An expedient approach to allenes and polycyclic structures using propargyl radicals

Article abstract of DOI:10.1016/j.tetlet.2005.11.154

A general approach to the synthesis of allenes and polycyclic structures has been developed, based on the addition of a xanthate to an enyne followed by ring-closure of the allenyl radical on to an internal olefin.

Full text of DOI:10.1016/j.tetlet.2005.11.154

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 913–916
An expedient approach to allenes and polycyclic structures using
propargyl radicals
*
´
Celia Alameda-Angulo, Beatrice Quiclet-Sire and Samir Z. Zard
`
´
Laboratoire de Synthese Organique associe au CNRS, Ecole Polytechnique, F-91128 Palaiseau, France
Received 14 October 2005; revised 24 November 2005; accepted 30 November 2005
Available online 20 December 2005
Abstract—A general approach to the synthesis of allenes and polycyclic structures has been developed, based on the addition of a
xanthate to an enyne followed by ring-closure of the allenyl radical on to an internal olefin.
Ó 2005 Elsevier Ltd. All rights reserved.
Propargyl radicals (or allenyl radicals, depending on
which canonical form is drawn) have rarely been applied
in organic synthesis, despite the popularity of radical
based synthetic methods.1 The underlying causes for
such neglect may be linked to the relatively unknown
nature of such species2 and to the lack of convenient
methods for generating them.
sary for good yields, otherwise capture of the rather
unreactive propargyl radical was very inefficient. The
propargyl radical was generated from the corresponding
bromide using stannyl radicals. One of the main limita-
tions of this route is the tendency of stannyl radicals to
add to terminal alkynes. In this letter, a new strategy for
generating and capturing propargyl radicals by exploit-
ing the advantages of the radical chemistry of xanthates
is presented. Thus addition to an enyne would give a
propargyl radical, which can cyclise to give the allene
(Scheme 2).
There are two methods for capturing a propargyl radical
as outlined in Scheme 1. The first approach, which
allows the introduction of an alkyne group, is of signif-
icant synthetic interest in view of the importance and
richness of acetylene chemistry.3 In the second, cyclisa-
tion of the allenyl radical provides the allene. Only four
examples of the latter variation have been recorded, a
few years ago, by Blechert and co-workers.4 Further-
more, it was observed that an activated olefin was neces-
The possibility of using an intermolecular addition in
the first step, allows the introduction of different func-
tionalities from various starting xanthates. Enynes sys-
tems 4, 20 and 8, which derive from ( )-isophorol and
R
R'
R'
R
R
R
n
n
R
n
n
R
R'
R'
R'
R'
R
R
n
n
Scheme 1. Different reactivities of propargyl radicals.
n
n
*
Corresponding author. Tel.: +33 1693 34872; fax: +33 1693 33851;
e-mail: zard@poly.polytechnique.fr
Scheme 2. Formation of an allene by a radical cascade.
0040-4039/$ - see front matter Ó 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.11.154

