A novel short approach to (Z)-pulchellalactam through transition-metal- catalyzed atom-transfer radical cyclization of 1-isopropylprop-2-enyl dichloroacetate

Article abstract of DOI:10.1055/s-2007-983709

A new, five-step route to (Z)-pulchellalactam, a CD45 protein tyrosine phosphatase inhibitor, is presented. Key steps are the copper(I) chloride-bipyridyl catalyzed atom-transfer radical cyclization of an appropriate allyl α,α-dichloroacetate and the subsequent dehydrochlorination/ prototropic rearrangement of the resulting dichlorolactone. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-983709

1
882
PAPER
A Novel Short Approach to (Z)-Pulchellalactam through Transition-Metal-
Catalyzed Atom-Transfer Radical Cyclization of 1-Isopropylprop-2-enyl
Dichloroacetate
a
b
b
c
d
b
S
F
hor
t
A
pproac
u
hto(
Z
)-Pulc
l
hellala
v
ctam ia Felluga, Franco Ghelfi,* Ugo M. Pagnoni, Andrew F. Parsons, Mariella Pattarozzi, Fabrizio Roncaglia,*
a
Ennio Valentin
a
Dipartimento di Scienze Chimiche, Università di Trieste, via Licio Giorgieri 1, 34127 Trieste, Italy
Dipartimento di Chimica, Università degli Studi di Modena e Reggio Emilia, via Campi 183, 41100 Modena, Italy
Fax +39(59)373543; E-mail: ghelfi.franco@unimore.it; E-mail: roncaglia.fabrizio@unimore.it
b
c
Department of Chemistry, University of York, Heslington, York YO10 5DD, UK
d
Dipartimento di Scienze Chimiche, Università degli Studi di Padova, via Marzolo 1, 35131 Padova, Italy
Received 27 March 2007; revised 17 April 2007
The restricted natural availability of this potent inhibitor
of CD45 PTP makes synthesis the only reliable source of
material for biological investigations, as well as allowing
Abstract: A new, five-step route to (Z)-pulchellalactam, a CD45
protein tyrosine phosphatase inhibitor, is presented. Key steps are
the copper(I) chloride–bipyridyl catalyzed atom-transfer radical
cyclization of an appropriate allyl a,a-dichloroacetate and the sub- the preparation of analogous structures for structure–
sequent dehydrochlorination/prototropic rearrangement of the re- activity relationship studies. Only five synthetic ap-
4
sulting dichlorolactone.
proaches to 1 are known. Four of them involve a similar
Key words: cyclizations, eliminations, lactams, lactones, radical strategy, involving the unsaturated N-Boc-protected lac-
tam 2 as a common intermediate (Scheme 1).4 The g-
alkylidene side chain was attached to 2 by aldol addition
with isobutyraldehyde, followed by migration of the Boc
group, and, finally, an E1cb elimination.4a
a–d
reactions
The protein tyrosine phosphatases (PTPases or PTPs)
constitute a family of closely related key enzymes control-
ling the status of tyrosine phosphorylation and regulating
the cellular function. Particularly CD45, a receptor-like
transmembrane PTP, has been shown to control the acti-
vation of both B and T cells. The ability to selectively in-
hibit this enzyme is therefore an important therapeutic
target for treating autoimmune and chronic anti-inflam-
1
a
O
N
O
O
N
O
O
O
1
H
refs. 4b,c
Boc
8
0%
ref. 4d
Boc
2
matory illness.
N
COOH
c or d
O
N
Ten years ago, in the course of an effort to find enzyme in-
hibitors from microbial sources, Alvi and co-workers
showed that the extract from the marine fungus Corol-
lospora pulchella had very potent CD45 activity, and the
active component (IC = 124 mg/mL) was identified as
ref. 4a
OH
b
Boc
2
O
N
H
ref. 4a 65%
ref. 4b 84%
ref. 4c 78%
ref. 4d 48%
1
O
N
5
0
82–86%
3
Boc
0%
the novel compound (Z)-pulchellalactam (1) (Figure 1).
This natural product contains 1,5-dihydro-2H-pyrrol-2-
8
one as a core structure, which could be an interesting
Scheme 1 Reagents and conditions: (a) HMDS, DMF, 100 °C; (b)
pharmacophore for the development of phosphatase in- 1. Meldrum’s acid, ClCO i-Pr, DMAP, CH Cl ; 2. EtOAc, reflux; (c)
2
2
2
1
a
i-PrCHO, NaH, THF (86% yield); (d) i-PrCHO, LDA, THF (82%
hibitors.
yield).
