On the mechanism of carbohydroxypalladation of enynes. Additional insights on the cyclization of enynes with electrophilic metal complexes

Article abstract of DOI:10.1002/ejoc.200390110

Different mechanisms have been proposed for the cyclization of enynes catalyzed by electrophilic metal halides or complexes. We present evidence to indicate that the previously reported "carbohydroxypalladation" and the "hydroxycyclization catalyzed by Pt^II" are closely related reactions. Thus, palladium complexes formed in situ from PdCl₂ and trisulfonated phosphane TPPTS or cyclic phosphite P(OCH₂)₃CEt as the ligands catalyze the methoxy- or hydroxycyclization of enynes with selectivities similar to those observed with Pt^II complexes. Deuteration studies indicate that activation of the alkyne by Pd^II promotes an anti-addition of the alkene. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003.

Full text of DOI:10.1002/ejoc.200390110

FULL PAPER
On the Mechanism of Carbohydroxypalladation of Enynes. Additional Insights
on the Cyclization of Enynes with Electrophilic Metal Complexes
[a]
[b]
[b]
[a]
´
Cristina Nevado, Lise Charruault, Veronique Michelet, Cristina Nieto-Oberhuber,
[a]
[a]
[b]
[b]
´
´
ˆ
˜
¨
M. Paz Munoz, Marıa Mendez, Marie-Noelle Rager, Jean-Pierre Genet,* and
Antonio M. Echavarren*[a]
Keywords: Palladium / Platinum / Enynes / Cyclization / Carbocycles
Different mechanisms have been proposed for the cyclization
P(OCH2)3CEt as the ligands catalyze the methoxy- or hydro-
of enynes catalyzed by electrophilic metal halides or com- xycyclization of enynes with selectivities similar to those ob-
plexes. We present evidence to indicate that the previously
reported ‘‘carbohydroxypalladation’’ and the ‘‘hydroxy-
cyclization catalyzed by PtII’’ are closely related reactions.
Thus, palladium complexes formed in situ from PdCl2
and trisulfonated phosphane TPPTS or cyclic phosphite
served with PtII complexes. Deuteration studies indicate that
activation of the alkyne by PdII promotes an anti-addition of
the alkene.
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2003)
Introduction
The coordination of electrophilic PtCl2 to an enyne
through the alkyne (I, Scheme 1) may promote the intramo-
lecular reaction of the alkene to form a cyclopropyl Pt-car-
bene intermediate II.[1] Subsequent attack of the nucleo-
phile (alcohol or water) at the cyclopropyl carbons labeled
a and b of II presumably gives rise to the formation of five-
(III) or six-membered (IV) intermediates, which evolve un-
der catalytic conditions to afford the carbo- or heterocycles
V or VI, respectively.[1] Although some of these reactions
are also catalyzed by AuCl3 and RuII complexes, the cycliza-
tion with these catalysts is more limited in scope.[1]
A
similar mechanism has been suggested for the intramolecu-
lar reaction of allylsilanes and allylstannanes with alkynes,
a process that is catalyzed by PtII, PdII, RuII, and, in some
cases, by AuIII, CuI, and AgI.[2]
Cyclopropyl Pd carbenes have been proposed by Trost
and Murai as intermediates for the reaction of some enynes
which give cyclopropane derivatives.[3,4] Similar interme-
diates might be involved in the skeletal rearrangement of
enynes that yield conjugated dienes.[5Ϫ8] Related interme-
diates have been proposed on the basis of DFT calculations
[a]
´
´
´
Departamento de Quımica Organica, Universidad Autonoma
de Madrid,
Scheme 1
Cantoblanco, 28049 Madrid, Spain
Fax: (internat.) ϩ 34-91/3973966
E-mail: anton.echavarren@uam.es
[b]
`
´
Laboratoire de Synthese Selective Organique et Produits
for the intramolecular reaction of furans with alkynes cata-
lyzed by PtII.[9]
In competition with the above pathway, a different mech-
anism may operate if PtCl2 coordinates both functional
´
Naturels, UMR CNRS 7573, Ecole Nationale Superieure de
Chimie de Paris 11,
rue Pierre et Marie Curie, 75231 Paris, France
Fax: (internat.) ϩ 33-1/44071062
E-mail: genet@ext.jussieu.fr
706
 2003 WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim 1434Ϫ193X/03/0204Ϫ0706 $ 20.00ϩ.50/0 Eur. J. Org. Chem. 2003, 706Ϫ713

The Mechanism of Carbohydroxypalladation of Enynes
FULL PAPER
groups of the enyne, as shown in VII (Scheme 2). In this
case the oxidative metallacycloaddition of VII would form
metallacyclopentene VIII,[1b] which then evolves by β-hy-
dride elimination to give the 1,4-diene cycloisomerization
products IX. The cycloisomerization pathway is favored in
the presence of polar non-nucleophilic solvents such as
acetone or 1,4-dioxane.
Scheme 2
Palladium complexes [Pd(L2)X2] favor the cycloiso-
merization pathway to give dienes IX.[10,11] However, when
the reaction of certain enynes was carried out with a cata-
lyst formed from PdCl2 and the trisulfonated phosphane
TPPTS in the presence of water, a new carbohydroxy-
palladation was observed.[12] Although the first mechanistic
hypothesis for this new reaction was different from that pro-
posed for the PtCl2-catalyzed process, subsequent experi-
ments indicate that the ‘‘carbohydroxypalladation’’ and the
‘‘hydroxycyclization’’ catalyzed by PtII and other elec-
trophilic metals are indeed related processes. Herein we re-
port results that demonstrate that the Pt-catalyzed hydroxy-
clization of enynes and the carbohydroxypalladation are
similar reactions, which presumably proceed by the same
mechanism.
