Tandem gold(I)-catalyzed cyclization/electrophilic cyclopropanation of vinyl allenes

Article abstract of DOI:10.1021/ol070788r

We have developed an expedient method for the synthesis of polycyclic compounds from propargyl acetates or vinyl allenes involving up to three Au(I)-catalyzed elemental steps: 3,3-rearrangement, metalla-Nazarov reaction, and electrophilic cyclopropanation. The reaction proceeds under very mild conditions and in short times. The mechanism has been studied by DFT computations.

Full text of DOI:10.1021/ol070788r

ORGANIC
LETTERS
2007
Vol. 9, No. 11
2207-2209
Tandem Gold(I)-Catalyzed Cyclization/
Electrophilic Cyclopropanation of Vinyl
Allenes
Gilles Lemie`re, Vincent Gandon, Kevin Cariou, Takahide Fukuyama,‡
Anne-Lise Dhimane, Louis Fensterbank,* and Max Malacria*
UniVersite´ Pierre et Marie Curie-Paris 6, Laboratoire de Chimie Organique
(UMR CNRS 7611), Institut de Chimie Mole´culaire (FR 2769), case 229, 4,
place Jussieu, 75252 Paris cedex 05, France
fensterb@ccr.jussieu.fr; malacria@ccr.jussieu.fr
Received April 5, 2007
ABSTRACT
We have developed an expedient method for the synthesis of polycyclic compounds from propargyl acetates or vinyl allenes involving up to
three Au(I)-catalyzed elemental steps: 3,3-rearrangement, metalla-Nazarov reaction, and electrophilic cyclopropanation. The reaction proceeds
under very mild conditions and in short times. The mechanism has been studied by DFT computations.
Gold and platinum salts are exquisite catalysts that activate
alkynes, alkenes, and allenes toward nucleophilic attack.1 In
that respect, vinyl allenes are converted into five-membered
ring systems, presumably via complexation of the allene
moiety and subsequent Nazarov-like cyclization2 leading to
a cyclopentenylidene intermediate (Scheme 1, eq I). Cyclo-
Scheme 1. Trapping of Cyclopentenylidene Complexes
‡ Osaka Prefecture University Sakai, Osaka 599-8531, Japan.
(1) For general reviews on “electrophilic” transition-metal-catalyzed
cycloisomerization reactions, see: (a) Jime´nez-Nu´n˜ez, E.; Echavarren, A.
M. Chem. Commun. 2007, 333-346. (b) Bruneau, C. Angew. Chem., Int.
Ed. 2005, 44, 2328-2334. (c) Diver, S. T.; Giessert, A. J. Chem. ReV. 2004,
104, 1317-1382. (d) Hashmi, A. S. K. Gold Bull. 2003, 36, 3-9. (e) Dyker,
G. Angew. Chem., Int. Ed. 2000, 39, 4237-4239. For selected recent
examples of Au- and Pt-catalyzed reactions involving allenes, see: (f) Liu,
Z.; Wasmuth, A. S.; Nelson, S. G. J. Am. Chem. Soc. 2006, 128, 10352-
10353. (g) Morita, N.; Krause, N. Angew. Chem., Int. Ed. 2006, 45, 1897-
1899. (h) Hyland, C. J. T.; Hegedus, L. S. J. Org. Chem. 2006, 71, 8658-
8660. (i) Zhang, Z.; Liu, C.; Kinder, R. E.; Han, X.; Kian, H.; Widenhoefer,
R. A. J. Am. Chem. Soc. 2006, 128, 9066-9073. (j) Lemie`re, G.; Gandon,
V.; Agenet, N.; Goddard, J.-P.; de Kozak, A.; Aubert, C.; Fensterbank, L.;
Malacria, M. Angew. Chem., Int. Ed. 2006, 45, 7596-7599. (k) Hashmi,
A. S. K.; Blanco, M. C.; Fisher, D.; Bats, J. W. Eur. J. Org. Chem. 2006,
1387-1389. (l) Zhou, C.-Y.; Chan, P. W. H. C.; Che, C.-M. Org. Lett.
2006, 8, 325-328. (m) Cadran, N.; Cariou, K.; Herve´, G.; Aubert, C.;
Fensterbank, L.; Malacria, M.; Marco-Contelles, J. J. Am. Chem. Soc. 2004,
126, 3408-3409.
pentadienes are finally obtained via 1,2-hydride migration
(R ) H, R′ ) aryl, alkyl).3 Alternatively, CH insertion (R
) R′ ) Me)3b or intramolecular nucleophilic addition of an
alkoxy group (R ) Me, R′ ) (CH2)2OH)3c has been
observed. Cyclopentadienylic acetate (or cyclopentenone
10.1021/ol070788r CCC: $37.00
© 2007 American Chemical Society
Published on Web 04/25/2007

