Missing cyclization pathways and new rearrangements unveiled in the gold(I) and platinum(II)-catalyzed cyclization of 1,6-enynes

Article abstract of DOI:10.1016/j.tet.2007.02.122

Cyclopropyl metal carbenes formed in the 6-endo-dig cyclization may evolve to form seven-membered ring intermediates. This has been achieved for the first time by using highly electrophilic platinum(II) and gold(I) complexes. Gold(I) also triggers a remar

Full text of DOI:10.1016/j.tet.2007.02.122

Tetrahedron 63 (2007) 6306–6316
Missing cyclization pathways and new rearrangements
unveiled in the gold(I) and platinum(II)-catalyzed
cyclization of 1,6-enynes
Catalina Ferrer, Mihai Raducan, Cristina Nevado, Christelle K. Claverie
*
and Antonio M. Echavarren
Institute of Chemical Research of Catalonia (ICIQ), Av. Pa€ısos Catalans 16, 43007 Tarragona, Spain
Received 22 January 2007; revised 25 February 2007; accepted 27 February 2007
Available online 2 March 2007
Abstract—Cyclopropyl metal carbenes formed in the 6-endo-dig cyclization may evolve to form seven-membered ring intermediates. This
has been achieved for the first time by using highly electrophilic platinum(II) and gold(I) complexes. Gold(I) also triggers a remarkable
rearrangement of certain enynes leading to complex cyclic systems. A new cationic platinacycle is described, which catalyzes skeletal rear-
rangements and other reactions of enynes at room temperature.
Ó 2007 Elsevier Ltd. All rights reserved.
H
1. Introduction
Z
Z
Z
H
H
R
R
R
R'
R'
The mechanistic scheme of metal-catalyzed reactions be-
tween alkynes and alkenes1–5 has been demonstrated in
the context of 1,6-enyne cyclization.6–8 Thus, work on
Pt(II)-,6,8 Pd(II)-,7 and Au(I)-catalyzed9,10 alkoxy- and
hydroxycyclizations has identified two general manifolds
upon monocoordination of the metal fragment to the alkyne
in 1: a 5-exo-dig cyclization via anti-cyclopropyl metal
carbenes 2 to give products 3 or 4,9 and the relatively less
common 6-endo-dig cyclization via 5 (Scheme 1). Recently,
the addition of electron-rich aromatic compounds as carbon
nucleophiles to 1,6-enynes has been achieved using cationic
gold(I) catalysts.11,12 In addition to the nucleophilic attack at
intermediates 2 to give products 3 or 4, certain carbon
nucleophiles also react at the carbene carbon12 in a process
that is similar to the intermolecular cyclopropanation with
alkenes catalyzed by gold(I).13 Elimination of a proton to
form dienes, a process that is different from the Alder-ene
isomerization reaction, has also been reported.10c,14 The
endocyclic pathway proceeds by a shift of the metal in 1
to C-2 of the alkyne to form intermediates 5, which can
evolve to give cyclopropanes 6, addition products 7,8 or
the corresponding endo skeletal rearrangement derivatives.9
However, the formation of seven-membered ring com-
pounds 8 or 9 by cleavage of bond b from 5 has not yet
been observed.15
H
R'
6
Nu
Nu
7
3
a
a
NuH
[M]
NuH
[M]
[M]
R'
H
R
5-exo-dig
6-endo-dig
a
Z
a
b
Z
Z
b
R
R
H
H
R'
5
R'
2
1
b
NuH
b
NuH
Z
Z
Z
or
R
R
R
R'
Nu R'
4
R'
Nu
9
8
Scheme 1.
We have tried to obtain seven-membered ring compounds 8
or 9 by using enol ethers as substrates (R0¼alkoxy group) to
facilitate cleavage of bond b in intermediates 5.16 However,
this strategy was not successful using PtCl2 as catalyst.15 We
reasoned that by using more electrophilic catalysts, cleavage
of bond b might be possible. Herein we report the realization
of this concept by using more electrophilic platinum(II) and
gold(I) catalysts, which allows the formation of compounds
of type 8 by a formal 7-endo-dig cyclization. Gold(I) may
also trigger a remarkable domino process leading to complex
cyclic systems via seven-membered ring intermediates.
Keywords: Gold; Platinum; Enynes; Cyclizations; Rearrangements.
* Corresponding author. Tel.: +34 977920218; fax: +34 977920225; e-mail:
aechavarren@iciq.es
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.122

C. Ferrer et al. / Tetrahedron 63 (2007) 6306–6316
6307
2. Results and discussion
is readily prepared from [PtCl2(PhCN)2] and (o-Tol)3P as
an insoluble solid by the procedure of Fornies et al. Cleavage
of the chloride bridges of dimeric 19 with AgSbF6 in aceto-
nitrile provided new complex 20 in good yield as a white
solid (Scheme 3). Complex 20 displays a 31P resonance at
d 19.8 (CDCl3) coupled to 195Pt (1JPtP¼4600 Hz). This cat-
ionic platinum complex is soluble in CH2Cl2 and partially
soluble in toluene at room temperature.
Enynes 10–12 are readily available substrates assembled in
a modular way in two steps by the addition of a-lithiated
enol ethers to aldehydes, followed by propargylation of the
resulting secondary alcohols. Cyclization of 10–12 was
cleanly carried out with 5 mol % PtCl2 in toluene (Scheme
2).15 No skeletal rearrangement was observed under these
conditions.2,3,17 The reactions of 10–12 proceeded with total
regiocontrol by 6-endo-dig cyclization, as a result of the ter-
minal substitution at the alkyne and the electronegative char-
acter of the tether.16 In addition, these reactions are highly
stereoselective. Thus, only in the case of 15a a C-2 epimer
was detected. The cyclization presumably proceeds via com-
plex 16, by the formation of two carbon–carbon bonds from
the face of the alkene opposite to the R2 substituent. The
intermediate carbene 17 then evolves by a hydrogen elimina-
tion to give enol ether 18.
R
P
R
Cl
MeOCH2CH2OH
Pt Pt
Cl
(o-Tol)3P
[PtCl2(PhCN)2] +
P
R
reflux
(84%)
R
19: R = o-Tol
AgSbF6,
MeCN, rt
(86%)
SbF6
R
P
R
NCMe
R2
Pt
R2
NCMe
O
PtCl2 (5 mol%)
H
O
20: R = o-Tol
H
toluene, 0-80 °C
2-48 h
O
O
R1
R1
Scheme 3.
10a: R1 = Ph, R2 = Me
10b: R1 = 2-Napht, R2 = Me
10c: R1 = Ph, R2 = Et
10d: R1 = R2 = Ph
13a (84%)
13b (97%)
13c (79%)
13d (72%)
13e (52%)
13f (61%)
13g (74%)
Complex 20 catalyzes the skeletal rearrangement of simple
1,6-enynes (Table 1). Thus, 21a–e reacted with 20
(5 mol %) in CH2Cl2 at room temperature to afford dienes
22a–e.3,4 In the case of enyne 21d (entry 4), endo-rearrange-
ment product 2310a,c and 24 were also obtained. We have
also obtained 24 in the gold(I)-catalyzed reaction of 21d per-
formed in DMSO and have demonstrated that this diene
results by the elimination of a proton from an intermediate
of type 2.10c,14 Reaction of tosylamide 21e with catalyst 20
affords 3-azabicyclo[4.1.0]hept-4-ene 25 as the major prod-
uct (entry 5), a result that is similar to that has been found
before in the reaction of 21e with Au(I) catalysts.10c In this
case, however, no endocyclic rearrangement was observed
with the Pt(II) catalyst. Remarkably, whereas in the absence
of donor ligands PtCl2 catalyzes the Alder-ene cycloisomeri-
zation of 1,6-enynes,6 this type of process was not observed
with platinum complex 20, which suggest that only one of the
acetonitrile ligands is substituted by the incoming enyne. A
preliminary kinetic study on the cyclization of 21c catalyzed
by 20 (entry 3) revealed first order dependence on the sub-
strate with an enthalpy of activation DHz¼12 kcal molꢀ1
10e: R1 = (E)-CH=CHMe, R2 = Me
10f: R1 = (E)-CH=CHPh, R2 = Me
10g: R1 = i-Pr R2 = Me
R2
R2
O
PtCl2 (5 mol%)
H
O
toluene, 50-80 °C
1-24 h
O
R1
O
R1
11a: R1 = Ph, R2 = Me
14a (58%)
14b (70%)
14c (71%)
11b: R1 = p-Tol, R2 = Et
11c: R1 = t-Bu, R2 = Me
Me
Me
PtCl2 (5 mol%)
O
O
toluene, 80 °C
2 h
OEt
OEt
R
R
15a (73%)
15b (54%)
12a: R = Ph
12b: R = i-Pr
[M]
and an entropy of activation DSz¼ꢀ2.6 cal molꢀ1 Kꢀ1 10f
.
R1
[M]
R1
R1
H
R4
- [M]
O
H
O
H
R4
R4
OR3
16
O
In addition to new Pt(II) complex 20, we assayed the cycli-
zations of substrates 10 and 11 with other Au(I) catalysts
(Fig. 1). Complex 2610d,19 proved to be the best Au(I) cata-
lyst, whereas 2713 led to poorer results, probably due to its
higher electrophilicity, which led to decomposition of the
acid-sensitive enol ethers used as substrates.
