Unusual approach to branched 3-alkynylamides and to 1,5-dihydropyrrol-2- ones

Article abstract of DOI:10.1021/ol902472r

[Chemical equation presented] Rare carboxamide branched alkynes such as 11a can be readily obtained by reaction of the electrophilic 4-alkylidene isoxazolinones with isocycanides followed by nitrosative cleavage of the heterocyclic ring. N-lodosuccinimide induced ring closure in the presence of a nucleophile results in the formation of new iodopyrrolinones such as 16c.

Full text of DOI:10.1021/ol902472r

ORGANIC
LETTERS
2010
Vol. 12, No. 3
416-419
Unusual Approach to Branched
3-Alkynylamides and to
1,5-Dihydropyrrol-2-ones
Igor Dias-Jurberg, Fabien Gagosz, and Samir Z. Zard*
Laboratoire de Synthe`se Organique, CNRS UMR 7652, Ecole Polytechnique,
91128 Palaiseau Cedex, France
zard@poly.polytechnique.fr
Received October 27, 2009
ABSTRACT
Rare carboxamide branched alkynes such as 11a can be readily obtained by reaction of the electrophilic 4-alkylidene isoxazolinones with
isocycanides followed by nitrosative cleavage of the heterocyclic ring. N-Iodosuccinimide induced ring closure in the presence of a nucleophile
results in the formation of new iodopyrrolinones such as 16c.
The carbon-carbon triple bond is arguably among the two
or three most important functional groups in organic syn-
thesis.1 Its versatility and utility can be gauged by the
unabated flow of countless transition metal catalyzed trans-
formations reported in the past decades. Indeed, the recent
explosive growth in the development and use of reactions
such as the enyne metathesis and gold catalyzed processes
is indicative of the central position occupied by alkynes.2
From this perspective, the design of new routes to alkynes
remains a very worthwhile endeavor.
nitrosation of the corresponding isoxazolinones 1 (in tauto-
meric equilibrium with 1′) by a combination of sodium nitrite
and acetic acid in the presence of iron sulfate, as shown in
Scheme 1. The iron sulfate is needed to generate nitric oxide
in situ and thus suppress an unwanted radical side reaction
leading to dimers. One aspect of the chemistry of isoxazoli-
none is the ability of 4-unsubstituted isoxazolinones to
undergo Knoevenagel type condensations with aldehydes and
ketones 3, leading to highly electrophilic 4-alkylidene
derivatives 4.4 These react readily with various nucleophiles,
including organometallic reagents, to give conjugate adducts
5,3c,f,5 and hence the corresponding branched alkynes 6. The
conversion of 4-benzylidene isoxazolinone 4a, obtained in
quantitative yield by condensation of commercially available
isoxazolinone 1a (1, R ) Ph, R′ ) H) with benzaldehyde, into
diyne 6a by way of adduct 5a is illustrative of this technology.
Some years ago, we devised a new synthesis of alkynes 2
starting from ꢀ-ketoesters.3 The method hinges on the
(1) (a) Modern Acetylene Chemistry; Stang, P. J., Diederich, F., Eds.;
Wiley-VCH: Weinheim, 1995. (b) Brandsma, L. PreparatiVe Acetylenic
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The Chemistry of the Carbon-Carbon Triple Bond; Patai, S., Ed.; John Wiley
& Sons: Chichester, 1978; chap. 18, p 755. (d) Ja¨ger, V. In Methoden
Organic Chemistry (Houben-Weyl); Georg Thieme Verlag: Stuttgart, 1977;
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1991, 32, 5321. (b) Boivin, J.; Huppe´, S.; Zard, S. Z. Tetrahedron
Lett. 1995, 36, 5737. (c) Boivin, J.; Huppe´, S.; Zard, S. Z. Tetrahedron
Lett. 1996, 37, 48–8735. (d) Boutillier, P.; Zard, S. Z. Chem. Commun.
2001, 1304. (e) Huppe´, S.; Rezaei, H.; Zard, S. Z. Chem. Commun. 2001,
1894. (f) Renard, D.; Rezaei, H.; Zard, S. Z. Synlett 2002, 8, 1257. (g)
Zard, S. Z. Chem. Comm. 2002, 1555. For an application in the synthesis
of odorant cycloalkynes, see: (h) Lehmann, J.; Tochtermann, W. Tetrahedron
1999, 55, 2639.
(2) Selected reviews on enyne and alkyne metathesis: (a) Villar, H.;
Frings, M.; Bolm, C. Chem. Soc. ReV. 2007, 36, 55. (b) Diver, S.; Giessert,
A. J. Chem. ReV. 2004, 104, 1317. (c) Barrett, A. G. M.; Baugh, S. P. D.;
Braddock, D. C.; Flack, K.; Gibson, V. C.; Procopiou, P. A. Chem. Commun.
1997, 1375. (d) Fu¨rstner, A.; Davies, P. W. Chem. Commun. 2005, 2307.
(e) Sashuk, V.; Ignatowska, J.; Grela, K. J. Org. Chem. 2004, 69, 77481.
Selected reviews on gold catalysis: (f) Hashmi, A. S. K. Chem. ReV. 2007,
107, 3180. (g) Gorin, D. J.; Toste, F. D. Nature 2007, 446, 395.
10.1021/ol902472r  2010 American Chemical Society
Published on Web 01/12/2010

