Hypervalent iodine(III)-mediated oxidative acetoxylation of 2-methoxyphenols for regiocontrolled nitrogen benzannulation

Article abstract of DOI:10.1016/S0040-4039(01)01514-3

Nitrogen-tethered 2-methoxyphenols are conveniently dearomatized into synthetically useful orthoquinol acetates by treatment with phenyliodine(III) diacetate in methylene chloride at low temperature. Subsequent fluoride- or base-induced intramolecular nucleophilic addition reactions furnish indole and quinoline derivatives. The potential of this methodology for the synthesis of a functionalized lycorine-type alkaloid skeleton is introduced here.

Full text of DOI:10.1016/S0040-4039(01)01514-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 7393–7396
Hypervalent iodine(III)-mediated oxidative acetoxylation of
2-methoxyphenols for regiocontrolled nitrogen benzannulation
Ste´phane Quideau,* Laurent Pouyse´gu, Anne-Virginie Avellan, Daniel K. Whelligan and
Matthew A. Looney
Laboratoire de Chimie des Substances Ve´ge´tales, Centre de Recherche en Chimie Mole´culaire, Universite´ Bordeaux 1,
351 cours de la Libe´ration, 33405 Talence Cedex, France
Received 4 July 2001; accepted 17 August 2001
Abstract—Nitrogen-tethered 2-methoxyphenols are conveniently dearomatized into synthetically useful orthoquinol acetates by
treatment with phenyliodine(III) diacetate in methylene chloride at low temperature. Subsequent fluoride- or base-induced
intramolecular nucleophilic addition reactions furnish indole and quinoline derivatives. The potential of this methodology for the
synthesis of a functionalized lycorine-type alkaloid skeleton is introduced here. © 2001 Elsevier Science Ltd. All rights reserved.
The oxidative activation of hydroxylated aromatic rings
or arenols is a valuable tactic for the synthesis of
polyoxygenated carbo- and heterocyclic motifs of natu-
ral products.1 This activation can easily find expression
in the displacement of two ring electrons through the
phenol unit to furnish a phenoxenium ion-type species
with concomitant loss of the phenolic hydrogen (e.g.
1“2, Scheme 1).2 In the presence of a nucleophile, this
electrophilic species is trapped either in a concerted or
a stepwise fashion to give rise to cyclohexadienone
derivatives. Various metallic reagents have traditionally
been used to mediate these oxidative nucleophilic sub-
stitutions,2,3 but hypervalent iodine(III) derivatives
have today become the reagents of choice because their
utilization is easy to implement, economic and non-
toxic.4–7
The first reagent bears nucleophilic acetate ligands that
can participate in the oxidative nucleophilic substitu-
tion reaction whereas the second one can release a
strong organic acid, trifluoroacetic acid (TFA, pKa=
0.23) into the reaction medium; this acidity can be
exploited for facilitating special bond cleavage in nucle-
ophilic addition cascades.8 With both iodine(III) spe-
cies, iodobenzene and residual organic acids are conve-
Our interest in the chemistry of hypervalent iodine(III)
reagents resides in their remarkable and versatile utility
in the transformation of functionalized 2-alkoxyarenols
1 into 6-alkoxycyclohexa-2,4-dienones 3 and 6-alkoxy-
cyclohexa-2,5-dienones 4 (Scheme 1). Reaction out-
comes can be controlled by the choice of the iodine(III)
ligands whose chemical reactivity can vary. The two
kinds of hypervalent iodine(III) reagents that we com-
monly use to oxidatively activate arenols are commer-
cially available phenyliodine(III) diacetate (PIDA) and
phenyliodine(III) bis(trifluoroacetate) (PIFA).
Keywords: hypervalent iodine; arene chemistry; oxidative activation;
orthoquinol acetate; heterocyclization.
* Corresponding author. Tel.: +33-556-84-64-30; fax: +33-556-84-64-
22; e-mail: s.quideau@ipin.u-bordeaux.fr
Scheme 1.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01514-3

