Synthesis of functionalized 1,4-dihydro-9,10-anthraquinones and anthraquinones by ring closing metathesis using Grubbs' catalyst

Article abstract of DOI:10.1055/s-2004-831299

A general and straightforward synthesis of anthraquinones was developed, in which diallylation of 1,4-naphthoquinones, followed by Ring Closing Metathesis (RCM) of the resulting diallylnaphthoquinones with Grubbs' catalyst and subsequent dehydrogenation using Pd/C afforded the desired anthraquinones with regiocontrol of substituents and in good yields.

Full text of DOI:10.1055/s-2004-831299

LETTER
1913
Synthesis of Functionalized 1,4-Dihydro-9,10-anthraquinones and Anthra-
quinones by Ring Closing Metathesis Using Grubbs’ Catalyst
S
T
ynthesis of Fu
u
nctionalized
y
1,4-Dihydro
e
-9,10-anthr
n
a
quinones and Anth
N
raquinones guyen Van, Matthias D’hooghe, Siegfried Pattyn, Norbert De Kimpe*
Department of Organic Chemistry, Faculty of Agricultural and Applied Biological Sciences, Ghent University, Coupure links 653,
000 Ghent, Belgium
9
Fax +32(9)2646243
Received 13 May 2004
as harsh reaction conditions, low yields or a difficult re-
giocontrol. For this reason, the development of a new and
general method for the synthesis of anthraquinones is of
scientific interest.
Abstract: A general and straightforward synthesis of anthraquino-
nes was developed, in which diallylation of 1,4-naphthoquinones,
followed by Ring Closing Metathesis (RCM) of the resulting dial-
lylnaphthoquinones with Grubbs’ catalyst and subsequent dehydro-
genation using Pd/C afforded the desired anthraquinones with
regiocontrol of substituents and in good yields.
In the past decade, ring closing metathesis (RCM) of (het-
eroatom) functionalized dienes has been presented as a
powerful method for the construction of an ever-broaden-
Key words: 1,4-dihydro-9,10-anthraquinones,
anthraquinones,
Grubbs’ catalyst
10
ing range of carbocycles and heterocycles. Very recent-
ly, a new protocol for benzoannulation involving double
Claisen rearrangment and RCM has been presented to-
wards one anthraquinone, namely 2,3-dimethyl-9,10-an-
thraquinone, one naphthoquinone (2,3-dimethyl-
Anthraquinones are widespread in nature as physiologi-
cally active constituents of plants, microorganisms, in-
1
–3
sects and marine animals.
The attractive biological
11
naphthoquinone) and some 5,12-naphthacenediones. In
activities of these anthraquinones, for example the antitu-
continuation of our interest in the synthesis of naturally
4
4
mor agents ametantrone (1), mitoxantrone (2) and the
12
occurring compounds, this communication discloses a
5
natural adriamycin (3), explain the great interest in the
more general methodology for the ring construction of
quinone systems utilizing RCM towards 1- and/or 3-sub-
stituted dihydroanthraquinones and anthraquinones with
regiocontrol of substituents.
quinone moiety as a target in organic synthesis (Figure 1).
Many synthetic strategies towards the synthesis of an-
thraquinones have already been developed. Formerly, an-
thraquinones have been prepared by Friedel–Crafts
1
,4-Naphthoquinones are either commercially available
6
reactions and related methods. Anthraquinones can also
or easily accessible compounds, which makes them attrac-
tive starting materials in natural product synthesis. 5,7-
Dimethoxy-1,4-naphthoquinone (5a) was prepared from
be synthesized by a Diels–Alder reaction between 1,4-
naphthoquinones and 1,3-dienes, followed by a dehydro-
7
genation step. The major part of the naturally occurring
1
,4-benzoquinone (4) using a well-known Diels–Alder
anthraquinones are accessible via a range of phthalide an-
ion strategies, e.g. the annulation of cyclohexenones with
the anion of 3-phenylsulfonylphthalide afforded tricyclic
species, which were subsequent oxidized with N-bromo-
13
methodology (Scheme 1). The appropriate diene, e.g.
