Consecutive reactions with sulfoximines: a direct access to 2-sulfonimidoylylidene tetrahydrofurans and 6-sulfonimidoylmethyl-3,4-dihydro-2H-pyrans

Article abstract of DOI:10.1016/j.tet.2009.09.080

2-Sulfonimidoylylidene tetrahydrofurans and 2-sulfonimidoylylidene-5-vinyl tetrahydrofurans were readily synthesized via a consecutive acylation/SN2 sequence with total regio- and chemoselectivity from Johnson's sulfoximine derivatives. The same consecuti

Full text of DOI:10.1016/j.tet.2009.09.080

Tetrahedron 65 (2009) 9756–9764
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Consecutive reactions with sulfoximines: a direct access to
2-sulfonimidoylylidene tetrahydrofurans and 6-sulfonimidoylmethyl-
3,4-dihydro-2H-pyrans
Marie-Alice Virolleaud, Vellaisamy Sridharan, Damien Mailhol, Damien Bonne, Cyril Bressy,
*
Gae¨lle Chouraqui, Laurent Commeiras, Yoann Coquerel, Jean Rodriguez
´
´
´ ˆ
Aix-Marseille Universite, Institut des Sciences Moleculaires de Marseille, ISM2 – UMR 6263, Centre Saint Jerome, Service 531, 13397 Marseille Cedex 20, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2009
Received in revised form
10 September 2009
Accepted 18 September 2009
Available online 22 September 2009
2-Sulfonimidoylylidene tetrahydrofurans and 2-sulfonimidoylylidene-5-vinyl tetrahydrofurans were
readily synthesized via a consecutive acylation/SN2 sequence with total regio- and chemoselectivity
from Johnson’s sulfoximine derivatives. The same consecutive reaction could also be applied to the
expeditious synthesis of 6-sulfonimidoylmethyl-3,4-dihydro-2H-pyrans.
Ó 2009 Elsevier Ltd. All rights reserved.
1. Introduction
available a,u-haloesters via an acylation/heterocyclization consec-
utive reaction to efficiently provide the functionalized 2-sulfoni-
Nature has produced a diverse array of molecules with wide-
spread biological activity. To obtain the large quantities of these
substances necessary for biological evaluation and drug de-
velopment, the pharmaceutical industry relies upon organic syn-
thesis.1 Indeed organic synthesis can often compete with nature in
supplying these molecules. However as the molecular complexity
of the natural products increases, the length of syntheses also in-
creases, which often translates into poor overall efficiency, pro-
hibitive cost, and the production of a considerable amount of waste.
In the current ‘economy’ context2,3 associated with environmental
considerations4 in the science of organic synthesis, the research for
new methodologies that allows for rapid and controlled synthetic
access to these target molecules is crucial. Consecutive and domino
processes have emerged as powerful tools for the efficient and eco-
compatible5 creation of molecular complexity and chemical di-
versity from simple substrates in a single operation.6
midoylylidene tetrahydrofuran 2a (Scheme 1).
1) n-BuLi (2 equiv), −20 °C , 30 min
2)
MeO2C
Cl
O
NMe
−80 °C to −40 °C, 1.5 h
O
O
NMe
S
Ph
S
Ph
3) work-up
1a
2a (86%)
Scheme 1.
Functionalized tetrahydrofurans are structural motifs in a num-
ber of highly interesting natural products (for example, nactin de-
rivatives, tetronasin, tetronomycin,10 terpenes,11 medium size
lactones,12 charlic, and charolic acids, terrestric acids,13 chalcog-
ran,14 and acetogenins15) and are of pharmacological relevance.16
Several methods17 have been developed for the construction of
these useful building blocks18 but there is still an interest in the
development of an efficient, convenient and stereoselective ap-
proach. The regio- and diastereoselective synthesis of 2-ylidene
tetrahydrofurans via anionic domino or consecutive reactions has
been developed in the past few years independently in our
group8,19 and the groups of Zhao,20 Hagiwara21 and Langer.17c
In this context, chiral sulfoximines particularly turned our at-
tention due to the presence of a modulable stereogenic sulfur atom
and their use in asymmetric synthesis is well-established.9,22 In fact
both the steric and electronic demand can be easily modified by
changing the nature of the substituent group on the nitrogen atom.
In our laboratory there is an ongoing interest in multiple bond-
forming transformations.7 In the course of our research program on
the reactions of bis-nucleophiles with bis-electrophiles, we have
recently reported8 preliminary results for the chemo- and regio-
selective synthesis of 2-sulfonimidoylylidene tetrahydrofurans by
a consecutive reaction of sulfoximines with
a,u-haloesters. The
dianion generated from Johnson’s sulfoximine9 (1a) and two
equivalents of n-butyllithium at ꢀ20 ꢁC reacts with readily
* Corresponding author. Fax: þ33 4 91 28 91 87.
E-mail address: jean.rodriguez@univ-cezanne.fr (J. Rodriguez).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.09.080

M.-A. Virolleaud et al. / Tetrahedron 65 (2009) 9756–9764
9757
Table 1
In addition this chiral auxiliary can be removed, recycled or even
exploited for further coupling.23
Consecutive reaction of sulfoximines 1 with methyl 4-chlorobutyrate
Herein we wish to report in full details our original methodology
for the synthesis of valuable 2-sulfonimidoylylidene tetrahydrofu-
rans, and its significant extension to the hydropyran series.
Entry
Product
R
Condition
Yield (%)
E/Z ratio
1
2
3
4
5
6
7
8
2a
2a
2b
2b
2c
2e
2e
2f
Me
Me
Ts
Ts
Allyl
TBS
TBS
Boc
Boc
Bz
Bz
Alloc
Piv
A
B
A
B
A
A
Aa
A
B
86
55
23
17
58
31b
35b
67
53
19
17
64
64c
70
48
49
52:48
86:14
61:39
70:30
41:59
d
2. Results and discussion
d
The requisite N-protected sulfoximines 1 were prepared. Known
compounds were obtained according to reported literature
procedures in similar yields,24 and three previously unknown
analogues (1h, 1k, and 1m) were also prepared. A range of
N-substituted sulfoximines bearing various electron-donating,
electron-withdrawing, and sterically hindered groups was obtained
(1a–m, Scheme 2).
37:63
57:43
53:47
53:47
37:63
21:79
35:65
36:64
37:63
9
2f
10
11
12
13
14
15
16
2g
2g
2h
2i
2j
2k
2l
A
B
A
A
A
A
A
Neopentyl
Cbz
Eoc
a
NaOH was added at rt.
The E isomer probably decomposed during silica gel flash chromatography.
21% of acyl product 3 was isolated.
N-substitution
NH
NR
O
O
b
c
S
S
60-100 %
Ph
Ph
1a-m
When the N-silylated sulfoximine 2e (Table 1, entries 6 and 7)
1a: R = Me (84%)24a
1b: R = Ts (92%)24b
1c: R = Allyl (77%)24c
1h: R = Alloc; ClCO2allyl, Py, THF, 0 °C (85%)
1i: R = Piv (97%)24h
was submitted to the consecutive acylation/SN2 reaction, the sole
isomer isolated was the Z one. Indeed, the E isomer appeared to be
unstable and decomposed during the flash chromatography on
silica gel, presumably after cleavage of the N–Si bond. In order to
validate this hypothesis we thought it could be relevant to study
the deprotection of the silyl group in the same pot. The depro-
tection successfully occurred in presence of TBAF under the same
experimental conditions but again with poor yields. However both
Z and E isomers of 2n were isolated in moderate yields with, as
expected,22b,27,28 an increased selectivity for the TBS substituent
compared to TMS (Scheme 4).
1j: R = neopentyl (60%)24h
1d: R = TMS (quant.)24d 1k: R = Cbz; CbzCl, Py, THF, 0 °C (78%)
1e: R = TBS (87%)24e
1f: R = Boc (84%)24f
1g: R = Bz (72%)24g
1l: R = Eoc (64%)24i
1m: R = Mes; MesBr, tBuOK, Pd2(dba)3 (2 mol%),
.
IPr HCl (2 mol%), dioxane, 80 °C (96%)24j
Abbreviations used:
Ts = p-toluenesulfonyl, TBS = tert-butyldimethylsilyl,
Alloc = allyloxycarbonyl, Boc = tert-butyloxycarbonyl,
Bz = benzoyl, Piv = pivaloyl, Cbz = benzyloxycarbonyl,
Eoc = ethoxycarbonyl, Mes = mesityl = 2,4,6-trimethylphenyl,
IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene.
Scheme 2.
