Intramolecular reactions of alkynes with furans and electron rich arenes catalyzed by PtCl2: The role of platinum carbenes as intermediates

Article abstract of DOI:10.1021/ja029125p

5-(2-Furyl)-1-alkynes react, with PtCl₂ as catalyst, to give phenols. On the basis of DFT calculations, a cyclopropyl platinacarbene complex was found as the key intermediate in the process. The cyclopropane and dihydrofuran rings of this intermediate open to form a carbonyl compound, which reacts with the platinum carbene to form an oxepin, which is in equilibrium with an arene oxide. When the reaction is carried out in the presence of water, dicarbonyl compounds are obtained, which support the proposed mechanism. Other cyclizations of alkynes with furans or electron-rich arenes give products of apparent Friedel-Crafts-type reactions, although these processes could also proceed by pathways involving the formation of cyclopropyl platinum carbenes.

Full text of DOI:10.1021/ja029125p

Published on Web 04/18/2003
Intramolecular Reactions of Alkynes with Furans and Electron
Rich Arenes Catalyzed by PtCl2: The Role of Platinum
Carbenes as Intermediates
Bele´n Mart´ın-Matute, Cristina Nevado, Diego J. Ca´rdenas, and
Antonio M. Echavarren*
Contribution from the Departamento de Qu´ımica Orga´nica, UniVersidad Auto´noma de Madrid,
Cantoblanco, 28049 Madrid, Spain
Received October 29, 2002; E-mail: anton.echavarren@uam.es
Abstract: 5-(2-Furyl)-1-alkynes react, with PtCl2 as catalyst, to give phenols. On the basis of DFT
calculations, a cyclopropyl platinacarbene complex was found as the key intermediate in the process. The
cyclopropane and dihydrofuran rings of this intermediate open to form a carbonyl compound, which reacts
with the platinum carbene to form an oxepin, which is in equilibrium with an arene oxide. When the reaction
is carried out in the presence of water, dicarbonyl compounds are obtained, which support the proposed
mechanism. Other cyclizations of alkynes with furans or electron-rich arenes give products of apparent
Friedel-Crafts-type reactions, although these processes could also proceed by pathways involving the
formation of cyclopropyl platinum carbenes.
Scheme 1
Introduction
The coordination of electrophilic PtCl2 to the alkyne of an
enyne (1, Scheme 1) promotes the intramolecular attack of the
alkene to form cyclopropyl Pt-carbene intermediates 2 and/or
3 by 5-exo-dig or 6-endo-dig pathways.1 The attack of the
nucleophile (alcohol or water) at the cyclopropane of complexes
2 and 3 gives rise to 4-6. Some of these cyclizations are also
catalyzed by AuCl3, Ru(II),1 and Pd(II) complexes,2 although
the reactions with these catalysts are more limited in scope.1
Similar intermediates may be also involved in the transition
metal-catalyzed intramolecular attack of allyl silanes and allyl
stannanes to alkynes.3 The involvement of cyclopropylmetal-
carbenes as intermediates was first proposed by Trost,4 Murai,5
(1) (a) Me´ndez, M.; Mun˜oz, M. P.; Echavarren, A. M. J. Am. Chem. Soc. 2000,
122, 11 549-11 550. (b) Me´ndez, M.; Mun˜oz, M. P.; Nevado, C.; Ca´rdenas,
D. J.; Echavarren, A. M. J. Am. Chem. Soc. 2001, 123, 10 511-10 520.
(c) Nevado, C.; Ca´rdenas, D. J.; Echavarren, A. M. Chem. Eur. J. 2003, 9,
in press.
(2) Nevado, C.; Charruault, L.; Michelet, V.; Nieto-Oberhuber, C.; Mun˜oz,
M. P.; Me´ndez, M.; Rager, M.-N.; Geneˆt, J. P.; Echavarren, A. M. Eur. J.
Org. Chem. 2003, 706-713.
(3) (a) Ferna´ndez-Rivas, C.; Me´ndez, M.; Echavarren, A. M. J. Am. Chem.
Soc. 2000, 122, 1221-1222. (b) Ferna´ndez-Rivas, C.; Me´ndez, M.; Nieto-
Oberhuber, C.; Echavarren, A. M. J. Org. Chem. 2002, 67, 5197-5201.
(4) (a) Trost, B. M.; Tanoury, G. J. J. Am. Chem. Soc. 1988, 110, 1636-
1638. (b) Trost. B. M.; Trost, M. K. Tetrahedron Lett. 1991, 32, 3647-
3650. (c) Trost, B. M.; Trost, M. K. J. Am. Chem. Soc. 1991, 113, 1850-
1852. (d) Trost, B. M.; Chang, V. K. Synthesis 1993, 824-832. (e) Trost,
B. M.; Yanai, M.; Hoogsten, K. J. Am. Chem. Soc. 1993, 115, 5294-
5295. (f) Trost, B. M.; Hashmi, A. S. K. Angew. Chem., Int. Ed. Engl.
1993, 32, 1085-1087. (g) Trost, B. M.; Hashmi, A. S. K. J. Am. Chem.
Soc. 1994, 116, 2183-2184. (h) Trost, B. M.; Krische, M. J. Synlett 1998,
1-16. (i) Trost, B. M.; Doherty, G. A. J. Am. Chem. Soc. 2000, 122, 3801-
3810. (j) Trost, B. M.; Toste, D. F.; Pinkerton, A. B. Chem. ReV. 2001,
101, 2067-2096.
(5) (a) Chatani, N.; Morimoto, T.; Muto, T.; Murai, S. J. Am. Chem. Soc. 1994,
116, 6049-6050. (b) Chatani, N.; Furukawa, N.; Sakurai, H.; Murai, S.