,3-dimethoxy-1-trimethylsilyloxy-1,3-butadiene, was
1
synthesized in 72% yield according to the procedure
of Ainsworth,14 using 1.2 equivalents of LDA and 1.2
equivalents of trimethylsilyl chloride in THF starting
from methyl 3-methoxy-2-butenoate. Since only the
naphthoquinones 5b and 5d are commercially available,
1
,2,8
succinimide to furnish 1-hydroxyanthraquinones.
Also
9
aryne annulation reactions have been described. Howev-
er, the reported methods still have some drawbacks such
OH
NH2
H
N
H
N
O
O
O
HN
HN
OH
OH
OH
OH
O
O
HN
HN
OH
OH
OMe O
OH
O
2
HCl
2
HCl
OH
COCH OH
H
N
H
N
2
O
OH
1
(ametantrone)
2 (mitoxantrone)
3 (adriamycin)
Figure 1
SYNLETT 2004, No. 11, pp 1913–1916
0
6
.0
9
.2
0
0
4
Advanced online publication: 17.08.2004
DOI: 10.1055/s-2004-831299; Art ID: G17404ST
Georg Thieme Verlag Stuttgart · New York
©

1
914
T. Nguyen Van et al.
LETTER
the methylated analogue 5c of naphthoquinone 5b had to naphthoquinone 7 to the corresponding naphthalenediol
be prepared utilizing 4 equivalents of iodomethane and 3 by SnCl , followed by methylation of one hydroxyl group
2
equivalents of Ag O in refluxing CH Cl for 12 hours by a nucleophilic attack onto the in situ liberated chlo-
2
2
2
(
Scheme 2).
romethane. Subsequently, the free hydroxyl group of
compound 8 was alkylated with 1.2 equivalents of crotyl
bromide in acetone under basic conditions (3 equiv of
K CO ) and reflux for 24 hours. The thus obtained (E)-1-
O
MeO
OMe O
OTMS
1.6 equiv
2
3
MeO
(
2¢-butenoxy)-4-methoxynaphthalene (9) was used as a
toluene, –78 °C, 30 min, r.t. 12 h
then ∆, 12 h, SiO2
MeO
substrate for a Claisen rearrangement upon reflux in
DMF, furnishing 1-hydroxynaphthalene 10, which was
easily oxidized with 3.1 equivalents of cerium ammonium
nitrate (CAN) in aqueous acetonitrile (1:1) resulting in
naphthoquinone 11.19 Finally, allylation with 3-butenoic
O
O
4
5a (59%)
Scheme 1
acid in the presence of diammonium persulfate and Ag O
resulted in the desired methyl substituted naphthoquinone
2
2
,3-Diallylnaphthoquinones 6 were prepared in good
yields (62–67%) from naphthoquinones 5 upon reaction
with 3 equivalents of 3-butenoic acid in acetonitrile in the
presence of 4 equivalents of diammonium persulfate and
a catalytic amount of silver nitrate. This reaction involves
formation of allyl radicals from 3-butenoic acid upon ex-
6
e in 65% yield (Scheme 3). This methodology might be
extended towards the regiocontrolled synthesis of for ex-
ample 5-methoxy-4-methyl-9,10-anthraquinone using the
Claisen rearrangement starting from 4,8-dimethoxy-1-
naphthol, since Diels–Alder reaction between 5-hydroxy-
2
+
+
pulsion of carbon dioxide by reduction of Ag to Ag ,
1
,4-naphothoquinone and pent-1,3-diene leads to the for-
2
+
which is continuously reoxidized to Ag by persulfate. A
double radical Michael addition on naphthoquinones 5
then affords the desired allylated compound 6. These dial-
lylated naphthoquinones 6 were subsequently purified by
means of flash chromatography over silica gel
mation of regioisomers 5-hydroxy-4-methyl-9,10-anthra-
quinone and 5-hydroxy-1-methyl-9,10-anthraquinone.20
The key step in the disclosed synthesis of anthraquinones
comprises a RCM of 2,3-diallylnaphthoquinones 6 using
Grubbs’ first generation catalyst. In this way, dihydroan-
thraquinones 12 were synthesized in high yields and high
purity utilizing 7 mol% of benzylidene-bis(tricyclohexyl-
phosphine)dichlororuthenium in toluene upon heating
1
5
(
Scheme 2). Formerly, dialkylation of 1,4-naphtho-
quinones with acetic acid under these conditions has led to
,3-dimethyl-1,4-naphthoquinone radical additions.16
Also allylation of naphthoquinones has been mentioned in
2
(
Scheme 4).21 In a final step, the easily obtained dihy-
1
7
the literature.
