Synthesis of 3-oxooxa- and 3-oxoazacycloalk-4-enes by ring-closing metathesis. Application to the synthesis of an inhibitor of cathepsin K

Article abstract of DOI:10.1016/j.tet.2007.03.066

3-Oxooxa- and 3-oxoazacycloalk-4-enes were obtained with good yield from 1-(ω-alkenyloxy)- and 1-(ω-alkenylamino)-but-3-en-2-ones by using a ring-closing metathesis. This methodology has been used to synthesize an inhibitor of cathepsin K.

Full text of DOI:10.1016/j.tet.2007.03.066

Tetrahedron 63 (2007) 4472–4490
Synthesis of 3-oxooxa- and 3-oxoazacycloalk-4-enes by
ring-closing metathesis. Application to the synthesis of an
inhibitor of cathepsin K
*
Catherine Taillier, Thomas Hameury, Veronique Bellosta and Janine Cossy
*
ꢀ
Laboratoire de Chimie Organique ESPCI, CNRS, 10 rue Vauquelin, 75231 Paris Cedex 05, France
Received 20 December 2006; revised 8 March 2007; accepted 9 March 2007
Available online 14 March 2007
Abstract—3-Oxooxa- and 3-oxoazacycloalk-4-enes were obtained with good yield from 1-(u-alkenyloxy)- and 1-(u-alkenylamino)-but-3-
en-2-ones by using a ring-closing metathesis. This methodology has been used to synthesize an inhibitor of cathepsin K.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
synthesize a broad range of acyclic a-alkoxy- and a-amino
enones of type B1 and B2 from u-unsaturated alcohols and
u-unsaturated amines (Scheme 1).
Cyclic ethers and amines1 are present in a great variety of
natural and non-natural products, which possess interesting
biological properties. The interest for these heterocyclic
compounds has stimulated the development of an array of
methods for their synthesis.2,3 The number of approaches
available for the construction of cyclic ethers and amines
has steadily increased and, among them, the ring-closing
metathesis (RCM) has proved to be efficient.4–6 We planned
to use this key reaction in order to develop a general and ver-
satile access to functionalized 3-oxooxacycloalk-4-enes and
3-oxoazacycloalk-4-enes of type A (Fig. 1).
R
R'
O
O
X = O
OH
n
RCM
X
X
n
n
R
R'
R'
R'
R
R
NHR''
n
X = NR''
n = 0, 1, 2 ...
A1 X = O
A2 X = NR''
B1 X = O
B2 X = NR''
Scheme 1.
When we began to investigate the synthesis of compounds
of type A, only few examples of RCM reactions involving
u-unsaturated conjugated ketones as partners had been repor-
ted.5d,7 Nevertheless, we decided to examine the reactivity
of 1-(u-alkenyloxy)- and 1-(u-alkenylamino)-but-3-en-2-
ones in the metathesis process with the aim of preparing
six-, seven- and eight-membered 3-oxooxa- and 3-oxoazacy-
cloalk-4-enes. Thus, a general route was required to
Recently, we disclosed our preliminary results related to the
synthesis of 3-oxooxa- and 3-oxoazacycloalk-4-enes of type
A1 and A2 by using an RCM reaction.8,9 Herein, we would
like to report a full account of our results and an application
to the synthesis of an inhibitor of cathepsin K.
O
2. Preparation of compounds of type B1 and B2
2.1. Synthesis of compounds of type B1
X
n = 1, 2 ...
X = O, NR
n
A
Two different methods have been developed to synthesize
compounds of type B1 (X¼O), depending on the nature of
the precursors, e.g. the u-unsaturated alcohols. The transfor-
mation of primary u-unsaturated alcohols of type C to com-
pounds of type B1 was achieved via u-unsaturated acyl
chloride of type E, conversion of secondary or tertiary u-un-
saturated alcohols D was performed via stabilized phosphor-
anes of type F (Scheme 2).
Figure 1.
Keywords: Ring-closing metathesis; Cathepsin K inhibitor; Enone; Cyclic
amines; Cyclic ethers.
* Corresponding authors. Tel.: +33 0 140794429; fax: +33 0 140794660
(J.C.); tel.: +33 0 140794415; fax: +33 0 140794660 (V.B.); e-mail
addresses: veronique.bellosta@espci.fr; janine.cossy@espci.fr
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.03.066

C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
4473
Table 1
Cl
O
OH
n
n
Cl
CO2H
NaH
THF, rt
OH
O
O
OH
n
C
E
n
1-3
O
4-6
n = 0, 1, 2
1) (COCl)2
DMF cat.
B1
2)
SnBu3
Pd(PPh3)2BnCl
R
R'
OH
R
R'
O
O
PPh3
n
n
n
O
O
7-9
D
F
Entry
1
Alcohols
a-Alkoxy acetic
acids (yield %)
a-Alkoxy enones
(yield %)
Scheme 2.
O
O
O
O
The synthesis of compounds 7–9 was achieved from the pri-
mary u-unsaturated alcohols 1–3, respectively. After con-
densation with chloroacetic acid, under basic conditions10
(NaH, 2.2 equiv) in THF at rt, the alcohols 1–3 were trans-
formed, respectively, to the corresponding a-alkoxy acetic
acids 4–6 in yields superior to 50%. The obtained a-alkoxy
acetic acids 4–6 were then treated with oxalyl chloride in the
presence of a catalytic amount of DMF, in benzene for 1 h at
rt, and the resulting acyl chlorides were then involved in
OH
OH
1
7 (37%)
4 (70%)
O
O
OH
2
O
O
2
3
OH
OH
2
2
2
8 (58%)
5 (56%)
O
O
OH
3
O
O
3
3
a
Pd-catalyzed reaction [Pd(PPh3)2BnCl 0.4 mol %,
3
9 (51%)
6 (51%)
HMPA, 65 ꢀC, 45 min]11 with tri-n-butylvinyltin to produce
the desired a-alkoxy enones 7–9 in yields greater than 37%.
The results are summarized in Table 1. It is worth noting that
Table 2
Cl
O
R
R'
R
R'
O
R
R'
O
Ph3P
NaH
CH2O
OH
PPh3
n
n
n
H2O/Et2O
rt
O
O
10-15
16-21
22-27
THF
rt or reflux
n = 0, 1, 2
Entry
1
Alcohols 10–15
i-Pr
Phosphoranes 16–21 (yield %)
i-Pr
a-Alkoxy enones 22–27 (yield %)
i-Pr
O
O
OH
PPh3
O
O
16 (94%)
22 (67%)
10
CH2OTr
CH2OTr
O
CH2OTr
2
3
4
5
O
OH
PPh3
O
O
17 (71%)
23 (70%)
11
i-Pr
i-Pr
i-Pr
O
O
OH
PPh3
O
O
18 (48%)
24 (49%)
12
Ph
Ph
O
Ph
O
PPh3
PPh3
OH
O
O
O
19 (70%)
25 (73%)
13
Me
Me
Me
O
Me
O
Me Me
OH
O
20 (82%)
26 (49%)
14
i-Pr
i-Pr
i-Pr
6
O
O
OH
PPh3
O
O
21 (76%)
27 (54%)
15

4474
C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
O
in the coupling reaction involving tri-n-butylvinyltin and
acyl chlorides of type E, generated from secondary and ter-
tiary u-unsaturated alcohols, non-identified products were
obtained.
R
R'
R
R'
N
R''
N R''
R'
PPh3
R''
n
N
H
n
O
nR
B2
G
H
As the second step of the above strategy failed when second-
ary or tertiary u-unsaturated alcohols were employed as
starting materials, the synthesis of the corresponding a-alk-
oxy enones of type B1 was envisioned from stabilized phos-
phoranes.12 The b-ketophosphoranes 16–21 were obtained
by alkylation of the secondary and tertiary alcohols 10–15.
After treatment of 10–15 with NaH (4 equiv) in THF,
followed by the addition of triphenylchloroacetonylphos-
phorane,13 the corresponding phosphoranes 16–21 were iso-
lated in yields greater than 48% and were converted to the
a-alkoxy enones 22–27 by condensation with formaldehyde
in yields up to 73%. The results are reported in Table 2.
Scheme 3.
(4 equiv) followed by the addition of triphenylchloroaceto-
nylphosphorane, the desired b-ketophosphorane 34 was
not obtained. However, when 28 was treated with n-BuLi
in THF, after addition of the triphenylchloroacetonylphos-
phorane, the b-ketophosphorane 34 was isolated in 85%
yield. The reaction turned out to be general as under these
latter conditions the u-unsaturated amines 29–31 and 33
were transformed, respectively, to the corresponding b-keto-
phosphoranes 34–37 and 39 (57–90% yield). It is worth not-
ing that the alkylation of the N-benzylbut-3-enylamine 32
was achieved under milder conditions e.g. with Et3N
(2 equiv) in the presence of n-Bu4NI, in acetonitrile from
rt to 50 ꢀC, as the use of n-BuLi produced polymers.
2.2. Synthesis of compounds of type B2
The synthesis of compounds of type B2 (X¼NR00) was
achieved from u-unsaturated amines H via stabilized phos-
phoranes of type G according to Scheme 3.
The obtained b-ketophosphoranes 34, 35, and 39 were then
treated with an excess of aqueous formaldehyde under
Wittig conditions (Et2O, 3 h, rt) to produce the corresponding
a-amino enones 40, 41, and 45 in 42–74% yields (Table 3,
The first attempt was achieved from allyltosylamine 28.
When allyltosylamine 28 was deprotonated by NaH
Table 3
Cl
O
R'
N
O
R'
N
O
Ph3P
R''CHO
PPh3
NHR'
n
n
n
n-BuLi, THF, rt
R''
R
28-33
R
R
40-45
34-39
n = 0, 1
Entry
1
Amines
NHTs
b-Ketophosphoranes
a-Amino enones (yield %)
Ts
N
O
Ts
N
O
PPh3
PPh3
28
29
30
31
32
40 (42%)
34 (85%)
Boc
N
O
Boc
N
O
NHBoc
2
3
4
5
41 (74%)
35 (80%)
Boc
N
O
Boc
N
O
NHBoc a
NHCbz a
NHBn a
PPh3
36 (74%)
42 (87%)
Cbz O
N
Cbz O
N
PPh3
PPh3
37 (90%)
43 (85%)
Bn
N
O
Bn
N
O
38 (60%)c
44 (53%)
Ts
N
O
Ts
N
O
NHTs b
PPh3
6
Ph
Ph
39 (57%)
Ph
33
45 (62%)
a
The protected homoallylamines 30–32 were prepared from the hydrochloride salt of but-3-enamine.14
Prepared by allylation of the N-tosyl imine derived from benzaldehyde.
Prepared by N-alkylation of 32 in the presence of Et3N (2 equiv), n-Bu4NI (0.5 equiv) in CH3CN from rt to 50 ꢀC.
b
c

C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
4475
entries 1, 2, and 6). We have to point out that the treatment of
b-ketophosphoranes 36–38 with formaldehyde led to the
formation of polymers, whereas replacement of formalde-
hyde by acetaldehyde produced the desired a-amino enones
42–44 in good yields (53–87%) (Table 3, entries 3–5). The
results are reported in Table 3.
(58% yield), 50 (90% yield), 51 (93% yield), and 52 (67%
yield) were obtained, respectively, from the corresponding
enones 8, 24, 25, 26 and yields were found to be good to ex-
cellent when 7-alkyl- or 7-aryl-3-oxooxacyclohept-4-enes
are formed. Eight-membered rings are difficult to obtain
by RCM and, we were particularly gratified that a-alkoxy
enones 9 and 27 were equally effective substrates in the
RCM as eight-membered ring compounds 53 and 54 were
respectively formed even when the reaction was performed
at a concentration of 10ꢂ2 M. The results are reported in
Table 4. However, we have to point out that for compound
27, a cyclic dimer 55 was isolated in 14% yield in which the
configuration of the two double bonds was (E). In the case of
a-alkoxy enone 56, the nine-membered-ring enone was
never observed even at low concentration (c 1ꢁ10ꢂ3 M).
The treatment of the a-alkoxy enone 56 with [Ru]-II led
only to the cyclic dimer 57 in 75% yield. The formation of
the cyclic dimers 55 and 57 can be explained by two succes-
sive metathesis reactions: a CM producing linear dimers 58
and 59 followed by an RCM reaction (Scheme 4).
3. Ring-closing metathesis (RCM)
The obtained u-unsaturated a-alkoxy enones 7–9, 22–27,
and the a-amino enones 40–45 were involved in RCM. All
the reactions were carried out with 2.5–15.0 mol % of the
Grubbs second generation catalyst [Ru]-II [(4,5-dihydro-
IMes)(PCy3)Cl2Ru]CHPh]15 at concentrations of 5ꢁ10ꢂ3
to 1ꢁ10ꢂ2 M in refluxing CH2Cl2.
3.1. RCM applied to a-alkoxy enones
The RCM was applied to a-alkoxy enones 7–9, 22–27 and
the corresponding cyclized products were obtained in mod-
erate to good yields. Compounds 7, 22, and 23 led to six-
membered alkoxy enones in 69%, 87%, and 68% yields,
respectively. Seven-membered cyclic alkoxy enones 49
3.2. RCM applied to a-amino enones
When u-unsaturated a-amino enones 40 and 41 were
involved in an RCM in the presence of [Ru]-II, the
Table 4
Entry
a-Alkoxy enones
Concentration (mol Lꢂ1
)
[Ru]-II (mol %)
3-Oxooxacycloalkenes
Yield %
69
O
O
1
2ꢁ10ꢂ2
2.5
O
O
7
46
i-Pr
i-Pr
O
2
4ꢁ10ꢂ3
5
87
O
O
47
O
22
CH2OTr
O
TrOCH2
O
3
4
5
1ꢁ10ꢂ3
2ꢁ10ꢂ2
5
15
5
68
58
90
O
48
O
23
O
O
O
O
8
49
i-Pr
O
O
1.3ꢁ10ꢂ2
O
i-Pr
O
50
O
24
Ph
O
6
7
2ꢁ10ꢂ2
5ꢁ10ꢂ3
2.5
4
93
67
Ph
O
51
O
25
Me
Me
O
O
O
O
26
52
O
O
8
1.3ꢁ10ꢂ2
1ꢁ10ꢂ2
10
66
35
O
O
9
53
i-Pr
O
9
2.5
O
+ dimer a
O
O
i-Pr
27
54
a
The dimer 55 was isolated in 14% yield.

4476
C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
R
the [Ru]-II catalyst by the nitrogen atom. These results are
reported in Table 5. The RCM allowed the transformation
of u-unsaturated a-amino enones to the corresponding cy-
clized products if the nitrogen is substituted by an electron-
withdrawing group such as in carbamates or sulfonamides.
O
n
O
27 R = i-Pr, n = 2
56 R = H, n = 3
3.3. Total synthesis of 65, an inhibitor of cathepsin K
CM
R
O
As this methodology was efficient in obtaining 3-oxoazacy-
clohept-4-enes from homoallylic amines, its application to
the total synthesis of a potent azepanone-based inhibitor of
the osteoclast-specific cysteine protease cathepsin K,16,17
compound 65, was achieved (Fig. 2).
O
n
O
n
O
R
58 R = i-Pr, n = 2
59 R = H, n = 3
RCM
R
O
O
n
H
N
N
H
O
O
O
4
O
O
O
N
O
S
n
O
N
R
65
55 R = i-Pr, n = 2 14%
57 R = H, n = 3 75%
Figure 2.
Scheme 4.
Two syntheses of 65 were reported: one 12-step non-stereo-
controlled synthesis,16 which led to two HPLC separable
epimers at C-4, and one enantioselective 15-step synthesis
involving an Evans aldol reaction as the key-step.18 By using
an RCM applied to an u-unsaturated a-amino enone of type
B2, a 10-step synthesis of 65 was envisioned from the hydro-
chloride salt of the homoallylamine. In order to introduce the
peptidic side-chain, the synthesis of 65 was planned from the
a-amino ketone I. This latter should be obtained from
3-oxoazacyclohept-4-ene J, which should be synthesized from
the hydrochloride salt of the homoallylamine 66 (Scheme 5).
corresponding 3-oxoazacyclohex-4-enes 60 and 61 were ob-
tained in good yields (65–80%). Excellent yields in tetrahy-
droazepinones 62, 63, 64, greater than 90%, were obtained
after the RCM was applied to a-amino enones 42, 43, and
45. However, no cyclized products but only polymers were
formed when N-benzyl protected enone 44 was subjected
to the RCM conditions, probably due to a coordination of
Table 5
O
Entrya
a-Amino enones
[Ru]-II
(mol %)
3-Oxoaza-
cycloalkenes
Yield %
65
Cl H3N
65
N
R
Ts
N
O
O
O
I
1
2
5
5
N
40
Ts
60
Boc
N
O
O
80
N
Boc
41
61
NH3
Cl
N
R
Boc
N
O
O
66
J
3
4
5
90
97
N
62
42
Boc
Scheme 5.
Cbz O
N
O
The hydrochloride salt of the but-3-enamine 6614 was treated
under basic conditions with 2-pyridinesulfonyl chloride19
(Et3N, CH2Cl2, rt) to produce 67 in 88% yield. The transfor-
mation of the N-pyridylsulfonyl but-3-enamine 67 to the de-
sired but-3-enamino enone 69 was achieved in two steps via
the stabilized phosphorane 68 (n-BuLi, triphenylchloroace-
tonylphosphorane, THF, rt) prepared in 94% yield, which
was converted to the a-amino enone 69 by condensation
with acetaldehyde in 94% yield. The obtained u-unsaturated
a-amino enone 69 was then involved in an RCM ([Ru]-II,
2.5 mol %, c 5ꢁ10ꢂ3 M, CH2Cl2, reflux, 12 h) and trans-
formed to the desired seven-membered azacyclic compound
2.5
N
63
43
Cbz
Ts
N
O
O
5
5
5
99
—
Ph
N
Ph
64
Ts
45
Bn
N
O
6
—
44
All the RCM reactions were performed at 5ꢁ10ꢂ3 M, in refluxing
a
CH2Cl2, for 12 h.

