Ruthenium/TFA-catalyzed coupling of activated secondary propargylic alcohols with cyclic 1,3-diones: Furan versus pyran ring formation

Article abstract of DOI:10.1021/jo800726u

(Chemical Equation Presented) A catalytic system consisting of the 16-electron allyl-ruthenium(II) complex [Ru(η³-2-C ₃H₄Me)(CO)(dppf)][SbF₆] (dppf = 1,1′-bis(diphenylphosphino)ferrocene) and trifluoroacetic acid (TFA) has been used to promote the coupling between secondary propargylic alcohols and cyclic 1,3-diketones. The nature of the resulting products was found to be dependent on the ring size of the dicarbonyl compound employed. Thus, whereas 6,7-dihydro-5H-benzofuran-4-ones have been selectively obtained starting from 1,3-cyclohexanediones, via furan-ring formation, the use of 1,3- cyclopentanedione leads instead to 6,7-dihydro-4H-cyclopenta[b]pyran-5-ones via a pyran-ring formation process.

Full text of DOI:10.1021/jo800726u

Ruthenium/TFA-Catalyzed Coupling of Activated Secondary
Propargylic Alcohols with Cyclic 1,3-Diones: Furan versus Pyran
Ring Formation
Victorio Cadierno,* Josefina D´ıez, Jose´ Gimeno,* and Noel Nebra
Departamento de Qu´ımica Orga´nica e Inorga´nica, Instituto UniVersitario de Qu´ımica Organometa´lica
“Enrique Moles” (Unidad Asociada al CSIC), Facultad de Qu´ımica, UniVersidad de OViedo,
E-33071 OViedo, Spain
jgh@unioVi.es; Vcm@unioVi.es
ReceiVed April 9, 2008
A
catalytic system consisting of the 16-electron allyl-ruthenium(II) complex [Ru(η3-2-
C3H4Me)(CO)(dppf)][SbF6] (dppf ) 1,1′-bis(diphenylphosphino)ferrocene) and trifluoroacetic acid (TFA)
has been used to promote the coupling between secondary propargylic alcohols and cyclic 1,3-diketones.
The nature of the resulting products was found to be dependent on the ring size of the dicarbonyl compound
employed. Thus, whereas 6,7-dihydro-5H-benzofuran-4-ones have been selectively obtained starting from
1,3-cyclohexanediones, via furan-ring formation, the use of 1,3-cyclopentanedione leads instead to 6,7-
dihydro-4H-cyclopenta[b]pyran-5-ones via a pyran-ring formation process.
Introduction
major research objective for over a century.1,3 Although several
general approaches are presently available, such as the classical
cyclocondensation of 1,4-diones (Paal-Knorr synthesis), the
search for new methodologies proceeding more efficiently and
involving readily available starting materials still remains an
active area of research. Among others, relevant contributions
to this field have recently emerged by the aid of transition-metal
catalysts because they allow the construction of complex furanic
molecules from accessible precursors under mild conditions, via
The furan ring is a common structural motif in many
biologically active molecules and pharmaceutical substances,
furans being also widely employed as versatile building blocks
in synthetic organic chemistry.1 The important role played by
these five-membered heterocycles in the field of flavors and
fragrances should also be highlighted.2 As a consequence, the
development of synthetic routes to produce furans has been a
(2) See, for example: (a) Bauer, K.; Garbe, D.; Surburg, H. In Common
Fragrance and FlaVor Materials; Wiley-VCH: Weinheim, 2001. (b) Ash, M.;
Ash, I. In Handbook of FlaVors and Fragrances; Synapse Information Resources,
Inc: New York, 2006.
(3) For recent reviews, accounts, and highlights dealing with the synthesis
of furans, see: (a) Hou, X. L.; Cheung, H. Y.; Hon, T. Y.; Kwan, P. L.; Lo,
T. H.; Tong, S. Y.; Wong, H. N. C. Tetrahedron 1998, 54, 1955. (b) Keay,
B. A. Chem. Soc. ReV. 1999, 28, 209. (c) Jeevanandam, A.; Ghule, A.; Ling,
Y.-C. Curr. Org. Chem. 2002, 6, 841. (d) Brown, R. C. D. Angew. Chem., Int.
Ed. 2005, 44, 850. (e) Kirsch, S. F. Org. Biomol. Chem. 2006, 4, 2076. (f)
D′Souza, D. M.; Mu¨ller, T. J. J. Chem. Soc. ReV. 2007, 36, 1095. (g) Patil,
N. T.; Yamamoto, Y. ARKIVOC 2007, (x), 121. (h) Balme, G.; Bouyssi, D.;
Monteiro, N. Heterocycles 2007, 73, 87.
