Gold-catalysed cascade rearrangements of ynamide propargyl esters

Article abstract of DOI:10.1039/c3cc00273j

The Au(i)-catalysed rearrangement of propargylic esters formed from an ynamide has been studied. The reaction is facile, and when conducted in the presence of a reactive indole nucleophile, leads to a cascade process whereby γ-indolyl α-acyloxyenamides are formed in good yield and excellent E-stereoselectivity. The Royal Society of Chemistry.

Full text of DOI:10.1039/c3cc00273j

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Gold-catalysed cascade rearrangements of ynamide
propargyl esters†
Cite this: Chem. Commun., 2013,
49, 2314
a
Stephen J. Heffernan,z James M. Beddoes,a Mary F. Mahon,a Alan J. Hennessyb
Received 12th January 2013,
Accepted 6th February 2013
and David R. Carbery*a
DOI: 10.1039/c3cc00273j
www.rsc.org/chemcomm
The Au(I)-catalysed rearrangement of propargylic esters formed
from an ynamide has been studied. The reaction is facile, and when
conducted in the presence of a reactive indole nucleophile, leads to
a
cascade process whereby c-indolyl a-acyloxyenamides are
formed in good yield and excellent E-stereoselectivity.
The development of many gold-catalysed transformations1 in recent
years has allowed rapid entries to a plethora of novel organic structural
scaffolds.2 Amongst these transformations, the Au(I)-catalyzed rearran-
gement of propargylic esters3 has attracted a substantial level of
interest in recent years.4 The mechanistic and regiochemical outcome
of this reaction is known to be highly sensitive to the electronic and
steric nature of the substrate alkynyl substituents. The prevailing
consensus is that, though gold-mediated alkyne activation, either a
1,2-acyloxy migration (I - II) or a 3,3-rearrangement (I - III) pathway
can occur. Generally, an electron withdrawing substituent at position
R3 promotes a 1,2-migratory pathway and in most other cases, a 3,3
rearrangement prevails. To the best of our knowledge, the effect of
alkynyl heteroatom substituent (for example, an ynamide5,6) on the
outcome of a Au-catalyzed [3,3]-rearrangement on propargylic ester
substrate has not been studied.7 This communication reports our
observations on such a class of substrate.
Recently, we reported the first LiHMDS-mediated Ireland–
Claisen [3,3]-sigmatropic rearrangement reaction of ynamide
propargylic ester substrates, such as 1a (Scheme 2).8 A facile
rearrangement was observed in this study, attributed to both the
presence of the alkynyl oxazolidinone and aryl acetate moieties. In
addition to studying the Au-catalysed reaction of ynamide esters,
we also speculated whether the aryl acetate may promote the
presence of the enol tautomer in turn leading to a potential C–C
Scheme 1 Ynamide propargylic ester mechanistic considerations.
bond forming, [3,3]-sigmatropic rearrangement with subsequent
decarboxylation (V - VI - VII, Scheme 1).
Our study initially started by examining the effect of an in situ
generated cationic Au(I) complex on ester 1a. Initially, CH2Cl2 was
chosen as solvent which is a common choice for similar [3,3]-sigma-
tropic transformations and the now familiar combination of Au(I) and
Ag(I) co-catalysts to generate a cationic gold species.9 Consumption of
the starting ynamide was rapid, resulting in a complex reaction profile,
with Z-2 the only product readily isolable (Scheme 2).
We initially postulated Z-2 was formed through a Au-catalyzed
hydrolytic degradation of an oxocarbenium intermediate (IV,
Scheme 1, R1 = Ph, R2 = Me, R3 = oxazolidinone), generated after
3,3-rearangement. It was hypothesised that the proposed a-acyloxy-
allenamide product III may be unstable in the presence of a
a Department of Chemistry, University of Bath, Claverton Down, UK BA2 7AY.
E-mail: d.carbery@bath.ac.uk; Tel: +44 1225 386144
b GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage,
UK SG1 2NY
† Electronic supplementary information (ESI) available: Experimental details and
NMR spectra of novel compounds. CCDC 918763. For ESI and crystallographic
data in CIF or other electronic format see DOI: 10.1039/c3cc00273j
‡ Current address: Syngenta, Jealott’s Hill International Research Centre, Brack-
nell, UK, RG42 6EY.