C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
4477
c)
a)
b)
NH3 Cl
NH-SO2-(2-Pyr)
N
N
PPh3
O
(2-Pyr)-S
O
O
(2-Pyr)-S O
2
2
66
67
68
69
d)
Al
O
O
O
O
N3
Br
g)
f)
e)
N
N
N
N
SO2-(2-Pyr)
SO2-(2-Pyr)
SO2-(2-Pyr)
SO2-(2-Pyr)
72
71
70
O
O
O
H
N
h)
N
H
O
O
O
O
N
N
S
O
O
O
H
N
65'
N
Cl
H3N
i)
j), k)
+
BocHN
O
N
N
SO2-(2-Pyr)
SO2-(2-Pyr)
O
H
N
74
73
N
H
O
O
S
O
65
N
Scheme 6. Reagents and conditions: (a) (2-Pyr)SO2Cl, Et3N, CH2Cl2, rt, 88%; (b) ClCH2(CO)C]PPh3, n-BuLi, THF, rt, 94%; (c) CH3CHO (10 equiv), THF, rt,
94%; (d) [Ru]-II, 2.5 mol %, CH2Cl2, reflux, 96%; (e) DIBAL-H (4 equiv), CuCN (2 equiv), n-BuLi (2 equiv), THF, ꢂ50 ꢀC, 2 h; then HMPA (3 equiv), MeLi
(1 equiv), ꢂ50 ꢀC, 30 min; (f) Br2 (10 equiv), ꢂ50 ꢀC to ꢂ20 ꢀC, 1 h; (g) NaN3, DMF, (45% from 70); (h) H2, 10% Pd/C, MeOH/HCl; (i) N-Boc-L-leucine,
EDCI, HOBt, Et3N, CH2Cl2, rt, 51% (two steps); (j) 4 M HCl in dioxane, MeOH, rt, 2.5 h; (k) benzofuran-2-carboxylic acid, EDCI, HOBt, Et3N, CH2Cl2,
rt, 52% (two steps).
70 in 96% yield. This tetrahydroazepinone was transformed
to the a-azido ketone 72 in two steps. The first step was the
formation of the a-bromo azepanone 71 via the 1,4-addition
of a ‘hydrido cuprate’ generated by the addition of DIBAL-H
(4 equiv) in the presence of a cyanocuprate [CuCN (2 equiv),
BuLi (2 equiv), THF, ꢂ50 ꢀC, 2 h] and activation of the re-
sulting enolate intermediate with MeLi (1 equiv) in the pres-
ence of HMPA (3 equiv, ꢂ50 ꢀC, 30 min) to form a more
reactive aluminate enolate, which was trapped with bromine
(10 equiv, ꢂ50 ꢀC to ꢂ20 ꢀC, 1 h) to furnish the a-bromo ke-
tone 71.20,21 Without purification, a-bromo ketone 71 was
converted to the a-azido ketone 72 in 45% overall yield
(from 70) by treatment with NaN3 in DMF, at rt. After hydro-
genation of 72 in acidic conditions (H2, 10% Pd/C, MeOH/
HCl) the resulting hydrochloride salt 73 was condensed
with the N-Boc-L-leucine22 (EDCI, HOBt, Et3N, CH2Cl2,
rt) to furnish the desired keto amide 74 in 51% overall yield
(from 72). After cleavage of the N-Boc group (4 M HCl in
dioxane, MeOH) and condensation with benzofuran-2-carb-
oxylic acid in the presence of EDCI and HOBt, compound 65
and its epimer 650 were obtained in 52% overall yield and 65
can be isolated by HPLC (Scheme 6).16,23
5. Experimental
5.1. General
All reactions were carried out under argon atmosphere. Unless
otherwise specified, materials were purchased from commer-
cial suppliers and used without purification. THF and diethyl
ether were distilled from sodium/benzophenone. Methylene
chloride, triethylamine, benzene, and toluene were distilled
from CaH2. Flash column chromatography was carried out
on Merck Geduran Si60 silica gel (40–63 mM) and analytical
thin-layer chromatography was performed on Merck pre-
coated silica gel (60 F254). Melting points (mp) are uncor-
rected. Elemental analysis were performed by the Centre
ꢀ
ꢀ
Regional de Microanalyses (Universite Pierre et Marie Curie,
Paris VI). Mass spectra with electronic impact (EIMS) were
recordedfromaHewlett–Packardtandem5890GC(12 mcap-
illary column)–5971 MS (70 eV): only selected ions are re-
ported. HRMS were performed at the Laboratoire de
ꢀ
Spectrochimie de l’Ecole Normale Superieure or by the
ꢀ
ꢀ
Groupe de Spectrometrie de Masse de l’Universite Pierre et
Marie Curie in Paris. Infrared (IR) spectra were recorded on
a Perkin–Elmer 298 or on a Bruker TENSORÔ 27 (IRFT),
wave-numbers are indicated in cmꢂ1. 1H NMR spectra were
recorded on a Bruker AC 300 at 300 MHz or on a Bruker
AVANCE 400 at 400 MHz in CDCl3 and data are reported
as follows: chemical shift in parts per million from tetrame-
thylsilane as an internal standard, multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, quint¼quintuplet, m¼multi-
plet or overlap of non-equivalent resonances, br¼broad), inte-
gration. 13C NMR spectra were recorded on a Bruker AC 300
at 75 MHz orona Bruker AVANCE400 at100 MHz in CDCl3
4. Conclusion
By applying an RCM to u-unsaturated a-alkoxy enones and
a-amino enones, six-, seven- and eight-membered ring 3-
oxooxa- and 3-oxoazacycloalkenes were obtained in good
to excellent yields. Furthermore, by using this methodology,
a short synthesis of 65, an inhibitor of cathepsin K, was
achieved.

4478
C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
and data are reported as follows: chemical shift in parts per
million from tetramethylsilane with the solvent as an internal
indicator(CDCl3 d 77.0 ppm), multiplicitywithrespect to pro-
ton (deduced from DEPT experiments, s¼quaternary C,
d¼CH, t¼CH2, q¼CH3).
and oxalyl chloride (0.57 mL, 0.84 g, 6.6 mmol, 1.1 equiv).
The reaction mixture was stirred at rt until complete conver-
sion of the starting material (followed by GC–MS). The
excess of oxalyl chloride and solvent were evaporated under
reduced pressure. The obtained crude acyl chloride was
dissolved in HMPA (4 mL) and this solution was placed in
a tube fitted with a screw-cap. Benzyl(chloro)-bis(triphenyl-
phosphine)palladium(II) (18 mg, 0.024 mmol, 0.4 mol %)
and tributyl(vinyl)stannane (1.9 mL, 6.6 mmol, 1.1 equiv)
were added and the reaction mixture was heated up to
65 ꢀC for 45 min. The mixture was then allowed to cool to rt,
poured into an aqueous NaCl solution (15 mL, 3% in water),
and extracted with diethyl ether (3ꢁ20 mL). The combined
organic extracts were washed with water, dried over
MgSO4, filtered, and concentrated under reduced pressure.
To the crude residue were added diethyl ether (20 mL) and
a half-saturated KF aqueous solution (15 mL). The biphasic
mixture was stirred for 1 h at rt. After filtration, the organic
layer was washed with water, dried over MgSO4, filtered, and
concentrated under reduced pressure. Purification by flash
chromatography on silica gel (petroleum ether/Et2O 95/5)
afforded 7 (278 mg, 2.21 mmol, 37%) as a colorless oil;
Rf : 0.8 (petroleum ether/EtOAc 80/20); IR (neat) 2890,
5.2. Prop-2-enyloxyacetic acid (4).24 Typical procedure
To a stirred suspension of NaH (2.8 g, 60% in oil, 70 mmol,
1.0 equiv), washed with hexanes, in anhydrous THF (50 mL)
at 0 ꢀC was added dropwise prop-2-en-1-ol 1 (4.75 mL,
4.06 g, 70 mmol, 1 equiv). After 15 min at 0 ꢀC, the reaction
mixture was stirred for 15 min at rt. Besides, to another sus-
pension of NaH (2.8 g, 70 mmol, 1.0 equiv), washed with
hexanes, in anhydrous THF (25 mL) at 0 ꢀC, was slowly
added a solution of bromoacetic acid (9.722 g, 70 mmol,
1.0 equiv) in anhydrous THF (25 mL). After 5 min at 0 ꢀC,
the previously prepared sodium alkoxide solution was added
(via cannula) and the reaction mixture was stirred for 2 h at rt
and then heated for 3 h at 70 ꢀC. After cooling to rt the reac-
tion mixture was hydrolyzed with water (100 mL) and THF
was removed by evaporation under reduced pressure. The
aqueous layer was washed with diethyl ether (2ꢁ100 mL),
and acidified until pH 3–4 with concentrated H2SO4. The
aqueous layer was extracted with diethyl ether and the com-
bined organic extracts were washed with water, dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash chromatography on silica gel (petrol-
eum ether/EtOAc 90/10) afforded 4 (5.68 g, 49 mmol,
70%) as a colorless oil; Rf: 0.2 (petroleum ether/EtOAc
80/20); IR (neat) 3420, 3080, 2910, 1730, 1425, 1215,
1695, 1400, 1115, 970, 930 cmꢂ1 1H NMR (CDCl3,
;
300 MHz) d 6.51 (dd, J¼17.6, 10.7 Hz, 1H), 6.30 (dd,
J¼17.6, 1.1 Hz, 1H), 5.96–5.76 (m, 2H), 5.32–5.15 (m,
2H), 4.23 (s, 2H), 4.03 (d, J¼5.9 Hz, 2H); 13C NMR
(CDCl3, 75 MHz) d 197.1 (s), 133.6 (d), 132.3 (d), 129.0
(t), 118.0 (t), 73.7 (t), 72.3 (t).
5.3.1. 1-(But-3-enyloxy)but-3-en-2-one (8). Yield: 58%
from 5; colorless oil; Rf: 0.7 (petroleum ether/EtOAc 80/
1
1115, 935 cmꢂ1; H NMR (CDCl3, 300 MHz) d 11.19 (br
s, 1H), 5.82 (ddt, J¼17.3, 10.3, 5.9 Hz, 1H), 5.23 (dq,
J¼17.3, 1.4 Hz, 1H), 5.16 (dq, J¼10.3, 1.4 Hz, 1H), 4.06
(s, 2H), 4.03 (dt, J¼5.9, 1.4 Hz, 2H); 13C NMR (CDCl3,
75 MHz) d 175.3 (s), 133.1 (d), 118.4 (t), 72.2 (t), 66.2 (t).
20); IR (neat) 2920, 2855, 1700, 1615, 1405, 1115 cmꢂ1
;
1H NMR (CDCl3, 300 MHz) d 6.54 (dd, J¼17.6, 10.7 Hz,
1H), 6.33 (dd, J¼17.6, 1.1 Hz, 1H), 5.90–5.75 (m, 2H),
5.15–5.02 (m, 2H), 4.25 (s, 2H), 3.55 (t, J¼6.6 Hz, 2H),
2.43–2.34 (m, 2H); 13C NMR (CDCl3, 75 MHz) d 197.4
(s), 134.6 (d), 132.2 (d), 129.0 (t), 116.6 (t), 74.8 (t), 70.9
(t), 33.9 (t); EIMS m/z (relative intensity) 99 (MꢂC3H+5,
20), 96 (3), 86 (4), 70 (34), 69 (20), 55 (100).
5.2.1. But-3-enyloxyacetic acid (5).25 Yield: 56% from but-
3-en-1-ol 2; colorless oil; Rf: 0.15 (petroleum ether/EtOAc
80/20); IR (neat) 3450, 3070, 2910, 1730, 1640, 1430,
1230, 1125, 915 cmꢂ1
;
1H NMR (CDCl3, 300 MHz)
d 10.65 (br s, 1H), 5.80 (ddt, J¼16.9, 10.3, 6.6 Hz, 1H),
5.16–5.01 (m, 2H), 4.13 (s, 2H), 3.61 (t, J¼6.6 Hz, 2H),
2.37 (apparent q, J¼6.6 Hz, 2H); 13C NMR (CDCl3,
75 MHz) d 175.2 (s), 134.3 (d), 116.7 (t), 71.0 (t), 67.5 (t),
36.5 (t); EIMS m/z (relative intensity) 89 (MꢂC3H+5, 45),
71 (6), 61 (100), 59 (15), 55 (36), 54 (46), 53 (9).
5.3.2. 1-(Pent-4-enyloxy)but-3-en-2-one (9). Yield: 51%
from 6; colorless oil; Rf: 0.7 (petroleum ether/EtOAc 80/
20); IR (neat) 2920, 2860, 1700, 1640, 1610, 1400, 1115,
1
990, 910 cmꢂ1; H NMR (CDCl3, 300 MHz) d 6.57 (dd,
J¼17.3, 10.7 Hz, 1H), 6.35 (dd, J¼17.3, 1.8 Hz, 1H),
5.89–5.75 (m, 2H), 5.08–4.94 (m, 2H), 4.24 (s, 2H), 3.52
(t, J¼6.6 Hz, 2H), 2.20–2.11 (m, 2H), 1.79–1.68 (m, 2H);
13C NMR (CDCl3, 75 MHz) d 197.4 (s), 137.8 (d), 132.2
(d), 128.9 (t), 114.7 (t), 74.8 (t), 70.9 (t), 29.9 (t), 28.5 (t).
5.2.2. Pent-4-enyloxyacetic acid (6).26 Yield: 51% from
pent-4-en-1-ol 3; yellow oil; Rf: 0.15 (petroleum ether/
EtOAc 80/20); IR (neat) 3200, 3110, 2970, 1730,
1130 cmꢂ1; 1H NMR (CDCl3, 300 MHz) d 9.57 (br s, 1H),
5.79 (ddt, J¼ 16.9, 10.3, 6.6 Hz, 1H), 5.05–4.91 (m, 2H),
4.10 (s, 2H), 3.55 (t, J¼6.6 Hz, 2H), 2.12 (apparent q,
J¼6.6 Hz, 2H), 1.70 (apparent quint, J¼6.6 Hz, 2H); 13C
NMR (CDCl3, 75 MHz) d 175.1 (s), 137.7 (d), 114.8 (t),
71.2 (t), 67.5 (t), 29.8 (t), 28.4 (t).
5.4. 2-Methylpent-4-en-3-ol (10)27
To a solution of vinylmagnesium chloride in anhydrous THF
(32.8 mL, 1.68 M, 55.0 mmol, 1.1 equiv) at ꢂ40 ꢀC was
slowly added freshly distilled isobutyraldehyde (4.5 mL,
3.6 g, 50 mmol, 1 equiv). After 1 h at ꢂ40 ꢀC, the reaction
mixture was poured into a saturated aqueous NH4Cl solution
(50 mL) and extracted with diethyl ether (3ꢁ100 mL). The
combined organic extracts were washed with water
(50 mL), and dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification by flash chromato-
graphy on silica gel (petroleum ether/Et2O 95/5) afforded
5.3. 1-(Prop-3-enyloxy)but-3-en-2-one (7). Typical
procedure
To a solution of acid 4, in anhydrous benzene (6 mL) were
successively added a catalytic amount of DMF (one drop)