Over the last decades the formation of s-bonds by radical
O
N
H
reactions has become one of the most reliable synthetic
5
tools in organic chemistry. Radical cyclizations are of
1
particular importance, as illustrated in various reviews
6
and monographs. One especially attractive and effective
Figure 1 (Z)-Pulchellalactam (1)
radical cyclization method, used for preparing five-mem-
bered heterocycles, is the transition-metal-catalyzed
7
atom-transfer radical cyclization (TMC-ATRC) of a-
8
9
halo allyl esters or a-halo N-allylamides. The redox cat-
SYNTHESIS 2007, No. 12, pp 1882–1886
Advanced online publication: 08.06.2007
DOI: 10.1055/s-2007-983709; Art ID: Z07907SS
x
x.
x
x
.
2
0
0
7
alysts of choice are, by far, copper(I) halide complexes
with polydentate nitrogen ligands,8
a–d,9a–e
and, less fre-
©
Georg Thieme Verlag Stuttgart · New York

PAPER
Short Approach to (Z)-Pulchellalactam
1883
quently, assorted ruthenium(II) or ruthenium(III) com-
Cl
Cl
Cl
H
Cl
9
f–h
plexes.
Homolytic cleavage of the C–X bond by the
a
b
c
transition-metal complex in the lower oxidation state gen-
erates an alkyl radical, while the metal complex is oxi-
dized and the metal increases its oxidation state by +1.
The radical then adds to the tethered double bond to give
a new radical, which abstracts a halogen atom from the
transition-metal complex in the higher oxidation state,
O
R
O
O
R
O
R
OH
R
O
O
4
a 96%
4b 95%
5a 72%
5b 60%
6a 86%
[cis/trans = 9:91]
a, R = pentyl
b, R = hexyl
6b 88%
[
cis/trans = 9:91]
Scheme 3 Reagents and conditions: (a) Cl CHCOCl, DMAP,
2
thus regenerating the active form of the metal catalyst. CH Cl , r.t., 2 h; (b) CuCl/bpy, 145 °C, MeCN; (c) Bu SnH, AIBN,
2
2
3
8
0 °C, toluene.
The method has some important advantages over other
radical techniques, and these include the following: (i)
7
high selectivity, (ii) low cost of the catalyst, (iii) ease of
workup, (iv) high productivity, and (v) preservation of the
carbon–halogen functionalities on conversion of a reac-
tant into a cyclic product.
ene in boiling benzene, he curiously recovered 5-[(benzyl-
oxy)methylidene]-3-methylfuran-2(5H)-one. A related
8e
result was observed with
a g-alkyl-3,3-dichloro-
12a
12b
butanolide
and a 5-alkyl-3-chlorofuran-2(5H)-one
A few years ago we described an elegant and concise when they were reacted with nitrogen bases. The common
route to 1, in which the TMC-ATRC of N-vinyl dichloro- feature of all these reactions is the involvement of a 5-
acetamide 3, catalyzed by [RuCl (PPh ) ], is the key syn- alkyl-3-chlorofuran-2(5H)-one intermediate, which un-
2
3 3
thetic step for the construction of the heterocyclic skeleton dergoes two consecutive base-catalyzed transformations:
4
e
3
4
(
Scheme 2). This approach was, however, vitiated by an (i) a double bond shift from D to D to form the 5-alkyl-
unsatisfactory overall yield (4%) and selectivity (the in- 3-chlorofuran-2(3H)-one structure and (ii) subsequent
termediate
5-alkylidene-1,5-dihydro-2H-pyrrol-2-one conjugated elimination of hydrogen chloride from the re-
was obtained as a 56:44 mixture of E- and Z-isomers).
arrangement product, involving loss of the a-hydrogen on
the chain bound to the C-5 position and the remaining
chlorine atom, four atoms apart, at the C-3 position.
O
N
Cl
Cl
In addition, we were also aware that the conversion of g-
alkylidenebutanolides into the corresponding g-alky-
lidene-g-lactams is a well-known and reliable transforma-
tion, attainable by treatment of the unsaturated lactones
O
H
a)
b)
c)
DMB
O
N
O
N
H
DMB
3
(19%)
+
13
(
32%)
1
(66%)
with NH /H .
