Palladium-catalyzed hydroacyloxylation of ynamides

Article abstract of DOI:10.1039/c1cc13595c

In the presence of substoichiometric Pd(OAc)₂, carboxylic acids undergo highly regio- and stereoselective additions to ynamides to provide α-acyloxyenamides.

Full text of DOI:10.1039/c1cc13595c

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Palladium-catalyzed hydroacyloxylation of ynamideswz
Donna L. Smith,a William R. F. Goundryb and Hon Wai Lam*a
Received 16th June 2011, Accepted 1st August 2011
DOI: 10.1039/c1cc13595c
In the presence of substoichiometric Pd(OAc)2, carboxylic acids
undergo highly regio- and stereoselective additions to ynamides
to provide a-acyloxyenamides.
resulting a-acyloxyenamides, which have rarely been explored
in organic synthesis. Herein we report highly regio- and
stereoselective palladium-catalyzed hydroacyloxylations of
ynamides.
Initially, the addition of propionic acid20 to oxazolidinone-
containing ynamide 1a was investigated and, although no
reaction was observed in the absence of a catalyst even at
elevated temperatures, a survey of metal salts21,22 identified
Pd(OAc)2 as an effective promoter. Heating a mixture of 1a
and propionic acid (2.0 equiv.) in toluene at 70 1C in the
presence of Pd(OAc)2 (2 mol%) for 5 h delivered a-acyl-
oxyenamide 2a in 76% yield as a single regio- and stereo-
isomer (Table 1, entry 1).23 Under these conditions, a range of
other carboxylic acids were also competent reaction partners,
undergoing additions to 1a with similarly high regio- and
stereoselectivities. In addition to butyric acid (entry 2), branched
aliphatic carboxylic acids were tolerated (entries 3 and 4),
The transition metal-catalyzed addition of carboxylic acids to
alkynes provides synthetically valuable enol esters.1–3 Although
mercury salts have long been known to be effective in this
reaction,4 the use of less toxic alternatives that exhibit increased
efficiency is desirable. Since Shvo and co-workers identified
Ru3(CO)12 as an effective precatalyst for this transformation,5
a significant majority of work in this field has targeted the
development of improved protocols using ruthenium-based
catalysts.6 Catalysts based upon other metals such as rhodium,7
iridium,2c,8 palladium,9 rhenium,10 silver,11 and gold12 have also
been described. However, with only a few exceptions,4d,5,6k,9,12,13
these studies have employed terminal alkynes as reaction
partners. Internal alkynes are more challenging substrates from
a reactivity standpoint, due to increased steric hindrance and the
unavailability of reaction pathways involving metal vinylidene
intermediates that have been implicated in anti-Markovnikov
additions to terminal alkynes.1b,f,14 Furthermore, for internal
alkynes flanked by substituents of similar steric and/or electronic
properties, controlling the regioselectivity of carboxylate addi-
tion can be difficult. The development of solutions to these
problems would be highly desirable to increase the range of enol
esters that may be accessed.
Table 1 Hydroacyloxylation of 1a with various carboxylic acidsa
As part of a program15 aimed at the development of new
applications of ynamides16 in organic synthesis, we became
interested in the catalytic hydroacyloxylation of ynamides17
for the following reasons. First, high regioselectivities have
been observed in the addition of heteroatom nucleophiles to
the triple bond of ynamides, where the addition usually occurs
a to the nitrogen atom.16–19 Second, these reactions would
provide an opportunity to investigate the chemistry of the
Entry
R
Product
Yield (%)b
1
2
3
Et
n-Pr
i-Pr
2a
2b
2c
76 (79)c
87
86 (84)d
4
2d
495
5
6
7
8
Ph
2e
2f
2g
2h
2i
495
83 (89)d
70
75
80
a EaStCHEM, School of Chemistry, University of Edinburgh,
Joseph Black Building, The King’s Buildings, West Mains Road,
Edinburgh, EH9 3JJ, United Kingdom. E-mail: h.lam@ed.ac.uk;
Tel: +44-131-650-4831
3,5-(MeO)2C6H3
4-NO2C6H4
2-HOC6H4
(E)-CHQCHPh
CRCPh
9
b AstraZeneca Process Research and Development, Charter Way,
Silk Road Business Park, Macclesfield, Cheshire, SK10 2NA,
United Kingdom
10e
2j
73
a
Reactions were conducted using 0.40 mmol of 1a in toluene (4 mL).
c
Isolated yield. Yield in parentheses refers to a reaction conducted
b
w This article is part of the ChemComm ‘Emerging Investigators 2012’
themed issue.
z Electronic supplementary information (ESI) available: Experimental
procedures, spectroscopic data for new compounds. CCDC 828301.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c1cc13595c
using 3.0 mmol of 1a, 3.3 mmol of propionic acid, and 1 mol% of
d
Pd(OAc)2 in toluene (30 mL) for 18 h. Numbers in parentheses refer
e
to reactions conducted using 1.1 equiv. of carboxylic acid. Using
4.0 equiv. of 3-phenylpropiolic acid.
c
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Chem. Commun., 2012, 48, 1505–1507 1505

