The first preparation of β-lactones by radical cyclization

Article abstract of DOI:10.1021/ol0340235

(Matrix presented) β-Lactones have, for the first time, been prepared by 4-exo-trig radical cyclization. Thus, α-ethenoyloxy radicals react in the presence of tributylstannane in a photothermal process to give β-lactones. Highest yields were obtained when groups capable of stabilizing a carbon-centered radical were present at the 3-position of the alkenoate acceptor.

Full text of DOI:10.1021/ol0340235

ORGANIC
LETTERS
2003
Vol. 5, No. 5
757-759
The First Preparation of â-Lactones by
Radical Cyclization
Kerstin Castle, Chee-San Hau, J. B. Sweeney,* and Craig Tindall†
Department of Chemistry, UniVersity of Reading, Reading RG6 6AD, U.K.
j.b.sweeney@reading.ac.uk
Received January 7, 2003
ABSTRACT
â-Lactones have, for the first time, been prepared by 4-exo-trig radical cyclization. Thus, r-ethenoyloxy radicals react in the presence of
tributylstannane in a photothermal process to give â-lactones. Highest yields were obtained when groups capable of stabilizing a carbon-
centered radical were present at the 3-position of the alkenoate acceptor.
The use of radical cyclization for construction of four-
membered rings has, until recently,1 been problematic as a
result of the preference for cyclobutylalkyl radicals 1 to
undergo ring-opening (eq 1, Scheme 1).2 In particular,
â-lactams have been prepared via several different types of
radical cyclization,3-5 However, to date no method has been
adumbrated that allows an analogous 4-exo-trig radical
cyclization to prepare â-lactones.
We reasoned that cyclization of an O-(alkenoyl)oxyalkyl
radical 2 (eq 2, Scheme 1), bearing radical-stabilizing
substituents R and R1, would allow for an unprecedented
4-exo-trig preparation of â-lactones (via (3-oxetanonyl)-
methyl radical 3). We here report the results of our
preliminary investigation of this reaction, which indicate that
the generation of radicals such as 2 is facile and that these
radicals do cyclize to give â-lactones. Thus, a dilute benzene
solution of (1-bromopropyl)-cinnamate (4)6 and Bu3SnH (9
mM in each reagent) was added via syringe pump to a
refluxing solution of AIBN (0.25 equiv) in the same solvent,
and the reaction was heated at reflux for 4 h (final
concentration 1.3 mM), yielding 3-benzyl-4-ethyloxetan-2-
one (5) in 17% yield (cis:trans 1:1)7 and the directly reduced
product, propyl cinnamate (6), in 20% yield (Scheme 2). It
is noteworthy that butyrolactone 7, the product of the
alternative 5-endo-cyclization, was not observed in the
product mixture.
When the reaction was repeated under the same conditions,
using toluene in the place of benzene, similar yields of the
same products were obtained (Table 1, entries 1-3). Again
no trace of the 5-endo-cyclization product (7) was observed
among the crude reaction products. In these reactions, the
Scheme 1. Radical Cyclization to Prepare Four-Membered
Rings
† Previous address: School of Chemistry, University of Bristol, Bristol
BS8 1TS, U.K.
(1) For early reports of formation of cyclobutanes by 4-exo-trig cycliza-
tion, see: Piccardi, P.; Modena, M.; Cavalli, L. J. Chem. Soc. C 1971,
3959-3966. Piccardi, P.; Massardo, P.; Modena, M.; Santoro, E. J. Chem.
Soc., Perkin Trans. 1 1971, 982-988.
(2) Walling, C.; Pearson, M. S. J. Am. Chem. Soc. 1964, 86, 2262-
2266. Walling, C.; Cooley, J. H.; Ponaras, A. A.; Racah, E. J. J. Am. Chem.
Soc. 1966, 88, 5361-5363. Julia, M. Acc. Chem. Res. 1971, 386-392.
Beckwith, A. L. J.; Schiesser, C. H. Tetrahedron 1985, 41, 3925-3941.
(3) Gill, G. B.; Pattenden, G.; Reynolds, S. J. Tetrahedron Lett. 1989,
30, 3229-3232. Pattenden, G.; Reynolds, S. J. Tetrahedron Lett. 1991, 32,
259-262. Gill, G. B.; Pattenden, G.; Reynolds, S. J. J. Chem. Soc., Perkin
Trans. 1 1994, 369-378. Pattenden, G.; Reynolds, S. J. J. Chem. Soc.,
Perkin Trans. 1 1994, 379-385.
10.1021/ol0340235 CCC: $25.00 © 2003 American Chemical Society
Published on Web 01/31/2003