Scheme 3
Reaction of substrate 6, bearing a more electron-rich aryl
ring, favors the addition of methanol to form 7a. Reaction
of 6 in [D4]methanol afforded 7b, selectively mono-
deuterated at the alkenyl as in 2-d2. However, the reaction
of more hindered 8 under these conditions gave complex
reaction mixtures. When the cyclization of 8 was carried out
with a catalyst prepared in situ from PdCl2 (10 mol %) and
cyclic phosphite P(OCH2)3CEt (10 mol %)[13] as the ligand,
9 was obtained in 18% yield. The low yield might be due
to decomposition of 9 under the reaction conditions, since
increasing the loading of palladium catalyst leads to lower
yields.
Results and Discussion
Hydroxy- and Methoxycyclization vs. Cycloisomerization
A key issue in the mechanism of the Pd-catalyzed cycliza-
tion of enynes is the determination of the stereochemistry
of the key CϪC bond formation step. This aspect can easily
be resolved by performing the cyclization reaction in the
presence of D2O. Thus, reaction of propargyl cinnamyl
ether (1) with PdCl2 and TPPTS as the ligand in a mixture
of 1,4-dioxane and D2O at 80 °C afforded selectively deu-
terated 2-d2 (Scheme 3). The same result was obtained be-
fore in the reaction of 1 catalyzed by PtCl2.[1b] We have also
prepared the deuterated alkyne 1-d1 by nBuLi depro-
tonation followed by D2O quenching. The reaction of 1-d1
with PdCl2 and TPPTS afforded the corresponding adduct
2-d1.
Interestingly, when the reaction of 1 was carried out with
PdCl2 in aqueous acetone at 55 °C for 17 h, in the absence
of a phosphane ligand, a 4:1 mixture of hydroxycyclized
derivative 2 and cyclopropyl aldehyde 3 was obtained in
50% yield (Scheme 4). Bicyclic aldehyde 3 has been ob-
tained before in 12% yield, along with 2, in the reaction of
1 with PtCl2 as the catalyst.[1b] Reaction of 1 in MeOH at
80 °C with PdCl2/TPPTS as the catalyst led to methoxycy-
clized derivative 4, along with 5, which can result from the
reaction of methanol with a π-allyl palladium intermediate. Scheme 4
Eur. J. Org. Chem. 2003, 706Ϫ713
707

ˆ
J.-P. Genet, A. M. Echavarren et al.
FULL PAPER
We compared the cyclization of several enynes with PdII
and PtII catalysts (Scheme 5 and Table 1). Enyne 10 reacted
with PdCl2/TPPTS in aqueous 1,4-dioxane to afford hydro-
xycyclized 11 (26%) and diene 12[14] (25%) (Table 1, entry
1). A similar result was obtained in aqueous acetonitrile.[15]
It is noteworthy that when the reaction was carried out with
PtCl2/TPPTS, under otherwise identical conditions, 11
could be obtained in 60% yield (entry 2). Similarly, reaction
of 10 in methanol with PdCl2/TPPTS afforded an insepa-
rable 1:1 mixture of diene 12 and methoxycyclized 13 in
42% yield (entry 3). With palladium catalysts, the best re-
sults were obtained with the P(OCH2)3CEt ligand, which
led to 13 in 70% yield (entry 4). The use of a platinum
catalyst gave 13 in 76% yield (entry 5). We also demon-
strated that neither 11 nor 13 evolve to form diene 12 in the
presence of PdCl2/TPPTS (MeOH or aqueous dioxane at
80 °C). Since no elimination of water or methanol takes
place under the reaction conditions, formation of diene 12
could be explained by isomerization of the primary cyclo-
isomerized diene catalyzed by palladium or traces of acid.
Table 1. PdII- vs. PtII-catalyzed cyclization of enynes
Entry Enyne Catalyst
Reaction conditions
Product(s)
(yield)
1
10
PdCl2 (10%)
1,4-dioxane, H2O
11 (26%) ϩ
12 (25%)
TPPTS (30%)
80 °C, 46 h
2
3
4
5
6
7
8
9
10
10
10
10
14
17
17
17
21
21
PtCl2 (10%)
TPPTS (30%)
PdCl2 (10%)
TPPTS (30%)
PdCl2 (10%)
P(OCH2)3CEt (30%)
PtCl2 (10%)
1,4-dioxane, H2O
80 °C, 108 h
MeOH, 80 °C, 113 h 12 (21%) ϩ
13 (21%)
MeOH, 65 °C, 17 h
11 (60%)
13 (70%)
MeOH, 80 °C, 68 h
13 (76%)
TPPTS (30%)
Pt(MeCN)2Cl2 (5%) acetone, H2O, 55 °C, 15 (44%) ϩ
17 h
1,4-dioxane, H2O
80 °C, 87 h
16 (30%)
18 (47%)
PtCl2 (10%)
TPPTS (30%)
PdCl2 (10%)
P(OCH2)3CEt (30%)
PtCl2 (10%)
TPPTS (30%)
PtCl2 (5%)
MeOH, 65 °C, 48 h
19 (30%) ϩ
20 (60%)
19 (94%)
MeOH, 80 °C, 17 h
acetone, 55 °C
Semiempirical calculations (PM3)[16] show that 12 is the 101
22 (35%) ϩ
23 (31%)
22 (65%)
most stable among all the possible dienes.
11
PdCl2 (10%)
MeOH, 65 °C, 17 h
TPPTS (30%)
12
13
21
25
Pt(MeCN)2Cl2 (5%) MeOH, 65 °C, 17 h
24 (62%)
26 (50%)
PtCl2 (10%)
TPPTS (30%)
PdCl2 (10%)
TPPTS (30%)
PtCl2 (10%)
TPPTS (30%)
1,4-dioxane, H2O
80 °C, 204 h
MeOH, 80 °C, 22 h
14
15
25
25
27 (34%)
27 (81%)
MeOH, 80 °C, 40 h
TPPTS as the catalyst, which gave carbocycle 19 in 94%
yield (entry 9).