3
(
overall 4%)
We have made use of these findings to accomplish a novel
synthesis of pulchellalactam (1), as outlined in Scheme 4.
-Methylhex-1-en-3-ol (8) was prepared by nucleophilic
addition of commercial vinylmagnesium bromide to iso-
valeraldehyde, and then acylated by dichloroacetyl chlo-
ride to form ester 9. ATRC of 9, carried out by the same
protocol employed for the preparation of Quercus lac-
tones, gave dichlorobutanolide 10 in satisfactory yield.
As observed for the cyclization of 4 to give 5
Scheme 3), a mixture of three diastereoisomers,
3a,4b,5a)-10a, (3a,4a,5b)-10b, and (3a,4b,5b)-10c
72:20:8), formed (Scheme 4). Their relative stereochem-
istry was assigned on the basis of difference NOE mea-
surements carried out on the mixture, whose
spectroscopic data agree fully with those already de-
scribed for compounds 5.10
Scheme 2 Reagents and conditions: (a) 1. DMBNH , toluene, re-
flux; 2. Cl CHCOCl, Et N, toluene, 0 °C; (b) [RuCl (PPh ) ], toluene,
reflux; (c) TFA, r.t.
2
2
3
2
3 3
5
We now report a completely different and more effective
synthetic route to pulchellalactam (1). This novel ap-
proach also employs a key TMC-ATRC step, but the pre-
cursor for the cyclization is an allyl dichloroacetate
derivative.
10
10
(
(
(
Recently we described a novel chemo-enzymatic synthe-
sis of Quercus lactones 6, in which the heterocyclic core
was obtained through an ATRC, promoted by a copper(I)
chloride–bpy complex, of the nonracemic allylic dichlo-
roacetates 4 (Scheme 3). Cyclization to form dichloro-
butanolides 5 required a high reaction temperature to
ensure O–CO bond rotation, so that the intermediate [(al-
lyloxy)carbonyl]methyl radical could adopt the appropri-
ate conformation to allow an interaction between the
1
0
Double dehydrochlorination of 10 was initially attempted
with 1,8-diazabicyclo[5.4.0]undec-7-ene, 2-ethylpyri-
dine, or triethylamine, but with no success. Conversely,
when pyridine was used and the reaction mixture heated,
for relatively short times, at 163 °C, pulchellalactone (11)
was obtained in an acceptable yield and completely ste-
reoselectively.
8
,11
radical and the C=C bond.
Adducts such as 5 (with two chloro groups located in
endo-a and exo-g positions with respect to the carbonyl
group) appear to be promising intermediates for the for-
mation of lactones with a g-alkylidene chain. In fact,
many years ago, Takano noted that, on attempting the de-
hydrochlorination of 4-(benzyloxy)-2-chloro-3-(chloro-
methyl)butanolide with 1,8-diazabicyclo[5.4.0]undec-7-
The Z-configuration of the exocyclic double bond was es-
tablished by a difference NOE experiment. Irradiation of
the methyl group at C-4 (d = 2.09) caused an enhancement
Synthesis 2007, No. 12, 1882–1886 © Thieme Stuttgart · New York

1
884
F. Felluga et al.
PAPER
Cl
Cl
new synthetic method should be applicable to the prepara-
tion of pulchellalactam analogues, as well as the corre-
sponding parent butenolides.
H
O
a
b
CHO
OH
O
7
8
77%
9 81%
c
Reagents and solvents were standard-grade commercial products,
purchased from Aldrich, Acros, Fluka, or RdH, and used without
further purification, except for MeCN and CH Cl that were dried
Cl
Cl
2
2
e
d
over three batches of 3-Å sieves (5% w/v, 12 h). Anhyd THF was
distilled from sodium/benzophenone under an inert atmosphere be-
fore use. The silica gel used for flash chromatography was Silica
O
N
H
O
O
O
O
1
13
Gel 60 Merck (0.040–0.063 mm). H (400 MHz) and C NMR
100.1 MHz) spectra were run on Jeol EX-400 and Bruker DPX 200
1
83%
11 67%
10 64%
(
instruments. IR and MS spectra were recorded on Jasco FT-IR 200
and HP 5890 GC–HP 5989A MS instruments, respectively. Hetero-
nuclear H,C NMR correlation techniques and homonuclear NOE
spectroscopy were used for the structural assignment of compounds
Scheme 4 Reagents and conditions: (a) H C=CH MgBr, THF,
2
2
–
15 °C to r.t.; (b) Cl CHCOCl, py, CH Cl , r.t., 2 h; (c) CuCl/bpy,
2 2 2
MeCN, 140 °C, 15 h; (d) py, 163 °C, 50 min; (e) 1. aq NH , 65 °C, 4
3
h, 2. aq HCl.