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S. Quideau et al. / Tetrahedron Letters 42 (2001) 7393–7396
butoxide in refluxing THF was identified as the best
base system to induce the desired benzannulation. The
2-oxindole 14a and the 3,4-dehydro-2-oxoquinoline 14b
were obtained in unoptimized yields of 17% and 38%,
respectively (Scheme 4).
niently removed by simple drying under vacuum. No
toxic metallic salts are generated in contrast to the
alternative use of lead- or thallium-based reagents in
Wessely or McKillop oxidation.9–11
PIDA is used to generate 6-acetoxy-6-alkoxycylohexa-
2,4-dienones 3 (Scheme 1, Nu=OAc from PIDA), com-
monly referred to as orthoquinol acetates, from
2-alkoxyarenols 1. Arenols are usually 2-methoxylated
because they are easily derived from commercially
available materials, and because the 2-methoxy group
has proved its efficacy at directing the attack of the
entering nucleophile on its carrier carbon rather than
on the other ortho and para electrophilic centers.2,12
Starting 2-methoxyarenols can be appended with oxy-
gen- or nitrogen-bearing tethers.1 Protecting groups are
placed on these centers when their nucleophilic power
otherwise permits intramolecular reactions to compete
with the desired acetoxylation. Such competitions usu-
ally lead to oxo- or azaspirocyclohexa-2,5-dienone
derivatives 4 (Scheme 1).13,14
This work is reminiscent of investigations by Kita,17
Wipf,18 Jacquesy19 and Ciufolini14 on the preparation
of hydroindolenones and hydroquinolenones using
PIDA or PIFA to transform various starting N-acyl
and N-alkylamino phenols into cyclohexa-2,5-dienone
intermediates that are adequately functionalized for
intramolecular Michael-type nitrogen additions. In our
work, Tsoc-protected amine, benzylated amide and car-
bamate nitrogens are induced to benzannulate from
cyclohexa-2,4-dienone intermediates.
Application of this methodology to natural products
synthesis is being explored for the construction of the
lycoran-type polycyclic skeleton of Amaryllidaceae
alkaloids such as lycorine (18) (Scheme 5).20,21 Thus,
the bis(orthoquinol acetate) Tsoc-protected secondary
amine 16 was derived in three steps from the known
secondary amine 1522 as indicated in Scheme 5. It was
then subjected to the fluoride ion-mediated deprotec-
Adequately protected orthoquinol acetates of type 3
can then be further transformed into benzannulated
heterocycles 5 via exo-trig cyclization (Scheme 1). Dif-
ferently sized benzannulated ether rings have been pre-
pared by this methodology.15 Nitrogen versions of these
oxygen heterocyclizations have now been implemented
for the construction of benzannulated nitrogen-contain-
ing five- and six-membered rings. Triisopropylsilyloxy-
carbonyl
(Tsoc)-protected16
amino-tethered
2-methoxyphenols 6a/b were submitted to PIDA-medi-
ated oxidative acetoxylation to furnish the orthoquinol
acetates 7a/b in excellent yields. Treatment with TBAF
as a source of fluoride ions for desilylation in THF
induced cyclizations to furnish the indoline 8a1 and the
tetrahydroquinoline 8b as the only isolated regioisomers
in good yields, both resulting from exo-trig cyclizations
(Scheme 2). The carbamate 9 directly furnished the
corresponding orthoquinol acetate 10 in good yield,
although a certain instability of this ketal species was
noticed in CDCl3 solution during the NMR analysis.
Nevertheless, the acetate 10 was cyclized upon treat-
ment with LiHMDS in THF to give the indoline 11 in
32% yield (Scheme 3). At this point, it is difficult to
attribute this rather moderate cyclization yield to the
instability of the orthoquinol acetate intermediate or to
the lower nucleophilic force of the carbamate nitrogen
when compared to that of the transient amino anion
released upon cleavage of the Tsoc group in 7a/b
(Scheme 2).
Scheme 2.
Amide nitrogen benzannulation was next investigated
with the aim of preparing functionalized 2-oxindoles
and 2-oxoquinolines, which can potentially constitute
interesting pharmacophores. Benzylated amido 2-
methoxyphenols 12a/b were thus transformed into
orthoquinol acetates 13a/b. Notwithstanding a certain
instability of these monoketal intermediates that was
here also noticed in CDCl3 and acetone-d6 solutions
over prolonged periods of time (ca. 5–10 h), base-
induced cyclizations were carried out. Potassium tertio-
Scheme 3.