We also examined the reaction of enyne 21, which has
been shown to react with PtCl2 in acetone to give a 1.1:1
mixture of 22 and cyclopropane 23 in 66% yield (entry
10).[1] The reaction of 21 with PdCl2/TPPTS in methanol
afforded selectively cycloisomerization product 22 in 65%
yield (entry 11). In contrast, the reaction of 21 with
[PtCl2(MeCN)2] as the catalyst in methanol gave 24 in 62%
yield (entry 12). Hydroxycyclization of 25 with PtCl2/
TPPTS in aqueous dioxane afforded 26 in 50% yield (entry
13). Methoxycyclization of 25 proceeded with PdCl2/
TPPTS in low yield (entry 14), while the reaction with the
platinum catalyst gave 27 in 81% yield (entry 15).
Scheme 5
All attempts to cyclize enynes 28 and 29 with PdII or PtII
The reaction of enyne 14 with PdCl2/TPPTS failed to catalysts in the presence of water or methanol failed to give
give any cyclized derivative. However, reaction of 14 with any cycloisomerization product or any hydroxy- or me-
[PtCl2(MeCN)2] as the catalyst in aqueous acetone led to thoxycyclized derivatives (Scheme 6). The only compound
15 in 44% yield together with rearrangement product 16 that could be isolated from 29 was methyl ketone 30, which
(entry 6). The hydroxycyclization of 17 was carried out with is the product of the alkyne hydration reaction.[15] Presum-
PtCl2/TPPTS to give 18, albeit in only 47% yield (entry 7). ably, addition of MeOH catalyzed by PtII gives the enol
On the other hand, reaction of 17 with PdCl2 and P(OCH2)3- ether, which is subsequently hydrolyzed during work-up.
CEt as the ligand in methanol under reflux for two days However, when enyne 29 was submitted to the methoxycy-
led to 19 (30%) along with cycloisomerization derivative 20 clization reaction using AuCl3 as catalyst, the unexpected
(60%) (entry 8). Addition of AgBF4 or AgOTf suppressed carbocycle 31 was isolated in low yield. This product could
the cycloisomerization, although the yield of 19 was low result from the cycloisomerized carbocycle 32 by addition
(10Ϫ20%). The best results were obtained with PtCl2/ of MeOH to the exocyclic methylene catalyzed by the Lewis
708
Eur. J. Org. Chem. 2003, 706Ϫ713

The Mechanism of Carbohydroxypalladation of Enynes
FULL PAPER
acid AuCl3. Indeed, semiempirical PM3 calculations[16] on
model carbocations indicate that protonation of the exo-
cyclic methylene of 32 is more favorable than at the isopro-
penyl side chain.
Scheme 7
sequently, intermediate XII might be attacked by methanol
or water in a Wacker-type process to form XIII, which
would evolve to XIV after reductive elimination to form
XIV. However, the deuteration results shown in Scheme 3
are not consistent with the configuration of the expected
deuterated XIV-d.
Scheme 6
The reaction of dienyne 33 with PtII afforded 34 (47%)
and methoxycyclization derivative 35 (36%) (Scheme 7).
The depropargylation product 34 was the only product
when 33 was heated with 5 mol % [PdCl2(MeCN)2] in
MeOH. When the reaction was performed in the presence
of water, carbocycle 36 was obtained in 44% yield, together
with bicyclic aldehyde 37, oxabicyclo[4.1.0]hept-4-ene 38
and alcohol 39[17] as minor products. Although a mixture
of compounds is obtained, the stereoselectivity of the pro-
cess is high since none of the stereoisomers of 35؊38 were
formed in significant amounts. The configurations of 35,
36, and 37 were confirmed by NOE experiments. The con-
figuration of 38 was assigned on the basis of the small vi-
cinal coupling constant (3J ϭ 1.8 Hz) between the bridge-
head hydrogen at C-1 and the hydrogen at C-2, in agree-
ment with a calculated dihedral angle of 81° (PM3 calcula-
3
tions) with a coupling constant J of about 2 Hz (Karplus
equation[18]). The dihedral angle of the alternative 2-epi
configuration would be 45° (calculated 3J ϭ 6.3 Hz).
Formation of 35؊38 can be explained by attack of the al-
kene on the alkyne coordinated to PtCl2, as shown in
model X.
Scheme 8
Formation of cyclopropyl aldehydes 3 and 37 from 1 and
33, respectively (Schemes 4 and 7) strongly suggests that a
cyclopropyl Pd-carbene similar to II (Scheme 1) is involved
as an intermediate in the Pd-catalyzed process. Addition-
Mechanistic Hypothesis
A reasonable hypothesis for the palladium-catalyzed ally, the fact that 2 is also obtained with PdCl2 as the cata-
cyclization based on the insertion of a palladium hydride XI lyst indicates that this reaction is actually catalyzed by PdII.
on the terminal alkyne to form XII is outlined in Scheme 8. Thus, even though one cannot rule out a competing path-
Hydrides of type XI could be formed in situ by the oxida- way, a mechanism similar to that proposed for the PtII-cata-
tive addition of Pd0 complexes to methanol or water. Sub- lyzed cyclization can also be postulated for the process cata-
Eur. J. Org. Chem. 2003, 706Ϫ713
709

ˆ
J.-P. Genet, A. M. Echavarren et al.