1) n-BuLi (2 equiv), –30 °C, 30 min
Due to the acidic character of the
deprotonation can be easily achieved by strong bases to yield the
corresponding
-metallated intermediates.25 Indeed, treatment of
a-protons in sulfoximines,
2)
MeO2C
–80 °C to –40 °C, 1.5 h
3) –40 °C, TBAF, rt, 1 h
Cl
O
NSiR3
O
O
NH
S
Ph
S
a
Ph
N-substituted sulfoximines 1 with two equivalents of n-butyl-
lithium at ꢀ30 ꢁC in THF generated the corresponding dianion (vide
infra). Subsequent addition of commercially available methyl 4-
chlorobutyrate at ꢀ80 ꢁC followed by low temperature hydrolysis
with 5% aqueous sodium hydroxide solution (conditions A) allowed
the formation of 2-sulfonimidoylylidene tetrahydrofurans (2), in
moderate to good yields, as an easily separable mixture of E and Z
isomers26 (Scheme 3 and Table 1). Although compounds with Ts,
TBS, and Bz (entries 3, 6, 7, and 10) on the nitrogen atom gave modest
yields, all other substituents gave synthetically valuable yields. At-
tempts to directly cyclize the lithiated intermediate by simply in-
creasing the reaction temperature to reflux (conditions B) failed to
improve either the yields or the selectivities (entries 2, 4, 9, and 11).
2n
1
from 1d (SiR3 = TMS): 37 %, E/Z = 43:57
from 1e (SiR3 = TBS): 22 %, E/Z = 86:12
Scheme 4.
A mechanism to account for the observed formation of 2-sul-
fonimidoylidene tetrahydrofurans 2 is proposed in Scheme 5. The
ortho-dilithiosulfoximine A undergoes a rearrangement to the
dilithiosulfoximine B, which then reacts chemoselectively with the
-halogenoester to give the -sulfonimidoylcarbanion C. The
assumption of a dianion species is based on work reported by Gais
a
,
a,a-
a,
u
a
and Mu¨ller on the
a,ortho to a,a-transmetallation of dilithiated
alkylphenylsulfones29 and dilithiosulfoximines, respectively.30
Depending on the work-up, different products would then be
produced. Addition of a 5% aqueous solution of sodium hydroxide
(conditions A) could lead after transmetallation, to the corre-
O
O
NR
1) n-BuLi (2 equiv), –30 °C, 30 min
2)
S
Ph
MeO2C
Cl
2
NR
–80 °C to –40 °C, 1.5 h
O
sponding
a-Na-sulfoximine D. The latter would then undergo
+
S
a rapid O-cyclization providing the observed sulfonimidoylylidene
tetrahydrofurans 2. Upon treatment with a saturated aqueous so-
lution of ammonium chloride the lithiated species C is simply hy-
drolyzed to the corresponding acyl adduct 3. In this case, no
product arising from the heterocyclization was detected thus con-
firming that the acylation precedes the O-cyclization. Finally
heating the reaction mixture to reflux for an hour (conditions B)
produced the same heterocycle 2 but in moderate to low yields. The
overall transformation consisted therefore in an acylation/SN2
cascade reaction.
Ph
3) A: –40 °C, 5 % NaOH, rt, 1 h
B: T up to rt, then reflux, 1 h
O
NR
O
1
S
Cl
Ph
3
Scheme 3.
It is interesting to note that under conditions A (5% NaOH hy-
drolysis) the N-pivaloyl group allowed the best selectivity in the
series (entry 13), but in this case the cyclization step is not efficient
as evidenced by the isolation of 21% of acyl product 3.

9758
M.-A. Virolleaud et al. / Tetrahedron 65 (2009) 9756–9764
R
R
R
S
R
O
R
N
O
O
N
X
O
N
n-BuLi
N
O
O
5 % NaOH
MeO
S
O
N
O
S
Li
X
S
X
S
Li
Ph
(2 equiv)
Ph
Ph
Ph
Li
Li
Na
Li
B
D
C
1
A
R
O- Na+
N
NH4Cl aq.
O
Δ
S
X
Ph
E
R
O
N
O
S
X
Ph
O
3
O
N
S
Ph
R
2
Scheme 5.
This consecutive one-pot acylation/SN2 reaction involved the
formation of two chemical bonds in the same operation (a C–O
bond and a C–C bond), thus providing a practical, chemo- and
regioselective access to versatile building blocks of type 2. In order
to generalize this multiple bond-forming transformation, we next
examined the reaction of the sulfoximine dianion with methyl es-
ters bearing an allylic bromide as the second electrophilic position,
namely methyl 6-bromo-hex-4-eneoate (4a, R1¼H) and methyl 5-
methyl-6-bromo-hex-4-eneoate (4b, R1¼Me). Both would allow for
the synthesis of the corresponding 2-sulfonimidoylylidene-5-vinyl
tetrahydrofurans via an intramolecular SN20 displacement. As an-
ticipated the reaction proceeded well under the previously opti-
mized reaction conditions (conditions A) and afforded the expected
compounds 5 in fair to good yields (Scheme 6 and Table 2). Con-
ditions B were proved less efficient (entries 2, 4, 6, and 8) and in
two cases, afforded predominately the corresponding acyl de-
rivatives 6 (entries 4 and 6). Finally, increasing the steric demand
on the nitrogen of the sulfoximine (entries 3, 9, and 10) led to an
increased diastereoselectivity in favor of the Z isomer.
Such consecutive acylation/SN20 transformations allow for the
installation of an extra vinyl group in a chemoselective and regio-
selective manner. This C-5 vinyl group should prove useful in the
context of natural products total synthesis.
Subsequently we extended our investigation to study the
equilibrium between E and Z isomers of 2a in the presence of
a base, to try to understand the reactivity of these stereoisomers
but mainly to find conditions leading to one major diastereomer.
Treatment of 2a (E or Z) with one equivalent of methyllithium in dry
THF under different conditions followed by quenching with water
gave a mixture of E and Z isomers along with dihydrofuran de-
rivative 7 (Scheme 7 and Table 3).
O
O
S
NMe
Ph
(E)-2a
+
O
NMe
Ph
O
MeLi (1 equiv)
S
O
NMe
S
Ph
O
O
THF
see Table 3
R1
1) n-BuLi (2 equiv), –30 °C, 30 min
O
(Z)-2a
O
NR
(E)-2a or (Z)-2a
R1
S
Ph
+
2)
4
MeO2C
Br
5
O
NR
S
O
–80 °C to –40 °C, 1.5 h
NMe
S
+
Ph
Ph
3) A: –40 °C, 5 % NaOH, rt, 1 h
B: T up to rt, then reflux, 1 h
R1
O
7
NR
O
1
S
Scheme 7.
Br
6
Table 3
Scheme 6.
Equilibrium studies of (E)-2a and (Z)-2a
Entry 2a Conditions
(E)-2a (%) (Z)-2a (%) 7 (%)
Table 2
Consecutive reactions of sulfoximines 1 with 4
1
2
3
4
5
6
(E)- ꢀ70 ꢁC, 2 h; then H2O
(Z)- ꢀ70 ꢁC, 2 h; then H2O
59
63
11
19
3
30
18
79
77
77
86
Entry
5
R
R1 Cond Yield of 5 (%) Yield of 6 (%) E/Z ratioa
(E)- ꢀ70 ꢁC, 2 h, then ꢀ30 ꢁC, 2 h; then H2O 18
(E)- ꢀ70 ꢁC, 2 h, then rt, 2 h; then H2O
18
5
1
2
3
4
5
6
7
8
9
10
5a Me
5a Me
H
H
H
H
Me
Me
Me
Me
H
A
B
A
B
A
B
A
B
A
A
40
9
79
6
81
12
56
41
60c
78
d
d
d
54
d
65
d
d
d
d
58:42
55:45
28:72
100:0
47:53
100:00
47:53
(Z)- ꢀ70 ꢁC, 2 h, then ꢀ30 ꢁC, 2 h; then H2O 20
3
(Z)- ꢀ70 ꢁC, 2 h, then rt, 2 h; then H2O
11
3
5b Boc
5b Boc
5c Boc
5c Boc
5d Me
5d Me
5e Piv
5f Neopentyl
First it should be noted that very comparable product distribu-
tions were obtained under similar conditions starting either with
(E)-2a or (Z)-2a, indicating that in each case the equilibrium is
reached. Upon treatment with MeLi at low temperature (ꢀ70 ꢁC)
for 2 h, the E isomer was the major product (ca. 60%) and the
remaining 40% was a mixture of Z isomer and 7 (entries 1 and 2)
irrespective of the configuration of the starting double bond. In-
creasing the temperature of the reaction mixture to ꢀ30 ꢁC or to
room temperature (entries 3–6) allowed the formation of
63:37b
Trace:100
24:76
H
a
Both E and Z isomers were obtained as a 1:1 mixture of diastereomers.
The diastereoselectivity of this previously reported reaction proved to be non-
b
reproducible.8
c
Yield based on recovered starting material (30% of starting material was
recovered).

M.-A. Virolleaud et al. / Tetrahedron 65 (2009) 9756–9764
9759
O
Ph
S
NMe
O
(E)-2a
H2O
Li
O
O
O
MeLi (1 equiv)
O
H2O
O
NMe
Ph
NMe
O
NMe
S
Ph
Ph
NMe
S
O
S
Ph
7
S
higher
temp
O
F
(E)-2a or (Z)-2a
H
low temp
O
NMe
S
Ph
Li
O
G
H2O
O
NMe
S
Ph
O
(Z)-2a
Scheme 8.
compound 7 (in 77–86% yield). Based on these results we came to
the conclusion that the anionic species F, G and H are in equilibrium
in the presence of methyllithium in THF (Scheme 8). Species F and G
are the direct lithiation products of E and Z isomers, respectively.31
At ꢀ70 ꢁC, F and G are in equilibrium and F predominates over G.