(1) See, for example: (a) Lipshutz, B. H. Chem. ReV. 1986, 86, 795. (b)
Heaney, H.; Ahn, J. S. In ComprehensiVe Heterocyclic Chemistry II; Katritzky,
A. R., ; Rees, C. W., ; Scriven, E. F. V., Eds.; Elsevier: Oxford, 1996; Vol. 2,
p 297. (c) Friedrichsen, W. In ComprehensiVe Heterocyclic Chemistry II;
Katritzky, A. R., ; Rees, C. W., ; Scriven, E. F. V., Eds.; Elsevier: Oxford,
1996; Vol. 2, p. 351. (d) Keay, B. A.; Dibble, P. W. In ComprehensiVe
Heterocyclic Chemistry II; Katritzky, A. R., ; Rees, C. W., ; Scriven, E. F. V.
Eds.; Elsevier: Oxford, 1996; Vol. 2, p 395. (e) Pozharskii, A. F.; Soldatenkov,
A. T.; Katritzky, A. R. In Heterocycles in Life and Society; John Wiley & Sons:
Chichester, 1997. (f) Wong, H. N. C.; Yu, P.; Yick, C.-Y. Pure Appl. Chem.
1999, 71, 1041. (g) Lee, H.-K.; Chan, K.-F.; Hui, C.-W.; Yim, H.-K.; Wu, X.-
W.; Wong, H. N. C. Pure Appl. Chem. 2005, 77, 139.
5852 J. Org. Chem. 2008, 73, 5852–5858
10.1021/jo800726u CCC: $40.75 2008 American Chemical Society
Published on Web 07/02/2008

Coupling of ActiVated Secondary Propargylic Alcohols
SCHEME 1. Direct Synthesis of Furans from Alkynols and 1,3-Dicarbonyl Compounds
uni- or bimolecular transformations as well as multicomponent
reactions (MCR).3 In the course of current studies focused on
the application of ruthenium complexes as catalysts in organic
synthesis,4,5 we recently disclosed a straightforward approach
to tetrasubstituted furans from inexpensive secondary propar-
gylic alcohols and acyclic 1,3-dicarbonyl compounds (Scheme
1).6,7 The process, which proceeds in a one-pot manner, involves
the initial trifluoroacetic acid promoted propargylic substitution
of the alkynol by the 1,3-dicarbonyl compound8 and subsequent
cyclization of the resulting γ-ketoalkyne A catalyzed by the
16-electron allyl-ruthenium(II) complex [Ru(η3-2-C3H4Me)-
(CO)(dppf)][SbF6] (1; dppf ) 1,1′-bis(diphenylphosphino)fer-
rocene).
By following this synthetic route, a large variety of furans
containing carbonyl functionalities on the aromatic ring could
be prepared in good yields starting from both terminal and
internal secondary alkynols and acyclic ꢀ-diketones or ꢀ-keto
esters.6 In order to extend the scope of this synthetic
methodology to the preparation of novel bicyclic furans, we
decided to explore analogous coupling reactions using
commercially available cyclic 1,3-diketones (B and C in
Figure 1). However, we have found that the nature of the
resulting products is strongly dependent on the ring size of
the dicarbonyl compound employed. Thus, whereas the
expected 6,7-dihydro-5H-benzofuran-4-ones (D) are selec-
tively obtained starting from 1,3-cyclohexanediones B, the
use of 1,3-cyclopentanedione C leads instead to 6,7-dihydro-
4H-cyclopenta[b]pyran-5-ones (E) in which the formation of
a pyran ring takes place. Full details of this research are
described in this article.
(4) Isomerization of allylic alcohols into carbonyl compounds: (a) Cadierno,
V.; Garc´ıa-Garrido, S. E.; Gimeno, J. Chem. Commun. 2004, 232. (b) Cadierno,
V.; Crochet, P.; Garc´ıa-Garrido, S. E.; Gimeno, J. Dalton Trans. 2004, 3635.
(c) Crochet, P.; D´ıez, J.; Ferna´ndez-Zu´mel, M. A.; Gimeno, J. AdV. Synth. Catal.
2006, 348, 93. (d) Crochet, P.; Ferna´ndez-Zu´mel, M. A.; Gimeno, J.; Scheele,
M. Organometallics 2006, 25, 4846. (e) Cadierno, V.; Garc´ıa-Garrido, S. E.;
Results and Discussion
´
Gimeno, J.; Varela-Alvarez, A.; Sordo, J. A. J. Am. Chem. Soc. 2006, 128, 1360.