Organometallics 1996, 15, 901-903. (c) Chatani, N.; Kataoka, K.; Murai,
S.; Furokawa, N.; Seki, Y. J. Am. Chem. Soc. 1998, 120, 9104-9105. (d)
Rearrangement of enynes catalyzed by GaCl3: Chatani, N.; Inoue, H.;
Kotsuma, T.; Murai, S. J. Am. Chem. Soc. 2002, 124, 10 294-10 295.
and Fu¨rstner,6 for the Pd(II), Rh(I), Ru(II), and Pt(II)-catalyzed
skeletal rearrangement of enynes that yield conjugated dienes.7,8
(6) (a) Fu¨rstner, A.; Szillat, H.; Gabor, B.; Mynott, R. J. Am. Chem. Soc. 1998,
120, 8305-8314. (b) Fu¨rstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem.
Soc. 2000, 122, 6785-6786. (c) Fu¨rstner, A.; Stelzer, F.; Szillat, H. J. Am.
Chem. Soc. 2001, 123, 11 863-11 869.
(7) For a more recent formulations of the reaction mechanism: (a) Oi, S.;
Tsukamoto, I.; Miyano, S.; Inoue, Y. Organometallics 2001, 20, 3704-
3709. See also: (b) Mainetti, E.; Mouries, V.; Fensterbank, L.; Malacria,
M.; Marco-Contelles, J. Angew. Chem., Int. Ed. 2002, 41, 2132-2135.
(8) For a review: Aubert, C.; Buisine, O.; Malacria, M. Chem. ReV. 2002,
102, 813-834.
9
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J. AM. CHEM. SOC. 2003, 125, 5757-5766
5757

A R T I C L E S
Mart´ın-Matute et al.
Scheme 2. Proposed Reaction Pathway for the Intramolecular
Scheme 3
Reaction of Furans with Alkynes18
phenols by using AuCl3 as the catalyst (Scheme 3).18 This
reaction was proposed to proceed by an intramolecular [4+2]
cycloaddition of 13, promoted by the η2-coordination of AuCl3
to the alkyne, followed by cleavage of the resulting oxabicyclic
adduct 14 to form phenols 15 and 16.19 This mechanistic
proposal is reasonable, as furans undergo Diels-Alder reactions
with a variety of alkynes to form the oxabicycloheptadienes.20
We also found that substrates 13 give phenols 15 and 16 in
the presence of PtCl2 as the catalyst.21 For this reaction, we
proposed a different mechanism based on the formation of a
cyclopropyl platinum carbene similar to 2. Herein, we report
in detail the scope and limitations of the intramolecular reaction
of furans with alkynes catalyzed by PtCl2, as well as a
mechanistic scheme based on DFT calculations and on the
trapping of some intermediates. We also observed 6-exo
cyclizations in the PtCl2-catalyzed reaction of other furan and
benzofuran with alkynes, as well as aryl propargyl ethers and
N-propargyl-N-tosylanilines.
Formation of cyclopropane derivatives of type 71c-d,6b-c also
supports the involvement of cyclopropyl Pt-carbene 3 as
intermediates.
Electron-rich arenes also react with alkynes in the presence
of electrophilic metal halides MXn (or complexes MLn) as
catalysts.9,10,11,12 Interestingly, 4-aryl-1-ynes react preferentially
by 6-endo pathways to afford six-membered cycles. The exo-
mode was preferred for the cyclization of 5-aryl-1-ynes and
6-aryl-1-ynes, leading to six- and seven-membered rings,
respectively.9 This cyclization has been proposed to take place
via a Friedel-Crafts-type process.9,12 The cyclization of terminal
alkynes can also proceed through vinylidene complexes.10,13,14,15
The metal-catalyzed cyclization of some π-excessive hetero-
cycles with alkynes is also possible. Thus, the 6-endo-cyclization
of substrates 8 gave fused heterocycles 9, presumably via a
Friedel-Crafts-type reaction (Scheme 2).10,12 A different mech-
anism for the cyclization was first demonstrated by Merlic for
the reaction of 10, which was shown to proceed through
ruthenium vinylidene 11 to form tetrahydronaphtho[1,2-b]furan
12.13,16,17
Results and Discussion
Synthesis of Furyl Alkynes and Related Substrates. Furyl
alkynes 17, 19-22, 24-30, and 32 were prepared by propar-
gylation of the corresponding alcohols with propargyl bromide
and NaH (Chart 1).22 Thiophene derivative 3123 and benzofuran
33 were also prepared by this method. The C-5 substituent of
24-26 was introduced by alkylation of the lithiated TBS
protected furfuryl alcohol. The precursor of 28 was prepared
by silylation of the lithiated TBS protected furfuryl alcohol. The
aryl substituents of substrates 27 and 30 were attached by Suzuki
or Stille coupling reactions of the corresponding arylboronic
acids or phenyltributylstannane, respectively, whereas 18 was
prepared by the Sonogashira reaction of iodobenzene with 17.
Substrate 23 was prepared by alkylation of the sodium enolate
In contrast with this reaction mode, Hashmi demonstrated
that the intramolecular reaction of furans with alkynes affords
(9) (a) Chatani, N.; Inoue, H.; Ikeda,. T.; Murai, S. J. Org. Chem. 2000, 65,
4913-4918. (b) Inoue, H.; Chatani, N.; Murai, S. J. Org. Chem. 2002, 67,
1414-1417.
(10) Dankwardt, J. W. Tetrahedron Lett. 2001, 42, 5809-5812.
(11) Herndon, J. W.; Zhang, Y.; Wang, K. J. Organomet. Chem. 2001, 634,
1-4.
(18) (a) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. J. Am. Chem. Soc. 2000,
122, 11 553-11 554. (b) Hashmi, A. S. K.; Frost, T. M.; Bats, J. W. Org.
Lett. 2001, 3, 3769-3771.
(12) Fu¨rstner, A.; Mamane, V. J. Org. Chem. 2002, 67, 6264-6267.
(13) The cyclization of alkynes with arenes can also be promoted by strong
protic acids: Tovar, J. D.; Swager T. M. J. Organomet. Chem. 2002, 653,
215-222, and references therein.
(19) This transformation is somewhat reminiscent of the synthesis of phenols
by intramolecular Diels-Alder reaction of alkynes with furans in the
presence of a base, a reaction that actually takes place by previous
isomerization of the alkyne to the allene: (a) Wu, H.-J.; Shao, W.-D. Ying,
F.-H. Tetrahedron Lett. 1994, 35, 729-732. (b) Wu, H.-J.; Ying, F.-H.;
Shao, W.-D. J. Org. Chem. 1995, 60, 6168-6172.