C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
4479
10 (1.99 g, 19.9 mmol, 40%) as a colorless oil; Rf : 0.85
(petroleum ether/EtOAc 80/20); IR (neat) 3360 (broad,
added freshly distilled benzaldehyde (2.03 mL, 2.12 g,
20 mmol, 1 equiv). After 15 min at 0 ꢀC, the reaction mix-
ture was stirred for 1 h at rt. The reaction mixture was then
poured into a saturated aqueous NH4Cl solution (15 mL)
and extracted with diethyl ether (3ꢁ30 mL). The combined
organic extracts were washed with a saturated aqueous
NaHCO3 solution (25 mL), dried over MgSO4, filtered,
and concentrated under reduced pressure. Purification by
flash chromatography on silica gel (petroleum ether/Et2O
95/5) afforded 13 (2.87 g, 19.4 mmol, 97%) as a colorless
oil; Rf : 0.7 (petroleum ether/EtOAc 80/20); IR (neat) 3380
1
OH), 2960, 2870, 1465, 1020, 990, 920 cmꢂ1; H NMR
(CDCl3, 300 MHz) d 5.81 (ddd, J¼16.9, 10.7, 6.2 Hz, 1H),
5.21–5.07 (m, 2H), 3.80 (apparent t, J¼6.2 Hz, 1H), 2.15
(br s, 1H), 1.69 (m, 1H), 0.89 (d, J¼6.8 Hz, 3H), 0.85 (d,
J¼6.8 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d 139.4 (d),
115.4 (t), 78.1 (d), 33.5 (d), 18.0 (q), 17.8 (q).
5.5. 1-Triphenylmethyloxy-but-3-en-2-ol (11)28
A mixture of but-3-en-1,2-diol (1.00 mL, 1.05 g, 11.9 mmol,
1 equiv), triphenylmethyl chloride (9.94 g, 35.7 mmol,
3 equiv), and 4-N,N-dimethylaminopyridine (5.80 g,
47.5 mmol, 4 equiv) in pyridine (100 mL) was refluxed for
3 h. After cooling to rt, the reaction mixture was diluted
with EtOAc (100 mL) and hydrolyzed with a saturated aque-
ous CuSO4 solution (100 mL). After decantation, the or-
ganic layer was separated, washed successively with
a saturated aqueous CuSO4 solution (2ꢁ50 mL), water
(50 mL), a saturated aqueous NaHCO3 solution (50 mL),
and brine (50 mL). The organic layer was dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash chromatography on silica gel (hexane/
CH2Cl2 60/40) afforded 11 (2.56 g, 7.75 mmol, 65%) as
a yellow oil; Rf: 0.60 (petroleum ether/EtOAc 80/20); IR
(neat) 3420 (broad, OH), 3050, 2860, 1590, 1485, 1445,
(broad, OH), 2915, 1640, 1450, 1045, 915, 760, 705 cmꢂ1
;
1H NMR (CDCl3, 300 MHz) d 7.35–7.21 (m, 5H), 5.78
(ddt, J¼16.9, 9.9, 7.3 Hz, 1H), 5.17–5.08 (m, 2H), 4.68
(td, J¼6.2, 2.9 Hz, 1H), 2.52–2.45 (m, 2H), 2.30 (br s,
1H); 13C NMR (CDCl3, 75 MHz) d 143.8 (s), 134.4 (d),
128.3 (d, 2C), 127.4 (d), 125.7 (d, 2C), 118.1 (t), 73.2 (d),
ꢃ
43.7 (t); EIMS m/z (relative intensity) 148 (M+ , 1), 108
(8), 107 (100), 105 (7), 79 (55), 78 (5), 77 (32), 51 (6).
5.8. 1,1-Dimethylbut-3-en-1-ol (14)31
To a solution of allylmagnesium chloride in anhydrous THF
(15.3 mL, 2 M, 30.6 mmol, 1.50 equiv) at 0 ꢀC was slowly
added dimethylketone (1.50 mL, 1.18 g, 20.4 mmol,
1 equiv). After 15 min at 0 ꢀC, the reaction mixture was
stirred for 1 h at rt. The reaction mixture was then poured
into a saturated aqueous NH4Cl solution (20 mL) and ex-
tracted with diethyl ether (3ꢁ30 mL). The combined organic
extracts were washed with a saturated aqueous NaHCO3 so-
lution (25 mL), dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification by distillation under re-
duced pressure (10–15 bars, bp 50 ꢀC) allowed to isolate 14
(1.29 g, 12.9 mmol, 63%) as a colorless oil; Rf: 0.35 (petro-
leum ether/EtOAc 90/10); IR (neat) 3385 (broad, OH), 3085,
1260, 1070 cmꢂ1 1H NMR (CDCl3, 300 MHz) d 7.78–
;
7.61 (m, 5H), 7.49–7.32 (m, 10H), 5.97 (ddd, J¼16.2,
11.4, 5.9 Hz, 1H), 5.45 (dt, J¼17.3, 1.5 Hz, 1H), 5.28 (dt,
1H, J¼10.6, 1.5 Hz, 1H), 4.43 (m, 1H), 3.43–3.29 (m,
2H), 2.86 (br s, 1H); 13C NMR (CDCl3, 75 MHz) d: 143.7
(s, 3C), 137.1 (d), 128.5 (d, 6C), 127.7 (d, 3C), 127.0 (d,
6C), 116.0 (t), 86.6 (s), 71.8 (d), 67.4 (t).
5.6. 2-Methylhex-5-en-3-ol (12)29
2985, 2915, 1640, 1465, 1380, 1180, 1150, 945, 915 cmꢂ1
;
1H NMR (CDCl3, 300 MHz) d 5.86 (m, 1H), 5.17–5.06
(m, 2H), 2.23 (d, J¼7.7 Hz, 2H), 1.89 (br s, 1H), 1.22 (s,
6H); 13C NMR (CDCl3, 75 MHz) d 134.1 (d), 118.3 (t),
70.2 (s), 48.0 (t), 28.9 (q, 2C); EIMS m/z (relative intensity)
99 (MꢂH+, 1), 96 (9), 81 (70), 68 (76), 67 (100), 57 (25), 55
(78), 54 (88), 53 (16).
To a solution of allylmagnesium chloride in anhydrous THF
(12 mL, 2 M, 24.0 mmol, 1.2 equiv) at 0 ꢀC was slowly
added freshly distilled isobutyraldehyde (1.82 mL, 1.44 g,
20 mmol, 1 equiv). After 15 min at 0 ꢀC, the reaction mix-
ture was stirred for 1 h at rt. The reaction mixture was then
poured into a saturated aqueous NH4Cl solution (25 mL)
and extracted with diethyl ether (2ꢁ50 mL). The combined
organic extracts were washed with a saturated aqueous
NaHCO3 solution, dried over MgSO4, filtered, and concen-
trated under reduced pressure. Purification by flash chroma-
tography on silica gel (petroleum ether/Et2O 95/5) afforded
12 (1.47 g, 12.9 mmol, 64%) as a colorless oil; Rf: 0.75 (pe-
troleum ether/EtOAc 80/20); IR (neat) 3480 (broad, OH),
5.9. 2-Methylhept-6-en-3-ol (15)32
To a suspension of magnesium (1.79 g, 73.80 mmol,
3.75 equiv) in anhydrous Et2O (10 mL) was added a solution
of 4-bromobut-1-ene (2.44 mL, 3.71 g, 24.6 mmol,
1.25 equiv) in anhydrous Et2O (25 mL) at such a rate to
maintain a regular reflux. At the end of the addition, the re-
action mixture was refluxed for an additional 10 min. After
cooling to rt, a solution of freshly distilled isobutyraldehyde
(1.8 mL, 1.4 g, 19.7 mmol, 1 equiv) in anhydrous Et2O
(15 mL) was added at such a rate to maintain a constant re-
flux. After cooling to rt, the reaction mixture was hydrolyzed
with a saturated aqueous NH4Cl solution (25 mL), extracted
with diethyl ether (2ꢁ50 mL) and EtOAc (50 mL). The
combined organic extracts were dried over MgSO4, filtered,
and concentrated under reduced pressure. Purification by
flash chromatography on silica gel (petroleum ether/Et2O
90/10) afforded 15 (1.77 g, 13.8 mmol, 70%) as a colorless
oil; Rf : 0.65 (petroleum ether/EtOAc 80/20); IR (neat) 3350
2960, 1460, 1415, 990, 910 cmꢂ1 1H NMR (CDCl3,
;
300 MHz) d 5.84 (m, 1H), 5.19–5.10 (m, 2H), 3.40 (m,
1H), 2.31 (m, 1H), 2.12 (m, 1H), 1.69 (m, 1H), 1.62 (br s,
1H), 0.95 (d, J¼6.6 Hz, 3H), 0.93 (d, J¼6.6 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) d 135.0 (d), 117.4 (t), 74.9 (d),
40.3 (t), 32.6 (d), 18.2 (q), 17.1 (q); EIMS m/z (relative inten-
sity) 113 (MꢂH+, 1), 74 (5), 73 (100), 71 (MꢂC3H+7, 16), 57
(6), 55 (51).
5.7. 1-Phenylbut-3-en-1-ol (13)30
To a solution of allylmagnesium chloride in anhydrous THF
(12 mL, 2 M, 24.0 mmol, 1.2 equiv) at 0 ꢀC was slowly
(broad, OH), 2950, 2930, 2870, 1635, 1465, 910 cmꢂ1
;

4480
C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
1H NMR (CDCl3, 300 MHz) d: 5.82 (ddt, J¼16.9, 10.3,
6.6 Hz, 1H), 5.02 (ddt, J¼17.3, 1.8, 1.8 Hz, 1H), 4.94
(ddt, J¼10.3, 1.8, 1.1 Hz, 1H), 3.34 (m, 1H), 2.30–2.01
(m, 2H), 1.82 (br d, J¼3.3 Hz, 1H), 1.71–1.36 (m, 3H),
0.89 (d, J¼7.0 Hz, 3H), 0.88 (d, J¼7.0 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) d 138.6 (d), 114.6 (t), 75.9 (d), 33.4 (d),
33.1 (t), 30.3 (t), 18.6 (q), 17.0 (q); EIMS m/z (relative inten-
3.83 (dsyst AB, J¼14.7 Hz, 1H), 3.53 (dd, J¼7.7, 6.6 Hz,
1H), 1.86 (m, 1H), 0.99 (d, J¼6.6 Hz, 3H), 0.89 (d,
J¼6.6 Hz, 3H); 13C NMR (CDCl3, 75 MHz) d 190.6 (s),
3
4
137.1 (d), 133.0 (d, JC–P¼10.3 Hz, 6C), 131.9 (d, JC–P
¼
¼
2.8 Hz, 3C), 128.7 (d, 2JC–P¼12.2 Hz, 6C), 127.0 (s, 1JC–P
3
90.2 Hz, 3C), 117.9 (t), 86.9 (d), 73.1 (t, JC–P¼12.7 Hz),
1
49.2 (d, JC–P¼108.7 Hz), 32.3 (d), 18.8 (q), 18.2 (q);
ꢃ
ꢃ
sity) 128 (M+ , 1), 95 (35), 86 (20), 85 (59), 81 (14), 73 (61),
EIMS m/z (relative intensity) 416 (M+ , 1), 373 (2), 318
(4), 304 (23), 303 (100), 289 (7), 183 (9).
71 (13), 69 (12), 68 (12), 67 (100), 57 (53), 56 (25), 55 (61),
54 (12).
5.11.1. 1-(Triphenyl-l5-phosphoranylidene)-3-(1-triphe-
nylmethyloxymethylallyloxy)propan-2-one (17). Yield:
71% from 11; wax; Rf : 0.40 (EtOAc); H NMR (CDCl3,
5.10. 1-Chloro-3-(triphenyl-l5-phosphanylidene)-
propan-2-one13
1
300 MHz) d 7.70–7.08 (m, 30H), 5.80 (ddd, J¼17.4, 10.3,
To a solution of a,a0-dichloroacetone (15.0 g, 118 mmol,
1 equiv) in THF (60 mL) was added triphenylphosphine
(30.95 g, 118 mmol, 1 equiv). The reaction mixture was
heated for 5 h at 70 ꢀC. After cooling to rt, the suspension
was filtered. The obtained solid was washed with anhydrous
THF (2ꢁ30 mL) and then dissolved at 65 ꢀC in methanol
(ca. 60 mL). EtOAc (20 mL) was added to the warm alco-
holic solution. After stirring overnight at rt, the suspension
was filtered and rinsed with EtOAc (20 mL). The resulting
solid was dried at 50 ꢀC for 48 h in an oven to afford triphe-
nylchloroacetonylphosphonium chloride as a white solid
(44.51 g, 114.5 mmol, 97%); mp 212 ꢀC.
7.3 Hz, 1H), 5.32 (d, J¼17.4 Hz, 1H), 5.18 (d, J¼10.3 Hz,
2
1H), 4.42 (br d, JH–P¼25.4 Hz, 1H), 4.18–3.94 (m, 3H),
3.34 (dd, Jsyst AB¼9.6, J¼6.6 Hz, 1H), 3.10 (dd, Jsyst AB
¼
9.6, J¼6.6 Hz, 1H); 13C NMR (CDCl3, 75 MHz) d 190.1
(s), 144.1 (s, 3C), 136.2 (d), 133.0 (d, 3JC–P¼10.2 Hz, 6C),
4
3
131.9 (d, JC–P¼2.6 Hz, 3C), 128.7 (d, JC–P¼12.1 Hz,
6C), 128.6 (d, 6C), 127.6 (d, 6C), 126.7 (d, 3C), 126.4 (s,
1JC–P¼90.1 Hz, 3C), 117.7 (t), 86.4 (s), 80.9 (d), 73.8 (t,
3JC–P¼12.6 Hz), 66.6 (t), 50.1 (d, 1JC–P¼109.3 Hz).
5.11.2. 1-(1-Isopropyl-but-3-enyloxy)-3-(triphenyl-l5-
phosphoranylidene)propan-2-one (18). Yield: 48% from
12; beige solid; mp 86–90 ꢀC; Rf : 0.55 (EtOAc/EtOH 90/
10); IR (CHBr3) 3050, 2960, 1530, 1480, 1435, 1400,
To a solution of the obtained phosphonium chloride (20.0 g,
51.4 mmol, 1.50 equiv) in methanol (30 mL) was added rap-
idly under stirring a solution of sodium carbonate (3.65 g,
34.4 mmol, 1.00 equiv) in water (20 mL). The resulting
white suspension was diluted with water (100 mL) and
stirred for 45 min at rt before it was filtered. The obtained
solid was dried under reduced pressure for several hours
leading to the desired triphenylchloroacetonylphosphorane
(17.76 g, 50.37 mmol, 98%) as white crystals. Physical
and spectral data match those previously reported.13 Mp
1
1105 cmꢂ1; H NMR (CDCl3, 300 MHz) d 7.69–7.36 (m,
15H), 5.88 (ddt, J¼16.9, 9.9, 7.4 Hz, 1H), 5.09–4.89 (m,
2H), 4.26 (m, 1H), 4.01 (dsyst AB, J¼14.8 Hz, 1H), 3.91
(dsyst AB, J¼14.8 Hz, 1H), 3.23 (apparent q, J¼5.5 Hz,
1H), 2.31–2.23 (m, 2H), 1.89 (m, 1H), 0.93 (d, J¼8.1 Hz,
3H), 0.89 (d, J¼8.1 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
3
d 190.3 (s), 136.0 (d), 133.0 (d, JC–P¼10.3 Hz, 6C), 132.0
4
2
(d, JC–P¼2.6 Hz, 3C), 128.8 (d, JC–P¼12.3 Hz, 6C),
1
126.7 (s, JC–P¼90.3 Hz, 3C), 116.1 (t), 84.8 (d), 74.3 (t,
1
1
182 ꢀC; Rf : 0.5 (EtOAc/EtOH 90/10); H NMR (CDCl3,
3JC–P¼12.5 Hz), 49.7 (d, JC–P¼109.6 Hz), 35.0 (t), 30.5
2
300 MHz) d 7.72–7.45 (m, 15H), 4.29 (br d, JH–P
24.3 Hz, 1H), 4.03 (s, 2H).
¼
(d), 18.2 (q), 18.1 (q); EIMS m/z (relative intensity) 430
ꢃ
(M+ , 1), 389 (3), 304 (23), 303 (100), 289 (9), 262 (4),
183 (8), 165 (4).
5.11. 1-(1-Isopropylprop-2-enyloxy)-3-(triphenyl-l5-
phosphoranylidene)propan-2-one (16). Typical
procedure
5.11.3. 1-(1-Phenylbut-3-enyloxy)-3-(triphenyl-l5-phos-
phoranylidene)propan-2-one (19). Yield: 70% from 13;
beige solid; mp 126–128 ꢀC; Rf: 0.7 (EtOAc/EtOH 90/10);
IR (CHBr3): 3050, 3010, 2900, 1530, 1480, 1435, 1400,
To a stirred suspension of NaH (1.6 g, 60% in oil, 40 mmol,
5.0 equiv), previously washed with hexanes, in anhydrous
THF (10 mL) at rt was slowly added a solution of alcohol
10 (1.0 g, 10 mmol, 1.25 equiv) in anhydrous THF
(15 mL). After 30 min at rt, neat triphenylchloroacetonyl-
phosphorane was added in one portion. The reaction mixture
was stirred at rt for 2 h and then heated at 70 ꢀC for 5 h. After
cooling to rt, the reaction mixture was poured on ice and
extracted with EtOAc (3ꢁ40 mL). The combined organic
extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification by flash chro-
matography on silica gel (EtOAc) afforded 16 (3.11 g,
7.48 mmol, 94%) as a beige solid; mp 78–80 ꢀC; Rf : 0.5
(EtOAc/EtOH 90/10); IR (CHBr3) 2950, 1525, 1480,
1140, 1100 cmꢂ1 1H NMR (CDCl3, 300 MHz) d 7.70–
;
7.21 (m, 20H), 5.84 (ddt, J¼16.9, 9.9, 7.4 Hz, 1H), 5.09–
4.90 (m, 2H), 4.51 (dd, J¼7.7, 5.9 Hz, 1H), 4.28 (br s,
1H), 3.95 (dsyst AB, J¼15.4 Hz, 1H), 3.78 (dsyst
,
AB
J¼15.4 Hz, 1H), 2.67 (m, 1H), 2.48 (m, 1H); 13C NMR
(CDCl3, 75 MHz) d 190.0 (s), 142.0 (s), 135.2 (d), 133.0
(d, JC–P¼10.1 Hz, 6C), 132.0 (d, JC–P¼6.1 Hz, 3C),
3
4
2
128.6 (d, JC–P¼12.2 Hz, 6C), 128.3 (d, 2C), 128.1 (d),
126.9 (s, 1JC–P¼90.4 Hz, 3C), 126.8 (d, 2C), 116.6 (t), 82.2
(d), 73.2 (t, 3JC–P¼13.1 Hz), 49.5 (d, 1JC–P¼109.2 Hz), 42.6
(t); EIMS m/z (relative intensity) 293 (1), 278 (39), 277
(100), 201 (14), 183 (14), 152 (8), 77 (10).
1435, 1400, 1140, 1100 cmꢂ1
;
1H NMR (CDCl3,
5.11.4. 1-(1,1-Dimethylbut-3-enyloxy)-3-(triphenyl-l5-
phosphoranylidene)propan-2-one (20). Yield: 82% from
14; beige wax; Rf: 0.1 (EtOAc); IR (CHBr3) 3050, 3020,
2970, 2920, 1530, 1515, 1435, 1400, 1140, 1105,
300 MHz) d 7.72–7.62 (m, 5H), 7.59–7.41 (m, 10H), 5.72
(ddd, J¼16.9, 10.6, 7.7 Hz, 1H), 5.26–5.16 (m, 2H), 4.26
2
(br d, JH–P¼26.1 Hz, 1H), 4.01 (dsyst AB, J¼14.7 Hz, 1H),