FULL PAPER
lyzed by palladium (Scheme 9). In this case, a square planar In the case of 29, AuCl3 was moderately successful, leading
PdCl2L2 complex (L ϭ TPPTS, P(OCH2)3CEt, MeCN) to the formation of six-membered ring 31.
would coordinate to the enyne through the more reactive
The present work also demonstrates that palladium or
alkyne to form complex XV, which would evolve to give platinum complexes bearing phosphanes or phosphites as
cyclopropylpalladium carbene complex XVI. Opening of the ligands can catalyze the cyclization of enynes with addi-
this intermediate by methanol or water would then give rise tion of methanol or water to the alkene. This suggests that
to XVII, which would undergo protonolysis to form XVIII. chiral ligands of this type could be used to control the en-
This mechanism accounts for the deuteration pattern found antioselectivity of the process. Efforts to further develop
in the reactions of 1 and 1-d1.
this maximum atom-economy reaction are in progress.
In agreement with the mechanism proposed in Scheme 9,
no cyclization was observed with freshly prepared Pd0 com-
plexes [Pd(PPh3)4] or [Pd2(dba)3]·dba. Phosphanes such as Experimental Section
TPPTS are known to reduce PdCl2 or Pd(OAc)2, leading
to Pd0Ln complexes.[19] Indeed, these complexes catalyze a
number of cross-coupling reactions,[20] as well as Heck
alkenylations,[20c] metal-catalyzed ene-reaction,[21] and
TsujiϪTrost reactions.[22] However, the cyclizations of en-
ynes are apparently catalyzed by small amounts of unre-
duced [PdCl2(TPPTS)2] or other PdII complexes formed in
situ from Pd(TPPTS)3.
General Remarks: The NMR determinations were carried out at 23
°C. Rf were determined on TLC aluminum sheets coated with
0.2 mm GF254 silica gel. Elemental analyses were performed at the
SIdI (UAM), at the ‘‘Service Regional de Microanalyse’’ (Univers-
´
´
ite Pierre et Marie Curie), and at the ‘‘Service de spectrometrie de
´
masse’’ (Ecole Normale Superieure). All reactions were carried out
under an atmosphere of Ar. Solvents were purified, dried by stand-
ard methods and degassed prior to use. Column chromatography
was performed with E. Merck 0.040Ϫ0.063 mm, Art. no. 11567,
silica gel. Florisil (100Ϫ200 Mesh) was purchased from Acros or
Avocado. [Pt(MeCN)2Cl2] was prepared by the procedure described
for the synthesis of [Pt(PhCN)2Cl2].[21] AuCl3 (Aldrich) was dried
under reduced pressure.
The following compounds have been described before: 1؊3,[1] 6,[12b]
8؊11,[1] 13,[1] 14,[1] 16,[1] 17,[24] 18,[1] 19,[1] 20,[25] 21,[1] 22؊24,[1]
28,[26] 30,[27] and 39.[28] Known enyne 29[29] was prepared by the
CoreyϪFuchs procedure.[30]
General Procedure for the Palladium- or Platinum-Catalyzed Alk-
oxy- and Hydroxycyclization of Enynes: A mixture of the enyne and
the catalyst was heated at 55Ϫ80 °C in methanol (screw-capped
tube at 80 °C), 14% aqueous 1,4-dioxane or 10% aqueous acetone.
After being cooled to room temperature, the solvent was evapor-
ated and the residue was chromatographed (hexanes/EtOAc mix-
tures) to give the desired carbocycles. The hydroxycyclization reac-
tions were carried out in acetone/H2O (ca. 9:1) at 60 °C and the
reaction mixtures were either dried with MgSO4 or extracted
(Et2O) prior to chromatography. The cyclization reactions in the
presence of TPPTS ligand were directly filtered through a short
pad of florisil gel (EtOAc) and the solvents evaporated under re-
duced pressure.
4-[1-Methoxy-(3,4-methylenedioxy)phenylmethyl]-3-methylene-
tetrahydrofuran (7a): This compound was obtained from enyne 6
as a colorless oil following the general procedure (54%): H NMR
Scheme 9
1
(200 MHz, CDCl3): δ ϭ 2.90 (m, 1 H), 3.18 (s, 3 H), 3.95 (m, 2
H), 4.16 (dd, J ϭ 9.0, 3.9 Hz, 1 H), 4.27 (m, 3 H), 4.81 (br. s, 1
H), 5.98 (s, 2 H), 6.81 (m, 3 H) ppm. 13C NMR (50 MHz, CDCl3;
DEPT): δ ϭ 50.80 (CH3), 56.38 (CH), 71.53 (CH2), 84.17 (CH),
100.87 (CH2), 106.79 (CH2), 107.52 (CH), 121.60 (CH), 133.84 (C),
147.07 (C), 147.65 (C) ppm. DCI/NH3-MS: m/z ϭ 249 [M ϩ H]ϩ,
266 [M ϩ NH4]ϩ. DCI/NH3-HRMS calcd for C14H17O4, 249.1127;
found 249.1122.
Conclusion
Although different mechanisms have been proposed for
the cyclization of enynes catalyzed by PdII and PtII com-
plexes, the experimental evidence suggest that the ‘‘carbo-
hydroxypalladation’’, and the hydroxy- and methoxy-
cyclization catalyzed by electrophilic metals are closely
related reactions.
Dimethyl
(E)-3-Benzylidene-4-methylcyclopent-2-ene-1,1-dicarb-
oxylate (12): This compound was obtained from enyne 10 following
Although both PdII and PtII catalysts cyclize 1,6-enynes,
PtII complexes are usually more reactive. A limitation has
been found in the cyclization of 1,7-enynes 28 and 29, which
the general procedure (25% by using PdCl2/TPPTS) as a colorless
1
oil: H NMR (200 MHz, CDCl3): δ ϭ 1.96 (s, 3 H), 3.51 (br. s, 2
H), 3.76 (s, 6 H), 5.98 (br. s, 1 H), 6.32 (br. s, 1 H), 7.32 (m, 5 H)
could not be cyclized with PdII or PtII catalysts (Scheme 6). ppm. 13C NMR (50 MHz, CDCl3; DEPT): δ ϭ 12.94 (CH3), 37.71
710
Eur. J. Org. Chem. 2003, 706Ϫ713

The Mechanism of Carbohydroxypalladation of Enynes
(CH2), 52.85 (CH3), 64.26 (C), 120.27 (CH), 126.55 (CH), 128.33 (td, J ϭ 6.3, 1.3 Hz, 2 H), 4.53 (m, 1 H), 6.02 (dt, J ϭ 15.8, 6.3 Hz,
FULL PAPER
(CH), 129.63 (CH), 137.34 (C), 144.06 (C), 145.60 (C), 171.11 (C)
ppm. CI-MS: m/z ϭ 287 [M ϩ Hϩ], 304 (M ϩ NH4ϩ). DCI/CH4-
HRMS calcd for C17H19O4: 287.1283; found 287.1284.