(14) For the cyclization of similar systems with iodonium salts: Barluenga, J.;
Gonza´lez, J. M.; Campos, P. J.; Asensio, G. Angew. Chem., Int. Ed. 1988,
27, 1546-1547.
(15) (a) Merlic, C. A.; Pauly, M. E. J. Am. Chem. Soc. 1996, 118, 11 319-
11 320. (b) Maeyama, K.; Iwasawa, N. J. Am. Chem. Soc. 1998, 120, 1928-
1929. (c) Maeyama, K.; Iwasawa, N. J. Am. Chem. Soc. 1942, 64, 1344-
1346.
(20) (a) Kappe, C. O.; Murphree, S. S.; Padwa, A. Tetrahedron 1997, 53,
14 179-14 233. (b) Moore, J. A.; Partain, E. M. J. Org. Chem. 1983, 48,
1105-1106.
(21) Mart´ın-Matute, B.; Ca´rdenas, D. J.; Echavarren, A. M. Angew. Chem., Int.
Ed. 2001, 40, 4754-4757.
(16) Akiyama, R.; Kobayashi, S. Angew. Chem., Int. Ed. 2002, 41, 2602-2604.
(17) Ruthenium vinylidenes were also suggested as intermediates in the synthesis
of 1H-naphtho[2,1-b]pyrans by reaction of phenols with propargyl alcohols
catalyzed by [Cp*RuCl(µ2-SMe)2RuCp*Cl]: Nishibayashi, Y.; Inada, Y.;
Hidai, M.; Uemura, S. J. Am. Chem. Soc. 2002, 124, 7900-7901.
(22) The preparation of substrates of Chart 1 is detailed in the Supporting
Information.
(23) Boese, R.; Harvey, D. F.; Malaska, M. J.; Vollhardt, K. P. C. J. Am. Chem.
Soc. 1994, 116, 11 153-11 154.
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Role of Platinum Carbenes as Intermediates
A R T I C L E S
Chart 1
in good yield, giving a 5:1 ratio of 42 and 43. The cyclization
of 17 with AuCl3 (3 mol %) as the catalyst in MeCN at room
temperature also afforded a mixture of 42 and 43, although the
yields were lower (30 and 1.5%, respectively). Only traces of
phenols were obtained with RuCl3 or RhCl3 in acetone under
reflux, whereas Pd(MeCN)2Cl2, Cu(MeCN)4PF6, or NiCl2‚6H2O
led only to recovered starting material. In general, we preferred
to use more readily available PtCl2 as the catalyst, without any
purification of the commercial chloride. Rigorous exclusion of
water from the solvents was not necessary.
The cyclization of 18, with a phenyl substituent at the alkyne,
failed to give any phenol derivative. On the other hand, reaction
of 19 took place in good yield to afford a 2.4:1 mixture of 44
and 45 (Table 1, entry 5). However, substrates 20-22 only gave
depropargylated alcohols as the major products. Substrate 23
behaved normally giving a mixture of 46 and 47 (Table 1, entry
6).
Reaction of 24 afforded selectively 4-hydroxyderivative 48
(Table 1, entry 7). In this case, traces of a second phenol (ca.
1% yield) could also be isolated. On the basis of the observation
of two singlets at 6.98 and 6.65 for the aryl hydrogens, structure
49 was assigned for this secondary product. The cyclization of
the homologous 25 proceeded in 94% yield to give 50 (Table
1, entry 8). Allyl substituted 26, which was obtained partially
contaminated with E-1-propenyl isomer (ca. 20%), reacted to
give an inseparable 2:1 mixture of 51 and 52 (Table 1, entry
9). Partial conjugation of the double bond with the aryl was
observed under all the conditions examined. Phenyl substituted
derivative 27 was cyclized in excellent yield with PtCl2 to give
53 (Table 1, entry 10). Identical result was obtained with Pt-
(MeCN)2Cl2 as the catalyst.
of dimethyl propargyl malonate with (2-furylmethyl)tetrameth-
ylenesulfonium hexafluorophosphate.24 All attempts to prepare
2-bromomethylfuran met with failure due to its instability.
However, treatment of 2-hydroxymethylbenzofuran25 with PBr3
provided 2-bromomethylbenzofuran, which reacted with the
sodium enolate of dimethyl propargyl malonate to afford 34.
2-Arylfuran 35 was prepared by the Sonogashira coupling
of trimethylsilylacetylene with 1,2-diiodobenzene, followed by
a Negishi coupling of the resulting 2-iodo-1-(trimethylsilyl-
ethynyl)benzene26 with furyl zinc chloride. Treatment of 35 with
NaOH furnished 36, which was methylated to give 37.
Substrates 38-41 were prepared by propargylation of the
corresponding phenol or N-tosyl anilines.
Synthesis of Phenols Catalyzed by PtCl2. By using PtCl2
(5 mol %) as the catalyst in acetone under reflux, 17 gave a
2.75:1 mixture of phenols 42 and 43 in 60% yield (Table 1,
entry 1). The reaction in toluene or 1,4-dioxane led to poor
results. Complex Pt(MeCN)2Cl2 could also be used as the
catalyst (Table 1, entry 2), whereas the reaction failed with Pt-
(COD)Cl2 in acetone (Table 1, entry 3). However, the cyclization
of 17 in 1,4-dioxane under reflux with Pt(COD)Cl2 proceeded
The reaction of tert-butyldimethylsilyl derivative 28 pro-
ceeded with partial cleavage of the silyl group. When the crude
reaction mixture was treated with trifluoroacetic acid, phenol
43 was isolated in good yield (Table 1, entry 11).27 This
procedure allowed for the selective synthesis of 43, a phenol
that was obtained as the minor product of cyclization of substrate
17. Reaction of 30 with PtCl2 led to 54 in moderate yield,
although more satisfactory results were obtained with Pt(COD)-
Cl2 in 1,4-dioxane (Table 1, entries 12-13). Analysis of the
crude reactions mixtures revealed the presence of aldehydes,
which suggests that the sterically demanding aryl substituent
of 30 interfered with the annulation process (see below). In
contrast with furan 17, the thiophene analogue 31 was recovered
unchanged under all the conditions examined.
