AuI-catalyzed cycloisomerization of 1,5-enynes bearing a propargylic acetate: Formation of unexpected bicyclo[3.1.0]hexene

Article abstract of DOI:10.1039/b602839j

The use of N-heterocyclic carbene (NHC) as a ligand in the gold(i)-catalyzed cycloisomerization of enyne results in the assembly of a new carbocyclic product. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b602839j

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AuI-catalyzed cycloisomerization of 1,5-enynes bearing a propargylic
acetate: formation of unexpected bicyclo[3.1.0]hexene{
Nicolas Marion,a Pierre de Fre´mont,a Gilles Lemie`re,b Edwin D. Stevens,a Louis Fensterbank,b
Max Malacriab and Steven P. Nolan*a
Received (in Bloomington, IN, USA) 24th February 2006, Accepted 13th March 2006
First published as an Advance Article on the web 13th April 2006
DOI: 10.1039/b602839j
The use of N-heterocyclic carbene (NHC) as a ligand in the
gold(I)-catalyzed cycloisomerization of enyne results in the
assembly of a new carbocyclic product.
Recent reports have employed gold(I) and gold(III) complexes as
Scheme 1 PtCl2-catalyzed cycloisomerization of 1.
homogeneous catalysts capable of facilitating several organic
transformations.1 For instance, gold catalysts in both oxidation
states perform enyne cycloisomerization,2 one of the most efficient
We subjected dienyne 1 to an equimolar mixture of IPrAuCl
and AgBF4 (2 mol%) in CH2Cl2 at rt. After 5 minutes, no starting
material remained; isolation and purification yielded 2 and 3 in
moderate yields, and a novel compound 4 as the major product.
means of converting acyclic precursors into complex polycyclic
structures.3 The reactivity of gold complexes toward enynes leads
notably to the formation of bicyclic [n.1.0] derivatives4 that are of
great synthetic interest, since the cyclopropane ring is a widely
encountered motif in natural products.5
1
The H NMR data suggested 4 was a cycloisomerized product
1
displaying three propanoid and one extra vinylic protons. H–1H
and 1H–13C HSQC (heteronuclear single quantum correlation)
NMR experiments did not permit the unequivocal assignment of
the structure of the new product. To determine unambiguously the
atom connectivity in 4, we prepared 19, the para-nitrobenzoate
analogue of 1, and subjected it to cycloisomerization conditions.11
Suitable crystals of the purified product were grown and the
structure was elucidated by X-ray diffraction (Fig. 2). Surprisingly,
in 49 the cyclopropane ring has migrated to the former propargylic
position, making 4 a formal vinylcyclopropane rearrangement of 3.
To examine the influence of the NHC ligand, we carried out
reactions with various (NHC)AuCl complexes in conjunction with
AgBF4 (Table 1). The widely studied IMes (N,N’-bis(2,4,6-
trimethylphenyl)imidazol-2-ylidene) and SIMes (N,N’-bis(2,4,6-
trimethylphenyl)imidazolin-2-ylidene) ligands12 presented similar
reactivities (Table 1, entries 1 and 2), affording, in good overall
yields, the three bicyclic compounds in comparable ratios; 4
remaining the major product. Slightly more encumbered than
IMes, IPr (N,N’-bis(2,6-diisopropylphenyl)imidazol-2-ylidene)
showedacomparablereactivity(Table1,entry3),whileitssaturated
counterpart SIPryielded 2and 4in equalproportion (Table 1, entry
4). When the extremely sterically demanding13 IAd (N,N’-1,
3-bis(adamantyl)imidazol-2-ylidene) was used, the cyclohexene
compound became major and both cyclopentene derivatives were
obtained in smaller amounts (Table 1, entry 5). At this point, it
seemed that the formation of 4 was disfavored for ligand steric
reasons. We then examined the sterically unencumbering ITM
As we recently reported the syntheses of several air- and
moisture-stable (NHC)AuCl complexes6 (NHC = N-heterocyclic
carbene) (Fig. 1), we were interested in testing these in such
cycloisomerization reactions. We focused our attention on the
specific dienyne 1, which bears an acetate at the propargylic
position, since we previously reported its reactivity in the presence
of PtCl2 (Scheme 1).7,8 Substrate 1 formally contains 1,6 and 1,5
enynes that lead, after 1,2 migration of the acetate, to 2 and 3,
respectively. With PtCl2, the bicyclo[4.1.0]heptene 2 is formed
preferentially, while the bicyclo[3.1.0] compound 3 is only a minor
product.Fu¨rstneretal.showedthatthistransformationwithsimple
enynes was catalyzed equally well by PtII or AuI.9 Since ligand
effects have been studied only scarcely in this chemistry, it was of
interest to examine whether AuI would provide a similar selectivity
to PtII in this specific system, and furthermore if ligands such as
NHCs could support such a transformation. To the best of our
knowledge, the influence of only a limited set of tertiary phosphine
and NHC ligands has been studied in this reaction to date.2e,10
Fig. 1 Structures of NHC ligands.