Scheme 2 Initial reactivity assessment.
c
2314 Chem. Commun., 2013, 49, 2314--2316
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Table 1 Reaction optimization
Table 2 Substrate scope
Entry
T (1C)
t (min)
Yield (%)
Entry R1
R2
Product Yield (%)
1
25
25
0
5
5
59
32
62
63
0
52
70
93
2a
3
1
2
3
4
5
6
Ph (1a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
H (3a)
4a
4b
4c
4d
4e
4f
93
85
74
87
79
92
56
89
82
92
99
53a
92
20
45
180
45
45
45
4-MeC6H4 (1b)
4-MeOC6H4 (1c)
4-Me2NC6H4 (1d)
4-FC6H4 (1e)
4-IC6H4 (1f)
4
5
ꢀ30
ꢀ78
ꢀ30 - 25
ꢀ30
ꢀ30
6
7b
8b,c
7
8
9
10
11
12
13
3,4-(OCH2O)C6H3 (1g) H (3a)
4g
4h
4i
H (1h)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
H (3a)
a
b
AgSbF6 used as additive. Both Ag and Au catalysts added in two
5-Me (3b)
5-I (3c)
5-F (3d)
5-CO2Me (3e) 4l
6-OMe (3f) 4m
c
portions. Fresh AgPF6 used.
4j
4k
Au(I) complex. Kimber has demonstrated that allenamides cleanly
react with C-nucleophiles, such as indoles, under Au(I)-catalysis to
form enamides.10,11 Accordingly, we chose to add indole in an attempt
to trap III to form g-indolyl a-acyloxyenamide 4a.12 The addition of
indole now allowed isolation of Z-4a in 59% (entry 1, Table 1) with no
product consistent with a C–C bond formation observed. Initially, the
nature of the Ag-additive was seen to effect the reaction with AgSbF6
leading to a reduced reaction efficiency (entry 2), however, tempera-
ture was found to significantly effect this cascade reaction. Cooling
the reaction to ꢀ78 1C (entry 5) prevented a successful reaction, whilst
reaction at either 0 1C or ꢀ30 1C did not improve the reaction (entries
3 and 4). It was the realisation, however, that a portion-wise addition
of both metal salts, in combination with the utilisation of fresh AgPF6,
that led to the isolation of a-acyloxyenamide Z-4a as a single
geometrical isomer in 93% yield (Table 1, entry 8).
a
Z-2 isolated in 24%.
Having optimized the Au(I)-catalyzed cascade process between
1a and 3a, we have quickly assessed substrate scope with respect
to both ester acyl and indole fragments (Table 2). Generally, the
reaction is robust and can accommodate different functionality
upon ester and indole. Alkyl esters also react without incident
(entry 8). However, the presence of an electron-withdrawing on
the indole leads to a diminishing of reaction yield (entry 12) with
concomitant isolation of Z-2.
Fig. 1 X-ray structure of Z-4f (CCDC 918763).
Iodoindole product 4f was observed to form crystals suitable
for X-ray analysis, with the structure displayed in Fig. 1. This
analysis not only confirms the g-indolyl a-acyloxyenamide
structure but also the presence of the Z-stereoisomer.
In an attempt to further explore the scope of this chemistry, a
selection of nucleophiles, which had been reported as effective in
Kimber’s report, have been examined (5a–c, Scheme 3). In contrast
to the use of indoles, the aniline (5a), anisole (5b) and 2-methyl-
furan (5c) all failed to incorporate the nucleophile, furnishing Z-2 in
good yield (eqn (i), Scheme 3). The formation of the Z-product is
particularly interesting as a recent report has highlighted the
Scheme 3 Effect of nucleophile and ynamide.
importance and difficulty of Z-selective enone formation.13
A
further point of contrast is now observed when sulphonamide 6 enone E-7 is formed with E-selectivity. This result may offer
is reacted with 3a, (eqn (ii), Scheme 3). In contrast to 1a–h, no synthetic versatility to N-acyl sulfonamides; a medicinal scaffold
indole is incorporated into the isolated product. In this instance, which has attracted recent interest.14
c
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affect this subtle balance of acidities of these protons and the
reactivity to the external nucleophile.
In conclusion, the presence of an alkynyl electron-donating
group, in the form of an ynamide-based substrate, has been studied
in the Au-catalyzed [3,3]-rearrangement of propargylic esters. Highly
reactive 1,10-substituted a-acyloxyallenamides are formed as the
immediate product, existing in equilibrium with a-vinyl gold oxo-
carbenium complexes, can be trapped through the reaction with
indole nucleophiles to form g-indolyl a-acyloxyenamides in good to
excellent yields and excellent E-stereoselectivity.
