Palladium-catalyzed formation of cyclic ethers - Regio-, stereo- and enantioselectivity of the reaction

Article abstract of DOI:10.1002/ejoc.200601019

An efficient and stereoselective synthesis of 3-alkyl-3-hydroxymethyl-5- vinyltetrahydrofurans is described by the Pd⁰-catalyzed cyclization of the methyl carbonates of ω,ω-bis(hydroxymethyl)-α,β- unsaturated alcohols. The use of chiral ligands

Full text of DOI:10.1002/ejoc.200601019

FULL PAPER
DOI: 10.1002/ejoc.200601019
Palladium-Catalyzed Formation of Cyclic Ethers – Regio-, Stereo- and
Enantioselectivity of the Reaction
Anna Zawisza,[a] Bernard Fenêt,[b] and Denis Sinou*[a]
Keywords: Cyclization / Palladium / Oxygen heterocycles / Diastereoselectivity / Enantioselectivity
An efficient and stereoselective synthesis of 3-alkyl-3-hy-
droxymethyl-5-vinyltetrahydrofurans is described by the
Pd0-catalyzed cyclization of the methyl carbonates of ω,ω-
bis(hydroxymethyl)-α,β-unsaturated alcohols. The use of chi-
ral ligands gave the corresponding THF derivatives in low to
moderate enantiomeric ratios.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
Introduction
Pd0-catalyzed intramolecular heteroannulation through
Pd is one of the most widely used transition metals for allylic alkylation, the so-called Tsuji–Trost reaction, gen-
the synthesis of heterocyclic compounds.[1] This is mainly erally employs allylic acetates,[7–11] benzoates,[12] carbon-
due to the mild reaction conditions used, the high yields, ates,[13–16] or vinyl epoxides[8,17,18] bearing a hydroxy group.
the tolerance of a large variety of functional groups, and Allylsilanes have also been used as precursors of the η3-allyl
the high regio- and stereoselectivity observed. One way to intermediates, starting from PdCl2 and CuCl2, affording the
synthesize oxygen heterocycles is to build the heterocyclic corresponding THF derivatives in quite good yields.[19] This
backbone itself. This approach, based on organometallic cyclization has also been achieved in an enantioselective
catalysis, could be divided into two pathways: (a) the Pd0- way in the presence of chiral ligands.[15,20–25]
catalyzed intramolecular allylation of oxygen nucleo-
The PdII-catalyzed cyclization of alkenyl alcohols has led
philes[2–4] and (b) the PdII-catalyzed intramolecular oxidat- to cyclic enols by a β-hydride elimination, or to oxygen het-
ive cyclization of hydroxyalkene nucleophiles.[2,3,5,6]
erocycles bearing a vinyl group through a β-hydroxy elimi-
Scheme 1.
nation, if the alkenol possesses an allyl alcohol moiety.[2,3,5]
A large variety of oxygen-containing heterocycles have been
obtained with this methodology,[26–34] even in an asymmet-
ric fashion.[35–37]
In our continuing interest in Pd-catalyzed access to sub-
stituted THFs and tetrahydropyrans, we were interested in
the synthesis of such functionalized oxygen heterocycles.
Recently it was reported that ω-hydroxy-α,β-unsaturated
alcohols underwent an intramolecular PdII-catalyzed cycli-
[a] Laboratoire de Synthèse Asymétrique, associé au CNRS, UMR
5181, CPE Lyon, Université Claude Bernard Lyon 1,
43, boulevard du 11 novembre 1918, 69622 Villeurbanne cedex,
France
Fax: +33-4-78898914
E-mail: sinou@univ-lyon1.fr
[b] Centre Commun de RMN, CPE Lyon, Université Claude Ber-
nard Lyon 1,
43, boulevard du 11 novembre 1918, 69622 Villeurbanne cedex,
France
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
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Selectivity of the Palladium-Catalyzed Formation of Cyclic Ethers
zation to give vinyltetrahydropyrans. We expected that the
FULL PAPER
In the first route, Pd0-catalyzed condensation of (Z)-4-
cyclization of ω,ω-bis(hydroxymethyl)-α,β-unsaturated hydroxybut-2-en-1-yl acetate (1)[38] with dimethyl benzyl-
alcohols or of the corresponding allylic carbonates would malonate, dimethyl (4-methylbenzyl)malonate, or dimethyl
afford functionalized oxygen heterocycles (Scheme 1). This (2-naphtylmethyl)malonate in THF at room temp. afforded
cyclization could occur in an exo- or endo-trigonal fashion substituted dimethyl (4-hydroxybut-2-en-1-yl)malonates
to afford heterocycle A or B. Moreover, since these unsatu- 4a–c in 54%, 55%, and 50% yield, respectively. Compounds
rated alcohols possess two enantiotopic hydroxymethyl 4a–c were generally obtained as a 90:10 mixture of the (E)
groups, a stereo- and enantioselective cyclization could take and (Z) stereoisomers, which could be separated by column
place. In this paper, we report a full account of the stereo- chromatography. The silylation of (E)-allylic alcohols 4a–c
chemical results in the Pd0- and PdII-catalyzed cyclization with tBuMe2SiCl in CH2Cl2 in the presence of Et3N and
reactions
of
ω,ω-bis(hydroxymethyl)-α,β-unsaturated imidazole gave the corresponding (E)-unsaturated silylated
alcohols and the corresponding allylic carbonates and pre- diesters 6a, 6b, and 6d, in 87%, 94%, and 79% yield, respec-
liminary results concerning the asymmetric Pd0-catalyzed tively.
The second route was the Pd0-catalyzed alkylation of
(Z)-4-[(tert-butyldimethylsilyl)oxy]but-2-en-1-yl acetate
cyclization of the allylic carbonates.
(2)[39] with dimethyl [(E)-3-phenylprop-2-en-1-yl]malonate,
dimethyl ethylmalonate, or dimethyl (cyclohexylmethyl)-
malonate, affording directly the corresponding unsaturated,
silylated, substituted dimethyl malonates 6e–g, having the
(E) configuration, in 86%, 86%, and 77% yield, respec-
tively.
