A new one-pot procedure for a ring contraction reaction using iodine/H 2O2

Article abstract of DOI:10.1055/s-0028-1083519

A new procedure for ring contraction from 1,2-quinones using aqueous H ₂O₂ (30%) and catalytic amount of I₂ in acetonitrile is reported.

Full text of DOI:10.1055/s-0028-1083519

LETTER
2625
A New One-Pot Procedure for a Ring Contraction Reaction using Iodine/H2O2
O
ne-Pot Proce
a
dure for
a
R
b
ing
C
ontrac
r
tion
R
ea
i
ctionunsingIodine/H2 2
a
O
B. Ferreira,a Carlos R. Kaiser,a Vitor F. Ferreira*b
a
Instituto de Química, LABRMN, Universidade Federal do Rio de Janeiro, Ilha do Fundão, 21949-900, Rio de Janeiro, Brazil
Instituto de Química, Departamento de Química Orgânica, Universidade Federal Fluminense, 24020-141 Niterói, Rio de Janeiro, Brazil
Fax +55(21)26292362; E-mail: cegvito@vm.uff.br
b
Received 17 March 2008
O
O
O
Abstract: A new procedure for ring contraction from 1,2-quinones
using aqueous H2O2 (30%) and catalytic amount of I2 in acetonitrile
is reported.
O
OH
Key words: ring contractions, quinones, lapachones, iodine, hy-
drogen peroxide
O
1
2
The cyclopentyl unit is present in several molecules, nat-
ural or non-natural, with remarkable biological activity. It
can be found in alkaloids,1a steroids,1b prostaglandins,1c
triquinanes,1d indans,1e and guaianes.1f Therefore, the de-
velopment of efficient methods for the construction of
such unit has been an important goal in organic synthesis.
Probably, the most used strategies to prepare complex
molecules possessing a functionalized cyclopentyl unit is
by way of the cyclization reaction or by way of direct
transformation of commercially available substrates that
already contain this moiety. Although less used, the ring
contraction of a carbocyclic compound is also a good
route to assemble cyclopentyl units, because, in several
cases, the reorganization of the bonds occurs with a high
level of selectivity, leading to compounds not easily ac-
cessed by other methodologies.
Figure 1 Structure of lapachone (1) and its precursor lapachol (2),
compound isolated from the lapacho tree
‘[3+3]-cyclization/Suzuki cross coupling/Friedel–Crafts
acylation’ strategy,7 and recently, Mal and co-workers re-
ported a two-step ring contraction of the generated
benz[a]anthracene-5,6-diones through benzil–benzilic
acid rearrangement for the preparation of the benzo[b] de-
rivative.8 Since 1996, several routes to the synthesis of
fluorenones have been developed.9
b-Lapachone (1) is a naturally occurring o-quinone de-
rived from the lapacho tree (Tabeuia avellanedae) native
to Central and South America. The synthesis and chemis-
try of b-lapachone and related compounds were initially
investigated in the late 19th and early 20th centuries by
the chemist Samuel Hooker,10 and this compound is the
most important one biogenetically related to lapachol (2;
Figure 1).11
Ring contraction reactions of carbocyclic compounds can
be carried out by acids, bases, oxidizers and photochemi-
cally. The ring contraction reactions are divided into five
main groups: (i) acid-induced ring contractions; (ii) base-
induced ring contractions; (iii) oxidative rearrangements;
(iv) photochemical rearrangements; and (v) Wolff rear-
rangements.2 Since the transformation of carbocyclic
compounds, particularly of quinones into different com-
pounds, adds new biological applications possibilities,3 it
seems that an interesting starting point is to transform bio-
active o-naphthoquinones, such as b-lapachone (1), into
new compounds, like fluorenones.
Fluorenone derivatives have been used in many polymers
as electron-transporting materials in organic photocon-
ductor devices and their electric and optical properties
were studied. In addition, these moieties have remarkable
medicinal interest since they can be found in natural com-
pounds such as dengibsin (3), dendroflorin (4) or
kinobscurinone (5), showing a range of interesting biolog-
ical activities (Figure 2).12a–c However, only few reports
are available for preparing such kind of compounds by
short and direct synthetic procedures.
Fluorenones can be prepared by intramolecular Friedel–
Crafts acylations of biaryls.4 The synthesis of fluorenones
was reported by Snieckus and co-workers based on re-
mote aromatic metalation5 and, Chan and co-workers re-
ported the synthesis of arenes by [3+3]-cyclization of 1,3-
bissilyl enol ethers with 3-(silyloxy)alk-2-en-1-ones.6
More recently, Langer and co-workers reported an
efficient synthetic approach to fluorenones based on a
Iodine and H2O2 are environmentally safe and inexpen-
sive reagents. The mixture of these reagents has been used
in several organic reactions. For example, Stavber et al.
found that the reaction using elemental iodine, enhanced
by 30% aqueous hydrogen peroxide in water with ke-
tones, 1,3-dicarbonyl derivatives and activated aromatic
molecules gave an efficient iodofunctionalization.13 Re-
cently, Zÿmitek and co-worker used these reagents with
different ketones that were directly converted into the cor-
responding gem-dihydroperoxides.14
SYNLETT 2008, No. 17, pp 2625–2628
x
x
.x
x
.2
0
0
8
Advanced online publication: 01.10.2008
DOI: 10.1055/s-0028-1083519; Art ID: S02608ST
© Georg Thieme Verlag Stuttgart · New York

