Synthetic equivalents of alkynyl and propargyl radicals

Article abstract of DOI:10.1039/b101751i

Radicals derived from β-ketoesters can, depending on the position of the unpaired electron, represent synthetic equivalents to the high energy and elusive alkynyl radicals or to the stabilised and relatively unreactive propargyl radicals by application of

Full text of DOI:10.1039/b101751i

Synthetic equivalents of alkynyl and propargyl radicals
Peter Boutillier 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) 23rd February 2001, Accepted 4th June 2001
First published as an Advance Article on the web 27th June 2001
Radicals derived from b-ketoesters can, depending on the
position of the unpaired electron, represent synthetic equiva-
lents to the high energy and elusive alkynyl radicals or to the
stabilised and relatively unreactive propargyl radicals by
application of the xanthate transfer reaction followed by
nitrosative cleavage of the corresponding isoxazolinones.
alkynyl radical. Both the radical addition and the nitrosative
cleavage occur under mild conditions and are tolerant of various
functional groups commonly encountered in organic synthesis.
In the case of the isoxazoline 5e derived from N-tosylallylamine
2e (entry 5), N-nitrosation occurred to give 6Ae (6, RA =
-CH2N(NO)Ts) in 46% yield, in addition to the ‘normal’ alkyne
6e, itself formed in 20% yield. The N-nitroso group in 6Ae could
be removed by warming with triethylamine in aqueous THF,
thus bringing the overall yield of alkyne 6e to 47%.8
For convenience, the xanthate group in the adduct was
reductively removed either by treatment with a stoichiometric
quantity of lauroyl peroxide in isopropanol (yields with an
asterisk in Table 1)9 or, more conventionally, with tributyl-
stannane; its presence, however, allows the insertion of another
radical transformation, namely cyclisation onto an aromatic
ring.10 This is illustrated by the synthesis of the 3-alkynyl
indoline pictured in Scheme 2. Thus, addition of xanthate 1c to
N-allyl-N-mesyl-p-bromoaniline 2e gave the expected adduct
12 in a reasonable yield (43%, along with 28% of recovered
xanthate). Exposure of this adduct to stoichiometric amounts of
lauroyl peroxide (added portion-wise over several hours) in
refluxing 1,2-dichloroethane resulted in ring-closure to indoline
13 (86%). Finally, conversion into the corresponding isox-
Retrosynthetic disconnections of acetylenic targets and inter-
mediates almost never encompass the possibility of using
synthons equivalent to propargyl or alkynyl radicals. Synthetic
plans rely mostly on the corresponding hypothetical anionic or
cationic species and on organometallic coupling or methathesis
reactions.1 Propargylic radicals are stabilised species and are
relatively unreactive: although they do undergo ring-closure to
non-activated olefins, intermolecular additions require acti-
vated olefins for success.2 Alkynyl radicals, in contrast, are
highly energetic species, accessible only with great difficulty3
and, as far as we know, have very rarely been used in synthesis.
One notable example is the photochemical generation of
phenylethynyl radical from phenyliodoacetylene and its capture
by aromatic compounds.4 The instability of alkynyl radicals is
reflected in the strength of the corresponding C–H bond,
estimated to be around 130 kcal mol21, nearly 20 kcal mol21
higher than that of an alkene C–H bond.3 In view of the central
role played by acetylenes in organic chemistry, it seemed
worthwhile developing a route which would be an overall
synthetic equivalent to either alkynyl or propargyl radicals.
Our approach is based on combining two reactions we have
developed in recent times: the nitrous acid mediated cleavage of
isoxazolinones5 with the intermolecular radical addition of
xanthates.6 As shown in the top sequence in Scheme 1, addition
of a radical located in position 2 of a b-ketoester and derived
from the corresponding xanthate 1 to olefin 2 gives an adduct 3,
where a new C–C bond has been formed in an intermolecular
manner. Reductive removal of the xanthate, formation of the
isoxazolinone 5 (only one tautomeric form is drawn),7 and
cleavage with nitrous acid finally provides the desired alkyne 6.
This compound corresponds formally to the addition of the
inaccessible alkynyl radical 7 to the starting olefin 2. If the
initial radical is located at position 4 of the b-ketoester (i.e.
starting with xanthate 8), the overall sequence leading to
acetylene 10 is equivalent to the addition of a propargyl radical
11 to the olefin. This approach, involving an electron attracting
a-acetonyl radical, complements the use of the propargyl
radical itself which, as was stated above, has a rather
nucleophilic character and therefore requires an olefin activated
by an electrophilic group as partner.
Scheme 1 Reagents and conditions: (i) lauroyl peroxide (5–20 mol%),
1,2-dichloroethane, reflux; (iia) lauroyl peroxide (100–110%), isopropanol,
reflux; (iib) Bu3SnH (AlBN), cyclohexane, reflux; (iii) NH2OH·HCl,
AcONa, EtOH, reflux; (iv) NaNO2, FeSO4, AcOH, H2O, RT.
The examples collected in Table 1 give an idea of the scope
of the sequence corresponding to the overall addition of an
Table 1 Yield (%) of compounds 3–6 (Piv = pivalate)
R
1
RA
2
3
4
5
6
Ph
Ph
c-C3H5-
c-C3H5-
c-C3H5-
Me
1a
1a
1b
1b
1b
1c
-CH2SiMe3
2a
2b
2c
2b
2d
2c
3a (86)
3b (78)
3c (74)
3d (68)
3e (65)
3f (75)
4a (75)
4b (85)
4c (75)*
4d (84)*
4e (92)
4f (72)*
5a (80)
5b (74)
5c (83)
5d (90)
5e (89)
5f (81)
6a (76)
6b (80)
6c (75)
6d (67)
6e (20)
6f (60)
-CH2PO(OEt)2
-(CH2)9OPiv
-CH2PO(OEt)2
-CH2NHTs
-(CH2)9OPiv
1304
Chem. Commun., 2001, 1304–1305
This journal is © The Royal Society of Chemistry 2001
DOI: 10.1039/b101751i