droanthraquinones 12 were aromatized by means of palla-
dium on active carbon in toluene under reflux, furnishing
the targeted anthraquinones 13 in excellent yields (88–
96%).22
R1
O
R1
COOH
.65 equiv AgNO3
3
equiv
O
O
0
R2
R2
4 2 2 8
4 equiv (NH ) S O
In conclusion, a general and straightforward synthetic de-
sign towards naturally occurring anthraquinones, based
on RCM of quinone moieties, was developed in good
yields. Diallylation of 1,4-naphthoquinones, followed by
RCM using Grubbs’ first generation catalyst and subse-
quent aromatization afforded the desired anthraquinones
in a very efficient and elegant way with regiocontrol of
substituents on the substituted ring.
O
CH CN/H O (1/1), 75 °C, 2 h
3
2
R1 = OMe, R2 = OMe
R1 = OH, R2 = H
R1 = OMe, R2 = H
R1 = R2 = H
5
5
5
5
a
6a (62%)
6b (65%)
6c (64%)
6d (67%)
b
c
d
4 equiv MeI, 3 equiv Ag2O,
CH2Cl2, ∆, 12 h, 93%
Scheme 2
In order to furnish 1-substituted anthraquinones, a Claisen Acknowledgment
rearrangement approach was applied towards the synthe-
The authors are indebted to the ‘Fund for Scientific Research –
Flanders’ (Belgium) (‘FWO-Vlaanderen’) and to Ghent University
sis of 2-(1-methyl-2-propenyl)-1,4-naphthoquinone (11)
after mono-O-allylation of the appropiate substrate for financial support.
Scheme 3). Very recently, a new protocol for the prepa-
(
ration of 2,3-dimethyl-9,10-anthraquinone, 2,3-dimethyl-
naphthoquinone and some 5,12-naphthacenediones has
been reported based on a double O-allylation of 1,4-dihy-
droxybenzenes, followed by Claisen rearrangement and
RCM. Naphthoquinone 7 was transformed into 1-hy-
droxy-4-methoxynaphthalene (8) in methanol in the pres-
References
(1) Thomson, R. H. Naturally Occurring Quinones, 2nd ed.;
Academic Press: London, 1971.
(2) Thomson, R. H. Naturally Occurring Quinones III: Recent
Advances; Chapman and Hall: New York, 1987.
1
1
(3) Thomson, R. H. Naturally Occurring Quinones IV: Recent
ence of 3.5 equivalents of SnCl and 12 N hydrochloric
2
Advances; Chapman and Hall: London, 1996.