aDepartment of Chemistry, University of New Orleans, New Orleans,
Louisiana 70148, USA. E-mail: snolan@uno.edu;
Fax: (+1) 504 280 6860; Tel: (+1) 504 280 6445
bUniversite´ Pierre et Marie Curie, Laboratoire de Chimie Organique,
UMR CNRS 7611, Institut de Chimie Mole´culaire FR 2769, Tour 44–54
case 229, 4 place Jussieu, 75252 Paris cedex 05, France
{ Electronic Supplementary Information (ESI) available: Experimental
procedures and compound characterization. See DOI: 10.1039/b602839j
Fig. 2 Stick representation of 49.
2048 | Chem. Commun., 2006, 2048–2050
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Table 1 Effect of NHC ligands on the cycloisomerization of 1a
Entry
L
2
3
4
1
2
3
4
5
6
7
IMes
SIMes
IPr
SIPr
IAd
26%
23%
30%
41%
54%
52%
50%
12%
9%
12%
13%
6%
40%
40%
42%
36%
35%
12%
12%
ITM
PPh3
8%
2%
a
NMR yields, averaged from two runs.
Fig. 3 Ball-and-stick representation of [(IPr)Au(NCMe)]PF6.
(1,3,4,5-tetramethylimidazol-2-ylidene), which favored even more
theformationof2(Table1,entry6).Interestingly,itappearsthatthe
formation of the unprecedented [3.1.0] derivatives requires very
specific steric and electronic properties from the ancillary ligand at
the gold center. Finally, the commercially available (PPh3)AuCl
showed similar selectivity as (ITM)AuCl (Table 1, entry 7).
Scheme 2 Cycloisomerization of 1catalyzed by [(IPr)Au(NCMe)]+PF6
2
.
Next, we examined the effect of salt additives (Table 2), and
found the 2 : 3 : 4 ratio to be significantly influenced by the
counterion. Formation of 4 was not observed using silver triflate,
while no reaction occurred with silver acetate14 (Table 2, entries 4
and 5). A different trend was observed with fluorinated anions,
which increased the ratio 2 : 4 from small (boron) to large
(antimony) perfluoro anions (Table 2, entries 1–3). Thus, it
appears that the formation of the bicyclo[4.1.0] derivative is
favored with more weakly bound counterions.
cationic nature of the catalytically-active species. Furthermore,
[(IPr)Au(NCMe)]PF6 allowed us to decrease the catalyst loading
to 1 mol% without increasing the reaction time and to 0.1 mol% if
the mixture was stirred for 1 hour.
Finally, to further test the scope of the reaction, we synthesized
two different 1,5-enynes (5 and 7) and subjected them to
cycloisomerization (Scheme 3). Amazingly, simple modifications
of the acetylenic substitution pattern appear crucial in controlling
the outcome of the reaction. While 1 yielded a mixture of three
products and 7 a mixture of unidentified products, 5 produced
exclusively 6, a bicyclo[3.1.0]hexene of type 4. The reasons for such
a selectivity are still unclear, but it is noteworthy that even in the
NMR spectrum of the crude product, no trace of other
cycloisomerized compounds was observed.
When coordinating acetonitrile was used as solvent in lieu of
CH2Cl2, the reaction time increased to 1 hour. Furthermore, two
control reactions were performed separately with IPrAuCl and
AgBF4. The former was inactive toward dienyne 1. The latter
afforded the allene corresponding to a [3,3]-transposition of the
propargyl acetate.15 These experiments support the notion of a
cationic gold complex as an active catalytic species. To obtain such
a complex, we reacted IPrAuCl with AgPF6 in acetonitrile. Despite
These results, and particularly the formation of the unprece-
dented product 4, led us to explore some mechanistic aspects of
this transformation. We first considered the possibility of a
reports accounting for the high instability of cationic gold(I)
complexes,16 we were able to isolate [(IPr)Au(NCMe)]+PF6
vinylcyclopropane rearrangement of
3 into 4. A thermal
2
,
rearrangement is easily ruled out since the reaction occurs at rt.