1
, 10, and 11.
5
-Methylhex-1-en-3-ol (8)
of the H-3 (2%) signal and, more significantly, an en-
hancement of the exocyclic vinylic hydrogen (5%) signal.
A 1 M soln of H C=CH MgBr in THF (100 mL) was slowly added
under a stream of argon to a soln of freshly distilled i-BuCHO (7;
2
2
According to the probable mechanism of the double elim- 8.6 g, 100 mmol) in anhyd THF (50 mL) at –15 °C in a three-necked
round-bottom flask, equipped with a dropping funnel, an argon in-
let, and a condenser. After the addition was completed, the mixture
was allowed to warm to r.t. and stirred until disappearance of the
starting material (monitored by TLC, light PE–EtOAc, 9:1). The
soln was cooled to 0 °C, 1 M HCl (50 mL) was added, the organic
ination from 10, the Z-configuration of the double bond in
1
1 may be explained by steric interactions in 14
8
e
(
Scheme 5). The periplanar conformation of 14 with the
isopropyl group pointing away from the methyl group is
likely to be favored, and elimination from this conforma-
tional form would give the Z-isomer (Scheme 5).
layer was separated, and the aqueous phase was extracted with Et O
2
(3 × 20 mL). The organic phase was dried (Na SO ), the solvent was
2
4
evaporated, and the residue was distilled; this gave pure 8.
Finally, pulchellalactam (1) was efficiently isolated after
reaction of pulchellalactone (11) with a concentrated so-
Yield: 9.8 g (77%); colorless liquid; bp 40–42 °C/10 Torr.
–
1
lution of ammonia, followed by an acidic workup IR (neat): 3465 (OH), 1654 (C=C) cm .
(
Scheme 4).
1
H NMR (400 MHz, CDCl ): d = 0.91 (d, J = 6.6 Hz, 3 H, CH CH),
3
3
0
.93 (d, J = 6.6 Hz, 3 H, CH CH), 1.32 (m, 1 H, H-5), 1.47 (m, 1 H,
3
H
Cl
H
H-5), 1.75 (br m, 2 H, H-4 and OH), 4.17 (m, 1 H, H-3), 5.09 (ddd,
Cl
Cl
Cl
2
2
3
4
3
J = 1.4 Hz, J = 1.4 Hz, J = 10.2 Hz, 1 H, H-1), 5.22 (ddd,
cis
Py
Py
4
3
H
J = 1.4 Hz, J = 1.4 Hz, J
= 17.2 Hz, 1 H, H-1), 5.86 (ddd,
J = 6.2 Hz, J = 10.2 Hz, J = 17.2 Hz, 1 H, H-2).
cis trans
trans
O
O
– HCl
O
O
3
3
O
O
10
12
13
13
C NMR (100 MHz, CDCl ): d = 22.4, 23.1, 24.5, 46.3, 71.6,
3
1
14.4, 141.7.
MS (EI, 70 eV): m/z (%) = 57 (100), 72 (16), 81 (7), 85 (5), 96 (3),
+
Cl
99 (2), 113 (1) [M – H] .
Me
Py
H
Anal. Calcd for C H O: C, 73.63; H, 12.36. Found: C, 73.45; H,
7 14
12.31.