2626
S. B. Ferreira, et al.
LETTER
O
was catalytic and the reaction time varied according the
o-quinones. An increase in the amount of H2O2 and an ex-
tended reaction time did not bring about any further im-
provement in yield. The best results for the synthesis of
products were achieved using a 0.1 M solution of o-naph-
thoquinone in acetonitrile, four equivalents of 30% aque-
ous H2O2, and 10 mol% of I2 at room temperature.
OH
O
OH
OH
OH
OH
MeO
MeO
4
3
HO
To determine the limitations of the method, we tested the
efficiency of this transformation with other types of o-qui-
nones (Table 1, entries 5 and 6), all of which worked very
well. However, this reaction was found to be limited to o-
quinones, since p-quinones (entries 7 and 8) did not pro-
duce the expected ring contraction products even at higher
catalyst concentrations and one week reaction time.
O
O
O
OH
5
Figure 2 Structures of different fluorenone derivatives
All derivatives were characterized by spectroscopic
1
means, e.g., by 1D and 2D H and 13C NMR techniques
O
(including COSY, HMBC and HMQC). The structures of
compounds 22 and 23 were confirmed by the comparison
of their spectra with those reported in literature, produced
by a different synthetic route.16a
O
O
R1
R1
i
R2
R2
Specifically, the 1H × 13C NMR spectrum was used to con-
firm the disappearance of one carbonyl signal and the cou-
pling of H-4 and C5, for example, in product 18. To our
knowledge, this ring contraction directly from b-lapa-
chone has not been reported previously. However, 18 was
obtained by Chan and co-workers17 as the major blood
metabolite of b-lapachone (1), also known as ARQ501, a
promising anticancer agent that is currently in multiple
phase II clinical trials. In this regard, the present iodine–
hydrogen peroxide reaction reproduces the same ring-
contraction product formed by biotransformation of 1. In
view of the easy transformation of b-lapachone (1) to 18
in the I2–H2O2 system, as well as in the human blood, and
knowing that it interacts with P450 reductase, producing
reactive species, superoxide anion radical,18 we speculate
that there may be a relationship between production of hy-
drogen peroxide by 1 and its biochemical degradation.
(See Table 1 for R1 and R2)
Scheme 1 General scheme of the reaction of o-quinones with I2–
H2O2. Reagents and conditions: (i) 30% aq H2O2, I2, MeCN, r.t.
In this communication we report a new approach to per-
form ring contraction in one-pot procedure from o-naph-
thoquinones in aqueous H2O2 (30%) and catalytic amount
of iodine in acetonitrile (Scheme 1).
Since iodine has proven to be a useful Lewis acid catalyst
for the activation of carbonyl compounds, including
acetalization reactions,15 it seems that the molecular io-
dine would activate one of the carbonyl carbons before
H2O2 addition (Scheme 2).
Then, using these reagents, the fluorenones derivatives
18–24 were obtained in high yield from several o-naph-
thoquinones (Table 1, entries 1–4). The amount of I2
I–
I–
H
+O
I
OH
O
I
O
OH
O
O
O
+
O
O
I2
H
H2O2
+
MeCN
O
O
O
HO
O
O
O
O
– I2
O
H
H2O
+
CO2
+
O
Scheme 2 Proposed mechanism for the ring contraction
Synlett 2008, No. 17, 2625–2628 © Thieme Stuttgart · New York

