A new synthesis of 1-chloroalkynes

Article abstract of DOI:10.1039/b106657a

4-Unsubstitued isoxazolinones derived from the corresponding β-ketoesters can be chlorinated and converted into 1-chloroalkynes upon treatment with sodium nitrite and ferrous sulfate in aqueous acetic acid.

Full text of DOI:10.1039/b106657a

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A new synthesis of 1-chloroalkynes
Sylvain Huppé, Hadi Rezaei and Samir Z. Zard*
Laboratoire de Synthèse Organique associé au CNRS, Ecole Polytechnique, 91128 Palaiseau, France.
E-mail: zard@poly.polytechnique.fr
Received (in Cambridge, UK) 24th July 2001, Accepted 9th August 2001
First published as an Advance Article on the web 4th September 2001
4-Unsubstitued isoxazolinones derived from the correspond-
ing b-ketoesters can be chlorinated and converted into
1-chloroalkynes upon treatment with sodium nitrite and
ferrous sulfate in aqueous acetic acid.
ride.6 However, upon exposure of 5b to a mixture of sodium
nitrite, aqueous acetic acid and ferrous sulfate at room
temperature under an inert atmosphere, a nearly 1+1 mixture of
the desired 1-chlorophenylacetylene 6b and benzonitrile was
obtained (Scheme 2). Benzonitrile is presumably formed
through the thermal fragmentation of the corresponding C-
nitroso intermediate as outlined in Scheme 2.
We reported a few years ago a new, practical, and versatile
synthesis of alkynes based on the nitrosative cleavage of
isoxazolinones using a combination of sodium nitrite, aqueous
acetic acid and ferrous sulfate (Scheme 1; only one tautomeric
form of the isoxazolinone is drawn).1 Ferrous sulfate is needed
to generate nitric oxide in situ in order to suppress an unwanted
radical side reaction leading to the dimerisation of the
isoxazolinone. The main limitation of this reaction is that it does
not, so far, allow access to terminal alkynes: neither R nor RA in
the starting isoxazolinone 2 can be a hydrogen atom, for the
reaction pathway of such substrates does not follow the desired
course upon nitrosation. For instance, isoxazolinone 2a gives a
good yield of oxime 8 following tautomerism of the C-nitroso
intermediate 7, whereas isoxazolinone 9 leads to a complex
mixture under the same reaction conditions.2 We have now
developed a simple solution to this difficulty hinging on the
elaboration of 1-chloroalkynes. Not only can these act as
surrogates for terminal alkynes3 but they also have a very rich
chemistry of their own.4 Noteworthy in this respect are the
numerous transition metal based couplings involving 1-haloalk-
ynes in general.5
Scheme 2 Reagents: (i) NaNO2, FeSO4, AcOH, H2O.
This undesired pathway could be almost totally eliminated by
the simple expedient of lowering the reaction temperature to
0–5 °C. The yield of 6b under these slightly modified conditions
increased to 89%. A number of chloroisoxazolinones were
prepared using well established routes to ketoester precursors
and subjected to the nitrosative cleavage (Scheme 3). In most
instances, the yield of the chloroalkynes was quite acceptable.
The synthesis of chloroalkyne 6e derived from 3,12-diacetoxy-
cholanic acid 10 is typical. Treatment of the corresponding acid
chloride 11 with Meldrum’s acid7 followed by heating with
methanol provided ketoester 12, which was cleanly converted
In a preliminary experiment, we prepared chloroisox-
azolinone 5b in 72% yield by treatment of commercially
available 3-phenylisoxazolin-5(4H)-one 2b with sulfuryl chlo-
Scheme 1 Reagents: (i) NH2OH; (ii) NaNO2, FeSO4, AcOH, H2O; (iii)
chlorinating agent.
Scheme 3 Reagents: (i) NH2OH·HCl, AcONa, EtOH, reflux; (ii) TMSCl,
Bu4NBr (Cat.), DMSO, THF; (iii) NaNO2, FeSO4, AcOH, H2O, 5 °C.
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Chem. Commun., 2001, 1894–1895
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b106657a