after hydrolysis) was also formed via Au(I)-catalyzed 3,3-
rearrangement of enynyl acetates, Nazarov reaction, and
1,2-H migration (eq III).3a,4,5
acetate 4a (1.9:1 ratio) was obtained in 44% total yield when
2 mol % of ClAu(2-biphenyldicyclohexylphosphine) 68 and
AgSbF6 were used (entry 2). We next reacted compound 2b,
which displays a methyl group at the internal position of
the 1,3-enyne framework. Whereas AuCl3 still proved poorly
efficient (entry 3), a quantitative yield was obtained with a
catalytic mixture of 6 and AgSbF6 (entry 4). However, the
formation of cyclopentadiene could not be suppressed (3b:
4b ) 2.6:1). The selective conversion of 2b into 3b was
finally realized in 92% yield using 2 mol % of AuClPPh3
and AgSbF6 (entry 5). Surprisingly, tertiary acetate 2c was
selectively converted into bicyclo[4.3.0]nonadiene 5c with
both AuCl3 and cationic triphenylphosphinegold(I) (entries
6 and 7). We suspect that this product arose from an
intramolecular (gold)-catalyzed type I Diels-Alder reaction
of the putative vinyl allene intermediate with the terminal
double bond.9
We anticipated that cyclopentenylidenegold species could
be trapped by carbon-carbon double bonds.6 If successful,
metalla-Nazarov cyclization followed by intramolecular
electrophilic cyclopropanation would give rise to highly
valuable polycyclic compounds in a single operational step
(eq II). Our initial attempts using precursor 1 were dis-
appointing, with complex mixtures being systematically
obtained using both Au(I) and Au(III) catalysts (Table 1).
Table 1. Catalyst Optimization and Substrate Scope
From this set of results, we anticipated that substitution
at the internal 1,3-enyne position would favor the formation
of compounds of type 3 compared to 5. Using the AuClPPh3/
AgSbF6 catalytic mixture, methyl-substituted substrates 2d-g
were efficiently converted into the corresponding 5/5/3 or
5/6/3 fused systems (Table 2, entry 1). Compounds 3d-g
Table 2. Gold(I)-Catalyzed Cycloisomerizationsa
a Isolated yields. b Not separated.
On the other hand, acetates 2a-c gave promising results;
although AuCl3 failed to convert 2a (entry 1), the desired
tricyclic compound 3a7 admixed with cyclopentadienylic
(2) For recent reviews about the Nazarov reaction and related transforma-
tions, see: (a) Frontier, A. J.; Collison, C. Tetrahedron 2005, 61, 7577-
7606. (b) Pellissier, H. Tetrahedron 2005, 61, 6479-6517. (c) Tius, M. A.
Eur. J. Org. Chem. 2005, 2193-2206.
(3) (a) Zhang, L.; Wang, S. J. Am. Chem. Soc. 2006, 128, 1442-1443.
(b) Funami, H.; Kusama, H.; Iwasawa, N. Angew. Chem., Int. Ed. 2007,
46, 909-911. (c) Lee, J. H.; Toste, F. D. Angew. Chem., Int. Ed. 2007, 46,
912-914.
a Reaction conditions: AuClPPh3 (2 mol %), AgSbF6 (2 mol %), substrate
in CH2Cl2, rt, 10 min. b Isolated yields after column chromatography.
c Overall yield including 30% of 4h and 42% of cyclopentenone formed
during column chromatography; reaction time 24 h. d GC purity of 85%
after column chromatography; yields are corrected accordingly.
(4) The Pt- and Au-catalyzed 3,3-rearrangement of propargyl acetates
is a well-known process; see inter alia: (a) Marion, N.; D´ıez-Gonza´lez, S.;
De Fre´mont, P.; Noble, A. R.; Nolan, S. P. Angew. Chem., Int. Ed. 2006,
45, 3647-3650. (b) Wang, S.; Zhang, L. J. Am. Chem. Soc. 2006, 128,
8414-8415. (c) Cariou, K.; Mainetti, E.; Fensterbank, L.; Malacria, M.
Tetrahedron 2004, 60, 9745-9755. (d) Sromek, A. W.; Kel’in, A. V.;
Gevorgyan, V. Angew. Chem., Int. Ed. 2004, 43, 2280-2282. (e) Fu¨rstner,
A.; Hanen, P. Chem. Commun. 2004, 2564-2547 and references therein.
(5) For homologue reactions leading to acetoxy bicyclo[3.1.0]hexenes,
see: Buzas, A.; Gagosz, F. J. Am. Chem. Soc. 2006, 128, 12614-12615.
(6) For related intramolecular trappings of alkylidenegold species by
olefins, see: Nieto-Oberhuber, C.; Mun˜oz, M. P.; Bun˜uel, E.; Nevado, C.;
Carden˜as, D. J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2004, 43, 2402-
2406.
were isolated in excellent yields as single diastereomers. That
the formation of compounds of type 4 can be avoided using
tertiary acetates is a sufficient, but not necessary feature, was
revealed by the selective conversion of 2d into 3d. Still, the
(7) When possible, the configuration of compounds of type 3 and 8
appearing in this study was ascertained by nOe experiments.
(8) Herrero-Go´mez, E.; Nieto-Oberhuber, C.; Lo´pez, S.; Benet-Buchholz,
J.; Echavarren, A. M. Angew. Chem., Int. Ed. 2006, 45, 5455-5459.
2208
Org. Lett., Vol. 9, No. 11, 2007