1
8
acid. This transformation involves the reduction of
Synlett 2004, No. 11, 1913–1916 © Thieme Stuttgart · New York

LETTER
Synthesis of Functionalized 1,4-Dihydro-9,10-anthraquinones and Anthraquinones
1915
O
O
OH
O
3
.5 equiv SnCl2
1
.2 equiv Br
HCl (12 N)
MeOH, ∆, 3 h
3 equiv K CO
2
3
Acetone, ∆, 24 h
OMe
OMe
7
8
9 (89%)
DMF
∆, 12 h
O
O
O
COOH
2
4
equiv
OH
0
.65 equiv AgNO3
3.1 equiv CAN
equiv (NH4
)
2S2O8
H2O, CH3CN
r.t., 1 h
O
CH3CN, H2O, 75 °C, 2 h
OMe
6e (65%)
11 (56%)
10
Scheme 3
PCy3
Cl
R1
R3
O
O
R1
R3
O
O
Ru
R1
O
O
R3
Cl
Ph
7
mol%
PCy3
Pd/C, Toluene
R2
R2
toluene, r.t., 12 h,
100 °C, 12 h
∆, 2–12 h
R2
1
2
3
6a
6b
6c
6d
6e
(R = R = OMe, R = H)
(R1 = OH, R2 = R3 = H)
(R1 = OMe, R2 = R3 = H)
(R1 = R2 = R3 = H)
12a (91%)
12b (93%)
12c (94%)
12d (88%)
12e (89%)
13a (91%)
13b (96%)
13c (92%)
13d (94%)
13e (88%)
(R1 = R2 = H, R3 = Me)
Scheme 4
(
4) (a) Krapcho, A. P.; Petry, M. E.; Getahun, Z.; Landi, J. J. Jr.;
Stallman, J.; Polsenberg, J. F.; Gallagher, C. E.; Maresch, M.
J.; Hacker, M. P. J. Med. Chem. 1994, 37, 828.
Org. Chem. 2003, 3693. (g) Grubbs, R. H.; Miller, S. J.; Fu,
G. C. Acc. Chem. Res. 1995, 28, 446. (h) Handbook of
Metathesis, Vol 1-3; Grubbs, R. H., Ed.; Wiley-VCH:
Berlin, Germany, 2003. (i) Kotha, S.; Sreenivasachary, N.
Indian J. Chem., Sect. B 2001, 40, 763.
(b) Moreley, J. O.; Krapcho, A. P.; Cummings, D. S. J.
Chem. Soc., Perkin Trans. 2 1996, 287. (c) Johnson, M. G.;
Kiyokawa, H.; Tani, S.; Koyama, J.; Morris-Natschke, S. L.;
Mauger, A.; Bowers-Drains, M. M.; Lange, B. C.; Lee, K.-
H. Bioorg. Med. Chem. 1997, 5, 1469.
(11) Kotha, S.; Mandal, K. Tetrahedron Lett. 2004, 45, 2585.
(12) Nguyen Van, T.; Debenedetti, S.; De Kimpe, N.
Tetrahedron Lett. 2003, 44, 4199.
(
(
5) Kokwaro, J. O. Medicinal Plants of East Africa; East
African Literature Bureau: Kampala, Nairobi, Dar Es
Salaam, 1976.
6) (a) Parham, W. E.; Bradsher, C. K.; Edgar, K. J. J. Org.
Chem. 1981, 46, 1057. (b) Edgar, K. J.; Bradsher, C. K. J.
Org. Chem. 1982, 47, 1585.
(13) (a) Brisson, C.; Brassard, P. J. Org. Chem. 1981, 46, 1810.
(b) Barker, D.; Brimble, M. A.; Do, P.; Turner, P.
Tetrahedron 2003, 59, 2441. (c) Kesteleyn, B.; Nguyen
Van, T.; De Kimpe, N. Tetrahedron 1999, 55, 2091.
(d) Kesteleyn, B.; De Kimpe, N. J. Org. Chem. 2000, 65,
640.
(
(
7) Rozeboom, M. D.; Tegmo-Larsson, I.-M.; Houk, K. N. J.
Org. Chem. 1981, 46, 2338.
8) (a) Kraus, G. A.; Cho, H.; Crowley, S.; Roth, B.; Sugimoto,
H.; Prugh, S. J. Org. Chem. 1983, 48, 3439. (b) Russell, R.
A.; Pilley, B. A. Synth. Commun. 1986, 16, 425.