1 H), 6.45 (d, J ϭ 15.8 Hz, 1 H), 7.29 (m, 7 H), 7.79 (d, J ϭ 8.3 Hz,
2 H) ppm. 13C NMR (50 MHz, CDCl3, DEPT): δ ϭ 21.41 (CH3),
45.40 (CH2), 123.97 (CH), 126.31 (CH), 127.11 (CH), 127.84 (CH),
128.45 (CH), 129.65 (CH), 132.99 (CH), 135.99 (C), 137.00 (C),
143.45 (C) ppm. C16H17NO2S: calcd. C 66.87, H 5.96, N 4.87;
found C 66.53, H 6.11, N 4.71.
The structure of 12 was confirmed by COSY, NOESY and HMQC
experiments. The most significant NOE enhancements are shown
below.
Step 3: Sodium hydride (205 mg, 5.11 mmol) was added por-
tionwise at 0 °C to a THF solution (0.13 ) of the resulting depro-
tected sulfonamide (2.00 g, 5.11 mmol). The mixture was allowed
to warm to room temperature. Then propargyl bromide (629 µL,
5.63 mmol) was added. The resulting mixture was heated under
reflux overnight and then quenched with water and extracted three
times with CH2Cl2. The combined organic layers were washed with
saturated aqueous NaCl solution, dried over MgSO4 and concen-
trated. The crude product was purified by silica gel flash chromato-
graphy (cyclohexane/EtOAc, 90:10) to give a white solid (1.26 g,
(3R*)-1,1-Bis(phenylsulfonyl)-3-[(1R*)-1-hydroxyethyl]-4-methylene-
cyclopentane (15): This compound was obtained from enyne 14 as
a white solid (44%) following the general cyclization procedure:
1
76%): m.p. 79Ϫ81 °C. H NMR (200 MHz, CDCl3): δ ϭ 2.07 (s, 1
H), 2.44 (s, 3 H), 4.00 (d, J ϭ 6.8 Hz, 2 H), 4.14 (m, 2 H), 6.09
(dt, J ϭ 15.8, 6.8 Hz, 1 H), 6.58 (d, J ϭ 15.8 Hz, 1 H), 7.32 (m, 7
H), 7.78 (d, J ϭ 8.3 Hz, 2 H) ppm. 13C NMR (50 MHz, CDCl3,
DEPT): δ ϭ 21.46 (CH3), 35.81 (CH2), 48.49 (CH2), 73.76 (CH),
76.53 (C), 122.81 (CH), 126.45 (CH), 127, 69 (CH), 127.98 (CH),
128.52 (CH), 129.43 (CH), 134.82 (CH), 135.98 (C), 143.53 (C)
ppm. C19H19NO2S: calcd. C 70.12, H 5.88, N 4.30; found C 70.00,
H 5.91, N 4.30.
1
m.p. 125Ϫ127 °C. H NMR (300 MHz, CDCl3): δ ϭ 1.18 (d, J ϭ
6.5 Hz, 3 H), 2.63 (dd, J ϭ 18.2, 12.2 Hz, 1 H), 2.84 (dd, J ϭ 18.2,
8.9 Hz, 1 H), 2.85 (m, 1 H), 3.12 (d, J ϭ 18.2 Hz, 1 H), 3.38 (dq,
J ϭ 18.2, 2.0 Hz, 1 H), 4.15Ϫ4.05 (m, 1 H), 4.94 (dd, J ϭ 4.4,
2.4 Hz, 1 H), 5.04 (dd, J ϭ 4.4, 2.0 Hz, 1 H), 7.60Ϫ7.57 (m, 4 H),
7.76Ϫ7.64 (m, 2 H), 8.10Ϫ7.80 (m, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 20.72, 30.68, 39.36, 49.95, 66.96, 91.19, 108.15,
128.75, 131.22, 131.33, 134.65, 134.76, 135.40, 136.43, 147.48 ppm.
C20H22O5S2: calcd. C 59.09, H 5.45, S 15.78; found C 58.38, H
5.42, S 15.71.
(3R*)-3-[(1R*)(1-Hydroxy)phenylmethyl]-4-methylene-N-tosyl-
pyrrolidine (26): This compound was obtained from enyne 25 as a
pale yellow oil (50%) following the general procedure: 1H NMR
(200 MHz, CDCl3): δ ϭ 2.44 (s, 3 H), 2.98 (m, 1 H), 3.23 (dd, J ϭ
9.8, 7.2 Hz, 1 H), 3.55 (dd, J ϭ 9.8, 5.2 Hz, 1 H), 3.80 (m, 2 H),
4.55 (br. s, 1 H), 4.67 (d, J ϭ 6.5 Hz, 1 H), 4.93 (br. s, 1 H), 7.31
(m, 7 H), 7.71 (d, J ϭ 8.3 Hz, 2 H) ppm. 13C NMR (50 MHz,
CDCl3; DEPT): δ ϭ 21.45 (CH3), 49.42 (CH2), 50.40 (CH), 52.53
(CH2), 73.74 (CH), 109.33 (CH2), 126.19 (CH), 127.82 (CH),
128.33 (CH), 129.58 (CH), 132.41 (C), 141.73 (C), 143.63 (C),
144.11 (C) ppm. DCI/NH3-MS: m/z ϭ 344 [M ϩ H]ϩ, 361 [M ϩ
NH4]ϩ. DCI/CH4-HRMS calcd for C19H22NO3S: 344.1320; found
344.1319.