H
H
OR3
R2
OR3
17
R2
R2
18
Scheme 2. Cyclization of enynes 10–12 catalyzed by PtCl2.
Almost identical results were obtained when PtCl4 was used
as the catalyst,17 which suggest that Pt(IV) is reduced to
Pt(II) under the reactions conditions. In search for a more ac-
tive platinum catalyst, we have previously found that a com-
bination of PtCl2 and bulky phosphine (o-Tol)3P provided
a catalytic system that outperformed PtCl2.10b Although
the exact nature of the active catalyst is not known, we
reasoned that under the reaction conditions known dimeric
Pt(II) complex 19 could be formed.18 Indeed, complex 19
Enynes 10a–c are cyclized with catalysts 20 and 26 to give
tricyclic compounds 13a–c (Table 2, entries 1–5). Best
yields are obtained with Au(I) catalyst 26 (entries 2, 4,
and 5). Reaction of enynes 10d with catalyst 26 provided
3,4,7,9-tetrahydro-2H-pyrano[2,3-c]oxepine 28a, in addi-
tion to the expected cyclopropane derivative 13d (entry 7).
Catalyst 27 led to oxepine 28a, albeit in low yield (entry 8).
Interestingly, whereas reaction of dienyne 10f with PtCl2

6308
C. Ferrer et al. / Tetrahedron 63 (2007) 6306–6316
Table 1. Skeletal rearrangement of 1,6-enynes catalyzed by Pt(II) complex
20
Table 2. Cyclizations of enynes 10–12 with catalysts 20, 26, or 27
Entry
Enyne
Catalyst Solvent Time (h) Product (yield, %)
Entry
1
Enyne
Time (min)
120
Product(s) (yield, %)
1
2
3
4
5
6
10a
10a
10b
10b
10c
10d
20
26
20
26
26
20
Toluene
2
13a (41)
13a (75)
13b (77)
13b (78)
13c (80)
13d (38)
CH2Cl2 0.2
CH2Cl2 0.7
CH2Cl2 0.5
CH2Cl2 0.5
MeOOC
MeOOC
MeOOC
MeOOC
22a (63)
21a
CH2Cl2
1
MeOOC
MeOOC
13d (45)
Ph
MeOOC
MeOOC
+
2
3
120
15
Ph
Ph
22b (55)
21b
7
8
10d
10d
26
27
CH2Cl2 0.3
O
MeOOC
MeOOC
O
MeOOC
MeOOC
Ph
Me
Me
28a (14)
22c (87)
21c
CH2Cl2
5
28a (12)
Me
Me
MeOOC
MeOOC
Me
Ph
O
H
O
22d
H
+
MeOOC
MeOOC
29 (25)
+
H
9
10f
26
CH2Cl2 0.2
MeOOC
MeOOC
Me
Me
Me
O
H
4
15
Me
23
Ph
H
O
Me
+
21d
MeOOC
MeOOC
30 (45)
Me
Me
H
O
H
H
24
O
10
20
Toluene 0.2
81(22d/23/24 =
O
O
2-Napht
2-Napht
10h
1:0.2:0.9)
13h (29)
TsN
Me
22e (22)
O
11
12
10h
10h
26
27
CH2Cl2 0.1
O
TsN
Me
+
5
20
2-Napth
31 (66)
TsN
21e
CH2Cl2 0.2
31 (50)
Me
25 (78)
H
O
H
H
Reactions carried out with 5 mol % catalyst in CH2Cl2 at room temperature.
O
Ph
proceeded selectively between the acetylene and the more
electron-rich enol ether to give 13f (Scheme 2), reaction of
10f with catalyst 26 afforded a mixture of regioisomeric cy-
clopropane 29 (25%) and tetracyclic acetal 30 (45%) (entry
9). The structure of this unexpected product of rearrange-
ment was secured by X-ray diffraction (Fig. 2).20 An inter-
esting difference in the reactivity of Pt(II) and Au(I)
catalysts was found in the reaction of substrate 10h. Thus,
14d (5)
O
+
13
20
Toluene 0.2
O
Ph
O
11d
O
Ph
28b (17)
14
15
11d
11d
26
27
CH2Cl2 0.1
CH2Cl2 0.1
28b (20)
28b (10)
t-Bu
t-Bu
SbF6
t-Bu
H
O
P
Au NCMe
H
O
H
t-Bu
O
P AuCl
16
20
Toluene 0.2
3
O
O
p-Tol
14e (5)
p-Tol
/ AgSbF6
11e
26
27
Figure 1. Gold(I) complexes with bulky ligands.
(continued)

C. Ferrer et al. / Tetrahedron 63 (2007) 6306–6316
6309
Table 2. (continued)
Claisen
rearrangement
AuCl
Entry
Enyne
Catalyst Solvent Time (h) Product (yield, %)
O
O
O
O
O
O
p-Tol
p-Tol
p-Tol
O
11e
17
11e
26
CH2Cl2 0.1
32
34
O
p-Tol
28c (20)
Me
Me
O
AuCl3
O
O
O
O
Ph
18
11e
AuCl CH2Cl2 16
Ph
O
p-Tol
10a
35
32 (60)
Scheme 4. Mechanism for the formation of allene 32.
H
Me
Me
O
Oxepines 28a–c are formed by an initial 6-endo-dig cycliza-
tion to give intermediates of type 36, which suffer cleavage
at bond b (see Scheme 1) leading to 37 (Scheme 5). Interme-
diates 37 undergo proton loss and a final protodemetalation
to afford 28a–c. The formation of 31 from 10h (Table 2,
entry 11) can be explained by an initial 5-exo-dig cyclization
via an intermediate of type 38.
O
O
H
Me
OEt
33a
O
O
+
H
19
26
CH2Cl2 0.2
OEt
O
12c
H
OEt
33b
(60, 3:1 33a/33b)
[M]
[M]
R1
R1
R1
n
O
Reactions carried out with 5 mol % catalyst at room temperature.
[M]
[M]
b
O
O
H
n
R2
O
R2
O
O
R2
n
whereas its reaction with catalyst 20 led to 13h in low yield,
Au(I) catalysts 26 and 27 gave bicyclic 31 (entries 10–12).
Seven-membered ring derivatives 28b,c were also obtained
in the reactions of 11d and 11e (entries 13–15 and 17).
Oxepine derivatives 28a–c are labile and suffer extensive de-
composition upon storage even at low temperatures (<0 ꢁC).
A totally different reactivity was found in the reaction of
substrate 11e with AuCl as catalyst (entry 18). In this case,
allene 32 was obtained in 60% yield. Reaction of 2-furyl de-
rivative 12c with 26 as catalyst led to cyclic acetals 33a,b,
as a 3:1 mixture of epimers (entry 19) with a cage structure
similar to that of 30.
38
R1 = H,
R2 = 1-Napth, n = 2
10-11
36
[M]
R1
H
R1
O
O
O
O
n
n
O
O
2-Napth
R2
R2
31
37
28a: R1 = R2 = Ph, n = 2
28b: R1 = H, R2 = Ph, n = 1
28c: R1 = H, R2 = p-Tol, n = 1
Scheme 5.
Allene 32 is formed by gold-catalyzed isomerization of 11e
to 34, followed by Claisen rearrangement that is also proba-
bly catalyzed by gold (Scheme 4). Interestingly, related
allene 35 had been obtained before in the reaction of 10a
with AuCl3 as catalyst,21 which points to the formation of
the same gold catalyst in reactions with AuCl and AuCl3.22
We also observed the formation of compounds related to 31
in the reaction of malonates 39a,b with Pt(II) or Au(I) cata-
lysts (Scheme 6). Thus, reaction of 39a with PtCl2 in MeOH
provided 40a in 88% yield. Reaction of 39a with a cationic
Au(I) catalyst generated in situ by reaction of [AuMe(PPh3)]
with phosphotungstic acid10a,c led to a 1:1 mixture of 40a
and 40b in 59% yield. On the other hand, treatment of 39b
with catalyst 27 in CH2Cl2 led to 40c in 40% yield. These
reactions probably take place through intermediates of
type 41, which open initially to give 42. Gold- or proton-
catalyzed isomerization of the exocyclic olefin of 42 then
gives products 40a–c.