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The resulting ketoester 15 was converted into the chloroisox-
azolinone 5f in the same way as above and subjected to the
nitrosative cleavage to give the desired chloroalkyne 6f in 54%
overall yield for the last three steps.
This approach to 1-chloroalkynes allies simplicity with the
use of readily available substrates and cheap, ecologically
acceptable, reagents. None of the yields has been optimised and
room for improvement certainly exists; nevertheless, in combi-
nation with the numerous routes to ketoester precurors, it
provides a flexible and rapid route to otherwise inaccessible
acetylenes.
Notes and references
1 J. Boivin, L. Elkaim, P. G. Ferro and S. Z. Zard, Tetrahedron Lett.,
1991, 32, 5321; J. Boivin, S. Huppé and S. Z. Zard, Tetrahedron Lett.,
1995, 36, 5737; J. Boivin, S. Huppé and S. Z. Zard, Tetrahedron Lett.,
1996, 37, 8735.
2 L. ElKaim and S. Z. Zard, unpublished observations.
3 A. S. Kende, P. Fludzinski, J. H. Hill, W. Swenson and J. Clardy, J. Am.
Chem. Soc., 1984, 106, 3551; E. J. Corey and P. Fuchs, Tetrahedron
Lett., 1972, 3769; J. Villieras, P. Perriot and J. F. Normant, Synthesis,
1975, 458.
Scheme 4 Reagents: (i) lauroyl peroxide (5–20 mol%), 1,2-dichloroethane,
reflux; (ii) lauroyl peroxide (80 mol%), propan-2-ol, reflux; (iii)
NH2OH·HCl, AcONa, MeOH, reflux; (iv) TMSCl, Bu4NBr (Cat.), DMSO,
THF; (iii) NaNO2, FeSO4, AcOH, H2O, 5 °C.
4 J. I. Dickstein and S. I. Miller, in The Chemistry of the Carbon–Carbon
Triple Bond, ed. S. Patai, John Wiley & Sons, Chichester, 1978, ch. 19,
pp. 813–955; V. Jäger, in Methoden Org. Chem. (Houben-Weyl), Georg
Thieme Verlag, Stuttgart, 1977, Vol. 5/2a; L. Brandsma, Preparative
Acetylenic Chemistry, Elsevier Science, New York, 1992; H. Hopf and
B. Witulski, in Modern Acetylene Chemistry, ed. J. Stang and F.
Diederich, Wiley-VCH, Weinheim, 1995, pp. 48–66.
5 K. Sonogashira, in Comprehensive Organic Synthesis, ed. B. M. Trost
and I. Fleming, Pergamon Press, Oxford, 1991, vol. 3, pp. 521–561.
6 J. B. Carr, H. G. Durham and D. K. Hass, J. Med. Chem. Soc., 1977, 20,
934.
into isoxazolinone 2e with hydroxylamine. Chlorination was
accomplished by a combination of trimethylchlorosilane,
DMSO and a catalytic amount of Bu4NBr. This reagent system,
reported by Fraser and Kong,8 turned out to be superior in
general to sulfuryl chloride for the chlorination of the
isoxazolinones. Finally, nitrosation of 5e furnished the desired
chloroalkyne 6e in 53% yield.
As shown by the sequence in Scheme 4, we were able to
combine this approach to chloroalkynes with a powerful process
for the creation of carbon–carbon bonds based on the radical
chemistry of xanthates.9,10 Thus, addition of xanthate 13
derived from commercially available ethyl 4-chloroacetoacetate
to 10-undecyl pivalate gave the expected adduct 14 in 81%
yield. Reductive removal of the xanthate group was achieved by
portion-wise addition of stoichiometric amounts of lauroyl
peroxide to a refluxing solution of 14 in isopropyl alcohol.11
7 Y. Oikawa, K. Sugano and O. Yonemitsu, J. Org. Chem., 1978, 43,
2083.
8 R. F Fraser and F. Kong, Synth. Commun., 1988, 18, 1071.
9 S. Z. Zard, Angew. Chem., Int. Ed. Engl., 1997, 36, 672; B. Quiclet-Sire
and S. Z. Zard, Phosphorus, Sulfur Silicon, 1999, 153–154, 137.
10 P. Boutillier and S. Z. Zard, Chem. Commun., 2001, 1304
11 A. Liard, B. Quiclet-Sire and S. Z. Zard, Tetrahedron Lett., 1996, 37,
5877.
Chem. Commun., 2001, 1894–1895
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