(14) Ainsworth, C.; Kuo, Y.-N. J. Organomet. Chem. 1972, 59.
(15) As a representative example, the synthesis of 2,3-diallyl-1,4-
naphthoquinone 6d is described. To a solution of
naphthoquinone 5d (0.22 g, 1.4 mmol) in MeCN (20 mL), 3-
butenoic acid (0.36 g, 4.2 mmol, 3.0 equiv) was added at r.t.,
(c) Okazaki, K.; Nomura, K.; Yoshii, E. Synth. Commun.
followed by the addition of a solution of AgNO (0.16 g,
3
1987, 17, 1021.
0.93 mmol, 0.65 equiv) in distilled H O (10 mL). The
2
(
9) Baburao, M. B.; Subhash, P. K.; Hongming, Z.; Edward, R.
resulting mixture was heated to 75 °C and diammonium
persulfate (1.31 g, 5.76 mmol, 4.00 equiv), dissolved in
B. J. Org. Chem. 1991, 56, 2846.
(
10) (a) Schmalz, H.-G. Angew. Chem., Int. Ed. Engl. 1995, 34,
833. (b) Schuster, M.; Blechert, S. Angew. Chem., Int. Ed.
distilled H O (10 mL), was added slowly, followed by a
stirring period of 2 h at 75 °C. Evaporation of the solvent,
2
1
Engl. 1997, 36, 2036. (c) Fürstner, A.; Langemann, K.
Synthesis 1997, 792. (d) Grubbs, R. H.; Chang, S.
extraction of the residue with EtOAc (3 × 40 mL), drying
(MgSO ), filtration of the drying agent and removal of the
4
Tetrahedron 1998, 54, 4413. (e) Jorgensen, M.; Hadwiger,
P.; Madsen, R.; Stutz, A. E.; Wrodnigg, T. M. Curr. Org.
Chem. 2000, 4, 565. (f) Felpin, F.-X.; Lebreton, J. Eur. J.
solvent in vacuo afforded the crude naphthoquinone, which
was purified by means of column chromatography (hexane–
EtOAc 99:1) yielding 2,3-diallyl-1,4-naphthoquinone (6d)
Synlett 2004, No. 11, 1913–1916 © Thieme Stuttgart · New York

1
916
T. Nguyen Van et al.
LETTER
(
0.22 g, 67%). Spectroscopic data of 2,3-diallyl-5,7-
anthraquinone (12d, 0.06 g, 88%). Spectroscopic data of 1,4-
dimethoxy-1,4-naphthoquinone (6a, 62%). Yellow crystals,
dihydro-5,7-dimethoxy-9,10-anthraquinone (12a, 91%).
Yellow crystals, mp 191 °C. H NMR (270 MHz, CDCl ):
1
mp 111 °C. Flash chromatography R = 0.08 (hexane–
f
3
1
EtOAc 4:1). H NMR (270 MHz, CDCl ): d = 3.35–3.40 (4
d = 3.19 (4 H, s), 3.94 and 3.96 (6 H, 2 × s), 5.84 (2 H, s),
3
6.71 (1 H, d, J = 2.2 Hz), 7.25 (1 H, d, J = 2.2 Hz). 1 C NMR
3
H, m), 3.93 and 3.96 (6 H, 2 × s), 5.03–5.23 (4 H, m), 5.79–
5
.93 (2 H, m), 6.71 (1 H, d, J = 2.3 Hz), 7.26 (1 H, d, J = 2.3
(67.8 MHz, CDCl ): d = 24.15, 24.58, 55.89, 56.37, 102.97,
3
1
3
Hz). C NMR (67.8 MHz, CDCl ): d = 30.60, 31.09, 55.90,
6.42, 102.93, 104.06, 116.62, 116.71, 133.99, 134.28,
36.06, 142.14, 147.04, 161.70, 164.40, 182.67, 184.90. IR
= 1651 cm . MS (70 eV): m/z (%) = 299 (100)
M + 1]. All other new compounds were fully characterized
103.92, 114.43, 122.55, 123.09, 135.96, 138.78, 143.63,
3
5
1
161.71, 164.37, 182.75 and 184.60. IR (KBr): n
= 1652
C=O
–
1
+
cm . MS (70 eV): m/z (%) = 271 (100) [M + 1], 269 (48).