O
O
O
O
– HCl
i-Pr
H
3
-Methyl-1-vinylbutyl Dichloroacetate (9)
14
(Z)-11
CH Cl (25.0 mL), 8 (5.4 g, 47.3 mmol), and pyridine (4.6 mL, 56.8
2
2
mmol) were introduced into a 100-mL double-necked round-bottom
flask, fitted with a dropping funnel and a reflux condenser, and
Cl
Me
Py
X
– HCl
i-Pr
closed on the top with a CaCl tube. A soln of Cl CHCOCl (5.02
2
2
O
O
O
O
mL, 52.07 mmol) in CH Cl (10 mL) was then carefully added over
2 2
H
H
1
5 min to the stirred soln, cooled in a water bath. Then the bath was
(
E)-11
removed and the mixture was stirred at r.t. for 2 h. The mixture was
washed with 10% (w/v) aq HCl (2 × 15 mL). The organic phase was
then separated and concentrated. Flash chromatography of the crude
Scheme 5 Probable mechanism of the double elimination from 10
product [silica gel, PE (bp 40–60 °C)–Et O, 10:0 to 9.5:0.5] afford-
ed 9.
2
In summary, we have developed a novel and practical
five-stage route to pulchellalactam (1), starting from iso-
valeraldehyde, in a satisfactory 22% overall yield. The
Yield: 8.59 g (81%); colorless oil.
heterocyclic core was constructed by exploiting the TMC- IR (neat): 1762 (C=O) cm–1
1
ATRC strategy. The two C–Cl groups in the product of
H NMR (200 MHz, CDCl ): d = 0.95 (d, J = 6.5 Hz, 3 H, CH CH),
3
3
the radical cyclization were profitably exploited to regio- 0.96 (d, J = 6.5 Hz, 3 H, CH
CH), 1.47 (m, 1 H, H-5), 1.71 (br m, 3
3
2
4
3
H, H-5 and OH), 5.25 (ddd, J = 1.4 Hz, J = 1.4 Hz, J = 10.1 Hz,
1
selectively introduce the two conjugated C=C bonds. This
cis
2
4
3
H, H-1), 5.36 (ddd, J = 1.4 Hz, J = 1.4 Hz, J
= 17.2 Hz, 1 H,
trans
Synthesis 2007, No. 12, 1882–1886 © Thieme Stuttgart · New York

PAPER
Short Approach to (Z)-Pulchellalactam
1885
3
3
3
5
H-1), 5.39 (m, 1 H, H-3), 5.80 (ddd, J = 7.1 Hz, J = 10.1 Hz,
J = 6.6, 9.5 Hz, 1 H, (CH ) CH], 5.16 (dd, J = 9.9 Hz, J = 0.8 Hz,
cis
3 2
3
4
5
Jtrans = 17.2 Hz, 1 H, H-2), 5.94 (s, 1 H, CHCl2).
1 H, =CH), 5.90 (dq, J = 1.4 Hz, J = 0.8 Hz, 1 H, COCH=).
1
3
13
C NMR (50.3 MHz, CDCl ): d = 22.2, 22.7, 24.3, 42.9, 64.6,
C NMR (100.1 MHz, CDCl ): d = 11.8, 22.6, 26.2, 116.0, 119.8,
3
3
1
18.1, 135.1, 163.8.
149.1, 155.0, 169.6.
MS (EI, 70 eV): m/z (%) = 55 (100), 57 (50), 81 (64), 96 (18), 97
MS (EI, 70 eV): m/z (%) = 68 (77), 81 (22), 96 (100), 109 (9), 124
(4), 137 (14), 152 (25) [M] .
+
+
(
32), 167 (5) [M – C H ] .
4
9
Anal. Calcd for C H Cl O : C, 48.02; H, 6.27. Found: C, 47.93; H,
Anal. Calcd for C H O : C, 71.03; H, 7.95. Found: C, 71.10; H,
9
14
2
2
9
12
2
6
.30.
7.90.
3
-Chloro-4-(chloromethyl)-5-isobutyldihydrofuran-2(3H)-one
(Z)-Pulchellalactam (1)
Lactone 11 (250 mg, 1.64 mmol) was placed in a cylindrical flask
(
10)
CuCl (305 mg, 3.08 mmol) and bpy (481 mg, 3.08 mmol) were
placed in a Schlenk tube fitted with a perforable septum (blocked by
a screw cap) and a magnetic stirrer bar. Anhyd MeCN (50 mL) was
added under argon, and, after 30 min, 9 (2.77 g, 12.3 mmol) was in-
troduced. The mixture was stirred at 140 °C for 15 h, cooled, and di-
luted with 10% (w/v) aq HCl (50 mL) and extracted with CH Cl
with a screw cap and equipped with a stirring bar, and then 33%
(w/v) aq NH (1 mL) was added. The colorless emulsion turned to
3
yellow and a white solid appeared. The mixture was stirred at 65 °C
for 4 h, then the excess ammonia was evaporated. A soln of 10%
(w/v) aq HCl (0.75 mL) was added, and, after stirring for 30 min,
the mixture was extracted with CH Cl (2 × 5 mL). The combined
2
2
2
2
(
50 mL). The aqueous phase was washed with CH Cl (20 mL) and
organic layers were finally concentrated. Flash chromatography of
2
2
the combined organic layers were concentrated. The crude product
was purified by flash chromatography [silica gel, PE (bp 40–
the crude product [silica gel, PE (bp 40–60 °C)–Et O, 1:1] gave (Z)-
2
pulchellalactam (1) as a thick colorless oil. Spectral data were in ac-
4
a
6
0 °C)–Et O, 10:0 to 9:1]. This gave lactones 10 as an inseparable
cord with that reported in literature.