Results and Discussion
Synthesis of the Starting Materials
The starting bis(hydroxymethyl) allylic alcohols 8a–i and
carbonates 9a–i were prepared according to Scheme 2 and
The third route used unsaturated, silylated, dimethyl ma-
Scheme 3. The key intermediates in these syntheses were the lonates 5a–c as intermediates. The Pd0-catalyzed alkylation
unsaturated dimethyl alkyl malonates 6a–i (Scheme 2).
of allylic acetate (2)[39] with dimethyl malonate afforded
Scheme 2. Synthesis of silylated dimethyl malonates 6a–i; reagents and conditions: (a) (i) Pd2(dba)3, dppb, THF, room temp., 0.5 h; (ii)
RCH2CH(CO2Me)2 (R = C6H5, 4-CH3C6H4, or 2-C10H7), NaH, THF; (iii) 1, THF, room temp., 24 h; (b) (i) Pd2(dba)3, dppb, THF,
room temp., 0.5 h; (ii) RCH2CH(CO2Me)2 (R = (E)-C6H5CH=CHCH2, CH3, or C6H11), NaH, THF; (iii) 2, THF, room temp., 24 h; (c)
(i) Pd2(dba)3, dppb, THF, room temp., 0.5 h; (ii) CH2(CO2Me)2, NaH, THF, room temp.; (iii) 2, THF, room temp., 24 h; (d) CH2(CO2-
Me)2, NaH, THF, DMF, reflux, 5 h; (e) tBuMe2SiCl, imidazole, Et3N, CH2Cl2, room temp., 15 h; (f) (i) 5, NaH, THF, DMF, room
temp., 0.5 h; (ii) RCH2Br (R = C6H5, or 2-CH3C6H5), reflux, 5 h.
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Scheme 3. Synthesis of dihydroxycarbonates 9a–i and Pd-catalyzed cyclization to oxygen heterocycles 10 and 11; reagents and conditions:
(a) AlH4Li, Et2O, 0 °C Ǟ room temp., 0.5 h; (b) Bu4NF·3H2O, THF, room temp., 15 h; (c) ClCO2CH3, C5H5N, CH2Cl2, 0 °C Ǟ room
temp., 2 h; (d) Pd2(dba)3, ligand, THF, 1 h, room temp.
compound (E)-5a in 85% yield after purification. Com-
Unsaturated dimethyl benzyl malonate 15 having the (Z)
pounds (E)-5b and (E)-5c were obtained in 51% and 83% stereochemistry was prepared according to Scheme 4. Di-
yield, respectively, by the alkylation of dimethyl malonate methyl acetylenic malonate 13 was obtained in 85% yield
in THF with unsaturated halides 3a–b with sodium hydride by the alkylation of dimethyl malonate with propargylic
as the base. Finally, the alkylation of dimethyl malonates bromide 12.[40] Hydrogenation of acetylenic compound 13
5a–c with 2-methylbenzyl bromide or benzyl bromide in in the presence of Lindlar’s catalyst afforded the (Z)-allylic
THF in the presence of sodium hydride afforded the corre- derivative 14 in 98% yield, whose alkylation with benzyl
sponding (E)-dimethyl benzylic malonates 6c, 6h, and 6i, in bromide in the presence of sodium hydride gave ethylenic
82%, 76%, and 93% yield, respectively.
dimethyl malonate 15 in 96% yield. The sequence of re-
The reduction of substituted, silylated, dimethyl malon- duction of the diester with lithium aluminum hydride in
ates 6a–i with lithium aluminum hydride in diethyl ether diethyl ether followed by desilylation in the presence of
afforded unsaturated diols 7a–i in 60–91% yield (Scheme 3). Bu4NF·3H2O in THF gave the corresponding triol 17 (55%
Triols 8a–i were obtained in 66–98% yield after purification overall yield), which was transformed into allylic carbonate
by treatment of compounds 7a–i with Bu4NF·3H2O in 18 in 54% yield.
THF. Condensation of these triols with one equivalent of
methyl chloroformate at 0 °C afforded bis(hydroxymethyl) access to a wide range of precursors for the catalytic cycliza-
allylic carbonates 9a–i in 40–72% yield. tions.
The above synthetic procedures provide a simple
Scheme 4. Synthesis of dihydroxycarbonate 18 and Pd-catalyzed cyclization; reagents and conditions: (a) CH2(CO2Me)2, NaH, THF,
DMF, reflux, 5 h, 85%; (b) H2, 1 bar, Pd Lindlar, cyclohexane, ethyl acetate, room temp., 48 h, 98%; (c) NaH, C6H5CH2Br, THF, DMF,
reflux, 5h, 96%; (d) AlH4Li, Et2O, 0 °C Ǟ room temp., 0.5 h, 73%; (e) Bu4NF·3H2O, THF, room temp., 15 h, 75%; (f) ClCO2CH3,
C5H5N, CH2Cl2, 0 °C Ǟ room temp., 2 h, 54%; (g) Pd2(dba)3, ligand, THF, 1 h, room temp.
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Selectivity of the Palladium-Catalyzed Formation of Cyclic Ethers
FULL PAPER
Pd0-Catalyzed Cyclization of Bis(hydroxymethyl) Allylic
Carbonates 9a–h and 18
The cyclization was first studied with bis(hydroxymethyl)
allylic carbonate 9a as the substrate (Scheme 3). Ring clo-
sure of carbonate 9a occurred readily in THF at room temp.
in the presence of a catalytic amount of Pd2(dba)3 associ-
ated with PPh3, providing exclusively THF derivatives 10a
and 11a as a 14:86 mixture and in 84% overall yield
(Table 1, Entry 1). The configuration assignment of com-
pounds 10a and 11a was based on NOESY experiments.
The major stereoisomer 11a showed a particularly strong
correlation between the 5-H signal at δ = 4.41 ppm and the
CH2OH group signal at δ = 3.48 ppm, while the minor one
10a showed a correlation between the 5-H signal at δ =
4.42 ppm and the benzylic proton signals at δ = 2.81 ppm
and 2.92 ppm (Figure 1).
Other ligands such as tris(o-tolyl)phosphane, dppe [1,2-
bis(diphenylphosphanyl)ethane], dppp [1,3-bis(diphenyl-
phosphanyl)propane], dppb [1,4-bis(diphenylphosphanyl)-
butane], or dppf [1,1Ј-bis(diphenylphosphanyl)ferrocene]
were associated with Pd in this cyclization reaction (Table 1,
Entries 2–6). All these ligands gave almost the same high
diastereoselectivities, compound 11a being obtained as the
major stereoisomer; however, dppe and dppf gave lower
yields (72% and 35%, respectively), even after a 20 h reac-
tion.
