A general and regioselective synthesis of cyclopentenone derivatives through nickel(0)-mediated [3 + 2] cyclization of alkenyl fischer carbene complexes and internal alkynes

Article abstract of DOI:10.1021/ja075106+

A broad range of substituted 2-cyclopentenone derivatives 3-6 are synthesized by the nickel-(O)-mediated [3 + 2] cyclization reaction of chromium alkenyl(methoxy)carbene complexes 1 and internal alkynes 2. The reaction takes place with complete regioselec

Full text of DOI:10.1021/ja075106+

Published on Web 10/30/2007
A General and Regioselective Synthesis of Cyclopentenone
Derivatives through Nickel(0)-Mediated [3 + 2] Cyclization of
Alkenyl Fischer Carbene Complexes and Internal Alkynes
Jose´ Barluenga,* Pablo Barrio, Lorena Riesgo, Luis. A. Lo´pez, and Miguel Toma´s
Contribution from the Instituto UniVersitario de Qu´ımica Organometa´lica “Enrique Moles”,
Unidad Asociada al CSIC, UniVersidad de OViedo, Julia´n ClaVer´ıa 8, 33071 OViedo, Spain
Received July 10, 2007; E-mail: barluenga@uniovi.es
Abstract: A broad range of substituted 2-cyclopentenone derivatives 3-6 are synthesized by the nickel-
(0)-mediated [3 + 2] cyclization reaction of chromium alkenyl(methoxy)carbene complexes 1 and internal
alkynes 2. The reaction takes place with complete regioselectivity with both unactivated alkynes and activated
alkynes (electron-withdrawing and electron-donating substituted alkynes). Representative cycloadducts
containing boron and tin substituents are further demonstrated to be active partners in classical Pd-catalyzed
C-C coupling processes to allow the production of 2-aryl- and 2-alkynyl-substituted cyclopentenones 9-13.
Scheme 1. Synthesis of Cyclopentenones from Fischer
Alkenylcarbene Complexes
Introduction
Cyclopentenones are important structural motifs of natural
products and pharmaceuticals.1 They are also of interest as useful
synthons for the construction of more complex molecules.2
Although a number of powerful methodologies for the synthesis
of the 2-cyclopentenone skeleton, including the Nazarov cy-
clization3 and the Pauson-Khand reaction,4 are currently
available, the scope of these processes has been limited due to
the poor reactivity and selectivity of simple reactive counterparts
or to functional group compability. As a result, the development
of new methodologies for the synthesis of cyclopentenones from
readily available substrates continues to be an important pursuit
in synthetic organic chemistry.5
On the other hand, the cyclization between appropriate C3
and C2 units are rather uncommon due to the difficulty of
accessing three-carbon dipolar species. In this respect, sym-
metrical oxyallyl cation species (2-oxa-1,3-dipoles) have become
somewhat useful toward activated alkenes.6 In recent years, we
Scheme 2. Ni(0)-Mediated Reactions of Fischer Alkenylcarbene
Complexes and Alkynes
and others have discovered that group 6 Fischer alkenyl carbene
complexes behave as efficient 1-oxa-1,3-dipole equivalents.7 For
instance (Scheme 1), their reaction with enamines provides
cyclopentenones via the [3 + 2] cyclization and amine elimina-
tion sequence,8 whereas the direct entry into 3,4-disubstituted
2-cyclopentenones has been brought about only in the case of
terminal or electron-poor alkynes by running the cyclization
reaction in the presence of catalytic amounts of Rh(I).9,10
Interestingly, a different type of reactivity was found for
chromium(0) carbene complexes in the presence of nickel(0).
(1) Review: Roberts, S. M.; Santoro, M. G.; Sickle, E. S. J. Chem. Soc., Perkin
Trans. 1 2002, 1735.
(2) For a review, see: Rezgui, F.; Amri, H.; Gaied, M. M. E. Tetrahedron
2003, 59, 1369.
(3) For selected reviews, see: (a) Habermas, K. L.; Denmark, S. E.; Jones, T.
K. Org. React. 1994, 45, 1. (b) Frontier, A. J.; Collison, C. Tetrahedron
2005, 61, 7577. (c) Pellissier, H. Tetrahedron 2005, 61, 6479.