2
mixture of diastereomers (3a,4b,5a)-10a, (3a,4a,5b)-10b, and
Yield: 207 mg (83%).
(
3a,4b,5b)-10c (72:20:8).
Yield: 1.77 g (64%); pale yellow oil.
IR (neat): 1786 (C=O), 1180 (C–O) cm–1
Acknowledgment
1
We thank the Ministero della Istruzione, dell’Università e della
Ricerca (MIUR).
H NMR (400 MHz, CDCl ): d (10a) = 0.98 (d, J = 6.6 Hz, 3 H,
3
CH CH), 1.00 (d, J = 6.6 Hz, 3 H, CH CH), 1.54 (m, 1 H), 1.65 (m,
1
3
3
3
3
H), 1.89 (m, 1 H), 2.59 (tdd, J = 2.9 Hz, J = 10.3 Hz, J = 3.3
4,5 3,4 3
Hz, J = 4.0 Hz, 1 H, H-4), 3.73 (part B of an ABX system,
JAB = 12.2 Hz, JBX = 3.3 Hz, 1 H, CHCl), 3.84 (part A of an ABX
4
References
system, J = 12.2 Hz, JAX = 4.0 Hz, 1 H, CHCl), 4.49 (dt,
(1) (a) Bialy, L.; Waldmann, H. Angew. Chem. Int. Ed. 2005, 44,
3814. (b) Dewang, P. M.; Hsu, N.-M.; Peng, S.-Z.; Li, W.-R.
Curr. Med. Chem. 2005, 12, 1.
AB
3
3
J4,5 = 2.9 Hz, J = 9.6 Hz, H-5), 4.61 (d, J = 10.3 Hz, 1 H, H-3).
3,4
Signals of 10b and 10c not overlapped with those of 10a: d (10b) =
2
.71 (m, 1 H, H-4), 3.57 (part B of an ABX system, J = 11.3 Hz,
(2) (a) Hooft van Huijsduijnen, R. Gene 1998, 225, 1.
(b) Trowbridge, I. S. Annu. Rev. Immunol. 1994, 12, 85.
(c) Neel, B. G. Curr. Opin. Immunol. 1997, 9, 405.
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(4) (a) Li, W.-R.; Lin, S. T.; Hsu, N.-M.; Chern, M.-S. J. Org.
Chem. 2002, 67, 4702. (b) Bessho, J.; Shimotsu, Y.;
Mizumoto, S.; Mase, N.; Yoda, H.; Takabe, K. Heterocycles
2004, 63, 1013. (c) Mangaleswaran, S.; Argade, N. P.
Synthesis 2004, 1560. (d) Langlois, N. Synth. Commun.
AB
JBX = 5.9 Hz, 1 H, CHCl), 3.65 (part A of an ABX, JAB = 11.3 Hz,
JAX = 2.9 Hz, 1 H, CHCl), 4.43 (dt, J = 8.1 Hz, J = 2.9 Hz, 1 H, H-
3
5
3
), 4.57 (d, J3 = 6.2 Hz, 1 H, H-3); d (10c) = 2.98 (m, 1 H, H-4),
,4
.70 (part AB of an ABX system, JAB = 11.7 Hz, J = 3.3 Hz,
AX
JBX = 4.0 Hz, 2 H, CH Cl), 4.36 (d, J = 6.6 Hz, 1 H, H-3), 4.86 (ddd,
2
J = 3.6, 4.0, 6.6 Hz, 1 H, H-5).