Reactions with PtCl2 in Aqueous Acetone. The reaction of
labile bromofuran 29 with PtCl2 as the catalyst gave complex
reaction mixtures. After much experimentation, a reaction
performed in aqueous acetone with PtCl2 as the catalyst (5 mol
%) gave 55 as the major compound (41%). This unexpected
product arises by cleavage of the propargyl group to form
5-bromofurfuryl alcohol, formal nucleophilic displacement of
(24) Zhang, S.; Marshall, D.; Liebeskind, L. S. J. Org. Chem. 1999, 64, 2796-
2804.
(25) Kundu, N. G.; Pal, M.; Mahanty, J. S.; De, M. J. Chem. Soc., Perkin Trans.
1 1997, 2815-2820.
(26) Maeyama, K.; Iwasawa, N. J. Org. Chem. 1999, 64, 1344-1346.
(27) For the accelerating effect of 5-silyl groups on the reactivity at C-2 of
furans towards electrophiles: Herrlich, M.; Hampel, N.; Mayr, H. Org.
Lett. 2001, 3, 1629-1632.
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A R T I C L E S
Mart´ın-Matute et al.
a
Table 1. Cyclization of Furylalkynes with PtCl2
a Unless otherwise stated, the reactions were carried out in acetone under refluxing conditions for 15-17 h with 5 mol % catalyst. b Reaction in 1,4-
dioxane. c The staring material contained ca. 20% conjugated isomer. d After treatment of the crude reaction mixture with TFA.
9
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Role of Platinum Carbenes as Intermediates
A R T I C L E S
Scheme 4
Chart 2
of an advanced intermediate, once the first C-C bond has
already been formed.
To determine the reaction profile for the intramolecular
reaction of alkynes and furans, we performed density functional
calculations (DFT) on 5-(2-furyl)-1-pentyne as a model com-
pound. Several pathways could be envisaged in principle starting
by coordination of the alkyne to the metal center (I, Chart 2),
which was assumed to be also coordinated to a water molecule.
This is not an unrealistic assumption because the cyclizations
were carried out with solvents that contained some water.
Moreover, we have shown that water is an excellent ligand for
Pt(II), which can displace an alkene from the coordination sphere
of square planar Pt(II).1b From complex I, a Diels-Alder
reaction between the furan and the coordinated alkyne could
give intermediate II.18 Alternatively, in analogy with the reaction
of enynes (Scheme 1), formation of a cyclopropyl Pt-carbene
III by reaction of the alkyne with the C2-C3 double bond of
furan could also be conceived.1,29 A third plausible mechanism
involves a Friedel-Crafts type reaction of the electron deficient
alkyne at C2 of the furan to form zwitterionic intermediate IV.
The Diels-Alder cycloaddition of complex I leads to endo
the bromide of a second molecule of 29, and Markovnikov
hydration of the alkyne.28
Reaction of 17 or 24 with PtCl2 in aqueous solvents led to
1
very complex reaction mixtures, whose NMR indicated the
presence of aldehydes. Thus, reaction of 17 in aqueous acetone
gave very labile 56 (Scheme 4), which could be isolated only
in low yield, along with phenols 42 and 43 and oligomeric
material. Reaction of 17 in a mixture of acetone and DMSO
provided 56. Although the yield was low (5%), it is significant
that in the presence of DMSO no phenols 42 and 43 were
formed. Reaction of 24 in aqueous acetone allowed for the
isolation of phenol 48 (38%), and keto aldehydes 57 (4%) and
58 (10%). Although furyl alkyne 18 failed to provide any phenol
under the standard conditions, its reaction with PtCl2 in aqueous
acetone gave keto aldehyde 59 as the major product, which was
isolated in 24% yield.
Mechanism for the Formation of Phenols in the PtCl2-
Catalyzed Cyclization of 5-(2-furyl)-1-Alkynes. Formation of
2,5-dihydrofurans 56-59 suggests that the formation of the
C-C bonds of the final phenols is a stepwise process that starts
by formation of a C-C bond between the R carbon of the furan
and C-2 of the alkyne. Similarly, formation of 59 in an aqueous
solvent indicates that the failure of 18 to give a phenol under
the standard conditions can be attributed to the lack of reactivity
adduct II in an endothermic transformation (+8.5 kcal mol-1
)
(Chart 2 and Figure 1).30 The transition state TS1 lies 30.2 kcal
mol-1 above I and shows relatively short C-C distances for
the bonds that are being formed, especially for the one involving
the alkyne terminal carbon (2.025 Å). The Cl-Pt-Cl angle
diminishes from I to II (171.6° to 161.9°) due to the steric
hindrance imposed by the side chain. Alternatively, the internal
carbon of the alkyne can react with the nucleophilic C2-C3
bond of the furan to give the cyclopropylcarbene III. This
complex shows a very short C(sp2)-Pt distance (1.890 Å),
similar to that found for model 2 (MCln ) Pt(H2O)Cl2, Z )
CH2; R ) Me) (1.881 Å).1b The formation of III is exothermic
(-3.4 Kcal mol-1) and the activation energy to reach transition
state TS2 is much lower (9.4 Kcal mol-1) than the corresponding
to the Diels-Alder reaction. The reaction of I to give III would
be the preferred pathway from both thermodynamic and kinetic
(29) Structure of Pt(II) carbenes: (a) Cucciolito, M. A.; Panunzi, A.; Rufo, F.;
Albano, V. G.; Monari, M. Organometallics 1999, 18, 3482-3489. (b)
Cave, G. W. V.; Hallett, A. J.; Errington, W.; Rourke, J. P. Angew. Chem.,
Int. Ed. Engl. 1998, 37, 3270-3272. (c) Anderson, G. K.; Cross, R. J.;
Manojlovic-Muir, L.; Muir, K. W.; Wales, R. A. J. Chem. Soc., Dalton
Trans. 1979, 4, 684-689.
