One-pot, two-step synthesis of substituted anthraquinones from chromium(0) alkynyl carbenes and isobenzofurans

Article abstract of DOI:10.1021/ol703037q

The reaction of alkynyl Fischer carbenes and isobenzofurans gives rise to the corresponding [4 + 2] cycloadducts. The newly formed carbene adducts are suitable for benzannulation processes in the presence of tert-butylisocyanide or carbon monoxide to yiel

Full text of DOI:10.1021/ol703037q

ORGANIC
LETTERS
2008
Vol. 10, No. 4
677-679
One-Pot, Two-Step Synthesis of
Substituted Anthraquinones from
Chromium(0) Alkynyl Carbenes and
Isobenzofurans
Jose´ Barluenga,* Silvia Mart´ınez, Angel L. Sua´rez-Sobrino, and Miguel Toma´s
Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”, Unidad
Asociada al CSIC, UniVersidad de OViedo, Julia´n ClaVer´ıa 8, 33071-OViedo, Spain
barluenga@unioVi.es
Received December 18, 2007
ABSTRACT
The reaction of alkynyl Fischer carbenes and isobenzofurans gives rise to the corresponding [4
+
2] cycloadducts. The newly formed carbene
adducts are suitable for benzannulation processes in the presence of tert-butylisocyanide or carbon monoxide to yield a variety of new highly
substituted polycyclic structures having the anthraquinone framework. The whole two-step process is conducted in a one-pot fashion from
easily available 1,4-dihydro-1,4-epoxynaphthalenes.
Alkynyl Fischer carbenes are recognized as highly activated
dienophiles in [4 + 2] cycloaddition reactions because of
the presence of the strongly electron-withdrawing pentac-
arbonyl carbene metal fragment.1 However, their major
advantage over the isolobal unsaturated esters relies on the
further elaboration of the cycloadduct by taking advantage
of the synthetic versatility of the remaining metal carbene
(Figure 1). In particular, the pentannulation2 (via A) and
benzannulation3 (via B) reactions have become very useful
(1) For reviews, see: (a) de Meijere, A.; Schirmer, H.; Duetsch, M.
Angew. Chem., Int. Ed. 2000, 39, 3964-4002. (b) Barluenga, J.; Rodriguez,
F.; Fan˜ana´s, F. J.; Flo´rez, J. Top. Organomet. Chem. 2004, 13, 59-121.
(c) Barluenga, J.; Ferna´ndez-Rodr´ıguez, M.; Aguilar, E. J. Organomet.
Chem. 2005, 690, 539-587. (d) Herndon, J. W. Coord. Chem. ReV. 2007,
251, 1158-1258.
(2) For a review of 1-metalla-1,3,5-hexatrienes, see: (a) Aumann, R.
Eur. J. Org. Chem. 2000, 17-31. (b) Barluenga, J.; Aznar, F.; Barluenga,
S. Chem. Commun. 1995, 1973-1974. (c) Barluenga, J.; Aznar, F.;
Barluenga, S.; Ferna´ndez, M.; Mart´ın, A.; Garc´ıa-Granda, S.; Pin˜era-Nicola´s,
A. Chem. Eur. J. 1998, 4, 2280-2298.
(3) (a) Merlic, C. A.; Burns, E. E.; Xu, D.; Chen, S. Y. J. Am. Chem.
Soc. 1992, 114, 8722-8724. (b) Merlic, C. A.; Xu, D. J. Am. Chem. Soc.
1991, 113, 7418-7420.
Figure 1. [4 + 2] Cycloaddition of alkynyl Fischer carbenes,
followed by pentannulation or benzannulation.
for polycyclic syntheses. Recently, the consecutive [4 + 2]
cycloaddition/pentannulation sequence of arylalkynyl(methox-
10.1021/ol703037q CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/24/2008

