in
solvents such as TFA, TFEA, HFIP, CHCl3, and 1,2-
dichloroethane. Use of p-ClPIFA in TFA improved the
yield of 2e to 74%. In the case of 1i, polymerization
occurred in TFA but the cyclizaton product 2i could be
obtained in 72% yield by changing the solvent from TFA
to 1,2-dichloroethane. Several aryl carbamates (1e-h )
a
b
d
A: PIFA. At room temperature. c 1.2 equiv. 1.1 equiv.
friendly. Herein, we report that nitrenium ions II pos-
sessing a pendant phenyl group undergo intramolecular
cyclization reactions to give benzannulated or spiro
benzannulated compounds.
Resu lts a n d Discu ssion
Syn th esis of Ben za n n u la ted Nitr ogen Heter o-
cycles. In preliminary studies, we examined the in-
tramolecular cyclization reaction mediated by the reac-
tion of N-phenylacetylaminophthalimide (1a ) with PIFA
in various solvents such as hexafluoroisopropyl alcohol
(HFIP), 2,2,2-trifluoroethanol (TFEA), trifluoroacetic acid
(TFA), acetic acid, chloroform, and dichloromethane.
N-Phthalimido-2-indolinone (2a ), the cyclization product,
was obtained in 53% yield in HFIP and in 81% yield in
TFEA after 1 h reaction. For the synthesis of other
benzannulated compounds the use of HFIP afforded
better results. Generally, reactions in poorly nucleophilic
polar solvents gave good results, while use of other polar
solvents such as dichloromethane, chloroform, acetic acid
and TFA did not give satisfactory results. For the control
experiment, we examined the cyclization reaction using
3-phenylpropionic acid N,N-dimethylhydrazide with PIFA
in HFIP at room temperature overnight. This gave
ambiguous results along with recovery of the starting
compound in 30% yield. This confirms that the phthal-
imido group plays an important role for the stabilization
of II and for promotion of further reaction. Several
N-acylaminophthalimides (1) reacted in a similar way,
and the results are presented in Table 1.
(10) Yadav, J . S.; Reddy, B. V. S.; Veerendhar, G.; Rao, R. S.;
Nagaiah, K. Chem. Lett. 2002, 318. Yadav, J . S.; Reddy, B. V. S.;
Kumar, G. M.; Madan, K. C. Synlett 2001, 1781. Dufresne, C.; Leblanc,
Y.; Berthelette, C.; McCooeye, C. Synth. Commun. 1997, 27, 3613.
Leblanc, Y.; Boudreault, N. J . Org. Chem. 1995, 60, 4268. Mitchell,
H.; Leblanc, Y. J . Org. Chem. 1994, 59, 682. Zaltsgendler, I.; Leblanc,
Y.; Bernstein, M. A. Tetrahedron Lett. 1993, 34, 2441.
(11) Reddy, G. M.; Bhavani, A. K. D.; Reddy, P. P.; Reddy, P. S. N.
Synthesis 2002, 1311.
(12) Zey, R. L.; Richter, G.; Randa, H. J . Heterocycl. Chem. 1989,
26, 1437. Zey, R. L. J . Heterocycl. Chem. 1988, 25, 847.
(13) Atkinson, R. S.; Rees, C. W. J . Chem. Soc., Chem. Commun.
1967, 1230.
Very recently, the similar compounds were synthesized
in moderate yields by intramolecular cyclization of aryl-
substituted unsymmetrical azodicarbonyl compounds,
generated from bishydrazides by oxidation, using BF3‚
Et2O.9 However, the reaction is limited to highly electron-
(14) Itoh, N.; Sakamoto, T.; Miyazawa, E.; Kikugawa, Y. J . Org.
Chem. 2002, 67, 7424.
(15) Mckillop, A.; Kemp, D. Tetrahedron 1989, 45, 3299. White, J .
D.; Caravatti, G.; Kline, T. B.; Edstrom, E.; Rice, K. C.; Brossi, A.
Tetrahedron 1983, 39, 2393.
(9) (a) Prata, J . V.; Clemente, D.-T. V.; Prabhakar, S.; Lobo, A. M.;
Mourato, I.; Branco, P. S. J . Chem. Soc., Perkin Trans. 1 2002, 513.
(b) Clemente, D.-T. V.; Lobo, A. M.; Prabhakar, S.; Marcelo-Curto, M.
J . Tetrahedron Lett. 1994, 35, 2043.
