Simple synthesis of 2-acetyl-5,8-dimethoxy-3,4-dihydronaphthalene: A key intermediate for the synthesis of 4-demethoxydaunomycinone

Article abstract of DOI:10.1039/a901526d

2-Acetyl-5,8-dimethoxy-3,4-dihydronaphthalene is prepared by using a 1,3-dipolar cycloaddition of nitrile oxide to the corresponding dihydronaphthalene.

Full text of DOI:10.1039/a901526d

View Article Online / Journal Homepage / Table of Contents for this issue
3
80 J. CHEM. RESEARCH (S), 1999
J. Chem. Research (S),
Simple Synthesis of 2-Acetyl-5,8-dimethoxy-3,4-
dihydronaphthalene: A Key Intermediate for the
Synthesis of 4-Demethoxydaunomycinone
1
999, 380^381y
Subhash P. Chavan,* Y. Tripura Subbarao and
Chittiboyina Amar Gopal
Division of Organic Chemistry: Technology, National Chemical Laboratory, Pune 411 008, India
2
-Acetyl-5,8-dimethoxy-3,4-dihydronaphthalene is prepared by using a 1,3-dipolar cycloaddition of nitrile oxide to
the corresponding dihydronaphthalene.
The anthracycline antibiotics Adriamycin
Daunomycin 2a have always been of topical interest
because of their clinically useful anticancer activity. Studies
on their structure-activity relationship have uncovered that
1
and
OMe
OMe
N
OMe
OMe
O
N
O
1
i
+
4
-demethoxy analogues exhibit 8^10 fold increased
2
anticancer activity and less cardiotoxicity. Since 2b cannot
be obtained by fermentation an e¤cient synthetic route
towards 3a/3b is desirable. Many di¡erent synthetic routes
OMe
OMe
1
: 3
4
6
5
ii
3
for the aglycones have been explored and well documented.
OMe
OMe
O
OMe OH
O
O
C
O
OH
O
iii
R2
D
B
A
OH
OMe
R1
OR3
3a
7
OH
1
2
2
R1 = OMe; R2 = OH
a R1 = OMe: R2 = H
b R1 = H; R2 = H
Scheme 1 Reagents: i, PhCNO, EtNO2, Et3N, EDC; ii, H3BO3,
MeOH� H2O; Raney-Ni; iii, MsCl, Et3N; DMAP
Me
=
O
R3
NH2
OH
OMe
B
O
OMe
O
be readily converted into 3b according to a reported
8
procedure.
A
OMe
OMe
3a
3b
OMe
OMe
O
i
We were interested in compounds 3a and 3b which are
key intermediates for the synthesis of 4-demethoxy-
daunomycin 2b. Although various routes for the synthesis
of 3a have been reported,4 this paper describes a novel
approach using a 1,3-dipolar cycloaddition reaction of
nitrile oxides towards the synthesis of the key intermediates
N
7
0%
OMe
OMe
OMe
8
9
ii 85%
OMe
OMe
OMe
3
a and 3b.
OH iii
As mentioned above, a cycloaddition reaction was carried
iii
90%
out on th 5,8-dimethoxy-3,4-dihydronaphthalene 4 (Scheme
) wherein the two regioisomeric isoxazolines 5 and 6 were
1
formed in 3 : 1 ratio. The desired isomer 5 was separated
and reduced to the hydroxy ketone 7 with Raney Nickel
OMe
O
OMe
O
O
6
12
10
11
Ref 8 75%
and was ¢nally converted into the a; b-unsaturated ketone
3
a in good yields.
Since the reaction of compound 4 was not regioselective
OMe
enough to give a single isomer, it was decided to perform
the reaction on a symmetrical system viz. 5,8-dimethoxy-
7
1
,4-dihydronaphthalene 8 which would give rise to a single
OMe
O
isomer and the product 11 too would serve as an intermedi-
ate to yield 4-demethoxydaunomycinone.
3b
The hydroxy ketone 10 however on elimination did not
yield the required product 11, instead tending to aromatize
under the conditions to yield the product 12 which can
The 1,3-dipolar cycloaddition strategy described herein is
the ¢rst report of its kind for the synthesis of an AB ring
synthon. Further conversion of these intermediates 3a
and 3b to the required 4-demethoxydaunomycin has also
been reported. All the steps involved in this approach
are mild, simple and easy to perform.
*
To receive any correspondence (e-mail: spchavan@dalton.ncl.res.in).
y This is a Short Paper as de¢ned in the Instructions for Authors,
Section 5.0 [see J. Chem. Research (S), 1999, Issue 1]; there is
therefore no corresponding material in J. Chem. Research (M).

