Direct access to 1,4-dihydroxyanthraquinones: The Hauser annulation reexamined with p-quinones

Article abstract of DOI:10.1021/jo062271j

(Chemical Equation Presented) 3-Phenylsulfanylphthalides (e.g. 8a) readily react with p-benzoquinones in the presence of LiO^tBu in THF to furnish 1,4-dihydroxyanthraquinones in good yields and one-pot operations.

Full text of DOI:10.1021/jo062271j

Direct Access to 1,4-Dihydroxyanthraquinones:
The Hauser Annulation Reexamined with
p-Quinones
Dipakranjan Mal,* Sutapa Ray, and Indrajeet Sharma
Department of Chemistry, Indian Institute of Technology,
Kharagpur 721 302, India
dmal@chem.iitkgp.ernet.in
ReceiVed NoVember 2, 2006
FIGURE 1. Structures of select anthracyclines.
of the reinvestigation stemmed from our past experiences with
the reactivity of 3-phenylsulfanylphthalides.3
The Hauser annulation4 is a base-promoted condensation
reaction between isobenzofuranones (e.g., 8) and compounds
with polarized multiple bonds to produce quinol-annulated
products. It is general, powerful, and regiospecific and has been
successfully applied to the total synthesis of quinonoid natural
products.4f However, this reaction is reported to fail with 8b
and p-benzoquinones due to facile aromatization (cf. eq 1) of
the initial Michael adducts rendering less reactive phenoxy
anions.5
3-Phenylsulfanylphthalides (e.g. 8a) readily react with p-
benzoquinones in the presence of LiOtBu in THF to furnish
1,4-dihydroxyanthraquinones in good yields and one-pot
operations.
1,4-Dihydroxyanthraquinones are common structural sub-
units of many biologically active quinonoids namely, anthra-
cyclines,1a dynemicins,1b mitoxantrones,1c anthraquinone-
steroid hybrids,1d and naphthacenedione organic dyes.1e
Consequently, they serve as useful synthetic intermediates.1f
They are particularly important for the synthesis of anti-
tumor anthracyclines (e.g. 1 and 2) that have proved to be the
most effective drugs in the treatment of various human
tumors for the past 35 years.1a An analogue development
program has led to the discovery of second generation
anthracyclines, including idarubicin (3) (Zavedos) and epirubicin
(4) (Farmorubicin), presently available to medical oncolo-
gists. Currently, a few more synthetic analogues, e.g., 5-7, with
improved properties are undergoing clinical studies.2
With a broad objective of developing improved and practicable
syntheses of anthracyclines and other quinonoid natural products,
we reexamined the Hauser annulation with p-quinones. The idea
In contrast, the corresponding masked quinones (i.e., quinone
monoketals) undergo facile annulation to give corresponding
anthraquinones and thus serve as the key intermediates in the
synthesis of anthracyclines including idarubicin (3).6 Herein,
we report successful execution of the title reaction (Scheme 1)
for the synthesis of 1,4-dihydroxyanthraquinones.
A few years ago, we demonstrated that 3-phenylsulfa-
nylphthalides (e.g., 8a) could be excellent annulating agents, if
(3) (a) Majumdar, G.; Pal, R. K.; Murty. K. V. S. N.; Mal, D. J. Chem.
Soc., Perkin. Trans. 1 1994, 309. (b) Ghorai, S. K.; Roy, H. N.;
Bandopadhyay, M.; Mal, D. J. Chem. Res. (S) 1999, 30. (c) Hauser, F. M.;
Dorsch, W. A.; Mal, D. Org. Lett. 2002, 4, 2237.
(4) (a) Hauser, F. M.; Rhee, R. P. J. Org. Chem. 1978, 43, 178. (b)
Hauser, F. M.; Mal, D. J. Am. Chem. Soc. 1983, 105, 5688-5690. (c)
Hauser, F. M.; Dorsch, W. A. Org. Lett. 2003, 5, 3753-3754. (d) Patra,
A.; Pahari, P.; Ray, S.; Mal, D. J. Org. Chem. 2005, 70, 9017-9020. (e)
Hassner, A.; Stumer, C. Organic Syntheses Based on Named Reactions;
Elsevier Science: UK, 2002; p 153. (f) Mal, D.; Pahari, P. Chem. ReV.