(4) For selected reviews, see: (a) Laschat, S.; Becheanu, A.; Bell, T.; Baro,
A. Synlett, 2005, 2547. (b) Gibson, S. E.; Stevenazzi, A. Angew. Chem.,
Int. Ed. 2003, 42, 1800. (c) Sugihara, T.; Yamaguchi, M.; Nishizawa, M.
Chem.-Eur. J. 2001, 7, 1589. (d) Brummond, K. M.; Kent, J. L. Tetrahedron
2000, 56, 3263. (e) Chung, Y. K. Coord. Chem. ReV. 1999, 188, 297. (f)
Oliver, G.; Schmalz, H. Angew. Chem., Int. Ed. 1998, 37, 911. (g) Schore,
N. E. Org. React. 1991, 40, 1.
(5) For a review on transition metal-mediated routes to cyclopentenones, see:
(a) Gibson, S. E.; Lewis, S. E.; Mainolfi, M. J. Organomet. Chem. 2004,
689, 3873. For recent approaches to the cyclopentenone skeleton, see: (b)
Davie, C. P.; Danheiser, R. L. Angew. Chem., Int. Ed. 2005, 44, 5867. (c)
Shi, X.; Gorin, D. J.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 5802. (d)
Herndon, J. W.; Zu, J. Org. Lett. 1999, 1, 15. (e) Zhang, L.; Wang, S. J.
Am. Chem. Soc. 2006, 128, 1442. (f) Moser, W. H.; Feltes, L. A.; Sun, L.;
Giese, M. W.; Farrell, R. W. J. Org. Chem. 2006, 71, 6542. (g) Kurahashi,
T.; Wu, Y.-T.; Meindl, K.; Ru¨hl, S.; de Meijere, A. Synlett 2005, 805.
(6) For instance, see: Masuya, K.; Domon, K.; Tanino, K.; Kuwajima, I. J.
Am. Chem. Soc. 1998, 120, 1724.
(7) For isolated examples of [3 + 2] cyclopentannulations based on 1-oxa-
1,3-dipole equivalents, see: (a) Huart, C.; Ghosez, L. Angew. Chem., Int.
Ed. Engl. 1997, 36, 634. (b) Takeda, K.; Fujisawa, M.; Makino, T.; Yoshii,
E.; Yamaguchi, K. J. Am. Chem. Soc. 1993, 115, 9351.
(8) (a) Barluenga, J.; Toma´s, M.; Ballesteros, A.; Santamar´ıa, J.; Brillet, C.;
Garc´ıa-Granda, S.; Pin˜era-Nicola´s, A.; Va´zquez, J. T. J. Am. Chem. Soc.
1999, 121, 4516. For other [3 + 2] cycloadditions involving a three-carbon-
atom synthon alkenylcarbene ligand, see, for example: (b) Hoffmann, M.;
Buchert, M.; Reissig, H.-U. Angew. Chem., Int. Ed. Engl. 1997, 36, 283.
(c) Flyn, B. L.; Funke, F. J.; Silveira, C. C.; de Meijere, A. Synlett 1995,
1007. (d) Wulff, W. D.; Bax, B. M.; Brandvold, T. A.; Chan, K. S.; Gilbert,
A. M.; Hsung, R. P.; Mitchell, J.; Clardy, J. Organometallics 1994, 13,
102.
(9) Barluenga, J.; Vicente, R.; Lo´pez, L. A.; Rubio, E.; Toma´s, M.; AÄ lvarez-
Ru´a, C. J. Am. Chem. Soc. 2004, 126, 470.
(10) The reaction of group 6 alkenyl Fischer carbene complexes with alkynes
leads to substituted phenols (benzannulation or Do¨tz reaction): Do¨tz, K.
H. Angew. Chem., Int. Ed. Engl. 1984, 23, 587.
9
14422
J. AM. CHEM. SOC. 2007, 129, 14422-14426
10.1021/ja075106+ CCC: $37.00 © 2007 American Chemical Society

Synthesis of Polysubstituted Cyclopentenones
A R T I C L E S
Table 1. [3+2] Cyclization Reaction of Chromium Alkenylcarbene
Complexes 1 with Nonactivated Internal Alkynes 2a-c
entry
carbene/alkyne
R1
R2
R3
3 (%)a
1
2
3
4
5
6
7
8
9
1a/2a
1a/2b
1b/2b
1c/2b
1d/2b
1e/2b
1f/2b
1b/2c
1d/2c
Ph
Ph
Et
Ph
Ph
Ph
Ph
Ph
Ph
t-Bu
t-Bu
Et
3aa (56)
3ab (58)
3bb (68)
3cb (71)
3db (65)
3eb (56)
3fb (52)
3bc (55)
3dc (65)
Me
Me
Me
Me
Me
Me
Me
Me
p-MeOC6H4
p-ClC6H4
2-Furyl
Me
t-Bu
p-MeOC6H4
2-furyl
Figure 1. Fischer carbene complexes 1 and alkynes 2 used in this work.