Formation of rearranged compounds 30 and 33 probably
also proceeds via seven-membered ring intermediates. For
simplicity the proposed mechanism is shown for the forma-
tion of acetal 30 (Scheme 7). Accordingly, 6-endo-dig cycli-
zation of 43 should give gold(I) carbene 44, whose opening
would afford oxonium cation 45. In this case, instead of the
loss of a proton, a ring contraction from 45 could lead to
Figure 2. ORTEP diagram of 30. Ellipsoids are shown at the 50% level.20

6310
C. Ferrer et al. / Tetrahedron 63 (2007) 6306–6316
Table 3
Me
Me
Z
[M] (2 mol%)
Z
MeO2C
MeO2C
PtCl2 (5 mol%)
H
Z
+
CH2Cl2, 23 °C
MeO2C
MeO2C
MeOH, 65 °C, 14 h
O
O
R
Ph
R
Ph
50a-e
51: Z = NTs
49a: Z = C(CO2Me)2, R = H
40a (88%)
39a
49b: Z = C(CH2OAc)2, R = H
[AuMe(PPh3)] (3 mol%)
H+, MeOH, 60 °C, 17 h
O
49c: Z =
, R = H
Me
O
Me
Me
49d: Z = C(CO2Me)2, R = n-Pr
49e: Z = NTs, R = H
40a +
MeO2C
MeO2C
O
Entry
Dienyne
[M]
Product(s) (yield, %)
Ph
40b
(59%, 1:1)
1
2
3
4
5
6
7
8
9
49a
49a
49a
49a
49b
49c
49d
49e
49e
20
26
50a (51)
50a (67)
50a (34)
50a (25)
50b (68)
50c (60)
Me
[AuCl(PPh3)]/AgSbF6
[AuCl(IMes)]/AgSbF6
26
26
26
26
AuCl
MeO2C
MeO2C
27 (2 mol%)
CH2Cl2, 23 °C, 0.5 h
MeO2C
MeO2C
O
O
p-Tol
p-Tol
40c (40%)
50d (18)
50e (33)+51 (44)
51 (67)
39b
R1
[M]
R1
H
Reactions carried out with 2 mol % catalyst in CH2Cl2 for 5–20 min.
MeO2C
40a-c
n
MeO2C
higher yields and cleaner reactions than [AuCl(PPh3)]/
AgSbF6 or [AuCl(IMes)]/AgSbF6
MeO2C
MeO2C
O
R2
41
10d,24
O
(IMes¼N,N-bis-
n
R2
42
mesitylimidazolylidene) (Table 3, entries 2–4). Divinyl-
cyclopentene 50d was obtained in low yield from 49d
(entry 7). On the other hand, tosylamide derivative 49e re-
acted with 26 or AuCl as catalysts by an endocyclic pathway,
leading to 51 as the major product (entries 8 and 9).
Scheme 6.
carbocation 46, which would react with the alkenyl-gold to
give 47. The cyclopropane ring could be formed as shown
to give 48, from which a protodemetalation would then
afford 30. A similar series of transformations could also
explain the formation of acetals 33.
3. Conclusion
In summary, as predicted by the mechanistic scheme origi-
nally proposed for the Pt(II)-catalyzed nucleophilic addi-
tions to 1,6-enynes,6b the cyclopropyl metal carbene
formed in the 6-endo-dig cyclization may evolve to form
seven-membered ring intermediates. This has been realized
by using more electrophilic platinum(II) and gold(I) com-
plexes. Gold(I) also triggers a remarkable rearrangement
leading to complex cyclic systems bearing up to six stereo-
genic centers in a single step from an achiral starting mate-
rial. Cleavage of bond b in cyclopropyl metal carbene
We also examined the cyclization of dienynes 49a–e in
which the vinyl group might also favor opening of the endo-
cyclic intermediates to form seven-membered rings. How-
ever, in these cases the preferred reaction pathway for
49a–d was the exocyclic skeletal rearrangement leading to
divinylcyclopentenes 50a–c. This type of compounds is
of interest as configurationally locked Z-hexatrienes.23 The
best results were obtained using catalyst 26, which led to
Au(L)
Me
Au(L)
Me
Au(L)
Me
O
O
O
O
H
Ph
Ph
H
O
Ph
O
Ph
44
43
45
H
H
H
Au(L)
Me
Au(L)
Me
Au(L)
Me
-H+
O
O
O
Ph
Ph
O
O
O
47
46
48
- Au(L)+
H+
30
Scheme 7.

C. Ferrer et al. / Tetrahedron 63 (2007) 6306–6316
6311
formed in the 5-exo-dig cyclization has also been observed
in the formation of 31 (Table 3, entry 11) and 40a–c
(Scheme 3).
(125 MHz, CDCl3, 50 ꢁC): d 156.9 (d, JP,C¼26 Hz, C),
142.0 (d, JP,C¼9 Hz, C), 133.3 (s, C), 133.2 (d, JP,C¼10 Hz,
CH), 132.8 (s, C), 132.4 (d, JP,C¼10 Hz, CH), 132.3 (s, CH),
131.9 (br s, CH), 131.3 (d, JP,C¼5 Hz, CH), 128.3 (d, JP,C
17 Hz, CH), 126.4 (d, JP,C¼14 Hz, CH), 126.3 (d, JP,C
¼
¼
Cationic complex 20 is the first platinacycle able to catalyze
cyclizations of enynes. It is noteworthy that this Pt(II) com-
plex bearing two acetonitrile ligands behaves similarly to
cationic Au(I) complexes leading to the selective activation
of the alkyne function of enynes.
13 Hz, CH), 119.7 (s, CN), 119.6 (s, CN), 22.7 (d,
JP,C¼8 Hz, CH3), 12.2 (s, CH2, Pt satellites, J¼702 Hz),
2.9 (d, JP,C¼1 Hz, CH3), 2.4 (s, CH3); 31P {1H} NMR
(162 MHz, CDCl3): d 19.8 (s, Pt satellites, J¼4600 Hz).
4.2. General procedure for the cyclization of substrates
10–12 (Scheme 2, Table 2)
4. Experimental
4.1. General
A mixture of enol ether (0.5 mmol, 1 equiv) and the stated
catalyst (PtCl2, 20, 26, or 27) (0.05 equiv) was dissolved
in toluene or CH2Cl2 (2.5 mL). The solution was stirred
under conditions stated in Scheme 2 and Tables 2 and 3
and then filtered through a short path of Celite. The solvent
was removed under reduced pressure and the residue was
purified by silica gel chromatography (100:1 hexane/EtOAc
containing 5% Et3N) to yield the corresponding product. For
40b a procedure detailed before was used.10a,c
Alcohols precursors of compounds 10a–d,25 12a,26 enyne
10a, 22b,10c,27 22c,28 22d,10c,28 23,27 24,10c,29 22e,10c,30
and 2510c,31 have been described. Experimental details for
the preparation of compounds 13a–g, 14a–c, 15a,b have
been reported.15
4.1.1. 2-(1-(But-2-ynyloxy)-2-ethoxyallyl)furan (12c).
Yield: 47% (800 mg, 3.29 mmol). Yellow oil. 1H NMR
(400 MHz, CDCl3): d 7.38 (dd, J¼1.8, 0.6 Hz, 1H), 6.37
(d, J¼3.2 Hz, 1H), 6.33 (dd, J¼3.2, 1.8 Hz, 1H), 5.02 (s,
1H), 4.39 (d, J¼2.3 Hz, 1H), 4.18 (d, J¼2.3 Hz, 1H),
4.17–4.15 (m, 2H), 3.38–3.76 (m, 2H), 1.85 (t, J¼2.3 Hz,
3H), 1.28 (t, J¼7.0 Hz, 3H); 13C NMR (100 MHz, CDCl3,
DEPT): d 158.5 (C), 152.3 (C), 142.4 (CH), 110.2 (CH),
108.7 (CH), 84.0 (CH2), 82.9 (C), 74.7 (C), 73.9 (CH), 63.3
(CH2), 56.5 (CH2), 14.3 (CH3), 3.7 (CH3). ESI-HRMS calcd
for C13H16O3Na [M++Na]: 243.0997, found: 243.0985.
4.2.1. Dimethyl 3-vinylcyclopent-3-ene-1,1-dicarboxylate
(22a). Colorless oil. H NMR (400 MHz, CDCl3): d 6.51–
1
6.44 (m, 1H), 5.58 (br s, 1H), 5.12–5.08 (m, 2H), 3.75 (s,
6H), 3.14 (br s, 2H), 3.11 (br s, 2H); 13C NMR (100 MHz,
CDCl3, DEPTQ): d 172.4 (C), 139.9 (C), 132.3 (CH),
126.8 (CH), 115.0 (CH2), 58.6 (C), 52.8 (CH3), 40.8 (CH2),
39.2 (CH2). ESI-HRMS calcd for C11H14O4Na [M++Na]:
233.0790, found: 233.0788.
4.2.2. 5,9-Diphenyl-3,4,7,9-tetrahydro-2H-pyrano[2,3-
c]oxepine (28a). Colorless oil. 1H NMR (400 MHz,
CDCl3): d 7.41–7.39 (m, 2H), 7.34–7.29 (m, 5H), 7.24–
7.20 (m, 3H), 6.15 (t, J¼6.8 Hz, 1H), 5.26 (s, 1H), 4.26
(dd, J¼11.2, 6.8 Hz, 1H), 4.14 (overlapped dd, J¼11.2,
6.8 Hz, 1H), 4.13–4.08 (overlapped m, 1H), 4.03–3.98 (m,
1H), 2.15–2.08 (m, 1H), 2.02–1.94 (m, 1H), 1.89–1.82 (m,
2H); 13C NMR (100 MHz, CDCl3, DEPT): d 156.3 (C),
149.1 (C), 139.6 (C), 139.2 (C), 128.3 (CH, 2C), 127.9
(CH, 2C), 127.7 (CH, 2C), 127.6 (CH), 127.5 (CH, 2C),
127.2 (CH), 124.7 (CH), 111.3, 77.8 (CH), 66.7 (CH2),
62.4 (CH2), 23.4 (CH2), 22.2 (CH2). ESI-HRMS calcd for
C21H20O2Na [M++Na]: 327.1361, found: 327.1364.