2007, 107, 1892-1918.
(5) (a) Russell, R. A.; Warrener, R. N. J. Chem. Soc., Chem. Commun.
1981, 108-110. (b) Majumdar, G.; Murty, K. V. S. N.; Mal, D. Tetrahedron
Lett. 1994, 35, 6139-6140.
(6) (a) Swenton, J. S.; Freskos, J. N.; Morrow, G. W.; Sercel, A. D.
Tetrahedron 1984, 40, 4625-4632. (b) Morrow, G. W.; Swenton, J. S.;
Filppi, J. A.; Wolgemuth, R. L. J. Org. Chem. 1987, 49, 714-719. (c)
Bennani, F.; Florent, J.-C.; Koch, M.; Monneret, C. Tetrahedron Lett. 1984,
25, 3975-3978. (d) Keay, B. A.; Rodrigo, R. Tetrahedron 1984, 40, 4597-
4607. (e) Ge, P.; Russell, R. A. Tetrahedron 1997, 53, 17477-17488. (f)
Achmatowicz, O.; Szechner, B. J. Org. Chem. 2003, 68, 2398- 2404. (g)
Ruano, J. L. G.; Paredes, C. G.; Aleman, J. ARKIVOC 2005, 253-265. (h)
Russell, R. A.; Day, A. I.; Pilley, B. A.; Leavy, P. J.; Warrener, R. N. J.
Chem. Soc., Chem. Commun. 1987, 1631-1633.
* Author to whom correspondence should be addressed. Tel: +91 3222
283318. Fax: +91 3222 255303.
(1) (a) (i) Priebe, W. Anthracycline Antibiotics: New Analogues,
Method of DeliVery, and Mechanisms of Action; ACS Symp. Ser.
No. 574; American Chemical Society: Washington, DC, 1995. (ii)
Arcamone, F. M. Biochimie 1998, 80, 201-206. (b) Smith, A. L.;
Nicolaou, K. C. J. Med. Chem. 1996, 39, 2103-2117. (c) Faulds,
D.; Balfour, J. A.; Chrisp, P.; Langtry, H. D. Drugs 1991, 41,
400-449. (d) Riccardis, F. D.; Izzo, I.; Filippo, M. D.;
Sodano, G. Tetrahedron 1997, 53, 10871-10882. (e) Sokolyuk, N. T.;
Romanov, V. V.; Pisulina, L. P. Russ. Chem. ReV. 1993, 62, 1005-1024.
(f) (i) Kotha, S.; Stoodley, R. J. Biorg. Med. Chem. 2002, 10, 621-624.
(ii) Krohn, K.; Priyono, W. Angew. Chem., Int. Ed. Engl. 1986, 25, 339-
340.
(2) Fokt, I.; Grynkiewicz, G.; Skibicki, P.; Przewloka, T.; Priebe, W.
Pol. J. Chem. 2005, 79, 349-359.
10.1021/jo062271j CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/19/2007
J. Org. Chem. 2007, 72, 4981-4984
4981

TABLE 1. Annulation of 3-Substituted Phthalides with
p-Benzoquinone (9a)
SCHEME 1. Proposed Direct Access to 1,4-Dihydroxy-
anthraquinones/6,11- Dihydroxynaphthacenediones
LiOtBu is used as the base.3b This important finding led us to
revisit the Hauser annulation with p-quinones. It was hoped that
the annulation might work out to provide an efficient method
for the preparation of biologically active naturally occurring
anthraquinones by averting protection-deprotection chemistry.
