Gold-catalyzed formal 1,6-acyloxy migration leading to 3,4-disubstituted pyrrolidin-2-ones

Article abstract of DOI:10.1002/anie.201207287

Mobile: The title reaction affords diastereomerically pure 3,4-disubstituted pyrrolidin-2-ones, which are important structural motifs in natural products, in good to high yields. Mechanistic investigations suggest the transformation proceeds through a tandem 1,3-acyloxy migration and a subsequent 1,5-acyloxy migration. DCE=1,2-dichloroethane, IPr=1,3-bis(2,6- diisopropylphenyl)imidazol-2-ylidene. Copyright

Full text of DOI:10.1002/anie.201207287

Angewandte
Chemie
DOI: 10.1002/anie.201207287
Gold Catalysis
Gold-Catalyzed Formal 1,6-Acyloxy Migration Leading to
3,4-Disubstituted Pyrrolidin-2-ones**
A. Stephen K. Hashmi,* Weibo Yang, Yang Yu, Max M. Hansmann, Matthias Rudolph, and
Frank Rominger
Homogeneous gold-catalyzed reactions involving the forma-
tion of carbo- or heterocycles have attracted much attention
in the last decade.[1] Among the broad variety of gold-
catalyzed reactions developed, gold-catalyzed migration
reactions have been proven to be useful for the construction
of natural products and complex molecules.[2] Noteworthy,
these products often cannot easily be synthesized by conven-
tional methods.
The most interesting and important rearrangement reac-
tions are conducted with propargylic esters; the latter can
undergo 1,2- or 1,3-acyloxy migration, providing the corre-
sponding gold carbene or allene intermediate.[3] The research
groups of Nolan, Toste, Zhang, Nevado, Gevorgyan, and
others have intensively investigated this type of reaction.[3,4]
In the case of an allene intermediate, there are two main
alternative reaction pathways for the further transformation
(Scheme 1): the allene moiety can act as a nucleophilic
reagent by selective coordination of the Au catalyst to the
neighbouring functional group (path a),[5] or it is activated by
the Au species and can behave as a potential electrophilic
reagent (path b).[6] So far, there have been no reports on long-
range 1,n-acyloxy migrations.
Scheme 1. Gold-catalyzed 1,3-acyloxy migration and subsequent further
transformations.
As shown in Scheme 2, we envisioned that easily acces-
sible substrates 1 after coordination to the gold catalyst would
eventually undergo the known [3,3] sigmatropic rearrange-
ment described above, and thus deliver B. A subsequent
We were interested in developing and expanding the
scope of the 1,n-acyloxy migration. Here we report a novel
rearrangement that includes a tandem 1,3-acyloxy migration
and 1,5-acyloxy migration, overall leading to a formal 1,6-
acyloxy migration. To our knowledge, such a migration is
unprecedented. Furthermore, we can utilize this transforma-
tion to access butyrolactams, which are important building
blocks for the total synthesis of natural products and the
development of new pharmaceuticals.[7]
[*] Prof. Dr. A. S. K. Hashmi, M. Sc. W. Yang, M. Sc. Y. Yu,
M. M. Hansmann, Dr. M. Rudolph, Dr. F. Rominger[+]
Organisch-Chemisches Institut
Ruprecht-Karls-Universitꢀt Heidelberg
Im Neuenheimer Feld 270, 69120 Heidelberg (Germany)
E-mail: hashmi@hashmi.de
Scheme 2. Proposed mechanism of gold-catalyzed 1,6-acyloxy migra-
tion.
Homepage: http://www.hashmi.de
[+] Crystallographic investigation.
[**] W.Y. and Y.Y. are grateful to the CSC for a fellowship. M.M.H. thanks
the Fonds der chemischen Industrie for a Chemiefonds scholarship
and the Studienstiftung des deutschen Volkes. Gold salts were
generously donated by Umicore AG & Co. KG. The computational
studies were supported by bwGRiD, member of the German d-Grid
initiative, funded by the Ministry for Education and Research and
the Ministry for Science, Research and Arts Baden-Wꢁrttemberg.
nucleophilic attack of the olefin at the activated allene should
deliver C, and in C a 1,5-migration of the acyloxy group
should provide the product 2.