These results are supported by Gais et al. observations. Indeed, they
reported that treatment of (Z)-alkenyl sulfoximines with MeLi at
Table 4
Consecutive reactions of sulfoximine 1 with 8
Entry Sulfoximine Cond. Yield of 9 (%) Yield of 10 (%) Yield of 11 (%)
1
2
3
1a (R¼Me)
1a (R¼Me)
1m (R¼Mes)
A
B
A
d
10a:35
10a:58
d
11a:36
11a:42
11m:14
d
(E)-9m:31
(Z)-9m: 53
(E)-9f: 7
(E)-9l:29a,b
(Z)-9l: 10a,b
4
5
1f (R¼Boc)
1l (R¼Piv)
A
A
10f:72
d
d
ꢀ78 ꢁC gave the (Z)-configured
a-lithioalkenyl sulfoximines, which
10l:32a
upon warming of the reaction mixture to ꢀ30 ꢁC underwent
a complete isomerization to the more stable (E)-isomers.25b,32
However in our case the isomerization was not complete and any
attempt to improve this ratio in favor of the E isomer led to the
formation of more of the endo olefin 7. The formation of the latter
could be rationalized by the generation of a novel ambident carb-
a
Yield based on recovered starting material (23% of starting material was
recovered).
b
The two diastereomers could not be separated by flash chromatography on
silica gel.
anion H, which can be regarded as a
g-lithiated a,b-unsaturated
With in mind the pioneering results of Umani-Ronchi and co-
sulfoximine. This hypothesis is based on Bellur and Langer’s ob-
servations, who first revealed the formation of this ambident
carbanion in their studies about the lithiation and alkylation of 2-
alkylidene tetrahydrofuran in the ester series.17e
With in hands a straightforward synthetic access to hydrofuran
derivatives exhibiting a chiral sulfur atom, we logically explored the
possibilities to extend the reaction to the hydropyran series. Thus,
the dianions obtained from the sulfoximines 1 were treated with
ethyl 5-bromovalerate (8) according to our optimized protocols.
The results are summarized on Scheme 9 and in Table 4.
workers in the sulfonyl series, the reactions were expected to yield
mixtures of C- and O-cyclization products.33 Very interestingly, we
showed that the regioselectivity of the reaction was in part con-
trolled by the electronic properties of the substituent at the nitro-
gen atom: indeed electron-rich substituent yielded a mixture of C-
and O-cyclization products (entries 1–3), while electron-with-
drawing substituent afforded only the O-cyclization product (en-
tries 4 and 5) in good overall yields in every cases. By contrast to the
sulfonyl series,33 reaction with sulfoximine 1a (entries 1 and 2),
gave only the endo isomer 10a, while sulfoximine 1m (entry 3) gave
only the exo isomers 9m. Sulfoximines 1f and 1l (entries 4 and 5,
respectively) proved unselective however. The ratio of the two O-
cyclization regioisomers appears to be highly dependent on the
substituent at the nitrogen atom. In this series, the best selectivity
(C- vs O-cyclization, and exo vs endo product) was obtained with
the sulfoximine 1f exhibiting a tert-butyloxycarbonyl (Boc) sub-
stituent at the nitrogen atom allowing the preparation of 10f in 72%
yield (entry 4).
O
O
S
NR
Ph
9
1) n-BuLi (2 equiv), –30 °C, 30 min
+
2)
EtO2C
–80 °C to –40 °C, 1.5 h
8
O
Br
O
NR
O
S
S
NR
Ph
Ph
3) A: –40 °C, 5 % NaOH, rt, 1 h
B: T up to rt, then reflux, 1 h
10
1
+
O
S
OH
NR
Ph
3. Conclusion
In conclusion, we have developed an efficient, chemo- and
regioselective method for the synthesis of functionalized 2-sulfo-
nimidoylylidene tetrahydrofurans, 2-sulfonimidoylylidene-5-vinyl
11
Scheme 9.

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M.-A. Virolleaud et al. / Tetrahedron 65 (2009) 9756–9764
tetrahydrofurans and 6-sulfonimidoylmethyl-3,4-dihydro-2H-py-
rans featuring a consecutive reaction of the chiral dilithiocarbanion
of S-methyl-S-phenyl-sulfoximines with a,u-halogenoesters. This
3H), 7.99 (d, J¼7.0 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 44.8, 67.0,
118.2, 127.7, 130.0, 132.7, 134.3, 138.6, 158.8. HRMS (ESI): m/z calcd
for C11H13NO3S [MþNa]þ 262.0508, found 262.0509.
study demonstrates that subtle variations of the substituent at the
nitrogen atom of the sulfonimidoyl group can have a profound
impact on both the reactivity and the selectivity in these reactions.
The balance between the steric and electronic properties observed
with the N-pivaloyl sulfoximine 1i appears the most promising for
further development in the hydrofuran series, while the N-tert-
butyloxycarbonyl sulfoximine 1f appears the most suitable in the
hydropyran series.
4.2.1.2. 1k. 23.21 g (78%), white solid. Mp 84–86 ꢁC. IR (neat)
nmax 1659, 1245, 1080 cmꢀ1 1H NMR (300 MHz, CDCl3)
. d 3.26 (s,
3H), 5.01 (d, J¼12.3 Hz, 1H), 5.01 (d, J¼12.3 Hz, 1H), 5.08 (d,
J¼12.3 Hz, 1H), 7.15–7.39 (m, 5H), 7.49–7.68 (m, 3H), 7.94 (d,
J¼7.4 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 44.7, 67.9, 127.5, 128.1,
128.3, 128.5, 129.8, 134.1, 136.4, 138.4, 158.7. HRMS (ESI): m/z calcd
for C15H15NO3S [MþH]þ 290.0845, found 290.0844.
These five- and six-membered ring heterocycles are syntheti-
cally important building blocks and should be amenable for further
transformations. For example Michael addition, cross coupling re-
action,23 cycloaddition transformations or subsequent multicom-
ponent/domino processes could be envisioned.9b–c,22b Studies
directed at the synthesis of naturally occurring products using this
methodology are under investigation in our laboratory and will be
reported in due course.
4.2.1.3. 1m. In a round bottom flask equipped with a condenser,
a solution of S-methyl-S-phenylsulfoximine (1.15 g, 7.37 mmol) and
bromomesitylene (1.03 mL, 1.34 mmol) in 1,4-dioxane (67 mL) was
prepared at room temperature. To this solution was added
Pd2(dba)3 (307 mg, 0.33 mmol), IPr$HCl (145 mg, 0.34 mmol), and
tBuOK (1.13 g, 10.1 mmol). The resulting dark brown solution was
heated at 80 ꢁC for 24 h and concentrated to afford the crude
product, which was directly purified by flash chromatography
eluted with ethyl acetate/petrol ether to afford 1.76 g of 1m (96%) as
4. Experimental
4.1. General
a brown solid. 1H NMR (300 MHz, CDCl3)
d 2.25 (s, 3H), 2.35 (s, 6H),
3.04 (s, 3H), 6.86 (s, 2H), 7.58 (d, J¼7.6 Hz, 2H), 7.61 (m, 1H), 8.16
(dd, J¼7.6, 1.6 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 19.9, 20.6, 43.2,
127.9, 129.0, 129.1, 132.3, 132.9, 133.7, 137.9, 141.3. MS (ESIþ) m/z
Anhydrous dichloromethane and tetrahydrofuran were
obtained from a Solvent Purification System. Anhydrous 1,4-di-
oxane was obtained by distillation over Na/benzophenone. All ex-
periments were performed under anhydrous conditions and an
inert atmosphere of argon and, using oven-dried glassware and
employing standard techniques for handling air-sensitive mate-
rials. Analytical thin layer chromatography (TLC) was carried out on
Merck Kieselgel 60 F254 plates. Visualization of chromatograms
was accomplished using ultraviolet light (254 nm) and/or heating
the plate after staining with either a solution of potassium per-
manganate w/v in H2O, anisaldehyde w/v in EtOH or phosphomo-
lybdic acid w/v in EtOH. Flash column chromatography was carried
[MþNa]þ 296.