When the yellow anion of 8a,3a generated by treating with
lithium tert-butoxide in THF at -60 °C, was stirred with a
solution of p-benzoquinone (9a), the reaction turned deep violet,
indicating the success of annulation. Indeed, workup of the
mixture followed by silica gel chromatographic purification of
the crude product provided the desired 1,4-dihydroxyan-
thraquinone (10a) in 56% yield. The structure of this product
was confirmed by obtaining a co-NMR spectrum with an
authentic sample. In order to discern the effect of the nucle-
ofuges, well-established Hauser donors 8b and 8c were sepa-
rately reacted with p-benzoquinone (9a) under the conditions
for 8a. The results were very similar to that of entry 1 (Table
1), except that with phthalide sulfone 8b,3a the yield of the
annulated product 10a was much poorer. Having established
that 8a is the best of the annulating agents, we then looked into
the effect of nuclear substituents of 8a on the annulation. As
noted in entries 5 and 6 (Table 1), there is no definite trend in
the yield, although all of the reactions successfully afforded the
respective annulation products 12 and 147 from 11 and 13.8
As the next step, we examined reactivity of 8a to 2-methyl-
p-benzoquinone (9b)9 to find if C-C double bonds in the latter
are discriminated by the annulation. Their reaction under the
conditions described previously furnished the expected annulated
anthraquinone 10b10 in 65% yield (Table 2). The structure of
the product was determined by comparison of the NMR data
with the reported data. The product arising out of annulation
on C2-C3 double bond was neither detected nor isolated. For
further generalization, we extended the study to 2,3-dimethyl-
1,4-benzoquinone (9c)11 as the Hauser acceptor. The desired
product 10c12 was isolated in 69% yield. Similarly, with
2-methoxy-p-benzoquinone (9d)11 and 2-(1-hydroxyethyl)-p-
benzoquinone (9e),13 the products 10d14 (67%) and 10e15 (43%)
were obtained. In both the cases, the annulation took place at
the more electrophilic double bonds, i.e., C5-C6 double bonds.
TABLE 2. Annulation of Phthalide 8a with Substituted
p-Benzoquinones
entry
quinone
R1
R2
product
yield, %
1
2
3
4
9b
9c
9d
9e
CH3
CH3
OCH3
H
CH3
H
10b
10c
10d
10e
65
69
67
43
(7) Satori, G.; Casnati, G.; Bigi, F.; Robles, P. Tetrahedron Lett. 1987,
28, 1533-1536.
(8) Mal, D.; Patra, A.; Roy, H. Tetrahedron Lett. 2004, 45, 7895-7898.
(9) Pratt, D. V.; Ruan, F.; Hopkins, P. S. J. Org. Chem. 1987, 52, 5053-
5055.
(10) Simoneau, B.; Brassard, P. Tetrahedron 1988, 44, 1015-1022.
(11) Ficht, S.; Mulbaier, M.; Giannis, A. Tetrahedron 2001, 57, 4863-
4866.
(12) Kerdesky, F. A. J.; Ardecky, R. J.; Lakshmikantham, M. V.; Cava,
M. P. J. Am. Chem. Soc. 1981, 103, 1992-1996.
(13) Fischer, A.; Henderson, G. N. Synthesis 1985, 641-643.
(14) Allevi, P.; Anastasia, M.; Fiecchi, A.; Sanvito, A. M.; Scala, A.
Synthesis 1991, 6, 438-440.
(15) Ge, P.; Russell, R. A. Tetrahedron 1997, 53, 17469-17476.
(16) Murahashi, S.; Naota, T.; Miyaguchi, N.; Noda, S. J. Am. Chem.
Soc. 1996, 118, 2509-2510.
CH(OH)CH3
H
Finally, the reactivities of various naphthoquinones were
studied for the entry to tetracyclic systems. As the first example,
we chose 5,6,7,8-tetrahydronaphthoquinone (18) and adopted
the reported procedure16 for its preparation from 5,6,7,8-
t
tetrahydro-2-naphthol (15). Treatment of 15 with BuOOH-
RuCl2(PPh3)3 gave peroxide 16 (Scheme 2). Treatment of 16
with TiCl4 furnished 5,6,7,8-tetrahydro-1,4-naphthalenediol
(17),17 contrasting with the original report of formation of 18.