Reduction of allylic alcohols into saturated alcohols: (f) Cadierno, V.; Francos,
Furan-Ring Formation Reactions: Synthesis of 6,7-Dihydro-
5H-benzofuran-4-ones and Related Compounds. As shown in
Table 1, treatment of terminal propargylic alcohols 2a-j (entries
1-10) with 1 equiv of 1,3-cyclohexanedione (4), in THF at 75
°C and in the presence of complex 1 (5 mol %) and TFA (50
mol %), results in the selective formation of 6,7-dihydro-5H-
benzofuran-4-ones 5a-j after only 3-5 h (except for 5e, which
required 21 h probably as a result of the strong inductive effect
of the chloride substituent in the meta position of the aromatic
ring).9 Internal alkynols can also participate in this coupling
reaction, as clearly exemplified in the synthesis of 2-benzyl-3-
(2-methoxyphenyl)-6,7-dihydro-5H-benzofuran-4-one (5k) start-
ing from 1-(2-methoxyphenyl)-3-phenyl-2-propyn-1-ol (3a) (a
J.; Gimeno, J.; Nebra, N. Chem. Commun. 2007, 2536. Cycloisomerization of
´
(Z)-enynols into furans: (g) D´ıaz-Alvarez, A. E.; Crochet, P.; Zablocka, M.;
Duhayon, C.; Cadierno, V.; Gimeno, J.; Majoral, J. P. AdV. Synth. Catal. 2006,
348, 1671. (h) Albers, J.; Cadierno, V.; Crochet, P.; Garc´ıa-Garrido, S. E.;
Gimeno, J. J. Organomet. Chem. 2007, 692, 5234. Intermolecular [2 + 2 + 2]
alkyne cyclotrimerizations: (i) Cadierno, V.; Garc´ıa-Garrido, S. E.; Gimeno, J.
J. Am. Chem. Soc. 2006, 128, 15094. Meyer-Schuster and Rupe isomerizations
of propargylic alcohols: (j) Cadierno, V.; D´ıez, J.; Garc´ıa-Garrido, S. E.; Gimeno,
J. Chem. Commun. 2004, 2716. (k) Cadierno, V.; Garc´ıa-Garrido, S. E.; Gimeno,
J. AdV. Synth. Catal. 2006, 348, 101. (l) Cadierno, V.; D´ıez, J.; Garc´ıa-Garrido,
S. E.; Gimeno, J.; Nebra, N. AdV. Synth. Catal. 2006, 348, 2125. Selective
deprotection of N-allylic amines, amides, and lactams: (m) Cadierno, V.; Garc´ıa-
Garrido, S. E.; Gimeno, J.; Nebra, N. Chem. Commun. 2005, 4086. (n) Cadierno,
V.; Gimeno, J.; Nebra, N. Chem. Eur. J. 2007, 13, 6590.
(5) For reviews and books highlighting the burgeoning role of ruthenium
catalysts in organic synthesis, see: (a) Bruneau, C.; Dixneuf, P. H. Chem.
Commun. 1997, 507. (b) Naota, T.; Takaya, H.; Murahashi, S.-I. Chem. ReV.
1998, 98, 2599. (c) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Chem. ReV
2001, 101, 2067. (d) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18.
(e) Ritleng, V.; Sirlin, C.; Pfeffer, M. Chem. ReV. 2002, 102, 1731. (f) Ruthenium
in Organic Synthesis; Murahashi, S.-I. Ed.; Wiley-VCH: Weinheim, 2004. (g)
Ruthenium Catalysts and Fine Chemistry; Bruneau, C., ; Dixneuf, P. H. Eds.;
Springer: Berlin, 2004. (h) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T. Angew.
Chem., Int. Ed. 2005, 44, 6630. (i) Bruneau, C.; De´rien, S.; Dixneuf, P. H. Top.
Organomet. Chem. 2006, 19, 295. (j) Bruneau, C.; Dixneuf, P. H. Angew. Chem.,
Int. Ed. 2006, 45, 2176. (k) Gimeno, J. Ruthenium Catalyzed Processes. Curr.
Org. Chem. 2006, 10 (2), 113–225. (a thematic issue devoted to this topic)
(6) Cadierno, V.; Gimeno, J.; Nebra, N. AdV. Synth. Catal. 2007, 349, 382.
(7) We note that when a primary amine is introduced in the reaction media
pyrroles instead of furans are selectively formed: (a) Cadierno, V.; Gimeno, J.;
Nebra, N. Chem. Eur. J. 2007, 13, 9973.
(8) Brønsted acid catalyzed propargylations of several organic substrates,
including 1,3-dicarbonyl compounds, with alkynols have been reported: (a) Sanz,
´
R.; Mart´ınez, A.; Alvarez-Gutie´rrez; J. M.; Rodr´ıguez, F. Eur. J. Org. Chem.
´
2006, 1383. (b) Sanz, R.; Miguel, D.; Mart´ınez, A.; Alvarez-Gutie´rrez, J. M.;
Rodr´ıguez, F. Org. Lett. 2007, 9, 727. (c) Sanz, R.; Mart´ınez, A.; Miguel, D.;
´
Alvarez-Gutie´rrez, J. M.; Rodr´ıguez, F. Synthesis 2007, 3252. (d) Yadav, J. S.;
Reddy, B. V. S.; Rao, T. S.; Krishna, B. B. M.; Kumar, G. G. K. S. N. Chem.
Lett. 2007, 36, 1472. In these works only 5 mol % of the acid is required to
promote efficiently the propargylation process. In our case the use of larger
quantities of TFA (50 mol %) is imperative in order to avoid the Meyer-Schuster
isomerization of the propargylic alcohol catalyzed by the ruthenium complex 1.