1
3
C NMR (100 MHz, CDCl ): d (10a) = 21.6, 23.15, 25.1, 40.6,
3
4
4
5
2.9, 52.7, 52.9, 77.9, 170.4; d (10b) = 21.1, 23.1, 25.15, 39.9, 42.8,
9.5, 54.2, 79.8, 170.3; d (10c) = 20.8, 23.4, 24.8, 37.9, 40.2, 50.2,
3.7, 78.4, 171.1.
2006, 36, 2253. (e) Bryans, J. S.; Chessum, N. E. A.; Huther,
N.; Parsons, A. F.; Ghelfi, F. Tetrahedron 2003, 59, 6221.
5) Radicals in Organic Synthesis; Renaud, P.; Sibi, M. P., Eds.;
Wiley-VCH: Weinheim, 2001.
(
MS (EI, 70 eV): m/z (%) = 69 (100), 70 (69), 75 (30), 95 (14), 103
+
(
19), 131 (11), 167 (7), 209 (<1) [M – CH ] .
3
(6) For recent reviews on radical cyclizations, see:
(a) Majumdar, K. C.; Basu, K. B.; Chattopadhyay, S. K.
Tetrahedron 2007, 63, 793. (b) Rossi, R. A.; Peñéñory, A.
B. Curr. Org. Synth. 2006, 3, 437. (c) Walton, J. C. Top.
Curr. Chem. 2006, 264, 163.
Anal. Calcd for C H Cl O : C, 48.02; H, 6.27. Found: C, 48.01; H,
9
14
2
2
6
.29.
(
Z)-4-Methyl-5-(2-methylpropylidene)furan-2(5H)-one (11)
Dichlorolactone 10 (3.97 g, 17.64 mmol) was placed in a Schlenk
tube fitted with a perforable septum (blocked by a screw cap) and a
magnetic stirrer bar, and then pyridine(4.7 mL, 58.2 mmol) was
added under argon. The mixture was stirred at 163 °C for 50 min,
cooled, diluted with 10% (w/v) aq HCl (8 mL), and extracted with
CH Cl (8 mL). The aqueous phase was washed with CH Cl (2 × 8
(7) (a) Clark, A. J. Chem. Soc. Rev. 2002, 31, 1.
(b) Nagashima, H.; Itoh, K. J. Synth. Org. Chem., Jpn. 1995,
53, 298.
(8) (a) Edlin, C. D.; Faulkner, J.; Helliwell, M.; Knight, C. K.;
Parker, J.; Quayle, P.; Raftery, J. Tetrahedron 2006, 62,
3004. (b) De Campo, F.; Lastécouères, D.; Verlhac, J.-B.
Chem. Commun. 1998, 2117. (c) Nagashima, H.; Seki, N.;
Ozaki, N.; Wakamatsu, H.; Itoh, K.; Tomo, Y.; Tsuji, J. J.
Org. Chem. 1990, 55, 985. (d) Terent’ev, A. B.; Vasil’eva,
T. T.; Kuz’mina, N. A.; Ikonnikov, N. S.; Orlova, S. A.;
Mysov, E. I.; Belokon’, Y. N. Russ. Chem. Bull. 1997, 46,
2
2
2
2
mL) and the combined organic layers were concentrated. The crude
product was purified by flash chromatography [silica gel, PE (bp
4
0–60 °C)–Et O, 10:0 to 8:2]; this gave lactone 11.
2
Yield: 1.79 g (67%); pale yellow oil.
IR (neat): 1772, 1748 (CO), 1673, 1608 (C=C) cm–1
2096. (e) Takano, S.; Nishizawa, S.; Akiyama, M.;
1
Ogasawara, K. Heterocycles 1984, 22, 1779.
H NMR (400 MHz, CDCl ): d = 1.10 [d, J = 6.6 Hz, 6 H,
3
4
(
CH ) CH], 2.14 (d, J = 1.5 Hz, 1 H, CH ), 2.99 [d of sept,
3
2
3
Synthesis 2007, No. 12, 1882–1886 © Thieme Stuttgart · New York

1
886
F. Felluga et al.
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(
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2
2
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(
2
3, 14031. (f) Severin, K. Curr. Org. Chem. 2006, 3, 437.
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Synthesis 2007, No. 12, 1882–1886 © Thieme Stuttgart · New York