Combined Multiple Claisen Rearrangement and Ring-closing Metathesis as a Route to Naphthalene, Anthracene, and Anthracycline Ring Systems

Article abstract of DOI:10.1246/cl.2003.1190

A new route involving double Claisen rearrangement of a suitable 1,4-diallyloxyarene system followed by ring-closing metathesis of the resulting diene has been developed for the synthesis of various benzannulated cyclohexenes. An important demonstration of this methodology is the construction of the tetracyclic quinophenolic ring system of the clinically important anthracyclines.

Full text of DOI:10.1246/cl.2003.1190

1190
Chemistry Letters Vol.32, No.12 (2003)
Combined Multiple Claisen Rearrangement and Ring-closing Metathesis
as a Route to Naphthalene, Anthracene, and Anthracycline Ring Systems
Shital K. Chattopadhyay,ꢀ Benoy K. Pal, and Susama Maity
Department of Chemistry, University of Kalyani, Kalyani 741235, West Bengal, India
(Received September 8, 2003; CL-030832)
1
A new route involving double Claisen rearrangement of a
suitable 1,4-diallyloxyarene system followed by ring-closing
metathesis of the resulting diene has been developed for the syn-
thesis of various benzannulated cyclohexenes. An important
demonstration of this methodology is the construction of the tet-
racyclic quinophenolic ring system of the clinically important
anthracyclines.
and 3 could not be made by H NMR spectroscopy. The lower
melting isomer previously5 characterised as 2, was converted in-
to its dimethyl ether 4 under conventional conditions. The RCM
of the diene 4 with Grubbs’ catalyst6 bis(tricyclohexylphos-
phine)benzylideneruthenium(IV) dichloride (5) in dichloro-
methane at ambient temperature proceeded smoothly to provide
the dihydronaphthalene derivative 6. The latter on oxidation
with DDQ provided the known 1,4-dimethoxynaphthalene in
an overall yield of 47% from 2.
The other isomer 3 on further alkylation with allyl bromide
provided the bisallyl ether 8 (87%) (Scheme 2). The compound 8
underwent smooth double Claisen rearrangement in refluxing
N,N-diethylaniline to provide the hexasubstituted benzene deriv-
ative 9 in moderate yield (63%). For convenience, 9 was con-
verted into its dimethyl ether 10 using conventional conditions.
Recently, the use of multiple RCM reactions of polyenes has
been exploited to deliver spirocyclic, annulated and other bicy-
clic systems from acyclic precursors in a single step.7 However,
few benzannulated constructs have appeared. We were pleased
to see that RCM of the tetraene 10 gave the tetrahydroanthracene
derivative 11 directly in good yield.
The ring-closing metathesis (RCM) reaction of olefins pro-
moted by metal carbenes has evolved in the last few years as an
efficient method for the construction of carbo- and heterocyclic
rings of varying size.1 The synthetic potential of the RCM reac-
tion has been further increased by combining various processes
with it, either in tandem or in sequence.2 We,3 and others4 have
recently demonstrated that combined Claisen rearrangement and
RCM reaction is an efficacious tactic for the synthesis of desired
structures. Herein, we wish to report that a combination of multi-
ple Claisen rearrangement and RCM reaction could be success-
fully exploited for the synthesis of a range of benzannulated cy-
clohexenes of interest.
Claisen rearrangement of hydroquinone diallyl ether (1) was
previously5 carried out in refluxing kerosene. But, isolation of
pure products from this solvent was reported to be problematic.
We have found that the rearrangement of 1, prepared following a
literature,5 proceeds effectively in refluxing N,N-diethylaniline
to give the regioisomeric products 2,3-diallylhydroquinone (2)
and 2,5-diallylhydroquinone (3) (Scheme 1) as a 1:1 mixture.
The products were separated by chromatography over silica
gel using 2% ethyl acetate in petroleum ether as eluent. The iso-
mer 3 eluted first. Distinction between the two regioisomers 2
OR
OMe
O
O
iv
ii
i
3
OR
OMe
9, R = H
10, R= Me
11
8
iii
Scheme 2. Reagents and conditions; (i) Allyl bromide, K2CO3,
acetone, reflux, 20 h, 87%; (ii) PhNEt2, reflux, 10 h, 63%; (iii)
MeI, K2CO3, acetone, reflux, 20 h, 77%; (iv) Grubbs’ catalyst
5 (6 mol %), CH2Cl2 (10 : 0.7 M), rt, 20 h, 69%.
OH
OH
O
i
+
We are further interested in seeing whether the tetracyclic
quinophenolic ring system of the clinically important anthracy-
clines could be prepared through the application of this tandem
double Claisen rearrangement and RCM methodology. With this
aim, 1,4-diallyloxyanthraquinone 12 (Scheme 3) was prepared
by allylation of commercially available 1,4-dihydroxyanthraqui-
none as reported.8 Claisen rearrangement of 12 to 13 was previ-
ously effected using sodium dithionite as the reducing agent9
which possibly in situ reduces the deactivating carbonyl groups
to anthraquinone radical anion. We have found that the rear-
rangement of 12 to 13 also proceeds effectively in the presence
of the organic reducing agent glucose in aqueous DMF thereby
avoiding the need of using unpleasant smelling dithionite.
Although the rearranged product 13 is known, it has not so far
been utilized in anthracycline synthesis. A ring-closing metathe-
OH
OH
O
2
3
1
ii
OMe
OMe
OMe
iii
iv
OMe
OMe
OMe
4
6
7
Scheme 1. Reagents and conditions; (i) PhNEt2, reflux, 5 h,
82%; (ii) MeI, K2CO3, acetone, reflux, 20 h, 87%; (iii) Grubbs’
catalyst 5 (6 mol %), CH2Cl2 (4 : 0.6 M), rt, 20 h, 76%; (iv)
DDQ, xylene, reflux, 12 h, 72%.
Copyright Ó 2003 The Chemical Society of Japan