See refs 4k and 4l.
J. Org. Chem. Vol. 73, No. 15, 2008 5853

Cadierno et al.
TABLE 1. Catalytic Synthesis of 6,7-Dihydro-5H-benzofuran-4-ones from Propargylic Alcohols and 1,3-Cyclohexanedionea
entry
propargylic alcohol
time (h)
yield (%)b
1
2
3
4
5
6
7
8
9
R1 ) H; R2 ) Ph (2a)
5
3
5
5
21
5
2
5
3
3
5a, 77
5b, 74
5c, 76
5d, 89
5e, 58
5f, 87
5g, 92
5h, 87
5i, 90
5j, 90
5k, 61
R1 ) H; R2 ) 1-naphthyl (2b)
R1 ) H; R2 ) 2-naphthyl (2c)
R1 ) H; R2 ) 2-C6H4Cl (2d)
R1 ) H; R2 ) 3-C6H4Cl (2e)
R1 ) H; R2 ) 4-C6H4Cl (2f)
R1 ) H; R2 ) 2-C6H4OMe (2g)
R1 ) H; R2 ) 3-C6H4OMe (2h)
R1 ) H; R2 ) 4-C6H4OMe (2i)
R1 ) H; R2 ) 2-thienyl (2j)
R1 ) Ph; R2 ) 2-C6H4OMe (3a)
10
11
21
a All reactions between propargylic alcohols 2 and 3 (1 mmol) and 1,3-cyclohexanedione (4) (1 mmol) were carried out in the presence of complex 1
(0.05 mmol) and CF3CO2H (0.5 mmol), in THF (0.5 mL) at 75 °C (sealed tube), for the indicated time. b Isolated yield.
propargylation-cyclization methodology.11 Gratifyingly, we
found that treatment of 4-hydroxycoumarin 8 with alkynol 2i,
under the standard reaction conditions, results in the selective
formation of the substituted furocoumarin 10, isolated in 72%
yield after chromatographic workup (Scheme 3). The molecular
structure of 10 was unambiguously confirmed by means of
single-crystal X-ray diffraction techniques (see Supporting
Information). The related compound 11 could also be synthe-
sized in high yield starting from 2i and 4-hydroxy-6-methylpy-
ran-2-one 9 (Scheme 3), confirming the generality of this
catalytic transformation.
Pyran-Ring Formation Reactions: Synthesis of 6,7-Dihydro-
4H-cyclopenta[b]pyran-5-ones. Remarkably, in contrast to the
FIGURE 1. Structure of compounds B-F.
reactions with 1,3-cyclohexanediones, when 1,3-cyclopen-
longer reaction time is also in this case required; entry 11).
Appropriate chromatographic workup allowed the isolation of
bicycles 5 in moderate to good yields (58-90%). The charac-
terization of the novel compounds 5a,c-k was achieved by
means of standard spectroscopic techniques (GC/MS, HRMS,
IR, and 1H and 13C NMR) and, in the case of solid samples, by
elemental analyses, all data being fully consistent with the
proposed formulations (details are given in Supporting Informa-
tion). We note that, as previously observed in our study with
acyclic substrates,6 only secondary aromatic and heteroaromatic
alkynols can be employed in this transformation. Thus, attempts
to promote related coupling reactions starting from alkyl-
monosubstituted propargylic alcohols, such as 1-octyn-3-ol or
3-butyn-2-ol, resulted in the formation of complicated reaction
mixtures from which the desired 6,7-dihydro-5H-benzofuran-
4-ones (ca. 10-20% GC/MS yields in the crude reaction
mixtures) could not be separated from the uncharacterized
byproduct.
tanedione is used as substrate, the expected 5,6-dihydro-
cyclopenta[b]furan-4-ones (F in Figure 1) are not formed,
the reactions giving instead 6,7-dihydro-4H-cyclopenta[b-
]pyran-5-ones (E in Figure 1). Table 2 collects the results
obtained when terminal 2a-i and internal 3a-c propargylic
alcohols were subjected to react with 1,3-cyclopentanedione
(12) under our standard reaction conditions, i.e., [alkynol]:
[12]:[TFA]:[Ru] ratio ) 20:20:10:1 in THF at 75 °C. The
corresponding 6,7-dihydro-4H-cyclopenta[b]pyran-5-ones 13
are in all cases formed exclusively, with the isomeric 5,6-
dihydro-cyclopenta[b]furan-4-ones (F) being not detected in
the crude reaction mixtures by GC/MS. The characterization
of compounds 13, isolated as solid samples in 61-94% yield
(9) In our previous work involving acyclic 1,3-dicarbonyl compounds (ref
6), the catalytic reactions were performed under “solvent-free” conditions,
employing the 1,3-dicarbonyl compound (10 equiv with respect to the alkynol)
itself as solvent. In order to avoid the waste of expensive reagents, we decided
to reduce the quantity of the 1,3-diketone (1 equiv per equivalent of the alkynol),
dissolving all the components of the catalytic reaction in the minimum amount
of tetrahydrofuran.
