Gold- and silver-mediated cycloisomerizations of N-propargylamides

Article abstract of DOI:10.1021/ol801847j

(Chemical Equation Presented) Substituted N-propargylamides have proven to be valuable substrates for alkyne-activated cycloisomerization reactions. N-Tosyl-N-propargylurea underwent reaction with AuCl₃ to give the corresponding dihydroimidazol

Full text of DOI:10.1021/ol801847j

ORGANIC
LETTERS
2008
Vol. 10, No. 19
4379-4382
Gold- and Silver-Mediated
Cycloisomerizations of
N-Propargylamides
Guido Verniest and Albert Padwa*
Department of Chemistry, Emory UniVersity, Atlanta, Georgia 30322
chemap@emory.edu
Received August 8, 2008
ABSTRACT
Substituted N-propargylamides have proven to be valuable substrates for alkyne-activated cycloisomerization reactions. N-Tosyl-N′-propargylurea
underwent reaction with AuCl3 to give the corresponding dihydroimidazolone, while N-propargyl-3-oxobutanamides and esters were used to
construct furanyl fused pyrrolidinones and dihydrofuranones via Ag(I)-mediated alkyne activation.
During the past several years, the application of homoge-
neous gold catalysis in organic synthesis has emerged as a
powerful tool for the preparation of a wide variety of carbo-
and heterocyclic compounds.1-4 The chemoselective alkyno-
philic properties of gold catalysts have been successfully
exploited to develop mild and efficient synthetic strategies
via alkyne activation and subsequent nucleophilic addition
to the triple bond. Although gold-catalyzed intermolecular
reactions of alkynes with nucleophiles have been reported,5
the majority of recent examples have focused on the
generation of new C-C and C-heteroatom bonds via
cycloisomerization reactions as well as beneficial skeletal
rearrangements.1-4,6 A particularly promising field of re-
search involves the intramolecular condensation of carbonyl
compounds with alkynes which give rise to reactive inter-
mediates that can then undergo structurally interesting
rearrangements. In this respect, it has been shown that
substituted 3-butyn-1-ones readily produce furans or 3-fura-
nones by a AuCl3-catalyzed 5-endo-dig cyclization.7 o-
Alkynylbenzaldehydes have also been used in Au-catalyzed
6-endo-dig cyclizations to generate pyrylium intermediates
which readily undergo cycloaddition to generate a variety
of polycyclic systems.8 Propargylic esters have also been
shown to be suitable substrates for intramolecular 5-exo-dig
cyclizations. These cyclization reactions often result in a 1,2-
or 1,3-acyl shift (cf. Rautenstrauch rearrangement) depending
on the substitution pattern on the propargylic ester.9 In many
of these cases, the mechanistic understanding is often limited,
and the exact reaction outcome is still hard to predict.
Analogous cyclizations using carbonates or carbamates have
(5) For examples, see: (a) Davies, P. W.; Albrecht, S. J.-C. Chem.
Commun. 2008, 238. (b) Hashmi, A. S. K.; Salathe´, R.; Frey, W. Eur. J.
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10.1021/ol801847j CCC: $40.75
Published on Web 09/03/2008
2008 American Chemical Society