Figure 1. Observed NOE effects.
ter a 1 h reaction (Table 1, Entries 8–13). The observed dia-
The (Z)-configured isomer 18 was also submitted to this stereoselectivities were quite similar to those obtained in the
cyclization procedure in the presence of dppb as the ligand cyclization of carbonate 9a, ranging from 20:80 to 12:88 in
(Scheme 4, Table 1, Entry 7); THFs 10a and 11a were ob- favor of the stereoisomer 11. Only bis(hydroxymethyl) al-
tained in an overall yield of 95% after 1 h and in a 14:86 lylic carbonate 9f gave a lower diastereoselectivity (31:69)
ratio, similar to the results observed in the case of the (E) in favor of the diastereoisomer 11f; this difference could be
isomer.
due to the presence of the less bulky ethyl group compared
This Pd0-catalyzed cyclization was extended to other to the other substituents.
bis(hydroxymethyl) allylic carbonates 9b–g bearing different
Then we extended the cyclization to allylic carbonate 9h,
substituents. In all cases, the corresponding THFs 10b–g having two methylenic units between the double bond and
and 11b–g were obtained in quite high yields (91–98%) af- the quaternary carbon bearing the two hydroxymethyl
Table 1. Pd0-catalyzed cyclization of allylic carbonates 9a–i and 18.[a]
Entry
Carbonate
Ligand
T [°C]
Time [h]
Yield (10 + 11) [%][b]
10/11 [%][c]
1
2
3
4
5
6
7
8
9a
9a
9a
9a
9a
9a
18
9b
9c
9d
9e
9f
PPh3
P(2-MeC6H4)3
dppe
dppp
dppb
dppf
dppb
dppb
dppb
dppb
dppb
dppb
dppb
dppb
dppb
dppb
dppb
dppb
25
25
25
25
25
25
25
25
25
25
25
25
25
25
25
55
25[d]
55[d]
1
84
84
72
90
92
35
95
95
94
94
98
91
95
84
14:86
20:80
24:76
20:80
15:85
26:74
14:86
17:83
15:85
13:87
20:80
31:69
12:88
57:43
–
1.5
20
1.5
1
20
1
1
1
1
1
1
1
20
20
20
20
20
9
10
11
12
13
14
15
16
17
18
9g
9h
9i
no reaction
9i
30
41
61
32:68
37:63
34:66
9i
9i
[a] [9] Or [18]:[Pd2(dba)3]:[dppb] = 40:1:2, THF or CH2Cl2, 1 h. [b] Yields refer to isolated pure products after column chromatography.
1
[c] Determined by H NMR spectroscopy. [d] 12 mL (6 + 6) of THF was used instead of 6 mL (see the Exp. Section).
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A. Zawisza, B. Fenêt, D. Sinou
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groups. Bis(hydroxymethyl) carbonate 9h afforded a 57:43
mixture of tetrahydropyrans 10h and 11h in 84% yield after
20 h (Table 1, Entry 14). The relative stereochemistry of
stereoisomers 10h and 11h was difficult to assign, due to
the overlapping of the 6-H and CH2OH signals at δ = 3.69–
3.81 ppm for one stereoisomer and of the 2-H and H–6 sig-
nals at δ = 3.78–3.87 ppm for the other stereoisomer. In
order to determine this stereochemistry, compounds 10h
and 11h were transformed into their dinitrobenzoates 19
and 20, respectively. The NOE spectrum of dinitrobenzoate
19 clearly shows a relation between the axial 2-H (δ =
3.39 ppm) and axial 6-H (δ = 3.78–3.85 ppm) and the axial
2-H and the CH2OCO hydrogens (δ = 4.03 ppm and 4.10
ppm, Figure 1); this indicates that these hydrogens are on
the same side of the molecule. For dinitrobenzoate 20, the
NOE spectrum clearly shows a relation between the axial
2-H (δ = 3.41 ppm) and axial 6-H (δ = 3.70–3.78 ppm) as
well as between the axial 2-H and the benzylic hydrogens (δ
= 2.53 ppm and 2.64 ppm), indicating that these hydrogens
are on the same side of the molecule.
Scheme 5. Mechanism of the Pd0-catalyzed cyclization.
The observed stereoselectivities could be explained ac-
cording to Figure 2. In all cases, the η3-allylPd cationic
complexes exist into two diastereoisomeric forms I and II.
For the cyclization of compounds 9a–g and 18, these η3-
allylPd cationic complexes adopt the conformations Ia and
IIa, with the more bulky substituent in the “equatorial” po-
sition. We assume also that there is a hydrogen bond be-
tween the hydroxy group and the alcoholate.[41,42] Confor-
mation Ia leads to the stereoisomer 10, whereas conforma-
tion IIa leads to the stereoisomer 11. The η3-allyl complex
Ia possesses an unfavorable strain between the allylic moi-
ety and the hydroxymethyl group, whereas such strain does
not exist for η3-allyl complex IIa. So the cyclization in these
cases proceeds by the more likely conformation IIA, giving
stereoisomer 11 as the major product.
Finally we studied the Pd0-catalyzed cyclization of allylic
carbonate 9i, having now three methylenic units between
the double bond and the quaternary carbon. Under the
above-mentioned conditions, the formation of cyclized
products was never observed; however a 32:68 mixture of
10i/11i was obtained in 30% yield when the reaction was
performed at 55 °C (Table 1, Entries 15 and 16). Since we
expected that an intermolecular reaction could compete in
this case, due to the slower cyclization process, we per-
formed the same reaction under more dilute conditions
(Table 1, Entries 17 and 18). When the reaction was per-
formed at 25 °C, the yield of 10i/11i increased to 41% after
20 h, whereas a 61% yield was obtained by performing the
reaction at 55 °C; it is to be noted that the stereoselectivity
was not dependent on the temperature or the reaction con-
centration.
The relative stereochemistry for stereoisomers 10i and 11i
was mainly based on the NOESY spectrum of compound
10i. The determination of compound 11i was difficult, due
to the overlapping of the signals of the 2-H and CH2OH
signals (δ = 3.54–3.60 ppm). Fortunately, we observed for
compound 10i a relation between the axial 2-H (δ =
3.44 ppm) and the axial 7-H (δ = 3.95–4.05 ppm) and
another relation between the axial 2-H and the benzylic
hydrogens (δ = 2.48 ppm and 2.64 ppm), in agree-
ment with the proposed structure for this stereoisomer
(Figure 1).
The reaction mechanism for this cyclization is shown in
Scheme 5. Bis(hydroxymethyl) carbonate 9 reacted with Pd0
to give an η3-allylPd complex. Exchange between the meth-
anoate formed and one of the hydroxy groups gave a new
cationic complex. Attack of the alcoholate nucleophile on
the η3-allyl intermediate gave the cyclized compounds 10
and 11. Since the same stereoselectivity was observed start-
ing from the (E) isomer 9a or the (Z) isomer 18, this implies
that the syn-anti isomerization of the η3-allylPd intermedi-
ate was very fast compared to the attack of the oxygen nu-
cleophile on this complex.
Figure 2. Models for Pd0-catalyzed cyclization.
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Selectivity of the Palladium-Catalyzed Formation of Cyclic Ethers
FULL PAPER
In the case of the cyclization of carbonate 9h, the confor- Table 2. PdII-catalyzed transformation of allylic alcohols 8a–i and
17.[a]
mations of the η3-allylPd cationic complexes are Ib and IIb.