(N,N)-Propargylcinnamyl-p-tosylamine (25): This known com-
pound[31] was obtained by an improved procedure in three high
yielding steps.
Step 1. Synthesis of (N,N)-tert-Butoxycarbonyl-cinnamyl-p-tosylam-
ine: NaH (295 mg, 7.37 mmol) was added portionwise at 0 °C to a
THF/DMF (2:1) solution (0.16 ) of N-(tert-butoxycarbonyl)-p-
toluenesulfonamide (2.00 g, 7.37 mmol). The mixture was allowed
to warm to room temperature. Then, trans-cinnamyl bromide
(1.6 g, 8.11 mmol) was added. The resulting mixture was heated
under reflux 12 h. The suspension was quenched with water and
extracted three times with CH2Cl2. The combined organic layers
were washed with saturated aqueous NaCl solution, dried over
MgSO4, filtered and concentrated. The crude product was purified
by silica gel flash chromatography (cyclohexane/EtOAc, 95:5 to
90:10) to give a white solid (2.18 g, 79%): m.p. 118Ϫ120 °C. 1H
NMR (200 MHz, CDCl3): δ ϭ 1.35 (s, 9 H), 2.41 (s, 3 H), 4.59
(dd, J ϭ 6.4, 0.9 Hz, 2 H), 6.27 (dt, J ϭ 15.8, 6.4 Hz, 1 H), 6.65
(d, J ϭ 15.8 Hz, 1 H), 7.32 (m, 7 H), 7.79 (d, J ϭ 8.3 Hz, 2 H)
ppm. 13C NMR (50 MHz, CDCl3, DEPT): δ ϭ 21.47 (CH3), 27.82
(CH3), 48.42 (CH2), 84.22 (C), 124.21 (CH), 126.48 (CH), 127.77
(CH), 128.00 (CH), 129.11 (CH), 133.79 (CH), 136.38 (C), 137.19
(C), 144.02 (C), 150.72 (C) ppm. C20H25NO4S: calcd. C 63.98, H
6.71, N 3.73; found C 64.82, H 6.72, N 3.32.
(3R*)-3-[-[(1R*)(1-Methoxy)phenylmethyl]-4-methylene-N-tosyl-
pyrrolidine (27): This compound was obtained from enyne 25 fol-
lowing the general procedure (34% with PdCl2/TPPTS and 81%
with PtCl2/TPPTS) as a pale yellow oil: 1H NMR (200 MHz,
CDCl3): δ ϭ 2.44 (s, 3 H), 2.85 (m, 1 H), 3.10 (s, 3 H), 3.25 (dd,
J ϭ 8.9, 6.9 Hz, 1 H), 3.71(dd, J ϭ 8.9, 5.0 Hz, 1 H), 3.91 (m, 2
H), 4.20 (br. s, 1 H), 4.76 (br. s, 1 H), 7.31 (m, 7 H), 7.73 (d, J ϭ
8.3 Hz, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ ϭ 21.43 (CH3),
50.38 (CH3), 52.20 (CH2), 56.72 (CH), 83.65 (CH), 109.91 (CH2),
127.44 (CH), 127.77 (CH), 127.92 (CH), 128.14 (CH), 129.56 (CH),
132.74 (C), 139.30 (C), 143.33 (C), 143.52 (C) ppm. DCI/NH3-MS:
m/z ϭ 358 [M ϩ H]ϩ, 375 [M ϩ NH4]ϩ. DCI/CH4-HRMS calcd
for C20H24NO3S: 358.1477; found 358.1476.
Step 2. Synthesis of (N)-Cinnamyl-p-tosylamine: Trifluoroacetic
acid (2.4 mL and then 1 mL, 43.1 mmol) was added at 0 °C to a (1R*,2S*,5R*)-2-Isopropenyl-1-methoxy-1,5-dimethylcyclohexane
solution (0.3 ) of the resulting sulfonamide (2.16 g, 5.75 mmol)
in anhydrous CH2Cl2. The resulting mixture was stirred at room
temperature, until completion of the reaction. Solvents were then
evaporated in vacuo. The residue was partitioned between CH2Cl2
and water and NaOH pellets were added. The aqueous layer was
extracted three times with CH2Cl2 and the combined organic layers
were washed with saturated aqueous NaCl solution, dried over
(31): This compound was obtained from enyne 29 as a colorless
oil (22%) following the general cyclization procedure: 1H NMR
(500 MHz, CDCl3): δ ϭ 0.91 (m, 1 H), 0.94 (d, J ϭ 6.5 Hz, 3 H),
1.14 (s, 3 H), 1.16 (t, J ϭ 12.3 Hz, 1 H), 1.45 (m, 1 H), 1.55 (td,
J ϭ 12.9, 3.8 Hz, 1 H), 1.63 (bd, J ϭ 13.3 Hz, 1 H), 1.72 (d, J ϭ
13.3 Hz, 1 H), 1.82 (ddd, J ϭ 12.2, 3.4, 2.0 Hz, 1 H), 1.87 (t, J ϭ
1.0 Hz, 3 H), 2.15 (dd, J ϭ 12.8, 3.8 Hz, 1 H), 3.24 (s, 3 H), 4.66
MgSO4 and concentrated to give a white solid (1.52 g, 92%): m.p. (m, 1 H), 4.92 (m, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ
105Ϫ107 °C. 1H NMR (200 MHz, CDCl3): δ ϭ 2.43 (s, 3 H), 3.77
Eur. J. Org. Chem. 2003, 706Ϫ713
18.85, 23.02, 25.97, 29.83, 30.42, 35.55, 46.15, 48.62, 50.97, 78.13,
711

ˆ
J.-P. Genet, A. M. Echavarren et al.