The required quinone 18 could smoothly be prepared by CAN
4982 J. Org. Chem., Vol. 72, No. 13, 2007

TABLE 3. Annulation of Phthalide 8a with p-Napthoquinonesa
SCHEME 2. Preparation of 5, 6,7,8-Tetrahydro-1,4-
naphthoquinone (18)
SCHEME 3. An Alternative Mechanism for the Hauser
Annulation
the results presented in the forgoing sections. A concerted [4
+ 2] cycloaddition of 8d with the acceptors may be considered
the initial step rather than the Michael addition followed by
intramolecular ring closure.23 This proposal was, in part,
corroborated by significant improvement in the yield of 10a
from 8a (i.e., 56% to 65%), when the anticipated anion of the
type 8d was quenched with TMSCl and then reacted with
quinone 9. Our attempts to trap the anion 8d (X ) SPh) as its
O-trimethylsilyl ether returned back the starting isobenzofura-
none 8a. Although 3-silyloxyisobenzofuranones are proposed
intermediates in many cases, such an intermediate has been
characterized in only one instance, by 1H NMR spectroscopy.24
Usually such intermediates have fleeting existence under
ambient conditions.
In conclusion, we have discovered the conditions of the title
reaction, which have been elusive for many years. Disclosure
of the finding may pave the way for a shorter synthesis of
idarubicin (3) and the like, in which cases the regiochemical
issues are unimportant. Further studies on improving the yields
and understanding the mechanism are underway.
a All reactions were carried out in the presence of LiOtBu.
Experimental Section
(ceric ammonium nitrate) oxidation of 17. Annulation of 18 with
8a under previously described conditions gave dihydroxynaph-
thacenedione 1918 in 66% yield (Table 3). Similarly, annulation
of 1,4-naphthoquinone (20) gave naphthacenone 21 in 44%
yield. It was characterized by its conversion to known dimethyl
ether 22.19 Annulation of furanoquinone 2320 also gave 24 in
66% yield. More interestingly, the annulation with naphtho-
quinones 25 and 2721 proceeded smoothly, although they had
free OH groups and the trihydroxy products 2622 and 28 were
duly characterized. Tolerance of free tertiary OH groups in the
quinone monoketals was noted earlier by Swenton et al.6a,b
Although we have not carried out detailed mechanistic studies,
we propose an alternative mechanism in Scheme 3 to explain
General Annulation Procedure. To a stirred solution of
lithium tert-butoxide (9.84 mmol) in THF (40 mL) at -60 °C
(chloroform/liquid N2 bath) under an inert atmosphere was
added a solution of phthalide (3.28 mmol) in THF (5 mL).
The resulting yellowish solution was stirred at -60 °C for
25 min, after which a solution of a Michael acceptor (1.0-1.5 equiv
unless otherwise stated) in THF (5 mL) was added to it. The
cooling bath was removed after about 1 h and further stirred
for 2-6 h. The reaction was then quenched with 10% NH4Cl
(15 mL), the resulting solution was diluted with ethyl acetate (50
mL), and the layers were separated. The aqueous layer was ex-
tracted with ethyl acetate (3 × 25 mL). The combined extracts
were washed with brine, water, dried (Na2SO4), and con-
centrated. The crude product was purified by column chrom-
atography on silica gel or by recrystallization to get a pure-
product.
(17) Malesani, G.; Grazia, M.; Masiero, S. J. Heterocycl. Chem. 1982,
19, 633-637.
(18) Lee, W. W.; Martinez, A. P.; Smith, T. H.; Henry, D. W. J. Org.
Chem. 1976, 41, 2296-2303.
(19) Khanapure, S. P.; Reddy, R. T.; Biehl, E. R. J. Org. Chem. 1987,
52, 5685-5690.
(23) (a) Friedrichsen, W. AdV. Heterocycl. Chem. 1999, 73, 1-99. (b)
Gokhale, S. M.; Joshi, R. R.; Narasimhan, N. S. Indian J. Chem. 1987,
26B, 1030-1034. (c) Wendt, J. A.; Gauvreau, P. J.; Bach, R. D. J. Am.
Chem. Soc. 1994, 116, 9921-9926. (d) Iwao, M.; Inoue, H.; kuraishi, T.
Chem. Lett. 1984, 1263-1266. (e) Ng, W.; Wege, D. Tetrahedron Lett.
1996, 37, 6797-6798.
(20) Brown, R. F. C.; Fallon, G. D.; Gatehouse, B. M.; Jones, C. M.;
Rae, I. D. Aust. J. Chem. 1982, 35, 1667-1678.
