A new protocol for benzoannulation by double Claisen rearrangement and ring-closing metathesis reactions as key steps

Article abstract of DOI:10.1016/j.tetlet.2004.01.149

A new methodology for benzoannulation has been developed by using double Claisen rearrangement followed by a one-pot ring-closing metathesis and DDQ oxidation sequence.

Full text of DOI:10.1016/j.tetlet.2004.01.149

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2585–2588
A new protocol for benzoannulation by double Claisen
rearrangement and ring-closing metathesis reactions as key steps
q
*
Sambasivarao Kotha and Kalyaneswar Mandal
Department of Chemistry, Indian Institute of Technology––Bombay, Powai, Mumbai 400 076, India
Received 15 November 2003; revised 17 January 2004; accepted 30 January 2004
Abstract—A new methodology for benzoannulation has been developed by using double Claisen rearrangement followed by a one-
pot ring-closing metathesis and DDQ oxidation sequence.
Ó 2004 Published by Elsevier Ltd.
Benzoannulated quinones are useful therapeutic com-
pounds for the treatment of a wide variety of disorders.
For example, anthracycline antibiotics such as idaru-
Benzoannulation reactions are used for appending an
aromatic ring to a pre-existing polycyclic structure.
There is interest therefore in designing new approaches,
which are capable of adding an aromatic moiety for the
synthesis of polyaromatic compounds. A variety of
synthetic methodologies have been developed for this
1
bicin 1, doxorubicin and daunorubicin have been widely
used as clinically effective antitumor agents against acute
leukemia, HodgkinÕs disease, lymphomas, breast carci-
2
4
nomas and sarcomas. In addition, various naphtha-
purpose starting from acyclic or cyclic precursors.
3
cenediones are used as antibiotics.
Herein, we report a simple methodology for benzoann-
ulation using a double Claisen rearrangement followed
by a one-pot ring-closing metathesis (RCM) and
dicyanodichloro-1,4-benzoquinone (DDQ) oxidation
reaction sequence (Scheme 1).
O
O
OH
OH
O
OH
In recent times, the RCM reaction using GrubbsÕ cata-
lysts has become a useful tool for synthetic chemists and
has been applied for the preparation of various hetero-
O
5
cyclic, carbocyclic and macrocyclic molecules. In the
present study, GrubbsÕ catalysts 2 or 3 have been used
for the ring-closing metathesis step (Fig. 1).
1
NH2
OH
O
Me
O
OH
OH
OR
double Claisen
rearrangement
one-pot RCM and
DDQ oxidation
OR
O
Scheme 1. Proposed route to benzoannulation sequence.
Keywords: Claisen rearrangement; Metathesis; Benzoannulation, Anthracyclines, Quinones.
q
A portion of this work was presented at the Group Monitoring Workshop on DST-Funded projects in Organic Chemistry, IIT-Kanpur, October
28, 2002, Kotha, S., Synthesis of novel polycyclics via catalytic metathesis reaction.
Corresponding author. Tel.: +91-22-2576-7160; fax: +91-22-2572-3480; e-mail: srk@chem.iitb.ac.in
*
0
040-4039/$ - see front matter Ó 2004 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2004.01.149

2586
S. Kotha, K. Mandal / Tetrahedron Letters 45 (2004) 2585–2588
O
O
OH
OH
Mes-N
Cl
N-Mes
Ph
PCy3
i
Cl
Cl
Ph
H
7
Ru
Ru
H
7
1%
Cl
PCy3
2
PCy3
3
1
0
O
Figure 1. GrubbsÕ catalysts used for RCM reaction.
ii
8
9
26%
The required precursors for the double Claisen rear-
rangement were prepared by O-allylation of the corre-
sponding 1,4-dihydroxybenzene derivatives following
conventional allylation conditions (Scheme 2).
O 11
O
O
iii
Treatment of the bis-allyloxy anthraquinone 7 with
sodium dithionite (1.0 mol equiv) in the presence of
sodium hydroxide (4 mol equiv) in dimethylformamide–
water (1:1) with heating for 1 h delivered the desired
49%
1
2
double rearranged product 10 in good yields (Scheme
6
2 2 4 2
Scheme 3. Reagents and conditions: (i) Na S O , DMF–H O (1:1),
0
3
).
130 °C; (ii) xylene, D; (iii) N,N -dimethylaniline, D.
Thermal Claisen rearrangement of the bis-allyloxy 2,3-
dimethylbenzene 8 and 5,8-bis-allyloxy-2,3-dimethyl-
without isolation by DDQ oxidation, gave moderate
overall yields of the benzoannulated products. Various
other examples studied are included in Table 1.
1
,4-dihydronaphthalene 9 gave the corresponding
7;8
bis-allyl quinones 11 and 12, respectively. Attempts to
improve the yields of the Claisen rearrangement prod-
ucts (11 and 12) were unsuccessful. Prolonged heating
gave an intractable polymeric material (Scheme 3).
O
O
OH
OH
2
Having the diallylated derivatives in hand, we first tried
the RCM reaction with compound 10. However,
GrubbsÕ catalysts (2 and 3) failed to give the required
product 13. The failure could be attributed to the
complexation of the phenolic -OH group with the metal
catalyst (Scheme 4).
10
1
3
Scheme 4.
Next, we protected the free hydroxy groups of 10
(Scheme 5) and these protected derivatives successfully
underwent the RCM reaction, then on aromatization
O
OMe
i
9
8%
O
O
OH
O
O
O
O
O
O
OMe
OEt
i
14
8
1%
4
7
OH
OH
ii
10
O
6
3%
i
O
O
OEt
8
2%
15
5
OH
OH
8 O
OAc
O
O
iii
5%
i
9
9
2%
O
OAc
6
9
OH
16
Scheme 2. Reagents and conditions: (i) allyl bromide, K
D.
2
CO
3
, acetone,
Scheme 5. Reagents and conditions: (i) MeI, acetone, rt; (ii) NaOH,
EtBr, NaI, acetone, reflux; (iii) Ac O, Py.
2

S. Kotha, K. Mandal / Tetrahedron Letters 45 (2004) 2585–2588
2587
Table 1. List of various benzoannulated products prepared by the RCM and DDQ oxidation sequence
a
Entry
Diallyl substrate
Conditions followed
RCM product
Benzoannulated product
Overall yield (%)
O
OMe
O
OMe
1
14
A
49
O
OMe
OEt
O
O
OMe
9
a
1
1
1
7
22
O
OEt
2
3
4
5
15
16
11
12
A
37
51
54
85
O
O
OEt
8
O
O
OEt
23
OAc
OAc
OAc
B
O
O
OAc
9
b
9
24
O
O
O
O
A
9c
2
0
25
O
O
O
A
O
9
d
2
1
26
A. (i) Catalyst 2, dry DCM, rt, 24 h.; (ii) DDQ, benzene, reflux.
B. (i) Catalyst 3, dry DCM, rt, 24 h.; (ii) DDQ, benzene, reflux.
a
Overall yield refers to the yield obtained after the RCM and aromatization sequence.
In summary, a simple protocol involving the double
Claisen rearrangement of bis-allyl aryl ethers followed
References and notes
by a one-pot RCM and DDQ oxidation sequence has
been developed to generate benzoannulated aromatics.
Also, the RCM products 17, 18 or 19 may be useful as
precursors for the synthesis of potent anticancer ana-
logues such as idarubicin 1 using simple transforma-
tions.
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Med.
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2002,
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7. Typical procedure for the RCM reaction and one-pot DDQ
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