(10) See, for example: (a) Donnelly, D. M. X.; Boland, G. M. Nat. Prod.
Rep. 1998, 241. (b) Misky, M.; Jakupovic, J. Phytochemistry 1990, 29, 1995.
(c) Schuster, N.; Christiansen, C.; Jakupovic, J.; Mungai, M. Phytochemistry
1993, 34, 1179. (d) Grese, T.; Pennington, L. D.; Sluka, J. P.; Adrian, M. D.;
Cole, H. W.; Fuson, T. R.; Magee, D. E.; Phillips, D. L.; Rowley, E. R.; Shetler,
P. K.; Short, L. L.; Venugopalan, M.; Yang, N. N.; Sato, M.; Glasebrook, A. L.;
Bryant, H. U. J. Med. Chem. 1998, 41, 1272. (e) Wang, X.; Bastow, K. F.; Sun,
C.; Lin, Y.; Yu, H.; Don, M.; Wu, T.; Nakamura, S.; Lee, K. J. Med. Chem.
2004, 47, 5816. (f) Zhao, L.; Brinton, R. D. J. Med. Chem. 2005, 48, 3463.
(11) Propargylation of coumarin derivatives with propargylic alcohols
catalyzed by Yb(OTf)3 has recently been reported: Huang, W.; Wang, J.; Shen,
Q.; Zhou, X. Tetrahedron 2007, 63, 11636.
Under the same reaction conditions, the closely related 6,7-
dihydro-5H-benzofuran-4-ones 7a,i,j could also be prepared in
good yields and with complete regioselectivity starting from
commercially available 5,5-dimethyl-1,3-cyclohexanedione (dime-
done) and the appropriate alkynol (Scheme 2).
Stimulated by these successful results and having in mind
the relevant biological activity of furocoumarins, key structural
units in many natural products,10 we wondered whether this type
of heterocycles would be accessible by using our one-pot
5854 J. Org. Chem. Vol. 73, No. 15, 2008

Coupling of ActiVated Secondary Propargylic Alcohols
SCHEME 2. Synthesis of 6,7-Dihydro-5H-benzofuran-4-ones 7 from Alkynols and Dimedone
SCHEME 3. Synthesis of Compounds 10 and 11
TABLE 2. Catalytic Synthesis of 6,7-Dihydro-4H-cyclopenta[b]pyran-5-ones from Propargylic Alcohols and 1,3-Cyclopentanedionea
entry
propargylic alcohol
time (h)
yield (%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
R1 ) H; R2 ) Ph (2a)
5
2
5
12
21
5
2
5
3
3
13a, 91
13b, 89
13c, 72
13d, 82
13e, 61
13f, 87
13g, 94
13h, 85
13i, 92
13j, 93
13k, 91
13l, 78
13m, 92
R1 ) H; R2 ) 1-naphthyl (2b)
R1 ) H; R2 ) 2-naphthyl (2c)
R1 ) H; R2 ) 2-C6H4Cl (2d)
R1 ) H; R2 ) 3-C6H4Cl (2e)
R1 ) H; R2 ) 4-C6H4Cl (2f)
R1 ) H; R2 ) 2-C6H4OMe (2g)
R1 ) H; R2 ) 3-C6H4OMe (2h)
R1 ) H; R2 ) 4-C6H4OMe (2i)
R1 ) H; R2 ) 2-thienyl (2i)
R1 ) Ph; R2 ) 2-C6H4OMe (3a)
R1 ) Me; R2 ) Ph (3b)
4
18
8
R1 ) Me; R2 ) 4-C6H4OMe (3c)
a All reactions between propargylic alcohols 2 and 3 (1 mmol) and 1,3-cyclopentanedione (12) (1 mmol) were carried out in the presence of complex
1 (0.05 mmol) and CF3CO2H (0.5 mmol), in THF (0.5 mL) at 75 °C (sealed tube), for the indicated time. b Isolated yield.
after appropriate chromatographic workup, was straightfor-
ward by following their analytical and spectroscopic data
(details are given in the Supporting Information). Moreover,
X-ray diffraction studies on compound 13j, containing a
thienyl substituent, unequivocally confirmed the formation
of a six-membered pyran ring in these catalytic reactions (see
Supporting Information).