4.3. Synthesis of 2-sulfonimidoylylidene tetrahydrofurans (2)
and the endocyclic compound 7
To a stirred cold solution of 1 (10 mmol) in THF (50 mL) at
ꢀ30 ꢁC was added n-BuLi (20 mmol, 2 equiv) and stirring was
continued for 30 min. The solution was cooled to ꢀ80 ꢁC and
methyl 4-chlorobutyrate (20 mmol, 2 equiv) was added. The re-
action mixture was warmed to ꢀ40 ꢁC during 1.5 h and 5% NaOH
solution (25 mL) was added and stirred for 1 h at room tempera-
ture, extracted with ether, dried (MgSO4) and concentrated. Pure
products of E and Z isomers were separated by silica column with
a gradient of ethyl acetate in petroleum ether. In every case, the E
isomer was eluted faster than the Z isomer.
out on Merck Kieselgel 40–63 mm silica gel under a positive pres-
sure generated by regulated compressed air. NMR data were
recorded at 300 MHz in CDCl3 using as internal standards the re-
sidual CHCl3 signal for 1H NMR (
d
¼7.26) and at 75 MHz using the
deuterated solvent signal for 13C NMR (
d
¼77.0). Chemical shift (
d)
are given in ppm and the usual abbreviations are used to describe
the signal multiplicity. Low resolution mass spectra (MS) were
obtained with an ion trap (ESI source), and high resolution mass
spectrometry (HRMS) were recorded at the Spectropole (http://
www.spectropole.u-3mrs.fr/).
4.3.1. (Z)-2b. Solid. Mp 98–99 ꢁC. IR (neat) nmax 3041, 2939, 1610,
1436, 1304, 1143, 1082 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d 1.83–2.20
(m, 2H), 2.32 (s, 3H), 2.60–2.70 (m, 2H), 4.09–4.22 (m, 1H), 4.23–
4.39 (m, 1H), 5.73 (s, 1H), 7.13 (d, J¼7.9 Hz, 2H), 7.39–7.70 (m, 3H),
7.79 (d, J¼8.1 Hz, 2H), 7.92 (d, J¼7.9 Hz, 2H). 13C NMR (75 MHz,
CDCl3)
d 21.6, 23.1, 32.5, 75.9, 96.2, 126.8, 127.6, 128.9, 129.2, 133.2,
4.2. Synthesis of sulfoximines 1
141.2, 141.5, 142.4, 172.0. HRMS (ESI): m/z calcd for C18H19NO4S2
[MþH]þ 378.0828, found 378.0825.34
4.2.1. General procedure for 1h and 1k. To a solution of S-methyl-S-
phenylsulfoximine (1 equiv) and pyridine (1.5 equiv) in dry THF
(0.5 M) at 0 ꢁC was slowly added the corresponding chloroformate
(1.5 equiv). A light pink suspension appeared. The temperature was
allowed to rise to room temperature and the solution was then
stirred for 15 h. A small portion of chloroformate (0.5 equiv) was
added and the mixture stirred for 5 h. The reaction mixture was
quenched by addition of water and the product was extracted three
times with diethyl ether. The joined ether extracts were washed
with HCl 1 N and saturated NaCl, dried over anhydrous MgSO4 and
concentrated to give the crude product, which was used without
further purification.
4.3.2. (E)-2c. Viscous liquid. IR (neat) nmax 2875, 2801, 1615, 1435,
1211, 1113 cmꢀ1 1H NMR (300 MHz, CDCl3)
. d 1.90–2.14 (m, 2H),
2.71–2.86 (m, 1H), 3.10–3.25 (m, 1H), 3.51 (ddd, J¼15.3, 5.5, 1.1 Hz,
1H), 3.64 (2ddd, J¼15.3, 5.4, 1.3 Hz, 2H), 4.08–4.24 (m, 2H), 5.02
(ddd, J¼10.2, 1.9, 1.5 Hz, 1H), 5.24 (ddd, J¼17.0, 3.8, 3.0, 1.9 Hz, 1H),
5.24 (dddd, J¼17.0, 3.8, 3.0, 1.9 Hz, 1H), 5.80 (d, J¼1.1 Hz, 1H), 5.95
(dddd, J¼17.0, 10.2, 5.5, 1.1 Hz, 1H), 7.39–7.65 (m, 3H), 7.89 (d,
J¼8.1 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 24.0, 29.0, 46.3, 72.2, 99.8,
114.4, 128.1, 129.1, 132.0, 138.5, 142.7, 173.6. HRMS (ESI): m/z calcd
for C14H17NO2S [MþH]þ 264.1053, found 264.1057.
4.3.3. (Z)-2c. Viscous liquid. IR (neat) nmax 3004, 1618, 1435, 1209,
4.2.1.1. 1h. 6.58 g (85%), white solid. Mp 91–92 ꢁC. IR (neat) nmax
1133, 1024 cmꢀ1 1H NMR (300 MHz, CDCl3)
. d 1.86–2.06 (m, 2H),
2995, 2903, 1656, 1218, 1118 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d
3.30
2.65 (dd, J¼8.0, 7.3 Hz, 2H), 3.48 (dddd, J¼15.1, 5.6, 4.1, 1.5 Hz, 1H),
3.64 (dddd, J¼15.3, 5.3, 1.7, 1.5 Hz, 1H), 4.16–4.26 (m, 1H), 4.30–4.40
(m, 1H), 5.00 (dd, J¼10.2, 1.3 Hz, 1H), 5.23 (dd, J¼17.0, 1.9 Hz, 1H),
(s, 3H), 4.53 (d, J¼5.7 Hz, 2H), 5.16 (dd, J¼10.4, 1.5 Hz, 1H), 5.26 (dd,
J¼17.2, 1.6 Hz, 1H), 5.88 (ddd, J¼17.2, 10.4, 5.7 Hz, 1H), 7.45–7.81 (m,

M.-A. Virolleaud et al. / Tetrahedron 65 (2009) 9756–9764
9761
5.48 (s, 1H), 5.94 (ddd, J¼17.0, 10.2, 5.7 Hz, 1H), 7.35–7.55 (m, 3H),
1H), 5.46 (s, 1H), 7.44–7.46 (m, 3H), 7.94–7.96 (m, 2H). 13C NMR
7.96 (d, J¼8.3 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d
22.9, 31.6, 45.8,
(75 MHz, CDCl3) d 23.5, 28.0, 31.9, 32.6, 55.5, 74.7, 98.3, 128.7, 131.8,
74.5, 97.3, 113.8, 128.1, 128.3, 131.6, 138.3, 141.8, 168.2. HRMS (ESI):
143.0, 168.1. HRMS (ESI): m/z calcd for C16H23NO2S [MþH]þ
m/z calcd for C14H17NO2S [MþH]þ 264.1053, found 264.1054.
294.1522, found: 294.1524.
4.3.4. (Z)-2e. tlsb .00102Liquid. IR (neat) nmax 3446, 2954, 2927,
4.3.12. (Z)-2k. Solid. Mp 52–53 ꢁC. IR (neat) nmax 3055, 2987, 1673,
2854, 1635, 1295, 1270, 1032, 830, 689 cmꢀ1
.
1H NMR (300 MHz,
1628, 1265, 739, 705 cmꢀ1 1H NMR (300 MHz, CDCl3)
. d 1.90–2.10
CDCl3)
d
0.04 (s, 3H), 0.05 (s, 3H), 0.93 (s, 9H), 1.91–2.04 (m, 2H),
(m, 2H), 2.65–2.75 (m, 2H), 4.14–4.21 (m, 1H), 4.32–4.41 (m, 1H),
5.02 (d, J¼12.4 Hz, 1H), 5.09 (d, J¼12.4 Hz, 1H), 5.69 (s, 1H), 7.18–
7.35 (m, 5H), 7.43–7.60 (m, 3H), 8.01 (d, J¼8.5 Hz, 2H). 13C NMR
2.54–2.63 (m, 2H), 4.20–4.38 (m, 2H), 5.46 (dd, J¼1.3, 1.3 Hz, 1H),
7.36–7.55 (m, 3H), 7.99 (dd, J¼7.8, 1.8 Hz, 2H). 13C NMR (75 MHz,
CDCl3)
d
ꢀ2.3, ꢀ2.2, 18.4, 23.5, 26.4, 31.8, 74.3, 104.7, 127.2, 128.4,
(75 MHz, CDCl3) d 22.3, 31.6, 66.5, 75.1, 94.7, 126.8, 127.2, 127.4,
131.3, 147.9, 165.6. HRMS (ESI): m/z calcd for C17H27NO2SiS [MþH]þ
127.7, 128.3, 132.2, 136.2, 140.4, 158.2, 171.6. HRMS (ESI): m/z calcd
338.1605, found 338.1600.34
for C19H19NO4S [MþH]þ 358.1108, found 358.1104.34
4.3.5. (E)-2f. Solid. Mp 113–114 ꢁC. IR (neat) nmax 3051, 2955, 1659,
4.3.13. (Z)-2l. Solid. Mp 92–93 ꢁC. IR (neat) nmax 3060, 2983, 2907,
1264, 1145 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d
1.29 (s, 9H), 1.88–2.14
1669, 1627, 1249, 1019, 875, 734 cmꢀ1 1H NMR (300 MHz, CDCl3)
.