4.1.2. Synthesis of [Pt{o-CH2C6H4P(o-tolyl)2-C,P}-
(CH3CN)2][SbF6] (20). (a) [PtCl2(PhCN)2] was prepared
by a modification of a known procedure.32 PtCl2 (0.508 g,
1.901 mmol) in benzonitrile (30 mL) was heated at
180 ꢁC. After 15 min, the mixture was cooled to room tem-
perature. The solvent was partially evaporated to ca. 1/3 of
the original volume (9 mbar, 55 ꢁC). Hexane (20 mL) was
added and the precipitate was filtered and washed
with hexane (3ꢂ10 mL) to yield [Pt(PhCN)2Cl2] (cis
and trans mixture) as a yellow powder (0.808 g, 90%). (b)
[Pt{CH2C6H4P(o-tolyl)2-C,P}(m-Cl)]2,18
a
mixture of
[PtCl2(PhCN)2] (cis+trans, 0.490 g, 1.04 mmol) and tri-o-
tolylphosphine (0.325 mg, 1.04 mmol) in 2-methoxyethanol
(6 mL), was refluxed for 30 min. The initial suspension was
dissolved to give a clear pale yellow solution and then a white
crystalline solid was deposited. After cooling, the solid was
filtered off, washed with methanol and Et2O to yield 19 as
a pale yellow insoluble solid (0.468 g, 84%). (c) [Pt{o-
CH2C6H4P(o-tolyl)2-C,P}(m-Cl)]2 (0.468 g, 0.44 mmol)
and AgSbF6 (0.307 g, 0.876 mmol) were stirred in aceto-
nitrile (10 mL) in the absence of light for 23 h. The mixture
was filtered and evaporated. The residue was dissolved in
CH2Cl2 then filtered through silica and evaporated to yield
a colorless oil that solidified on addition of a few drops of
Et2O. Complex 20 was obtained as a white solid (0.615 g,
4.2.3. 8-Phenyl-2,3,6,8-tetrahydrofuro[2,3-c]oxepine
(28b). Colorless oil. H NMR (500 MHz, CDCl3): d 7.39–
1
7.30 (m, 5H), 6.04 (d, J¼10.5 Hz, 1H), 5.81 (dt, J¼10.5,
5.1 Hz, 1H), 5.51 (br s, 1H), 4.39–4.30 (m, 2H), 4.18 (dd,
J¼15.3, 5.1 Hz, 1H), 4.08 (dd, J¼15.4, 5.3 Hz, 1H), 2.94–
2.83 (m, 2H); 13C NMR (125 MHz, CDCl3, DEPT):
d 157.9 (C), 139.2 (C), 128.5 (CH, 2C), 128.4 (CH), 128.4
(CH, 2C), 127.1 (CH), 124.7 (CH), 109.7 (C), 80.3 (CH),
69.8 (CH2), 64.9 (CH2), 33.9 (CH2). ESI-HRMS calcd for
C14H14O2Na [M++Na]: 237.0891, found: 237.0897.
4.2.4. 8-p-Tolyl-2,3,6,8-tetrahydrofuro[2,3-c]oxepine
(28c). Colorless oil. H NMR (500 MHz, CDCl3): d 7.25
1
1
86%). H NMR (500 MHz, CDCl3, 50 ꢁC): d 7.45 (tt,
J¼7.3, 1.6 Hz, 2H), 7.39–7.30 (m, 4H), 7.20 (t, J¼7.2 Hz,
2 H), 7.08 (td, J¼7.2, 2.7 Hz, 1H), 6.93 (dd, J¼10.4, 7.7 Hz,
1H), 3.42 (br s, 2H, Pt satellites, J¼100 Hz), 2.58 (br s, 6H),
2.46 (d, J¼1.0 Hz, 3H), 2.09 (s, 3H); 13C {1H} NMR
(d, J¼8.1 Hz, 2H), 7.16 (d, J¼7.9 Hz, 2H), 6.03 (d,
J¼10.5 Hz, 1H), 5.79 (dt, J¼10.5, 5.2 Hz, 1H), 5.47 (s,
1H), 4.38–4.30 (m, 2H), 4.18 (dd, J¼15.3, 5.1 Hz, 1H),
4.06 (dd, J¼15.4, 5.4 Hz, 1H), 2.93–2.82 (m, 2H), 2.33 (s,

6312
C. Ferrer et al. / Tetrahedron 63 (2007) 6306–6316
3H); 13C NMR (125 MHz, CDCl3, DEPT): d 158.1 (C),
138.2 (C), 136.3 (C), 129.2 (CH, 2C), 128.4 (CH, 2C),
127.1 (CH), 124.7 (CH), 109.6, 80.0 (CH), 69.8 (CH2),
64.8 (CH2), 33.9 (CH2), 21.2 (CH3). ESI-HRMS calcd for
C15H16O2Na [M++Na]: 251.1048, found: 251.1044.
minor), 141.3 (CH, major), 110.7 (CH, major), 110.1 (CH,
minor), 107.2 (minor), 106.9 (CH, minor), 106.8 (CH, ma-
jor), 106.5 (major) (C), 62.3 (CH2, major), 62.2 (CH2, minor),
57.6 (CH, minor), 57.4 (CH, major), 44.3 (CH, major), 43.6
(CH, minor), 38.2 (CH2, major), 35.6 (CH2, minor), 23.9
(CH, major), 23.3 (CH, minor), 21.0 (minor) (C), 20.6
(major) (C), 15.6 (CH3, major), 15.5 (CH3, minor), 14.2
(CH3, major), 14.0 (CH3, minor). ESI-HRMS calcd for
C13H16O3Na [M++Na]: 243.0997, found: 243.1005.
4.2.5. 2-(3,4-Dihydro-2H-pyran-6-yl)-6-methyl-7-phen-
yl-3-oxabicyclo[4.1.0]hept-4-ene (29). Colorless oil. 1H
NMR (400 MHz, CDCl3): d 7.31–7.27 (m, 2H), 7.21–7.17
(m, 3H), 6.27 (d, J¼5.9 Hz, 1H), 5.18 (d, J¼5.9 Hz, 1H),
4.97 (t, J¼3.9 Hz, 1H), 4.17 (br s, 1H), 4.07 (dd, J¼5.9,
4.4 Hz, 2H), 2.47 (d, J¼5.7 Hz, 1H), 2.06–2.02 (m, 2H),
1.89 (dd, J¼5.7, 1.6 Hz, 1H), 1.87–1.81 (m, 2H), 0.91 (s,
3H); 13C NMR (100 MHz, CDCl3, DEPT): d 153.0 (C),
140.8 (CH), 138.2 (C), 129.0 (CH, 2C), 128.1 (CH, 2C),
126.0 (CH), 111.5 (CH), 97.9 (CH), 70.6 (CH), 66.5
(CH2), 35.0 (CH), 32.0 (CH), 22.4 (CH2), 20.0 (CH2), 19.9
(C), 17.9 (CH3). ESI-HRMS calcd for C18H20O2Na
[M++Na]: 291.1361, found: 291.1356.
4.2.7. (2-(Propa-1,2-dienyl)tetrahydrofuran-2-yl)(p-
tolyl)methanone (32). Colorless oil. H NMR (400 MHz,
1
CDCl3): d 8.05 (d, J¼8.3 Hz, 2H), 7.21 (d, J¼7.9 Hz, 2H),
5.49 (t, J¼6.6 Hz, 1H), 4.90 (dd, J¼11.3, 6.6 Hz, 1H),
4.84 (dd, J¼11.3, 6.3 Hz, 1H), 4.02 (dt, J¼14.3, 7.6 Hz,
1H), 3.87 (dt, J¼14.3, 7.6 Hz, 1H), 2.70–2.62 (m, 1H),
2.39 (s, 3H), 2.14–2.07 (m, 1H), 2.01–1.95 (m, 1H), 1.90–
1.84 (m, 1H); 13C NMR (100 MHz, CDCl3, DEPT):
d 207.2 (C), 198.8 (C), 143.5 (C), 132.1 (C), 130.5 (CH,
2C), 128.7 (CH, 2C), 95.0 (CH), 89.3 (C), 78.7 (CH2),
68.9 (CH2), 34.7 (CH2), 25.0 (CH2), 21.6 (CH3). ESI-
HRMS calcd for C15H16O2Na [M++Na]: 251.1048, found:
251.1038.
Acetal 30: white solid. 1H NMR (400 MHz, CDCl3): d 7.38–
7.36 (m, 2H), 7.28–7.24 (m, 2H), 7.19–7.14 (m, 1H), 6.51 (d,
J¼15.9 Hz, 1H), 6.16 (dd, J¼15.9, 8.5 Hz, 1H), 3.91–3.82
(m, 2H), 3.71 (d, J¼4.2 Hz, 1H), 2.60 (d, J¼8.3 Hz, 1H),
1.72–1.69 (m, 1H), 1.61–1.57 (m, 2H), 1.45–1.42 (m, 2H),
1.21 (dd, J¼4.3, 1.0 Hz, 1H), 1.17 (s, 3H); 13C NMR
(100 MHz, CDCl3, DEPT): d 137.4 (C), 132.2 (CH), 128.3
(CH, 2C), 127.0 (CH), 126.3 (CH, 2C), 126.2 (CH), 103.6
(C), 65.2 (CH2), 56.4 (CH), 48.5 (CH), 43.3 (CH), 24.7
(CH), 24.1 (C), 23.7 (CH2), 20.8 (CH2), 11.6 (CH3). ESI-
HRMS calcd for C18H20O2Na [M++Na]: 291.1361, found:
291.1358.