(28) (a) Hiscox, W.; Jennings, P. W. Organometallics 1990, 9, 1997-1999. (b)
Hartman, J. W.; Hiscox, W.; Jennings, P. W. J. Org. Chem. 1993, 58,
7613-7614. (c) Kataoka, Y.; Osamu, M.; Tani, K. Organometallics 1996,
15, 5246-5249. (d) Baidossi, W.; Lahav, M.; Blum, J. J. Org. Chem. 1997,
62, 669-672. (e) Weber, L.; Barlmeyer, M.; Quasdorff, J.-M.; Sievers, H.
L.; Stammler, H.-G.; Neumann, B. Organometallics 1999, 18, 2497-2504.
(30) Atomic coordinates for the structures of Figures 1 and 2 are given in the
Supporting Information.
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A R T I C L E S
Mart´ın-Matute et al.
Figure 1. Reaction coordinate for the first (two alternative pathways) and the second steps of intramolecular reaction of furans with alkynes with PtCl2.
ZPE corrected energies are given in kcal mol-1
.
Scheme 5
the formation of the isolated phenols (i.e. 65), has also been
proposed by Hashmi in the AuCl3-catalyzed synthesis of
phenols.18 In the last step, it was demonstrated that the OH of
the phenol is derived from the oxiranyl oxygen.18b,31 The
isolation of phenol 49 from 24 indicates that arene oxide 64
could rearrange to form an isomeric arene oxide by the “oxygen
walk” mechanism,32 although this is only a minor side
process.18b,33
Formation of dicarbonyl derivatives 56-59 when the reaction
was carried out in the presence of aqueous acetone can be
explained by the addition of water to the platinum carbene to
give 66 (Scheme 6), which could be cleaved by traces of acid
to form 67. Isomerization of 67 via 68, would give more stable
dicarbonyl compounds 69. Alternatively, decomposition of 66
could give 70, which would suffer cis to trans isomerization to
yield 71.34 The transformation of 66 to 70 involves a formal
â-hydrogen elimination to form a platinum hydride that
decomposes to give Pt(0) and HCl. We have previously observed
the formation of an aldehyde from a proposed platinum carbene
intermediate that could take place by a similar process.1b,35
DMSO as a cosolvent might also oxidize carbene 62 to give
dicarbonyl compounds of type 71.36
reasons. The attack of the furan takes place on the opposite
side to the metal through an early asymmetric transition state
with very different C-C distances (2.528 and 2.293 Å for a
and b in TS2, Figure 1). The formation of a Friedel-Crafts
complex IV was also considered but the only minimum energy
structure that could be located was again III. Apparently, the
delocalization of the positive charge in IV is not enough to
compensate the stability of the Pt-cyclopropylcarbene III.
Cleavage of the cyclopropane bond a of III takes place with
the concerted opening of the dihydrofuran to form complex V
in an exothermic transformation (-9.8 kcal mol-1) that implies
only bond dissociations and proceeds with an activation energy
of 7.6 kcal mol-1 (Figure 1).
These findings led to the mechanistic proposal summarized
in Scheme 5. The initially formed complex 60 would give
intermediate 61 exothermically. An intramolecular [2+2] cy-
cloaddition of the platinum carbene of 62 with the carbonyl
could then give 63, which would suffer reductive elimination
to form arene oxide 64. This last intermediate, which explains
(31) For reviews on arene oxides and their isomeric oxepins: (a) Vogel, E.;
Gu¨nther, H. Angew. Chem., Int. Ed. Engl. 1967, 6, 385-401. (b) Boyd, D.
R.; Sharma, N. D. Chem. Soc. ReV. 1996, 25, 289-296. (c) For a recent
lead reference on the structure of arene oxides, see: Jia, Z. S.; Brandt, P.;
Thibblin, A. J. Am. Chem. Soc. 2001, 42, 10 147-10 152.
(32) (a) Bruice, P. Y.; Kasperek, G. J.; Bruice, T. C.; Yagi, H.; Jerina, D. M. J.
Am. Chem. Soc. 1973, 95, 1673-1674. (b) Kasperek, G. J.; Bruice, P. Y.;
Bruice, T. C.; Yagi, H.; Jerina, D. M. J. Am. Chem. Soc. 1973, 95, 6041-
6046.
(33) The preferred formation of 5-hydroxy derivatives in the cyclizations of
17, 19, and 23 presumably reflects the higher stability of the corresponding
carbocationic intermediates. Modeling the opening of 1,3-dihydroisoben-
zofuran-4,5-oxide (64, R1 ) H) by H+, we estimated a difference of 2.7
kcal.mol-1 in the ∆Hf (PM3 calculations) favoring the intermediate that
leads to major isomer 42.
(34) The isomerization of 67 into R,â-unsaturated-1,6-dicarbonyl derivative 69
is a thermodinamically driven process [∆Hcalc ) -12.8 kcal.mol-1 (R1 )
R2 ) H) or -10.8 kcal.mol-1 starting from the E isomer of 72; PM3
calculations].
(35) For the related oxidation of a nickel carbene intermediate, see: Chowdhury,
S. K.; Amarasinghe, K. K. D.; Heeg, M. J.; Montgomery, J. J. Am. Chem.
Soc. 2000, 122, 6775-6776.