LETTER
One-Pot Procedure for a Ring Contraction Reaction using Iodine/H2O2
2627
Table 1 Reactants, Time, Products and Yields of the Reactions
Entry Reactant
Time (h) Product
Yield (%)a
O
O
6
O
5
1: R1 = H; R2 = R3 = Me
24
24
24
18: R1 = H; R2 = R3 = Me 87
7
4
1
6: R1 = Br; R2 = R3 = Me
7: R1 = R2 = H; R3 = Ph
19: R1 = Br; R2 = R3 = Me 75
8
R1 20: R1 = R2 = H; R3 = Ph
90
9
2
O
O
R2
R1
R3
R3
O
R2
O
O
2
3
8
24
21
90
O
O
O
O
6
5
O
O
9: R1 = R2 = N
10: R1 = R2 = C
48
48
22: R1 = R2 = N
23: R1 = R2 = C
65
88
7
4
8
R1
3
R1
R2
R2
O
2
O
4
11
12
24
24
25
89
76
O
O
O
O
7
O
1
6
5
6
24
2
5
3
4
OMe
R4
OMe
O
O
13: R1 = R2 = R3 = R4 = Cl
14: R1 = R3 = H;
48
48
26: R1 = R2 = R3 = R4 = Cl 78
R1
R2
R1
R2
O
5
1
27: R1 = R3 = H;
R2 = R4 = t-Bu
75
2
R2 = R4 = t-Bu
4
R4
3
R3
R3
O
O
R1
R2
O
15: R1 = R2 = Me
One week
One week
7
8
28
29
Not formed
Not formed
16: R1 = H; R2 = Ph
O
O
O
O
O
17
One week
O
O
a Yield after column chromatography.
In conclusion, iodine-catalyzed ring contraction of o-qui- Acknowledgment
nones with aqueous H2O2–I2 in acetonitrile is a straight-
Thanks are due to the CNPq (National Council of Research of Bra-
zil), the CAPES, the FINEP, the FAPERJ, the UFF and the UFRJ
for funding this work. S. B. Ferreira thanks the CNPq and the
FAPERJ for her doctoral fellowship.
forward and efficient method for the synthesis of
cyclopentyl units and fluorenone derivatives.19
Synlett 2008, No. 17, 2625–2628 © Thieme Stuttgart · New York