6740 J . Org. Chem., Vol. 68, No. 17, 2003

Formation of Lactams and Spiro-Fused Lactams
TABLE 2. Syn th esis of Ben za n n u la ted Com p ou n d s fr om N-Acyla m in op h th a lim id es Bea r in g P h en oxy F u n ction
a
b
d
A: PIFA. B: p-ClPIFA [4-ClC6H4I(OCOCF3)2]. At room temperature. c 1.1 equiv. 1.3 equiv. e 2.0 equiv. f At reflux.
and 1i reacted in this way, and the results are presented
in Table 2. N-Phthalimido-3H-benzoxazol-2-ones (2e-g)
and 4H-benzo[1,4]oxazin-3-one (2i) were obtained in
synthetically useful yields.
It is interesting to note that phenyl N-methoxycar-
bamate (the phthalimido group replaced with a methoxy
group) failed to cyclize with PIFA, giving instead an
unidentifiable product mixtures.16
spiroannulated product. It is generally accepted that the
spirodienones are the major or the exclusive products
whenever the aromatic ring bears a methoxy group para
to the alkyl side chain.3,9 We have reported the similar
formation of N-methoxyspirodienones by the ipso attack
of N-methoxy-N-acylnitrenium ions generated from the
o- and p-methoxyphenyl-N-methoxyamide derivatives.5c
In our earlier work,18 we developed procedures for the
synthesis of spirodienones from (4-halogenophenyl)-N-
methoxyamides, more readily accessible compounds than
the corresponding methoxy compounds, with HTIB in
TFEA. We have applied this procedure to the synthesis
of spirodienones bearing 1-azaspiro[4.5]decane skeleton
using N-acylaminophthalimides bearing a pendant 4-ha-
logenophenyl group (1k -p ) with HTIB in TFEA. The
results are presented in Table 3.
Syn th esis of Sp ir od ien on es. Spirodienones bearing
the 1-azaspiro[4.5]decane skeleton have recently at-
tracted considerable attention because of their presence
in various natural products.17 In our previouis work, we
converted N-methoxy-3-phenylpropionamide and the cor-
responding N-chloro compound to 1-methoxy-1-azaspiro-
[4.5]deca-6,9-diene-2,8-dione with PIFA17 in 80% yield
6
and with Zn(OAc)2 in 83% yield, respectively. Very
Two equivalents of HTIB to 1k -p was needed to obtain
a high yield of 4j,m -p . Use of PIFA (2 molar equiv)
instead of HTIB gave 4j in low yield (Table 3, entry 2).
Halogens have nonbonded electron pairs, which stabilize
the cationic intermediate through their “back-donation”
ability and promote further reaction.19 The yields of
spirodienones are directly related to the degree of “back-
donation” and the best results are obtained with the 2,4-
difluorophenyl compound (1m ) (93%, Table 3, entry 5).
recently, it was reported that methyl N2-(3-phenylpro-
pionyl)carbazate was oxidized to 1-methoxycarbonylamino-
1-azaspiro[4.5]deca-6,9-diene-2,8-dione with phenyliodine-
(III) diacetate in 25% yield.9a We now have applied our
present methodology to the synthesis of spirodienones.
Thus, treatment of 1j with PIFA in TFEA at room
temperature for 3 h gave 4j in 77% yield. The ipso
position is activated by an electron-donating methoxy
group and is attacked by the nitrenium ion to give the
(18) Miyazawa, E.; Sakamoto, T.; Kikugawa, Y. J . Org. Chem. 2003,
68, 5429.
(19) Olah, G. A.; Singh, B. P.; Liang, G. J . Org. Chem. 1984, 49,
2922. Miyazawa, E.; Sakamoto, T.; Kikugawa, Y. J . Chem. Soc., Perkin
Trans. 2 1998, 7.
(16) Romero, A. G.; Darlington, W. H.; J acobsen, E. J .; Mickelson,
J . W. Tetrahedron Lett. 1996, 37, 2361.
(17) Miyazawa, E.; Sakamoto, T.; Kikugawa, Y. Heterocycles 2003,
59, 149.
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Kikugawa et al.
TABLE 3. Cycliza tion of N-Acyla m in op h th a lim id es w ith HIBT in TF EA
a
b
d
A: PIFA (2.0 equiv). C: HIBT (2.0 equiv). At room temperature. c 1.0 equiv. 2.8 equiv.
These substances, themselves of potential synthetic
interest, can be converted into quinolone derivatives by
acid treatment.9
provide valuable intermediates for the synthesis of a
variety of organic compounds.20 Several unactivated
benzenoid compounds reacted similarly, and the results
are presented in Table 4.