View Article Online
J. CHEM. RESEARCH (S), 1999 381
Experimental
3-Acetyl-2-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene
0. d (CDCl3) 2.28 (s, 3 H); 2.84 (m, 5 H); 3.73 (s, 3 H); 3.79
1
General Procedure for Isoxazoline Preparation.öPhenyl
isocyanate (1 mmol) and unsaturated compound (0.5 mol) were taken
in 25 ml of dry ethylene dichloride to which was added nitroethane
(
s, 3 H); 4.66 (br, 1 H); 6.69 (s, aromatic, 3 H) (Found: C, 66.89;
‡
H, 7.1; C7H9O4 requires C, 67.18; H, 7.25%). m/z 250 (M †.
(
0.5 mol) and 10 drops of triethyl amine. After stirring the reaction
for 12 h, the product was ¢ltered and concentrated under reduced
pressure. The residue was extracted with chloroform, washed with
brine solution and dried over anhydrous Na2SO4. Evaporation of
the solvent under reduced pressure furnished a residue which was
chromatographed over silica gel to yield the isoxazolines.
Y.T.S. and C.A.G thank the Council for Scienti¢c and
Industrial Research (CSIR) for the award of fellowships.
Funding from CSIR under the Young Scientist Award (YSA)
scheme is also gratefully acknowledged. We are thankful to
Dr. T. Ravindranathan, Head, OCT for constant encourage-
ment and Dr V.H. Deshpande for helpful discussions.
3
-Methyl-6,9-dimethoxy-3a,4,5,9b-tetrahydronaphtho[2,1-d]isoxa-
zoline 5. mp 98^100 8C, d (CDCl3) 1.84 (m, 2 H); 2.05 (s, 3 H);
2
5
.46 (m, 1 H); 2.76 (m, 1 H); 3.34 (m, 1 H); 3.78 (s, 3 H); 3.84 (s, 3 H);
.8 (d, J ˆ 10 Hz, 1 H); 6.72 (d, J ˆ 9 Hz, 1 H); 6.79 (d, J ˆ 9 Hz, 1
Received, 24th February 1999; Accepted, 1st March 1999
Paper E/9/01526D
H) (Found: C, 67.81; H, 6.76; N, 5.6. C14H17NO3 requires C, 67.99;
H, 6.92; N, 5.66%). m/z 247 (M ).
‡
1
-Methyl-6,9-dimethoxy-3a,4,5,9b-tetrahydronaphtho[1,2-d]isoxa-
ꢀ
zoline 6. mp 104^106 C d (CDCl3) 1.43 (m, 1 H); 1.76 (s, 3 H); 2.3^2.5
References
(m, 2 H); 3.0 (m, 1 H); 3.78 (s, 3 H); 3.81 (s, 3 H); 4.86 (d, J ˆ 11 Hz,
1
1
2
3
H. S. El Khadem, (Editor), Anthracycline Antibiotics, Academic
Press, New York, 1982; F. Arcamone, Doxerubicin Anticancer
Antibiotics, Academic Press, New York, 1981.
F. Arcamone, L. Bernardi, P. Giardino, B. Patelli, A. DiMarco,
A. M. Casazza, G. Pratesi and P. Reggiani, Cancer Treat. Rept.,
H); 5.0 (d, J ˆ 11 Hz, 1 H); 6.69 (d, J ˆ 9 Hz, 1 H); 6.74 (d,
J ˆ 9 Hz, 1 H) (Found: C, 67.41; H, 6.86; N, 5.6. C14H17NO3 requires
‡
C, 67.99; H, 6.92; N, 5.66%). m/z 247 (M ).
3
-Methyl-5,8-dimethoxy-3a,4,5,9a-tetrahydronaphtho[2,3-d]isoxa-
zoline 9. mp 166^106 8C,
d (CDCl3) 1.87 (s, 3 H); 2.62 (m,
1
976, 60, 829; S. Niedle, Nature (London), 1977, 268, 195.
