Gold(I)-catalyzed intramolecular acetylenic Schmidt reaction

Article abstract of DOI:10.1021/ja053804t

Substituted pyrroles were prepared by a gold(I)-catalyzed acetylenic Schmidt reaction of homopropargyl azides. The reaction allows for regiospecific substitution at each position of the pyrrole ring under mild conditions. A mechanism in which azides serve as nucleophiles toward gold(I)-activated alkynes with subsequent gold(I)-aided expulsion of dinitrogen is proposed. Copyright

Full text of DOI:10.1021/ja053804t

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Gold(I)-Catalyzed Intramolecular Acetylenic Schmidt Reaction
David J. Gorin, Nicole R. Davis, and F. Dean Toste*
Department of Chemistry, UniVersity of California, Berkeley, California 94720
Received June 10, 2005; E-mail: fdtoste@berkeley.edu
Table 1. Catalyst Optimization
Gold(I) complexes have seen increased utility as catalysts for
the activation of alkynes toward addition by a variety of nucleo-
philes.1,2 Recently, we proposed that back-bonding from gold into
an electron-deficient intermediate may play a role in mediating the
formation of bicyclo-[3.1.0]-hexene products from 1,5-enynes.1d
This metal carbenoid-like behavior (eq 1) has been proposed in
other transformations,3 although chirality transfer in the course of
a gold(I)-catalyzed Rautenstrauch rearrangement suggests that full
carbene character is not present in all cases.4 On the basis of these
results, we sought to extend the reactivity of gold beyond the
paradigm of electrophilic activation and further develop reactions
around the mechanistic hypothesis wherein gold serves both as a
π-acid and as an electron donor. We envisioned exploiting this
reactivity by gold(I)-promoted addition of a leaving-group-bearing
nucleophile to an acetylene with subsequent gold(I)-assisted loss
of the leaving group (eq 2).
% azide
% pyrrole
entry
catalyst
(1)a
(2)a
1
2
3
4
5
6
7
8
5% PPh3AuCl, 5% AgSbF6
5% (4-MeO-C6H4)3PAuCl, 5% AgSbF6
5% (4-CF3-C6H4)3PAuCl, 5% AgSbF6
2.5% (dppm)Au2Cl2, 5% AgSbF6
2.5% (dppp)Au2Cl2, 5% AgSbF6
5% AuCl3
9
23
42
0
0
>95
>95
>95
72
58
51
93
86
0
0
trace
5% CuI
5% AgSbF6
a Conversion by 1H NMR against an internal standard (1,2,3-trimethoxy-
benzene).
Scheme 1. Mechanistic Hypothesis
We hypothesized that this reactivity could be employed in
modification of the Schmidt reaction5 wherein alkyl azides serve
as nucleophiles toward gold(I)-activated alkynes with subsequent
gold(I)-aided expulsion of dinitrogen. To this end, treatment of
homopropargyl azide 1 with 5 mol % of Ph3PAuCl/AgSbF6 in
dichloromethane produced 2,5-dibutylpyrrole 2 in 72% yield (Table
1). While modification of the triarylphosphine ligand resulted in a
deterioration in the yield of 2 (entries 2 and 3), bidentate phosphine
digold(I)6 complexes proved to be optimal catalysts for the
cyclization (entries 4 and 5). In sharp contrast, other group 11 metal
complexes7 were not viable catalysts for this transformation (entries
6-8).
We were pleased to find that the gold(I)-catalyzed Schmidt
reaction allowed for the preparation of pyrroles with a variety of
substitution patterns (Table 2). Primary (entries 2 and 5-8) and
secondary azides both participated in the gold(I)-catalyzed cycliza-
tion, allowing for introduction of C2 substituents. Additionally,
gold(I)-catalyzed reaction of azide 7 substituted at the propargyl
position produced trisubstituted pyrrole 8 in 73% yield (entry 4).
The reaction tolerated substitution of the alkyne with both alkyl
and aryl groups. Notably, substitution of the latter with electron-donat-
ing (entry 6) or electron-withdrawing (entry 7) substituents did not
affect the course of the reaction. Additionally, azide 13, containing
a 1,5-enyne moiety, chemoselectively underwent the acetylenic
Schmidt reaction at the expense of the cycloisomerization, albeit
in slightly diminished yield (27% recovered 13) (entry 10).
A mechanistic hypothesis involving gold(I)-induced activation
of the alkyne toward addition by the proximal nitrogen of the azide
is detailed in Scheme 1. Subsequent loss of dinitrogen produces
cationic intermediate 15,8 which is stabilized by electron donation
from gold(I). A formal 1,2-shift9 regenerates the cationic gold(I)
catalyst and produces a 2H-pyrrole that tautomerizes to the 1H-
pyrrole product. While a mechanism involving generation of a
nitrene-like intermediate10 cannot be fully excluded, the observation
that nonhomopropargylic alkyl azides are unreactive under the
reaction conditions disfavors a mechanism initiated by gold(I)-
promoted decomposition of the azide.
On the basis of this proposed mechanism, we envisioned taking
advantage of intermediate 15 to prepare 2,3-substituted pyrroles
by replacing the migrating hydrogen with alternative migrating
groups. To this end, gold(I)-catalyzed rearrangement of cyclobutyl
azide 16a afforded trisubstituted pyrrole 17a in 80% yield (eq 3).
This cyclization-ring expansion strategy also allowed for the
synthesis of tetrasubstituted pyrrole 17b in 84% yield. These tandem
9
11260
J. AM. CHEM. SOC. 2005, 127, 11260-11261
10.1021/ja053804t CCC: $30.25 © 2005 American Chemical Society

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C O M M U N I C A T I O N S
Table 2. Au(I)-Catalyzed Acetylenic Schmidt Reactiona
Research Laboratories, Bristol-Myers Squibb, Amgen Inc., DuPont,
GlaxoSmithKline, and Eli Lilly & Co. for financial support.
Supporting Information Available: Experimental procedures and
compound characterization data. This material is available free of charge
via the Internet at http://pubs.acs.org.
References
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CH2Cl2 at 35 °C for 20-40 min.
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In summary, we have developed a gold(I)-catalyzed acetylenic
Schmidt reaction of homopropargyl azides for the synthesis of
multiply substituted pyrroles.11 The reaction is characterized by mild
conditions and simple preparation of the catalyst and allows for
regiospecific substitution at each position of the pyrrole ring. A
mechanism in which gold(I) serves both to activate the alkyne
toward nucleophilic addition and also to donate electron density
back into an electron-deficient π-system is proposed. The develop-
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(I) complexes is ongoing in our laboratories and will be reported
in due course.
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Acknowledgment. We gratefully acknowledge the University
of California, Berkeley, NIHGMS (R01 GM073932-01), Merck
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