C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
4481
1
875 cmꢂ1; H NMR (CDCl3, 300 MHz) d 7.72–7.40 (m,
(d), 132.4 (d), 129.0 (t), 128.7 (d, 6C), 127.7 (d, 6C),
127.0 (d, 3C), 118.8 (t), 86.7 (s), 81.3 (d), 73.1 (t), 66.5 (t).
15H), 5.91 (ddt, J¼17.3, 10.3, 7.4 Hz, 1H), 5.10–5.00 (m,
2
2H), 4.28 (br d, JH–P¼27.0 Hz, 1H), 3.92 (s, 2H), 2.32 (d,
J¼7.4 Hz, 2H), 1.22 (s, 6H); 13C NMR (CDCl3, 75 MHz)
5.12.2. 1-(1-Isopropylbut-3-enyloxy)but-3-en-2-one (24).
Yield: 49% from 18; colorless oil. In order to avoid polymer-
ization compound 24 has to be kept in solution (cw0.2 M in
Et2O or CH2Cl2). Rf: 0.8 (petroleum ether/EtOAc 80/20); IR
(neat): 2960, 2920, 2870, 1700, 1680, 1640, 1615, 1465,
d 191.2 (s), 134.9 (d), 132.7 (d, 3JC–P¼10.8 Hz, 6C), 131.8
4
2
(d, JC–P¼2.8 Hz, 3C), 128.6 (d, JC–P¼12.3 Hz, 6C),
1
127.2 (s, JC–P¼90.0 Hz, 3C), 116.9 (t), 74.9 (s), 66.7 (t,
3JC–P¼12.5 Hz), 49.0 (d, JC–P¼108.8 Hz), 45.3 (t), 25.2
1
ꢃ
(q, 2C); EIMS m/z (relative intensity) 416 (M+ , 1), 304
(23), 303 (100), 289 (9), 262 (7), 183 (9).
1400, 1100, 1065, 990, 915 cmꢂ1 1H NMR (CDCl3,
;
300 MHz) d 6.66 (dd, J¼17.7, 10.7 Hz, 1H), 6.36 (dd,
J¼17.7, 1.5 Hz, 1H), 5.94–5.77 (m, 2H), 5.15–5.01 (m,
5.11.5. 1-(1-Isopropylpent-3-enyloxy)-3-(triphenyl-l5-
phosphoranylidene)propan-2-one (21). Yield: 76% from
15; wax; Rf: 0.40 (EtOAc/EtOH 90/10); IR (film) 3050,
2H), 4.28 (dsyst AB, J¼16.5 Hz, 1H), 4.19 (dsyst
,
AB
J¼16.5 Hz, 1H), 3.16 (apparent q, J¼5.5 Hz, 1H), 2.34–
2.26 (m, 2H), 1.88 (m, 1H), 0.94 (t, J¼6.6 Hz, 6H); 13C
NMR (CDCl3, 75 MHz) d 197.6 (s), 135.1 (d), 132.3 (d),
128.8 (t), 116.7 (t), 85.5 (d), 74.4 (t), 34.9 (t), 30.2 (d),
18.1 (q), 17.8 (q).
2950, 1530, 1480, 1435, 1400, 1100 cmꢂ1 1H NMR
;
(CDCl3, 300 MHz) d 7.78–7.40 (m, 15H), 5.82 (ddt,
J¼16.9, 10.3, 6.6 Hz, 1H), 5.03–4.87 (m, 2H), 4.30 (br d,
2JH–P¼27.0 Hz, 1H), 4.00 (s, 2H), 3.19 (apparent dt,
J¼7.3, 4.8 Hz, 1H), 2.34–2.06 (m, 2H), 1.93 (m, 1H),
1.67–1.49 (m, 2H), 0.93 (d, J¼6.2 Hz, 3H), 0.91 (d,
5.12.3. 1-(1-Phenylbut-3-enyloxy)but-3-en-2-one (25).
Yield: 73% from 19; colorless oil. In order to avoid polymer-
ization compound 25 has to be kept in solution (cw0.2 M in
Et2O or CH2Cl2). Rf: 0.65 (petroleum ether/EtOAc 80/20);
IR (neat): 3060, 3020, 2970, 2860, 1695, 1610, 1400,
ꢃ
J¼6.2 Hz, 3H); EIMS m/z (relative intensity) 444 (M+ , 1),
304 (22), 303 (100), 262 (11), 183 (14).
1
5.12. 1-(1-Isopropylprop-2-enyloxy)but-3-en-2-one (22).
Typical procedure
1100, 1065, 990, 915 cmꢂ1; H NMR (CDCl3, 300 MHz)
d 7.29–7.26 (m, 5H), 6.55 (dd, J¼17.6, 10.7 Hz, 1H), 6.29
(dd, J¼17.6, 1.5 Hz, 1H), 5.90–5.74 (m, 2H), 5.11–5.01
To a solution of ylide 16 (2.0 g, 4.8 mmol, 1 equiv) in diethyl
ether (30 mL) was added an aqueous solution of formalde-
hyde (36 mL, 37% in water, 0.48 mmol, 100 equiv). The
biphasic reaction mixture was stirred overnight at rt. The
aqueous layer was extracted with diethyl ether (3ꢁ20 mL)
and the combined organic extracts were dried over
MgSO4, filtered, and concentrated under reduced pressure.
Purification by flash chromatography on silica gel (petro-
leum ether/diethyl ether 95/5) afforded 22 (539 mg,
3.21 mmol, 67%) as a colorless oil. In order to avoid poly-
merization compound 22 has to be kept in solution (c
w0.2 M in Et2O or CH2Cl2). Rf : 0.85 (petroleum ether/
EtOAc 80/20); IR (neat) 2960, 2930, 2870, 1700, 1625,
1400, 1095 cmꢂ1; 1H NMR (CDCl3, 300 MHz) d 6.58 (dd,
J¼17.7, 10.7 Hz, 1H), 6.31 (dd, J¼17.6, 1.5 Hz, 1H),
5.77 (dd, J¼10.7, 1.5 Hz, 1H), 5.63 (ddd, J¼17.3, 10.3,
8.5 Hz, 1H), 5.25 (br dd, J¼10.3, 1.8 Hz, 1H), 5.15 (ddd,
J¼17.3, 1.8, 0.7 Hz, 1H), 4.23 (dsyst AB, J¼16.9 Hz, 1H),
4.07 (dsyst AB, J¼16.9 Hz, 1H), 3.38 (m, 1H), 1.83 (m,
1H), 0.96 (d, J¼7.0 Hz, 3H), 0.87 (d, J¼7.0 Hz, 3H);
13C NMR (CDCl3, 75 MHz) d 197.7 (s), 136.1 (d), 132.4
(d), 128.6 (t), 119.0 (t), 87.5 (d), 72.5 (t), 32.3 (d),
18.4 (q), 18.0 (d); EIMS m/z (relative intensity) 168
(m, 2H), 4.39 (dd, J¼7.4, 6.3 Hz, 1H), 4.16 (dsyst
,
AB
J¼16.9 Hz, 1H), 4.04 (dsyst AB, J¼16.9 Hz, 1H), 2.70 (m,
1H), 2.49 (m, 1H); 13C NMR (CDCl3, 75 MHz) d 196.9
(s), 140.5 (s), 134.3 (d), 132.3 (d), 128.8 (t), 128.4 (d, 2C),
127.9 (d), 126.7 (d, 2C), 117.1 (t), 82.4 (d), 72.5 (t), 42.2
ꢃ
(t); EIMS m/z (relative intensity) 216 (M+ , 1), 175
(MꢂC3H+5, 100), 173 (16), 131 (4), 105 (1), 91 (3), 77 (1),
69 (3).
5.12.4. 1-(1-Dimethylbut-3-enyloxy)but-3-en-2-one (26).
Yield: 49% from 20; colorless oil. In order to avoid polymer-
ization compound 26 has to be kept in solution (cw0.2 M in
Et2O or CH2Cl2). Rf: 0.70 (petroleum ether/EtOAc 80/20);
IR (neat): 2970, 2920, 1740, 1700, 1620, 1400, 1100,
915 cmꢂ1
;
1H NMR (CDCl3, 300 MHz) d 6.69 (dd,
J¼17.6, 10.7 Hz, 1H), 6.36 (dd, J¼17.6, 1.8 Hz, 1H),
5.93–5.77 (m, 2H), 5.11–5.03 (m, 2H), 4.14 (s, 2H), 2.30
(d, J¼7.2 Hz, 2H), 1.20 (s, 6H); 13C NMR (CDCl3,
75 MHz) d 198.2 (s), 134.0 (d), 132.2 (d), 128.7 (t), 117.6
(t), 75.9 (s), 67.1 (t), 44.9 (t), 24.9 (q, 2C); EIMS m/z (rela-
ꢃ
tive intensity) 168 (M+ , 1), 127 (100), 113 (8), 95 (2), 85 (8),
83 (56), 69 (99), 67 (11), 59 (8), 55 (92).
ꢃ
(M+ , 1), 125 (100), 99 (24), 83 (40), 70 (14), 69 (61), 67
(12), 55 (84).
5.12.5. 1-(1-Isopropylpent-4-enyloxy)but-3-en-2-one
(27). Yield: 54% from 21; colorless oil. In order to avoid
polymerization compound 27 has to be kept in solution
(c w0.2 M in Et2O or CH2Cl2). Rf : 0.60 (petroleum ether/
EtOAc 80/20); IR (neat) 3065, 2955, 2870, 1700, 1640,
5.12.1. 1-(1-Triphenylmethyloxymethylallyloxy)but-3-
en-2-one (23). Yield: 70% from 17; colorless oil. In order
to avoid polymerization compound 23 has to be kept in so-
lution (c w0.2 M in Et2O or CH2Cl2). Rf: 0.70 (petroleum
1610, 1465, 1400, 1105, 1065, 910 cmꢂ1
;
1H NMR
(CDCl3, 300 MHz) d 6.65 (dd, J¼17.6, 10.7 Hz, 1H), 6.35
1
ether/EtOAc 80/20); H NMR (CDCl3, 300 MHz) d 7.51–
(dd, J¼17.6, 1.5 Hz, 1H), 5.89–5.74 (m, 2H), 5.07–4.93
7.44 (m, 5H), 7.31–7.15 (m, 10H), 6.69 (dd, J¼17.3,
10.7 Hz, 1H), 6.33 (dd, J¼17.3, 1.5 Hz, 1H), 5.78–5.64
(m, 2H), 5.29–5.19 (m, 2H), 4.31 (dsyst AB, J¼16.7 Hz,
1H), 4.19 (dsyst AB, J¼16.7 Hz, 1H), 3.93 (m, 1H), 3.35
(dd, J¼9.9, 7.0 Hz, 1H), 3.17 (dd, J¼9.9, 7.0 Hz, 1H); 13C
NMR (CDCl3, 75 MHz) d 197.6 (s), 143.9 (s, 3C), 135.0
(m, 2H), 4.26 (dsyst AB, J¼16.5 Hz, 1H), 4.20 (dsyst AB
,
J¼16.5 Hz, 1H), 3.13 (apparent dt, J¼7.7, 4.4 Hz, 1H),
2.32–2.03 (m, 2H), 1.90 (m, 1H), 1.68–1.48 (m, 2H), 0.92
(d, J¼7.0 Hz, 3H), 0.91 (d, J¼7.0 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) d 197.4 (s), 138.4 (d), 132.3 (d), 128.7
(t), 114.5 (t), 85.1 (d), 74.2 (t), 30.2 (d), 29.7 (t), 29.1 (t),

4482
C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
18.0 (q), 17.5 (q); EIMS m/z (relative intensity) 153 (4), 141
(2), 135 (6), 127 (14), 111 (23), 107 (6), 95 (8), 83 (7), 71
(18), 70 (10), 69 (100), 67 (25), 55 (48).
silica gel (hexane/EtOAc 90/10) afforded 29 (5.98 g,
38.1 mmol, 95%) as a white solid; mp 36 ꢀC; Rf : 0.40
(hexane/EtOAc 90/10); IR (film) 3440, 3350, 2970, 1700,
1500, 1390, 1365, 1265, 1170, 740 cmꢂ1; 1H NMR (CDCl3,
300 MHz) d 5.84 (m, 1H), 5.22–5.07 (m, 2H), 4.74 (br s,
1H), 3.74 (m, 2H), 1.45 (s, 9H); 13C NMR (CDCl3,
75 MHz) d 155.6 (s), 134.8 (d), 115.4 (t), 79.1 (s), 42.9 (t),
28.2 (q, 3C).
5.12.6. 1-(Hex-5-enyloxy)but-3-en-2-one (56). To a stirred
suspension of NaH (1.2 g, 60% in oil, 30 mmol, 5.0 equiv),
washed with hexanes, in anhydrous THF (12.5 mL) at rt
was slowly added a solution of hex-6-en-1-ol 10 (0.9 g,
7.5 mmol, 1.25 equiv) in anhydrous THF (15 mL). After
30 min at rt, neat triphenylchloroacetonylphosphorane was
added in one portion. The reaction mixture was stirred at rt
for 14 h and then poured on ice and extracted with EtOAc
(3ꢁ20 mL). The combined organic extracts were dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. Purification by flash chromatography on silica gel
(EtOAc/EtOH 99/1 to 80/20) afforded 1-(hex-5-enyloxy)-3-
5.15. tert-Butyl but-3-enylcarbamate (30)35
To a suspension of homoallylamine hydrochloride salt14
(1.08 g, 10.0 mmol, 1 equiv) in anhydrous CH2Cl2
(50 mL), at 0 ꢀC, were added Et3N (4.2 mL, 30 mmol,
3 equiv) and then di-tert-butyldicarbonate (2.4 g, 11 mmol,
1.1 equiv) by small portions. After 15 min of stirring at
0 ꢀC, the reaction mixture was stirred for 60 h at rt and
then concentrated under reduced pressure. Purification by
flash chromatography on silica gel (petroleum ether/EtOAc
90/10 and then 80/20) afforded 30 (1.13 g, 6.60 mmol,
66%) as a colorless oil; Rf: 0.60 (hexane/EtOAc 70/30); IR
(neat): 3450, 3360, 2985, 1700, 1500, 1390, 1365, 1265,
(triphenyl-l5-phosphoranylidene)propan-2-one
(2.50 g,
6.05 mmol, 80%) as a beige solid; mp 84–86 ꢀC. The ob-
tained ylide was directly treated with aqueous formaldehyde
in Et2O following the general procedure. Purification by
flash chromatography (petroleum ether/Et2O 90/10) af-
forded 56 (656 mg, 3.90 mmol, 65%) as a colorless oil; Rf:
0.8 (petroleum ether/EtOAc 80/20); IR (neat) 2915,
1170, 920, 745, 735, 710 cmꢂ1
;
1H NMR (CDCl3,
2850, 1700, 1610, 1400, 1115 cmꢂ1
;
1H NMR (CDCl3,
300 MHz) d 5.70 (ddt, J¼17.4, 10.3, 6.9 Hz, 1H), 5.10–
4.95 (m, 2H), 4.65 (br s, 1H), 3.14 (m, 2H), 2.19 (apparent
q, J¼6.9 Hz, 2H), 1.39 (s, 9H); 13C NMR (CDCl3,
75 MHz) d 155.7 (s), 135.2 (d), 116.7 (t), 78.8 (s), 39.5 (t),
34.0 (t), 27.7 (q, 3C).
300 MHz) d 6.49 (dd, J¼17.7, 10.7 Hz, 1H), 6.25 (dd,
J¼17.7, 1.6 Hz, 1H), 5.78–5.63 (m, 2H), 4.95–4.82 (m,
2H), 4.13 (s, 2H), 3.41 (t, J¼6.6 Hz, 2H), 2.04–1.94 (m,
2H), 1.61–1.50 (m, 2H), 1.45–1.33 (m, 2H); 13C NMR
(CDCl3, 75 MHz) d 197.3 (s), 138.3 (d), 132.2 (d), 128.7
(t), 114.4 (t), 74.8 (t), 65.5 (t), 33.2 (t), 28.7 (t), 25.0 (t);
5.16. Benzyl but-3-enylcarbamate (31)36
ꢃ
EIMS m/z (relative intensity) 168 (M+ , 1), 95 (19), 86
(16), 83 (22), 71 (14), 70 (36), 69 (12), 67 (11), 55 (100).
To a suspension of homoallylamine hydrochloride salt14
(1.07 g, 10.0 mmol, 1 equiv) in anhydrous CH2Cl2
(100 mL) was added a solution of sodium carbonate
(3.29 g, 31.0 mmol, 3.1 equiv) in water (8 mL). The bi-
phasic mixture was cooled to 0 ꢀC and benzyl chloroformate
(2.3 mL, 16 mmol, 1.6 equiv) was added dropwise. After
15 min of stirring at 0 ꢀC, the reaction mixture was stirred
for 14 h at rt. The reaction mixture was diluted with
CH2Cl2 (100 mL) and water (50 mL) was added. The aque-
ous layer was extracted with CH2Cl2 (3ꢁ100 mL) and the
combined organic layers were washed with water, dried
over MgSO4, filtered, and concentrated under reduced pres-
sure. Purification by flash chromatography on silica gel (pe-
troleum ether/EtOAc 90/1) afforded 31 (1.46 g, 7.12 mmol,
71%) as a colorless oil; Rf: 0.70 (petroleum ether/EtOAc 80/
20); 1H NMR (CDCl3, 300 MHz) d 7.40–7.20 (m, 5H), 5.72
(m, 1H), 5.20–4.90 (m, 3H), 5.08 (s, 2H), 3.22 (m, 2H), 2.23
(m, 2H); 13C NMR (CDCl3, 75 MHz) d 156.3 (s), 136.6 (s),
135.0 (d), 128.3 (d, 3C), 127.9 (d, 2C), 117.0 (t), 66.4 (t),
40.0 (t), 34.0 (t).
5.13. N-(Prop-2-enyl)-4-methylbenzenesulfonamide
(28)33
To a solution of allylamine (0.5 g, 8.8 mmol, 1 equiv) in an-
hydrous CH2Cl2 (10 mL), at 0 ꢀC, were added successively
Et3N (1.6 mL, 12 mmol, 1.36 equiv) and tosyl chloride
(2.00 g, 10.6 mmol, 1.2 equiv). After stirring for 4 h at
0 ꢀC, the reaction mixture was hydrolyzed with water
(10 mL) and extracted with CH2Cl2 (3ꢁ15 mL). The com-
bined organic layers were washed with water, dried over
Na2SO4, filtered, and concentrated under reduced pressure.
The crude solid was purified by recrystallization (hexane/
Et2O 50/50) to afford 28 (1.76 g, 8.36 mmol, 95%) as
a pale yellow solid. Physical and spectral data match those
1
previously reported.33 Mp 60 ꢀC (lit.:33 mp 59–61 ꢀC); H
NMR (CDCl3, 300 MHz) d 7.80–7.73 (m, 2H), 7.36–7.29
(m, 2H), 5.73 (ddt, J¼16.2, 10.3, 5.9 Hz, 1H), 5.22–5.06
(m, 2H), 4.65 (br t, J¼5.9 Hz, 1H), 3.59 (m, 2H), 2.44 (s,
ꢃ
3H); EIMS m/z (relative intensity) 211 (M+ , 4), 155 (32),
147 (12), 92 (22), 91 (100), 65 (22), 56 (41).
5.17. N-Benzyl-N-(but-3-enyl)amine (32)37
5.14. tert-Butyl allylcarbamate (29)34
To a solution of benzylamine (7.71 mL, 70.6 mmol, 5 equiv)
and 4-bromobut-1-ene (1.44 mL, 14.2 mmol, 1 equiv) in
EtOH (20 mL), degassed by argon bubbling for 20 min, so-
dium iodide (ca. 80 mg) was added. The reaction mixture
was heated at 75 ꢀC for 4 h. After cooling to rt, the reaction
mixture was diluted with CH2Cl2 (200 mL) and an aqueous
solution of KOH (1 M, 200 mL) was added. The aqueous
layer was extracted with CH2Cl2 (3ꢁ70 mL) and the com-
bined organic layers were dried over K2CO3, filtered, and
To a solution of allylamine (2.28 g, 40.0 mmol, 1 equiv) in
anhydrous CH2Cl2 (200 mL), at rt, was added Et3N
(11.1 mL, 80 mmol, 2 equiv). The solution was cooled to
0 ꢀC and di-tert-butyldicarbonate (9.6 g, 44 mmol,
1.1 equiv) was added by small portions. After stirring for
21 h at rt, the reaction mixture was concentrated under re-
duced pressure. Purification by flash chromatography on