y)carbenes with o-quinodimethane species was reported to
provide the benzo[b]fluorene nucleus (via A).4
Table 1. [4 + 2] Cycloaddition of Akynyl Fischer Carbenes 3
and Isobenzofurans 2
We were motivated to accomplish a new protocol that
would allow to access the C6-C6-C6-C6 polycyclic structure
(via B), which represents the basic skeleton of the angucy-
clinone antibiotic family (Figure 1).5 Herein we report that
various types of tri- and tetracyclic structures are efficiently
assembled by the [4 + 2] cycloaddition of isobenzofuran
dienes with aryl- and alkenyl-substituted alkynyl(methoxy)-
carbenes of chromium followed by benzannulation in the
presence of tert-butylisocyanide or carbon monoxide.
We have selected isobenzofurans 2 because (i) they are
readily available as well as highly reactive and easy-to-handle
dienes, and (ii) they would produce cycloadducts with a
synthetically useful ether bridge, e.g., as precursor of the
quinone moiety.6 The isobenzofuran dienes 2a,b were
generated, as already described, by the [4 + 2] cycloaddition/
double [4 + 2] retrocycloaddition process between 1,4-
dihydro-1,4-epoxynaphthalenes 1a,b and 3,6-di(pyridin-2′-
yl) s-tetrazine (Scheme 1).7
entry
X
carbene
M
R
product yield (%)a
1
2
3
4
5
6
7
8
9
H
H
H
H
H
H
OMe
H
H
3a
3b
3c
3d
3e
3f
3d
3g
3h
3i
Cr 1-cyclopentenyl
Cr 1-cyclohexenyl
Cr (E)-CHdCHPH
Cr Ph
Cr p-MeOC6H4
Cr 1-naphthyl
Cr Ph
4a
4b
4c
4d
4e
4f
4g
4h
4i
72
b
c
85
75
64
81
70
60
74
Cr p-ClC6H4
Cr t-Bu
10
H
W
Ph
4j
a Isolated yields after SiO2 chromatography (hexanes/EtOAc 5:1). b Not
isolated; see below and Scheme 3. c Not purified; decomposes in SiO2.
Scheme 1. Synthesis of Isobenzofurans 2
process would give rise in a later step to polycyclic
compounds containing a functionalized anthraquinone skel-
eton (Scheme 2).8 Thus, metal carbene 4a was stirred
Scheme 2. [4 + 2] Cycloaddition/Benzannulation Sequence
from Fischer Carbenes 3, Isobenzofurans 2, and t-BuNC or CO
Thus, the model process involves in situ preparation of
isobenzofuran 2 in THF at room temperature followed by
addition of the metal carbene 3 (1.1 equiv) at the same
temperature. The reaction mixture was stirred at room
temperature for 2-24 h and then chromatographed on silica
gel (hexanes/EtOAc, 5:1) to afford the expected metal
carbene cycloadducts 4 in general with high yield (60-85%)
(Table 1). Therefore, this [4 + 2] cycloaddition provides an
efficient entry into diverse oxabenzonorbornadiene carbenes
having an alkenyl or aryl substituent adequately placed to
accomplish a further cyclization. Moreover, it should be
noted that the alkyl-substituted alkynyl carbene 3h (R )
t-Bu) gives rise to the cycloadduct 4i (60% yield), though it
is not relevant within the context of the present study (see
below). We observed that the pentacarbonyl[phenylethynyl-
(methoxy)carbene] tungsten(0) complex 3i produces the
corresponding cycloadduct 4j in somewhat lower yield (74%)
than the analogous chromium carbene (product 4d, 85%) (see
Supporting Information).
overnight with tert-butylisocyanide (2.1 equiv) in THF at
room temperature to afford the cycloadduct 5a in 90% yield
after purification of the reaction mixture by column chro-
matography. The benzannulation reaction is well established
to proceed through the isocyanide insertion intermediate I,
which evolves by electrocyclic ring closure and aromatiza-
tion.
Significantly, the whole process could be effected in one
pot from the epoxynaphthalene 1, which makes it more
attractive in terms of simplicity and efficiency. Such a
Having the carbene cycloadducts in hand, we considered
the possibility to undertake the benzannulation reaction in
the presence of isocyanide3a or carbon monoxide.3b Such a
(4) Barluenga, J.; Fena´ndez-Rodriguez, M. A.; Aguilar, E. Org. Lett.
2002, 4, 3659-3662.
(5) Rohr, J.; Thiericke, R. Nat. Prod. Rep. 1992, 9, 104-137.
(6) Rodrigo, R. Tetrahedron 1988, 44, 2093-2135.
(7) Warrener, R. N.; Hammer, B. C.; Russell, R. A. J. Chem. Soc., Chem.
Commun. 1981, 942-943.
(8) The anthraquinone unit is part of a large group of naturally occurring
compounds with a number of different biological properties specially
antitumor activity. See: Tietze, L. F.; Gericke, K. M.; Schuberth, I. Eur. J.
Org. Chem. 2007, 4563-4577 and references therein.
678
Org. Lett., Vol. 10, No. 4, 2008