Scheme 1
Table 1. Formation of Carboxamide Branched Alkynes 11
We anticipated that the electrophilicity of the 4-alkylidene
isoxazolinones 4 would be sufficiently high to invite a
nucleophilic attack by an isonitrile, as depicted in Scheme
2.6 While this nucleophilic attack leading to intermediate 8
Scheme 2
is expected to be reversible, the ring closure of the carbonyl
oxygen on the incipient iminium ion would furnish 9, the
hydrolysis of which would result in the irreversible formation
of amide 10. Nitrosative cleavage of the isoxazoline ring
would finally provide the desired alkynylamide 11. Such
alkynylamides are relatively uncommon as they are not
readily accessible by classical routes.7
The first reactions were studied starting with commercially
available isoxazolinone 1a (1, R ) Ph, R′ ) H). As
summarized in Table 1, condensation with cyclopropanecar-
(4) (a) Lang, S. A.; Lin, Y.-I. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press: Oxford, 1984; Vol.
6, pp 103-105. (b) Boulton, A. J.; Katritzky, A. R. Tetrahedron 1961, 12,
41. (c) Wollweber, H. G.; Wentrup, C. J. Org. Chem. 1985, 50, 2041, and
references cited therein.
(5) (a) Mustafa, A.; Asker, W.; Harhash, A. H.; Kassab, N. A. L.;
Elnagdi, M. H. Tetrahedron 1964, 20, 1133. (b) Mustafa, A.; Asker, W.;
Harhash, A. H.; Kassab, N. A. L. Tetrahedron 1963, 19, 1577.
(6) For recent reviews on isocyanides in multicomponent reactions, see:
(a) Do¨mling, A. Chem. ReV. 2006, 106, 17. (b) Orru, R. V. A.; Greef, M.
Synthesis 2003, 1471. (c) Bienayme´, H.; Hulme, C.; Oddon, G.; Schmitt,
P. Chem.sEur. J. 2000, 6, 3321. (d) Zhu, J.; Bienayme´, H. Multicomponent
Reactions; Wiley-VCH: Weinheim, 2005. For a very recent application,
see: . (e) Shaabani, A.; Soleimani, E.; Rezayan, A. H.; Sarvary, A.; Khavasi,
H. R. Org. Lett. 2009, 11, 3342.
boxaldehyde in the presence of piperidine furnished the
corresponding 4-alkylidene isoxazolinone 4a in 85% yield.
(7) (a) Takahashi, K.; Midiro, M.; Kawano, K.; Ishihara, J.; Hatakeyama,
S. Angew. Chem., Int. Ed. 2008, 47, 6244. (b) Usugi, S.; Yorimitsu, H.;
Shinokubo, H.; Oshima, K. Bull. Chem. Soc. Jpn. 2002, 75, 2687. (c)
Nussbaumer, P.; Leitner, I.; Mraz, K.; Stu¨tz, A. J. Med. Chem. 1995, 38,
1831.
Org. Lett., Vol. 12, No. 3, 2010
417