(m, 2H), 2.59–2.75 (m, 1H), 3.10–3.25 (m, 1H), 4.05–4.27 (m, 2H),
d
1.14 (t, J¼7.2 Hz, 3H), 1.86–2.09 (m, 2H), 2.57–2.80 (m, 2H), 3.91–
5.81 (s, 1H), 7.37–7.60 (m, 3H), 7.87 (d, J¼7.9 Hz, 2H). 13C NMR
4.06 (m, 2H), 4.12–4.21 (m, 1H), 4.30–4.40 (m, 1H), 5.65 (s, 1H),
(75 MHz, CDCl3)
d
23.8, 28.2, 29.4, 72.9, 80.0, 98.3, 127.1, 129.2,
7.40–7.56 (m, 3H), 7.96 (dd, J¼8.2, 1.5 Hz, 2H). 13C NMR (75 MHz,
132.7, 142.3, 157.8, 175.3. HRMS (ESI): m/z calcd for C16H21NO4S
[MþH]þ 324.1264, found 324.1270.
CDCl3) d 14.6, 23.2, 32.4, 61.7, 75.6, 96.2, 127.7, 128.9, 132.8, 141.1,
159.3, 171.4. HRMS (ESI): m/z calcd for C14H17NO4S [MþH]þ
296.0951, found 296.0950.34
4.3.6. (Z)-2f. Solid. Mp 150–151 ꢁC. IR (neat) nmax 3108, 3008, 1651,
1437, 1259, 1147 cmꢀ1
.
1H NMR (300 MHz, CDCl3)
d
1.35 (s, 9H),
4.3.14. (E)-2n. Solid. Mp. 96–97 ꢁC. IR (neat) nmax 3224, 3043, 2883,
1.88–2.11 (m, 2H), 2.61–2.76 (m, 2H), 4.14–4.24 (m, 1H), 4.34–4.43
1622,1435,1212,1156 cmꢀ1.1H NMR (300 MHz, CDCl3)
d 1.90–2.15 (m,
(m, 1H), 5.68 (s, 1H), 7.40–7.57 (m, 3H), 7.99 (d, J¼7.5 Hz, 2H). 13C
2H), 2.77–2.94 (m, 1H), 3.11–3.26 (m, 1H), 4.06–4.26 (m, 2H), 5.82 (s,
NMR (75 MHz, CDCl3)
d
23.0, 28.0, 32.1, 75.3, 79.5, 96.2, 127.4, 128.6,
1H), 7.35–7.60 (m, 3H), 7.93 (dd, J¼8.4–1.0 Hz, 2H). 13C NMR (75 MHz,
132.3, 141.3, 157.9, 170.9. HRMS (ESI): m/z calcd for C16H21NO4S
[MþH]þ 324.1264, found 324.1270.
CDCl3) d 24.1, 29.1, 72.3, 101.9, 127.2, 129.2, 132.2, 146.2, 173.4. HRMS
(ESI): m/z calcd for C11H13NO2S [MþH]þ 224.0740, found 224.0744.
4.3.15. (Z)-2n. Solid. Mp. 100–102 ꢁC. IR (neat) nmax 3043, 2913,
4.3.7. (Z)-2g. Viscous liquid. IR (neat) nmax 3041, 2901, 1596, 1438,
1263, 1121 cmꢀ1
.
1H NMR (300 MHz, CDCl3)
d
1.92–2.11 (m, 2H),
1660, 1604, 1240, 1079 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d 1.93–2.05
2.65–2.85 (m, 2H), 4.15–4.25 (m, 1H), 4.32–4.44 (m, 1H), 5.85 (s,
(m, 2H), 2.56–2.75 (m, 2H), 4.22–4.42 (m, 2H), 5.50 (s, 1H), 7.37–
1H), 7.30–7.64 (m, 6H), 8.06–8.12 (m, 2H), 8.13–8.20 (m, 2H). 13C
7.58 (m, 3H), 8.03 (dd, J¼7.9–1.3 Hz, 2H). 13C NMR (75 MHz, CDCl3)
NMR (75 MHz, CDCl3)
d
23.4, 32.5, 75.6, 96.2, 127.7, 128.2, 129.1,
d 23.4, 32.2, 75.1, 100.2, 127.9, 128.8, 132.3, 145.7, 168.4. HRMS (ESI):
129.6, 132.0, 132.8, 136.7, 141.6, 171.1, 174.3. HRMS (ESI): m/z calcd
for C18H17NO3S [MþH]þ 328.1002, found 328.0999.34
m/z calcd for C11H13NO2S [MþH]þ 224.0740, found 224.0742.
4.3.16. 7. Viscous liquid. IR (neat) nmax 2882.5, 1618.5, 1230.3,
4.3.8. (Z)-2h. Solid. Mp 97–99 ꢁC. IR (neat) nmax 3070, 2914, 1661,
1136.6 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d
2.55–2.61 (m, 2H), 2.76 (s,
3H), 3.99 (s, 2H), 4.13–4.25 (m, 2H), 4.87 (t, J¼3.0 Hz, 1H), 7.52–7.61
(m, 3H), 7.87–7.90 (m, 2H). 13C NMR (75 MHz, CDCl3)
30.2, 30.6,
1614, 1239 cmꢀ1.1H NMR (300 MHz, CDCl3)
d 1.90–2.15 (m, 2H), 2.64–
2.81 (m, 2H), 4.18–4.28 (m,1H), 4.35–4.45 (m,1H), 4.48–4.55 (m, 2H),
5.13 (ddd, J¼10.6, 2.9, 1.4 Hz, 1H), 5.25 (ddd, J¼17.3, 3.1, 1.5 Hz, 1H),
5.71 (s,1H), 5.88 (ddd, J¼17.3,10.6, 5.6 Hz,1H), 7.45–7.62 (m, 3H), 8.20
d
56.2, 70.7, 103.6, 129.3, 130.0, 133.3, 137.7, 147.4. HRMS Calcd for
C12H15NO2S: 238.0896, found: 238.0894.
(d, J¼8.3 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 23.1, 32.4, 66.4, 75.6,
95.9,117.5,127.6,128.9,132.8,133.0,140.9,158.9,171.6. HRMS(ESI): m/
z calcd for C15H17NO4S [MþH]þ 308.0951, found 308.0951.34
4.4. Synthesis of 5-vinyl-sulfonimidoylylidene
tetrahydrofurans (5)
4.3.9. (Z)-2i. Solid. Mp. 113–114 ꢁC. IR (neat) nmax 2928.1, 2846.7,
1615.4, 1283.3, 1163.6 cmꢀ1 1H NMR (300 MHz, CDCl3)
. d 1.22 (s,
9H), 1.99–2.06 (m, 2H), 2.71–2.76 (m, 2H), 4.15–4.24 (m, 1H), 4.34–
To a stirred cold solution of 1 (10 mmol) in THF (50 mL) at
ꢀ30 ꢁC was added n-BuLi (20 mmol, 2 equiv) and stirring was
continued for 30 min. The solution was cooled to ꢀ80 ꢁC and
methyl 6-bromo-hex-4-enoate (4a) or methyl 5-methyl-6-bromo-
hex-4-enoate (4b) (12–15 mmol) was added. The reaction mixture
was warmed to ꢀ40 ꢁC during 1.5 h and 5% NaOH solution (25 mL)
was added and stirred for 1 h at room temperature, extracted with
ether, dried (MgSO4) and concentrated. Products 5 were separated
by silica column with a gradient of ethyl acetate in petroleum ether.
In every case, the E isomer was eluted faster than the Z isomer.
4.41 (m, 1H), 5.70 (s, 1H), 7.47–7.54 (m, 3H), 8.01–8.10 (m, 2H). 13C
NMR (75 MHz, CDCl3) d 23.5, 28.2, 32.4, 41.7, 75.5, 96.6, 127.7, 129.0,
132.7, 141.9. HRMS (ESI): m/z calcd for C16H21NO3S [MþH]þ
308.1315, found: 308.1312.34
4.3.10. (E)-2j. Solid. Mp. 76–77 ꢁC. IR (neat) nmax 2928.4, 1617.5,
1232.9, 1115.5 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d 0.94 (s, 9H), 1.96–
2.11 (m, 2H), 2.59 (d, J¼12.0 Hz,1H), 2.74 (d, J¼12.0 Hz,1H), 2.82–2.96
(m, 1H), 3.14–3.26 (m, 1H), 4.11–4.23 (m, 2H), 5.74 (s, 1H), 7.47–7.60
(m, 3H), 7.88–7.91 (m, 2H).13C NMR (75 MHz, CDCl3)
d 24.3, 28.1, 29.2,
32.7, 55.8, 72.2,100.4,128.3,129.1,131.9,143.5,173.2. HRMS (ESI): m/z
4.4.1. (E)-5a. First eluted diastereomer, viscous liquid. IR (neat)
nmax 2894.7, 1618.9, 1230.1, 1138.8 cmꢀ1. 1H NMR (300 MHz, CDCl3)
calcd for C16H23NO2S [MþH]þ 294.1522, found: 294.1521.
d
1.79–1.92 (m, 1H), 2.13–2.24 (m, 1H), 2.69 (s, 3H), 2.71–2.77 (m,
4.3.11. (Z)-2j. Solid. Mp. 59–60 ꢁC. IR (neat) nmax 2928.1, 1620.2,
1H), 3.31–3.41 (m, 1H), 4.70–4.81 (m, 1H), 5.22–5.34 (m, 2H), 5.76–
1230.4, 1118.9 cmꢀ1. 1H NMR (300 MHz, CDCl3)
d
0.91 (s, 9H), 1.91–
5.88 (m, 2H), 7.50–7.54 (m, 3H), 7.86–7.89 (m, 2H). 13C NMR
2.03 (m, 2H), 2.55–2.74 (m, 4H), 4.10–4.23 (m, 1H), 4.30–4.41 (m,
(75 MHz, CDCl3)
d 29.0, 29.8, 30.1, 84.6, 100.0, 118.3, 128.3, 129.4,

9762
M.-A. Virolleaud et al. / Tetrahedron 65 (2009) 9756–9764
132.2, 135.8, 142.2, 173.1. HRMS (ESI): m/z calcd for C14H17NO2S
[MþH]þ 264.1053, found: 264.1052.