protocol was followed to access cycloadducts 5b-g. Thus,
3,6-di(pyridin-2′-yl) s-tetrazine was added to a solution of
epoxynaphthalenes 1 and stirred at room temperature for 30
min to generate isobenzofurans 2 (see Scheme 1). Then,
carbene complexes 3 were added at room temperature, and
the mixture was stirred for 2-24 h. When the cycloaddition
reaction was complete (according to TLC), tert-butylisocya-
nide was added to the mixture at room temperature, and the
mixture was stirred for 1 min and then heated at 60 °C (for
complexes 3c-e) or stirred at room temperature (for
complexes 3a,b,f) for 12 h. Finally, the solvent was removed,
and the products 5 were purified by flash chromatography
on silica gel (hexanes/EtOAc, 10:1)
Scheme 4. Synthesis of Phenols 8 and Quinones 9 from
Benzannulated Products 5
Therefore, excellent yields were reached for the whole
sequence regardless of whether an alkenyl (compounds 5a-
c) or an aryl (compounds 5d-g) group participates in the
benzannulation step. In the same way, the benzannulation
reaction in the presence of carbon monoxide was undertaken.
Cycloadduct 4d, generated from epoxynaphthalene 1a and
phenylalkynylcarbene 3d, evolved under a carbon monoxide
atmosphere (rt, hυ, 12 h) to furnish dihydrotetraphene 6 (84%
yield), with high and orthogonal oxygen functionalization.
to be rather unstable, rapid purification of 8b allowed for
complete NMR characterization. The structure of the O-silyl
precursor of 8c was confirmed by NOESY experiments
(NOE involving both H’s of the bay-region; t-BuSi-OMe;
t-BuN-OMe) (see Supporting Information). The transforma-
tion of the latter structure to the quinone moiety was
undertaken on compounds 8a,b, which yielded 9a,b by
oxidation with O2/K2CO3 in methanol.11,12 The oxidation step
was effected without purification of alcohols 8, the overall
yield from 5 being 69-71%.
In conclusion, we have demonstrated that alkynyl Fischer
carbenes 3 behave as excellent dienophiles in [4 + 2]
cycloaddition reactions toward isobenzofurans 2. Signifi-
cantly, the resulting carbene cycloadducts are suitable
precursors for the benzannulation reaction, making thus easily
accessible a number of highly susbtituted polycyclic struc-
tures having the anthraquinone framework. In addition the
whole two-step process is conducted in a one-pot fashion
from commercially available 1,4-dihydro-1,4-epoxynaphtha-
lenes. The protocol described herein should find application
in the total synthesis of some members and derivatives of
the angucyclinone family.
It should be noted that the cycloadduct 5b, derived from
the alkynylcarbene 3b (R ) 1-cyclohexenyl) and the isoben-
zofuran 2a, was isolated in only 35% yield after column
chromatography.9 In this particular case, the pentannulation
reaction of the dienylcarbene precursor (see Figure 1, via
A) was the major reaction pathway, affording the cyclopen-
tadienone adduct 7 (see the structure in Scheme 3) as a
Scheme 3. Pentannulation Reaction to Compound 7
yellow solid in 49% yield. In fact, stirring at room temper-
ature a THF solution of 2a and 3b in the absence of
isocyanide led exclusively, after aqueous acid hydrolysis, to
compound 7 (75% yield) via the carbene intermediate 4b
(Scheme 3) (see Supporting Information).
Acknowledgment. This research was partially supported
by the Spanish and Principado de Asturias Governments
(CTQ2004-08077 and IB05-136) and MEC and ESF (Juan
de la Cierva contract to S.M.).
Since compounds 5 potentially contain the skeleton of
anthraquinone, the transformation of the ether bridge to the
quinone function was next attempted (Scheme 4). First, the
ether bridge could be selectively cleaved to afford the
hydroxy derivatives 8a-c by basic treatment of 5a,d (X )
H; t-BuLi, THF/hexane) and 5g (X ) OMe; (i) 2,6-lutidine,
TBSOTf, (ii) TBAF).10 Although alcohols 8a,b were found
Supporting Information Available: Experimental pro-
cedures and charaterization data for all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL703037Q
(10) Magnus, P.; Eisenbeis, S. A.; Fairhurst, R. A.; Iliadis, T.; Magnus,
N. A.; Parry, D. J. Am. Chem. Soc. 1997, 119, 5591-5607.
(11) Yamaguchi, M.; Hasabe, K.; Higshi, H.; Uchida, M.; Irie, A.;
Minami, T. J. Org. Chem. 1990, 55, 1611-1623.
(12) Unfortunately these standard oxidation conditions were not effective
in the case of the dimethoxy derivative 8c.
(9) The benzannulation reaction using tungsten carbenes was found less
efficient. Thus, attempts to improve the yield of compound 5b using the
corresponding tungsten enynylcarbene were unsuccesful.
Org. Lett., Vol. 10, No. 4, 2008
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