The reaction of 3 under cyclization conditions resulted in the
recovery of the starting material at rt and its degradation upon
heating, excluding a hypothetical Au-catalyzed rearrangement. In
order to explain the formation of the three bicyclic cyclopropyl
compounds, we propose a cationic pathway (Scheme 4). The route
leading to III and IV (that can be viewed as gold-methylidenes III9
and IV9) is similar to the one we proposed for the PtCl2-catalyzed
cycloisomerization.7,18 From IV, a 6-endo cyclization process,
followed by collapse of the carbon–gold bond, would provide 3.
Cationic rearrangement of intermediates V or VI, leading to a
whose structure was confirmed by X-ray diffraction studies
(Fig. 3).{ Interestingly, this complex decomposes rapidly when
dried under vacuum but is stable in an acetonitrile solution for
several days.17 Next, we performed the cycloisomerization of
dienyne 1 with this novel cationic species. Without the need for
silver additives, which are usually very hygroscopic and light-
sensitive, we obtained similar results as when an equimolar mixture
of IPrAuCl and AgPF6 (Scheme 2). This result supports the
Table 2 Effect of silver salt additive on the cycloisomerization of 1a
Entry
AgX
2
3
4
1
2
3
4
5
AgBF4
AgPF6
AgSbF6
AgOTf
AgOAc
30%
32%
40%
63%
12%
19%
18%
13%
42%
39%
27%
—
Starting material recovered
a
NMR yields, averaged from two runs.
Scheme 3 Au-catalyzed cycloisomerization of 1,5-enynes.
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Scheme 4 Proposed mechanism for the cycloisomerization of 1.
5 For a review on cyclopropane motifs in natural products, see: L. A.
Wessjohann, W. Brandt and T. Thiemann, Chem. Rev., 2003, 103,
1625–1648.
6 P. de Fre´mont, N. M. Scott, E. D. Stevens and S. P. Nolan,
Organometallics, 2005, 24, 2411–2418.
bicyclo[3.1.0]hexane cation VII, which could be further stabilized
via an oxonium, would produce unprecedented 4.
In summary, we have reported the formation of an unprece-
dented bicyclo[3.1.0]hexene in the cycloisomerization of 1,5-enynes,
catalyzed by (NHC)Au complexes. Moreover, we have shown that
the nature of the ligand on gold and the counterion have a
significant effect on the outcome of the reaction. Studies aimed at
improving the selectivity and understanding the mechanistic
aspects of this reaction are ongoing.§
7 E. Mainetti, V. Mourie`s, L. Fensterbank, M. Malacria and J. Marco-
Contelles, Angew. Chem., Int. Ed., 2002, 41, 2132–2135.
8 For related transformations with PtCl2, see: (a) N. Chatani, K. Kataoka
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I. Tsukamoto, S. Miyano and Y. Inoue, Organometallics, 2001, 20,
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Notes and references
{ Crystal data. (C19H21NO4), M = 327.37, triclinic, space group P-1, a =
7.194(1), b = 8.756(2), c = 13.875(3) s, a = 82.241(4), b = 81.536(4), c =
80.279(4)u, V = 846.6(3) s3, T = 273(2) K, Z = 2, m = 0.090 mm21, 1018
reflections measured using a Bruker SMART 1 K CCD diffractometer, 301
unique (Rint = 0.0587), wR2 = 0.1612, R1 = 0.0668 for all data. CCDC
267108. For crystallographic data in CIF or other electronic format see
DOI: 10.1039/b602839j
§ The National Science Foundation is gratefully acknowledged for its
financial support of this work. We thank Prof. L. Cavallo (Universita` di
Salerno) for calculations on 2, 3 and 4 and Dr N. M. Scott (University of
New Orleans) for partial resolution of 49.
10 M. P. Mun˜oz, J. Adrio, J. C. Carretero and A. M. Echavarren,
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11 Similar distribution to 1 was observed; 29 : 39 : 49, 27% : 8% : 46%.
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D. Bourissou, O. Guerret, F. P. Gaba¨ı and G. Bertrand, Chem. Rev.,
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14 Probably, because in this case there is no generation of a cationic gold
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bound to the gold center. For an example of (NHC)Au(OAc), see:
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2050 | Chem. Commun., 2006, 2048–2050
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