Unprecedented reactivity pattern of chromium Fischer carbene complexes. Direct application to one-pot synthesis of 4-aryl-3,4-dihydrocoumarins on a multigram scale

Article abstract of DOI:10.1021/ol060702e

Reaction of alkenyl carbene chromium(0) complexes and ketene acetals triggers the formation of 4-aryl-3,4-dihydrocoumarins. The reaction can be carried out as a simple one-pot protocol in air atmosphere. The huge interest of dihydrocoumarins has prompted

Full text of DOI:10.1021/ol060702e

ORGANIC
LETTERS
2006
Vol. 8, No. 13
2703-2706
Unprecedented Reactivity Pattern of
Chromium Fischer Carbene Complexes.
Direct Application to One-Pot Synthesis
of 4-Aryl-3,4-dihydrocoumarins on a
Multigram Scale
Jose´ Barluenga,* Facundo Andina, and Fernando Aznar
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 March 22, 2006
ABSTRACT
Reaction of alkenyl carbene chromium(0) complexes and ketene acetals triggers the formation of 4-aryl-3,4-dihydrocoumarins. The reaction
can be carried out as a simple one-pot protocol in air atmosphere. The huge interest of dihydrocoumarins has prompted us to optimize a
multigram-scale process.
Traditional Chinese and Japanese medicines have used
tannin-containing plant extracts for the treatment of infections
and diseases for centuries.1 Tannins and other natural
products, such as flavonoids, present the skeleton of
4-aryldihydrocoumarins in their structure.2 The important
biological activities that dihydrocoumarin derivatives present
(inhibition of aldose reductase2b and protein kinases,2c
antiherpetic activity,3 and selective inhibition of HIV replica-
tion4) make them attractive candidates for new lead com-
pounds in biological testing. The preparation of dihydro-
coumarins (DHCs) has been accomplished in different ways,5
but the most common approaches are based on hydroaryl-
ation processes.6
On the other hand, the versatility and efficiency of Fischer
carbene complexes (FCCs)7 has been widely demonstrated
(4) Tillekeratne, L. M. V.; Sherette, A.; Grossman, P.; Hupe, L.; Hupe,
D.; Hudson, R. A. Bioorg. Med. Chem. Lett. 2001, 11, 2763.
(5) (a) Donnelly, D. M. X.; Boland, G. In The FlaVonoids. AdVances in
Research since 1986; Hardborne, J. B., Ed.; Chapman&Hall: London, 1993.
(b) Wagner, H.; Seligmann, O.; Chari, M. V.; Wollenweber, E.; Dietz, V.
H.; Donnelly, D. M. X.; Meegan, M. J.; O’Donnell, B. Tetrahedron Lett.
1979, 20, 4269. (c) Iinuma, M.; Matsura, S.; Asai, F. Heterocycles 1983,
20, 1923. (c) Krishnamoorthy, T. V.; Rajagopalan, K.; Balasubramanian,
K. K. Tetrahedron Lett. 1994, 26, 1747. (d) Stephan, E.; Rocher, R.;
Aubouet, J.; Pourcelot, G.; Cresson, P. Tetrahedron: Asymmetry 1994, 5,
41. (e) Asai. F.; Iinuma, M.; Tanka, T.; Mizuno, M. Chem. Pharm. Bull.
1990, 38, 1079. (e) Wilkinson, J. A.; Rossington, S. B.; Leonard, J.; Hussain.
N. Tetrahedron Lett. 2004, 45, 5481.
(6) (a) Aresta, M.; Armor, J. N.; Barteau, M. A.; Bechman, E. J.; Bell
A. T.; Bercaw, J. E.; Creutz, C.; Dinjus, E.; Dixon, D. A.; Domen, K.;
Dubois, D. L.; Eckert, J.; Fujita, E.; Gibson, D. H.; Goddard, W. A.;
Manzaer, L. E.; Marks, T. J.; Morokuma, K.; Nicholas, K. M.; Periana, R.;
Que, L.; Rostrup-Nielson, J.; Sachtler, W. M. H.; Schmidt, L. D.; Sen, A.;
Somorjai, G. A.; Stair, P. C.; Stults, B. R.; Tumas, W. Chem. ReV. 2001,
101, 953. (b) Li, K.; Foresee, L. N.; Tunge, J. A. J. Org. Chem. 2005, 70,
2881. (c) Aoki, S.; Amamoto, C.; Oyamada, J.; Kitamura, T. Tetrahedron
2005, 61, 9291.
(1) (a) Yoshida, T.; Ohbayashi, G.; Ishihara, K.; Ohwashi, W.; Haba,
K.; Okano, Y.; Shingu, T.; Okuda, T. Chem. Pharm. Bull. 1991, 39, 2233.
(b) Okuda, T.; Hatano, T.; Yakazi, K. Chem. Pharm. Bull. 1983, 31, 333.
(c) Saijio, R.; Nonaka, G.-I.; Nishioka, I. Chem. Pharm. Bull. 1989, 37,
2063. For more information about natural coumarins, see: Murray, R. D.
H.; Medez, J.; Brown, S. A. The Natural Coumarins: Occurrence,
Chemistry and Biochemistry; Wiley: New York, 1982.
(2) (a) Iinuma, M.; Tanaka, T.; Asai, F. Phytochemistry 1994, 36, 941.
(b) Iinuma, M.; Tanaka, T.; Mizuno, M.; Katsuzaki, T.; Ogawa, H. Chem.
Pharm. Bull. 1989, 37, 1813. (c) Hsu, F.-L.; Nonaka, G.-I. Nishioka, I.
Chem. Pharm. Bull. 1985, 33, 3142. (d) Nonaka, G.-I. Kawahara O.;
Nishioka, I. Chem. Pharm. Bull. 1982, 30, 4277.
(3) Takechi, M.; Tanaka, Y.; Takehara, M.; Nonaka, G.-I. Nishioka, I.
Phytochemistry 1985, 24, 2245.
10.1021/ol060702e CCC: $33.50
© 2006 American Chemical Society
Published on Web 05/25/2006