C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
4483
concentrated under reduced pressure. Purification by flash
chromatography on silica gel (hexanes/EtOAc/Et3N 100/
10/02) allowed to isolate 32 (2.08 g, 12.09 mmol, 91%) as
a colorless oil; Rf : 0.20 (hexane/EtOAc/Et3N 100/10/02);
1H NMR (CDCl3, 300 MHz) d 7.36–7.20 (m, 5H), 5.79
(ddt, J¼17.3, 10.3, 7.0 Hz, 1H), 5.13–5.01 (m, 2H), 3.79
(s, 2H), 2.70 (t, J¼7.0 Hz, 2H), 2.28 (qt, J¼7.0, 1.1 Hz,
2H), 1.50 (br s, 1H); 13C NMR (CDCl3, 75 MHz) d 140.3
(s), 136.3 (d), 128.2 (d, 2C), 128.0 (d, 2C), 126.7 (d),
116.2 (t), 53.7 (t), 48.2 (t), 34.2 (t); EIMS m/z (relative inten-
a solution of n-BuLi (0.28 mL, 2.5 M in hexanes,
0.7 mmol, 1.1 equiv). The reaction mixture was stirred for
10 min at rt and neat triphenylchloroacetonylphosphorane
(0.225 g, 0.64 mmol, 1 equiv) was added at once. After stir-
ring at rt for 5 h, the reaction mixture was poured into water
(5 mL). The aqueous layer was extracted with EtOAc
(3ꢁ10 mL) and the combined organic layers were washed
with water, dried over MgSO4, filtered, and concentrated un-
der reduced pressure. Purification by flash chromatography
on silica gel (EtOAc and then EtOAc/EtOH 90/10) allowed
to isolate phosphorane 34 (285 mg, 0.54 mmol, 85%) as
ꢃ
sity) 161 (M+ , 1), 120 (54), 91 (100), 65 (8).
1
a viscous yellow oil; Rf: 0.25 (EtOAc); H NMR (CDCl3,
5.18. 4-Methyl-N-(1-phenylbut-3-enyl)benzenesulfon-
amide (33)39
300 MHz) d 7.77–7.42 (m, 17H), 7.24–7.18 (m, 2H), 5.72
(ddt, J¼16.5, 9.9, 6.5 Hz, 1H), 5.15 (dd, J¼16.5, 1.3 Hz,
1H), 5.09 (m, 1H), 4.13 (br s, 1H), 3.99 (d, J¼6.5 Hz, 2H),
3.80 (s, 2H), 2.38 (s, 3H); 13C NMR (CDCl3, 75 MHz)
A solution of benzaldehyde (5.1 mL, 50 mmol, 1 equiv),
p-TSA (8.55 g, 50 mmol, 1 equiv), and sodium p-toluene
sulfinate (8.9 g, 50 mmol, 1 equiv)in amixtureofformicacid
(75 mL) and water (75 mL) was stirred for 12 h at rt. The re-
sulting white precipitate was filtered, rinsed with water (2ꢁ
50 mL) and pentane (50 mL), and then dissolved in CH2Cl2
(500 mL). To this solution was added a saturated aqueous
NaHCO3 solution (350 mL) and the resulting biphasic mix-
ture was stirred for 2 h at rt. The aqueous layer was then ex-
tracted with CH2Cl2 (2ꢁ200 mL) and the combined organic
layers were dried over MgSO4, filtered, and concentrated
under reduced pressure to afford N-benzylidene-4-methyl-
benzenesulfonamide (7.70 g, 29.7 mmol, 59%) as white
crystals, which can be recrystallized in a 1/1 mixture of
CH2Cl2 and petroleum ether. Physical and spectral data of
the obtained tosyl imine match those previously reported.35
Mp 107–108 ꢀC (lit.:38b mp 116 ꢀC, lit.:38a mp 104 ꢀC).
3
d 187.0 (s), 142.7 (s), 137.2 (s), 133.0 (d, JC–P¼10.3 Hz,
6C), 132.2 (d), 132.0 (d, 4JC–P¼2.9 Hz, 3C), 129.3 (d, 2C),
128.7 (d, 2JC–P¼12.2 Hz, 6C), 127.3 (d, 2C), 126.6 (s, 1JC–P
¼
90.6 Hz, 3C), 118.8 (t), 54.3 (t, 3JC–P¼14.9 Hz), 51.6 (t), 51.3
(d), 21.3 (q); EIMS m/z (relative intensity) 479 (1), 279 (7),
278 (43), 277 (100), 201 (17), 199 (19), 183 (17), 152 (10),
77 (10).
5.19.1. tert-Butyl allyl[2-oxo-3-(triphenyl-l5-phosphor-
anylidene)propyl]carbamate (35). Yield: 80% from 29;
viscous yellow oil; Rf : 0.20 (EtOAc); IR (neat) 3050, 2990,
1
1680, 1420, 1160, 900 cmꢂ1; H NMR (CDCl3, 300 MHz)
d 7.69–7.41 (m, 15H), 5.84 (m, 1H), 5.22–5.04 (m, 2H),
4.06–3.74 (m, 2H), 3.97 (d, JH–P¼25.8 Hz, 1H), 3.81 (s,
2
2H), 1.44 (s, 9H); 13C NMR (CDCl3, 75 MHz) d 189.1 (s),
3
155.7 (s), 133.8 (d), 132.9 (d, JC–P¼10.1 Hz, 6C), 131.9
2
1
(d, 3C), 128.7 (d, JC–P¼12.2 Hz, 6C), 126.8 (s, JC–P
¼
3
To a solution of N-benzylidene-4-methylbenzenesulfona-
mide (0.26 g, 1.0 mmol, 1 equiv), in THF (3 mL), cooled
at ꢂ15 ꢀC was added allylmagnesium chloride (0.75 mL,
2 M in THF, 1.5 mmol, 1.5 equiv). The reaction mixture
was stirred for 5 h at ꢂ15 ꢀC and quenched by addition of
an aqueous saturated NH4Cl solution (7 mL). The aqueous
layer was extracted with EtOAc (3ꢁ10 mL) and the com-
bined organic layers were washed with brine (10 mL), dried
over MgSO4, filtered, and concentrated under reduced
pressure. Purification by flash chromatography on silica
gel (petroleum ether/Et2O 60/40) afforded 33 (282 mg,
0.940 mmol, 94%) as white crystals; mp 77–78 ꢀC (lit.:39
mp 78 ꢀC); Rf: 0.70 (petroleum ether/Et2O 20/80); IR
(CHBr3) 3250, 2900, 1640, 1600, 1495, 1455, 1320, 1290,
90.5 Hz, 3C), 116.4 (t), 79.2 (s), 54.4 (t, JC–P¼13.5 Hz),
50.2 (t), 48.7 (d, 1JC–P¼109.1 Hz), 28.3 (q, 3C).
5.19.2. tert-Butyl but-3-enyl[2-oxo-3-(triphenyl-l5-phos-
phoranylidene)propyl]carbamate (36). Yield: 74% from
30; viscous yellow oil; Rf: 0.10 (EtOAc); IR (neat) 3050,
2970, 2930, 1680, 1530, 1480, 1440, 1385, 1240, 1170,
1
1105, 755, 720, 700 cmꢂ1; H NMR (CDCl3, 300 MHz)
d (rotamers) 7.59–7.24 (m, 15H), 5.65 (m, 1H), 4.98–4.81
(m, 2H), 3.89–3.64 (m, 3H), 3.32 (m, 2H), 2.23 (m, 2H),
1.35 and 1.32 (2s, 9H); 13C NMR (CDCl3, 75 MHz) d (ro-
tamers) 189.0 and 188.8 (s), 155.6 (s), 135.5 and 135.3
3
(d), 132.8 (d, JC–P¼10.1 Hz, 6C), 131.9 (d, 3C), 128.6 (d,
1
2JC–P¼12.1 Hz, 6C), 126.6 (s, JC–P¼90.6 Hz, 3C), 116.0
1160, 1090, 1060 cmꢂ1
;
1H NMR (CDCl3, 300 MHz)
(t), 78.9 (s), 55.3 and 54.8 (t, JC–P¼13.7 Hz), 48.8 (d,
3
d 7.61–7.55 (m, 2H), 7.19–7.06 (m, 7H), 5.53 (m, 1H),
5.44 (d, J¼7.0 Hz, 1H), 5.08–5.00 (m, 2H), 4.39 (dt,
J¼7.0, 7.0 Hz, 1H), 2.58–2.39 (m, 2H), 2.37 (s, 3H); 13C
NMR (CDCl3, 75 MHz) d 142.9 (s), 140.3 (s), 137.5 (s),
133.1 (d), 129.2 (d, 2C), 128.2 (d, 2C), 127.1 (d), 127.0 (d,
2C), 126.5 (d, 2C), 118.9 (t), 57.2 (d), 41.7 (t), 21.3 (q);
EIMS m/z (relative intensity) 262 (6), 261 (18), 260
(MꢂC3H+5, 100), 156 (5), 155 (54), 104 (7), 91 (60), 65 (8).
1JC–P¼109.1 Hz), 47.5 (t), 32.8 and 32.3 (t), 28.2 (q, 3C).
5.19.3. Benzyl but-3-enyl[2-oxo-3-(triphenyl-l5-phos-
phoranylidene)propyl]carbamate (37). Yield: 90% from
31; viscous colorless oil; Rf: 0.25 (EtOAc); IR (neat) 2970,
2930, 1690, 1540, 1435, 1385, 1225, 1105, 735, 695 cmꢂ1
;
1H NMR (CDCl3, 300 MHz) d (rotamers) 7.70–7.10 (m,
20H), 5.77 (m, 1H), 5.29 and 5.16 (2s, 2H), 5.20–4.94 (m,
2
2H), 4.02 and 3.93 (2s, 2H), 3.77 (d, JH–P¼24.3 Hz, 1H),
5.19. N-Allyl-4-methyl-N-[2-oxo-3-(triphenyl-l5-phos-
phoranylidene)propyl]benzenesulfonamide (34).
Typical procedure
3.49 (m, 2H), 2.36 (m, 2H); 13C NMR (CDCl3, 75 MHz)
d (rotamers) 188.5 and 188.3 (s), 156.3 (s), 137.0 (s),
3
4
135.4 (d), 132.9 (d, JC–P¼10.3 Hz, 6C), 132.0 (d, JC–P
¼
2
2.8 Hz, 3C), 128.9 and 128.7 (d, 2C), 128.7 (d, JC–P
12.4 Hz, 6C), 128.2 and 128.1 (d, 2C), 127.5 and 127.4
(d), 126.6 (s, JC–P¼91.0 Hz, 3C), 116.5 and 116.4 (t),
¼
To a solution of protected allylamine 28 (0.15 g, 0.7 mmol,
1.1 equiv) in anhydrous THF (3 mL) was added dropwise
1

4484
C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
66.7 (t), 55.0 (t, 3JC–P¼14.6 Hz), 49.4 (d, 1JC–P¼108.5 Hz),
stirred for 3 h at rt. After concentration of the reaction mix-
ture under reduced pressure, purification of the crude mate-
rial by flash chromatography on silica gel allowed to isolate
the corresponding azadiene.
48.1 (t), 32.7 and 32.3 (t).
5.19.4. 4-Methyl-N-[2-oxo-3-(triphenyl-l5-phosphoranyl-
idene)propyl]-N-(1-phenylbut-3-enyl)benzenesulfon-
amide (39). Yield: 57% from 33; viscous yellow oil; Rf : 0.30
(EtOAc); 1H NMR (CDCl3, 300 MHz) d 7.76–7.03 (m, 24H),
5.50 (ddt, J¼17.1, 10.3, 6.8 Hz, 1H), 5.07 (dd, J¼10.3,
5.3 Hz, 1H), 4.90 (dd, J¼17.1, 1.8 Hz, 1H), 4.84 (br d,
J¼10.3 Hz, 1H), 3.86 (dsyst AB, J¼17.6 Hz, 1H), 3.78
5.21.1. N-Allyl-4-methyl-N-(2-oxobut-3-enyl)benzene
sulfonamide (40). Yield: 42% from 34, following the gen-
eral procedure with formaldehyde; colorless oil. In order
to avoid polymerization compound 40 has to be kept in so-
lution (c w0.2 M in Et2O or CH2Cl2). Rf: 0.40 (petroleum
2
1
(dsyst AB, J¼17.6 Hz, 1H), 3.72 (br d, JH–P¼24.0 Hz, 1H),
ether/EtOAc 80/20); H NMR (CDCl3, 300 MHz) d 7.76–
2.84 (m, 1H), 2.49 (m, 1H), 2.34 (s, 3H); 13C NMR
(CDCl3, 75 MHz) d 187.9 (s), 142.7 (s), 138.1 (s), 137.9 (s),
7.70 (m, 2H), 7.35–7.29 (m, 2H), 6.51 (dd, J¼17.6,
10.7 Hz, 1H), 6.32 (dd, J¼17.6, 1.3 Hz, 1H), 5.86 (dd,
J¼10.7, 1.3 Hz, 1H), 5.66 (ddt, J¼16.9, 9.9, 6.6 Hz, 1H),
5.19–5.13 (m, 2H), 4.19 (s, 2H), 3.84 (br d, J¼6.6 Hz,
2H), 2.45 (s, 3H); 13C NMR (CDCl3, 75 MHz) d 194.4 (s),
143.4 (s), 136.4 (s), 132.8 (d), 132.0 (d), 129.5 (d, 2C),
129.4 (t), 127.3 (d, 2C), 120.0 (t), 53.3 (t), 51.0 (t), 21.4 (q).
3
4
134.5 (d), 133.0 (d, JC–P¼10.2 Hz, 6C), 131.9 (d, JC–P
¼
2
2.2 Hz, 3C), 129.2 (d, 2C), 128.9 (d, 2C), 128.6 (d, JC–P
12.1 Hz, 6C), 128.3 (d), 127.5 (d, 2C), 127.1 (d, 2C), 126.1
¼
1
3
(s, JC–P¼91.1 Hz, 3C), 117.1 (t), 61.2 (d), 51.7 (t, JC–P
¼
14.8 Hz), 51.2 (d, 1JC–P¼103.8 Hz), 35.6 (t), 21.3 (q).
5.20. 1-(Benzyl but-3-enylamino)-3-(triphenyl-l5-phos-
phoranylidene)propan-2-one (38)
5.21.2. tert-Butyl allyl(2-oxobut-3-enyl)carbamate (41).
Yield: 74% from 35, following the general procedure with
formaldehyde; colorless oil. In order to avoid polymeriza-
tion compound 41 has to be kept in solution (c w0.2 M in
Et2O or CH2Cl2). Rf: 0.40 (petroleum ether/Et2O 80/20);
To a solution of protected homoallylamine 32 (0.5 g,
3.1 mmol, 1.1 equiv) in CH3CN (30 mL) at rt, were added
Et3N (0.87 mL, 6.2 mmol, 2 equiv), triphenylchloroaceto-
nylphosphorane (1.0 g, 2.8 mmol, 1 equiv), and n-Bu4NI
(0.57 g, 1.5 mmol, 0.5 equiv). The reaction mixture was
stirred at rt for 36 h and then heated at 50 ꢀC for 7 h. After
cooling to rt, the reaction mixture was hydrolyzed with a sat-
urated aqueous NH4Cl solution (20 mL) and extracted with
EtOAc (3ꢁ60 mL). The combined organic extracts were
dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification by flash chromatography on silica gel
(EtOAc/MeOH 98/2) afforded the phosphorane 38 (0.884 g,
1.85 mmol, 60%) as a viscous yellow oil; Rf: 0.30 (EtOAc/
MeOH 98/2); IR (neat) 2920, 1730, 1520, 1435, 1390, 1140,
IR (neat) 3050, 1685, 1420, 1265, 740, 705 cmꢂ1 1H
;
NMR (CDCl3, 300 MHz) d (rotamers) 6.41 and 6.40 (2dd,
J¼17.6, 10.3 Hz, 1H), 6.28 (dd, J¼17.6, 1.5 Hz, 1H), 5.83
(dd, J¼10.3, 1.5 Hz, 1H), 5.75 (m, 1H), 5.17–5.04 (m,
2H), 4.20 and 4.06 (2s, 2H), 3.93 and 3.84 (2d, J¼5.7 Hz,
2H), 1.44 and 1.38 (2s, 9H); 13C NMR (CDCl3, 75 MHz)
d (rotamers) 195.3 (s), 155.5 and 155.0 (s), 133.6 and
133.5 (d), 133.2 (d), 128.7 and 128.6 (t), 117.4 and 116.6
(t), 80.2 (s), 53.7 and 53.3 (t), 50.5 and 50.3 (t), 28.1
and 28.0 (q, 3C); EIMS m/z (relative intensity) 171 (3),
170 (28), 169 (11), 152 (9), 114 (19), 70 (69), 57 (t-Bu+,
100).
1
1105, 745, 720, 690, 660, 650 cmꢂ1; H NMR (CDCl3,
300 MHz) d 7.71–7.26 (m, 20H), 5.79 (ddt, J¼17.3, 10.3,
5.21.3. tert-Butyl but-3-enyl(2-oxopent-3-enyl)carbamate
(42). Yield: 87% from 36, following the general procedure
with acetaldehyde; yellow oil; Rf: 0.55 (petroleum ether/
EtOAc 70/30); IR (neat) 2975, 2929, 1689, 1639, 1422,
7.0 Hz, 1H), 4.99 (dd, J¼17.3, 1.8 Hz, 1H), 4.90 (br d,
2
J¼10.3 Hz, 1H), 4.44 (br d, JH–P¼25.7 Hz, 1H), 3.78 (s,
2H), 3.18 (s, 2H), 2.66 (t, J¼7.0 Hz, 2H), 2.31 (apparent
q, J¼7.0 Hz, 2H); 13C NMR (CDCl3, 75 MHz) d 191.5 (s),
1397, 1365, 1241, 1168, 969, 913, 888, 772 cmꢂ1 1H
;
3
139.8 (s), 137.1 (d), 132.9 (d, JC–P¼10.2 Hz, 6C), 131.9
NMR (CDCl3, 400 MHz) d (rotamers) 6.95 (dq, J¼14.6,
7.0 Hz, 1H), 6.19 (m, 1H), 5.76 (m, 1H), 5.05 (m, 2H),
4.16 and 4.03 (2s, 2H), 3.34 and 3.28 (2t, J¼7.0 Hz, 2H),
2.27 (m, 2H), 1.91 (apparent t, J¼6.0 Hz, 3H), 1.48 and
1.39 (2s, 9H); 13C NMR (CDCl3, 100 MHz) d (rotamers)
195.3 and 195.2 (s), 155.8 and 155.2 (s), 143.7 and 143.5
(d), 135.4 (d), 128.8 and 128.3 (d), 116.6 (t), 80.0 (s), 55.6
and 54.8 (t), 48.0 (t), 33.0 and 32.7 (t), 28.3 and 28.2 (q,
3C), 18.4 (q); EIMS m/z (relative intensity) 212
(MꢂC3H+5, 8), 184 (12), 128 (20), 112 (32), 84 (64), 69
(32), 57 (100), 56 (13), 55 (17).
4
2
(d, JC–P¼2.6 Hz, 3C), 128.7 (d, JC–P¼11.9 Hz, 6C),
128.4 (d, 2C), 128.0 (d, 2C), 127.0 (s, 1JC–P¼90.6 Hz, 3C),
3
126.6 (d), 115.1 (t), 63.0 (t, JC–P¼13.5 Hz), 59.0 (t), 53.7
(t), 50.8 (d, 1JC–P¼108.5 Hz), 31.7 (t).
5.21. Formation of azadienes by Wittig reaction; general
procedure
With formaldehyde. To a solution of ylide (1 equiv) in anhy-
drous Et2O (c 6–40 mmol Lꢂ1) at rt was added a solution of
formaldehyde (37% in water, 100 equiv). The biphasic reac-
tion mixture was stirred for 3 h at rt. The aqueous layer was
extracted with Et2O and the combined organic layers were
dried over MgSO4, filtered, and concentrated under reduced
pressure. Purification by flash chromatography on silica gel
allowed to isolate the corresponding azadiene.
5.21.4. Benzyl but-3-enyl(2-oxopent-3-enyl)carbamate
(43). Yield: 85% from 37, following the general procedure
with acetaldehyde; colorless oil; Rf: 0.35 (petroleum ether/
Et2O 70/30); IR (neat) 2920, 1705, 1690, 1640, 1470,
1440, 1425, 1225 cmꢂ1; 1H NMR (CDCl3, 300 MHz) d (ro-
tamers) 7.39–7.23 (m, 5H), 6.93 (m, 1H), 6.16 (m, 1H), 5.74
(m, 1H), 5.17 and 5.09 (2s, 2H), 5.07–4.96 (m, 2H), 4.23 and
4.15 (2s, 2H), 3.38 (m, 2H), 2.29 (m, 2H), 1.90 and 1.87
(2dd, J¼7.0, 1.5 Hz, 3H); 13C NMR (CDCl3, 75 MHz)
With acetaldehyde. To a solution of ylide (1 equiv) in anhy-
drous THF (c 0.1–0.2 mol Lꢂ1) at rt was added freshly dis-
tilled acetaldehyde (10 equiv). The reaction mixture was