914
C. Alameda-Angulo et al. / Tetrahedron Letters 47 (2006) 913–916
S
OH
1
S
O
a,b
EtO
a
S
R
S
or
EtO
EtO2C
H
9
(62%,
over 2 steps)
4
+
O
2
S
OAc
c, R= Me
d, R= H
S
OEt
10
EtO2C
11a, R= CH2C(O)CH3 (60%)
11b, R= CH(CO2Et)2 (68%)
R
R
R
b
e
OAc
OAc
OH
13a, R= CH2C(O)CH3 (80%)
13b, R= CH(CO2Et)2 (87%)
4, R= Me (70% over 2 steps, dr: 1.4:1)
20, R= H (78% over 2 steps, dr: 1.4:1)
3, R= Me
19, R= H
Scheme 5. Reagents and conditions: (a) lauroyl peroxide (DLP,
0.15 equiv/0.3 equiv), D, 1,2-dichloroethane; (b) nBu3SnH, AIBN,
PhMe, 100 °C, 1.5 h.
Scheme 3. Reagents and conditions: (a) butyl vinyl ether, Hg(OAc)2,
D, 18 h; (b) sealed tube, 215 °C, 45 min; (c) 2-methyl-1-buten-3-yne, n-
BuLi, THF, À78 °C, 3 h; (d) 3-buten-1-yne, n-BuLi, THF, À78 °C, 3 h;
(e) Ac2O, DMAP, CH2Cl2, 0 °C, 2 h.
S
S
cyclopent-2-enyl-acetic acid, respectively, were chosen as
model substrates. Treatment of ( )-isophorol 1 with bu-
tyl vinyl ether in the presence of mercuric acetate fur-
nished the corresponding allyl vinyl ether, which was
heated at 215 °C for 45 min in a sealed tube to afford
aldehyde 2 by a Claisen rearrangement.5 Treatment of
the aldehyde with n-BuLi and either 2-methyl-1-buten-
3-yne6 or 3-buten-1-yne7 furnished alcohols 3 and 19,
respectively. These were acetylated with acetic anhy-
dride to afford compounds 4 and 20 in good overall yield
(Scheme 3).
EtO
R
a
8 + (9,10)
OAc
b
12a, R= CH2C(O)CH3 (67%)
12b, R= CH(CO2Et)2 (57%)
c
R
OAc
14a, R= CH2C(O)CH3 (68%, dr: 6:4)
14b, R= CH(CO2Et)2 (74%, dr: 1.1:1)
Successive treatment of cyclopent-2-enyl-acetic acid
with oxalyl chloride and then with N,O-dimethylhydr-
oxylamine hydrochloride afforded the corresponding
Weinreb amide 6.8 Exposure of this amide to the action
of n-BuLi and 2-methyl-1-buten-3-yne furnished ketone
7, which was reduced to the alcohol with sodium boro-
hydride and acetylated with acetic anhydride to afford
finally compound 8 in good overall yield (Scheme 4).
The reduction was undertaken to allow a more direct
comparison with substrates 4 and 20, but compound 7
is also an interesting partner for the radical sequence.
Scheme 6. Reagents and conditions: (a) xanthate 9, lauroyl peroxide
(DLP, 0.1 equiv), D, 1,2-dichloroethane; (b) xanthate 10, lauroyl
peroxide (DLP, 0.3 equiv), D, 1,2-dichloroethane; (c) nBu3SnH, AIBN,
PhMe, 100 °C, 1.5 h.
We were pleased to observe that enynes 4 and 8 success-
fully underwent the envisaged radical sequence of addi-
tion/cyclisation with a-xanthyl ketone 9 and a-xanthyl
malonate 10. These radical transformations led to the
formation of cis-fused bicyclic compounds, 11a,b and
12a,b, respectively, as mixtures of diastereoisomers
(Schemes 5 and 6). The xanthate function of allenes
11a,b and 12a,b was reductively removed with nBu3SnH
furnishing, respectively, 13a,b and 14a,b in good yields.
O
O
a,b
OMe
(87%,
over 2 steps)
OH
N
Heating allenes 13a,b and 14a,b in refluxing aqueous
acetic acid caused their rearrangement to a,b-unsatur-
ated ketones 15a,b and 16a,b, isolated as mixtures of
diastereoisomers in moderate yields (trifluoroacetic acid
and formic acid were tested but the best results were
obtained with a mixture of acetic acid/water). Exposure
of these ketones to DBU in methanol furnished the tri-
cyclic structures 17a,b and 18a,b, respectively (Schemes
7 and 8) in an useful overall yield. Thus, the ketone
adduct underwent a Robinson annelation whereas the
malonate derivative could only evolve by a Michael
addition to give a fused tricyclic structure. The relative
stereochemistry was determined by NMR analysis
(NOESY experiments).
6
Me
5
c
(83%)
d,e
(82%, over 2
steps, dr: 1:1)
OAc
O
7
8
Scheme 4. Reagents and conditions: (a) oxalyl chloride, DMF, 0 °C,
CH2Cl2, 1.5 h; (b) HN(OMe)MeÆHCl, py, CH2Cl2, 0 °C, 3 h; (c) 2-
methyl-1-buten-3-yne, n-BuLi, THF, À78 °C, 3 h; (d) NaBH4, MeOH,
0 °C, 2 h; (e) Ac2O, DMAP, CH2Cl2, 0 °C, 2 h.