Scheme 4 Attempted chirality transfer.
Notes and references
1 (a) A. Fu¨rstner and P. W. Davies, Angew. Chem., Int. Ed., 2007,
46, 3410; (b) D. J. Gorin, B. D. Sherry and F. D. Toste, Chem. Rev.,
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p. 585; (b) S. Ma, Eur. J. Org. Chem., 2004, 1175.
3 L. Zhang, J. Am. Chem. Soc., 2005, 127, 16804.
4 For reviews of Au-catalyzed propargyl ester rearrangements,
see: (a) S. Wang, G. Zhang and L. Zhang, Synlett, 2010, 692;
(b) N. Marion and S. P. Nolan, Angew. Chem., Int. Ed., 2007, 46, 2750;
(c) J. Marco-Contelles and E. Soriano, Chem.–Eur. J., 2007, 13, 1350.
5 For recent reviews detailing ynamide chemistry, see: (a) K. A. De
Korver, H. Li, A. G. Lohse, R. Hayashi, Z. Lu, Y. Zhang and
R. P. Hsung, Chem. Rev., 2010, 110, 5064; (b) G. Evano, A. Coste
and K. Jouvin, Angew. Chem., Int. Ed., 2010, 49, 2840.
Scheme 5 Mechanistic considerations.
6 For Pt- and Cu-catalyzed rearrangement reactions of related ynol
ether propargylic esters, see: J. Barluenga, L. Riesgo, R. Vicente,
L. A. Lopez and M. Tomas, J. Am. Chem. Soc., 2007, 129, 7772.
7 For recent Au-catalyzed reactions of ynamides, see: (a) R. B. Dateer,
K. Pati and R.-S. Liu, Chem. Commun., 2012, 48, 7200; (b) G. Ung,
D. Mendoza-Espinosa and G. Bertrand, Chem. Commun., 2012,
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L. Dumitrescu, Angew. Chem., Int. Ed., 2011, 50, 8931;
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F. Gagosz and T. Skrydstrup, Angew. Chem., Int. Ed., 2011,
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9 For the complexity of mixing Ag and Au precatalysts, see: D. Wang,
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D. R. Carbery, Org. Biomol. Chem., 2008, 6, 3455.
12 For a recent Pd(II)-catalyzed synthesis of a-acyloxyenamides from
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15 For a recent example of enantioenriched propargylic esters furnish-
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Primarily as a mechanistic probe, S-1a has been examined
when reacting with 5-iodoindole (Scheme 4). Under the same
reaction conditions as previously described, this enantioen-
riched ynamide furnished rac-4f in a reasonable yield of 60%.
The experimental observations discussed in this communi-
cation, namely no chirality transfer and the sensitivity of
the reaction outcome to both ynamide and nucleophile struc-
ture, deserve comment (Scheme 5). The complete absence of
point - axial - point chirality transfer during the conversion
of S-1a to 4f under the presently discussed mild conditions
(ꢀ30 1C, 1 h, Scheme 4) strongly suggests the direct inter-
mediacy of an achiral species. Accordingly, we feel chiral
a-acyloxyallenamide 8 is in equilibrium with the achiral a-vinyl
gold oxocarbenium complex 9. A similar observation of 100%
racemisation in a recent Au(I)-promoted rearrangement cascade
of propargylic pivalates has supported the intermediacy of
a-vinyl gold oxocarbenium species.15 The formation of 4a can
now occur through the addition of indole to either 8 or 9.
However, we feel the consideration of 9 may help in appreciating
the sensitivity of reaction outcome. Depending on the nature of
N-substitution and nucleophile, 9a can either promote conjugate
addition of 3a, to form 4a, or undergo E 2 Z equilibration
(9a 2 9b) through vinylogous enolization, prior to proto-
deauration and the formation of Z-2 or E-7. The presence of
the O-acyloxocarbenium moiety would be expected to signifi-
cantly increase the acidity of both the enone g-proton and the
acyl a-methylene protons, thus assisting both E 2 Z equili-
bration and intramolecular proto-deauration. The electron
donating ability of the N-centre and the nucleophilicity will
c
2316 Chem. Commun., 2013, 49, 2314--2316
This journal is The Royal Society of Chemistry 2013