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including an N-protected a-amino acid (entry 4). Aromatic
carboxylic acids were also effective, as demonstrated by
the successful addition of a variety of benzoic acids to 1a
(entries 5–7). The reaction was not affected by the free phenol
of salicylic acid (entry 8). While the addition of cinnamic acid
also occurred smoothly (entry 9), 4.0 equivalents of 3-phenyl-
propiolic acid were required to achieve acceptable results
(entry 10), as incomplete conversion was observed under
the standard conditions. However, employing only 1.1 equiva-
lents of the carboxylic acid was tolerated in several cases
(entries 1, 3, and 6, yields in parentheses), and a larger scale
reaction conducted using 1 mol% of Pd(OAc)2 provided
comparable results to the standard conditions (entry 1,
footnote c).
a diverse range of carboxylic acids and various aryl-substituted
ynamides to result in the highly regio- and stereoselective
synthesis of a-acyloxyenamides in generally good yields.
Future work will target further developments of this methodo-
logy, along with efforts to shed light upon the mechanism of
hydroacyloxylation.25
This work was supported by the EPSRC and AstraZeneca.
We are grateful to the EPSRC for the award of a Leadership
Fellowship to H. W. L. We thank Suresh Reddy Chidiupdi for
the preparation of ynamides 1b and 1h, and Christopher
Cameron for assistance with X-ray crystallography. We also
thank the EPSRC National Mass Spectrometry Service Centre
at the University of Wales, Swansea, for providing high
resolution mass spectra.
Having demonstrated that the process is compatible with
a wide range of carboxylic acids, investigation of the scope
with respect to the ynamide was undertaken (Table 2).
Oxazolidinone-substituted ynamides 1b–1d containing 2-naphthyl,
4-fluorophenyl, or 3-nitrophenyl groups, respectively, were
effective substrates, providing products 3a–3e in 67–81% yield.
However, ynamide 1e containing an electron-rich 4-methoxy-
phenyl group was less reactive, and the addition of propionic
acid to 1e provided 3f in only 43% yield, even with an increased
loading of Pd(OAc)2 (4 mol%). Imidazolinone-substituted
ynamide 1f reacted efficiently with isobutyric acid to give 3g.
Acyclic ynamides 1g and 1h were also competent substrates, as
demonstrated by the formation of 3h and 3i in modest to good
yields. Again, the use of only 1.1 equivalents of the carboxylic
acid provided good results in several cases (products 3c, 3g,
and 3i, yields in parentheses). At present, the reactions work
best with aryl-substituted ynamides; substrates containing an
aliphatic substituent on the alkyne provide low yields of the
desired a-acyloxyenamides, accompanied by reduction of the
ynamide and other unidentified products.
Table 2 Scope of the Pd-catalyzed ynamide hydroacyloxylationa
With an efficient synthesis of a-acyloxyenamides in hand, a
preliminary investigation of their reactivity was undertaken
(Scheme 1). First, heating 2a with a substoichiometric quantity
of DMAP initiated an O - C-acyl transfer to provide
b-ketoimide 4 in 91% yield. Second, treatment of 2a with
m-CPBA led to a-propionoxyimide 6 in 79% yield, pre-
sumably via ring-opening and intramolecular acyl transfer of
the intermediate epoxide 5.24