C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
4485
d (rotamers) 194.5 and 194.4 (s), 156.3 and 155.8 (s), 143.9
(d), 136.5 and 136.4 (s), 135.0 and 134.9 (d), 128.6 (d), 128.3
and 128.2 (d, 2C), 127.8 and 127.7 (d), 127.6 (d, 2C), 116.8
and 116.7 (t), 67.2 and 67.1 (t), 55.0 and 54.9 (t), 48.3 and
47.6 (t), 32.8 and 32.3 (t), 18.3 (q); EIMS m/z (relative inten-
(6), 68 (100), 53 (2); HRMS (CI+, CH4) calcd for C5H7O2
(M+H+) 99.0446. Found 99.0441.
5.22.2. 6-Isopropyl-6H-pyran-3-one (47). Yield: 87% from
22; colorless oil; Rf: 0.60 (petroleum ether/EtOAc 80/20); IR
(neat) 2960, 2930, 2870, 2810, 1695, 1465, 1385, 1260,
ꢃ
sity) 287 (M+ , 1), 246 (11), 202 (15), 174 (17), 91 (100), 69
1
(11).
1160, 1100 cmꢂ1; H NMR (CDCl3, 300 MHz) d 6.99 (dd,
J¼10.7, 1.8 Hz, 1H), 6.12 (dd, J¼10.7, 2.4 Hz, 1H), 4.22
(dsyst AB, J¼16.2 Hz, 1H), 4.08–3.99 (m, 2H), 1.95 (m,
1H), 0.97 (d, J¼6.8 Hz, 3H), 0.95 (d, J¼6.8 Hz, 3H); 13C
NMR (CDCl3, 75 MHz) d 195.0 (s), 150.7 (d), 127.3 (d),
78.1 (d), 71.4 (t), 32.0 (d), 18.1 (q), 17.4 (q); EIMS m/z (rel-
5.21.5. 1-(Benzylbut-3-enylamino)pent-3-en-2-one (44).
Yield: 53% from 38, following the general procedure with
acetaldehyde; bright yellow oil; Rf: 0.30 (petroleum ether/
Et2O 70/30); IR (neat): 2920, 1670, 1450, 1375,
ꢃ
1
705 cmꢂ1; H NMR (CDCl3, 300 MHz) d 7.35–7.20 (m,
ative intensity) 140 (M+ , 29), 110 (45), 98 (100), 97 (59), 95
5H), 6.91 (dq, J¼15.6, 6.6 Hz, 1H), 6.37 (dq, J¼15.6,
1.6 Hz, 1H), 5.78 (ddt, J¼16.9, 10.3, 7.0 Hz, 1H), 5.09–
4.95 (m, 2H), 3.66 (s, 2H), 3.31 (s, 2H), 2.61 (m, 2H),
2.26 (m, 2H), 1.86 (dd, J¼6.6, 1.6 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) d 199.0 (s), 142.7 (d), 138.6 (s), 136.5
(d), 129.0 (d), 128.9 (d, 2C), 128.1 (d, 2C), 127.0 (d),
115.5 (t), 62.1 (t), 58.6 (t), 53.8 (t), 31.6 (t), 18.1 (q);
(93), 70 (35), 69 (24), 68 (10), 67 (40), 65 (10), 55 (31);
HRMS (CI+, CH4) calcd for C8H13O2 (M+H+) 141.0916.
Found 141.0911.
5.22.3. 6-Triphenylmethyloxymethyl-6H-pyran-3-one
(48). Yield: 68% from 23; wax; Rf: 0.70 (petroleum ether/
EtOAc 80/20); IR (neat) 3050, 2920, 2870, 1695, 1490,
ꢃ
EIMS m/z (relative intensity) 243 (M+ , 1), 202 (9), 175
1450, 1265, 1160, 1105 cmꢂ1 1H NMR (CDCl3,
;
(11), 174 (79), 91 (100), 65 (7).
300 MHz) d 7.48–7.42 (m, 5H), 7.33–7.19 (m, 10H), 7.02
(dd, J¼10.5, 1.8 Hz, 1H), 6.16 (dd, J¼10.5, 2.2 Hz, 1H),
4.44 (m, 1H), 4.31 (dsyst AB, J¼16.5 Hz, 1H), 4.10 (dd,
J¼16.5, 1.8 Hz, 1H), 3.41 (dd, J¼9.9, 5.7 Hz, 1H), 3.26
(dd, J¼9.9, 5.7 Hz, 1H); 13C NMR (CDCl3, 75 MHz)
d 194.5 (s), 149.3 (d), 143.5 (s, 3C), 128.5 (d, 6C), 127.8
(d, 6C), 127.2 (d), 127.1 (d, 3C), 86.7 (s), 73.1 (d), 71.2
(t), 64.5 (t); EIMS m/z (relative intensity) 244 (23), 243
(100), 166 (5), 165 (32), 105 (7), 77 (4); HRMS (ESI) calcd
for C25H22NaO3 (M+Na+) 393.14612. Found 393.14636.
5.21.6. 4-Methyl-N-(2-oxobut-3-enyl)-N-(1-phenylbut-3-
enyl)benzene sulfonamide (45). Yield: 62% from 39, fol-
lowing the general procedure with formaldehyde; colorless
oil. In order to avoid polymerization compound 45 has to
be kept in solution (cw0.2 M in Et2O or CH2Cl2). Rf: 0.45
(petroleum ether/Et2O 60/40); IR (neat) 3050, 2980, 2920,
1700, 1425, 1345, 1270, 1150, 1095, 750, 735, 710 cmꢂ1
;
1H NMR (CDCl3, 300 MHz) d 7.82–7.78 (m, 2H), 7.37–
7.17 (m, 7H), 6.34 (dd, J¼17.3, 10.3 Hz, 1H), 6.11 (dd,
J¼17.3, 1.5 Hz, 1H), 5.61 (dd, J¼10.3, 1.5 Hz, 1H), 5.50
(ddt, 1H, J¼16.9, 10.3, 6.8 Hz, 1H), 5.03 (dd, J¼10.3,
5.5 Hz, 1H), 4.99–4.85 (m, 2H), 4.09 (dsyst AB, J¼18.0 Hz,
1H), 3.88 (dsyst AB, J¼18.0 Hz, 1H), 2.65 (m, 1H), 2.46 (s,
3H), 2.40 (m, 1H); 13C NMR (CDCl3, 75 MHz) d 195.5
(s), 143.5 (s), 137.3 (s), 136.6 (s), 133.8 (d), 131.9 (d),
129.5 (d, 2C), 128.6 (d, 2C), 128.5 (t), 128.1 (d), 127.6 (d,
2C), 124.4 (d, 2C), 117.6 (t), 60.5 (d), 51.4 (t), 34.9 (t),
5.22.4. 6,7-Dihydrooxepin-3-one (49).41 Yield: 58% from
8; yellow oil; Rf: 0.35 (petroleum ether/EtOAc 80/20); IR
(neat) 3020, 2920, 2860, 1655, 1265, 1140 cmꢂ1; 1H NMR
(CDCl3, 300 MHz) d 6.56 (dt, J¼12.5, 4.4 Hz, 1H), 6.03
(dt, J¼12.5, 1.8 Hz, 1H), 4.29 (s, 2H), 3.92 (t, J¼5.5 Hz,
2H), 2.71–2.64 (m, 2H); 13C NMR (CDCl3, 75 MHz)
d 204.1 (s), 144.9 (d), 130.2 (d), 78.8 (t), 69.5 (t), 35.0 (t);
ꢃ
EIMS m/z (relative intensity) 112 (M+ , 30), 85 (20), 84
ꢃ
21.4 (q); EIMS m/z (relative intensity) 369 (M+ , 1), 329
(14), 328 (68), 314 (21), 184 (10), 155 (35), 132 (12), 131
(100), 91 (68).
(64), 82 (48), 81 (53), 69 (13), 56 (17), 55 (33), 54 (100),
53 (49), 51 (11); HRMS (CI+, CH4) calcd for C6H9O2
(M+H+) 113.0603. Found 113.0598.
5.22. General procedure for the RCM reaction applied
to a-alkoxy enones
5.22.5. 7-Isopropyl-6,7-dihydrooxepin-3-one (50). Yield:
90% from 24; colorless oil; Rf: 0.30 (petroleum ether/Et2O
80/20); IR (neat): 2960, 2870, 1665, 1630, 1395, 1345,
1
To a solution of diene (1 equiv) in anhydrous CH2Cl2
(c 2ꢁ10ꢂ2 to 5ꢁ10ꢂ3 mol Lꢂ1), degassed by argon bubbling
for 20 min, Grubbs catalyst [Ru]-II15b (0.025–0.15 equiv)
was added. The reaction mixture was heated at 40 ꢀC for
12 h. After cooling to rt and concentration under reduced
pressure, the crude residue was purified by flash chromato-
graphy on silica gel.
1275, 1125 cmꢂ1; H NMR (CDCl3, 300 MHz) d 6.54 (dt,
J¼12.3, 4.4 Hz, 1H), 6.00 (d, J¼12.3, 1.8 Hz, 1H), 4.41
(dsyst AB, J¼18.4 Hz, 1H), 4.15 (dsyst AB, J¼18.4 Hz, 1H),
3.31 (apparent q, J¼6.3 Hz, 1H), 2.61–2.54 (m, 2H), 1.74
(m, 1H), 0.97 (d, J¼6.8 Hz, 3H), 0.93 (d, J¼6.8 Hz, 3H);
13C NMR (CDCl3, 75 MHz) d 204.7 (s), 145.3 (d), 129.5
(d), 84.7 (d), 78.1 (t), 37.5 (t), 33.2 (d), 18.5 (q), 17.7 (q);
ꢃ
EIMS m/z (relative intensity) 154 (M+ , 10), 111 (41), 95
5.22.1. 6H-Pyran-3-one (46).40 Yield: 69% from 7; color-
less oil; Rf: 0.30 (petroleum ether/EtOAc 80/20); IR (neat)
2930, 2850, 1710, 1680, 1440, 1390, 1265, 1160, 1095,
(14), 94 (20), 86 (11), 85 (21), 83 (100), 82 (82), 81 (94),
79 (11), 71 (11), 70 (12), 69 (21), 68 (79), 67 (11), 55
(43), 54 (25), 53 (47); HRMS (CI+, CH4) calcd for
C9H15O2 (M+H+) 155.1072. Found 155.1068.
970 cmꢂ1
;
1H NMR (CDCl3, 300 MHz) d 7.12 (dt,
J¼10.5, 2.9 Hz, 1H), 6.19 (dt, J¼10.5, 1.8 Hz, 1H), 4.39
(apparent t, J¼2.6 Hz, 2H), 4.18 (s, 2H); 13C NMR
(CDCl3, 75 MHz) d 194.3 (s), 152.8 (d), 126.8 (d), 72.1
5.22.6. 7-Phenyl-6,7-dihydrooxepin-3-one (51). Yield:
93% from 25; white solid; mp 126–128 ꢀC; Rf: 0.60 (petro-
leum ether/EtOAc 80/20); IR (CHBr3) 3020, 2880, 1665,
ꢃ
(t), 64.4 (t); EIMS m/z (relative intensity) 98 (M+ , 37), 69