Syn th esis of Sp ir od ien e Com p ou n d s. The present
reaction is influenced greatly by the choice of solvent. For
example, in the reaction of 1b with PIFA, the use of
TFEA instead of HFIP resulted in unexpected attack of
the nitrenium ion on the ipso position to give a spirodiene
derivative (6b) in 76% yield along with the 3,4-dihydro-
carbostyril derivative (2b) (17%). Similarly, reaction of
N-(4-phenylbutyroyl)aminophthalimide (1c) under these
conditions gave the corresponding spirobenzannulated
compound (6c) and the benzannulated compound (2c) in
44% and 46% yields, respectively. From o-tolyl derivative
(1q), the spirodiene compound (6q) was exclusively
obtained (88%, Table 4, entry 4). Most reactions of
unactivated monobenzenoid aromatics lead to substitu-
tion rather than addition. Formation of the spirodiene
derivatives (6) by this ipso cyclization, which resulted in
loss of aromaticity without any other substituents on the
phenyl group, is an unusual result. Transformation of
benzenoid compounds to nonbenzenoid compounds can
Illustrative of the procedure, stirring a mixture of 1b,
PIFA, and TFEA for 3 h at room temperature causes an
intramolecular ipso attack of the electron-deficient hy-
drazide nitrogen with subsequent trapping of the cation
with a trifluoroethoxide ion to give the spirodiene 6b. The
critical part of the process involves a coupled attack on
the benzenoid ring by external nucleophilic trifluoro-
ethanol and internal electrophilic acylnitrenium ion, the
over-all results being 1,4-addition. In the case of 1r , the
trifluoroethoxy group of the transient spirodiene inter-
mediate might be eliminated to afford the exo methylene
compound and subsequent addition of TFEA to the
(20) (a) Gassman, P. G.; Campbell, G. A. J . Chem. Soc., Chem.
Commun. 1970, 427. (b) Corey, E. J .; Barcza, S.; Klotmann, G. J . Am.
Chem. Soc. 1969, 91, 4782.
(21) Winters, G.; Odasso, G.; Conti, M.; Tarzia, G.; Galliani, G. Eur.
J . Med. Chem. 1984, 19, 215.
(22) Blout, E. R.; Silverman, D. C. J . Am. Chem. Soc. 1944, 66, 1442.
6742 J . Org. Chem., Vol. 68, No. 17, 2003

Formation of Lactams and Spiro-Fused Lactams
TABLE 4. Cycliza tion of N-Acyla m in op h th a lim id es w ith P IF A in TF EA
a
b
d
A: PIFA (1.0 equiv). At room temperature. c 2,2,3,3-Tetrafluoro-1-propanol was used for solvent. Small amounts of a mixture of
benzannulated regioisomers were obtained.
SCHEME 2
ever, in HFIP, a secondary alcohol, the benzannulated
product was formed without formation of the spirodiene
compound. This is probably due to steric hindrance and
the low nucleophilicity of this solvent (Table 1). Trans-
formation of benzenoid compounds to nonbenzenoid
compounds provides an attractive strategy for the syn-
thesis of a variety of functionalized six-membered ring
compounds.20 Conversion of 1 to spirodienones (4) and
spirodienes (6) bearing the nitrogen atom bound to the
spiro carbon should offer valuable intermediates for the
synthesis of a variety of organic compounds.
methylene group gave 6r (Scheme 2, path a). Compound
2r might be formed through direct ortho attack or
through ipso attack followed by C-N bond migration
(Scheme 2, path b).9
It is noteworthy that in the fluorine-containing primary
alcohol, 2,2,3,3-tetrafluoro-1-propanol, the corresponding
spirodiene compound (6b′) having a 2,2,3,3-tetrafluoro-
1-propanoxy group was formed (Table 4, entry 2). How-
Con clu sion s
In summary, we have generated a new class of reactive
nitrenium ions II by the reaction of 1 with hypervalent
J . Org. Chem, Vol. 68, No. 17, 2003 6743

Kikugawa et al.
iodine compounds. The phthalimido group is a good
protecting group and also effectively stabilizes II to
promote further reactions. The interesting transforma-
tions that derive form II can be summarized as follows.
PIFA reacts with the amide nitrogen in HFIP to form
an intermediate, which presumably is decomposed to
generate an electron deficient nitrogen. This, in turn,
undergoes intramolecular electrophilic aromatic substitu-
tion reactions to afford N-aminonitrogen heterocycles in
high yield. In TFEA, ipso attack of the nitrenium ion is
observed to give spirodienone and spirodiene derivatives.
The latter involves loss of aromaticity in the absence of
other activating substituents on the phenyl group, a
process that is very unusual.
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
J O0347009
6744 J . Org. Chem., Vol. 68, No. 17, 2003