Again, molecular models show unambiguously an unfavor-
able strain between the allylic moiety and the hy-
droxymethyl group in conformation Ib; however, in confor-
mation IIb, there is a 1,3-diaxial repulsive interaction for
the η3-allyl moiety. In this case, the stabilities of the two
conformers are probably very close, affording a 1:1 mixture
of two stereoisomers 10h and 11h.
Finally the cyclization of carbonate 9i affords predomi-
nantly diastereoisomer 11i. This stereoselectivity could be
also related to the two conformations Ic and IIc; some un-
favorable strain between the allylic moiety and the hy-
droxymethyl group was observed for conformation Ic.
Entry Alcohol
Solvent
Yield (10 + 11) 10/11 [%][c]
Yield 21
[%][b]
[%][b]
1
2
3
4
5
6
7
8
8a
8a
8a
8a
8a
8a
8a
8a
17
8b
8c
8d
8e
8f
THF
32
63
83
86
80
42
58
4
27
31
23
19
75
51
36
72
89
10:90
47:53
52:48
54:46
52:48
48:52
30:70
50:50
9:91
68
30
14
13
15
0
CH3OH
CH2Cl2
CH3CN
C6H6
THF[d]
THF[e]
THF[f]
THF
THF
THF
THF
THF
THF
THF
39
0
9
70
61
75
78
19
46
60
23
0
10
11
12
13
14
15
16
17
9:91
9:91
0:100
20:80
27:73
7:93
57:43
56:44
8g
8h
8i
PdII-Catalyzed Cyclization of Bis(hydroxymethyl) Allylic
Alcohols 8a–i and 17
THF
THF
We expected that the PdII-catalyzed cyclization of bis(hy-
droxymethyl) allylic alcohols 8a–i and 17 would also afford
the corresponding oxygen heterocyclic compounds[43]
[a] [8]:[PdCl2(CH3CN)2] = 20:1, room temp., 24 h. [b] Yields refer
to isolated pure products after column chromatography. [c] Deter-
mined by 1H NMR spectroscopy. [d] NEt3 (2 equiv./Pd) was added.
[e] CuCl2 (1 equiv./8a) was added. [f] Pd(OAc)2 was used as a cata-
through an intramolecular oxypalladation reaction, accord- lyst.
ing to the recent work of Uenishi et al.[30–33] When bis(hy-
droxymethyl) allylic alcohol 8a was treated with 5 mol-% of
PdCl2(MeCN)2 in THF at room temp., stereoisomeric
This methodology was also extended to other allylic
THFs 10a and 11a were obtained as a 10:90 mixture in 32% alcohols. Bis(hydroxymethyl) allylic alcohols 8b, 8c, and 8d,
yield, together with dioxabicyclo[2.2.2]octane 21a in 68% afforded the corresponding dioxabicyclooctanes 21b, 21c,
yield (Table 2, Entry 1, Scheme 6). When the reaction was and 21d as the major products, respectively (61%, 75%, and
performed in methanol, CH2Cl2, acetonitrile, or benzene, a 78% yield, respectively, Table 2, Entries 10–12); THFs 10b–
mixture of these three compounds was also obtained c and 11b–c were obtained in 31% and 23% yields as a 9:91
(Table 2, Entries 2–5); however, the amount of bicyclic com- mixture, while stereoisomer 11d was exclusively formed in
pound 21a decreased drastically, and the stereoisomeric 19% yield starting from allylic alcohol 8d.
THFs 10a and 11b were obtained as a 1:1 mixture.
The PdII-catalyzed reaction of compound 8e bearing a
Performing the reaction in THF in the presence of Et3N cinnamyl group as the substituent, gave a quite different
afforded THFs 10a and 11a only as a 1:1 mixture, although result (Table 2, Entry 13); dioxabicyclooctane derivative 21e
the chemical yield decreased to 42% (Table 2, Entry 6). Ad- was now obtained as the minor compound (19% yield), and
dition of 1 equiv. of CuCl2 to the reaction gave a 30:70 mix- a 20:80 mixture of THFs 10e and 11e was formed in 75%
ture of THFs 10a and 11a, together with dioxabicyclooc- yield. Bis(hydroxymethyl) allylic alcohol 8f afforded bicyclic
tane 21a in 39% yield (Table 2, Entry 7). Finally, with derivative 21f in 46% yield together with a 27:73 mixture of
Pd(OAc)2 as the catalyst instead of PdCl2(CH3CN)2 gave a THFs 10f and 11f in 51% yield (Table 2, Entry 14), whereas
very low yield (Table 2, Entry 8).
bicyclic compound 21g was obtained in 60% yield together
The PdII-catalyzed cyclization of (Z)-bis(hydroxymethyl) with a 7:93 mixture of THFs 10g and 11g in 36% yield
allylic alcohol 17 in THF gave results very similar to those starting from allylic alcohol 8g (R = C6H11, Table 2, Entry
obtained with the (E) stereoisomer; dioxabicyclooctane de- 15).
rivative 21a was obtained in 70% yield, together with a 9:91
mixture of 10a and 11a in 27% yield (Table 2, Entry 9).
Finally, allylic alcohols 8h and 8i were also treated by
PdCl2(CH3CN)2 in THF. Compound 8h gave predomi-
Scheme 6. PdII-catalyzed cyclization of triols 8a–i and 17.
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A. Zawisza, B. Fenêt, D. Sinou
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nantly a 57:43 mixture of THFs 10h and 11h in 72% yield, lar oxypalladation of hydroxyalkenes leading to dioxabicy-
together with dioxabicyclo derivative 21h in 23% yield clo compounds has already been published.[46–48]
(Table 2, Entry 16). The formation of the dioxabicyclo de-
The high stereoselectivities observed in the formation of
rivative was never observed in the cyclization of allylic heterocycles 10 and 11 in the PdII-catalyzed cyclization of
alcohol 8i (Table 2, Entry 17), and only a 56:44 mixture of allylic alcohols 8a–g could be explained according to Fig-
THF derivatives 10i and 11i was obtained in 89% yield.
ure 3. The π complex adopts on of the two conformations
The reaction mechanism we proposed is quite similar to A or B, the bulky substituent being in an equatorial posi-
the mechanism postulated recently by Uenishi et al.[33] tion, if we assume that the hydroxymethyl group is associ-
(Scheme 7). The first step is the coordination of PdCl2 to ated with the Pd. Conformation A leads to the THF 11,
the double bond and to the allylic hydroxy group to give the whereas conformation B leads to THF 10. Since the confor-
π complex A, which is in equilibrium with the π complex B mation B possess an unfavorable interaction between the
obtained by a simple hydroxy group exchange at Pd. The double bond and the hydroxymethyl group, the cyclization
next step is an intramolecular syn attack of this hydroxy proceeds through conformation A to give THF 11 as the
group from the same side of the Pd complex[44,45] occurring major product. This reaction pathway is in good agreement
in a 5-exo-trig or a 6-endo-trig fashion to give the σ-Pd with the formation of stereoisomer 11d only when R = β-
complexes C and D, respectively. A syn elimination of naphthyl and the increase in the formation of 10f when R
PdCl(OH) from intermediate C generates the oxygen het- = CH3.