ester (8)8 and subjected it to the conditions described above
(Table 1, entries 8-10). Once again, cyclization to give 5
was observed, but the yield of â-lactone was lower than
previously observed (cf. entries 1-4); in this case, excluding
AIBN and utilizing in its place photothermal initiation (using
a simple desk lamp fitted with a 300-W tungsten bulb) gave
the best yield of 5 (entry 10). Observing that in no reaction
of 8 did the yield of â-lactone surpass that obtained using
bromide 4, it seemed reasonable to deduce that the manner
of generation of the first-formed radical (2) was not as
important as the stabilization of the radical (3) produced via
cyclization. Thus, we examined the use of 3,3-disubstituted
enoates bearing groups capable of stabilizing an unpaired
electron, in the desire of improving cyclization yields by
enhancing the stability of 3. The results are summarized in
Table 2.
Scheme 2. Preparation of 3-Benzyl-4-ethyl Oxetan-2-one 5 by
4-exo-Cyclization
mode of addition of the reagents and the concentration was
crucial. When a solution of stannane and AIBN was added
slowly to a heated toluene solution of bromide 4, no cyclized
products were isolated, and after chromatography 6 was the
only product of the reaction, (45% yield, entry 5), while
increasing the final concentration (to 28 mMol, entry 6) also
encouraged reduction and obviated cyclization. When slow
addition of the reagents was not employed, no lactone was
obtained (entry 7). To examine the effect of the nature of
the radical precursor, we prepared N-hydroxypyridine thione
Table 2. Preparation of â-Lactones (11) via Radical
Cyclization of R-Functionalized Esters of Substituted Enoates
(10)
Table 1. 4-exo-trig Radical Cyclization of Functionalized
Cinnamate Esters 4 and 8
yield (%)b
entrya
R
R1
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
PhS
PhS
TolS
R2
R3
R4
11
12
13
1
2c
3d
4
5e
6f
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Et
Et
Et
Me
Me
Me
H
H
H
Et
Et
Et
H
H
H
Me
Me
Me
H
H
H
PTOC
PTOC
PTOC
PTOC
PTOC
PTOC
PTOC
PTOC
PTOC
PTOC
PTOC
PTOC
59
47
56
61
57
13
32
15
27
55
51
52
5
10
7
7
6
49
23
50
39
14
21
18i
2
3
8
8
10
15
10
13
12
4
7
8g
9h
10
11h
12
yield (%)
addition
reaction
Ph
entry
R
timea (h) timeb (h) initiation
5
6
9
PhS
PhS
TolS
H
H
H
8
0
1
2
3
4
5
6c
7d
8
9
10
Br
Br
Br
Br
Br
Br
Br
PTOCe
PTOC
PTOC
1
1
1
2
3
3
-
2
2
2
2.5
3.5
4.5
3
5
12
4.5
3
3
AIBN
AIBN
AIBN
AIBN
AIBN
AIBN
AIBN
AIBN
AIBN
300 Wf
20 24
20 20
17 23
23 23
tr 45
tr 45
a General procedure: 50 mL of a 0.5 mM toluene solution of ester and
hydride was added over a 2 h period via syringe pump to a heated vessel
(irradiated by a 300-W tungsten lamp) containing toluene (300 mL), after
which the reaction was continued until the substrate had been consumed
(5-8 h). b Isolated yield (cis:trans ≈ 1:1). c Heated at 110°C. d 150-W lamp
used. e Separate solutions of substrate and hydride added via syringe pumps.
f Solution of hydride added to solution of ester in toluene. g AIBN used in
place of 300-W lamp. h Final concentration of 2.5 mM. i Solvent acetonitrile/
hexane (1/1), reaction temperature 59 °C.
0
0
50
71
0
7
4
10 40
22 38
4
a Time taken to add solution of reagents to reaction vessel. b Total
reaction time. c Final concentration of 28 mM. d Reagents combined directly.
e PTOC ) pyridine-2-thione-N-oxycarbonyl. f Flask irradiated (300-W
tungsten bulb).
Thus, the presence of an additional phenyl substituent in
the 3-position of the enoate (compound 10a, prepared from
3-phenyl cinnamic acid) greatly enhanced cyclization at the
758
Org. Lett., Vol. 5, No. 5, 2003