4.3. Procedure for the preparation of 39a and 39b
4.3.1. (5,6-Dihydro-4H-pyran-2-yl)(phenyl)methyl ace-
tate. A mixture of (5,6-dihydro-4H-pyran-2-yl)(phenyl)-
methanol (1.00 g, 5.20 mmol), DMAP (32 mg, 0.30 mmol),
and DIPEA (1.1 mL, 6.30 mmol) was dissolved in CH2Cl2
(5 mL) and cooled at 0 ꢁC. Then, Ac2O (0.6 mL, 6.30 mmol)
was added and the mixture was stirred at 23 ꢁC for 4 h. The
reaction mixture was diluted with CH2Cl2, washed with
H2O, and dried over MgSO4. After evaporation of the sol-
vent, the residue was chromatographed (10:1 hexane/EtOAc
with 5% Et3N) to give the title compound as a colorless oil.
Yield: 88% (1.10 g, 5.90 mmol). 1H NMR (300 MHz,
CDCl3): d 7.41–7.29 (m, 5H), 6.14 (s, 1H), 4.85 (t, J¼
3.8 Hz, 1H), 3.98 (td, J¼5.7, 1.4 Hz, 2H), 2.14 (s, 3H),
2.06–2.03 (m, 2H), 1.84–1.76 (m, 2H); 13C NMR
(75 MHz, CDCl3): d 170.6, 152.3, 138.5, 128.9, 128.7,
127.8, 100.4, 75.9, 67.2, 22.7, 21.9, 20.7. EI-HRMS calcd
for C14H16O3: 232.1099, found: 232.1101.
4.2.6. 5-Methylene-8-(naphthalen-2-yl)-2,3,4,5,6,8-hexa-
hydropyrano[3,4-b]pyran (31). Colorless oil. 1H NMR
(500 MHz, CDCl3): d 7.85–7.81 (m, 4H), 7.52 (dd, J¼8.5,
1.5 Hz, 1H), 7.48–7.46 (m, 2H), 5.28 (s, 1H), 4.74 (s, 1H),
4.63 (s, 1H), 4.32 (d, J¼13.3 Hz, 1H), 4.24 (d, J¼13.3 Hz,
1H), 4.06–3.97 (m, 2H), 2.36 (dt, J¼16.5, 6.5 Hz, 1H),
2.26 (dtd, J¼16.4, 6.6, 2.2 Hz, 1H), 2.02–1.96 (m, 2H);
13C NMR (125 MHz, CDCl3, DEPT): d 151.4 (C), 140.6
(C), 135.9 (C), 133.4 (C), 133.1 (C), 128.2 (CH), 128.2
(CH), 127.8 (CH), 127.7 (CH), 126.2 (CH), 126.1 (CH),
126.0 (CH), 106.9 (C), 101.0 (CH2), 76.6 (CH), 66.9 (CH2),
66.7 (CH2), 22.3 (CH2), 19.2 (CH2). ESI-HRMS calcd for
C19H18O2Na [M++Na]: 301.1204, found: 301.1216.
4.3.2. Dimethyl 2-[(5,6-dihydro-4H-pyran-2-yl)(phenyl)-
methyl]malonate. A mixture of the above acetate (89 mg,
0.40 mmol), triphenylphosphine (10 mg, 0.04 mmol), and
Pd(PPh3)4 (31 mg, 0.03 mmol) was refluxed in THF (1 mL)
for 2 h. In a separate flask, dimethyl malonate (0.2 mL,
1.60 mmol) was slowly added to a suspension of NaH
(60% in mineral oil, 6.3 mg, 1.60 mmol) in THF (3 mL)
and stirred for 20 min. The resulting solution was added in
one portion to the former and the combined mixture refluxed
for 72 h. The reaction mixture was diluted with Et2O and wa-
ter, the aqueous phase was extracted with ether (3ꢂ10 mL),
and the ether extracts were dried over MgSO4. The solvent
was evaporated and the residue was purified by chromato-
graphy (30:1 hexane/EtOAc with 5% Et3N) yielding the cor-
responding product as a pale yellow oil. Yield: 18% (21 mg,
1
Acetals 33a,b: yellow oil, 3:1 isomer mixture. H NMR
(400 MHz, CDCl3): d 7.37–7.36 (m, 1H, minor), 7.34 (dd,
J¼1.7, 0.8 Hz, 1H, major), 6.33 (overlapped dd, J¼3.2,
1.8 Hz, 1H, minor), 6.32 (overlapped dd, J¼3.2, 1.8 Hz, 1H,
major), 6.19 (d, J¼3.1 Hz, 1H, major), 6.13–6.12 (m, 1H,
minor), 3.95–3.87 (m, 1H, minor), 3.84 (d, J¼4.2 Hz,
1H, major), 3.81–3.77 (overlapped m, 1H, minor), 3.78
(overlapped d, J¼4.9 Hz, 1H, minor), 3.63 (q, J¼7.1 Hz,
2H, major), 3.14 (s, 1H, major), 3.06 (s, 1H, minor), 1.74
(d, J¼10.1 Hz, 1H, major), 1.70 (d, J¼10.1 Hz, 1H, minor),
1.65 (d, J¼10.1 Hz, 1H, major), 1.40 (d, J¼10.2 Hz, 1H,
minor), 1.38 (overlapped d, J¼3.2 Hz, 1H, minor), 1.36
(overlapped d, J¼4.4 Hz, 1H, major), 1.30 (s, 3H, minor),
1.26 (s, 3H, major), 1.24 (t, J¼7.1 Hz, 3H, minor), 1.15 (t,
J¼7.1 Hz, 3H, major); 13C NMR (100 MHz, CDCl3,
DEPT): d 153.3 (C, minor), 152.4 (C, major), 141.8 (CH,
1
0.07 mmol). H NMR (300 MHz, CDCl3): d 7.38–7.23 (m,
5H), 4.73 (t, J¼3.6 Hz, 1H), 4.17 (d, J¼11.7 Hz, 1H), 4.04
(d, J¼11.7 Hz, 1H), 4.05–3.89 (m, 2H), 3.80 (s, 3H), 3.50
(s, 3H), 2.04–1.97 (m, 2H), 1.79–1.72 (m, 2H); 13C NMR

C. Ferrer et al. / Tetrahedron 63 (2007) 6306–6316
6313
(75 MHz, CDCl3): d 169.0, 168.8, 153.4, 140.1, 128.9,
128.7, 127.7, 98.6, 67.1, 55.8, 53.2, 53.0, 51.2, 22.8, 20.9.
EI-HRMS calcd for C17H20O5: 304.1311, found: 304.1322.
1.6 Hz, 3H); 13C NMR (75 MHz, CDCl3, DEPT): d 170.7
(C), 169.5 (C), 149.6 (C), 137.8 (C), 131.3 (C), 129.0
(CH), 128.3 (CH), 127.5 (CH), 114.8 (CH), 108.5 (C),
66.2 (CH2), 58.5 (C), 52.7 (CH3), 52.2 (CH3), 48.1 (CH),
25.9 (CH2), 22.4 (CH2), 20.2 (CH2), 13.6 (CH3). EI-
HRMS calcd for C21H24O5: 356.1624, found: 356.1610.
4.3.3. Dimethyl 2-(4,5-dihydrofuran-2-yl)(p-tolyl-methyl)-
malonate. Yield: 43% (570 mg, 1.74 mmol). White solid.
1H NMR (500 MHz, CDCl3): d 7.20 (d, J¼8.1 Hz, 2H),
7.10 (d, J¼8.1 Hz, 2H), 4.74 (t, J¼2.5 Hz, 1H), 4.33–4.22
(m, 3H), 4.03 (d, J¼11.3 Hz, 1H), 3.78 (s, 3H), 3.49 (s,
3H), 2.60–2.54 (m, 2H), 2.31 (s, 3H); 13C NMR
(125 MHz, CDCl3, DEPT): d 168.2 (C), 167.7 (C), 157.4
(C), 137.0 (C), 135.2 (C), 129.1 (CH, 2C), 128.1 (CH, 2C),
95.9 (CH), 70.3 (CH2), 55.8 (CH), 52.7 (CH3), 52.4 (CH3),
44.5 (CH), 29.9 (CH2), 21.1 (CH3). ESI-HRMS calcd for
C17H20O5Na [M++Na]: 327.1208, found: 327.1198.