We began our investigation with an optimization of the
reaction conditions for the conversion of this model substrate
1a. The results obtained with various catalysts are summar-
ized in Table 1. No reaction did occur even after 24 h when
Yb(OTf)3 or p-TsOH were employed (Table 1, entries 1 and
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201207287.
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Table 1: Optimization studies on the 1,6-acyloxy migration of 1a.[a]
With the optimized conditions in hand, the scope of the
gold-catalyzed 1,6-acyloxy migration was investigated with
a variety of substrates 1. Various substituents at the alkyne
were tested (Scheme 3). n-Butyl, n-pentyl, and cyclopropyl
gave a good yield (2a–c), only the more bulky cyclohexyl
substitutent provided a low yield (2d). A phenyl group was
also tolerated, but the yield decreased to 43% (2e). The
structure of 2e was further established by using an HMBC
spectrum and an X-ray crystallographic analysis; the latter
unambiguously proved the connectivity and the relative
Entry
Catalyst
Solvent
Time [h]
Yield
1
2
3
4
5
6
Yb(OTf)3
p-TsOH
AgNTf2
IPrAuCl
AgSbF6
AuCl
DCE
DCE
DCE
DCE
DCE
DCE
24
24
24
24
24
24
NR
NR
trace
trace
trace
unselective
configuration of the three consecutive stereocenters.[9]
A
similar yield was observed with the substrate synthesized
7
DCE
24
unselective
8
9
[SPhosAuCl]/AgSbF6
[IPrAuCl]/AgSbF6
[IPrAuCl]/AgSbF6
[IPrAuCl]/AgNTf2
[IPrAuCl]/AgOTs
[IPrAuCl]/AgSbF6
[IPrAuCl]/AgSbF6
[IPrAuCl]/AgSbF6
[IPrAuCl]/AgSbF6
DCE
DCE
DCE
DCE
DCE
DCE
DCE
CH3CN
toluene
24
0.5
0.3
1
24
12
24
24
24
11%
45%
70%
66%
15%
61%
NR
10[b]
11[b]
12[b]
13[b,c]
14[b,d]
15[b]
16[b]
trace
38%
[a] Reaction conditions: Substrate (100 mmol), solvent (2 mL), in air;
entries 1–7: 5 mol% of the catalyst/entries 8–16: [Au] (5 mol%), [Ag]
(5 mol%); the reaction was monitored by TLC; DCE=1,2-dichloro-
ethane, IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene,
SPhos=2-dicyclohexylphosphino-2’,6’-dimethoxybiphenyl; [b] reaction
carried out in the presence of 4 ꢂ MS; [c] 608C; [d] room temperature.
2). When we chose [IPrAuCl], AgNTf2, or AgSbF6 alone
(Table 1, entries 3–5), these showed a very low activity under
the same conditions. When switching to AuCl or dichloro(2-
picolinato)gold(III),[8] in the thin-layer chromatogram (TLC)
only an unselective conversion was visible (Table 1, entries 6
and 7). In the presence of 5 mol% of [SPhosAuCl]/AgSbF6 in
DCE at 808C, the expected 1,6-acyloxy migration indeed
occurred to give 2a in 11% yield (Table 1, entry 8). The use of
[IPrAuCl] together with AgSbF6 resulted in complete con-
sumption of the starting material after 0.5 h, and the migra-
tion product could be isolated in 45% yield (Table 1, entry 9).
Remarkably, when the reaction was carried out in the
presence of 4 ꢀ MS as an additive, the yield of 2a increased
to 70% (Table 1, entry 10). A similar result was obtained
when [IPrAuCl]/AgNTf2 was employed as catalyst and 4 ꢀ
MS as an additive in DCE (Table 1, entry 11). Somewhat
surprisingly, change of the counterion to AgOTs under the
same conditions resulted in a much lower yield of 15% even
after 24 h (Table 1, entry 12). Decrease of the temperature to
608C led to 2a in 61% within 12 h (Table 1, entry 13). No
conversion was observed when the reaction was conducted at
room temperature (Table 1, entry 14). Furthermore, an
investigation of the solvent effect gave the best results in
DCE (Table 1, entries 15 and 16).