during the past 2 decades. Significant examples of their rich
and varied chemistry are their participation in the key step
of the synthesis of several natural products,8 their ability to
form differently sized complex carbo-9 and heterocycles10
from nonelaborated starting materials, and their participation
in multicomponent and cascade reactions.11
complexes is greatly diminished by steric hindrance. There-
fore, to inhibit this reaction pathway we decided to use
substituted ketene acetals. After screening several reaction
conditions, we found that the reaction of FCC 1 with 3 equiv
of the corresponding ketene acetal in THF at 90 °C furnished
the 4-aryl-3,4-dihydrocoumarins 4 in good yields (Table 1).
The reaction of ketene acetals with alkynyl Fischer carbene
complexes is a well-known process and generally leads to
[2 + 2] cycloadducts.12 Moreover, as reported by Wulff,13
aryl- and alkyl-substituted FCCs react with ketene acetals
to furnish butyrolactones.
Table 1. Synthesis of 4-Aryl-3,4-dihydrocoumarins
However, the reaction of ketene acetals with alkenyl FCCs
has not been previously studied. Taking into account the
behavior of alkenyl FCCs as “chemical multitalents”,14 we
decided to investigate this reaction, in the expectation that
it might follow a novel reaction pathway.
entry
R1
Me
Me
Me
Me
(CH2)2I
R2
R3
Arc
Ph
2-Fu
2-Tf
Ph
4 (%)a
a
b
c
d
e
Me
Me
Me
-(CH2)5-
Me
Me
Me
Me
71
68
64b
56
53
First, we tested the reaction of chromium carbene complex
1a with the nonsubstituted ketene acetal 2a (Scheme 1). The
Me
2-Tf
Scheme 1. First Attempt: Reaction of Alkenylcarbene
Complex 1a with a Nonsubstituted Ketene Acetal
a Isolated yield based on the starting carbene complex considering two
carbene units in the final product. b Structure confirmed by X-ray analysis
(see Supporting Information). c 2-Fu ) fur-2-yl, 2-Tf ) thiophen-2-yl.
Moreover, by using an appropriate ketene acetal we were
able to obtain the spirodihydrocoumarin 4d (Table 1, entry
d).
During the course of the investigation we observed that
the presence of humidity in the reaction media triggered the
formation of esters 5 instead of the desired DHCs 4 (Table
2). Several reaction conditions were tested to find a simple
and convenient protocol. The performance of the reaction
in air and with wet THF provided esters 5 as unique reaction
reaction afforded a mixture of lactone 3, the analogue of
that obtained in the reactions with aryl and alkyl lactones,
in 65% yield, and a minor compound, which was identified
by NMR experiments as DHC 4-H, in 20% yield.
In agreement with the mechanistic proposal reported by
Wulff for the reaction of aryl- and alkyl-substituted FCCs,13
the formation of 3 might be initiated by a 1,2-attack of 2a
to the carbene complex. It has been previously observed that
the 1,2-addition of nucleophiles to alkenyl Fischer carbene
Table 2. Synthesis of 4-Aryl-3,4-dihydrocoumarins in Air
(7) Fischer, E. O.; Maasbo¨l, A. Angew. Chem. 1964, 76, 645.
(8) Recent examples: (a) Barluenga, J.; Ferna´ndez-Rodr´ıguez M. A.;
Aguilar, E. Ferna´ndez-Mar´ı, F.; Salinas, A.; Olano, B. Chem. Eur. J. 2001,
7, 3533. (b) Minatti, A.; Do¨tz, K. H. J. Org. Chem. 2005, 70, 3745. (c)
Gupta, A.; Sen, S.; Harmata, M. J. Org. Chem. 2005, 70, 7422.
(9) For some representative examples, see: (a) Barluenga, J.; Die´guez,
A.; Rodr´ıguez, F.; Florez, J.; Fan˜ana´s, F. J. J. Am. Chem. Soc. 2002, 124,
9056. (b) Barluenga, J.; Lo´pez, S.; Trabanco, A. A.; Ferna´ndez-Aceves,
A.; Florez, J. J. Am. Chem. Soc. 2000, 122, 8145. (c) Barluenga, J.; Aznar,
F.; Palomero, M. A. Angew. Chem., Int. Ed. 2000, 39, 4346. (d) Barluenga,
J.; Alonso, J.; Rodr´ıguez, F.; Fan˜ana´s, F. J. Angew. Chem., Int. Ed. 2000,
39, 2460. (e) Barluenga, J.; Aznar, F.; Valde´s, C.; Mart´ın, A.; Garc´ıa-Granda,
S.; Mart´ın, E. J. Am. Chem. Soc. 1993, 115, 4403. (f) Barluenga, J.; Aznar,
F.; Mart´ın, A.; Va´zquez, J. T. J. Am. Chem. Soc. 1995, 117, 9419.
(10) Barluenga, J.; Santamar´ıa, J.; Toma´s, M. Chem. ReV. 2004, 104,
2259.
(11) Barluenga, J.; Ferna´ndez- Rodr´ıguez, M. A.; Aguilar, E. J. Organo-
met. Chem. 2005, 690, 539.
(12) (a) Camps, F.; Miravitlles, C.; Moreto´, J. M.; Molins, E.; Vin˜as, J.
M. Ricart, S. Chem. Commun. 1989, 1560 (b) Camps, F.; Llebrar´ıa, A.
Moreto´, J. M.; Ricart, S.; Vin˜as, J. M. Tetrahedron Lett. 1990, 31, 2479.
(13) Wang, S. L. B.; Su, J.; Wulff, W. D. J. Am. Chem. Soc. 1992, 114,
10665.
4 (%)a
4(%)a
entry
R1
Me
Me
Me
Me
R2
R3
Arb
5 (%)a (via b) (via a)
a
b
c
d
e
Me
Me
Me
-(CH2)5-
Me
Me
Me
Me
Ph
69
63
63
57
54
55
48
50
41
42
70
65
62
41
50
2-Fu
2-Tf
Ph
(CH2)2I Me
2-Tf
a Isolated yield based on the starting carbene complex considering two
(14) (a) De Meijere, A. Pure Appl. Chem. 1996, 68, 61. (b) De Meijere,
A.; Schirmer, H.; Duestsch, M. Angew. Chem., Int. Ed. 2000, 39, 3964. (c)
Wu, Y.-T.; De Meijere, A. Top. Organomet. Chem. 2004, 13, 21.
carbene units in the final product. b 2-Fu ) fur-2-yl, 2-Tf ) thiophen-2-yl.
2704
Org. Lett., Vol. 8, No. 13, 2006