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of the isoxazolinone, and nitrosative cleavage gave compound
20 containing the delicate, skipped enyne motif. This sequence
corresponds to effecting the addition of stabilised and un-
reactive propargylic radical 21 to the unactivated olefin present
in 2e. Incidentally, the elaboration of a b-ketoester in the
4-position under neutral conditions via xanthate 8a is worth
underlining. Usually, it is necessary to resort to the highly basic
di-anion10 or to the bis-silylenol ether under Lewis acid
catalysis11 in order to functionalise position 4 without affecting
the much more acidic position 2 of the ketoester.
In summary, the present approach complements existing
methods by allowing the rapid assembly of a variety of
otherwise inaccessible alkynes. It also brings a practical
solution to the longstanding problem of finding synthetically
useful and tame surrogates for the unavailable and unruly
alkynyl radicals.
Notes and references
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Scheme 2 Reagents and conditions: (i) lauroyl peroxide (5–30 mol%),
1,2-dichloroethane, reflux; (ii) lauroyl peroxide (100–110%), 1,2-dichloro-
ethane, reflux; (iii) NH2OH.HCl, AcONa, EtOH, reflux; (iv) NaNO2,
FeSO4, AcOH, H2O, RT; (v) allyl bromide, K2CO3, acetone, reflux.
9 A. Liard, B. Quiclet-Sire and S. Z. Zard, Tetrahedron Lett., 1996, 37,
5877.
10 A. Liard, B. Quiclet-Sire, R. N. Saicic and S. Z. Zard, Tetrahedron Lett.,
1997, 38, 1759; N. Cholleton and S. Z. Zard, Tetrahedron Lett., 1998,
39, 7295; T.-M. Ly, B. Quiclet-Sire, B. Sortais and S. Z. Zard,
Tetrahedron Lett., 1999, 40, 2533.
11 S. N. Huckin and L. Weiler, J. Am. Chem Soc., 1974, 96, 1082.
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azolinone and nitrosation furnished the desired alkyne 15 in
70% yield for the two steps.
A similar sequence can be used to illustrate the case of a
propargyl radical equivalent. As shown in the bottom part of
Scheme 2, radical addition of xanthate 8a to the same olefin 2e
and similar ring closure provided indoline 17 in 42% overall
yield. Allylation of the ketoester with allyl bromide, formation
Chem. Commun., 2001, 1304–1305
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