Chemistry Letters Vol.32, No.12 (2003)
1191
us (BKP) is thankful to CSIR, New Delhi for a research fellow-
ship.
OR
OR
O
O
O
O
OR
O
O
References and Notes
ii
i
1
R. H. Grubbs and S. Chang, Tetrahedron, 54, 4413 (1998);
T. M. Trnka and R. H. Grubbs, Acc. Chem. Res., 34, 18
(2001).
O
O
OR
14, R = H
16, R = Me
2
P. Evans, R. Grigg, M. I. Ramzan, V. Sridharan, and M.
York, Tetrahedron Lett., 40, 3021 (1999); V. B. Birman
and V. H. Rawal, J. Org. Chem., 63, 9146 (1998).
S. K. Chattopadhyay, S. Maity, and S. Panja, Tetrahedron
Lett., 43, 7781 (2002).
T. N. Van, S. Debenedetti, and N. De Kimpe, Tetrahedron
Lett., 44, 4199 (2003); C. J. Davies and C. J. Moody, Synlett,
2002, 1874; K.-S. Huang and E.-C. Wang, Tetrahedron Lett.,
42, 6155 (2001); M. Moreno-Manas, R. Plexats, and A.
Santamaria, Synlett, 2001, 1784.
13, R = H
15, R = Me
iii
12
OMe
O
O
OMe
O
O
3
4
OH
iv
v
16
O
OMe
OMe
17
OMe
18
Scheme 3. Reagents and conditions; (i) Glucose, DMF–H2O,
120 ꢁC, 12 h, 66%; (ii) Grubbs’ catalyst 5 (5–10 mol %), CH2Cl2
(13 or 15 : 0.01 M), rt, 4 h, 63–86%; (iii) MeI, K2CO3, acetone,
reflux, 20 h, 77%; (iv) m-CPBA, CH2Cl2, 0–4 ꢁC, 12 h, 95%; (v)
p-TsOH, methanol, reflux, 4 h, 87%.
5
6
7
L. F. Fieser, W. P. Campbell, and E. M. Fry, J. Am. Chem.
Soc., 61, 2206 (1939).
P. Schwab, R. H. Grubbs, and J. W. Ziller, J. Am. Chem.
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Ma and B. Ni, Org. Lett., 4, 639 (2002); A. S. Edwards, R.
A. J. Wybrow, C. Johnstone, H. Adams, and J. P. A. Harrity,
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R. C. Cambie, Z.-D. Huang, W. I. Noall, P. S. Rutledge, and
P. D. Woodgate, Aust. J. Chem., 34, 819 (1981).
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Woodgate, Aust. J. Chem., 37, 1511 (1984).
sis of the diene 13 was then considered for such an application.
Pleasingly, the diene 13 underwent smooth RCM in the presence
of the catalyst 5 to afford the tetracycle 14 in an acceptable yield
of 63%. The RCM of the dimethyl ether 15, prepared by straight-
forward methylation of the bis-phenol 13, proved to be more ef-
ficient under identical conditions and the tetracyclic compound
16 was obtained (86%) as a yellow crystalline solid, mp
135 ꢁC.10
We reasoned that the olefinic unit in 16 should serve as an
effective handle for the installation of functionalities relevant
to anthracycline synthesis, and we considered a few options
along this direction. The attempted dihydroxylation11 of 16
(OsO4/NMO) proved to be problematic due to its poor solubility