In particular, the reaction of alkenylcarbene complexes of Cr-
(0) with terminal alkynes gave neither benzannulation nor [3
+ 2] cyclization products, but a novel [3 + 2 + 2] carbocy-
clization was accomplished (Scheme 2).11 In this article, we
report on the Ni(cod)2-mediated reaction of chromium alkenyl-
carbene complexes with a variety of internal alkynes that
allowed establishing a general and selective access to an array
of substituted cyclopentenones which complements existing
methodologies.
a Yields of isolated products after column chromatography.
Table 2. [3 + 2] Cyclization Reaction of Chromium
Alkenylcarbene Complexes 1 with Electron-Rich Alkynes 2d,e
The carbene complexes 1a-g and internal alkynes 2a-j
outlined in Figure 1 were employed to undertake the present
study.
entry
carbene/alkyne
R1
R2
3 (%)a
1
2
3
4
5
6
7
1a/2d
1d/2d
1f/2d
1a/2e
1b/2e
1d/2e
1f/2e
Ph
CH2Ph
CH2Ph
CH2Ph
TMS
TMS
TMS
3ad (48)
3dd (43)
3fd (41)
3ae (49)
3be (47)
3de (45)
3fe (40)
Results and Discussion
2-furyl
t-Bu
Nickel(0)-Mediated Reactions of Chromium Alkenylcar-
bene Complexes 1 and Unactivated Alkynes 2a-c. On the
outset, we treated alkenylcarbene complex 1a (R1 ) Ph) with
3-hexyne 2a (3 equiv) at -10 °C in acetonitrile in the presence
of a stoichiometric amount of Ni(cod)2, and the reaction mixture
was allowed to warm to 20 °C over 2 h. The solvent and excess
of alkyne were removed in vacuo, and the resulting residue was
subjected to column chromatography. Thus, the initially formed
enolether underwent hydrolysis to furnish pure cyclopentenone
3aa in 56% overall yield (Table 1, entry 1). Neither the [3 + 2
+ 2] cyclization product11 nor the phenol derivative resulting
from the Do¨tz reaction10 were observed in the crude reaction
mixture.
Next, the issue of the regiochemistry of this new [3 + 2]
cyclization reaction was addressed by reacting 1-phenylpropyne
2b with a series of alkyl-, aryl-, and heteroaryl-substituted
carbene complexes 1. In all the cases examined, the reaction
exhibited complete regioselectivity yielding the 3-phenylsub-
stituted cyclopentenones 3ab-fb (R2 ) Ph) in 52-71% yield
(Table 1, entries 2-7). The reaction takes place also with total
regioselectivity in the case of the tert-butylmethylacetylene 2c
yielding the cyclopentenones 3bc and 3dc in acceptable yield
(Table 1, entries 8 and 9).
Ph
p-MeOC6H4
2-furyl
t-Bu
TMS
a Yields of isolated products after column chromatography.
about the suitability of alkynes having electron-withdrawing and
-donating substituents to undergo this [3 + 2] cyclization was
then investigated. In such an event it would allow access to
functionalized cyclopentenones and thus would importantly
expand the scope of the reaction.
First, we studied the reaction of representative carbene
complexes with electron-rich alkynes, such as benzyl- and
trimethylsilyl-substituted ynol ethers 2d,e, under the above
reaction conditions. Although the chemical yields of this
cyclization reaction were rather moderate (40-49%), the
resulting cycloadducts 3ad-fe were formed as a sole regioi-
somer (Table 2). The regiochemistry of the cycloadducts was
readily inferred by 2D NOESY experiments which clearly reveal
a vicinal arrangement between the R1 and OEt appendages.
Structurally, the cyclopentenones prepared feature a synthetically
useful functionalization since the ethoxy (entries 1-7) and TMS
(entries 4-7) substituents are potentially exchangeable with
nucleophiles and electrophiles, respectively.