HRMS (ESI): m/z calcd for C19H25NO4S [MþH]þ 364.1577, found
364.1571.
4.4.2. (E)-5a. Second eluted diastereomer, viscous liquid. IR (neat)
nmax 2890.2, 2852.1, 1620.2, 1225.0, 1140.6 cmꢀ1. 1H NMR (300 MHz,
4.4.8. (E)-5d. Mixture of two diastereomers, viscous liquid. IR
(neat) nmax 3394, 3062, 2916, 2801, 629, 1445, 1244, 832, 754 cmꢀ1
.
CDCl3)
d
1.69–1.81 (m, 1H), 2.20–2.30 (m, 1H), 2.52–2.62 (m, 1H),
1H NMR (300 MHz, CDCl3)
d 1.35–1.43 (m, 0.5H), 1.66 (s, 1.5H), 1.70
2.69 (s, 3H), 3.00–3.08 (m, 1H), 4.74–4.83 (m, 1H), 5.19–5.32 (m,
(s, 1.5H), 1.72–1.94 (m, 1H), 2.08–2.28 (m, 1H), 2.68 (s, 1.5H), 2.69 (s,
1.5H), 2.98–3.13 (m, 1H), 3.37 (dddd, J¼17.9, 8.9, 4.7, 1.3 Hz, 0.5H),
4.65–4.78 (m, 1H), 4.86 (s, 0.5H), 4.90 (s, 0.5H), 4.93 (s, 0.5H), 4.97
(s, 0.5H), 5.80 (d, J¼1.6 Hz, 0.5H), 5.83 (d, J¼1.6 Hz, 0.5H), 7.41–7.60
2H), 5.73–5.83 (m, 2H), 7.50–7.54 (m, 3H), 7.87–7.90 (m, 2H). 13C
NMR (75 MHz, CDCl3)
d 29.3, 29.7, 30.1, 84.8, 99.8, 118.5, 128.2,
129.4, 132.2, 135.7, 142.2, 173.1. HRMS (ESI): m/z calcd for
C14H17NO2S [MþH]þ 264.1053, found: 264.1052.
(m, 3H), 7.79–7.96 (m, 2H). 13C NMR (75 MHz, CDCl3)
d 17.7, 17.9,
28.3, 28.4, 28.8, 29.1, 29.5, 86.4, 86.5, 99.3, 99.5, 112.6, 113.8, 128.0,
128.1, 129.1, 129.2, 132.0, 142.0, 141.9, 142.1, 142.2, 173.1. HRMS (ESI):
m/z calcd for C15H19NO2S [MþH]þ 278.1209, found 278.1203.
4.4.3. (Z)-5a. Mixture of two diastereomers, viscous liquid. IR
(neat) nmax 2895.2, 2852.4, 1621.5, 1228.1, 1138.8 cmꢀ1 1H NMR
.
(300 MHz, CDCl3) d 1.61–1.80 (m, 1H), 2.08–2.20 (m, 1H), 2.63–2.69
(m, 2H), 2.66 (s, 1.5H), 2.71 (s, 1.5H), 4.73–5.00 (m, 2H), 5.15–5.27
(m,1H), 5.40–5.56 (m,1.5H), 5.70–5.88 (m, 0.5H), 7.44–5.51 (m, 3H),
4.4.9. (Z)-5d. Mixture of two diastereomers, viscous liquid. IR (neat)
nmax 3388, 3064, 2917, 1633, 1239, 1147, 862, 691 cmꢀ1 1H NMR
.
7.93–7.99 (m, 2H). 13C NMR (75 MHz, CDCl3)
d
29.3, 29.4, 29.6, 29.7,
(300 MHz, CDCl3) d 1.24 (s, 1.5H), 1.35 (s, 1.5H), 1.63–1.84 (m, 2H),
31.4, 31.6, 86.6, 86.8, 97.9, 98.7,116.8,117.6,128.8,128.9,129.0,129.2,
132.1, 135.3, 135.5, 141.4, 141.8, 167.7. HRMS (ESI): m/z calcd for
C14H17NO2S [MþH]þ 264.1053, found: 264.1053.
2.02–2.15 (m, 2H), 2.64 (s, 1.5H), 2.71 (s, 1.5H), 4.46 (s, 0.5H), 4.65 (s,
0.5H), 4.76–4.94 (m, 2H), 5.41 (s, 0.5H), 5.53 (s, 0.5H), 7.38–7.63 (m,
3H), 7.85–8.04 (m, 2H). 13C NMR (75 MHz, CDCl3)
d 17.2, 17.7, 27.5,
27.6, 29.1, 29.3, 31.4, 88.7, 88.9, 97.3, 98.1, 112.0, 112.2, 128.4, 128.5,
128.6, 128.9, 131.7, 132.9, 141.0, 141.4, 141.6, 141.7, 167.4, 167.5. HRMS
(ESI): m/z calcd for C15H19NO2S [MþH]þ 278.1209, found 278.1206.
4.4.4. (E)-5b. Mixture of two diastereomers, viscous liquid. IR
(neat) nmax 2906.6, 1655.7, 1436.9, 1266.2, 1146.7 cmꢀ1 1H NMR
.
(300 MHz, CDCl3)
d 1.37 (s, 9H), 1.74–1.96 (m, 1H), 2.18–2.36 (m,
1.5H), 2.60–2.71 (m, 0.5H), 2.92–3.02 (m, 0.5H), 3.12–3.26 (m,
0.5H), 3.36–3.47 (m, 0.5H), 3.60–3.67 (m, 0.5H), 4.78–4.87 (m,
0.5H), 5.22–5.35 (m, 1.5H), 5.72–5.91 (m, 2H), 7.53–7.59 (m, 3H),
4.4.10. (E)-5e. Mixture of two diastereomers, viscous liquid. IR
(neat) nmax 2930.0, 1618.4, 1233.4, 1115.1 cmꢀ1. 1H NMR (300 MHz,
CDCl3) d 0.94 (s, 9H),1.73–1.91 (m, 1H), 2.18–2.28 (m, 1H), 2.56–2.80
(m, 3H), 3.06–3.13 (m, 0.5H), 3.32–3.45 (m, 0.5H), 3.59–3.69 (m,
0.5H), 4.10–4.20 (m, 0.5H), 4.71–4.81 (m, 0.5H), 5.19–5.34 (m, 2H),
5.74–5.89 (m, 1.5H), 7.50–7.62 (m, 3H), 7.86–7.92 (m, 2H). 13C NMR
7.94–7.97 (m, 2H). 13C NMR (75 MHz, CDCl3)
d
28.4, 29.5, 29.9, 80.3,
85.4, 98.5, 98.8, 118.7, 118.8, 127.3, 129.5, 132.9, 135.4, 142.5, 158.0,
174.8. HRMS (ESI): m/z calcd for C18H23NO4S [MþH]þ 350.1421,
found: 350.1423.
(75 MHz, CDCl3)
d 29.5, 30.5, 30.8, 31.6, 34.2, 57.2, 85.8, 85.9, 101.9,
102.1, 119.6, 119.7, 129.6, 129.7, 130.6, 133.4, 137.3, 137.4, 144.9, 173.9.
HRMS Calcd for C18H25NO2S: 334.1471, found: 334.1473.
4.4.5. (Z)-5b. Mixture of two diastereomers, solid. Mp. 74–75 ꢁC. IR
(neat) nmax 2957.0, 1655.2, 1437.0, 1264.3, 1150.9 cmꢀ1 1H NMR
.
(300 MHz, CDCl3)
d
1.37 (s, 9H), 1.63–1.85 (m, 1H), 2.10–2.25 (m,
4.4.11. (Z)-5e. Mixture of two diastereomers, solid. Mp. 72–73 ꢁC.
1H), 2.68–2.75 (m, 2H), 4.65–5.03 (m, 2H), 5.19–5.50 (m, 1.5H),
IR (neat) nmax 2943.4, 1618.1, 1277.5, 1175.5 cmꢀ1 1H NMR
.