4.3.7. Dimethyl 5-ethyl-3,4-dihydro-8-phenyl-2H-chro-
mene-7,7(8H)-dicarboxylate (40b). Colorless oil. 1H
NMR (300 MHz, CDCl3): d 7.32–7.20 (m, 5H), 5.36 (dd,
J¼2.4, 1.0 Hz, 1H), 4.09 (d, J¼2.4 Hz, 1H), 3.80–3.61 (m,
2H, overlapped), 3.78 (s, 3H), 3.75 (s, 3H), 2.35 (q,
J¼7.5 Hz, 2H), 1.68–1.37 (m, 4H), 1.26 (t, J¼7.5 Hz, 3H);
13C NMR (75 MHz, CDCl3): d 170.3, 169.5, 151.8, 136.4,
127.9, 127.2, 97.7, 95.2, 61.6, 56.0, 52.9, 52.1, 50.9, 32.9,
27.2, 24.6, 11.3.
4.3.4. Dimethyl 2-(but-2-ynyl)-2-[(5,6-dihydro-4H-
pyran-2-yl)(phenyl)methyl]malonate (39a). To a suspen-
sion of NaH (60% in mineral oil, 3 mg, 0.07 mmol) in
DMF (0.5 mL) at 0 ꢁC a solution of dimethyl 2-[(5,6-
dihydro-4H-pyran-2-yl)(phenyl)methyl]malonate (21 mg,
0.07 mmol) in DMF (1 mL) was added. The mixture was
stirred for 5 min and 1-bromo-2-propyne (9 mL, 0.07 mmol)
was then added. The reaction mixture was stirred for 3 h at
room temperature and then quenched with an ice-water mix-
ture and extracted with Et2O. The organic layer was washed
with water (3ꢂ1 mL), dried over MgSO4, and concentrated
in vacuo. The residue was purified by chromatography (50:1
hexane/EtOAc with 2% Et3N) to give 39a as a yellow oil.
Yield: 80% (20 mg, 0.06 mmol). 1H NMR (300 MHz,
CDCl3): d 7.50–7.45 (m, 2H), 7.33–7.25 (m, 3H), 4.75 (t,
J¼3.6 Hz, 1H), 4.26 (s, 1H), 4.03–3.92 (m, 2H), 3.76 (s,
3H), 3.72 (s, 3H), 2.80 (dq, J¼16.6, 2.4 Hz, 1H), 2.72 (dq,
J¼16.6, 2.4 Hz, 1H), 2.09–1.97 (m, 2H), 1.80–1.77 (m,
2H), 1.75 (t, J¼2.4 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d 171.1 (C), 171.1 (C), 153.0 (C), 139.0 (C), 131.0 (CH),
128.2 (CH), 127.6 (CH), 100.8 (CH), 79.0 (C), 75.1 (CH),
66.8 (CH2), 61.0 (C), 54.9 (CH or CH3), 53.0 (CH or
CH3), 52.8 (CH or CH3), 26.3 (CH2), 22.6 (CH2), 21.1
(CH2), 4.2 (CH3). FAB-HRMS calcd for C21H24O5:
356.1624, found: 356.1613.
4.3.8. Dimethyl 4-methyl-7-p-tolyl-2,3-dihydrobenzo-
furan-6,6(5H)-dicarboxylate (40c). Colorless oil. 1H
NMR (400 MHz, CDCl3): d 7.34 (d, J¼8.2 Hz, 2H), 7.07 (d,
J¼7.9 Hz, 2H), 4.26 (t, J¼7.4 Hz, 2H), 3.60 (s, 6H), 3.00 (s,
2H), 2.66 (br s, 2H), 2.29 (s, 3H), 1.85 (s, 3H); 13C NMR
(100 MHz, CDCl3, DEPT): d 172.6 (2C), 152.9 (C), 135.6
(C), 133.4 (C), 128.8 (CH, 2C), 128.5 (CH, 2C), 127.6 (C),
126.5 (C), 100.2 (C), 70.5 (CH2), 61.5 (C), 52.6 (CH3, 2C),
39.2 (CH2), 26.6 (CH2), 21.2 (CH3), 19.6 (CH3). ESI-HRMS
calcd for C20H22O5Na [M++Na]: 365.1365, found: 365.1356.
4.4. Synthesis of dienynes 49a–e dienynes (Table 3)
4.4.1. Dimethyl 2-(2-methylenebut-3-enyl)-2-(prop-2-
ynyl)propanedioate (49a). (a) To a solution of dimethyl
2-(2-bromo-2-propenyl)malonate (1.25 g, 5.0 mmol) in tol-
uene (10 mL) was added [Pd(PPh3)4] (289 mg, 0.25 mmol).
The solution was stirred at room temperature for 15 min and
tributylvinyltin (1.75 mL, 6 mmol) was added. The mixture
was heated to reflux for 2 h. After extractive workup
(EtOAc/saturated aqueous solution of KF) and chromato-
graphy (9:1 hexane/EtOAc), dimethyl 2-(2-methylene-3-
butenyl)malonate was obtained as a colorless oil. Yield:
1
75% (731 mg, 3.75 mmol). H NMR (400 MHz, CDCl3):
d 6.35 (dd, J¼11.0, 17.7 Hz, 1H), 5.26 (d, J¼17.7 Hz,
1H), 5.12 (d, J¼11 Hz, 1H), 5.08 (s, 1H), 5.04 (s, 1H), 3.74
(s, 6H), 3.66 (dt, J¼7.5, 1.5 Hz, 1H), 2.86 (d, J¼7.5 Hz, 2H);
13C NMR (100 MHz, CDCl3, DEPT): d 169.4 (C), 142.3 (C),
137.7 (CH), 117.9 (CH2), 113.9 (CH2), 52.5 (CH3), 50.6
(CH), 30.5 (CH2). ESI-HRMS calcd for C10H14O4Na
[M++Na]: 221.0790, found: 221.0789. (b) To a cold suspen-
sion of NaH (60% in mineral oil, 165.5 mg, 4.14 mmol) in
dry DMF (5 mL) was added via cannula a solution of the
above diene (820 mg, 4.14 mmol) in dry DMF (5 mL).
The reaction mixture was stirred at this temperature for
30 min before adding propargyl bromide (80% wt in toluene,
461 mL, 4.14 mmol). The cooling bath was removed and the
reaction mixture was stirred for 12 h at room temperature.
After extractive workup (Et2O/10% aqueous HCl) and chro-
matography (9:1 hexane/EtOAc), enyne 49a was obtained as
a colorless oil, which solidifies on standing at <0 ꢁC. Yield:
83% (815 mg, 3.44 mmol). The spectroscopic data were in
agreement with those reported.33
4.3.5. Dimethyl 2-(4,5-dihydrofuran-2-yl)(p-tolylmethyl)-
2-(prop-2-ynyl)malonate (39b). Yield: 98% (560 mg,
1.53 mmol). Colorless oil. H NMR (500 MHz, CDCl3):
1
d 7.25 (d, J¼7.9 Hz, 2H), 7.08 (d, J¼7.9 Hz, 2H), 4.76 (br
s, 1H), 4.43 (s, 1H), 4.33–4.24 (m, 2H), 3.75 (s, 3H), 3.70
(s, 3H), 2.79 (dd, J¼16.8, 2.5 Hz, 1H), 2.66 (dd, J¼16.8,
2.8 Hz, 1H), 2.56–2.52 (m, 2H), 2.31 (s, 3H), 1.99 (t,
J¼2.8 Hz, 1H); 13C NMR (125 MHz, CDCl3, DEPT):
d 170.0 (C), 169.7 (C), 156.3 (C), 137.2 (C), 133.6 (C),
130.0 (CH, 2C), 128.7 (CH, 2C), 98.8 (CH), 79.8 (C), 71.0
(CH), 70.3 (CH2), 60.2 (C), 52.6 (CH3), 52.5 (CH3), 48.5
(CH), 29.9 (CH2), 25.0 (CH2), 21.1 (CH3). ESI-HRMS calcd
for C20H22O5Na [M++Na]: 365.1365, found: 365.1359.