Next, the reaction of chromium alkenylcarbene complexes 1
toward electron-deficient alkynes 2f,g was explored, and the
results are collected in Table 3. Thus, stirring a mixture of
carbene 1, the acetylene diester 2f, and Ni(cod)2 in acetonitrile
followed by solvent removal and column chromatography
purification resulted in the formation of the cyclopentadiene
tautomers 4 (entries 1-2) or 5 (entries 3-4), depending on the
The regiochemistry of compounds 3ab-3dc was ascertained
by NMR experiments (including HSQC, HMBC, COSY, and
NOESY). Moreover, an X-ray analysis was performed on
compound 3db (see Supporting Information).
Nickel(0)-Mediated Reactions of Chromium Alkenylcar-
bene Complexes 1 and Activated Alkynes 2d-g. The study
(11) Barluenga, J.; Barrio, P.; Lo´pez, L. A.; Toma´s, M.; Garc´ıa-Granda, S.;
AÄ lvarez-Ru´a, C. Angew. Chem., Int. Ed. 2003, 42, 3008.
9
J. AM. CHEM. SOC. VOL. 129, NO. 46, 2007 14423

A R T I C L E S
Barluenga et al.
Table 3. [3 + 2] Cyclization Reaction of Chromium
Alkenylcarbene Complexes 1 with Electron-Poor Internal Alkynes
2f,g
Table 4. [3 + 2] Cyclization Reaction of Chromium
Alkenylcarbene Complexes 1 with Boron- and Tin-Alkynes 2h-j
R1
R2
X
3 (%)a
entry
carbene/alkyne
R1
R2
R3
4/5 (%)a
entry
carbene/alkyne
1
2
3
4
5
1a/2f
1d/2f
1e/2f
1g/2f
1d/2g
Ph
2-furyl
Me
CO2Me CO2Me 4af (53)
CO2Me CO2Me 4df (62)
CO2Me CO2Me 5ef (51)
1
2
3
4
5
6
7
8
1b/2h
1c/2h
1d/2h
1b/2i
1d/2i
1a/2j
1c/2j
1d/2j
p-MeOC6H4
p-ClC6H4
2-furyl
p-MeOC6H4
2-furyl
Ph
p-ClC6H4
2-furyl
t-Bu
t-Bu
t-Bu
Me
Me
Ph
PinB
PinB
PinB
Bu3Sn
Bu3Sn
Bu3Sn
Bu3Sn
Bu3Sn
3bh (47)
3ch (40)
3dh (43)
3bi (44)b
3di (45)b
3aj (75)
3cj (51)
3dj (70)
(E)-CHdCHPh CO2Me CO2Me 5gf (66)
2-furyl Me CO2Me 5dg (58)
a Yields of isolated products after column chromatography.
Ph
Ph
Scheme 3. Acid Hydrolysis of Cyclopentadiene Derivative 5dg
a Yields of isolated products after column chromatography. b A separable
10:1 mixture of regioisomers was obtained.
Scheme 4. Proposed Mechanism for the Formation of
Cyclopentenones 3 and Cyclopentadienes 4 and 5
substitution pattern. In the same way, the cyclization of carbene
1d with methyl 2-butynoate 2g provided the cyclopentadiene
5dg as the sole isomer (entry 5). The regiochemistry of 5dg
was readily inferred by 2D NOESY experiments. A positive
NOE interaction between the C3-H of the furyl substituent (R1)
and the CH3O of the methoxycarbonyl group (R3) allowed us
to confirm the vicinal arrangement of these groups.
Furthermore, compound 5dg was quantitatively transformed
into the functionalized trans-cyclopentenone 6 upon treatment
with aqueous hydrochloric acid (Scheme 3). The structure of 6
has been determined by an X-ray crystal analysis after crystal-
lization from CH2Cl2/Et2O (see Supporting Information).