2628
S. B. Ferreira, et al.
LETTER
(16) (a) Zhao, J.; Yue, D.; Campo, M. A.; Larock, R. C. J. Am.
Chem. Soc. 2007, 129, 5288. (b) Wong, K. T.; Chen, R. T.;
Fang, F. C.; Wu, C. C.; Lin, Y. T. Org. Lett. 2005, 7, 1979.
(17) Miao, X. S.; Song, P.; Savage, R. E.; Yang, R. Y.; Kizer, D.;
Wu, H.; Volckova, E.; Ashwell, M. A.; Chan, T. C. K. Drug
Metab. Dispos. 2008, 36, 641.
(18) Molina Portela, M. P.; Fernandez Villamil, S. H.;
Perissinotti, L. J.; Stoppani, A. O. Biochem. Pharmacol.
1996, 52, 1875.
(19) Preparation of 18; Representative Procedure for
Ketones 18–27: To a solution of I2 (0.1 mmol, 25.4 mg) and
30% aq H2O2 (4 mmol, 0.45 mL) in MeCN (10 mL),
b-lapachone (1; 1 mmol, 154 mg) was added and the solution
was stirred at r.t. for 24 h. The reaction mixture was
concentrated under reduced pressure and added to CH2Cl2
(10 mL). The organic phase was separated and washed with
aqueous solution of sat. Na2S2O3 (3 × 10 mL), dried over
anhyd Na2SO4 and evaporated. The crude product was
purified by flash column chromatography on silica gel using
hexane–EtOAc as eluent.
References and Notes
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M. J.; Pinto, M. C. F. R.; Pinto, A. V.; Zalis, M. G.;
Carvalho, L. H.; Krettli, A. Bioorg. Med. Chem. Lett. 2004,
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V. F. Tetrahedron Lett. 2007, 48, 6171. (c) Jorqueira, A.;
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H. P.; Bourguignon, S. C. Parasitol. Res. 2006, 9, 429.
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M. N.; de Souza, M. C. B. V.; Gouvêa, R. M.; Rodrigues,
C. R.; Pinto, A. V.; Castro, H. C.; Santos, D. O.; Araújo,
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I. R. Arkivoc 2007, (ii), 145.
2,2-Dimethyl-3,4-dihydro-2H-indeno[1,2-b]pyran-5-one
(18): yellow solid; mp 54–56 °C. 1H NMR (300 MHz,
CDCl3): d = 1.23 (s, 3 H, Me), 1.46 (s, 3 H, Me), 1.98–2.08
(m, 1 H, H-3a), 2.21–2.29 (m, 2 H, H-3b, H-4a), 2.95–3.04
(m, 1 H, H-4b), 7.82 (m, 2 H, H-9), 8.04 (ddd, J = 0.5, 1.2,
8.3 Hz, 1 H, H-6), 8.22 (ddd, J = 0.5, 1.2, 8.3 Hz, 1 H, H-9).
13C NMR (75 MHz, CDCl3): d = 27.5 (Me), 29.0 (Me), 32.6
(C-3), 36.4 (C-4), 88.2 (C-2), 110.0 (C-4a), 126.5 (C-9),
128.5 (C-9a), 130.1 (C6), 131.4 (C-6a), 134.1 (C-7), 134.9
(C8), 162.4 (C-9b), 187.2 (C=O). Anal. Calcd for C14H14O2:
C, 78.48; H, 6.59. Found: C, 78.28; H, 6.82.
5H-Cyclopenta[2,1-b:3,4-b¢]dipyridin-5-one (22): pale
yellow solid; mp 213–215 ºC. 1H NMR (300 MHz, CDCl3):
d = 7.36 (dd, J = 5.2, 7.3 Hz, 2 H, H-4, H-6), 7.98 (dd, J =
1.9, 7.3 Hz, 2 H, H-3, H-7), 8.78 (dd, J = 1.9, 5.2 Hz, 2 H,
H-2, H-8). 13C NMR (75 MHz, CDCl3): d = 124.6 (C-3,
C-7), 128.9 (C-4, C-6), 131.4 (C-4a, C-5a), 154.7 (C-2, C-8),
163.0 (C-8a, C8b), 188.5 (C=O). Anal. Calcd for C11H6N2O:
C, 72.52; H, 3.32; N, 15.38. 8.78. Found: C, 72.45; H, 3.30;
N, 15.28.
3-Methoxy-1H-inden-1-one (25): pale yellow solid; mp
67–69 °C. 1H NMR (300 MHz, CDCl3): d = 3.98 (s, 3 H,
OMe), 5.58 (s, 1 H, H-2), 7.45 (m, 4 H, H-4, H-5, H-6, H-7).
13C NMR (75 MHz, CDCl3): d = 55.5 (OMe), 97.0 (C-2),
122.3 (C-4), 122.5 (C-5), 123.3 (C-3a), 127.0 (C-6), 130.1
(C-7a), 123.2 (C-7), 160.2 (C-3), 190.5 (C=O). Anal. Calcd
for C10H8O2: C, 74.99; H, 5.03. Found: C, 75.00; H, 5.00.
2,4-Di-tert-butylcyclopentadienone (27): yellow solid; mp
32–35 °C. 1H NMR (300 MHz, CDCl3): d = 1.14 (s, 9 H,
Me), 1.20 (s, 9 H, 3 × Me), 7.70 (s, 1 H, H-5), 6.40 (s, 1 H,
H-3). 13C NMR (75 MHz, CDCl3): d = 27.6 (Me), 28.9 (Me),
32.4 (C-t-B), 33.5 (C-t-Bu), 110.5 (C-5), 135.6 (C-3), 140.0
(C-2), 170.5 (C-4), 190.5 (C=O). Anal. Calcd for C13H20O:
C, 80.44; H, 9.82. Found: C, 80.55; H, 9.90.
(12) (a) Talapatra, S. K.; Bose, S.; Mallik Asok, K.; Talapatra, B.
Tetrahedron 1985, 41, 2765. (b) Sargent, M. V. J. Chem.
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