4.3.6. (5E)-Dimethyl 5-ethylidene-3,4,5,6-tetrahydro-8-
phenyl-2H-chromene-7,7(8H)-dicarboxylate (40a). Col-
orless oil. H NMR (300 MHz, CDCl3): d 7.32–7.28 (m,
1
5H), 5.43 (qd, J¼6.9, 2.0 Hz, 1H), 4.34 (s, 1H), 4.10–4.03
(m, 1H), 3.82–3.74 (m, 1H), 3.76 (s, 3H), 3.56 (s, 3H), 3.16
(dd, J¼16.2, 1.6 Hz, 1H), 2.66 (dquint, J¼16.2, 2.0 Hz, 1H),
2.32–2.15 (m, 2H), 1.99–1.82 (m, 2H), 1.77 (dd, J¼6.9,
4.4.2. 2-(2-Methylenebut-3-enyl)-2-(prop-2-ynyl)pro-
pane-1,3-diyl diethanoate (49b). (a) To a solution of diester

6314
C. Ferrer et al. / Tetrahedron 63 (2007) 6306–6316
49a (815 mg, 3.45 mmol) in Et2O (20 mL) at 0 ꢁC was
added LiAlH4 portionwise (131 mg, 3.45 mmol). The reac-
tion mixture was stirred at this temperature for 1 h before
being quenched with a saturated solution of sodium potas-
sium tartrate. After extractive workup (EtOAc/water) and
chromatography (7:3 hexane/EtOAc), 2-(2-methylene-3-
butenyl)-2-(2-propynyl)-1,3-propanediol was obtained as a
(400 MHz, CDCl3): d 6.02 (d, J¼15.9 Hz, 1H), 5.72 (td,
J¼6.9, 15.9 Hz, 1H), 4.93 (s, 1H), 4.88 (s, 1H), 3.73 (s,
3H), 3.67 (s, 3H), 3.65 (t, J¼7.6 Hz, 1H), 2.83 (d, J¼
7.6 Hz, 2H), 2.07 (q, J¼7.0 Hz, 2H), 1.42 (sextuplet,
J¼7.3 Hz, 2H), 0.90 (t, J¼7.3 Hz, 3H); 13C NMR
(100 MHz, CDCl3, DEPT): d 170.0 (C), 140.9 (C), 131.8
(CH), 131.1 (CH), 117.2 (CH2), 79.5 (C), 52.5 (CH3), 71.7
(CH), 52.6 (CH), 35.0 (CH2), 33.4 (CH2), 22.8 (CH2), 22.4
(CH2), 13.8 (CH3). (b) To a cold suspension of NaH (60%
in mineral oil, 25.3 mg, 0.633 mmol) in dry DMF (2 mL)
was added via cannula a solution of the above diene
(152.2 mg, 0.633 mmol) in dry DMF (1 mL). The reaction
mixture was stirred at this temperature for 30 min before
adding propargyl bromide (80% wt in toluene, 70.5 mL,
0.633 mmol). The cooling bath was removed and the reac-
tion mixture was stirred overnight at room temperature. Af-
ter extractive workup (10% HCl, Et2O) and chromatography
(85:15 hexane/EtOAc), dienyne 49d was obtained as a color-
less oil. Yield: 81% (142.8 mg, 0.51 mmol). 1H NMR
(400 MHz, CDCl3): d 5.98 (d, J¼15.9 Hz, 1H), 5.83 (td,
J¼6.8, 15.9 Hz, 1H), 5.08 (s, 1H), 4.93 (s, 1H), 3.72 (s,
6H), 3.00 (s, 2H), 2.84 (d, J¼2.6 Hz, 2H), 2.07–2.02 (m,
3H), 1.40 (sextuplet, J¼7.4 Hz, 2H), 0.90 (t, J¼7.4 Hz, 3H);
13C NMR (100 MHz, CDCl3, DEPT): d 170.7 (C), 141.2 (C),
132.2 (CH), 131.4 (CH), 117.6 (CH2), 79.9 (C), 72.0 (CH),
57.6 (C), 53.0 (CH3), 35.3 (CH2), 33.7 (CH2), 23.1 (CH2),
22.8 (CH2), 14.1 (CH3). CI-HRMS calcd for C16H23O4
[M++H]: 279.1596, found: 279.1596.
1
colorless oil. Yield: 47% (295 mg, 1.62 mmol). H NMR
(400 MHz, CDCl3): d 6.43 (dd, J¼10.8, 17.5 Hz, 1H), 5.40
(d, J¼17.5 Hz, 1H), 5.24 (s, 1H), 5.15 (s, 1H), 5.08 (d,
J¼10.8 Hz, 1H), 4.62 (s, 4H), 2.57 (br s, 2H), 2.34 (s, 2H),
2.30 (d, J¼2.7 Hz, 2H), 2.07 (t, J¼2.7 Hz, 1H); 13C NMR
(100 MHz, CDCl3, DEPT): d 142.3 (C), 140.2 (CH), 119.8
(CH2), 114.0 (CH2), 85.0 (C), 71.3 (CH), 67.4 (CH2), 42.8
(C), 32.2 (CH2), 21.9 (CH2). ESI-HRMS calcd for
C11H16O2Na [M++Na]: 203.1048, found: 203.1053. (b) To
a solution of the above diol (151.5 mg, 0.84 mmol), diiso-
propylethylamine (351 mL, 2.02 mmol), and acetic anhy-
dride (275 mL, 2.02 mmol) in CH2Cl2 (1.5 mL) was added
DMAP (5.1 mg, 0.04 mmol). After 30 min, the mixture
was diluted with CH2Cl2. After extractive workup and chro-
matography (85:15 hexane/EtOAc), diacetate 49b was ob-
tained as a colorless oil. Yield: 57% (126.8 mg, 0.48 mmol).
1H NMR (400 MHz, CDCl3): d 6.38 (dd, J¼10.8, 17.5 Hz,
1H), 5.34 (d, J¼17.5 Hz, 1H), 5.26 (s, 1H), 5.08 (s, 1H),
5.065 (d, J¼10.8 Hz, 1H), 4.00 (s, 4H), 2.44 (s, 2H), 2.31
(s, 2H), 2.07 (br s, 7H); 13C NMR (100 MHz, CDCl3,
DEPT): d 170.6 (C), 141.0 (C), 139.6 (CH), 120.1 (CH2),
113.9 (CH2), 79.8 (C), 71.8 (CH), 65.4 (CH2), 40.3 (C),
31.9 (CH2), 22.5 (CH2), 20.8 (CH3). ESI-HRMS calcd for
C15H20O4Na [M++Na]: 287.1259, found: 287.1251.
4.4.5. 4-Methyl-N-(2-methylene-3-butenyl)-N-(2-propy-
nyl)benzenesulfonamide (49e). (a) To a suspension of
NaH (60% in mineral oil, 294.8 mg, 7.37 mmol) in DMF
(20 mL) was added portionwise TsNHBoc34 (2.0 g,
7.37 mmol) at 0 ꢁC. The reaction mixture was stirred for
1 h at this temperature before adding 2,3-dibromopropene
(80%, 820 mL, 7.37 mmol) and the mixture was left to
warm up overnight. After extractive workup (Et2O/water)
the solvent was evaporated to give a thick orange oil, which
solidifies on standing. The product was recrystallized from
hexane to give N-(2-bromo-2-propenyl)-N-[(2,2-dimethyl-
propanoyl)oxy]-4-methylbenzenesulfonamide as a white
beige solid. Yield: 56% (1.61 g, 4.13 mmol). Mp 96–
97.5 ꢁC. 1H NMR (400 MHz, CDCl3): d 7.84 (d, J¼8.4 Hz,
2H), 7.32 (d, J¼8.4 Hz, 2H), 5.88–5.87 (m, 1H), 5.66–5.64
(m, 1H), 4.68 (appt t, J¼1.5 Hz, 2H), 2.46 (s, 3H), 1.39 (s,
9H); 13C NMR (100 MHz, CDCl3, DEPT): d 150.3 (C),
144.5 (C), 136.6 (C), 129.2 (CH), 128.4 (CH), 127.9 (C),
117.9 (CH2), 84.9 (C), 53.1 (CH2), 27.8 (CH3), 21.6 (CH3).
ESI-HRMS calcd for C15H20O4SBrNa [M++Na]: 412.0194,
found: 412.0201. (b) To a solution of the abovevinyl bromide
(780.6 mg, 2.0 mmol) in toluene (6 mL) was added
[Pd(PPh3)4] (115.6 mg, 0.1 mmol) followed by tributylvinyl-
tin (700 mL, 2.4 mmol). The mixture was heated to reflux for
2 h. The crude mixture was directly chromatographed (9:1
hexane/EtOAc) to give N-[(2,2-dimethylpropanoyl)oxy]-
4-methyl-N-(2-methylene)-3-butenyl)benzenesulfonamide
was obtained as an oil. Yield: 62% (418 mg, 1.24 mmol). 1H
NMR (400 MHz, CDCl3): d 7.84 (d, J¼8.4 Hz, 2H), 7.30 (d,
J¼8.1 Hz, 2H), 6.44 (dd, J¼11.2, 17.9 Hz, 1H), 5.26 (d,
J¼17.9 Hz, 1H), 5.19 (s, 1H), 5.135 (s, 1H), 5.09 (s, 1H),
4.65 (s, 2H), 2.44 (s, 3H), 1.36 (s, 9H); 13C NMR
(100 MHz, CDCl3, DEPT): d 150.8 (C), 144.3 (C), 141.0
(C), 137.0 (C), 136.7 (CH), 129.1 (CH), 128.3 (CH), 115.2
4.4.3. 2,2-Dimethyl-5-(2-methylene-3-butenyl)-5-(2-pro-
pynyl)-1,3-dioxane (49c). To a solution of 2-(2-methyl-
ene-3-butenyl)-2-(2-propynyl)-1,3-propanediol (143.5 mg,
0.77 mmol) in dimethoxypropane (3 mL) at 0 ꢁC was added
p-TSA (15 mg, 0.077 mmol). After 30 min the reaction mix-
ture was quenched with Et3N (200 mL) and the solvent was
evaporated. After extractive workup (Et2O/10% aqueous
NaOH) and chromatography (basic alumina, 19:1 hexane/
EtOAc), acetonide 49c was obtained as a colorless oil. Yield:
1
58% (101 mg, 0.45 mmol). H NMR (400 MHz, CDCl3):
d 6.24 (dd, J¼11.0, 17.5 Hz, 1H), 5.40 (d, J¼17.5 Hz,
1H), 5.06 (s, 1H), 5.01 (s, 1H), 4.93 (d, J¼11.0 Hz, 1H),
3.60 (s, 4H), 2.35 (s, 2H), 2.29 (s, 2H), 1.76 (t, J¼2.6 Hz,
1H), 1.35 (s, 3H), 1.32 (s, 3H); 13C NMR (100 MHz, C6D6,
DEPT): d 142.9 (C), 140.8 (CH), 120.5 (CH2), 115.0 (CH2),
98.6 (C), 82.0 (C), 72.4 (CH), 67.4 (CH2), 36.4 (C), 33.9
(CH2), 25.8 (CH3), 23.8 (CH2), 23.4 (CH3). ESI-HRMS
calcd for C14H20O2Na [M++Na]: 243.1361, found:
243.1351.
