Tandem Au-catalyzed 3,3-rearrangement-[2 + 2] cycloadditions of propargylic esters: Expeditious access to highly functionalized 2,3-indoline-fused cyclobutanes

Article abstract of DOI:10.1021/ja056419c

The treatment of readily available propargylic indole-3-acetates with a catalytic amount of AuCl(PPh₃)/AgSbF₆ leads to tandem activations of the propargylic esters and the in situ generated allenylic esters, resulting in expeditious access to highly functionalized cyclobutanes with fused 2,3-indoline and γ-lactone rings and an exocyclic E-double bond through sequential 3,3-rearrangement and [2 + 2] cyclization. Copyright

Full text of DOI:10.1021/ja056419c

Published on Web 11/11/2005
Tandem Au-Catalyzed 3,3-Rearrangement-[2 + 2] Cycloadditions of
Propargylic Esters: Expeditious Access to Highly Functionalized
2,3-Indoline-Fused Cyclobutanes
Liming Zhang
Department of Chemistry/216, UniVersity of NeVada, Reno, 1664 North Virginia Street, Reno, NeVada 89557
Received September 18, 2005; E-mail: lzhang@chem.unr.edu
Table 1. AuCl(PPh3)/AgSbF6-Catalyzed Formation of Highly
Functionalized Cyclobutanes
Gold salts have been recently demonstrated to be exceptional
reagents for the activation of C-C triple bonds1 toward addition
of a range of nucleophiles, including H2O/alcohols,2 carbon3 and
nitrogen4 nucleophiles, and carbonyl groups.5 These catalytic reac-
tions generally proceed under exceedingly mild reaction conditions
and with high efficiency. However, the activation of related allenes
by Au salts has been largely unexplored.6,7 Herein, I report tandem
cationic Au(I)-catalyzed activations of both propargylic esters and
the in situ generated allenylic esters, resulting in the expeditious
formation of highly functionalized 2,3-indoline-fused cyclobutanes
via sequential 3,3-rearrangement and [2 + 2] cycloaddition.
During the study of the general reactivities of propargylic
carboxylates in the presence of Au salts, non-2-yn-4-yl indole-3-
8
acetate (1) was treated with 1 mol % of AuCl(PPh3)/AgSbF6 at
ambient temperature. A clean and complete conversion was
observed in 2 h. The isolated product was identified as tetracyclic
cyclobutane 2 with fused 2,3-indoline and γ-lactone rings and an
exocyclic E-double bond (eq 1). The Z-double bond isomer was
not observed. While the initial structural analysis relied on extensive
NMR work, this assignment was subsequently confirmed by X-ray
crystallography of 4c (Figure 1).
The efficient formation of highly functionalized cyclobutane 2
from readily available propargylic ester 1 prompted us to further
study its scope. As shown in Table 1, alkyl substitution at the indole
nitrogen was tolerated, and N-methylindole-3-acetate 3a reacted
smoothly to give N-methylindoline derivative 4a in good yield
(entry 1). A phenyl group at the propargylic position did not affect
the reactivity; for example, cyclobutane 4b was obtained in 98%
yield (entry 2). 3-Bromopropyl-substituted propargylic ester (3c)
reacted smoothly in the presence of Au(I), giving cyclobutane 4c
in excellent yield (entry 3). The structure of 4c was verified by
X-ray crystallography. Aryl alkyne 3d showed diminished reactivity,
and 10 mol % of AuCl(PPh3)/AgSbF6 was needed to drive the
reaction to completion; compound 4d was obtained in 86% yield
a AuCl(PPh3)/AgSbF6 (1 mol %) was initially added; after 6h, an
additional batch was added. b Compound 4e is contaminated with an
unknown impurity. c Combined yield of compound 4g and 5.
(entry 4). More bulky substituents at either the propargylic position
(entry 5) or the alkyne terminus (entry 6) affected the reaction.
Longer reaction times and higher catalyst loadings were necessary
for the reaction of 3e and 3f. Cyclobutanes 4e and 4f were obtained
in moderate to good yields. Interestingly, the treatment of ester 3g
with a 2-propenyl group at the propargylic position with 1 mol %
of AuCl(PPh3)/AgSbF6 resulted in a 1:4 mixture of the desired
cyclobutane 4g and cyclopentenone derivative 5,9 respectively (entry
7). There was no reaction with the parent propargyl indole-3-acetate
(R ) R1 ) R2 ) H). When the propargylic position was substituted
with two methyl groups (R2 ) n-Bu), the desired product was not
detected, although the starting material was completely consumed.