Nickel(0)-Mediated Reactions of Chromium Alkenylcar-
bene Complexes 1 with Boron- and Tin-Substituted Alkynes
2h-j. Having in mind the potential of the carbon-boron and
carbon-tin linkages for carbon-carbon coupling, the prepara-
tion of boron- and tin-substituted cyclopentenones was then
envisaged by using boron- and tin-substituted alkynes (Table
4).12,13 Gratifyingly, we found that 2-(3,3-dimethylbutynyl)-
4,4,5,5-tetramethyl-1,3,2-dioxaborolane 2h (PinB ) pinacol
boronate) and tributyltin alkynes 2i,j smoothly react with
complexes 1 under the above reaction conditions to provide
cyclopentenones 3bh-dj in 40-75% yield after column chro-
matography purification. The cyclization proved to be totally
regioselective, affording 2-heteroatom substituted 2-cyclopen-
tenones, except for cycloadducts resulting from methyltribu-
tyltinacetylene 2i wherein a separable 10:1 mixture of 2- and
3-tributyltin-substituted cyclopentenones was obtained (entries
4 and 5). The regiochemistry of the cycloadducts was readily
inferred by 2D NOESY experiments which clearly reveal a
vicinal arrangement between the R1 and R2 groups. This
assignment is chemically supported since the tributyltin-phenyl
exchange in compound 3bi affords the opposite regioisomer of
3bb which is reported in Table 1 (vide infra; Scheme 5,
compound 10).
Proposed Mechanism. A possible pathway for the formation
of cyclopentenones 3 and cyclopentadienes 4 and 5 is depicted
in Scheme 4. This is based on the previously reported Ni(0)-
mediated [3 + 2 + 2] cyclization of chromium carbenes 1 with
terminal alkynes which was proposed to involve Cr-Ni
exchange followed by two consecutive nickel carbene-alkyne
insertion reactions and cyclization.11 Thus, the regioselective
insertion of a disubstituted alkyne unit into the nickel carbene
complex I would generate the new carbene species II which
do not undergo a second alkyne insertion; however, ring-closing
leading to cyclopentadienes IV, probably through the nickela-
cyclohexadiene species III, seems to be the preferred path-
way.14,15 Since the origin of the regioselectivity lies on the
alkyne insertion step, the corresponding species IIa-d arising
from the different types of alkynes are independently displayed
(Scheme 4, bottom). In all cases (IIa,16 IIb,17 IIc,18 IId12,13),
the sense of selectivity follows the trend found in the insertion
of these types of alkynes into Fischer carbene complexes of
chromium.
(12) For the benzannulation reaction of chromium Fischer carbene complexes
with alkynylboronates, see: (a) Davies, M. W.; Johnson, C. N.; Harrity, J.
P. Chem. Commun. 1999, 2107. (b) Davies, M. W.; Johnson, C. N.; Harrity,
J. P. A. J. Org. Chem. 2001, 66, 3525.
(13) For the benzannulation reaction of chromium Fischer carbene complexes
with stannylacetylenes, see: Chamberlin, S.; Waters, M. L.; Wulff, W. D.
J. Am. Chem. Soc. 1994, 116, 3113.
(14) None of the intermediates I-IV could be detected under the standard
reaction conditions. On the other hand, no reaction was observed under
milder conditions.
9
14424 J. AM. CHEM. SOC. VOL. 129, NO. 46, 2007

Synthesis of Polysubstituted Cyclopentenones
A R T I C L E S
Scheme 5. Some Useful Synthetic Transformations of
Cyclopentenones 3 (see the Text and the Supporting Information
for the Reaction Conditions)
conditions [Pd(PPh3)4 (10 mol %), Na2CO3, DME:H2O (3:1),
85 °C] produced the 2-phenylcyclopentenone 9 in 90% yield
(eq 2). Cyclopentenone stannanes also were found to work well
toward iodoarenes (Stille coupling) (eq 3). Thus, unsymmetri-
cally substituted 2,4-diaryl- and 2,3,4-triaryl-2-cyclopentenones
10-11 are easily accessible as a single regioisomer by coupling
of the [3 + 2] stannane adducts 3bi and 3cj with the
corresponding iodoarene [80-85% yield; Pd(PPh3)4 (10 mol
%), CuI (1 equiv), DMF, 60 °C]. In addition, the cyclopentenone
stannanes are useful precursors of the 2-halo-2-cyclopentenone
framework whose importance comes not only from its potential
in coupling reactions but also because of the antitumor activity
associated with this structural motif.1 Thus, the tributyltin-
iodine exchange was accomplished by treatment of cylopen-
tenone 3aj with I2 in THF affording 2-iodo-2-cyclopentenone
12 in 85% yield (eq 4). Finally, the Sonogashira coupling of
12 toward trimethylsilylacetylene efficiently produced the
2-alkynyl-2-cyclopentenone 13 [82% yield; Pd(PPh3)4 (10 mol
%), CuI (10 mol %) THF/Et3N (10:1), rt].
