Spiro cyclohexadienones from the reaction of phenolic enaminone derivatives with hypervalent iodine reagents

Article abstract of DOI:10.3390/50600874

Phenolic enamino compounds, prepared from 2-(4-hydroxyphenyl)-ethylamine and the corresponding β-keto carbonyl compounds, afford spiro cyclohexadienone derivatives on reaction with hypervalent iodine reagents.

Full text of DOI:10.3390/50600874

Molecules 2000, 5, 874-879
molecules
ISSN 1420-3049
http://www.mdpi.org
Spiro Cyclohexadienones from the Reaction of Phenolic
Enaminone Derivatives with Hypervalent Iodine Reagents
Anna Asmanidou, Ioannis Papoutsis, Spyros Spyroudis* and Anastasios Varvoglis
Laboratory of Organic Chemistry, Chemistry Department, University of Thessaloniki, Thessaloniki
54006, Greece
Tel.: 003031-997833, Fax: 003031-997679, E-mail: sspyr@chem.auth.gr
Received: 6 May 2000 / Accepted: 25 May 2000 / Published: 9 June 2000
Abstract: Phenolic enamino compounds, prepared from 2-(4-hydroxyphenyl)-ethylamine
and the corresponding ꢀ-keto carbonyl compounds, afford spiro cyclohexadienone deriva-
tives on reaction with hypervalent iodine reagents.
Keywords: Spiro cyclohexadienones, hypervalent iodine, enamino esters.
Introduction
The action of hypervalent iodine compounds on phenols gives rise to a variety of products depen-
ding on the nature of the phenol and the reaction conditions. The most interesting reaction pathway is
oxidation of the phenolic moiety with simultaneous nucleophilic attack on the para position of the
phenolic ring. When this attack occurs place intramolecularly, a variety of spirodienone derivatives are
formed with considerable synthetic possibilities [1-3]. Especially noteworthy is the oxidative coupling
of phenolic derivatives of ꢀ-phenylethylamine, studied extensively by Kita and coworkers [4]. This
coupling, outlined below, offers an easy access to pharmacologically interesting natural products,
when the substituent on nitrogen is an aromatic or a quinone ring.
©
2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.

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Molecules 2000, 5
O
OH
I (III)
NH
N
H
Figure 1.
Results and Discussion
Continuing the exploration of the chemistry of hypervalent iodine reagents [5], we investigated the
possibility of analogous cyclization reactions using enamino carbonyl systems of type I. Recently we
reported the isolation of stable iodonium salts of type II, resulting from enamino carbonyl compounds
such as amino quinones [6], aminocrotonates [7] and cyclic enaminones [8] (in the last case the Ph of
the iodonium salt group had been replaced by the CF CH group). We have also reported the oxida-
3
2
tive cyclization of analogous enamino carbonyl compounds with an indole ring, resulting into the for-
mation of tetrahydro-ꢀ-carbolines [9].
OH
TsO
O
C
O
C
PhI
H
NH
II
NH
I
Figure 2.
Interesting results were obtained from the reaction of amino crotonic esters 1 with [(hy-
droxy)(tosyloxy)iodo]benzene, 2. These esters, easily prepared from the reaction of 2-(4-
hydroxyphenyl)-ethylamine with the corresponding ꢀ-keto acetate according to the literature method
°
[
10], react with 2 under mild conditions (CH Cl , 0 C) to give the products indicated in the scheme
2 2
below. All new compounds have spectral and analytical data consistent with their structure.