9
5762 J. AM. CHEM. SOC. VOL. 125, NO. 19, 2003

Role of Platinum Carbenes as Intermediates
A R T I C L E S
Scheme 6
Scheme 7
unsaturated rhodium(I) carbenes to afford oxepins, which finally
evolve to afford substituted phenols.42
On the basis of these mechanistic proposals, two alternative
cyclization pathways for complex 62 were considered (Scheme
7). Thus, an 8π-electrocyclization of 62, similar to that proposed
by Padwa,42 would give 72. On the other hand, a direct attack
of the carbonyl oxygen to the electrophilic carbene carbon would
generate intermediate 73. Oxepin 74 could be formed by
reductive elimination of PtCl2 from 72, or by a cleavage of the
C-Pt bond of 73.43 Equilibration of oxepin 74 with arene oxide
64,31,32,44 and epoxide opening (as in Scheme 5) would finally
afford phenols 65. Alternatively, 73 could directly cyclize to
give arene oxide 64. Valence tautomers 74 and 64 probably
coexist in solution, favoring the more stable oxepins,45 because
the activation energy for the isomerization has been shown to
be low.44
Although the reactions in the presence of water give support
for the involvement of intermediate 62 in the reaction pathway,
the proposed [2+2] cycloaddition and subsequent reductive
elimination37 was somewhat speculative. Related rhodium
carbenes have been shown by Murai to react intramolecularly
with alkenes to from cyclopropanes.5c However, the transforma-
tion of 62 to 63 appears to have no precedent. In support for
this transformation, we performed DFT calculations for the
[2+2] cycloaddition between Cl2(H2O)PtdCH2 and formalde-
hyde as a simplified model system.38 Although the calculations
were in rough agreement with the mechanistic proposal ad-
vanced in Scheme 5, the activation energy for the [2+2]
cycloaddition was found to be rather high (31.4 kcal mol-1).
We therefore searched for alternative evolutions of intermediate
62 in route to the final phenols.
Herndon has proposed that the intramolecular reaction of
aldehydes with Fischer chromium carbenes gives tetrahedral
intermediates by attack of the carbonyl oxygen to the carbene
carbon.39 Similarly, rhodium carbenes react with carbonyl
compounds to form carbonyl ylides.40,41 Particularly relevant
is the proposal by Padwa of an 8π-electrocyclization of
Two different mechanisms for the evolution of intermediate
V were considered. First, an intramolecular attack of the
aldehyde oxygen on the carbene carbon would afford an oxepin
derived complex such as VI (Figure 2). This slightly endother-
mic transformation is geometrically feasible due to the s-cis
conformation of the carbene of V′, a slightly less stable
(41) (a) Doyle, M. P.; Hu, W.; Timmons, D. J. Org. Lett. 2001, 3, 933-935.
(b) Chiu, P.; Chen, B.; Cheng, K. F. Org. Lett. 2001, 3, 1721-1724. (c)
Hamaguchi, M.; Matsubara, H.; Nagai, T. Tetrahedron Lett. 2000, 41,
1457-1460. (d) Jiang, B.; Zhang, X.; Luo, Z. Org. Lett. 2002, 4, 2453-
2455.
(42) Padwa, A.; Kassir, J. M.; Xu, S. L. J. Org. Chem. 1997, 62, 1642-1652.
(43) Oxepins have also been proposed as intermediates in the synthesis of phenols
from (2-acylcyclopropyl)vinylidene-metal (Cr, Mo, W) complexes: Ohe,
K.; Yokoi, T.; Miki, K.; Nishino, F.; Uemura, S. J. Am. Chem. Soc. 2002,
124, 526-527.
(36) Oxidation of carbenes with DMSO: (a) Casey, C. P.; Anderson, R. L. J.
Am. Chem. Soc. 1974, 96, 1230-1231. (b) Do¨tz, K. H. J. Organomet. Chem.
1979, 182, 4869. (c) Ezquerra, J.; Pedregal, C.; Merino, I.; Flo´rez, J.;
Barluenga, J.; Garc´ıa-Granda, S.; Llorca, M. A. J. Org. Chem. 1999, 64,
6554-6565. (d) See also: Perdicchia, D.; Licandro, E.; Maiorana, S.;
Vandoni, B.; Baldoli, C. Org. Lett. 2002, 4, 827-830.
(37) Formation of epoxides from four-membered ring oxametallacycles: (a)
Mavrikakis, M.; Doren, D. J.; Barteau, M. A. J. Phys. Chem. B 1998, 101,
394-399. (b) Linic, S.; Barteau, M. A. J. Am. Chem. Soc. 2002, 124, 310-
317.
(44) For theoretical work on the oxepin/arene oxide equilibrium: (a) Hayes, D.
M.; Nelson, S. D.; Garland, W. A.; Kollman, P. A. J. Am. Chem. Soc.
1980, 102, 1255-1262. (b) Schulman, J. M.; Disch, R. L.; Sabio, M. L. J.
Am. Chem. Soc. 1984, 106, 7696-7700. (c) Bock, C. W.; George, P.;
Stezowski, J. J.; Glusker, J. P. Struct. Chem. 1990, 1, 33-39. (d) Bock, C.
W.; George, P.; Glusker, J. P. THEOCHEM 1991, 80, 227-246. (e)
Contreras, J. G.; Madariaga, S. T. Bol. Soc. Chil. Qu´ım. 2001, 46, 471-
480.
(38) Calculations on the formation of epoxides by [2+2] cycloaddition/reductive
elimination are given as part of the Supporting Information.
(39) (a) Herndon, J. W.; Wang, H. J. Org. Chem. 1998, 63, 4564-4565. (b)
Jiang, D.; Herndon, J. W. Org. Lett. 2000, 2, 1267-1269. (c) Zhang, Y.;
Herndon, J. W. J. Org. Chem. 2002, 67, 4177-4185. (d) Ghorai, B. K.;
Herndon, J. W.; Lam, Y.-F. Org. Lett. 2001, 3, 3535-3538.
(45) According to PM3 calculations, the oxepins 74 (Z ) O, CH2; R1 ) H, Ph)
are 10.3-12.7 kcal.mol-1 more stable than the corresponding arene oxides.
(40) Padwa, A.; Weingarten, M. D. Chem. ReV. 1996, 96, 223-270.
9
J. AM. CHEM. SOC. VOL. 125, NO. 19, 2003 5763

A R T I C L E S
Mart´ın-Matute et al.
Scheme 8
Figure 2. Reaction coordinate for the evolution of intermediate V. ZPE
corrected energies are given in kcal mol-1
.
conformer of V lying on the way to VI. The reaction takes place
through TS4 with an activation energy of 2.9 kcal mol-1. The
alternative electrocyclization pathway (62 f 72, Scheme 7)
would give complex VII with much higher energy than TS4.