been found to afford the corresponding dioxolanone or
oxazolidinone system bearing an exo-alkylidene substituent.10
AninterestingexampleoftheAu-catalyzedcarbonyl-alkyne
cycloisomerization involves 5-exo-dig oxazole formation
starting from an N-propargyl-substituted amide. Since only
two reports of this transformation can be found in the
literature,11 we decided to further investigate the synthetic
potential of using substituted N-propargylamides and related
derivatives for the metal catalyzed synthesis of various
heterocyclic compounds. Catalytic alkyne cyclization of
N-propargylamides and related urea derivatives 1 can occur
either by cyclization of the carbonyl oxygen atom with the
alkynyl group leading to structure 2 or by reaction at the
in toluene in the presence of p-TsOH, the 4-methylene-2-
imidazolidinone derivative 7 very slowly isomerized to the
thermodynamically more stable 4-methyl-1,3-dihydroimida-
zol-2-one 9 (Scheme 2).
As a consequence of the preference of N-propargylureas
to form dihydroimidazolones instead of aminooxazoles, our
attention was next directed toward another class of N-
propargylamides bearing two nucleophilic centers, both of
which are capable of attacking the triple bond. With this in
mind, 3-oxo-N-propargylbutanamides 10 were synthesized
via standard procedures and were subjected to reaction using
AuCl3 as the catalyst in acetonitrile at room temperature
(Scheme 3). Under these conditions, amide 10a (R ) H)
was smoothly cyclized to the corresponding oxazole in 59%
yield. In contrast, when the amido nitrogen atom contained
a methyl group (i.e., 10b), no reaction occurred even at
elevated temperatures or by using other gold catalysts. Only
when 10b was allowed to react with in situ generated
Au(PPh3)OTf (derived from Au(PPh3)Cl and AgOTf) was a
small amount (<10%) of 5,6-dihydrofuro[3,4-c]pyrrol-4-one
14 detected in the crude reaction mixture by NMR spec-
troscopy. Since the other gold catalysts examined did not
produce any of compound 14, we thought that the presence
of trace amounts of a Ag salt in the mixture might be
responsible for the observed reactivity. Indeed, it is known
in the literature that aside from gold catalysts, other π-Lewis
Scheme 1
nucleophilic center (Nu) to produce a cyclized compound
such as 3 (Scheme 1).
In view of our group’s interest in substituted aminoox-
azoles, urea derivatives 4 were evaluated as potential
substrates for the gold-catalyzed formation of these structur-
ally interesting oxazoles (i.e., 8) (Scheme 2). We found that
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Scheme 2
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the reaction of N-phenyl- and N-acyl-N′-propargylureas 4a,b
with Au(I)(PPh3)Cl or Au(III)Cl3 did not lead to any oxazole
formation as only starting material was recovered. However,
when N-tosyl-N′-propargylurea 4c was treated with AuCl3,
a clean conversion (68%) to the cyclic urea derivative 7 was
observed. This represents the first example of imidazolidi-
none formation by a Au-catalyzed reaction. Upon heating
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4380
Org. Lett., Vol. 10, No. 19, 2008