in the usual solvents. However, it could be successfully epoxi-
dised to 17 using m-chloroperbenzoic acid as oxidant. Acid cat-
alysed opening of the meso-epoxide 17 with methanol smoothly
afforded the racemic product 18.
8
9
10 All new compounds reported gave satisfactory spectroscopic
and/or analytical data. Preparation of 16: To a stirred solu-
tion of 15 (175 mg, 0.5 mmol) in dry and degassed dichloro-
methane (50 mL), Grubbs’ catalyst 5 (20 mg) was added un-
der argon atmosphere and the solution was stirred for four
hours at room temperature. The reaction mixture was then
concentrated in vacuo and chromatographed over silica gel
using a mixture of toluene and petroleum ether (2:3) as elu-
ent to give the product 16 (136 mg, 86%) as an yellow crys-
talline solid. mp 135 ꢁC. 1H NMR (300 MHz, CDCl3) ꢀ 8.19
(2H, m), 7.74 (2H, m), 5.93 (2H, s), 3.92 (6H,s), 3.49 (4H, s).
13C NMR (75 MHz, CDCl3) ꢀ 182.9 (s), 154.8 (s), 138.9 (s),
134.1 (s), 133.4 (d), 126.5 (d), 124.3 (s), 123.0 (d), 61.3 (q),
24.8 (t). Elemental analyses: C, 75.06%; H, 5.11%; calcd. for
C20H16O4 C, 74.99%; H, 5.03%. Mass (EI, 70 eV): m=z, 321
(Mþ +1).
Although various routes are available,12 development of
new synthetic routes to the anthracyclines continues to be of cur-
rent interest.13 The simplicity of our methodology may make the
route complementary to those existing in the literature and the
compounds 14 and 16–18 may prove to be valuable intermedi-
ates for the synthesis of drug candidates belonging to the anthra-
cycline family.
In short, we have demonstrated that tandem multiple Claisen
rearrangement and ring-closing metathesis is an effective route
for the preparation of 1,4-dioxygenated naphthalene derivatives,
9,10-dioxygenated anthracene derivatives and the tetracyclic
quinophenolic ring system of the anthracyclines. The methodol-
ogy developed may become useful for accessing other related
products of interest.
11 V. VanRheenen, R. C. Kelly, and D. Y. Cha, Tetrahedron
Lett., 23, 1973 (1976).
12 For reviews, see: K. Krohn, Tetrahedron, 46, 291 (1990); K.
Krohn, Angew. Chem., Int. Ed., 25, 790 (1986); J. W. Lown,
Chem. Soc. Rev., 1993, 165; S. R. Rajski and R. N. Williams,
Chem. Rev., 98, 2723 (1998).
´
13 D. Rodriguez, L. Castedo, D. Dominquez, and C. Saa, Org.
Lett., 5, 3119 (2003).
Financial assistance from the DST, New Delhi (Grant
No. SR/SI/OC-24/02) is gratefully acknowledged and one of
Published on the web (Advance View) November 27, 2003; DOI 10.1246/cl.2003.1190