S. Quideau et al. / Tetrahedron Letters 42 (2001) 7393–7396
7395
Acknowledgements
We wish to thank the De´le´gation Re´gionale a` la
Recherche et a` la Technologie pour l’Aquitaine
(FEDER Grant Z0131) and the Conseil Re´gional
d’Aquitaine (Grant 990209003) for financially support-
ing this research. We are also grateful to the Centre de
Recherche en Chimie Mole´culaire (CNRS, Fe´de´ration
d’Unite´s FR1981) for its contribution to the postgradu-
ate fellowships to Daniel K. Whelligan (Cambridge
University, UK) and Matthew A. Looney (Texas Tech
University, USA).
References
1. Quideau, S.; Pouyse´gu, L.; Oxoby, M.; Looney, M. A.
Tetrahedron 2001, 57, 319–329.
2. Quideau, S.; Pouyse´gu, L. Org. Prep. Proc. Int. 1999, 31,
617–680.
Scheme 4.
3. Barton, D. H. R.; Berge´-Lurion, R.-M.; Lusinchi, X.;
Pinto, B. M. J. Chem. Soc., Perkin Trans. 1 1984, 2077–
2080.
4. Varvoglis, A. Hypervalent Iodine in Organic Synthesis;
Academic Press: San Diego, 1997.
5. Varvoglis, A. Tetrahedron 1997, 53, 1179–1255.
6. Koser, G. F. In The Chemistry of Functional Groups;
Patai, S.; Rappoport, Z., Eds. Hypervalent halogen com-
pounds; Wiley: New York, 1983; pp. 721–811.
7. Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96,
1123–1178.
8. Quideau, S.; Looney, M. A.; Pouyse´gu, L. Org. Lett.
1999, 1, 1651–1654.
9. Wessely, F.; Sinwel, F. Monatsh. Chem. 1950, 81, 1055–
1070.
10. Bubb, W. A.; Sternhell, S. Tetrahedron Lett. 1970, 51,
4499–4502.
11. McKillop, A.; Perry, D. H.; Edwards, M.; Antus, S.;
Farkas, L.; No´gra´di, M.; Taylor, E. C. J. Org. Chem.
1976, 41, 282–287.
12. Ku¨rti, L.; Herczegh, P.; Visy, J.; Simonyi, M.; Antus, S.;
Pelter, A. J. Chem. Soc., Perkin Trans. 1 1999, 379–380.
13. Tamura, Y.; Yakura, T.; Haruta, J.-I.; Kita, Y. J. Org.
Chem. 1987, 52, 3927–3930.
14. Braun, N. A.; Ousmer, M.; Bray, J. D.; Bouchu, D.;
Peters, K.; Peters, E.-M.; Ciufolini, M. A. J. Org. Chem.
2000, 65, 4397–4408.
Scheme 5.
15. Quideau, S.; Pouyse´gu, L.; Looney, M. A. J. Org. Chem.
tion–cyclization conditions described here. Heterocy-
clization occurred in a moderate yield of 33% leading to
the indole product 17,23 but not to a dehydroindole like
in the case of the conversion of 7a into 8a (Scheme 2).1
This oxidation of an initially formed dehydroindole
product is concomitant with the reduction of the sec-
ond orthoquinol acetate moiety of 16.
1998, 63, 9597–9600.
16. Lipshutz, B. H.; Papa, P.; Keith, J. M. J. Org. Chem.
1999, 64, 3792–3793.
17. Kita, Y.; Tohma, H.; Kikuchi, K.; Inagaki, M.; Yakura,
T. J. Org. Chem. 1991, 56, 435–438.
18. Wipf, P.; Kim, Y. Tetrahedron Lett. 1992, 33, 5477–5480.
19. Karam, O.; Martin, A.; Jouannetaud, M.-P.; Jacquesy,
J.-C. Tetrahedron Lett. 1999, 40, 4183–4186.
20. Hoshino, O. In The Alkaloids; Cordell, G. A., Ed. The
Amaryllidaceae alkaloids. Academic Press: New York,
1998; Vol. 51, pp. 323–433.
21. Lewis, J. R. Nat. Prod. Rep. 1998, 15, 107–110.
22. Kametani, T.; Ohkubo, K.; Takano, S. Yakugaki Zasshi
1967, 87, 563–569.
We are now working on elucidating this apparent
intramolecular oxido-reduction process for identifying
reaction conditions that will enable a domino formation
of the nitrogenꢀcarbon and carbonꢀcarbon bonds of
the lycorine-type ABCD tetracyclic system prior to any
rearomatization.

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S. Quideau et al. / Tetrahedron Letters 42 (2001) 7393–7396
23. Experimental procedure and characterization data for
indole 17: To a stirring ice-cold solution of orthoquinol
acetate 16 (150 mg, 0.24 mmol) in dry THF (5 mL) was
added dropwise a commercial solution of TBAF (1 M in
THF, 1.1 equiv). The reaction mixture immediately
became darker. After 20 min, the ice bath was removed,
and the reaction was stirred at room temperature for an
additional 20 min period. Progression of the reaction was
monitored by the disappearance of the orthoquinol ace-
tate, as indicated by TLC [hexanes–Et2O (1:4)]. The
mixture was diluted with EtOAc (50 mL), washed with
brine (2×10 mL), dried over Na2SO4, filtered and evapo-
rated at room temperature. The resulting brown residue
was purified by column chromatography, eluting with
hexanes–Et2O (1:4), to afford the indole derivative 17 as
a dark oil (23.9 mg, 33%); IR (NaCl) 3535, 3456, 1588
cm−1 1H NMR (acetone-d6, 200 MHz): l 3.79 (s, 3H),
;
3.87 (s, 3H), 5.21 (s, 2H), 6.34 (dd, J=0.7, 3.2 Hz, 1H),
6.67 (dd, J=2.0, 8.1 Hz, 1H), 6.78 (d, J=8.1 Hz, 1H),
6.89 (d, J=0.7 Hz, 1H), 6.92 (d, J=2.0 Hz, 1H), 7.09 (s,
1H), 7.16 (d, J=3.2 Hz, 1H); 13C NMR (acetone-d6, 62.9
MHz): l 148.3, 146.8, 144.5, 144.2, 132.2, 130.5, 127.3,
122.1, 120.7, 115.7, 111.7, 103.0, 101.4, 96.6, 56.6, 56.1,
50.4; EIMS m/z (relative intensity) 301 (1), 300 (MH+,
11), 299 (M+, 60), 163 (93), 137 (100); HRMS (EI) calcd
for C17H17NO4 299.1157, found 299.1156.