Mechanistic Proposals. We assume that formation of 6,7-
dihydro-5H-benzofuran-4-ones 5 and 7 (Table 1 and Scheme
2) follows the same reaction pathway previously proposed by
us in the coupling of propargylic alcohols with acyclic 1,3-
dicarbonyl compounds.6 It involves the initial TFA-promoted
propargylation of the 1,3-cyclohexanediones 4 and 6 with the
alkynols to afford the corresponding γ-ketoalkyne intermedi-
ates,8 which undergo a subsequent ruthenium-catalyzed cycliza-
tion to give the final reaction products (see Scheme 1). We note
that, although not isolated, the γ-ketoalkynes G (Scheme 4) can
be detected in the reaction media by monitoring the catalytic
reactions by GC/MS. Transformation of intermediates G into
the final 6,7-dihydro-5H-benzofuran-4-ones involves the initial
activation of the Ct C bond of the alkyne, via π-coordination
to ruthenium (intermediates H; see Scheme 4). Subsequent
J. Org. Chem. Vol. 73, No. 15, 2008 5855

Cadierno et al.
SCHEME 4. Proposed Reaction Pathway for the Cyclization of γ-Ketoalkynes G into 6,7-Dihydro-5H-benzofuran-4-ones
described to date.13 The only related work is the cyclization of
the terminal secondary alkynols 2 with 1,3-cyclohexanedione
4 to yield 4,6,7,8-tetrahydrochromen-5-ones, via a pyran-ring
formation process, catalyzed by the thiolate-bridged diruthe-
nium(III) complexes [Cp*RuCl(µ2-SR)2RuCp*Cl] (R ) Me, nPr,
iPr) (Scheme 6).14 The reaction proceeds through the initial
nucleophilic attack of the carbon atom of 1,3-cyclohexanedione
(4) to the Cγ atom of the intermediate allenylidene complex K,
generated by activation of the terminal propargylic alcohol.15
The resulting vinylidene intermediate L evolves into the alkenyl
complex M by intramolecular nucleophilic attack of the enolic
hydroxyl group to the electrophilic R-carbon of the vinylidene
chain. Final demetalation of M liberates the 4,6,7,8-tetrahydro-
chromen-5-ones and regenerates the catalytically active ruthe-
nium species.16
The different outcome of our catalytic reaction is probably
based on the reluctance of the π-alkyne intermediates H (when
R1 ) H) to undergo tautomerization into the corresponding
vinylidene isomers (analogous to L), which leads to the
formation of five-membered furan rings instead of the six-
membered pyrans obtained by Nishibayashi and co-workers.
Moreover, the involvement of π-alkyne intermediates H instead
of vinylidenes L is also in complete accord with the fact that
internal alkynols, unable to form vinylidene species, also
undergo the cyclization reaction to afford the corresponding 6,7-
dihydro-5H-benzofuran-4-ones (entry 11 in Table 1), in marked
contrast to Nishibayashi’s case where internal alkynols are
unreactive.
SCHEME 5. TFA-Promoted Propargylation of
4-Hydroxycoumarin
intramolecular nucleophilic attack of the enolic form of the keto
group at the C2 position of the coordinated alkyne generates
the alkenyl-ruthenium derivatives I (exo cyclization), which by
protonolysis liberates the heterocycles J, regenerating the
catalytically active ruthenium species. Final aromatization of
J, promoted by the Brønsted acid TFA or the Lewis acid
ruthenium species present in solution, leads to the final reaction
products.12
Formation of furocoumarin 10 and the furo[3,2-c]pyran-4-
one 11 (Scheme 3) most probably involves the same cyclization
sequence. In order to unambiguously confirm that initial TFA-
promoted propargylation of the carbonylic substrates is involved
in the catalytic cycle, the reactivity of alkynol 2i toward
4-hydroxycoumarin (8) using only CF3CO2H (50 mol %) in the
absence of complex 1 was studied (Scheme 5). In accord with
the proposed mechanism, the reaction affords the γ-ketoalkyne
14, which is selectively formed after only 1.5 h. Chromato-
graphic workup allowed the isolation (85%) and spectroscopic
characterization of this functionalized alkyne (see Supporting
Information). As expected, treatment of 14 with complex 1 and
TFA, in THF at 75 °C, cleanly generates the furocoumarin 10.
To the best of our knowledge, the synthesis of 6,7-dihydro-
5H-benzofuran-4-ones through the direct coupling of propargylic
alcohols with 1,3-cyclohexanedione derivatives has not being
Concerning the synthesis of the 6,7-dihydro-4H-cyclo-
penta[b]pyran-5-ones 13 (Table 2), we propose that in this
case an endo-cyclization of the initially formed γ-ketoalkynes
N (also detected by GC/MS) takes place via intramolecular
nucleophilic attack of the enol at the C1 position of the
(14) Nishibayashi, Y.; Yoshikawa, M.; Inada, Y.; Hidai, M.; Uemura, S. J.
Org. Chem. 2004, 69, 3408.
(15) Transformation of terminal propargylic alcohols into allenylidene ligands
in the coordination sphere of transition metals is a well-known process. For
reviews on this topic, see: (a) Bruce, M. I. Chem. ReV. 1998, 98, 2797. (b)
Cadierno, V.; Gamasa, M. P.; Gimeno, J. Eur. J. Inorg. Chem. 2001, 571. (d)
King, R. B. Vinylidene, Allenylidene and Metallacumulene Complexes. Coord.