The alternative five-coordinated complex, without the second
molecule of water, is even less stable than VII. Therefore, attack
of the aldehyde oxygen to the carbene carbon would be the
preferred reaction. The calculations of the evolution of inter-
mediate V agree with the proposal by Herndon for the
intramolecular reaction of carbonyl groups with Fischer carbene
complexes.39 A similar pathway might be also followed by the
Rh(I) carbenes involved in the reaction of cyclopropenes with
alkynes catalyzed by [RhCl(CO)2]2.42
Scheme 9
The result of Figure 2 sheds light on the nature of the Pt-C
bonds in complexes III, V, and V′, which display relatively
short Pt-C distances (1.890, 1.885, and 1.878 Å, respectively).29
The electrophilic behavior of the coordinated carbon suggests
a Fischer type carbene character for these complexes.
Cyclizations that Proceed through (apparent) Friedel-
Crafts-Type Reactions. According to the mechanistic proposal
of Scheme 5, attaching the alkyne-containing chain at C-3 of
the furan was expected to give intermediate 75, which might
evolve in this case by cleavage of the bond labeled b of the
cyclopropyl ring to form 76, which could afford a furan by
deprotonation (Scheme 8).
In the event, treatment of 3-furylmethyl propargyl ether (32)
with PtCl2 (5 mol %) led to 77 as the only new product, although
the isolated yield was low due to its ready polymerization. For
this reason, the crude product was immediately hydrogenated
to give 78 (Scheme 8). Curiously, the best result (34% overall
yield) was realized in the presence of allyl chloride, although
the role of this additive in not clear. In contrast, the use of Pd-
(MeCN)2Cl2 (5 mol %) as the catalyst (Et2O, reflux) gave rise
to chloroallylation of the terminal alkyne46 furnishing 79.
Benzofuran 33 suffered depropargylation under the standard
cyclization conditions. However, malonate derivative 34 reacted
with PtCl2 by an exo-mode attack of C-3 of the benzofuran to
the alkyne to give 80 (70%) (Scheme 9). Formation of 80 can
be rationalized by the formation of intermediate 81, which would
suffer preferential opening via cleavage of bond b to form 82,
and then 80. Although cleavage of bond a appears to be possible
(as in 61, Scheme 6), benzannulation probably prevents
subsequent formation of an intermediate similar to 62.
According to the proposal of Scheme 5, a tether of one or
two atoms between the furan and the alkyne should not favor
formation of an intermediate like 61, because a three or four-
membered ring would have to be formed. Thus, 36 reacted with
PtCl2 by a different pathway to that followed by 5-(2-furyl)-1-
alkynes, leading to naphthol[1,2-b]furan (83)47 in excellent yield
(Scheme 10). This result is in keeping with shown in Scheme
2 for heterocycles 8.10,12 Trimethylsilyl substituted substrate 35
failed to react under these conditions, while the reaction of 37
was very sluggish, leading to 84 in only 10% yield after 80 h.
Arylalkynes 38-41 also reacted with PtCl2 (Scheme 9). Aryl
propargyl ether 38 was cyclized with Pt(MeCN)2Cl2 in refluxing
acetone to give 85. Although this transformation proceeds in
excellent yield (95%), decomposition of 85 by traces of acids
(46) (a) Kaneda, K.; Uchiyama, T.; Fujiwara, Y.; Imanaka, T.; Teranishi, S. J.
Org. Chem. 1979, 44, 55-63. (b) Ba¨ckvall, J.-E.; Nilsson, Y. I. M.; Gatti,
R. G. P. Organometallics 1995, 14, 4242-4246, and references therein.
(47) Narasimhan, N. S.; Mali, R. S. Tetrahedron 1975, 31, 1005-1009.
9
5764 J. AM. CHEM. SOC. VOL. 125, NO. 19, 2003

Role of Platinum Carbenes as Intermediates
A R T I C L E S
Scheme 10
Scheme 11
Scheme 12
methanol-d4, almost complete deuteration was observed at both
C-4 and C-5 of 83. This unexpected result could be explained
by the ready deuteration of the relatively acidic arylalkyne
facilitated by η2-coordination to PtCl2. It is important to note
that substrate analogous to 37, with a pyrrole instead of a furan,
was cyclized in excellent yield by Danwardt,10 which excluded
the vinylidene pathway.
The results of Scheme 10 could be explained by invoking an
electrophilic aromatic substitution pathway (Friedel-Crafts-type
reaction).9,12 Although this proposal is quite plausible, alternative
explanations based on the formation of cyclopropyl platinum
carbenes also account for the experimental results. Thus, the
exo-cyclization of 36 and 37 would have formed high energy
intermediates such as 90 (Scheme 11), less likely than cyclo-
propyl platinum carbenes 91, which would open to form
zwitterionic intermediates 92, precursors of 83 and 84.
Deuteration studies exclude the participation of vinylidenes
in the reactions of 38-41, which would have led to deuteration
at C-4 by methanol-d4. In these cases, a mechanism involving
formation of cyclopropyl platinum carbenes 93, which would
open to form 94, nicely justifies the formation of 2H-chromenes
and 1,2-dihydroquinolines by endo cyclizations (Scheme 12).
The alternative exo pathways, via 95 and 96, would be clearly
disfavored processes.
or by radical pathways led in occasions to much lower yields.
When the reaction mixture was immediately hydrogenated (1
atm H2, Pd/C), dihydro-6H-[1,3]dioxolo[4,5-g]chromene could
be obtained in 83% overall yield. The reaction of 38 in toluene
under refluxing conditions afforded a mixture of 85, the
regioisomer resulting from attack at C-2 of the aryl, and
depropargylated phenol. However, at 80 °C in toluene, only 85
was obtained. Deuterated derivative 38-d1 furnished 85-d1
exclusively.
Aniline derivatives 39-41 reacted with PtCl2 under reflux
in acetone or toluene, although the best results were obtained
in toluene. The reaction of 39 was quite slow and gave 86 in
poor yield along with substantial amounts of depropargylated
material.48 Substrate 40 gave 87 (48%) and N-tosyl-3,4-
dimethoxyaniline (50%). More electron-rich 41 gave 88 and
N-tosyl-3,4,5-trimethoxyaniline in 76% and 20% yield, respec-
tively. When the reactions of 40 and 41 were carried out in the
presence of methanol-d4, deuterated 87-d1 and 88-d1 were
obtained.