–
1
1
(
[
KBr): n
All other new compounds were fully characterized by H
C=O
+
13
NMR, C NMR, IR and MS.
1
13
by H NMR, C NMR, IR and MS.
16) Ashnagar, A.; Malcolm Bruce, J.; Lloyd-Williams, P. J.
(22) As a representative example, the synthesis of 9,10-
anthraquinone 13d is described. A solution of 1,4-dihydro-
9,10-anthraquinone (12d, 50.70 mg, 0.238 mmol) and
palladium on active carbon (10%) (25.3 mg, 0.024 mmol,
0.10 equiv) in dry toluene (10 mL) was refluxed for 12 h.
(
(
Chem. Soc., Perkin Trans. 1 1988, 559.
17) (a) Araki, S.; Katsumura, N.; Butsugan, Y. J. Organomet.
Chem. 1991, 415, 7. (b) Hagiwara, E.; Hatanaka, Y.; Gohda,
K.-I.; Hiyama, T. Tetrahedron Lett. 1995, 36, 2773.
18) Nguyen Van, T.; Kesteleyn, B.; De Kimpe, N. Tetrahedron
®
The cooled reaction mixture was filtered over Celite and
(
washed with CH Cl (3 × 10 mL). Removal of the solvent in
2
2
2001, 57, 4213.
vacuo afforded the pure 9,10-anthraquinone 13d (46.50 mg,
94%). The anthraquinones 13 were recrystallized from
EtOH. 1,3-Dimethoxy-9,10-anthraquinone (13a, 91%). The
spectral data correspond well with those reported in the
(
(
19) Naruta, Y. J. Am. Chem. Soc. 1980, 102, 3774.
20) Motoyoshiya, J.; Kameda, T.; Asari, M.; Miayamoto, M.;
Narita, S.; Aoyama, H.; Hayashi, S. J. Chem. Soc., Perkin
Trans. 2 1997, 1845.
2
3
23
literature. Yellow crystals, mp 159 °C (Lit. mp 158–
1
(
21) As a representative example, the synthesis of 1,4-dihydro-
160 °C). H NMR (270 MHz, CDCl ): d = 3.99 and 4.02 (6
3
9,10-anthraquinone 12d is described. To a solution of 2,3-
H, 2 × s), 6.80 (1 H, d, J = 2.3 Hz), 7.47 (1 H, d, J = 2.3 Hz),
1
3
diallyl-1,4-naphthoquinone (6d, 0.08 g, 0.330 mmol) in
7.67–7.81 (2 H, m), 8.20–8.29 (2 H, m). C NMR (67.8
CH Cl (35 mL), Grubbs’ catalyst was added [benzylidene-
bis(tricyclohexylphosphine)dichlororuthenium, 0.02 g,
MHz, CDCl ): d = 56.44, 57.02, 103.81, 105.25, 116.60,
2
2
3
126.97, 127.69, 132.85, 133.30, 134.79, 135.63, 138.01,
0
1
.023 mmol, 0.07 equiv] at r.t. After heating under reflux for
2 h, the cooled reaction mixture was filtered over silica gel
163.09, 165.23, 181.76, 183.99. IR (KBr): n
= 1673
C=O
–
1
+
cm . MS (70 eV): m/z (%) = 269 (100) [M + 1].
and washed with CH Cl (3 × 50 mL). Removal of the
(23) Khanapure, S. P.; Reddy, R. T.; Biehl, E. R. J. Org. Chem.
1987, 52, 5685.
2
2
solvent in vacuo afforded pure 1,4-dihydro-9,10-
Synlett 2004, No. 11, 1913–1916 © Thieme Stuttgart · New York