Chem. ReV. 2004, 248 (15-16), 1531–1703.
(12) We note that such a reaction pathway is proposed in the closely related
metal-catalyzed cyclizations of (Z)-enynols into furans. See, for example: (a)
Seiller, B.; Bruneau, C.; Dixneuf, P. H. Tetrahedron 1995, 51, 13089. (b)
Gabriele, B.; Salerno, G.; Lauria, E. J. Org. Chem. 1999, 64, 7687.
(13) No cyclizative C-C coupling reactions between alkynols and 1,3-
cyclohexanediones have been reported. See, for example: (a) Gabbutt, C. D.;
Hepworth, J. D.; Heron, B. M.; Partington, S. M.; Thomas, D. A. Dyes Pigm.
2001, 49, 65. (b) Nakatsuji, S.; Yahiro, T.; Nakashima, K.; Akiyama, S.;
Nakazumi, H. Bull. Chem. Soc. Jpn. 1991, 64, 1641.
(16) Such a reaction pathway involving vinylidene intermediates is in
complete accord with recent stoichiometric studies performed with mononuclear
allenylidene-ruthenium(II) complexes containing the electron-rich fragment
[Cp*Ru(dippe)]+: (a) Bustelo, E.; Jime´nez-Tenorio, M.; Puerta, M. C.; Valerga,
P. Organometallics 2007, 26, 4300.
5856 J. Org. Chem. Vol. 73, No. 15, 2008

Coupling of ActiVated Secondary Propargylic Alcohols
SCHEME 6. Coupling of Terminal Alkynols with 1,3-Cyclohexanedione to Afford 4,6,7,8-Tetrahydrochromen-5-ones Catalyzed
by Complexes [Cp*RuCl(µ2-SR)2RuCp*Cl]14
SCHEME 7. Proposed Reaction Pathway for the Formation
of 6,7-Dihydro-4H-cyclopenta[b]pyran-5-ones
Experimental Section
General Procedure for the Catalytic Reactions. The corre-
sponding propargylic alcohol (2a-j or 3a-c; 1 mmol) and the
appropriate 1,3-dicarbonyl compound or coumarin (4, 6, 8, 9,
or 12; 1 mmol) were introduced into a sealed tube under nitrogen
atmosphere. THF (0.5 mL), [Ru(η3-2-C3H4Me)(CO)(dppf)][SbF6]
(1) (0.049 g, 0.05 mmol), and CF3CO2H (37 µL, 0.5 mmol) were
then added at room temperature, and the resulting solution heated
at 75 °C for the indicated time (see Tables 1 and 2 and Schemes
2 and 3; the course of the reaction was monitored by regular
sampling and analysis by GC/MS). After removal of volatiles
under vacuum, the residue was purified by column chromatog-
raphy (silica gel) using a mixture EtOAc/hexanes (1:20) as eluent
(a 1:50 mixture of EtOAc/hexanes was used for compounds 10
and 11). Compounds 2-methyl-3-(1-naphthyl)-6,7-dihydro-5H-
benzofuran-4-one (5b)6 and 4-phenyl-6,7-dihydro-4H-cyclopent-
a[b]pyran-5-one (13a)14 have been previously reported. Ana-
lytical and spectroscopic data for all new compounds are included
in Supporting Information. Representative examples are:
2-Methyl-3-phenyl-6,7-dihydro-5H-benzofuran-4-one (5a). Col-
orless oil; IR (Nujol, cm-1): ν 1575 (CdC), 1682 (CdO). 1H NMR
(300.1 MHz, CDCl3): δ 2.14 (m, 2H), 2.31 (s, 3H), 2.46 (m, 2H),
2.88 (m, 2H), 7.26-7.34 (m, 5H) ppm; 13C NMR (75.4 MHz,
CDCl3): δ 11.9, 22.4, 23.6, 38.5, 119.6, 125.2, 126.9, 127.8, 129.7,
131.6, 148.7, 165.9, 194.4 ppm; MS (EI, 70 eV): m/z 226 (M+,
100), 211 (5), 198 (90), 183 (5), 170 (50), 155 (15), 141 (10);
HRMS (EI): m/z ) 226.09839, C15H14O2 requires 226.09883.
3-(4-Methoxyphenyl)-2-methyl-furo[3,2-c]chromen-4-one (10).
White solid; IR (Nujol, cm-1): ν 1594, 1615 and 1629 (CdC), 1738
coordinated alkyne (intermediate O; see Scheme 7). Final
protonolysis of the resulting alkenyl species P liberates the
6,7-dihydro-4H-cyclopenta[b]pyran-5-ones. The preference
shown by intermediates O to undergo the endo versus the
expected exo cyclization probably arises from the higher ring
strain in the hypothetical 5,6-dihydro-cyclopenta[b]furan-4-
ones (F in Figure 1). We note that the coupling of alkynol
2a with 1,3-cyclopentanedione 12 to afford 13a was already
described by Nishibayashi and co-workers using the dinuclear
catalyst [Cp*RuCl(µ2-SMe)2RuCp*Cl].14 As in the case of
1,3-cyclohexanedione (Scheme 6), they also proposed an
intramolecular nucleophilic attack of the enolic hydroxyl
group to the electrophilic R-carbon in the corresponding
vinylidene intermediate as a key step in the catalytic cycle.