Scheme 2. Mechanistic Proposal
products. Furthermore, subsequent treatment with sub-
Interestingly, when the FCC 1a was stirred at room
temperature in the presence of 3 equiv of ketene acetals 6,
a mixture of alkynes 7M (mayor isomer) and 7m (minor
isomer) were obtained in a 5:1 ratio. The mayor isomer, 7M,
was isolated with moderated yields (Via a). Moreover,
reaction of the alkyne 7M with an additional load of carbene
1a provided lactones 8.
stoichiometric amounts of Bu4NF (30 mol %) furnished the
DHCs 4 (Via b in the scheme of Table 2). In this case yields
are lower than the ones in Table 1 but an alternative one-
pot protocol can be used to increase them (Via a in the
scheme of Table 2).
When this one-pot protocol was applied to ketene acetals
derived from five- and six-membered lactones (6a and 6b),
a unique isomer of phenols 8 were obtained (Table 3).
Several reaction conditions were tested in an attempt to
obtain the corresponding DHCs from the phenols 8, but none
of them was successful.
These observations clearly suggested that alkynes 7 might
be intermediates in the formation of esters 5 and dihydro-
coumarins 4 and allowed us to delineate the mechanistic
proposal represented in Scheme 2.
The first step would be a Michael-type addition of the
ketene acetal 2 to the FCC 1, to give the intermediate I,
which would evolve to form the vinylidenechromium(0)
complex II. This process could be aided by an interaction
between the methoxy and the trimethylsilyl groups and would
finally release the methyl trimethylsilyl ether. A 1,3-H shift
on vinylidene complex II would generate the metal hydride
III. Subsequent reductive elimination would lead to alkyne
IV, which is the intermediate 7 that was isolated when ketene
acetals derivated from lactones were used (Table 3).
Table 3. Reaction with Ketene Acetals Derived from Lactones
It is worth noting that the formation of vinylidene
complexes of group VI metals from alkynes is a well-
established process in organometallic chemistry,15 but the
inverse reaction, to the best of our knowledge, has no
precedent. Although some examples with other metals are
known,16 this is the first time that formation of alkynes from
vinylidenechromium(0) complexes has been observed.
The second and third steps of our mechanistic proposal
are well-established reactions. Alkynes IV react with another
FCC moiety to generate phenols 9 in a classical Do¨tz
entry
n
7M (%)a
8 (%)a (via a)
8 (%)a (via b)
a
b
1
2
53
42
31
27
71
65
(15) For a review, see: Weyershausen, B.; Do¨tz, K. H. Eur. J. Inorg.
Chem. 1999, 1057.
(16) (a) Akita, M.; Sugimoto, S.; Takabuchi, A.; Tanaka, M.; Moro-
oka, Y. Organometallics 1993, 12, 2925. (b) Slugovc, C.; Sapunov, V. N.;
Wiede, P.; Mereiter, K.; Schmid, R.; Kirchner, K. J. Chem. Soc., Dalton
Trans. 1999, 4209.
a Isolated yield based on the starting carbene complex considering two
carbene units in the final product.
Org. Lett., Vol. 8, No. 13, 2006
2705