The Contribution of the Present Cyclization within the
Cyclopentenone Synthesis Area. Last, it may be appropriate
to set up the present reaction within the scenario of the
cyclopentenone synthesis through carbocyclization reactions. In
this respect, there are two particularly useful strategies which
are based on [3 + 2] and [2 + 2 + 1] cyclization reactions.
While the former has not been developed to a great extent
primarily because of the difficulty of accessing all-carbon 1,3-
dipoles (for instance, trimethylenemethane species and oxyallyl
cations), the Pauson-Khand reaction is recognized as the most
powerful access to the 2-cyclopentenone ring, particularly for
synthesis of fused cyclopentenones via intramolecular cycliza-
tion. We would like to emphasize at this point the synthetic
complementarity of the Pauson-Khand reaction and the pro-
cedure described in this work for the synthesis of 2-cyclopen-
tenones (Figure 2). The former consists of a multicomponent
cyclization (alkene + alkyne + CO) wherein the regiochemical
course is well defined, the larger substituents of alkyne and
alkene being placed at the C-2 and C-5 positions of the
cyclopentenone ring.4,19 Moreover, using activated alkynes
results in the formation of cyclopentenones with the activating
group (electron-donating) at C-2. The successful participation
of stannylalkynes and alkynylboronic esters in the Pauson-
Khand reaction has not been reported.20 In the present work a
completely different approach is established that is based on
Useful Synthetic Transformations of Cyclopentenones 3.
Finally, a few transformations of those 2-heteroatom-substituted
cyclopentenones (vide supra) are shown which may have
application for designing new synthetic routes to cyclopentenone
derivatives (Scheme 5, eq 1-4). First, the protonolysis of the
C-Si and C-Sn bonds was readily accomplished starting from
3fe (1.1 equiv of TBAF, THF, rt) and 3dj (12 N HCl, MeOH,
rt), respectively, to provide 3,4-disubstituted cyclopentenones
7-8 (85-95% yield) which are not directly accessible from
the corresponding alkenylcarbene complexes and terminal
alkynes (eq 1). The hindered boron-substituted cyclopentenone
3ch was selected for the Suzuki coupling reaction. Thus,
treatment of 3ch with iodobenzene under the standard reaction
(15) In relation to the different ability of terminal versus internal alkynes to
participate in a multiple insertion sequence, there is a precedent in the
chemistry of simple chromium carbenes. (a) Wulff, W. D.; Kaesler, R.
W.; Petersen, G. A.; Tang, P.-C. J. Am. Chem. Soc. 1985, 107, 1060 (double
insertion of terminal alkynes). (b) Challener, C. A.; Wulff, W. D.; Anderson,
B. A.; Cheamberlin, S.; Faron, K. L.; Kim, O. K.; Murray, C. K.; Xu,
Y.-C.; Yang, D. C.; Darling, S. D. J. Am. Chem. Soc. 1993, 115, 1359
(single insertion of internal alkynes). We also found a different behavior
in the Ni(0)-mediated reactions of simple chromium aryl and alkyl carbene
complexes with alkynes: thus, while terminal alkynes afforded cyclohep-
tatriene derivatives resulting from a [2 + 2 + 2 + 1] cyclization (ref 11),
internal alkynes yielded cyclopentadienes arising from a [2 + 2 + 1]
cyclization (Barluenga, J.; Barrio, P.; Riesgo, L.; Lo´pez, L. A.; Toma´s, M.
Tetrahedron 2006, 62, 7547)
(16) For the regioselectivity of the insertion of 1-phenylpropyne into the CrdC
bond of Fischer carbene complexes, see: (a) Do¨tz, K. H.; Mu¨hlemeier, J.;
Schbert, U.; Orama, O. J. Organomet. Chem. 1983, 247, 187. See also:
(b) Barluenga, J.; Lo´pez, L. A.; Mart´ınez, S.; Toma´s, M. J. Org. Chem.
1998, 63, 7588.
(17) The reaction of chromium Fischer carbene complexes with alkoxyacetylenes
has been much less studied. For an isolated example, see: Yamashita, A.;
Toy, A. Tetrahedron Lett. 1986, 27, 3471.