5.68–5.85 (m, 1.5H), 7.46–7.58 (m, 3H), 8.01–8.03 (m, 2H). 13C NMR
(300 MHz, CDCl3)
d 1.22 (s, 9H), 1.68–1.79 (m, 1H), 2.12–2.21 (m,
(75 MHz, CDCl3)
d
28.4, 29.3, 31.9, 80.0, 80.1, 87.5, 97.2, 97.6, 117.1,
1H), 2.69–2.74 (m, 2H), 4.09–4.16 (m, 0.5H), 4.75–5.02 (m, 1.5H),
5.15–5.22 (m, 1H), 5.45–5.56 (m, 0.5H), 5.66–5.77 (m, 1.5H), 7.49–
117.9, 128.1, 128.3, 128.9, 132.7, 135.0, 141.6, 141.7, 158.4, 170.0, 170.5.
HRMS (ESI): m/z calcd for C18H23NO4S [MþH]þ 350.1421, found:
350.1420.
7.61 (m, 3H), 8.00–8.06 (m, 2H). 13C NMR (75 MHz, CDCl3)
d 28.1,
28.2, 29.3, 31.8, 41.7, 87.3, 96.8, 97.2, 117.3, 117.8, 127.8, 128.9, 132.8,
135.0, 135.2, 141.6, 141.8, 169.2, 170.1, 188.2. HRMS (ESI): m/z calcd
for C18H23NO3S [MþH]þ 334.1471, found: 334.1468.
4.4.6. (E)-5c. Mixture of two diastereomers, viscous liquid. IR
(neat) nmax 2957, 2906, 1656, 1437, 1267, 1147 cmꢀ1 1H NMR
.
(300 MHz, CDCl3)
d
1.14–1.41 (m, 9H), 1.46–1.75 (m, 3H), 2.01–2.50
4.4.12. (E)-5f. Mixture of two diastereomers, viscous liquid. IR (neat)
nmax 2930.0, 1618.4, 1233.4, 1115.1 cmꢀ1. 1H NMR (300 MHz, CDCl3)
(m, 0.5H), 2.52–2.80 (m, 1H), 2.84–3.01 (m, 0.5H), 3.05–3.20 (m,
0.5H), 3.25–3.47 (m, 0.5H), 3.51–3.71 (m, 1H), 4.34–4.44 (m, 0.5H),
4.54–4.66 (m, 0.5H), 4.70–4.85 (m, 0.5H), 4.81–4.97 (m, 1H), 5.05–
5.15 (m, 0.5H), 5.43 (bs, 0.5H), 5.83–5.88 (m, 0.5H), 7.39–7.73 (m,
d
0.94 (s, 9H),1.73–1.91 (m,1H), 2.18–2.28 (m,1H), 2.56–2.80 (m, 3H),
3.06–3.13 (m, 0.5H), 3.32–3.45 (m, 0.5H), 3.59–3.69 (m, 0.5H), 4.10–
4.20 (m, 0.5H), 4.71–4.81 (m, 0.5H), 5.19–5.34 (m, 2H), 5.74–5.89 (m,
1.5H), 7.50–7.62 (m, 3H), 7.86–7.92 (m, 2H).13C NMR (75 MHz, CDCl3)
3H), 7.80–8.01 (m, 2H). 13C NMR (75 MHz, CDCl3)
d 17.7, 17.9, 27.9,
28.0, 28.1, 28.2, 29.4, 29.7, 80.1, 80.9, 87.2, 87.3, 98.1, 98.3, 112.9,
113.2, 127.1, 128.2, 129.3, 129.7, 132.7, 141.9, 142.2, 157.8, 174.8.
HRMS (ESI): m/z calcd for C19H25NO4S [MþH]þ 364.1577, found
364.1577.
d 29.5, 30.5, 30.8, 31.6, 34.2, 57.2, 85.8, 85.9, 101.9, 102.1, 119.6, 119.7,
129.6, 129.7, 130.6, 133.4, 137.3, 137.4, 144.9, 173.9. HRMS (ESI): m/z
calcd for C18H25NO2S [MþH]þ 320.1679, found: 320.1678.
4.4.13. (Z)-5f. First eluted diastereomer, viscous liquid. IR (neat)
nmax 2929.2, 1622.4, 1231.9, 1122.0 cmꢀ1. 1H NMR (300 MHz, CDCl3)
4.4.7. (Z)-5c. Mixture of two diastereomers, viscous liquid. IR
(neat) nmax 3044, 2956, 1656, 1616, 1437, 1267, 1148 cmꢀ1. 1H NMR
d
0.95 (s, 9H), 1.69–1.84 (m, 1H), 2.05–2.18 (m, 1H), 2.64–2.77 (m,
(300 MHz, CDCl3)
d
1.34 (s, 4.5H), 1.36 (s, 4.5H), 1.61 (s, 1.5H), 1.66
4H), 4.81–4.87 (m, 1H), 5.15–5.28 (m, 2H), 5.45 (s, 1H), 5.71–5.82
(s, 1.5H), 2.05–2.21 (m, 2H), 2.65–2.79 (m, 2H), 4.39 (d, J¼1.0 Hz,
0.5H), 4.65 (s, 0.5H), 4.76 (dd, J¼7.2, 7.1 Hz, 0.5H), 4.89 (d,
J¼1.0 Hz, 0.5H), 4.93 (dd, J¼7.2, 7.1 Hz, 0.5H), 4.98 (d, J¼1.0 Hz,
0.5H), 5.68 (s, 0.5H), 5.79 (s, 0.5H), 7.40–7.69 (m, 3H), 8.01 (d,
(m, 1H), 7.43–7.50 (m, 3H), 8.00–8.03 (m, 2H). 13C NMR (75 MHz,
CDCl3)
d 28.1, 29.4, 31.4, 32.7, 55.8, 86.4, 98.6, 117.4, 128.7, 129.1,
131.9, 135.6, 143.1, 167.0. HRMS (ESI): m/z calcd for C18H25NO2S
[MþH]þ 319.1606, found: 319.1673.
J¼7.5 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 17.3, 18.0, 27.7, 27.8, 28.1,
28.2, 32.0, 79.9, 80.0, 89.5, 90.0, 96.9, 97.2, 112.6, 112.7, 127.9, 128.2,
128.7, 128.8, 132.5, 141.3, 141.4, 141.6, 158.1, 158.2, 169.8, 170.4.
4.4.14. (Z)-5f. Second eluted diastereomer, Mp. 90–91 ꢁC. IR (neat)
nmax 2929.5, 1626.0, 1231.6, 1120.7 cmꢀ1 1H NMR (300 MHz,
.

M.-A. Virolleaud et al. / Tetrahedron 65 (2009) 9756–9764
9763
CDCl3)
2.76 (m, 4H), 4.75–4.99 (m, 3H), 5.48–5.59 (m, 2H), 7.43–7.50 (m,
3H), 7.95–7.99 (m, 2H). 13C NMR (75 MHz, CDCl3)
28.1, 29.3, 31.4,
32.7, 55.5, 86.4, 99.7, 116.8, 128.7, 129.4, 131.8, 135.5, 142.8, 167.0.
HRMS (ESI): m/z calcd for C18H25NO2S [MþH]þ 319.1606, found:
319.1671.
d
0.92 (s, 9H), 1.63–1.74 (m, 1H), 2.10–2.21 (m, 1H), 2.51–
157.5. HRMS (ESI): m/z calcd for C17H24NO4S [MþH]þ 338.1426,
found: 338.1433.
d
4.5.8. 10l. Viscous oil. 1H NMR (300 MHz, CDCl3)
d 1.23 (s, 9H),
1.54–1.68 (m, 2H), 1.87–1.98 (m, 2H), 3.56–3.65 (m, 2H), 4.05 (d,
J¼13.8 Hz, 1H), 4.47 (d, J¼13.8 Hz, 1H), 4.70 (dd, J¼3.9, 3.6 Hz, 1H),
7.48–7.65 (m, 3H), 7.92 (d, J¼7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d
20.3, 21.3, 27.7, 41.5, 60.4, 66.1, 105.7, 128.4, 128.6, 133.4, 137.1,
143.1, 188.5. HRMS (ESI): m/z calcd for C17H24NO3S [MþH]þ
4.5. Synthesis of 9–11
322.1477, found: 322.1470.
The protocol for the preparation of compounds 9–11 is identical
to the protocol for the preparation of 5 except that ethyl 5-bro-
movalerate (8) was used instead of 4a,b.
4.5.9. 11a (known compound35). Viscous oil. 1H NMR (300 MHz,
CDCl3) d 1.42–1.92 (m, 5H), 2.15–2.51 (m, 3H), 2.61 (s, 3H), 7.42–7.64
(m, 3H), 7.79 (d, J¼6.3 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 21.2, 21.9,
22.6, 27.9, 30.3, 97.3, 128.7, 129.1, 132.5, 138.0, 166.2. MS (ESIþ): m/z
4.5.1. (E)-9m. Viscous oil. 1H NMR (300 MHz, CDCl3)
d 1.40–1.86
274 [MþNa]þ.