Once again, the results obtained with the internal alkynols
3a-c (entries 11-13 in Table 2) allow us to discard the
involvement of vinylidene species in our catalytic reac-
tions.
1
(CdO). H NMR (300.1 MHz, CDCl3): δ 2.52 (s, 3H), 3.86 (s,
3H), 6.99 (d, 2H, J ) 8.5 Hz), 7.26-7.49 (m, 5H), 7.87 (d, 1H, J
) 7.4 Hz) ppm; 13C NMR (75.4 MHz, CDCl3): δ 12.5, 55.2, 109.7,
112.8, 113.7, 117.0, 120.0, 120.5, 122.1, 124.2, 130.1, 131.0, 151.2,
152.2, 156.1, 157.8, 159.1 ppm; MS (EI, 70 eV): m/z 306 (M+,
100), 291 (10), 263 (5); HRMS (EI): m/z ) 306.08786, C19H14O4
requires 306.08866.
3-(4-Methoxyphenyl)-2,6-dimethyl-furo[3,2-c]pyran-4-one (11).
White solid; IR (Nujol, cm-1): ν 1574, 1601 and 1615 (CdC), 1738
1
(CdO). H NMR (300.1 MHz, CDCl3): δ 2.33 (s, 3H), 2.42 (s,
3H), 3.84 (s, 3H), 6.37 (s, 1H), 6.97 (m, 2H), 7.41 (m, 2H) ppm;
13C NMR (75.4 MHz, CDCl3): δ 12.4, 20.1, 55.2, 95.4, 107.5,
113.6, 118.6, 122.4, 130.9, 142.6, 149.4, 158.9, 159.1, 160.6 ppm;
MS (EI, 70 eV): m/z 270 (M+, 100), 255 (10), 227 (10); HRMS
(EI): m/z ) 270.08836, C16H14O4 requires 270.08866.
In summary, in this paper we have described a simple and
highly efficient one-pot catalytic protocol for the preparation
of 6,7-dihydro-5H-benzofuran-4-ones and 6,7-dihydro-4H-cy-
clopenta[b]pyran-5-ones. These synthetic routes, starting from
readily accessible propargylic alcohols and commercially avail-
able cyclic 1,3-dicarbonyl compounds, represent appealing
methodologies that are either scarcely documented, i.e., the
synthesis of 6,7-dihydro-4H-cyclopenta[b]pyran-5-ones,14 or
unprecedented, i.e., the synthesis of 6,7-dihydro-5H-benzofuran-
4-ones.
4-(1-Naphthyl)-6,7-dihydro-4H-cyclopenta[b]pyran-5-one (13b).
Orange solid; IR (Nujol, cm-1): ν 1614 and 1666 (CdC), 1698
(CdO). 1H NMR (300.1 MHz, CDCl3): δ 2.52 (m, 2H), 2.68-2.88
(m, 2H), 5.12 (br, 1H), 5.30 (dd, 1H, J ) 6.0 and 3.7 Hz), 6.54
(dd, 1H, J ) 6.0 and 1.7 Hz), 7.22-7.89 (m, 6H), 8.20 (d, 1H, J
) 8.5 Hz) ppm; 13C NMR (75.4 MHz, CDCl3): δ 25.7, 30.2, 32.9,
108.9, 116.7, 122.8, 125.5, 125.6, 125.8, 126.2, 127.5, 128.9, 130.7,
J. Org. Chem. Vol. 73, No. 15, 2008 5857

Cadierno et al.
134.0, 138.3, 138.7, 180.1, 203.7 ppm; MS (EI, 70 eV): m/z 262
(M+, 100), 245 (80), 135 (80); Anal. Calcd for C18H14O2: C, 82.42;
H, 5.38. Found: C, 82.25; H, 5.40.
Supporting Information Available: General experimental
1
methods, characterization data and copies of the H and 13C
NMR spectra of all new compounds (5a, 5c-k, 7a, 7i, 7j,
10, 11, 13b-m, and 14), and a CIF file giving crystal-
lographic data for compounds 10 and 13j. This material is
available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are indebted to the Ministerio de
Educacio´n y Ciencia (MEC) of Spain (Projects CTQ2006-
08485/BQU and Consolider Ingenio 2010 (CSD2007-00006))
for financial support. N.N. and V.C. thank MEC and the
European Social Fund for the award of a PhD grant and a
”Ramo´n y Cajal” contract, respectively.
JO800726U
5858 J. Org. Chem. Vol. 73, No. 15, 2008