erocycles 10 and 11. On the other hand, a β-hydride elimi-
In the cyclization of allylic alcohol 8h, the two possible
nation from intermediate D gives the new π-Pd complex E. conformations are C and D, with the bulky benzyl substitu-
Subsequent hydropalladation of this intermediate affords ent in the equatorial position and avoiding any 1,3-diaxial
the σ-Pd complex F; a syn elimination of PdCl(OH) affords interaction involving the olefin. Since there is no preferable
the oxygen heterocycle G, which is readily cyclized to the conformation, the cyclization leads to an equal mixture of
dioxabicyclo derivative 21 in the presence of a catalytic tetrahydropyrans 10h and 11h. The same scheme could be
amount of HCl. It is to be noted that this cyclization was applied to the cyclization of allylic alcohol 8i, leading to a
not observed in the presence of Et3N. Such an intramolecu- mixture of oxygen heterocycles 10i and 11i.
Scheme 7. Mechanism of the PdII-catalyzed cyclization.
2302
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2296–2309

Selectivity of the Palladium-Catalyzed Formation of Cyclic Ethers
FULL PAPER
meric ratio (er) of 59:41, while the minor diastereoisomer
10a exhibited an er of 43:57. With CH2Cl2 as the solvent,
the er of the minor stereoisomer increased to 64:36, the
other enantiomer now being obtained as the major one;
under these conditions, the major stereoisomer 11a was ob-
tained as an essentially racemic mixture (Table 3, Entry 2).
No modification was observed when acetic acid was added
to the reaction mixture in CH2Cl2 (Table 3, Entry 3).[49] The
use of (R,S)-Josiphos as the chiral ligand afforded quite
similar diastereoselectivity (10a/11a 32:68), although the
yield was lower (only 39% after 20 h); the minor isomer was
obtained in an er of 25:75, while the major one exhibited an
er of 59:41 (Table 3, Entry 4). Increasing the reaction time
to 48 h increased the yield to 82%, with the same diastereo-
and enantioselectivities being observed. Performing the re-
action at 55 °C gave the cyclized products in 83% yield after
20 h, with a 82:18 diastereoselectivity in favor of stereoiso-
mer 11a; the minor isomer was obtained in a higher er of
15:85, while the major isomer exhibited an er of 64:36
(Table 3, Entry 5). The same diastereoselectivities were ob-
tained with (S,S)-BDPP or (R)-PheBox as the ligands (a
10a/11a of 24:76 and 25:75, respectively); the er values of
the major isomer 11a were very low, while those of the
minor isomer 10a were 66:34 and 65:35, respectively
(Table 3, Entries 6 and 7).
Figure 3. Models for PdII-catalyzed cyclization.
Pd0-Catalyzed Asymmetric Cyclization
In the Pd0-catalyzed cyclization depicted in Scheme 5,
the two hydroxymethyl groups are enantiotopic, so we ex-
pected that the asymmetric cyclization could occur if the
cyclization reaction is performed in the presence of a Pd
complex associated with a chiral catalyst.
The Pd0-catalyzed cyclization of bis(hydroxymethyl) al-
lylic carbonates 9b–d and 9d in the presence of Trost’s li-
gand in THF or in CH2Cl2 gave the cyclized products 10b–
d and 11b–d in high yields, stereoisomer 11 being the major
one (Table 3, Entries 8–13). In the cyclization of com-
pounds 9b and 9d, quite low er values were obtained for
the two stereoisomers when the reaction was performed in
THF (Table 3, Entries 8 and 12); however, when CH2Cl2
was used as the solvent, these values were increased to 80:20
We first studied the Pd0-catalyzed cyclization of bis(hy-
droxymethyl) carbonate 9a in the presence of (R,R)-Trost’s
ligand. When the reaction was performed in THF, we ob-
served the same diastereoselectivity as that obtained pre-
viously with dppb as the ligand (Table 3, Entry 1); the
major diastereoisomer 11a was obtained with an enantio- and 23:77 for the minor stereoisomers 10b and 10d, respec-
Table 3. Asymmetric Pd0-catalyzed cyclization of some allylic carbonates.[a]
Entry Carbonate Ligand
Solvent
Time [h]
Yield (10 + 11) [%][b] 10/11 [%][c]
er of 10[d]
er of 11[d]
1
2
3
9a
9a
9a
9a
9a
9a
9a
9b
9b
9c
9c
9d
9d
9h
9h
(R,R)-Trost
(R,R)-Trost
(R,R)-Trost
(R,S)-Josiphos
(R,S)-Josiphos
(S,S)-BDPP
(R)-PheBox
(R,R)-Trost
(R,R)-Trost
(R,R)-Trost
(R,R)-Trost
(R,R)-Trost
(R,R)-Trost
(R,S)-Josiphos
(R,S)-Josiphos
(R,S)-Josiphos
THF
1
99
96
94
39 (82)
83
76
50
95
90
92
87
99
94
63
83
45
20:80
20:80
23:77
32:68 (36:64)
18:82
24:76
25:75
17:83
23:77
15:85
25:75
13:87
17:83
69:31
69:31
28:72
43:57
64:36
66:34
25:75
15:85
66:34
65:35
48:52
80:20
42:58
58:42
40:60
23:77
60:40
61:39
66:34
59:41
51:49
48:52
59:41
64:36
41:59
52:48
62:38
48:52
60:40
48:52
53:47
47:53
34:66
35:65
33:67
CH2Cl2[e]
CH2Cl2
THF
THF
THF
THF
THF
CH2Cl2
THF
CH2Cl2
THF
1.5
1.5
20 (48)
20
20
20
1
1.5
1
1.5
1.5
1.5
48
4
5[f]
6
7
8
9
10
11
12
13
14
15[f]
CH2Cl2
THF
THF
20
20
16[g] 9i
THF
[a] [9]:[Pd2(dba)3]:[ligand] = 40:1:2, room temp., 1 h; (R,R)-Trost’s ligand: (1R, 2R)-1,2-bis[(2Ј-diphenylphosphanyl)benzoylamino]cyclo-
hexane; (R,S)-Josiphos: (R)-1-{(S)-2-diphenylphosphanyl]ferrocenyl}ethyldicyclohexylphosphane; (S,S)-BDPP: (2S,4S)-2,4-bis(diphenyl-
phosphanyl)pentane; (R)-PheBox: (R)-2,2Ј-Isopropylidenebis(4-phenyl-2-oxazoline). [b] Yields refer to isolated pure products after column
chromatography. [c] Determined by 1H NMR spectroscopy. [d] Enantioselectivity (er) was measured by chiral stationary phase HPLC on
a Chiral OD-H column; the first value corresponds to the enantiomer being eluted first. [e] Acetic acid (1 equiv./Pd) was added. [f]
Reaction performed at 55 °C. [g] 12 mL (6 + 6) of THF was used instead of 6 mL (see the Exp. Section).