(m, 4H), 2.22 (s, 3H), 2.32 (s, 6H), 2.39–2.57 (m, 1H), 2.71–2.84 (m,
1H), 3.88–4.17 (m, 2H), 5.74 (s, 1H), 6.81 (s, 2H), 7.44–7.59 (m, 3H),
4.5.10. 11m. Viscous oil. Isolated as a mixture with (E)-9m after
8.06 (dd, J¼8.1, 1.8 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d
18.2, 19.9,
flash chromatography on silica gel. Selected data: 13C NMR
20.6, 23.0, 24.0, 68.1, 106.6, 127.3, 128.7, 128.8, 131.8, 131.9, 133.9,
138.5, 143.9, 169.7. HRMS (ESI): m/z calcd for C21H26NO2S [MþH]þ
356.1684, found: 356.1678.
(75 MHz, CDCl3) d 19.6, 20.6, 22.0, 22.0, 22.7, 30.3, 97.1, 126.8, 128.8,
128.8, 132.0, 133.4, 135.0, 135.3, 141.2, 167.4. MS (ESIþ): m/z 378
[MþNa]þ.
4.5.2. (Z)-9m. Viscous oil. 1H NMR (300 MHz, CDCl3)
(m, 4H), 2.12–2.28 (m, 2H), 2.22 (s, 3H), 2.33 (s, 6H), 3.55–3.73 (m,
d 1.50–1.71
Acknowledgements
2H), 5.56 (s, 1H), 6.81 (s, 2H), 7.39–7.58 (m, 3H), 8.13 (dd, J¼8.4,
The Agence Nationale pour la Recherche (A.N.R. 07-BLAN-0269),
1.8 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 19.4, 20.1, 20.6, 22.8, 28.1,
´
´
the C.N.R.S. and the Universite Paul Cezanne (UMR 6263) are
gratefully acknowledged for financial support. The authors thank
Dr. Jean-Luc Parrain for fruitful discussions.
68.1, 105.3, 128.0, 128.3, 128.7, 131.6, 131.7, 134.0, 139.0, 143.7, 164.6.
HRMS (ESI): m/z calcd for C21H26NO2S [MþH]þ 356.1684, found:
356.1676.
References and notes
4.5.3. (E)-9f. Viscous oil. 1H NMR (300 MHz, CDCl3)
d 1.33 (s, 9H),
1.49–1.88 (m, 4H), 2.17–2.36 (m, 2H), 3.49–3.60 (m, 1H), 3.92–4.03
1. For a discussion see: Wilson, R. M.; Danishefsky, S. J. J. Org. Chem. 2006, 71,
8329–8351.
2. Step economy: Wender, P. A.; Verma, V. A.; Paxton, T. J.; Pillow, T. H. Acc. Chem.
Res. 2008, 41, 40–49 and references therein.
3. (a) Atom economy: Trost, B. M. Acc. Chem. Res. 2002, 35, 695–705 and refer-
ences therein; (b) Redox economy: Burns, N. Z.; Baran, P. S.; Hoffmann, R. W.
Angew. Chem., Int. Ed. 2009, 48, 2854–2867.
(m, 1H), 5.81 (s, 1H), 7.43–7.58 (m, 3H), 7.98 (d, J¼6.9 Hz, 2H). 13C
NMR (75 MHz, CDCl3) d 18.8, 22.6, 27.9, 28.0, 68.5, 79.7, 105.1, 127.8,
128.4, 132.2, 141.4, 158.0, 167.9. HRMS (ESI): m/z calcd for
C17H24NO4S [MþH]þ 338.1426, found: 338.1431.
4. For a recent special issue on green chemistry see: Chem. Rev. 2007, 107, 2167–
2820.
4.5.4. (E)-9l. Viscous oil. Isolated as the major component of
a mixture with (Z)-9l after flash chromatography on silica gel. 1H
5. We define eco-compatible as both economically and ecologically compatible.
6. For representative reviews see: (a) Tietze, L. F.; Beifuss, U. Angew. Chem., Int. Ed.
Engl. 1993, 32, 131–163; (b) Tietze, L. F. Chem. Rev. 1996, 96, 115–136; (c) Tietze,
L. F.; Lieb, M. E. Curr. Opin. Chem. Biol. 1998, 2, 363–371; (d) Rodriguez, J. Synlett
1999, 505–518; (e) For a recent monograph see: Tietze, L. F.; Brasche, G.; Ger-
icke, K. M. Domino Reactions in Organic Synthesis; Wiley-VCH: Weinheim, 2006.
7. (a) Simon, C.; Constantieux, T.; Rodriguez, J. Eur. J. Org. Chem. 2004, 4957–4980;
(b) Lie´by-Mu¨ller, F.; Constantieux, T.; Rodriguez, J. J. Am. Chem. Soc. 2005, 127,
17176–17177; (c) Coquerel, Y.; Bensa, D.; Doutheau, A.; Rodriguez, J. Org. Lett.
NMR (300 MHz, CDCl3)
d 1.17 (s, 9H), 1.51–1.79 (m, 4H), 2.24–2.32
(m, 2H), 3.52–3.62 (m,1H), 3.83–3.92 (m,1H), 5.78 (s,1H), 7.41–7.58
(m, 3H), 7.97 (d, J¼7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 18.9, 22.6,
27.7, 27.9, 41.1, 68.3, 104.9, 127.5, 128.3, 132.1, 141.5, 167.2, 188.0.
HRMS (ESI): m/z calcd for C17H24NO3S [MþH]þ 322.1477, found:
322.1471.
´
¨
2006, 8, 4819–4822; (d) Lieby-Muller, F.; Simon, C.; Constantieux, T.; Rodriguez,
J. QSAR Comb. Sci. 2006, 25, 432–438; (e) Habib-Zahmani, H.; Viala, J.; Hacini, S.;
4.5.5. (Z)-9l. Viscous oil. Isolated as the minor component of
a mixture with (E)-9l after flash chromatography on silica gel. Se-
´
¨
Rodriguez, J. Synlett 2007, 1037–1042; (f) Lieby-Muller, F.; Constantieux, T.;
Rodriguez, J. Synlett 2007, 1323–1325; (g) Coquerel, Y.; Filippini, M.-H.; Bensa,
D.; Rodriguez, J. Chem.dEur. J. 2008, 14, 3078–3092; (h) Bonne, D.; Salat, L.;
Dulce`re, J.-P.; Rodriguez, J. Org. Lett. 2008, 10, 5409–5412; (i) Sotoca, E.; Allais,
C.; Constantieux, T.; Rodriguez, J. Org. Biomol. Chem. 2009, 7, 1911–1920; (j)
Boddaert, T.; Coquerel, Y.; Rodriguez, J. Adv. Synth. Catal. 2009, 351, 1744–1748;
(k) Coquerel, Y.; Boddaert, T.; Presset, M.; Mailhol, D.; Rodriguez, J. In Ideas in
Chemistry and Molecular Sciences: Advances in Synthetic Chemistry; Pignataro, B.,
Ed.; Wiley-VCH: Weinheim, in press.
lected data: 13C NMR (75 MHz, CDCl3)
d 18.2, 24.4, 28.1, 30.1, 41.7,
68.6, 105.2, 127.2, 129.4, 132.8, 142.6, 172.5, 188.2. HRMS (ESI): m/z
calcd for C17H24NO3S [MþH]þ 322.1477, found: 322.1471.
4.5.6. 10a. Viscous oil. 1H NMR (300 MHz, CDCl3)
d 1.47–1.69 (m,
2H), 1.75–1.99 (m, 2H), 2.64 (s, 3H), 3.54–3.72 (m, 2H), 3.71 (d,
J¼14.3 Hz, 1H), 3.79 (d, J¼14.3 Hz, 1H), 4.56–4.62 (m, 1H), 7.39–
7.59 (m, 3H), 7.77 (d, J¼7.2 Hz, 2H). 13C NMR (75 MHz, CDCl3)
8. Coquerel, Y.; Rodriguez, J. Tetrahedron Lett. 2006, 47, 8503–8506.
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synthesis of nonactates from 2-alkylidenetetrahydrofurans, see: Lygo, B.;
d
20.2, 21.3, 29.6, 61.9, 66.0, 104.8, 128.6, 129.5, 132.5, 137.1, 143.6.
HRMS (ESI): m/z calcd for C13H18NO2S [MþH]þ 252.1058, found:
252.1067.
4.5.7. 10f. Viscous oil. 1H NMR (300 MHz, CDCl3)
d 1.28 (s, 9H),
1.44–1.57 (m, 2H), 1.73–87 (m, 2H), 3.41–3.59 (m, 2H), 3.95 (d,
J¼13.8 Hz, 1H), 4.15 (d, J¼13.8 Hz, 1H), 4.55–66 (m, 1H), 7.37–7.58
(m, 3H), 7.82 (d, J¼8.1 Hz, 2H). 13C NMR (75 MHz, CDCl3)
d 19.9,
20.9, 27.6, 60.9, 65.8, 79.8, 105.8, 128.2, 128.4, 133.2, 136.2, 142.3,

9764
M.-A. Virolleaud et al. / Tetrahedron 65 (2009) 9756–9764
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