4486
C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
1630, 1395, 1345, 1275, 1125 cmꢂ1
;
1H NMR (CDCl3,
J¼16.5 Hz, 2H), 3.98 (dsyst AB, J¼16.5 Hz, 2H), 3.05–2.96
300 MHz) d 7.42–7.24 (m, 5H), 6.57 (ddd, J¼12.5, 4.8,
(m, 2H), 2.64–2.48 (m, 2H), 2.37–2.25 (m, 2H), 2.00–1.86
(m, 2H), 1.80–1.58 (m, 4H), 0.88 (d, J¼6.6 Hz, 6H), 0.83
(d, J¼6.6 Hz, 6H); 13C NMR (CDCl3, 75 MHz) d 197.9 (s,
2C), 194.2 (d, 2C), 126.2 (d, 2C), 84.8 (d, 2C), 74.3 (t,
2C), 29.8 (d, 2C), 28.6 (t, 2C), 28.0 (t, 2C), 18.7 (q, 2C),
4.4 Hz, 1H), 6.11 (d, J¼12.5 Hz, 1H), 4.69 (dd, J¼8.1,
4.8 Hz, 1H), 4.50 (dsyst AB, J¼18.4 Hz, 1H), 4.32 (dsyst AB
,
J¼16.9 Hz, 1H), 2.87–2.80 (m, 2H); 13C NMR (CDCl3,
75 MHz) d 203.9 (s), 144.3 (d), 141.6 (s), 130.3 (d), 128.5
(d, 2C), 127.8 (d), 125.4 (d, 2C), 81.2 (d), 77.5 (t), 42.0
ꢃ
16.5 (q, 2C); EIMS m/z (relative intensity) 336 (M+ , 45),
ꢃ
(t); EIMS m/z (relative intensity) 188 (M+ , 8), 157 (2),
294 (18), 293 (100), 275 (34), 189 (15), 161 (12), 147
(12), 135 (11), 133 (15), 121 (15), 119 (10), 109 (18), 107
(21), 105 (13), 95 (30), 93 (17), 91 (15), 83 (15), 82 (19),
81 (22), 79 (25), 77 (11), 71(11), 70 (10), 69 (35), 67 (19),
55 (33); HRMS (CI+, CH4) calcd for C20H33O2 (M+H+)
337.2379. Found 337.2370.
129 (100), 104 (2), 82 (5), 77 (2), 54 (2); HRMS (CI+,
CH4) calcd for C12H13O2 (M+H+) 189.0916. Found
189.0913.
5.22.7. 7,7-Dimethyl-6,7-dihydrooxepin-3-one (52).
Yield: 67% from 26; colorless oil; Rf : 0.40 (petroleum
ether/EtOAc 80/20); IR (neat) 2970, 2930, 2870, 1675,
5.22.10. (E,E)-1,10-Dioxacyclooctadeca-4,13-diene-3,12-
dione (57). Yield: 75% from 56; white solid; mp 90–
92 ꢀC; Rf: 0.30 (petroleum ether/EtOAc 80/20); IR
1465, 1390, 1370, 1275, 1090 cmꢂ1 1H NMR (CDCl3,
;
300 MHz) d 6.64 (dt, J¼11.2, 6.8 Hz, 1H), 6.10 (d,
J¼11.2 Hz, 1H), 4.07 (s, 2H), 2.43 (d, J¼6.8 Hz, 2H),
1.24 (s, 6H); 13C NMR (CDCl3, 75 MHz) d 205.2 (s),
142.5 (d), 133.1 (d), 75.1 (s), 70.2 (t), 39.6 (t), 26.9 (q,
(CHBr3) 2925, 2860, 1690, 1665, 1615, 1140, 1115 cmꢂ1
;
1H NMR (CDCl3, 300 MHz) d 7.23 (apparent dt, J¼15.8,
5.5 Hz, 2H), 6.57 (apparent dt, J¼15.8, 1.8 Hz, 2H), 4.04
(s, 4H), 3.49 (t, J¼5.1 Hz, 4H), 2.35–2.25 (m, 4H), 1.80–
1.62 (m, 8H); 13C NMR (CDCl3, 75 MHz) d 199.7 (s, 2C),
149.5 (d, 2C), 124.4 (d, 2C), 76.0 (t, 2C), 71.2 (t, 2C),
32.1 (t, 2C), 29.5 (t, 2C), 24.7 (t, 2C); EIMS m/z (relative in-
ꢃ
2C); EIMS m/z (relative intensity) 140 (M+ , 15), 125 (9),
112 (3), 95 (100), 85 (26), 82 (15), 81 (14), 68 (10), 67
(36), 56 (10), 54 (22); HRMS (CI+, CH4) calcd for
C8H13O2 (M+H+) 141.0916. Found 141.0920.
ꢃ
tensity) 280 (M+ , 2), 141 (13), 140 (12), 125 (20), 124 (13),
5.22.8. 7,8-Dihydro-6H-oxocin-3-one (53). Yield: 66%
from 9; white solid; mp 86–88 ꢀC; Rf : 0.30 (petroleum
ether/EtOAc 80/20); IR (CHBr3) 2930, 2880, 1690, 1615,
123 (14), 122 (12), 111 (12), 109 (33), 108 (20), 107 (19), 98
(11), 97 (18), 96 (10), 95 (32), 85 (11), 83 (20), 82 (16), 81
(100), 80 (23), 79 (42), 69 (11), 68 (27), 67 (41), 66 (13), 55
(26), 54 (21), 53 (24); HRMS (CI+, CH4) calcd for C16H25O4
(M+H+) 281.1753. Found 281.1759.
1
1430, 1340, 1110, 985 cmꢂ1; H NMR (CDCl3, 300 MHz)
d 7.00 (dt, J¼15.6, 7.3 Hz, 1H), 6.64 (dt, J¼15.6, 1.5 Hz,
1H), 4.00 (s, 2H), 3.49 (t, J¼5.5 Hz, 2H), 2.54–2.45 (m,
2H), 1.92–1.82 (m, 2H); 13C NMR (CDCl3, 75 MHz)
d 199.3 (s), 151.0 (d), 125.6 (d), 76.2 (t), 69.3 (t), 28.1 (t),
27.6 (t); CI+ MS m/z (relative intensity) 127 (M+H+, 10),
109 (100), 106 (13); HRMS (CI+, CH4) calcd for C7H11O2
(M+H+) 127.0759. Found 127.0754.
5.23. General procedure for the RCM reaction applied
to a-amino enones
To a solution of diene (1 equiv) in anhydrous CH2Cl2
(c 5ꢁ10ꢂ3 mol Lꢂ1), degassed by argon bubbling for 20 min,
Grubbs catalyst [Ru]-II15b (0.025–0.05 equiv) was added.
The reaction mixture was heated at 40 ꢀC for 12 h. After
cooling to rt and concentration under reduced pressure, the
crude residue was purified by flash chromatography on silica
gel.
5.22.9. 8-Isopropyl-7,8-dihydro-6H-oxocin-3-one (54)
and (E,E)-8,16-diisopropyl-1,9-dioxacyclohexadeca-
4,12-diene-3,11-dione (55). When the RCM reaction was
performed on diene 27 following the general procedure,
the purification by flash chromatography of the crude residue
allowed to isolate 54 in 35% yield and 55 in 14% yield.
5.23.1. 1-[(4-Methylphenyl)-1-sulfonyl]-1,6-dihydro-2H-
pyridine-3-one (60).42 Yield: 65% from 40; colorless oil;
Rf : 0.30 (petroleum ether/EtOAc 70/30); 1H NMR
(CDCl3, 300 MHz) d 7.70 (m, 2H), 7.39–7.65 (m, 2H),
6.93 (dt, J¼10.5, 3.7 Hz, 1H), 6.07 (dt, J¼10.5, 2.2 Hz,
1H), 3.98 (m, 2H), 3.81 (s, 2H), 2.45 (s, 3H); 13C NMR
(CDCl3, 75 MHz) d 190.9 (s), 144.7 (d), 144.3 (s), 132.8
(s), 129.9 (d, 2C), 127.8 (d), 127.5 (d, 2C), 52.7 (t), 44.3
Compound 54: colorless oil; Rf : 0.60 (petroleum ether/
EtOAc 80/20); IR (neat) 1950, 1875, 1720, 1675, 1465,
1385, 1115 cmꢂ1 1H NMR (CDCl3, 300 MHz) d 6.39
;
(dt, J¼12.9, 6.0 Hz, 1H), 5.78 (d, J¼12.9 Hz, 1H), 4.34
(dsyst AB, J¼18.0 Hz, 1H), 3.95 (dsyst AB, J¼18.0 Hz, 1H),
3.19 (m, 1H), 2.56–2.23 (m, 2H), 1.90–1.65 (m, 3H), 1.00
(d, J¼6.3 Hz, 3H), 0.94 (d, J¼6.3 Hz, 3H); 13C NMR
(CDCl3, 75 MHz) d 206.8 (s), 155.0 (d), 126.4 (d), 88.6
(d), 76.0 (t), 30.9 (d), 26.6 (t), 26.2 (t), 19.3 (q), 19.0 (q);
ꢃ
(t), 21.4 (q); EIMS m/z (relative intensity) 251 (M+ , 7),
155 (4), 96 (29), 91 (18), 68 (100), 65 (9); HRMS (ESI) calcd
for C12H13NNaO3S (M+Na+) 274.05084. Found 274.05094.
ꢃ
EIMS m/z (relative intensity) 168 (M+ , 3), 125 (8), 111
(19), 108 (12), 97 (16), 96 (15), 95 (15), 87 (12), 82 (13),
81 (21), 79 (13), 69 (17), 68 (100), 67 (23), 55 (12);
HRMS (CI+, CH4) calcd for C10H17O2 (M+H+) 169.1229.
Found 169.1228.
5.23.2. tert-Butyl 3-oxo-3,6-dihydro-2H-pyridine-1-carb-
oxylate (61).43 Yield: 80% from 41; colorless oil; Rf : 0.45
(petroleum ether/EtOAc 70/30); IR (neat) 3050, 2980,
1690, 1420, 1380, 1265, 740, 705 cmꢂ1; 1H NMR (CDCl3,
300 MHz) d 7.00 (m, 1H), 6.13 (dt, J¼10.3, 2.2 Hz, 1H),
4.20 (m, 2H), 4.07 (s, 2H), 1.44 (s, 9H); 13C NMR
(CDCl3, 75 MHz) d 193.2 (s), 154.1 (s), 147.1 (br d),
127.5 (d), 81.0 (s), 51.9 (br t), 42.7 (br t), 28.3 (q, 3C);
Compound 55: white solid; mp 90–92 ꢀC; Rf : 0.40 (petro-
leum ether/EtOAc 80/20); IR (CHBr3) 2950, 1685, 1615,
1140, 1100 cmꢂ1 1H NMR (CDCl3, 300 MHz) d 6.98–
;
ꢃ
6.85 (m, 2H), 6.50 (d, J¼15.8 Hz, 2H), 4.20 (dsyst
,
EIMS m/z (relative intensity) 197 (M+ , 12), 142 (13), 141
AB

C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
4487
(33), 128 (28), 97 (27), 68 (45), 57 (t-Bu+, 100), 56 (12);
HRMS (ESI) calcd for C10H15NNaO3 (M+Na+)
220.09441. Found 220.09442.
dried over MgSO4, filtered, and concentrated under reduced
pressure to afford (2-pyridyl)sulfonyl chloride as a colorless
oil. Physical and spectral data match those previously re-
ported.19 1H NMR (CDCl3, 300 MHz) d 8.85 (m, 1H),
8.25–8.10 (m, 2H), 7.80 (m, 1H); 13C NMR (CDCl3,
75 MHz) d 158.8 (s), 150.6 (d), 139.2 (d), 129.3 (d),
121.9 (d).
5.23.3. tert-Butyl 3-oxo-2,3,6,7-tetrahydroazepin-1-carb-
oxylate (62). Yield: 90% from 42; colorless oil; Rf : 0.45 (pe-
troleum ether/EtOAc 70/30); IR (neat) 2970, 1690, 1420,
1370, 1265, 1165, 740, 710 cmꢂ1 1H NMR (CDCl3,
;
300 MHz) d (rotamers) 6.45 (m, 1H), 5.97 (dt, J¼12.5,
1.8 Hz, 1H), 4.24 and 4.12 (2s, 2H), 3.55 (m, 2H), 2.66
(m, 2H), 1.45 and 1.40 (2s, 9H); 13C NMR (CDCl3,
75 MHz) d (rotamers) 201.6 and 201.5 (s), 154.4 (s), 144.3
and 143.5 (d), 130.3 and 130.2 (d), 80.5 and 80.3 (s), 58.0
and 57.8 (t), 45.3 and 44.9 (t), 32.5 and 30.9 (t), 28.2 and
5.24.2. N-(But-3-enyl)-2-pyridine sulfonamide (67). To a
suspension of but-3-enylammonium chloride 6614 (0.87 g,
8.13 mmol, 1 equiv) in CH2Cl2 (40 mL), at 0 ꢀC, was added
triethylamine (3.42 mL, 24.4 mmol, 3 equiv). A solution of
(2-pyridyl)sulfonyl chloride (1.59 g, 8.95 mmol, 1.1 equiv)
in CH2Cl2 (10 mL) was then added dropwise. After 20 min
at 0 ꢀC, the reaction mixture was stirred for 14 h at rt and
then hydrolyzed with a saturated aqueous NH4Cl solution
(30 mL). The aqueous layer was extracted with CH2Cl2
(3ꢁ50 mL) and the combined organic layers were washed
with water, dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification by flash chromato-
graphy on silica gel (petroleum ether/EtOAc 70/30 and then
80/20) allowed to isolate 67 (1.43 g, 7.14 mmol, 88%) as
a colorless oil; Rf: 0.25 (petroleum ether/EtOAc 70/30); IR
(neat) 3270 (broad, NH), 3070, 2980, 2925, 1730, 1640,
1580, 1565, 1425, 1325, 1165, 1120, 1080, 980, 920, 780,
ꢃ
28.1 (q, 3C); EIMS m/z (relative intensity) 211 (M+ , 1),
155 (8), 138 (12), 111 (60), 110 (20), 83 (15), 82 (13), 81
(26), 68 (13), 57 (t-Bu+, 100); HRMS (ESI) calcd for
C11H17NNaO3 (M+Na+) 234.11006. Found 234.11013.
5.23.4. Benzyl 3-oxo-2,3,6,7-tetrahydroazepin-1-carb-
oxylate (63). Yield: 97% from 43; colorless oil; Rf : 0.45
(petroleum ether/EtOAc 60/40); IR (neat): 2970, 1700,
1660, 1460, 1425, 1260, 1215, 1180, 1110 cmꢂ1; 1H NMR
(CDCl3, 300 MHz) d (rotamers) 7.40–7.28 (m, 5H), 6.51
and 6.43 (2dt, J¼12.5, 4.6 Hz, 1H), 6.01 (m, 1H), 5.17 and
5.13 (2s, 2H), 4.35 and 4.28 (2s, 2H), 3.65 (m, 2H), 2.77–
2.62 (m, 2H); 13C NMR (CDCl3, 75 MHz) d (rotamers)
200.9 and 200.7 (s), 155.3 and 154.9 (s), 144.3 and 143.6
(d), 136.2 and 136.0 (s), 130.3 and 130.2 (d, 2C), 128.5
and 128.4 (d), 128.1 and 128.0 (d), 127.8 and 127.7 (d,
2C), 67.5 and 67.4 (t), 58.2 and 57.7 (t), 45.6 and 45.2 (t),
1
740 cmꢂ1; H NMR (CDCl3, 300 MHz) d 8.74 (m, 1H),
8.15–7.90 (m, 2H), 7.60 (m, 1H), 6.00 (m, 1H), 5.70 (m,
1H), 5.10–4.95 (m, 2H), 3.35 (m, 2H), 2.25 (m, 2H); 13C
NMR (CDCl3, 75 MHz) d 157.2 (s), 149.8 (d), 138.1 (d),
134.2 (d), 126.6 (d), 122.1 (d), 117.4 (t), 42.5 (t), 33.7 (t);
EIMS m/z (relative intensity) 172 (8), 171 (100), 107 (18),
79 (12), 78 (63), 51 (13); HRMS (ESI) calcd for
C9H12N2NaO2S (M+Na+) 235.05117. Found 235.05115.
ꢃ
32.5 and 31.1 (t); EIMS m/z (relative intensity) 245 (M+ ,
13), 217 (5), 173 (11), 91 (100), 81 (13), 65 (11); HRMS
(ESI) calcd for C14H15NNaO3 (M+Na+) 268.09441. Found
268.09431.
5.24.3. N-But-3-enyl-N-[2-oxo-3-(triphenyl-l5-phosphor-
anylidene)]-2-pyridine sulfonamide (68). To a solution of
protected homoallylamine 67 (1.3 g, 6.5 mmol, 1.1 equiv)
in anhydrous THF (35 mL), at 0 ꢀC, was added dropwise
a solution of n-BuLi (2.6 mL, 2.5 M in hexanes, 6.5 mmol,
1.1 equiv). The reaction mixture was stirred for 5 min at rt
and solid triphenylchloroacetonylphosphorane (2.06 g,
5.85 mmol, 1 equiv) was added in one portion. After stirring
for 22 h at rt, the reaction mixture was hydrolyzed with a sat-
urated aqueous NH4Cl solution (20 mL). The aqueous layer
was extracted with EtOAc (3ꢁ30 mL) and the combined or-
ganic layers were dried over MgSO4, filtered, and concen-
trated under reduced pressure. Purification of the residue
by flash chromatography on silica gel (petroleum ether/
EtOAc 98/2 to 95/5) allowed to isolate phosphorane 68
(2.83 g, 5.48 mmol, 94%) as a pale yellow solid, which de-
composed at Tꢄ50 ꢀC; Rf: 0.15 (EtOAc/EtOH 98/2); IR
(neat) 3050, 2980, 1735, 1575, 1565, 1540, 1435, 1425,
5.23.5. 1-[(4-Methylphenyl)-1-sulfonyl]-7-phenyl-
2,3,6,7-tetrahydroazepin-3-one (64). Yield: 99% from
45; colorless oil; Rf : 0.45 (petroleum ether/EtOAc 70/30);
1H NMR (CDCl3, 300 MHz) d 7.56–7.51 (m, 2H), 7.35–
7.17 (m, 7H), 6.62 (ddd, J¼11.8, 8.1, 5.5 Hz, 1H), 5.90 (br
d, J¼11.8 Hz, 1H), 5.40 (dd, J¼10.7, 5.5 Hz, 1H), 4.37
(m, 1H), 3.83 (dsyst AB, J¼18.4 Hz, 1H), 2.96 (ddd,
J¼16.2, 8.1, 5.5 Hz, 1H), 2.78 (m, 1H), 2.41 (s, 3H); 13C
NMR (CDCl3, 75 MHz) d 200.6 (s), 143.5 (s), 140.9 (d),
139.7 (s), 136.8 (s), 133.1 (d), 129.4 (d, 2C), 128.8 (d,
2C), 127.8 (d), 127.2 (d, 2C), 126.1 (d, 2C), 58.4 (d), 53.9
(t), 35.2 (t), 31.3 (q); EIMS m/z (relative intensity) 341
ꢃ
(M+ , 3), 186 (31), 158 (21), 157 (21), 130 (46), 129 (36),
128 (14), 118 (27), 115 (13), 105 (10), 104 (100), 91 (84),
65 (13); HRMS (ESI) calcd for C19H19NNaO3S (M+Na+)
364.09779. Found 364.09817.
1395, 1340, 1265, 1170, 1110, 735 cmꢂ1 1H NMR
;
(CDCl3, 300 MHz) d 8.54 (m, 1H), 7.96 (m, 1H), 7.77 (m,
5.24. Synthesis of the inhibitor of cathepsin K, 65
1H), 7.64–7.41 (m, 15H), 7.30 (m, 1H), 5.72 (ddt, J¼17.3,
2
5.24.1. (2-Pyridyl)sulfonyl chloride.44 To a solution of 2-
mercaptopyridine (2.0 g, 18 mmol, 1 equiv) in concentrated
sulfuric acid (50 mL), at 0 ꢀC, was added dropwise an aque-
ous sodium hypochlorite solution (112 mL, 12%). At the end
of the addition, the reaction mixture was stirred for a further
30 min at 0 ꢀC and then diluted with water (30 mL) and
CH2Cl2 (30 mL). The aqueous layer was extracted with
CH2Cl2 (2ꢁ22 mL) and the combined organic layers were
10.3, 7.0 Hz, 1H), 5.05–4.92 (m, 2H), 4.04 (br d, JH–P
24.3 Hz, 1H), 3.98 (s, 2H), 3.61 (m, 2H), 2.42 (m, 2H);
¼
2
13C NMR (CDCl3, 75 MHz) d 187.2 (s, JC–P¼3.6 Hz),
3
158.1 (s), 149.7 (d), 137.5 (d), 134.9 (d), 132.9 (d, JC–P
¼
¼
10.3 Hz, 6C), 132.1 (d, 4JC–P¼2.7 Hz, 3C), 128.7 (d, 2JC–P
1
12.3 Hz, 6C), 126.4 (s, JC–P¼91.0 Hz, 3C), 126.0 (d),
3
122.2 (d), 116.6 (t), 56.0 (t, JC–P¼15.0 Hz), 50.8 (d,
1JC–P¼109.8 Hz), 49.5 (t), 32.9 (t). Anal. Calcd for