Heating with t-butyl isocyanide 7a afforded the expected
amide 10a in quantitative yield. Other aldehydes such as
p-tolualdehyde and thiophene-2-carboxaldehyde could be
used, as well as ketones such as acetone and cyclopentanone.
As for the isocyanides, t-butyl isocyanide 7a gave generally
the best results. Yields with ethyl isocyanoacetate 7b and
benzyl isocyanide 7c tended to be significantly lower.
Modifications in the isoxazolinone partner 1 could be readily
introduced as illustrated by the obtention of compounds 4f-i
and their conversion into amides 11h-n.
Having established a convenient access to branched
isoxazolinyl amides, their conversion to the corresponding
alkynes was next attempted. We were concerned by the
possible formation of N-nitrosoamides by nitrosation of the
amide group under the nitrosating conditions. This is
expected to be a reversible process and did not prove to be
a complicating factor in practice. Thus, reaction of 10a in
aqueous acetic acid with a combination of ferrous sulfate
and sodium nitrite resulted in its clean transformation into
alkyne 11a, which could be isolated in 92% yield.
Finally, elimination of hydrogen iodide generates the ob-
served iodopyrrolinone 16a in the yield shown.
It is not clear at this moment if the ring-closure proceeding
through the nitrogen of the amide is under kinetic or
thermodynamic control (or both). Thermodynamic control
would imply reversibility of the cyclization step. Iodola-
conization of unsaturated amides often leads to lactones
rather than lactams9 and it is interesting to note, in the present
context, the observation by Dembinski and co-workers, who
found that the reaction of ynones with NIS gave rise to an
iodofuran.10
This transformation is amenable to a number of variations,
both in the structure of the starting alkyne and in the nature
of the nucleophile, as indicated by the examples compiled
in Table 2. In particular, water may be replaced by an alcohol
Table 2. Formation of Iodopyrrolinones 16
The remaining isoxazolinones behaved in the same manner
giving alkynes 11b-n efficiently, except for 11h and 11i,
which were produced in poor yield. This is presumably due
to the presence of the ester moiety in a position that causes
the ready isomerization of the desired alkynes into highly
reactive electrophilic allenes.
We were disappointed, however, to find that exposure of
these alkynylamides to the action of a few typical gold-based
catalysts did not result in clean or useful transformations. In
contrast, reaction of alkynylamide 11a with N-iodosuccin-
imide (NIS) furnished smoothly iodopyrrolinone 16a in 72%
yield. A plausible mechanism for its formation is outlined
in Scheme 3. Thus, electrophilic attack by NIS on the alkyne
Scheme 3
such as methanol (cf. 16b and 16e), or, more interestingly,
allylic alcohol (cf. 16c). In the latter case, it becomes possible
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group to give iodonium species 12a is followed by closure
through the nitrogen of the amide to give cyclic enamide
13a.8
This compound is nucleophilic enough to undergo a second
reaction with NIS leading to intermediate 14a, which is
readily quenched by a nucleophile in the medium, a molecule
of water in the present case, to afford diiodo compound 15a.
(8) As one referee pointed out, it is possible that that iodination occurs
first on the nitrogen of the amide to give the corresponding N-iodoamide,
which in turn reacts with the alkyne.
(10) (a) Sniady, A.; Wheeler, K. A.; Dembinsky, R. Org. Lett. 2005, 7,
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418
Org. Lett., Vol. 12, No. 3, 2010

to apply the Heck reaction to construct a second ring as
illustrated by the example displayed in Scheme 4. Indeed,
components, namely an isoxazolinone, an aldehyde or a
ketone, and an isocyanide. Since the first partner is made by
reaction of a ꢀ-ketoester with hydroxylamine, and therefore
very readily accessible, a vast number of combinations are
possible. Furthermore, the structural diversity can be aug-
mented by exploiting the efficient NIS induced ring-closure,
which incorporates an additional, fourth component, in
particular water or an alcohol as shown in Scheme 3 and
Table 2, but other nucleophilic reagents may prove suitable.
Scheme 4
Acknowledgment. We respectfully dedicate this paper to
Prof. Albert Padwa (Emory University). We thank Dr. Hadi
Rezaei (Ecole Polytechnique) for preliminary experiments
and Ecole Polytechnique for a grant to I.D.-J.
the presence of the vinylic iodide allows the enlisting of
numerous transition metal-catalyzed processes to augment
considerably the number of possible combinations and
opportunities for creating diversity. Access to pyrrolinones
by previous methods remains somewhat limited,11 despite
the fact that compounds with related motifs sometimes
display interesting biological activities.12
In summary, we have now in hand a very practical,
efficient, and quite general process for the synthesis of
alkynylamides of type 11. It consists in assembling three
Supporting Information Available: Experimental pro-
1
cedures, full spectroscopic data and copies of H and 13C
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL902472R
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