(21) Wipf, P.; Hopkins, T. D.; Jung, J.-K.; Rodriguez, S.; Birmingham,
A.; Southwick, E. C.; Lazo, J. S.; Powis, G. Bioorg. Med. Chem. Lett. 2001,
11, 2637-2641.
(22) Allen, J. G.; Hentemann, M. F.; Danishefsky, S. J. J. Am. Chem.
Soc. 2000, 122, 571-575.
(24) Bloomer, J. L.; Lankin, M. E. Tetrahedron Lett. 1992, 33, 2769-
2772.
J. Org. Chem, Vol. 72, No. 13, 2007 4983

6-Chloro-7-methoxy-3-phenylthiophthalide (11). To a stirred
solution of 6-chloro-7-methoxy phthalaldehydic acid25 (200 mg,
0.93 mmol) and p-toluenesulfonic acid (10 mg) in dry benzene (5
mL) was added thiophenol (0.2 mL, 1.03 mmol). The mixture was
heated at reflux for 2 h with a Dean-Stark apparatus. The reaction
mixture was then cooled, and benzene was removed to get a crude
solid. It was recrystallized from a mixture of ethyl acetate and
petroleum ether to give the pure crystalline product (260 mg, 91%).
mp 80-82 °C; IR (KBr) cm-1: 1782, 1752, 1590, 1473, 1049,
113.2, 112.1, 61.6; HRMS m/e calcd. for C15H10O5Cl (MH)+
305.0213, found 305.0195.
2,3-Dihydro-2,2-dimethyl-4,11-dihydroxyanthra[2,3-b]furan-
5,10-dione (24). mp 200-202 °C; IR (KBr) cm-1 : 2923, 1725,
1583, 1469, 1259, 1018, 800; 1H NMR (200 MHz, CDCl3): δ 13.55
(s, 1H), 13.01 (s, 1H), 8.34-8.28 (m, 2H), 7.83-7.75 (m, 2H),
3.14 (s, 2H), 1.62 (s, 6H); 13C NMR (50 MHz, CDCl3): δ 187.4,
184.8, 157.2, 156.2, 145.5, 134.4, 133.9, 133.6, 133.2, 126.8, 126.7,
122.3, 113.9, 107.5, 92.2, 40.0, 28.4; HRMS m/e calcd. for C18H15O5
(MH)+ 311.0919, found 311.0886.
1
943; H NMR (200 MHz, CDCl3): δ 7.78 (d, 1H, J ) 7.9 Hz),
7.49-7.42 (m, 2H), 7.30-7.20 (m, 4H), 6.62 (s, 1H), 4.00 (s, 3H);
13C NMR (50 MHz, CDCl3): δ 165.6, 154.7, 147.0, 136.4, 134.2,
129.4, 129.1, 129.0, 128.6, 118.7, 118.6, 85.2, 62.8; HRMS m/e
calcd. for C15H12O3ClS (MH)+ 307.0192, found 307.0154.
5-Methoxy-6-chloro-1,4-dihydroxyanthraquinone (12). mp
190-191 °C; IR (KBr) cm-1 3448, 2948, 2364, 1621, 1457, 1259,
1025, 777; 1H NMR (200 MHz, CDCl3): δ 13.11(s, 1H), 12.83 (s,
1H), 8.16 (d, 1H, J ) 8.4 Hz), 7.85 (d, 1H, J ) 8.4 Hz), 7.31 (s,
2H), 4.02 (s, 3H); 13C NMR (50 MHz, CDCl3): δ 186.0, 185.6,
157.8, 157.6, 157.0, 138.0, 135.9, 133.8, 130.0, 128.9, 127.1, 124.0,
Acknowledgment. This research was supported by the
Department of Science and Technology, New Delhi. S.R. thanks
CSIR, New Delhi, for a senior research fellowship.
Supporting Information Available: Preparation of starting
quinones, preparation of 17 and 18, and characterization data for
9b-e, 10a-e, 13, 14, 17, 18, 19, 21, 22, 23, 26, 27, 28, 29. This
material is available free of charge via the Internet at http://pubs.acs.
org.
(25) Dey, S.; Mal, D. Tetrahedron 2006, 62, 9589-9602.
JO062271J
4984 J. Org. Chem., Vol. 72, No. 13, 2007