Surprisingly, there was no reaction with R ) H, R1 ) BnOCH2,
and R2 ) n-Bu, while a complex reaction mixture was formed with
R ) H, R1 ) n-pentyl, and R2 ) BnOCH2.
Figure 1. X-ray structure of cyclobutane 4c.
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10.1021/ja056419c CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Scheme 1. Proposed Mechanism for the Formation of
Cyclobutane 4
Acknowledgment. This research was supported by the Uni-
versity of Nevada, Reno. I thank Professor Vincent J. Catalano for
solving the X-ray structure, and Professor Sergey A. Kozmin for
helpful discussions. The X-ray diffractometer purchase was sup-
ported by NSF Grant CHE-0226402.
Supporting Information Available: Experimental procedures,
compound characterization data, and X-ray file. This material is
available free of charge via the Internet at http://pubs.acs.org.
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The proposed mechanism for the formation of cyclobutane 4 is
shown in Scheme 1. Activation of the C-C triple bond in
propargylic ester 3 by [Au(PPh3)]+ promotes a 3,3-rearrangement
of the indole-3-acetoxy group, which leads to the formation of
allenylic ester 6. The allene moiety of 6 is further activated by the
cationic Au(I) complex, resulting in the formation of either oxonium
A with Au trans to the R1 group or B with the opposite double
bond geometry.10 While A suffers A1,3-strain, B is relatively less
strained due to the long C(sp2)-Au bond.11 Consequently, equili-
bration of A and B via allenylic ester 6 would result in thermo-
dynamically favored B as the predominant oxonium species.
Cyclobutane 4 with an exocyclic E-double bond is formed via
cyclization of the oxonium group in B to the 3-position of the indole
ring, followed by intramolecular trapping of the iminium with the
alkenylgold(I).12
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1
This mechanism is supported by the H NMR observation of
(6) (a) See ref 5a. (b) Sromek, A. W.; Rubina, M.; Gevorgyan, V. J. Am.
Chem. Soc. 2005, 127, 10500-10501.
allenylic ester 6f. When propargylic ester 3f with R2 ) cyclohexyl
was treated with 1 mol % of AuCl(PPh3)/AgSbF6, a 1:1 inseparable
mixture of 6f and cyclobutane 4f was isolated in 2 h. 6f was
independently prepared through AuCl3-catalyzed 3,3-rearrangement
of 3f (eq 2). Not surprisingly, treatment of 6f with the cationic
Au(I) catalyst (5 mol %) for 8 h gave 4f in 74% yield. Remarkably,
AuCl3 did not catalyze the formation of 4f, and extended reaction
led to the decomposition of 6f. Other allenylic ester intermediates
were not observed, likely because the [2 + 2] cyclizations of these
allenylic esters were faster than the 3,3-rearrangements of the
corresponding propargylic esters. In contrast, 6f reacted with Au(I)
slower than 3f due to the steric bulk of the cyclohexyl group,
resulting in the accumulation of 6f and the slow formation of 4f. It
is noteworthy that Au salts have been shown previously to catalyze
2,3-rearrangements of propargylic esters3d,13 but not their 3,3-
rearrangements.14
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(10) The formation of oxonium species A and B is supported by the following
observation. This result and further studies will be published soon.
(11) ConQuest searching of the Cambridge structural database resulted eight
hits with similar C(sp2)-Au(I)(PPh3) bonds. The average bond length is
2.043 Å, while the bond length of C(sp2)-C(sp3) is 1.50 Å.
(12) An alternative kinetic explanation for the exclusive formation of the
E-double bond is that oxoniums B and A are in equilibrium with extremely
fast interconversion rate, and B cyclizes much faster than A.
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In summary, we have demonstrated that the cationic Au(I)
complex derived from AuCl(PPh3)/AgSbF6 activates both pro-
pargylic esters and allenylic esters. Tandem Au(I)-catalyzed 3,3-
rearrangement-[2 + 2] cyclizations of readily available propargylic
indole-3-acetates lead to the formation of highly functionalized 2,3-
indoline-fused cyclobutanes with high efficiency. Further studies
in utilizing this tandem process as well as the application of these
cyclobutanes in alkaloid synthesis will be reported in due course.
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