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Molecules 2000, 5
R
N
H
R
N
OTs
COR'
COR'
H
N
R
H
H
PhI(OH)(OTs)
R
O
OTs
COR'
H
COR'
2
OH
OH
O
1
a,b
3a 45%
4a 12%
4b 35%
5a 15%
5b 11%
3
b 11%
a, R = Me, b, R = Ph
Scheme 1.
The first step of the reaction involves probably the formation of an iodonium intermediate, 6. This
affords the tosyloxy derivative 3 through an internal nucleophilic displacement of the phenyliodonio
group by the tosylate. This displacement takes place with retention of the configuration and was ob-
served in analogous isolable iodonium salts [7]. Enamino tosylates 3 were partially hydrolyzed to keto
tosylates 4 during work-up.
OTs
H O
2
R
N
IPh
3
4
-PhI
H
COR'
R
COR'
-PhI, -TsOH
HN
O
H
5
6
O
Figure 3.
A second reaction pathway leads to the formation of spiro cyclohexadienone derivatives 5, by attack
of the electron rich aromatic ring on the electrophilic carbon bearing the phenyliodonio group, with the
simultaneous elimination of p-toluenesulfonic acid.
The same reaction was tried using the trimethyl silyl ethers of the phenolic derivatives 1. Under
conditions described by Kita [4], (CF CH OH as solvent, PhI(OCOCF ) as oxidant) the reaction af-
3 2
3
2
forded a complicated mixture of products and no spiro cyclohexadienone derivatives were detected
among them.

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Molecules 2000, 5
This cyclization reaction was extended to other enamino carbonyl systems. Thus, enamino com-
pound 7, prepared from the condensation reaction of dimedone with 2-(4-hydroxyphenyl)-ethylamine,
afforded spiro cyclohexadienedione 9 as the sole isolable product. This time the cyclization was ef-
fected by [bis(trifluroacetoxy)iodo]benzene 8 in CH Cl at room temperature in 12 hours.
2
2
O
N
H
N
H
PhI(OCOCF3)2
8
O
OH
30%
7
O
9
Scheme 2.
In contrast, enaminone 10, prepared analogously from acetylacetone, afforded a complex mixture of
products with [bis(trifluroacetoxy)iodo]benzene. However, it reacted smoothly with [(hy-
droxy)(tosyloxy)iodo]benzene to afford the tosyloxy enaminone 11 in 45% yield, but no cyclization
product was isolated.
H C
3
H
H C
3
OTs
N
COCH3
N
COCH3
H
H
PhI(OH)(OTs)
2
OH
OH
10
11
Scheme 3.
Conclusion
The reported oxidative cyclization offers an interesting entry to spiro cyclohexadienones; research
will be continued to explore the scope of the reaction with other enamino carbonyl systems.