4488
C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
C30H29N2O3PS: C, 68.16; H, 5.53; N, 5.30. Found: C, 67.98;
H, 5.51; N, 5.11.
mixture. The aqueous layer was separated and extracted
with EtOAc (2ꢁ30 mL). The combined organic layers
were washed with saturated aqueous sodium metabisulfite
(30 mL), water (2ꢁ30 mL), and brine (30 mL), dried over
MgSO4, filtered, and concentrated under reduced pressure.
The crude mixture (0.77 g) was used without purification
in the next step. Rf : 0.50 (petroleum ether/EtOAc 60/40);
IR (neat) 2923, 2853, 1732, 1339, 1172, 1116, 1036, 898,
5.24.4. N-But-3-enyl-N-(2-oxopent-3-enyl)-2-pyridine
sulfonamide (69). The Wittig reaction was performed on
ylide 68 (0.57 g, 1.1 mmol, 1 equiv) in THF (10 mL) with
acetaldehyde (0.52 mL, 11 mmol, 10 equiv) according to
the general procedure. Purification of the crude residue by
flash chromatography on silica gel (petroleum ether/EtOAc
70/30) afforded diene 69 (304 mg, 1.03 mmol, 94%) as a col-
orless oil. In order to avoid polymerization compound 69 has
to be kept in solution (cw0.2 M in CH2Cl2). Rf : 0.35 (petro-
leum ether/EtOAc 70/30); IR (neat) 2979, 2920, 1710, 1685,
1
739 cmꢂ1; H NMR (CDCl3, 300 MHz) d 8.68 (m, 1H),
7.99–7.92 (m, 2H), 7.53 (m, 1H), 5.11 (m, 1H), 4.43 (dd,
J¼18.5, 1.1 Hz, 1H), 4.18 (dsyst AB, J¼18.5 Hz, 1H), 3.69
(m, 1H), 3.16 (m, 1H), 2.38 (m, 1H), 2.16–1.99 (m, 3H);
13C NMR (CDCl3, 75 MHz) d 200.9 (s), 157.0 (s), 150.2
(d), 138.3 (d), 127.1 (d), 122.4 (d), 58.1 (t), 54.8 (d), 50.7
(t), 34.1 (t), 27.8 (t); EIMS m/z (relative intensity) 253 (1),
225 (16), 189 (100), 171 (9), 162 (15), 133 (14), 110 (10),
96 (10), 84 (21), 83 (25), 82 (22), 80 (22), 79 (64), 78
(75), 55 (26), 51 (23).
1
1640, 1575, 1425, 1340, 1170, 1115, 920, 755 cmꢂ1; H
NMR (CDCl3, 300 MHz) d 8.64 (m, 1H), 7.92–7.82 (m,
2H), 7.46 (m, 1H), 6.92 (m, 1H), 6.25 (m, 1H), 5.63 (m,
1H), 5.20–4.90 (m, 2H), 4.32 (s, 2H), 3.40 (t, J¼7.5 Hz,
2H), 2.22 (m, 2H), 1.87 (m, 3H); 13C NMR (CDCl3,
75 MHz) d 194.0 (s), 157.7 (s), 149.7 (d), 144.5 (d), 137.7
(d), 134.3 (d), 128.0 (d), 126.5 (d), 121.9 (d), 117.0 (t),
55.7 (t), 48.9 (t), 32.6 (t), 18.3 (q); EIMS m/z (relative inten-
sity) 253 (MꢂC3H+5, 22), 226 (12), 225 (91), 211 (16), 171
(100), 152 (18), 144 (12), 133 (12), 110 (39), 107 (23), 82
(13), 79 (14), 78 (92), 69 (34), 67 (14), 55 (29), 51 (15).
5.24.7. 4-Azido-1-(pyridine-2-sulfonyl)azepan-3-one
(72). To a suspension of sodium azide (487.5 mg,
7.5 mmol, 5 equiv) in DMF (9 mL) at rt, was added a solu-
tion of crude bromoketone 71 (0.77 g) in DMF (15 mL).
The reaction mixture was stirred for 2.5 h at rt, then hydro-
lyzed with water (40 mL) and diluted with EtOAc (80 mL).
The aqueous layer was extracted with EtOAc (80 mL) and
the combined organic layers were washed with brine
(3ꢁ40 mL), dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification by flash chromato-
graphy on silica gel (petroleum ether/EtOAc 60/40) afforded
the azidoketone 72 (198.5 mg, 0.67 mmol, 45% from 70) as
an oil; Rf: 0.50 (petroleum ether/EtOAc 50/50); IR (neat)
5.24.5. 1-(Pyridine-2-sulfonyl)-2,3,6,7-tetrahydroazepin-
3-one (70). The RCM reaction was performed on diene 69
(0.44 g, 1.5 mmol, 1 equiv) in anhydrous degassed CH2Cl2
(150 mL, 0.01 M) in the presence of Grubbs catalyst
[Ru]-II15b (32 mg, 0.037 mmol, 0.025 equiv) following the
general procedure. Purification of the residue by flash chro-
matography on silica gel (petroleum ether/EtOAc 50/50)
afforded azepanone 70 (363 mg, 1.44 mmol, 96%) as a
yellowish gray solid; mp 98–100 ꢀC; Rf : 0.30 (petroleum
ether/EtOAc 50/50); IR (neat) 2900, 1660, 1425, 1340,
1
2923, 2853, 2100, 1727, 1337, 1172, 1116, 753 cmꢂ1; H
NMR (CDCl3, 300 MHz) d 8.69 (m, 1H), 7.98–7.93 (m,
2H), 7.53 (m, 1H), 4.75–4.59 (m, 2H), 4.10 (m, 1H), 3.78
(dsyst AB, J¼18.8 Hz, 1H), 2.77 (m, 1H), 2.24–1.88 (m,
3H), 1.76 (m, 1H); 13C NMR (CDCl3, 75 MHz) d 204.4
(s), 157.0 (s), 150.1 (d), 138.3 (d), 127.1 (d), 122.4 (d),
66.3 (d), 58.5 (t), 50.8 (t), 30.3 (t), 28.2 (t); EIMS m/z (rela-
tive intensity) 267 (MꢂN2+, 18), 207 (26), 171 (29), 125
(100), 124 (65), 97 (44), 79 (61), 69 (35), 51 (25).
1
1175, 740 cmꢂ1; H NMR (CDCl3, 300 MHz) d 8.63 (m,
1H), 7.93–7.86 (m, 2H), 7.48 (m, 1H), 6.42 (dt, J¼12.5,
4.6 Hz, 1H), 5.96 (dt, J¼12.5, 1.9 Hz, 1H), 4.25 (s, 2H),
3.65 (t, J¼5.7 Hz, 2H), 2.71 (m, 2H); 13C NMR (CDCl3,
75 MHz) d 199.1 (s), 157.2 (s), 149.9 (d), 143.8 (d), 138.0
(d), 130.2 (d), 126.8 (d), 122.1 (d), 59.7 (t), 47.9 (t), 33.7 (t);
EIMS m/z (relative intensity) 188 (3), 171 (8), 120 (17), 110
(100), 82 (30), 81 (55), 80 (23), 78 (42), 55 (13), 54 (20), 53
(22), 52 (12), 51 (26). Anal. Calcd for C11H12N2O3S: C,
52.37; H, 4.79; N, 11.10. Found: C, 52.34; H, 4.61; N, 11.03.
5.24.8. tert-Butyl 4-methyl-1-oxo-1-[3-oxo-1-(pyridine-2-
sulfonyl)azepan-4-ylamino]pentan-2-ylcarbamate (74).
To a solution of azidoketone 72 (197.7 mg, 0.64 mmol,
1 equiv) in MeOH (40 mL), at rt, were added 37% aqueous
HCl (170 mL) and Pd/C (58 mg, 10% w/w, 0.05 mmol,
8.4 mol %). The reaction mixture was then stirred for 16 h
at rt, and filtered through Celite. After concentration under
reduced pressure, the crude hydrochloride salt 73 was used
directly in the next step.
5.24.6. 4-Bromo-1-(pyridine-2-sulfonyl)azepan-3-one
(71). To a suspension of copper cyanide (269 mg,
3.0 mmol, 2 equiv) in THF (14 mL), at ꢂ20 ꢀC, was added
dropwise a solution of n-BuLi (1.31 mL, 2.28 M in hexanes,
3.0 mmol, 2 equiv). The resulting brown solution was stirred
for 30 min at ꢂ20 ꢀC and then cooled to ꢂ50 ꢀC. A DIBAL-
H solution (4.96 mL, 1.21 M in toluene, 6.0 mmol, 4 equiv)
was added dropwise. After 1 h stirring, at ꢂ50 ꢀC, a solution
of enone 70 (378 mg, 1.5 mmol, 1 equiv) in THF (5 mL) was
added dropwise. After stirring for 2 h at ꢂ50 ꢀC, HMPA
(780 mL, 4.5 mmol, 3 equiv) and a solution of methyllithium
(0.95 mL, 1.6 M in Et2O, 1.5 mmol, 1 equiv) were added
successively, and the solution was stirred for 15 min at
ꢂ50 ꢀC. Bromine (0.8 mL, 15.5 mmol, 10.3 equiv) was
added dropwise and the reaction mixture was warmed to
ꢂ20 ꢀC over 1 h. The reaction was quenched with water
(20 mL) and EtOAc (30 mL) was added to the reaction
To a solution of the crude hydrochloride salt 73 (0.64 mmol,
1 equiv) in CH2Cl2 (8.6 mL), at 0 ꢀC, were added succes-
sively N-Boc-L-leucine (219.1 mg, 0.95 mmol, 1.5 equiv),
HOBt (129.7 mg, 0.96 mmol, 1.5 equiv), and EDCI
(184 mg, 0.96 mmol, 1.5 equiv). After being stirred for
10 min at 0 ꢀC, Et3N (0.27 mL, 1.92 mmol, 2 equiv) was
added. After 1.5 h at 0 ꢀC, the reaction mixture was stirred
for 18 h at rt, then diluted with EtOAc (40 mL) and hydro-
lyzed with aqueous 1 M HCl (30 mL). The organic layer
was separated and washed with a saturated aqueous K2CO3
solution (30 mL), water (30 mL), and brine (30 mL), dried

C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
4489
over MgSO4, filtered, and concentrated under reduced pres-
sure. Purification of the residue by flash chromatography
on silica gel (CH2Cl2/MeOH 99/1) afforded the azepanone
74 (156.9 mg, 0.33 mmol, 51%) as a colorless amorphous
solid; Rf: 0.45 (CH2Cl2/MeOH 97/3); IR (neat) 3306, 2926,
(M+H+, 100), 386 (51), 358 (6), 340 (20), 308 (6), 270 (6),
258 (8), 176 (7); HRMS (CI+, CH4) calcd for
C26H31N4O6S (M+H+) 527.1886. Found 527.1969.
1
1692, 1655, 1505, 1339, 1170, 1117, 1040, 776 cmꢂ1; H
References and notes
NMR (CDCl3, 400 MHz) d (diastereoisomers) 8.69 (m,
1H), 8.02–7.90 (m, 2H), 7.53 (m, 1H), 7.14 and 7.06 (2d,
J¼6.0 Hz, 1H), 5.11 (m, 1H), 4.99 and 4.95 (2d, J¼7.5 and
8.0 Hz, 1H), 4.78 and 4.74 (2dd, J¼19.1, 1.5 and 1.0 Hz,
1H), 4.23–4.04 (m, 2H), 3.83 (dd, J¼19.1, 1.5 Hz, 1H),
2.71 (m, 1H), 2.27–2.07 (m, 2H), 1.90–1.80 (m, 1H), 1.75–
1.58 (m, 2H), 1.54–1.36 (m, 2H), 1.46 and 1.45 (2s, 9H),
0.98–0.91 (m, 6H); 13C NMR (CDCl3, 100 MHz) d (diaste-
reoisomers) 205.8 (s), 171.7 (s), 157.2 (s), 155.5 (s), 150.2
(d), 138.2 (d), 127.0 (d), 122.4 (d), 80.1 (s), 58.7 (t), 57.7
(d), 53.1 (d), 51.3 (t), 41.6 and 41.3 (t), 31.8 and 31.6 (t),
28.4 (t), 28.3 (3q), 24.8 and 24.7 (d), 23.0 (q), 22.9 (q); MS
(CI+, CH4) m/z (relative intensity) 483 (M+H+, 85), 427
(67), 383 (30), 342 (100), 329 (37), 314 (56), 286 (86), 268
(23), 224 (28), 175 (14); HRMS (CI+, CH4) calcd for
C22H35N4O6S (M+H+) 483.2199. Found 483.2271.
1. (a) Doblem, M. Ionophores and Their Structures; Wiley-
Intersciences: New York, NY, 1981; (b) Polyethers
Antibiotics; Westley, J. W., Ed.; Marcel Dekker: New York,
NY, 1982; Vols. I and II; (c) Erickson, K. L. Marine Natural
Products; Scheuer, P. J., Ed.; Academic: New York, NY,
1983; Vol. 5, Chapter 4, pp 131–257; (d) Yasumoto, T.;
Murata, M. Chem. Rev. 1993, 93, 1897; (e) Faulkner, D. J.
Nat. Prod. Rep. 2000, 17, 1; (f) Faulkner, D. J. Nat. Prod.
Rep. 2000, 17, 7 and earlier reviews in the same series; (g)
Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1; (h) Faulkner,
D. J. Nat. Prod. Rep. 2002, 19, 1.
2. For recent reviews on cyclic ethers syntheses, see: (a) Boivin,
T. L. B. Tetrahedron 1987, 43, 3309; (b) Moody, C. J.;
Davies, M. Studies in Natural Product Chemistry; Atta-ur-
Rahman, Ed.; Elsevier: Amsterdam, 1992; Vol. 10, pp 201–
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ꢁ
5.24.9. N-{(2S)-4-Methyl-1-oxo-1-[(4RS)-3-oxo-1-(pyri-
dine-2-sulfonyl)azepan-4-ylamino]pentan-2-yl}benzo-
furan-2-carboxamide (65 and 650). To a solution of
carbamate 74 (97.7 mg, 0.20 mmol, 1 equiv) in MeOH
(1 mL), at rt, was added 4 M HCl in dioxane (1 mL). The re-
action mixture was then stirred for 2.5 h at rt. After concen-
tration under reduced pressure, the crude hydrochloride salt
was used directly in the next step.
Figadere, B. Tetrahedron: Asymmetry 1993, 4, 1711; (e)
Koert, U. Synthesis 1995, 115; (f) Alvarez, E.; Candenas,
M.-L.; Perez, R.; Ravelo, J. L.; Martin, J. D. Chem. Rev. 1995,
95, 1953; (g) Hoberg, J. O. Tetrahedron 1998, 54, 12631; (h)
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2002, 2301; (l) Sasaki, M.; Fuwa, H. Synlett 2004, 1851.
3. For recent reviews on cyclic amines syntheses, see: (a) Pichon,
To a solution of the crude hydrochloride salt (0.20 mmol,
1 equiv) in CH2Cl2 (5 mL), at 0 ꢀC, were added successively
benzofuran-2-carboxylic acid (32.4 mg, 0.20 mmol,
1 equiv), HOBt (27.0 mg, 0.20 mmol, 1 equiv), and EDCI
(38.3 mg, 0.20 mmol, 1 equiv). After 5 min at 0 ꢀC, Et3N
(60 mL, 0.43 mmol, 2.1 equiv) was added. The reaction mix-
ture was stirred for 18 h at rt, then diluted with EtOAc
(20 mL) and hydrolyzed with aqueous 1 M HCl (15 mL).
The organic layer was separated and washed with a saturated
aqueous K2CO3 solution (15 mL), water (15 mL), and brine
(15 mL), dried over MgSO4, filtered, and concentrated under
reduced pressure. Purification of the residue by flash chro-
matography on silica gel (CH2Cl2/MeOH 99/1) afforded
a 1/1 mixture of azepanones 65 and 650 (54.2 mg,
0.10 mmol, 52%) as a colorless amorphous solid; Rf: 0.60
(CH2Cl2/MeOH 97/3); IR (neat) 3293, 2955, 2923, 2869,
ꢁ
M.; Figadere, B. Tetrahedron: Asymmetry 1996, 7, 927; (b)
Nadin, A. Contemp. Org. Synth. 1997, 4, 387; (c) Nadin, A.
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2000, 2862.
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€
Angew. Chem., Int. Ed. 2000, 39, 2073; (c) Furstner, A. Angew.
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Chem., Int. Ed. 2000, 39, 372; (b) Crimmins, M. T.; Emmitte,
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Wallace, D. J.; Bulger, P. G.; Kennedy, D. J.; Ashwood,
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(m) Heck, M.-P.; Baylon, C.; Nolan, P. S.; Mioskowski, C.
1
1727, 1645, 1509, 1338, 1173, 1117, 749 cmꢂ1; H NMR
(CDCl3, 400 MHz) d (65+650) 8.68 (m, 1H), 8.00–7.88 (m,
2H), 7.66 (d, J¼8.0 Hz, 1H), 7.55–7.46 (m, 3H), 7.43 (t,
J¼8.0 Hz, 1H), 7.29 (t, J¼8.0 Hz, 1H), 7.14 (d, J¼6.5 Hz,
1H), 7.10 and 7.04 (d, J¼8.5 and 6.5 Hz, 1H), 5.15 (m,
1H), 4.82–4.67 (m, 2H), 4.11 (m, 1H), 3.86 and 3.81 (2d,
J¼10.0 and 10.0 Hz, 1H), 2.73 (m, 1H), 2.32–1.38 (m,
7H), 1.04–0.96 (m, 6H); 13C NMR (CDCl3, 100 MHz)
d (65+650) 205.7 (s), 170.8 and 170.7 (s), 158.8 and 158.6
(s), 157.2 (s), 154.9 (s), 150.2 (d), 148.2 and 148.1 (s),
138.2 (d), 127.5 (s), 127.0 (d), 126.8 (d), 123.7 (d), 122.7
(d), 122.5 and 122.4 (d), 111.9 (d), 111.1 and 110.9 (d),
58.6 (t), 57.9 (d), 51.5 (t), 51.3 (d), 41.9 and 41.5 (t), 31.7
and 31.5 (t), 28.4 (t), 24.9 (d), 23.0 and 22.9 (q), 22.2 and
22.1 (q); MS (CI+, CH4) m/z (relative intensity) 527

4490
C. Taillier et al. / Tetrahedron 63 (2007) 4472–4490
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