FULL PAPER
111.99, 148.50 ppm. EI-HRMS calcd. for C12H22O: 182.1761;
found 182.1761.
The structure of 31 was confirmed by COSY, NOESY, HMBC and
HMQC experiments. The most significant NOE enhancement are
shown below.
(2R*,3S*)-3-[(1S*)-(1-Hydroxy)phenylmethyl]-2-(2-methyl-2-
propenyl)-4-methylenetetrahydrofuran (36): This compound was ob-
tained from enyne 33 in 44% yield as a colorless oil following the
general cyclization procedure: 1H NMR (300 MHz, CDCl3): δ ϭ
1.63 (s, 3 H), 1.87 (dd, J ϭ 14.1, 5.1 Hz, 1 H), 2.10 (ddd, J ϭ 14.1,
8.2, 0.8 Hz, 1 H), 2.18 (d, J ϭ 3.5 Hz, 1 H), 2.73 (m, 1 H), 4.34
(m, 2 H), 4.40 (dt, J ϭ 8.1, 4.7 Hz, 1 H), 4.64 (m, 1 H), 4.69 (dd,
J ϭ 4.2, 2.2 Hz, 1 H), 4.73 (br. s, 1 H), 4.86 (dd, J ϭ 6.1, 3.4 Hz,
1 H), 5.00 (q, J ϭ 4.0 Hz, 1 H), 7.61Ϫ7.20 (m, 5 H) ppm. 13C
NMR (75 MHz, CDCl3; DEPT): δ ϭ 22.25 (CH3), 42.97 (CH2),
55.67 (CH), 75.02 (CH), 70.59 (CH2), 78.91 (CH), 106.76 (CH2),
112.31 (CH2), 126.28 (CH), 127.63 (CH), 128.27 (C), 142.10 (C),
142.77 (C), 148.52 (C) ppm. IR (neat): ν˜ ϭ 3418, 3073, 3030,
5-Methyl-1-phenyl-3-(2-propynyloxy)-1,5-hexadiene (33): A solution
of 5-methyl-1-phenyl-1,5-hexadien-3-ol[32] (2.0 g, 10.63 mmol) in
DMF (10 mL) was added to a suspension of NaH (60% in mineral
oil, 467 mg, 11.69 mmol) in DMF (25 mL) at 0 °C, followed by
propargyl bromide (80%, 1.3 mL, 11.69 mmol). The mixture was
stirred for 17 h at 23 °C and then quenched with H2O and extracted
(Et2O). The organic layer was washed three times with 10% HCl,
dried over MgSO4 and concentrated. The residue was purified by
chromatography (hexane/EtOAc, 9:1) to give 32 as a pale yellow
2967 cmϪ1
.
The structure of 36 was confirmed by COSY and NOESY experi-
ments (the most significant NOE enhancements are shown below).
1
oil (1.04 g, 42%). H NMR (300 MHz, CDCl3): δ ϭ 1.78 (s, 3 H),
2.30 (dd, J ϭ 14.1, 6.1 Hz, 1 H), 2.41 (t, J ϭ 2.4 Hz, 1 H), 2.48
(dd, J ϭ 13.7, 6.9 Hz, 1 H), 4.09 (dd, J ϭ 15.8, 2.4 Hz, 1 H), 4.23
(d, J ϭ 15.8, 2.4 Hz, 1 H), 4.28 (q, J ϭ 6.1 Hz, 1 H), 4.80 (m, 2
H), 6.02 (dd, J ϭ 16.2, 8.5 Hz, 1 H), 6.61 (d, J ϭ 16.2 Hz, 1 H),
7.42Ϫ7.21 (m, 5 H) ppm. 13C NMR (75 MHz, CDCl3; DEPT): δ ϭ
22.78 (CH3), 43.98 (CH2), 55.11 (CH2), 74.07 (C), 77.70 (CH),
80.04 (CH), 112.94 (CH2), 127.89 (CH), 128.59 (CH), 128.67 (CH),
133.39 (CH), 136.29 (C), 141.78 (C) ppm. C16H18O: calcd. C 84.91,
H 8.10; found C 84.38, H 8.02.
(1R*,4S*,5R*,6S*)-1-Formyl-4-(2-methyl-2-propenyl)-6-phenyl-3-
oxabicyclo[3.1.0]hexane (37): This compound was obtained from
enyne 33 as a colorless oil (3%) following the general cyclization
procedure: 1H NMR (300 MHz, CDCl3): δ ϭ 1.82 (s, 3 H), 2.17
(ddd, J ϭ 13.7, 6.9, 1.2 Hz, 1 H), 2.29 (ddd, J ϭ 14.2, 7.2, 1.0 Hz,
1 H), 2.90 (d, J ϭ 5.7 Hz, 1 H), 2.93 (d, J ϭ 5.7 Hz, 1 H), 3.97 (d,
J ϭ 9.3 Hz, 1 H), 4.32 (d, J ϭ 9.3 Hz, 1 H), 4.35 (t, J ϭ 7.3 Hz, 1
H), 4.79 (m, 1 H), 4.89 (m, 1 H), 7.36Ϫ7.25 (m, 5 H), 8.94 (s, 1 H)
ppm. 13C NMR (75 MHz, CDCl3; DEPT): δ ϭ 22.76 (CH), 34.67
(CH), 35.99 (CH), 42.00 (CH), 46.79 (CH2), 65.88 (CH2), 77.95
(CH), 113.24 (CH2), 127.50 (CH), 128.82 (CH), 128.87 (CH),
133.92 (CH), 141.56 (C), 198.22 (CH) ppm. EI-HRMS calcd for
C16H18O: 242.1307; found 242.1308.