C. Alameda-Angulo et al. / Tetrahedron Letters 47 (2006) 913–916
915
X
O
EtO
S
R
a
9
a
13a
20
O
+
(53%)
10
OAc
15a (dr: 1:1)
O
21a, R= CH2C(O)CH3, X= S (50%)
21b, R= CH(CO2Et)2, X= S (40%)
b
(82%)
b
22a, R= CH2C(O)CH3, X= O (35%)
22b, R= CH2(CO2Et)2, X= O (60%)
O
17a
(dr: 6:4)
c
O
CO2Et
CO2Et
O
S
EtO
R
a
13b
(50%)
15b (dr: 6:4)
b
23a, R= CH2C(O)CH3, (30%, dr: 1.1:1)
23b, R= CH(CO2Et)2, (30%, dr: 4:1)
O
(65%)
Scheme 9. Reagents and conditions: (a) lauroyl peroxide (DLP,
0.15 equiv), D, 1,2-dichloroethane; (b) PhSeO2H, THF, rt, 2 h; (c)
AcOH/H2O, D, 5 h.
CO2Et
CO2Et
17b
(dr: 1:1)
compound 26, which underwent intramolecular cyclisa-
tion to afford cis-fused bicyclic compound 27 as a mix-
ture of diastereoisomers (Scheme 10). As in the case of
compounds 21a,b, the xanthate was oxidised with phen-
ylselenic acid into thiocarbonate 28. Rearrangement
under acidic conditions afforded an inseparable mixture
of the desired a,b-unsaturated ketone 29 and various
impurities in undetermined but poor yield. The forma-
tion of these unidentified products might be the result
of the fragility of the unsubstituted allene function un-
der the conditions employed.
Scheme 7. Reagents and conditions: (a) AcOH/H2O, D, 1.5 h; (b)
DBU, MeOH/EtOH, D, 5 h.
O
a
b
16a
16b
14a
14b
(55%, dr: 1:1)
(65%)
18a (dr: 1:1)
O
a
b
Other methods to rearrange cleanly the various allenes
obtained into a,b-unsaturated ketones or other useful
(61%, dr: 1.1:1)
(50%)
CO2Et
CO2Et
18b (dr: 1.1:1)
X
Scheme 8. Reagents and conditions: (a) AcOH/H2O, D, 1.5 h; (b)
DBU, MeOH/EtOH, D, 5 h.
a,b
2
Enyne 20 underwent radical addition/cyclisation with
xanthates 9 and 10, to afford cis-fused bicyclic com-
pounds 21a,b, respectively (Scheme 9), as mixtures of
diastereoisomers. Surprisingly, the xanthate group could
not be cleanly reduced with stannane, presumably
because of side reactions involving addition of stannyl
radicals to the less substituted allene group.9 Xanthates
21a,b were therefore converted in moderate yield into
thiocarbonates 22a,b by oxidation of the thiocarbonyl
group using phenylselenic acid.10 Rearrangement by
refluxing in a mixture of acetic acid/water afforded the
desired a,b-unsaturated ketones, 23a,b as a mixture of
diastereoisomers. The yield was poor due to the forma-
tion of several unidentified side products.
OAc
25, X= Cl
c
26, X= SC(S)OEt (dr: 1:0.7)
(62% over 3 steps)
S
O
d
EtO
S
EtO
S
e
OAc
OAc
O
27
28
(60%, dr: 6:4)
O
(70%)
EtO
S
f
29
It was also possible to generate the desired propargyl
radical by directly placing the xanthate in a propargyl
position. Thus, successive treatment of aldehyde 2 with
propargyl chloride/nBuLi and then acetic anhydride
afforded compound 25. Displacement of the chloride
by reaction with the potassium salt of xanthic acid gave
Scheme 10. Reagents and conditions: (a) propargyl chloride, n-BuLi,
THF, À78 °C, 3 h; (b) Ac2O, DMAP, CH2Cl2, 0 °C, 2 h; (c) potassium
salt of xanthic acid, CH3CN, rt, 2 h; (d) lauroyl peroxide (DLP,
0.3 equiv), D, 1,2-dichloroethane; (e) PhSeO2H, THF, rt, 2 h; (f)
AcOH/H2O, D, 1.5 h.

916
C. Alameda-Angulo et al. / Tetrahedron Letters 47 (2006) 913–916
groups using transition metal based reagents11 are cur-
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In summary, these preliminary model studies demon-
strate the feasibility and flexibility of the strategy for
the synthesis of variously substituted allenes and poly-
cyclic structures. Various combinations of rings can be
constructed by modifying either the xanthate or the sub-
strates. It is worth noting that in contrast to the earlier
observations of Blechert and co-workers, there is no
need for an activated olefin to capture efficiently the
propargyl radicals.
3. Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc. 1996, 118,
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Acknowledgements
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´
We thank Dr. Jean-Luc Renaud (Universite Rennes 1)
for HMRS analyses and Ecole Polytechnique for a
Bourse Monge (to C.A.-A.).
7. Baldwin, J. E.; Reddy, V. P. J. Org. Chem. 1989, 54, 5264.
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adduct intermediate radical arising from the addition of
the stannyl radical to the thiocarbonyl group could also
add to the now less hindered allene.
10. Cussans, N. J.; Ley, S. V.; Barton, D. H. R. J. Chem. Soc.,
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