Scheme 3. Scope of the AuI-catalyzed formal 1,6-acyloxy migration
(reaction conditions: substrate (100 mmol), [IPrAuCl] (5 mol%),
AgSbF6 (5 mol%), DCE (2 mL), 4 ꢂ MS (100 mg); the reaction was
monitored by TLC).
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from deuterated acetic anhydride (2 f). The reaction also
readily proceeded to the migration products bearing fluoro
and chloro substituents at the C4-or C2-position of the phenyl
group (2g–k). When switching the acetyl to a pivaloyl func-
tional group, we found that all the pivaloyl-substituted esters
proceeded smoothly to give the corresponding products in
high yields (2l–2n).
After having demonstrated a broad scope of the reaction
with the NHC gold(I) complex as the catalyst, our attention
turned to explore the mechanism of this formal 1,6-acyloxy
migration. Initially, crossover experiments were carried out.
Equimolar amounts of 1g and 1l were reacted (Scheme 4).
B could be formed in situ by a [3,3]-sigmatropic rearrange-
ment via A. In B the gold(I) complex automatically (initially)
would end up at the p face anti to the acetoxy group and
subsequently triggers a direct nucleophilic attack of the
alkene to provide C. This stereoselectivity would lead to the
vinylgold intermediate with a trans arrangement of both
substituents on the lactam ring and a trans configuration of
the olefin. This olefin geometry would be essential for the
possibility of an intramolecular migration of the acyloxy
group. Two possible reaction pathways are conceivable for
this acyloxy shift, either an eight-membered ring (D) or a six-
membered ring (E). The facial selectivity at the benzylic
cation correlates with the conformation depicted for C, with
the group R1 pointing away from the other substituents and
towards the carbonyl group. Owing to the trans position of the
side chains, the six-membered intermediate is geometrically
unfavorable. Finally, the triple bond would be regenerated by
elimination of the gold catalyst and the ester group. This is
fully supported by computational chemistry (Scheme 5,
Scheme 5. Reaction pathways for the final acetate shift. Pathways via
six- and eight-membered intermediates are shown for the two diaste-
reomers that lead to the observed product.
Scheme 4. Evidence for an intramolecular reaction and the importance
Figure 1). The two pathways of lowest energy indeed proceed
via the eight-membered intermediate and not the six-mem-
bered, which is significantly higher in energy. Within the error
of the method it is not possible to decide which of the two
minima F1 or F2 is more stable; since the gold fragment then
is eliminated and 2 is the final product, this is not important.
In conclusion, an unprecedented homogeneous gold-
catalyzed formal 1,6-acyloxy migration has been developed,
and the mechanistic investigation suggests that this novel
transformation proceeds through tandem 1,3-acyloxy migra-
tion and a subsequent 1,5-acyloxy migration. This reaction
can be utilized to access diastereomerically pure 3,4-disub-
stituted pyrrolidin-2-ones, which are very important structural
motifs in natural products, in good to excellent yields.
of an initial propargylic rearrangement.
From the analysis of GC–MS and GC, no crossover products
could be observed, but only the corresponding products 2g
and 2l were detected. This clearly indicated that this novel
1,6-acyloxy migration is an intramolecular reaction, and no
elimination of the acetoxy group occurs. To provide addi-
tional evidence for the exclusion of a fragmentation reaction,
we also synthesized 1o with a phenyl substituent instead of
the alkynyl group. Then the acyloxy group can be easily
eliminated, since the carbocation could be stabilized even
better by the phenyl substituent and then induce the cycliza-
tion step. However, we could not observe any products from
TLC monitoring. This highlighted the fact that the alkynyl
group is necessary and important for the initial-stage 1,3-
acyloxy migration.
Received: September 9, 2012
Published online: December 4, 2012
Based on this evidence, the mechanism shown in
Scheme 2 indeed seems to operate for the formation of the
3,4-disubstituted pyrrolidin-2-ones. The triple bond should be
activated by the gold(I) complex, then an allene intermediate
Keywords: gold · homogeneous catalysis · lactams ·
rearrangement
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Figure 1. Reaction profile for the acetate shift. H white, C gray, O red, N blue, P orange, Au yellow.
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