Eur. J. Org. Chem. 2007, 2296–2309
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2303

A. Zawisza, B. Fenêt, D. Sinou
FULL PAPER
General Procedures for the Preparation of Malonates 6a–i and 15
tively, while the er values of the major stereoisomers 11b
and 11d were quite low (Table 3, Entries 9 and 13). In the
cyclization of allylic carbonate 9c, bearing a o-tolyl substit-
uent, the minor stereoisomer 10c was obtained with the
same er but with a reversal of configuration going from
THF (42:58) to CH2Cl2 (58:42), while the major stereoiso-
mer 11c was obtained in an er of 60:40 in THF (Table 3,
Entries 10–11).
Route A: To a solution of unsaturated alcohol 4a–c (10 mmol) in
CH2Cl2 (50 mL) were successively added at 0 °C, imidazole
(34.7 mg, 5 mmol), Et3N (1.87 mL, 13.4 µmol), and tBuMe2SiCl
(2.02 g, 13.4 mmol). The mixture was stirred for 15 h at room temp.
Water (5 mL) was added, and the organic phase was separated and
dried (Na2SO4). Evaporation of the solvent under reduced pressure
gave a residue that was purified by column chromatography on
silica gel to give the O-silylated dimethyl malonate 6a, 6b, or 6d.
Finally the asymmetric cyclization of allylic carbonates
9h and 9i was performed in THF in the presence of (R,S)-
Josiphos as the chiral ligand. The cyclization of compound
9h at room temp. or at 55 °C, afforded a 69:31 mixture of
stereoisomers 10h and 11h, moderate er values for the two
stereoisomers 10h and 11h being obtained (60:40 and 34:66
for 10h and 11h, respectively, Table 3, Entries 14 and 15).
Oxepanes 10i and 11i were obtained in 45% yield under the
same conditions, in a 28:72 ratio, with er values of 66:34
and 33:67, respectively, starting from allylic carbonate 9i
(Table 3, Entry 16).
Dimethyl Benzyl{(E)-[4-(tert-butyldimethylsilyl)oxy]but-2-en-1-yl}-
malonate (6a): Colorless oil, 3.53 g, 87% yield. Rf = 0.84 (petro-
leum ether/ethyl acetate, 3:1). 1H NMR (300 MHz, CDCl3): δ =
0.00 (s, 6 H, SiMe2), 0.84 (s, 9 H, CMe3), 2.47 (d, J = 6.2 Hz, 2 H,
CH2-CH=), 3.15 (s, 2 H, CH2Ph), 3.62 (s, 3 H, OMe), 4.05–4.11
(m, 2 H, CH2O), 5.50 (dt, J = 15.3, 6.2 Hz, 1 H, -CH=), 5.58 (dt,
J = 15.3, 4.3 Hz, 1 H, -CH=), 6.95–7.05 (m, 2 H, Harom), 7.10–7.15
(m, 3 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = –4.8, 18.7,
26.3, 35.3, 38.6, 52.7, 59.6, 63.8, 127.4, 128.7, 130.3, 134.6, 136.3,
171.6 ppm. C22H34O5Si (406.58): calcd. C 64.99, H 8.43; found C
64.82, H 8.50.
Route B: A solution of Pd2(dba)3 (13.6 mg, 0.02 mmol) and dppb
(17.1 mg, 0.04 mmol) in THF (3 mL) in a Schlenk tube was stirred
at room temp. for 30 min. This solution was then added to a mix-
ture of the corresponding alkylated dimethyl malonate (1.1 mmol)
and sodium hydride (26.4 mg, 1.1 mmol) in THF (3 mL), followed
by a solution of allylic acetate 2 (244.4 mg, 1 mmol) in THF
(1 mL). After completion as shown by chromatography, the reac-
tion was quenched with water (20 mL), the organic product was
extracted with diethyl ether (100 mL), and the organic layers were
dried (Na2SO4). Evaporation of the solvent under reduced pressure
gave a residue that was purified by flash column chromatography
on silica gel to give dimethyl malonate 6e, 6f, or 6g.
Conclusions
We have described a Pd0-catalyzed synthesis of 3-alkyl-
3-hydroxymethyl-5-vinyltetrahydrofurans in very high yields
with good diastereoselectivities starting from 5-alkyl-6-hy-
droxy-5-(hydroxymethyl)hexenyl methyl carbonates, the
major product isomers being those where the vinyl and the
alkyl group are on the same side of the heterocycle. The
use of chiral ligands in association with Pd afforded the
corresponding THF stereoisomers in low to moderate er
values (up to 80:20). On the other hand, the PdII-catalyzed
cyclisation of 5-alkyl-5-(hydroxymethyl)hex-2-ene-1,6-diol,
the precursor of the above mentioned carbonates, afforded
Dimethyl {(E)-4-[(tert-Butyldimethylsilyl)oxy]but-2-en-1-yl}[(E)-3-
phenylprop-2-en-1-yl]malonate (6e): Colorless oil, 398 mg, 86%
yield. Rf = 0.75 (petroleum ether/ethyl acetate, 5:1). 1H NMR
(300 MHz, CDCl3): δ = 0.00 (s, 6 H, SiMe2), 0.82 (s, 9 H, CMe3),
2.61 (d, J = 7.2 Hz, 2 H, CH2-CH=), 2.71 (d, J = 7.5 Hz, 2 H,
CH2-CH=), 3.66 (s, 6 H, OMe), 4.07 (d, J = 4.5 Hz, 2 H, CH2O),
5.47 (dt, J = 15.3, 7.2 Hz, 1 H, -CH=), 5.60 (dt, J = 15.3, 4.5 Hz,
1 H, -CH=), 5.97 (dt, J = 15.6, 7.5 Hz, 1 H, -CH=), 6.38 (d, J =
15.6 Hz, 1 H, PhCH=), 7.10–7.30 (m, 5 H, Harom) ppm. 13C NMR
(75 MHz, CDCl3): δ = –4.8, 18.8, 26.3, 36.0, 36.7, 52.8, 58.5, 63.8,
124.1, 124.3, 126.6, 127.8, 128.9, 134.4, 134.6, 137.5, 171.6 ppm.