expense of reduction and lactone 11a (R ) R1 ) Ph, R2 )
H, R3 ) Et) was isolated in 59% yield as a roughly 1:1
mixture of (separable) cis- and trans-isomers (entry 1). The
reaction of an analogous ester containing a gem-dimethyl
substituent pattern (compound 10b, entry 4) led to lactone
11b (R ) R1 ) Ph, R2 ) Me, R3 ) Me) in 61% yield, while
the parent ester 10c gave 11c (R ) R1 ) Ph, R2 ) R3 ) H)
less efficiently (entries 7-9), presumably because of the high
reactivity of the intermediate primary radical.
These reactions have shown for the first time that the
inherent instability of (oxetan-2-one-4-yl)methyl radicals of
the general structure 3 can be tamed to allow for the
preparation of â-lactones. However, although of utility in
this transformation, the gem-diphenyl motif of the products
of these latter reactions does not readily lend itself to
subsequent synthetic transformations.
In an attempt to ameliorate this deficiency, we next
examined the reactions of arylthio-substituted analogues in
the reaction process.4 We were gratified to observe that
compounds 10d and 10e (both prepared from 3,3-dichloro-
acrylic acid) undergo 4-exo-cyclization in synthetically useful
yields, to give thioacetal lactones 11d (R ) R1 ) SPh, R2
) H, R3 ) Et) and 11e (R ) R1 ) STol, R2 ) H, R3 ) Et)
(Table 2, entries 10-12). The thioacetal functionality of these
lactones is far riper for further reaction than in the case of
lactones 11 and 12, thereby offering a new potential entry
to bioactive â-lactones and their analogues by this methodol-
ogy.
Thus we have demonstrated for the first time that, despite
the inherent instability of the intermediate radicals, func-
tionalized â-lactones may be prepared via 4-exo-trig radical
cyclization. The extrapolation of these preliminary data is
currently the focus of intense scrutiny in our laboratories.
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Tetrahedron Lett. 1991, 32, 1725-1728. Ishibashi, H.; Kameoka, C.;
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Acknowledgment. We thank EPSRC and Glaxo-
Wellcome for financial support and acknowledge the guid-
ance and advice of Mr. G. Buchman.
(5) (a) Esker, J. L.; Newcomb, M. Tetrahedron Lett. 1993, 34, 6877-
6880. (b) Boivin, J.; Yousfi, M.; Zard, S. Z. Tetrahedron Lett. 1994, 35,
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Supporting Information Available: Experimental pro-
cedures and spectroscopic data for compounds 5 and 11a,
b, and e. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL0340235
(7) Stereochemical assignment of â-lactones were made following the
observations of Mulzer et al.: Mulzer, J.; Pointner, A.; Chucholowski, A.;
Bruentrup, G. J. Chem. Soc., Chem. Commun. 1979, 52-54.
(8) Barton, D. H. R.; Crich, D.; Motherwell, W. B. J. Chem. Soc., Chem.
Commun. 1983, 939-941.
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