In summary, Fischer alkenyl carbenes react in a unknown
manner with ketene acetals to generate alkynes (isolated in
some cases). From a synthetic point of view, we have
optimized a simple and efficient protocol to obtain 4-aryl-
3,4-dihydrocoumarins in only one step and from unelaborated
materials. A modification of this protocol could be used to
obtain the same DHCs in a multigram scale and under an
atmosphere of air.
Scheme 3. Synthesis of Dihydrocoumarins on a Multigram
Scale
Acknowledgment. Financial support for this work by
MCT is acknowledged (MCT-04-CTQ-2004-08077-C02-
C01). F.A. thanks the Ministerio de Ciencia y Tecnolog´ıa
for predoctoral fellowship.
reaction. Finally, when the lactonization is possible, it occurs
to give rise to the corresponding dihydrocoumarins.
Given the simplicity of the experimental protocol for the
formation of the dihydrocoumarins, we decided to optimize
the process for a multigram scale. Thus, FCC 1a (20 mmol)
was treated with 2.4 equiv of the commercial ketene acetal
2b in refluxing THF during 5 h. Then Bu4NF was added
and heated for an additional 1 h. After crystallization, 2.58
g (72% yield) of the didhydrocoumarin 4a was obtained.
Supporting Information Available: Experimental pro-
cedures and characterization data of products, including a
file in CIF format. This material is available free of charge
via the Internet at http://pubs.acs.org.
OL060702E
2706
Org. Lett., Vol. 8, No. 13, 2006