In conclusion, we have developed the first palladium-
catalyzed hydroacyloxylation of ynamides. The process tolerates
a
Reactions were conducted using 0.40 mmol of 1a in toluene (4 mL).
Numbers in parentheses refer to reactions conducted using 1.1 equiv.
b
c
of carboxylic acid. Reaction time of 6 h. Reaction conducted using
e
4 mol% of Pd(OAc)2. Reaction time of 24 h.
d
Scheme 1 Transformations of a-acyloxyenamide 2a.
1506 Chem. Commun., 2012, 48, 1505–1507
c
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Notes and references
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20 The product resulting from the addition of acetic acid to 1a
was relatively unstable, and underwent decomposition into
N-phenylacetyloxazolidin-2-one during attempted purification on
silica.
21 Several ruthenium salts surveyed were unsatisfactory. For
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24 h in the presence of RuCl3 hydrate (7 mol%) provided only 23%
conversion into 2a. The use of [RuCp*(MeCN)3]PF6 (2 mol%) led
to complete consumption of 1a after heating in toluene at 70 1C for
3 d, but a mixture of 2a and N-phenylacetyloxazolidin-2-one
(3 : 2 ratio) was produced. The use of [RuCl2(p-cymene)]2
(1 mol%), P(2-Fur)3 (2 mol%), and Na2CO3 (4 mol%) in
toluene/THF at 70 1C for 24 h, which are conditions similar to
those described by Goossen and co-workers for the addition of
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22 Other metal salts surveyed for the addition of acetic acid or
propionic acid to 1a included Zn(OTf)2, Au(PPh3)Cl, Ni(acac)2,
Ni(PPh3)2Cl2, CuOAc, and Cu(OAc)2H2O. In these cases, only
starting materials were observed. For the addition of acetic acid or
propionic acid to 1a, the use of Pd(TFA)2, [Rh(cod)(MeCN)2]BF4,
or Pd(dba)2 gave significant quantities of hydroacylation products,
but side products were also present.
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23 The regio- and stereoselectivities of the hydroacyloxylation reac-
tions herein were assigned by analogy to the reaction producing 3e,
the structure of which was determined by X-ray crystallography.
See ESI for details. In addition, the formation of products 4 and 6
from 2a (Scheme 1) lends further support for the regioselectivity of
the reaction producing 2a (Table 1, entry 1).
24 For similar rearrangements observed during the epoxidation of enol
esters, see: (a) E. Alvarez-Manzaneda, R. Chahboun, E. Alvarez,
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25 In the absence of additional experiments, we cannot speculate
on the most likely mechanism for the Pd-catalyzed hydroacyl-
oxylations described herein. However, possibilities include: (i) the
generation of palladium hydride intermediates from oxidative
addition of the carboxylic acid to Pd(0), hydropalladation of
the ynamide, and C–O reductive elimination, or (ii) carboxylate
addition to N-acylketeniminium intemediates generated either by
ynamide protonation or p-Lewis acid activation of the ynamide by
Pd(II).
14 B. M. Trost and A. McClory, Chem.–Asian J., 2008, 3, 164–194.
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3802–3803; (b) B. Gourdet, M. E. Rudkin, C. A. Watts and
c
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Chem. Commun., 2012, 48, 1505–1507 1507