4.4.4. Dimethyl 2-[(E)-2-methylene-3-heptenyl]-2-(2-pro-
pynyl)malonate (49d). (a) To a stirred solution of dimethyl
2-(2-bromo-2-propenyl)malonate (500 mg, 1 mmol) in THF
(30 mL) were added under N2, Pd(dba)2 (99.6 mg,
0.05 mmol), tri-o-tolyl phosphine (60 mg, 0.1 mmol),
penten-1-boronic acid (340 mg, 1.5 mmol) and CsF
(912 mg, 4.5 mmol). The reaction mixture was heated up
to reflux overnight. After extractive workup (EtOAc, water)
and chromatography (90:10 hexane/EtOAc), dimethyl 2-
[(E)-2-methylene-3-heptenyl]malonate was obtained as a
1
colorless oil. Yield: 64% (308.1 mg, 0.64 mmol). H NMR

C. Ferrer et al. / Tetrahedron 63 (2007) 6306–6316
6315
1
(CH2), 113.9 (CH2), 84.3 (C), 47.5 (CH2), 27.8 (CH3), 21.6
(CH3). ESI-HRMS calcd for C17H23NO4SNa [M++Na]:
360.1245, found: 360.1252. (c) To a solution of Boc pro-
tected amine (395 mg, 1.17 mmol) in CH2Cl2 (2 mL) at
0 ꢁC was added TFA (350 mL) dropwise. The reaction mix-
ture was stirred at room temperature for 2 h. After extractive
workup (CH2Cl2/saturated aqueous NaHCO3) and chromato-
graphy (90:5:5 to 85:10:5 hexane/EtOAc/Et3N), 4-methyl-N-
(2-methylene-3-butenyl)benzenesulfonamide was obtained
as a white solid. Yield: 76% (211 mg, 0.89 mmol). The spec-
troscopic data were in agreement with those reported.35 (d)
To a slurry of NaH (60% in mineral oil, 33 mg, 0.83 mmol)
in DMF (1.0 mL) at 0 ꢁC was added dropwise a solution of
the above amine (196 mg, 0.83 mmol) in DMF (1.0 mL).
The solution was stirred for 30 min at this temperature before
adding propargyl bromide (80% wt in toluene, 92.0 mL,
0.82 mmol) and the solution was left to reach room temper-
ature and stirred for 12 h. After extractive workup (Et2O/
water) and chromatography (90:8:2 hexane/EtOAc/Et3N),
enyne 49e was obtained as a white solid. Yield: 84%
(191 mg, 0.70 mmol). The spectroscopic data were in agree-
ment with those reported.36
(dec). H NMR (400 MHz, CDCl3): d 7.75 (d, J¼8.2 Hz,
2H), 7.33 (d, J¼8.2 Hz, 2H), 6.6 (dd, J¼10.9, 17.6 Hz,
2H), 5.23 (d, J¼11.0 Hz, 2H), 5.08 (d, J¼17.6 Hz, 2H),
4.30 (s, 4H), 2.42 (s, 3H); 13C NMR (100 MHz, CDCl3,
DEPT): d 143.6 (C), 133.9 (C), 132.5 (C), 129.8 (CH),
127.5 (CH), 126.9 (CH), 117.2 (CH2), 55.0 (CH2), 21.5
(CH3). ESI-HRMS calcd for C15H17NO2NaS [M++Na]:
298.0878; found: 298.0880.
4.4.11. (1R*,6S*)-3-[(4-Methylphenyl)sulfonyl]-1-vinyl-
3-azabicyclo[4.1.0]hept-4-ene (51). White solid. Mp 55–
55.5 ꢁC. 1H NMR (400 MHz, CDCl3): d 7.66 (d, J¼
8.2 Hz, 2H), 7.32 (d, J¼8.2 Hz, 2H), 6.35 (d, J¼7.7 Hz,
1H), 5.48 (dd, J¼10.3, 17.7 Hz, 1H), 5.42 (dd, J¼5.8,
7.7 Hz, 1H), 4.97 (d, J¼10.3 Hz, 1H), 4.93 (d, J¼17.7 Hz,
1H), 3.97 (d, J¼11.1 Hz, 1H), 2.99 (d, J¼11.1 Hz, 1H),
2.42 (s, 3H), 1.21–1.16 (m, 1H), 0.95–0.92 (m, 1H), 0.81
(t, J¼4.8 Hz, 1H); 13C NMR (100 MHz, CDCl3, DEPT):
d 143.8 (C), 140.3 (CH), 134.9 (C), 129.8 (CH), 127.0
(CH), 121.3 (CH), 112.0 (CH2), 111.8 (CH), 43.1 (CH2),
32.2 (C), 21.5 (CH), 19.6 (CH2), 17.2 (CH). ESI-HRMS
calcd for C15H17NO2NaS [M++Na]: 298.0878, found:
298.0891.
4.4.6. Dimethyl 3,4-divinyl-3-cyclopentene-1,1-dicarb-
oxylate (50a). H NMR (400 MHz, CDCl3): d 6.75 (dd,
1
J¼10.3, 17.7 Hz, 2H), 5.182 (d, J¼10.3 Hz, 2H), 5.178 (d,
J¼17.7 Hz, 2H), 3.74 (s, 6H), 3.26 (s, 4H); 13C NMR
(100 MHz, CDCl3, DEPT): d 172.3 (C), 135.2 (C), 129.1
(CH), 115.9 (CH2), 56.7 (C), 52.9 (CH3), 40.9 (CH2). ESI-
HRMS calcd for C13H16O4Na [M++Na]: 259.0946, found:
259.0934.
Acknowledgements
We are grateful to the MEC (project CTQ2004-02869, Con-
solider Ingenio 2010, Grant CSD2006-0003, and PFU pre-
doctoral fellowship to M.R.), the AGAUR (project 2005
SGR 00993, predoctoral and postdoctoral fellowships to
C.F. and C.K.C., respectively), the Comunidad de Madrid
(predoctoral fellowship to C.N.), and the ICIQ Foundation
4.4.7. 1-[(Acetyloxy)methyl]-3,4-divinyl-3-cyclopenten-
1-yl methyl acetate (50b). H NMR (400 MHz, CDCl3):
1
ꢀ
for financial support. We also thank E. Escudero-Adan and
Dr. J. Benet-Buchholz (X-ray diffraction unit, ICIQ) for
d 6.80 (dd, J¼10.8, 17.2 Hz, 2H), 5.15–5.11 (m, 4H), 4.04
(s, 4H), 2.51 (4H), 2.07 (s, 6H); 13C NMR (100 MHz,
CDCl3, DEPT): d 171.1 (C), 136.1 (C), 129.7 (CH), 115.5
(CH2), 67.2 (CH2), 42.5 (C), 39.2 (CH2), 20.8 (CH3).
EI-HRMS calcd for C13H16O4: 236.1049, found: 236.1055.
the structure of 30.
References and notes
4.4.8. 8,8-Dimethyl-2,3-divinyl-7,9-dioxaspiro[4,5]dec-2-
ene (50c). 1H NMR (400 MHz, C6D6): d 6.74 (dd, J¼10.7,
17.2 Hz, 2H), 5.09–5.02 (m, 4H), 3.41 (s, 4H), 2.35 (4H),
1.40 (s, 6H); 13C NMR (100 MHz, C6D6, DEPT): d 137.0
(C), 130.5 (CH), 115.1 (CH2), 97.8 (C), 69.3 (CH2), 40.7
(CH2), 38.4 (C), 24.2 (CH3). ESI-HRMS calcd for
C14H21O2: 221.1542, found: 221.1535.
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tene-1,1-dicarboxylate (50d). 1H NMR (400 MHz,
CDCl3): d 6.76 (dd, J¼11.4, 17.1 Hz, 1H), 6.46 (d, J¼
15.8 Hz, 1H), 5.69 (dt, J¼7.1, 15.8 Hz, 1H), 5.133 (d, J¼
11.4 Hz, 1H), 5.125 (d, J¼17.1 Hz, 1H), 3.750 (s, 3H),
3.748 (s, 3H), 3.24 (s, 4H), 2.13 (q, J¼7.3 Hz, 2H), 1.43
(sextuplet, J¼7.3 Hz, 2H), 0.92 (t apparent dd, J¼7.6 and
7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3, DEPT): d 172.5
(C), 135.2 (C), 133.7 (CH), 132.6 (C), 129.4 (CH), 122.1
(CH), 114.8 (CH2), 56.8 (C), 52.9 (CH3), 41.6 (CH2), 40.8
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Copies of the data can be obtained, free of charge, on appli-
cation to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK
(fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.
ac.uk).
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Jimenez-Nunez, E.; Nevado, C.; Herrero-Gomez, E.; Raducan,
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