then followed by an oxidative cyclization of the transient
enol intermediate 15b to give 14.13 The subsequent oxidation
step is presumably responsible for the need of 2 equiv of
AgNO3 in the reaction medium. In the case where compound
1614 is transformed into 17,15 only 1 equiv of AgNO3 is
needed for this cycloisomerization (Scheme 3). We also
found that by using these optimal reaction conditions,
O-propargyl esters of type 1816 gave rise to the corresponding
furo- (17, 19a) and pyrrolo-fused furanones (19b).
Scheme 3
A very recent discovery in our laboratory showed that the
Au(I)-catalyzed reaction of indole-2-carboxamides produces
ꢀ-carbolines in good yield.17 In order to further evaluate the
potential of this transformation for heterocyclic synthesis,
we prepared the indolyl-tethered amides 20 and 22 from
readily accessible indoles18 and studied their gold-catalyzed
intramolecular cyclizations (Scheme 4). The reaction of
Scheme 4
acids such as platinum and silver salts can be used for alkyne
activation.12
After screening a variety of reaction conditions using 10b
with different Ag(I) salts, we found that an optimal yield of
78% of compound 14 could be obtained when 2.2 equiv of
AgNO3 was used in the presence of NaOAc (Scheme 3). A
logical mechanism for this process would involve a Ag(I)-
induced nucleophilic attack of the enol moiety of 12 onto
the triple bond to initially give 13 followed by direct
protonation of the vinyl metal bond to furnish 15a. This is
(12) (a) Yamamoto, Y. J. Org. Chem. 2007, 72, 7817. (b) Godet, T.;
Vaxelaire, C.; Michel, C.; Milet, A.; Belmont, P. Chem. Eur. J. 2007, 13,
5632. and cited references. For examples of the use of Pt in alkyne
activation, see: (c) Dieguez-Vazquez, A.; Tzschucke, C. C.; Lam, W. Y.;
Ley, S. V. Angew. Chem., Int. Ed. 2008, 47, 209. (d) Kusama, H.; Ishida,
K.; Funami, H.; Iwasawa, N. Angew. Chem., Int. Ed. 2008, 47, 4903. (e)
Pujanauski, B. G.; Bhanu Prasad, B. A.; Sarpong, R. J. Am. Chem. Soc.
2006, 128, 6786.
amides of type 20 with AuCl3 proceeded rapidly and
furnished the oxazole tethered indoles 21a-d in good yield.
A most interesting reaction was encountered when the
N-propargylamidoindole 22 was treated with 5 mol % AuCl3.
(14) Garanti, L.; Sala, A.; Zecchi, G. Synthesis 1975, 10, 666.
(15) Padwa, A.; Kinder, F. R. J. Org. Chem. 1993, 58, 21.
(16) Mottet, C.; Hamelin, O.; Garavel, G.; Depres, J.-P.; Greene, A. E.
J. Org. Chem. 1999, 64, 1380.
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Org. Lett. 2007, 9, 5111. (b) Kennedy-Smith, J. J.; Staben, S. T.; Toste,
F. D. J. Am. Chem. Soc. 2004, 126, 4526. (c) Staben, S. T.; Kennedy-
Smith, J. J.; Toste, F. D. Angew. Chem., Int. Ed. 2004, 43, 5350. (d)
Mezailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133. (e) Atsuko,
O.; Hideto, I.; Masaya, S. J. Am. Chem. Soc. 2006, 128, 16486. (f) Pan,
J.-H.; Yang, M.; Gao, Q.; Zhu, N.-Y.; Yang, D. Synthesis 2007, 2539.
(17) England, D.; Padwa, A. Org. Lett. 2008, 10, 3631.
(18) (a) Maertens, F.; Van den Bogaert, A.; Compernolle, F.; Hoornaert,
G. J. Eur. J. Org. Chem. 2004, 22, 4648. (b) Philips, R. S.; Cohen, L. A.
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Org. Lett., Vol. 10, No. 19, 2008
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When dry acetonitrile was used as the reaction solvent, the
expected oxazole 23 was formed in 77% yield. However, a
3:2 mixture of 23 and 2H-pyrazino[1,2-a]indolone 24 was
obtained when aqueous acetonitrile was used as the solvent.
A much higher yield of 24 was achieved by simply heating
the crude oxazole 23 in aqueous dichlorobenzene. It would
seem as though a trace of acid promotes cyclization of the
oxazole nitrogen atom onto the adjacent alkyne to give 25
as a transient species which is further converted to the
thermodynamically more stable product 24 under the aqueous
conditions employed (Scheme 4).
Scheme 5
We also thought it to be of interest to determine whether
the Au(I)-catalyzed cycloisomerization of N-propargylamides
can be extended to substituted 4-pentynamides. With this
thought in mind, N-acyl-δ-valerolactam 26 was synthesized
in two steps from δ-valerolactam. The reaction of 26 with a
variety of gold catalysts did not lead to the formation of the
desired amidofuran 27, and only starting imide was recov-
ered. However, the cyclization of 26 could be induced to
occur by its treatment with p-TsOH in refluxing dichlo-
robenzene which gave rise to 9-methyl-1,2,6,7-tetrahydro-
5H-pyrido[3,2,1-ij]quinolin-3-one (29) in 31% yield (Scheme
5).19 We propose that this novel transformation occurs by
an initial acid-promoted cycloisomerization to first give
amidofuran 27 as a transient species which spontaneously
undergoes an intramolecular [4 + 2]-cycloaddition followed
by loss of water to eventually form tetrahydropyrido[3,2,1-
ij]quinolin-3-one 29.
N-propargyl-3-oxobutanamides and esters were used to
construct furanyl-fused pyrrolidinones and dihydrofuranones
via Ag(I)-mediated alkyne activation. In addition, the Au-
catalyzed cyclization of indolyl tethered N-propargylamides
gave rise to both oxazoles as well as a pyrazinoindolone
depending on the solvent system used. The applicability of
the methodology to natural product synthesis is currently
under study and will be the subject of future reports.
Acknowledgment. We appreciate the financial support
provided by the National Science Foundation (CHE-
0742663). G.V. is a Postdoctoral Fellow of the Research
Foundation - Flanders (FWO - Vlaanderen, Belgium) and is
indebted to this organization for financial support.
In conclusion, substituted N-propargylamides proved to
be valuable substrates for alkyne-activated cycloisomerization
reactions. N-Tosyl-N′-propargylurea underwent reaction with
AuCl3 to give the corresponding dihydroimidazolone, while
Supporting Information Available: Spectroscopic data
and experimental details for the preparation of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) Although the formation of 29 proceeds in low yield, the acid-
catalyzed reaction is of interest because it suggests, that in certain
circumstances, an acid source can be a better catalyst than gold for alkyne
activation.
(20) Rosenfeld, D. C.; Shekhar, S.; Takemiya, A.; Utsunomiya, M.;
Hartwig, J. F. Org. Lett. 2006, 8, 4179.
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