The cycloisomerization of 36 into 83 could take place through
vinylidene 89 (Scheme 11),10,13 although such a process would
be impossible for substituted derivative 37. It could be argued,
however, that the slow reaction and low yield of this reaction
indicates that the system is forced to follow an alternative, higher
energy pathway. Deuteration experiments do not exclude the
participation of intermediate 89 in the cyclization of 36. Thus,
when the reaction of 36 was performed in the presence of
Conclusions
In summary, the intramolecular reaction of furans with
alkynes catalyzed by PtCl2 is mechanistically related to that of
enynes in polar solvents and is initiated by the nucleophilic
attack of the furan on a (η2-alkyne)platinum(II) complex 60
(Scheme 13) to form a cyclopropyl platinum carbene 61. This
step is followed by cleavage of a C-C and a C-O bond of the
tricyclic intermediate to form a carbonyl compound 62, which
cyclizes to form 73. The active Pt(L)Cl2 catalyst is then probably
eliminated to form oxepin 74 in equilibrium with arene oxide
(48) N-tosyl-1,2-dihydroquinolines have been prepared by Pd(II)-catalyzed
cyclization of o-allylic tosylanilides: Larock, R. C.; Hightower, T. R.;
Hasvold, L. A., Peterson, K. P. J. Org. Chem. 1996, 61, 3584-3585.
9
J. AM. CHEM. SOC. VOL. 125, NO. 19, 2003 5765

A R T I C L E S
Mart´ın-Matute et al.
Scheme 13
Computational Methods
The calculations were performed with the GAUSSIAN 98 series of
programs.50 The geometries of all complexes were optimized applying
the density at the functional theory (DFT) at the generalized gradient
approximation using the B3LYP51 hybrid functional. The standard
6-31G(d) basis set was used for C, H, and Cl. For Pt we used the
standard LANL2DZ basis set, which includes a relativistic ECP and
the explicit description of 18 valence electrons by a double-ú basis
set. Harmonic frequencies were calculated at B3LYP level to character-
ize the stationary points and to determine the zero-point energies (ZPE).
The starting approximate geometries for the transition states (TS) were
located graphically. Intrinsic reaction coordinate calculations (IRC)
showed that the TS found actually connect the reagents and the products.
Acknowledgment. This work is dedicated to Prof. T. Ross
Kelly on the occasion of his 60th birthday. We are grateful to
the MCyT (Project BQU2001-0193-C02-01) for support of this
research. We also acknowledge the Ministerio de Ciencia y
Tecnolog´ıa and the Comunidad Auto´noma de Madrid for
predoctoral fellowships to B. M.-M. and C. N., respectively.
We acknowledge the Centro de Computacio´n Cient´ıfica (UAM)
for computation time and Johnson Matthey PLC for a generous
loan of PtCl2.
64, which is then transformed to substituted phenol 65.18,31,32
In this remarkable transformation, the first C-C bond is formed
in the first step, whereas the second C-C bond formation takes
place in the oxepin tautomerization, the penultimate step of the
process. An alternative pathway involving a [2+2] cycloaddition
of the carbonyl with the carbene seems less likely because of
the high activation energy involved.
Supporting Information Available: Experimental details,
characterization data for new compounds, results for the
calculation on the [2+2] cycloaddition/reductive elimination
pathway, and atomic coordinates for computed structures. This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA029125P
This work also sheds light on the reactivity of intermediate
platinum carbenes formed in the PtCl2-catalyzed reactions of
alkynes with alkenes or furans, which behave as reactive
Fischer-type carbenes toward nucleophiles. Other cyclizations
of alkynes with furans or electron-rich arenes give products of
apparent Friedel-Crafts-type reactions, although these trans-
formations could also be explained by mechanisms involving
the formation of cyclopropyl platinum carbenes.9,12,49
(50) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M.
A.; Cheeseman, J. R.; Zakrzewski, V. G.; Montgomery, J. A., Jr.; Stratmann,
R. E.; Burant, J. C.; Dapprich, S.; Millam, J. M.; Daniels, A. D.; Kudin,
K. N.; Strain, M. C.; Farkas, O.; Tomasi, J.; Barone, V.; Cossi, M.; Cammi,
R.; Mennucci, B.; Pomelli, C.; Adamo, C.; Clifford, S.; Ochterski, J.;
Petersson, G. A.; Ayala, P. Y.; Cui, Q.; Morokuma, K.; Malick, D. K.;
Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.; Cioslowski, J.; Ortiz,
J. V.; Stefanov, B. B.; Liu, G.; Liashenko, A.; Piskorz, P.; Komaromi, I.;
Gomperts, R.; Martin, R. L.; Fox, D. J.; Keith, T.; Al-Laham, M. A.; Peng,
C. Y.; Nanayakkara, A.; Gonzalez, C.; Challacombe, M.; Gill, P. M. W.;
Johnson, B. G.; Chen, W.; Wong, M. W.; Andres, J. L.; Head-Gordon,
M.; Replogle, E. S.; Pople, J. A. Gaussian 98, revision A.9; Gaussian,
Inc.: Pittsburgh, PA, 1998.
(49) Carbenoids (LnM-CRR′X) could be favored over carbenes (LnXM)CRR′)
with some metals: (a) Bernardi, F.; Bottoni, A.; Miscione, G. P.
Organometallics 2000, 19, 5529-5532. (b) For platinum carbenoids:
Hanks, T. W.; Ekeland, R. A.; Emerson, K.; Larsen, R. D.; Jennings, P.
W. Organometallics 1987, 6, 28-32.
(51) (a) Stephens, P. J.; Devlin, F. J.; Chabalowski, C. F.; Frisch, M. J. J. Phys.
Chem. 1994, 98, 11623-11627. (b) Kohn, W.; Becke, A. D.; Parr, R. G.
J. Phys. Chem. 1996, 100, 12 974-12 980.
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5766 J. AM. CHEM. SOC. VOL. 125, NO. 19, 2003