(E)-3-Methoxy-5-methyl-1-phenyl-1,5-hexadiene (34): This com-
pound was obtained from enyne 33 as a by-product of the reactions
catalyzed by PtCl2 and was isolated in the cyclization catalyzed
1
by [PdCl2(MeCN)2] as a colorless oil (47%): H NMR (300 MHz,
CDCl3): δ ϭ 1.76 (d, J ϭ 1.2 Hz, 3 H), 2.25 (dd, J ϭ 14.2, 6.2 Hz,
1 H), 2.43 (ddd, J ϭ 14.2, 7.3, 1.2 Hz, 1 H), 3.31 (s, 3 H), 3.87 (m,
1 H), 4.76 (m, 1 H), 4.79 (m, 1 H), 6.04 (dd, J ϭ 16.2, 8.1 Hz, 1
H), 6.53 (d, J ϭ 16.2 Hz, 1 H), 7.40Ϫ7.21 (m, 5 H) ppm. 13C NMR
(75 MHz, CDCl3; DEPT): δ ϭ 22.84 (CH3), 44.18 (CH2), 56.31
(CH3), 80.88 (CH), 112.76 (CH2), 126.48 (CH), 127.70 (CH),
128.57 (CH), 129.86 (CH), 132.27 (CH), 136.57 (C), 142.09 (C)
ppm. EI-MS: m/z ϭ 186 (1) [Mϩ Ϫ 16], 170 (14), 147 (100).
(1R*,2R*,6S*,7R*)-2-(2-Methyl-2-propenyl)-7-phenyl-3-
oxabicyclo[4.1.0]hept-4-ene (38): This compound was obtained from
enyne 33 as a colorless oil (10%) following the general cyclization
(2R*,3S*)-3-[(1S*)-(1-methoxy)phenylmethyl]-4-methylene-2-(2-
methyl-2-propenyl)tetrahydrofuran (35): This compound was ob-
tained from enyne 33 as a pale yellow oil (36%) following the gen-
1
procedure: H NMR (500 MHz, CDCl3): δ ϭ 1.56 (m, 1 H), 1.82
(s, 3 H), 1.94 (ddd, J ϭ 9.0, 5.1, 1.9 Hz, 1 H), 2.32 (dd, J ϭ 4.5,
4.3 Hz, 1 H), 2.39 (dd, J ϭ 14.1, 6.0 Hz, 1 H), 2.50 (dd, J ϭ 14.1,
7.4 Hz, 1 H), 4.03 (ddd, J ϭ 7.6, 7.5, 1.8 Hz, 1 H), 4.81 (br. s, 1
H), 4.87 (br. s, 1 H), 5.35 (dd, J ϭ 5.3, 5.5 Hz, 1 H), 6.23 (d, J ϭ
5.8 Hz, 1 H), 7.32Ϫ7.05 (m, 5 H) ppm. 13C NMR (125 MHz,
CDCl3; DEPT): δ ϭ 19.44 (CH), 22.80 (CH3), 29.17 (CH), 29.69
(CH), 32.21 (CH), 43.85 (CH2), 69.06 (CH), 104.97 (CH), 113.06
(CH2), 125.71 (CH), 128.37 (CH), 141.35 (CH), 141.54 (CH),
141.75 (C) ppm. EI-HRMS: m/z ϭ 226.1 (17) [Mϩ], 171.1 (79), 143
(70), 141 (64), 128 (100). APCI-MS: m/z ϭ 227.3 [Mϩ ϩ 1]. Calcd
for C16H18O: 226.1357; found 226.1358.
1
eral cyclization procedure: H NMR (300 MHz, CDCl3): δ ϭ 1.74
(d, J ϭ 1.2 Hz, 3 H), 2.08 (dd, J ϭ 14.1, 4.9 Hz, 1 H), 2.18 (ddd,
J ϭ 14.1, 9.3, 1.2 Hz, 1 H), 2.63 (m, 1 H), 3.21 (s, 3 H), 4.10 (d,
J ϭ 8.1 Hz, 1 H), 4.25 (m, 1 H), 4.29 (m, 2 H), 4.47 (m, 1 H), 4.72
(m, 1 H), 4.78 (m, 1 H), 4.80 (q, J ϭ 2.0 Hz, 1 H), 7.37Ϫ7.24 (m,
5 H) ppm. 13C NMR (75 MHz, CDCl3; DEPT): δ ϭ 22.31 (CH3),
42.87 (CH2), 55.49 (CH), 56.89 (CH3), 70.28 (CH2), 79.93 (CH),
84.69 (CH), 107.26 (CH2), 112.08 (CH2), 127.64 (CH), 127.95
(CH), 139.75 (C), 142.90 (C), 147.33 (C) ppm. FAB-HRMS cacld
for C17H21O2: 257.1541 [Mϩ Ϫ H]; found 257.1539.
The structure of 35 was confirmed by COSY and NOESY experi-
The structure of 38 was confirmed by COSY and NOESY experi-
ments (the most significant NOE enhancement are shown below).
ments.
712
Eur. J. Org. Chem. 2003, 706Ϫ713

The Mechanism of Carbohydroxypalladation of Enynes
FULL PAPER
[12] [12a]
ˆ
J.-C. Galland, M. Savignac, J. P. Genet, Tetrahedron Lett.
Acknowledgments
We are grateful to the MCyT (Project BQU2001Ϫ0193-C02Ϫ01)
for their support of this research, the Comunidad Autonoma de
Madrid (predoctoral fellowship to C. N.), the MEC (predoctoral
fellowships to M. P. M. and M. M.), the MCyT (predoctoral fel-
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Recherche (grant to L. Charruault, 2000Ϫ2003). We also acknow-
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