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Molecules 2000, 5
Experimental
Typical procedure for the preparation of 5 and 9
[
(Hydroxy)(tosyloxy)iodo]benzene (1 mmol) was added to a stirred solution of enamino carbonyl
°
derivative 1 (1 mmol) in CH Cl (10 mL) at 0 C under argon. The reaction mixture was allowed to
2
2
reach room temperature and, after all enamino ester was consumed (5 h), it was concentrated and
chromatographed on column (SiO , hexanes-ethyl acetate) to afford, after iodobenzene, 3 and 4 as
2
oils; Finally spiro cyclohexadienones 5a and 5b were eluted as light-yellow crystals.
2-Methyl-3-carboxyethyl-1,4,5,6-tetrahydropyridino-4-spiro-4'-cyclohexa-2',5'-dien-1'-one 5a
°
-1 1
Mp 180-182 C (dec.). IR (Nujol): 3320, 1645, 1710, 1605, 1115 cm ; H NMR (CDCl ): / 1.07
3
(
t, J = 7 Hz, 3H), 1.83 (t, J = 5 Hz, 2H) 2.32 (s, 3H), 3.33 (m, 2H), 3.95 (q, J = 7 Hz, 2H), 4.65 (s, br,
+
1
H), 6.21 (d, J = 10 Hz, 2H), 6.94 (d, J = 10 Hz, 2H); MS m/z 247 (M , 50), 202 (45), 174 (93), 146
(
100), 91 (60). Anal. Calcd for C H NO : C, 68.00; H, 6.93; N, 5.66. Found: C, 67.42; H, 7.03; N,
4 17
1
3
5
.31.
2-Phenyl-3-carboxyethyl-1,4,5,6-tetrahydropyridino-4-spiro-4'-cyclohexa-2',5'-dien-1'-one 5b
°
-1 1
Mp 199-201 C. IR (Nujol): 3310, 1650 cm ; H NMR (CDCl ): / 0.73 (t, J = 7 Hz, 3H), 1.94 (t, J
3
=
5 Hz, 2H), 3.47 (m, 2H), 3.69 (q, J = 7 Hz, 2H), 4.70 (s, br, 1H), 6.27 (d, J = 10 Hz, 2H), 7.05 (d, J =
1
3
1
0 Hz, 2H), 7.27-7.38 (m, 5H); C NMR (CDCl /DMSO-d ): / 13.39, 34.73, 38.54, 41.22, 58.99,
3 6
+
9
2
4.63, 127.32, 127.52, 128.12, 128.80, 139.26, 155.63, 156.12, 166.92, 186.15 ; MS m/z 309 (M , 7),
36 (31), 208 (100), 105 (50), 77 (47). Anal. Calcd for C H NO : C, 73.77; H, 6.19; N, 4.53.
1
9 19
3
Found: C, 73.57; H, 5.94; N, 4.22.
7,7-Dimethyl-1,2,3,4,5,6,7,8-octahydro-quinoline-5-one-4-spiro-4'-cyclohexa-2',5'-dien-1'-one 9
°
-1 1
Mp 130-135 C. IR (Nujol): 3320, 1660 cm ; H NMR (CDCl /DMSO-d ): / 1.03 (s, 6H), 1.74 (t,
3
6
J = 5 Hz, 2H), 2.04 (s, 2H), 2.29 (s, 2H), 3.33 (m, 2H), 6.12 (d, J = 10 Hz, 2H), 6.88 (d, J = 10 Hz,
1
3
2
H), 7.52 (s, br, 1H) ; C NMR (CDCl /DMSO-d ): / 27.60, 31.18, 33.76, 37.05, 38.07, 42.24,
3 6
+
5
0.40, 100.82, 126.02, 155.70, 159.15, 185.37, 190.26 ; MS m/z 257 (M , 24). Anal. Calcd for
C H NO : C, 74.68; H, 7.44; N, 5.44. Found: C, 74.59; H, 7.17; N, 5.63.
6 19
1
2

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Molecules 2000, 5
References and Notes
1
.
Varvoglis, A. The Organic Chemistry of Polycoordinated Iodine; VCH: New York, 1992; pp 80-
2.
8
2
.
.
Varvoglis, A. Hypervalent Iodine in Organic Synthesis; Academic Press: London, 1997; pp 56-60.
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reagents. Advances in Heterocyclic Chemistry; Academic Press: London, 1998, 69, 1-86.
Kita, Y.; Takada, T.; Gyoten, M.; Tohma, H.; Zenk, M.; Eichhorn, J. An oxidative intra-molecular
phenolic coupling reaction for the synthesis of amaryllidaceae alkaloids using a hypervalent io-
dine(III) reagent. J. Org. Chem. 1996, 61, 5857-5864 and references cited therein.
3
4
.
5.
6.
7.
8.
Varvoglis, A.; Spyroudis, S. Hypervalent iodine chemistry: 25 years of development at the Uni-
versity of Thessaloniki. SynLett. 1998, 221-232.
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amino-1,4-naphthoquinones: preparation and reactivity. Tetrahedron 1997, 53, 6097-6112.
Papoutsis, I.; Spyroudis, S.; Varvoglis, A. Reactivity of a new alkenyl phenyliodonium tosylate
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3
8, 8401-8404.
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1
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Papadopoulou, D.; Papoutsis, I.; Spyroudis, S.; Varvoglis, A. Cyclisation of tryptamine enami-
nones to functionalised tetrahydro-ꢀ-carbolines induced by [bis(trifluoroacetoxy)iodo] benzene.
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0. Sukari, M.A.; Vernon, J.M. Oxidation of enamine esters with lead tetraacetate – part 3. Tetrahe-
dron 1983, 39, 793-796.
Samples Availability: Not available.
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2000 by MDPI (http://www.mdpi.org). Reproduction is permitted for noncommercial purposes.