2
1
6
H); 3.12 (dd, J ˆ 4:3 15 Hz, 1 H); 3.27 (dd, J ˆ 4, 15 Hz,
G. J. Thomas, in Recent Progress in the Chemical Synthesis of
Antibiotics, Springer-Verlag, Berlin, Heidelberg, 1990, pp.
H); 3.66 (m, 1 H); 3.8 (s, 6 H); 5.06 (ddt, J ˆ 4:3 11 Hz, 1 H);
.70 (s, 2 H). (Found: C, 67.78; H, 6.70; N, 5.5. C14H17NO3
4
68-496; K. Krohn, Tetrahedron, 1990, 46, 291; Prog. Chem.
Org. Nat. Prod., 1989, 55, 37; Angew. Chem., Int. Ed. Engl.,
986, 25, 790; M. J. Broadhurst, C. H. Hassall and G. J.
‡
requires C, 67.99; H, 6.92; N, 5.66%). m/z 247 (M †.
General Procedure for the Conversion of Isoxazolines to Hydroxy
Ketones.öTo a solution of isoxazolines (1.8 mmol) in MeOH� H2O
1
Thomas, Chem. Ind. (London), 1985, 106; T. R. Kelly,
Tetrahedron (Symposia in print 17), 1984, 40, 4537.
ꢁ
5 : 1; 10 ml) was added boric acid (3,7 mmol) and spatula tip of ca.
1
0^20 mg of freshly prepared Raney Nickel. The reaction mixture
4
S. Terashima, K. Tanno and K. Koga, Tetrahedron Lett., 1980,
was repeatedly evacuated and £ushed with hydrogen gas by means
of a balloon ¢lled with hydrogen, then ¢ltered after 4^6 h through
Celite into
dichloromethane. After separation, the aqueous layer was extracted
twice with dichloromethane and the combined layers were washed
with brine, dried over anhydrous sodium sulfate and concentrated
under vacuum to furnish the crude hydroxy ketone ꢁ&90%) which
was chromatographed to yield the pure compound as a white solid.
2
1, 2749; A. V. Rama Rao, V. H. Deshpande, B. Rammohan
Rao and K. Ravichandran, Tetrahedron Lett., 1982, 23, 1115;
A. V. Rama Rao, J. S. Yadav, K. B. Reddy and A. R.
Mehendale, Tetrahedron, 1984, 40, 4643; M. P. Reddy and
G. S. Krishna Rao, Tetrahedron Lett., 1981, 22, 3549; R. A.
Russell, G. J. Collin, P. S. Gee, A. S. Krauss and R. N.
Warrener, Aust. J. Chem., 1984, 37, 1721.
a
separating funnel containing water and
5
T. Mukaiyama and T. Hoshino, J. Am. Chem. Soc., 1960, 82,
2
-Acetyl-1-hydroxy-5,8-dimethoxy-1,2,3,4-tetrahydronaphthalene
. mp 88^90 8C, d (CDCl3) 2.01 (m, 2 H); 2.35 (s, 3 H); 2.55
m, 2 H); 3.05 (dddd, 1 H); 3.78 (s, 3 H); 3.87 (s, 3 H); 4.46 (d,
5
339; G. Bianchi, C. De Micheli and R. Gandol¢, J. Chem.
7
(
Soc., Perkin Trans. 1, 1976, 1518.
6
7
8
D. P. Curran, J. Am. Chem. Soc., 1983, 105, 5826.
O. Diels and K. Alder, Chem. Ber., 1929, 62, 2337.
A. V. Rama Rao, V. H. Deshpande and N. Laxma Reddy,
Tetrahedron Lett., 1982, 23, 4373.
J ˆ 3:4, 1 H); 6.70 (d, J ˆ 11 1 H); 6.75 (d, J ˆ 9 Hz, 1 H)
(
Found: C, 66.63; H, 7.08; C14H18N4 requires C, 67.19; H,
‡
7
.25%). m/z 250 (M ).