C24H36O5Si (432.63): calcd. C 66.63, H 8.39; found C 66.49, H
8.33.
a
mixture
of
3-alkyl-3-hydroxymethyl-5-vinyltetra-
hydrofurans and 1-methyl-4-alkyl-2,6-dioxobicyclo[2.2.2]-
octanes, the latter generally being obtained as the major
products.
Experimental Section
General: All commercially available chemical reagents were used
without further purification. Technical solvents were distilled by
standard literature methods before use.[50] Dimethyl ethylmalon-
ate,[51] dimethyl benzylmalonate,[52] dimethyl (4-methylbenzyl)ma-
lonate,[52] dimethyl (2-naphtylmethyl)malonate,[53] dimethyl [(E)-3-
phenylprop-2-en-1-yl]malonate,[54] dimethyl (cyclohexylmethyl)-
malonate,[55] (Z)-4-hydroxybut-2-en-1-yl acetate (1),[38] (Z)-4-{[tert-
butyl(dimethyl)silyl]oxy}but-2-en-1-yl acetate (2),[39] (E)-5-chlo-
ropent-2-en-1-ol,[56] (E)-6-bromohex-2-en-1-ol,[57] and [(4-bro-
mobut-2-yn-1-yl)oxy](tert-butyl)dimethylsilane (12)[40] were pre-
pared by literature methods. Tin-layer chromatography was per-
formed on aluminum-backed plates Merck silica gel 60 F254. Silica
gel 60 (40–63 µm, Merck) was used for column chromatography.
Chiral HPLC analyses were performed with a Chiraldex OD-H col-
umn (0.46 cm X 25 cm) at 25 °C, flow rate: 0.5 mL/min with n-
hexane/2-propanol as the eluent. 1H and 13C NMR spectra were
Route C: A mixture of dimethyl malonate 5a–c or 14 (12.5 mmol)
and sodium hydride (0.38 g, 16 mmol, 60% in mineral oil) in THF
(20 mL) and N,N-dimethylformamide (5 mL) was stirred at room
temp. for 30 min. Benzyl bromide (for substrates 5b–c or 14) or 1-
(bromomethyl)-2-methylbenzene (for substrate 5a, 18 mmol) was
then added, and the mixture was refluxed for 5 h. Hexane (5 mL)
and water (30 mL) were added at room temp., and the aqueous
phase was separated and extracted with a 1:1 mixture of diethyl
ether and hexane (2ϫ20 mL). The combined organic phases were
dried (Na2SO4). Evaporation of the solvents under reduced gave a
residue that was purified by flash chromatography on silica gel to
give dimethyl malonate 6c, 6h, 6i, or 15.
Dimethyl {(E)-4-[(tert-Butyldimethylsilyl)oxy]but-2-en-1-yl}(2-meth-
ylbenzyl)malonate (6c): Colorless oil, 4.22 g, 82% yield. Rf = 0.65
1
recorded with 300 MHz or 500 MHz spectrometers. Mass spectra (petroleum ether/ethyl acetate, 5:1). H NMR (300 MHz, CDCl3):
were obtained with a Micromass ZABSpecTOF spectrometer.
δ = 0.00 (s, 6 H, SiMe2), 0.83 (s, 9 H, CMe3), 2.23 (s, 3 H, CH3),
2304
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2296–2309

Selectivity of the Palladium-Catalyzed Formation of Cyclic Ethers
2.58 (d, J = 6.0 Hz, 2 H, CH2-CH=), 3.25 (s, 2 H, ArCH2), 3.61 J = 6.4 Hz, 2 H, CH2OCO2), 5.69 (dt, J = 15.3, 6.4 Hz, 1 H,
FULL PAPER
(s, 6 H, OMe), 4.05 (d, J = 4.5 Hz, 2 H, CH2O), 5.55 (dt, J = 15.4,
4.5 Hz, 1 H, -CH=), 5.60 (dt, J = 15.4, 6.0 Hz, 1 H, -CH=), 6.92–
7.08 (m, 4 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = –4.8,
18.7, 20.3, 26.3, 35.1, 36.3, 52.7, 59.8, 63.8, 126.1, 127.2, 130.4,
131.0, 134.4, 135.0, 137.6, 172.1 ppm. C23H36O5Si (420.61): calcd.
C 65.68, H 8.63, found C 65.94, H 8.76.
-CH=), 5.91 (dt, J = 15.3, 7.5 Hz, 1 H, -CH=), 7.19–7.27 (m, 5 H,
Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 35.1, 38.2, 43.4,
55.2, 67.9, 68.8, 126.7, 127.2, 128.5, 130.8, 132.7, 137.8, 156.1 ppm.
C16H22O5 (294.34): calcd. C 65.29, H 7.53; found C 65.47, H 7.72.
Typical Procedure for the Pd0-Catalyzed Cyclization Reaction: The
Pd catalyst was prepared by stirring Pd2(dba)3 (6.8 mg, 0.01 mmol)
and dppb (8.6 mg, 0.02 mmol) or the chiral ligand (0.02 mmol) at
room temp. in THF (3 mL) for 30 min. To this solution was added
allylic carbonate 9 or 18 (0.8 mmol) dissolved in THF (3 mL). After
being stirred for the indicated time, the solvent was evaporated,
and the residue was purified by column chromatography on silica
gel.
Typical Procedure for the Synthesis of Diols 7a–i and 16: A solution
of O-silylated dimethyl malonates 6 or 15 (13 mmol) in diethyl
ether (10 mL) was added at 0 °C to a stirred suspension of LiAlH4
(0.43 g, 13 mmol) in diethyl ether (15 mL). The reaction mixture
was stirred at room temp. for 30 min and then quenched by the
addition of water (1 mL) at 0 °C, followed by aqueous sodium hy-
droxide (15%, 4 mL). The mixture was extracted with ethyl acetate
(3ϫ10 mL). The organic phase was dried (Na2SO4) and concen-
trated under reduced pressure to give a residue that was purified
by flash column chromatography on silica gel to give diol 7a–i or
16.