tether length seems to dictate the outcome, as shown by the
selective conversion of 2h into cyclopentadiene 4h (entry
2). Tetracyclic fused structures could also be assembled using
2i and 2j (entries 3 and 4). Although 3i was obtained as a
single diastereomer, 3j was isolated as an inseparable
diastereomeric mixture. Nevertheless, the construction of
angular triquinanes such as 3j has always been the target of
many synthetic efforts.10 Since the substitution at the internal
enyne position facilitates the production of compounds of
type 3, we finally decided to reinvestigate the case of
preformed vinyl allenes. Gratifyingly, unlike compound 1,
vinyl allenes 7a-c proved to be suitable substrates for the
stereoselective cycloisomerizations into 8a-c (entry 5).
kcal/mol. From C, Nazarov-type cyclization leads to carbene
D.11 It requires 7.8 kcal/mol of enthalpy of activation and is
exothermic by 11.9 kcal/mol.12 Concerted electrophilic
cyclopropanation follows (red pathway), giving complex E
which exhibits two cis ring fusions. This step requires 10.2
kcal/mol of enthalpy of activation and is exothermic by 17.2
kcal/mol.
Alternatively, 1,2-hydrogen migration may occur (blue
pathway), leading to gold-complexed cyclopentadiene H.
This hydrogen shift appears less favored kinetically and
thermodynamically compared to the electrophilic cyclopro-
panation, the enthalpy of activation being evaluated as 14.5
kcal/mol and the exothermicity as 13.7 kcal/mol. This result
is in satisfactory agreement with the experimental results
described in Table 1. In E, gold still coordinates to a
cyclopropyl bond. It then migrates to the acetoxy group via
The mechanism of the title reaction is hypothesized in
Figure 1 and supported by DFT/B3LYP computations.
a very low-lying transition state (∆Hq ) 0.1 kcal/mol).
298
This shift is appreciably exothermic by 11.1 kcal/mol.
Decomplexation of the species F gives the final product G
and regenerates the catalyst.13,14
In conclusion, we have developed a novel method for the
synthesis of polycyclic compounds from propargyl acetates
and vinyl allenes involving up to three Au(I)-catalyzed
elemental steps: 3,3-rearrangement, metalla-Nazarov reac-
tion, and electrophilic cyclopropanation. Application of this
new methodology to asymmetric and total synthesis is
currently under active investigation in our laboratory.
Acknowledgment. This work was supported by CNRS,
MRES, IUF, UPMC (T.F.). and ANR BLAN 06-2_159258.
We thank the computing facilities of CRIHAN (project 2006-
013).
Supporting Information Available: An additional ex-
periment in which the incipient vinyl allene can be isolated
and transformed into a 6,6-fused system via thermal Diels-
Alder cycloaddition, experimental procedures, and spectral
data; computational details. This material is available free
of charge via the Internet at http://pubs.acs.org.
Figure 1. Proposed reaction mechanism supported by DFT/B3LYP
calculations (M ) AuPMe2Ph+). ∆H298 (kcal/mol) values relative
to C are given in parentheses. ∆Hq298 values are depicted in bold.
Isomerization of propargyl acetates into 3-acetoxy 1,2,4-
trienes such as A was taken for granted at this stage.4
Coordination of gold to the allene framework gives rise to
diastereomers B and C, the latter being more stable by 2.9
OL070788R
(11) The C-Au distance is 2.04 Å. Gold carbenes present Au-C bonds
of 2.0-2.1 Å; see inter alia: Nevado, C.; Ca´rdenas, D. J.; Echavarren, A.
M. Chem.sEur. J. 2003, 9, 2627-2635.
(12) From B, the enthalpy of activation is 10.4 kcal/mol (13.3 kcal/mol
relative to C).
(13) For related computations on gold(I)-catalyzed Rautenstrauch re-
arrangement, see: Faza, O. N.; Silva Lo´pez, C.; AÄ lvarez, R.; de Lera, A.
R. J. Am. Chem. Soc. 2006, 128, 2434-2437. For precedent computed
cyclopropanations involving gold carbenes, see ref 11.
(14) Once E is formed, the demetalation could also be assisted by a
molecule of the starting substrate to release G.
(9) (a) For related thermal examples, see: Gibbs, R. A.; Bartels, K.;
Lee, R.; Okamura, W. H. J. Am. Chem. Soc. 1989, 111, 3717-3725. (b)
For a general discussion, see: Rega´s, D.; Ruiz, J. M.; Afonso, M. M.;
Galindo, A.; Palenzuela, J. A. Tetrahedron Lett. 2003, 44, 8471-8474. (c)
For a discussion about gold-catalyzed Diels-Alder reactions, see: Rabaaˆ,
H.; Engels, B.; Hupp, T.; Hashmi, A. K. Int. J. Quantum Chem. 2007, 107,
359-365.
(10) Mehta, G.; Srikrishna, A. Chem. ReV. 1997, 97, 671-719.
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