(19) For an exception to this general trend, see: Goettmann, F.; Le Floch, P.;
Sanchez, C. Chem. Commun. 2006, 180.
(20) For an isolated, low-yield example of an intramolecular Pauson-Khand
reaction, see: Mukai, C.; Kozaka, T.; Suzuki, Y.; Kim, I. J. Tetrahedron
2004, 60, 2497.
(21) See, for example: Kraft, M. E. Tetrahedron Lett. 1988, 29, 999.
(22) The Pauson-Khand reaction of electron-rich alkynes to yield 2-hetero-
substituted cyclopentenones has been reported. For ynamines, see: (a)
Balsells, J.; Va´zquez, J.; Moyano, A.; Perica`s, M. A.; Riera, A. J. Org.
Chem. 2000, 65, 7291. (b) Shen, L.; Hsung, R. P. Tetrahedron Lett. 2003,
44, 9353. For alkoxyacetylenes, see: (c). Verdaguer, X.; Va´zquez, J.; Fuster,
G.; Bernardes-Ge´nisson, V.; Greene, A. E.; Moyano, A.; Perica`s, M. A.;
Riera, A. J. Org. Chem. 1998, 63, 7037. For acetylene thioethers, see: (d)
Marchuela, I.; Montenegro, E.; Panov, D.; Poch, M.; Verdaguer, X.;
Moyano, A.; Perica`s, M. A.; Riera, A. J. Org. Chem. 2001, 66, 6400.
(23) For regiochemical studies of intermolecular Pauson-Khand reactions
involving internal electron-deficient alkynes, see: (a) Kraft, M. E.; Romero,
R. H.; Scott, I. L. J. Org. Chem. 1992, 57, 5277. (b) Hoye, T. R.; Suriano,
J. A. J. Org. Chem. 1993, 58, 1659.
(18) The regioselectivity of the benzannulation reaction of alkenyl Fischer
carbene complexes of chromium with alkynes bearing electron-withdrawing
groups has been investigated: Wulff, W. D.; Chang, K.-S.; Tang, P.-C. J.
Org. Chem. 1984, 49, 2293.
(24) For the intramolecular Pauson-Khand reaction of enynes with a trimeth-
ylgermyl group at the alkyne terminus, see: (a) Mukai, C.; Kozakz, T.;
Suzuki, Y.; Kim, I. J. Tetrahedron Lett. 2002, 43, 8575. (b) See also ref
20.
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A R T I C L E S
Barluenga et al.
Figure 2. Complementary approaches to the cyclopentenone skeleton synthesis.
cyclopentenones from readily available starting materials. The
reaction takes place with total regiochemistry with a number
of nonsymmetrical alkynes. The wide scope of the process is
noteworthy as neutral and activated alkynes as well as silicon-,
boron-, and tin-substituted alkynes are suitable partners in this
cyclopentenone annelation. Since most of these types of
cyclopentenones are not accessible by established methodolo-
gies, the reported process complements previously reported
approaches to the cyclopentenone skeleton. Further studies
aimed at the development of catalytic and asymmetric variants
of this cyclization are underway.
Acknowledgment. We are grateful to the Ministerio de
Educacio´n y Ciencia (MEC, Project CTQ2004-08077), the
Principado de Asturias (Project PR-01-GE-9), and the Fundacio´n
Ramo´n Areces for the support of this research. We acknowledge
the MEC for a predoctoral fellowship to L.R. We are also
grateful to Dr. Ce´sar J. Pastor (SidI, Universidad Auto´noma de
Madrid) for his assistance in the collection of the X-ray data.
Figure 3. Diverse cyclopentanone structures available by combining the
PKR and the [3 + 2] methodology described in this work.
the [3 + 2] cyclization between a very unusual C3 dipole
equivalent [(OdC-CHdCHR]( and alkynes of a different sort.
According to the above comments, the great synthetic
diversity in the area of the cyclopentenone skeleton that can be
reached by combining the Pauson-Khand reaction and the
cyclization of metal carbene complexes with alkynes is sum-
marized in Figure 3.
Supporting Information Available: Full experimental details
and spectral and analytical data for all products. This material
is available free of charge via the Internet at http://pubs.acs.org.
In summary, we have described a general and simple
experimental procedure for the synthesis of polysubstituted
JA075106+
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14426 J. AM. CHEM. SOC. VOL. 129, NO. 46, 2007