3-Benzyl-3-hydroxymethyl-5-vinyltetrahydrofuran (10a) and (11a):
Colorless oil, 160 mg, 90% yield. Mixture of rac-(3R,5S)-10a and
rac-(3S,5S)-11a, which were separated by column chromatography.
rac-(3R,5S)-10a: Colorless oil. Rf = 0.32 (petroleum ether/diethyl
ether, 1:1). 1H NMR (500 MHz, CDCl3): δ = 1.48 (dd, J = 13.0,
8.3 Hz, 1 H, CH2), 1.57 (s, 1 H, OH), 2.07 (dd, J = 13.0, 7.5 Hz, 1
H, CH2), 2.81 (d, J = 13.4 Hz, 1 H, C6H5CH2), 2.92 (d, J =
13.4 Hz, 1 H, C6H5CH2), 3.46 (d, J = 10.5 Hz, 1 H, CH2OH), 3.52
(d, J = 10.5 Hz, 1 H, CH2OH), 3.67 (d, J = 8.9 Hz, 1 H, CH2O),
3.83 (d, J = 8.9 Hz, 1 H, CH2O), 4.42 (ddd, J = 8.3, 7.5, 6.4 Hz, 1
H, CH-CH=), 5.12 (ddd, J = 10.4, 1.1, 1.1 Hz, 1 H, CH=CH2),
5.27 (ddd, J = 17.0, 1.1, 1.1 Hz, 1 H, CH=CH2), 5.88 (ddd, J =
17.0, 10.4, 6.4 Hz, 1 H, CH=CH2), 7.20–7.40 (m, 5 H, Harom) ppm.
13C NMR (75 MHz, CDCl3): δ = 40.2, 40.9, 50.3, 66.9, 75.4, 80.3,
116.0, 126.8, 128.7, 130.3, 130.5, 138.5, 139.2 ppm. C14H18O2
(218.29): calcd. C 77.03, H 8.31; found C 76.78, H 8.22.
2-Benzyl-2-{(E)-4-[(tert-butyldimethylsilyl)oxy]but-2-en-1-yl}-
propane-1,3-diol (7a): Colorless oil, 3.65 g, 80% yield. Rf = 0.46
1
(petroleum ether/ethyl acetate, 3:1). H NMR (300 MHz, CDCl3):
δ = 0.00 (s, 6 H, SiMe2), 0.84 (s, 9 H, CMe3), 1.92 (d, J = 7.0 Hz,
2 H, CH2-CH=), 2.53 (s, 1 H, OH), 2.59 (s, 2 H, CH2Ph), 3.40–
3.55 (m, 4 H, CH2OH), 4.06 (br. d, J = 4.9 Hz, 2 H, CH2O), 5.55
(dt, J = 15.3, 4.9 Hz, 1 H, -CH=), 5.70 (dt, J = 15.3, 7.0 Hz, 1 H,
-CH=), 7.12–7.19 (m, 5 H, Harom) ppm. 13C NMR (75 MHz,
CDCl3): δ = –4.7, 18.8, 26.4, 35.0, 38.0, 43.4, 64.1, 68.2, 126.3,
126.6, 128.5, 128.5, 130.8, 130.9, 133.3, 138.0 ppm. C20H34O3Si
(350.57): calcd. C 68.52, H 9.78; found C 68.63, H 9.65.
Typical Procedure for the Synthesis of Triols 8a–i and 17: A mixture
of silylated diol 7 or 16 (4.8 mmol) and Bu4NF·3H2O (1.5 g,
4.8 mmol) in THF (50 mL) was stirred at room temp. for 15 h.
After evaporation of the solvent, diethyl ether (30 mL) was added,
and the organic phase was washed with brine (2ϫ25 mL). Evapo-
ration of the solvent under reduced pressure gave a residue that
was purified by column chromatography on silica gel to give triol
8a–i or 17.
The separation of the enantiomers was performed by HPLC with
n-hexane/2-propanol (90:10) as the eluent: tR = 18.7 min and tR
=
22.8 min.
rac-(3S,5S)-(11a): Colorless oil. Rf = 0.24 (petroleum ether/diethyl
ether, 1:1). 1H NMR (500 MHz, CDCl3): δ = 1.64 (dd, J = 12.8,
8.8 Hz, 1 H, CH2), 1.85 (s, 1 H, OH), 1.97 (dd, J = 12.8, 7.0 Hz, 1
H, CH2), 2.78 (d, J = 13.4 Hz, 1 H, C6H5CH2), 2.88 (d, J =
13.4 Hz, 1 H, C6H5CH2), 3.48 (s, 2 H, CH2OH), 3.68 (d, J =
8.9 Hz, 1 H, CH2O), 3.77 (d, J = 8.9 Hz, 1 H, CH2O), 4.41 (ddd,
J = 8.8, 7.0, 6.6 Hz, 1 H, CH-CH=), 5.10 (ddd, J = 10.4, 1.3,
1.3 Hz, 1 H, CH=CH2), 5.24 (ddd, J = 17.0, 1.3, 1.3 Hz, 1 H,
CH=CH2), 5.86 (ddd, J = 17.0, 10.4, 6.6 Hz, 1 H, CH=CH2), 7.15–
7.35 (m, 5 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 40.9,
50.3, 65.5, 75.0, 80.3, 115.7, 126.8, 128.7, 130.3, 130.5, 138.6, 139.5
ppm. HRMS (EI): calcd. for C14H18O2 [M]+· 218.1307; found
218.1305.
(E)-5-Benzyl-5-(hydroxymethyl)hex-2-ene-1,6-diol (8a): Colorless
1
oil, 1.11 g, 98% yield. Rf = 0.45 (ethyl acetate/methanol, 25:1). H
NMR (300 MHz, CDCl3): δ = 2.01 (d, J = 6.8 Hz, 2 H, CH2-CH=),
2.63 (s, 2 H, CH2Ph), 3.53 (s, 4 H, CH2OH), 3.69 (s, 3 H, OH),
4.09 (d, J = 5.1 Hz, 2 H, =CHCH2OH), 5.70 (dt, J = 15.3, 5.1 Hz,
1 H, -CH=), 5.80 (dt, J = 15.3, 6.8 Hz, 1 H, -CH=), 7.19–7.27 (m,
5 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 34.7, 38.0,
43.4, 63.6, 67.0, 126.7, 128.3, 128.5, 128.6, 130.9, 132.7, 137.8 ppm.
HRMS (ESI): calcd. for C14H21O3 [M + H]+ 237.1491; found
237.1493.
The separation of the enantiomers was performed by HPLC with
n-hexane/2-propanol (90:10) as the eluent: tR = 17.2 min and tR
18.7 min.
=
Typical Procedure for the Synthesis of Allylic Carbonates 9a–i and
18: A solution of triol 8a–i or 17 (4.7 mmol) in CH2Cl2 (50 mL)
cooled to 0 °C was treated with pyridine (0.4 mL, 9.3 mmol) and
methyl chloroformate (0.36 mL, 4.7 mmol). After 2 h at room
temp., the reaction mixture was quenched with water (10 mL) and
extracted with CH2Cl2 (2ϫ100 mL). The combined organic phases
were dried (Na2SO4) and evaporated under reduced pressure. The
crude product was purified by flash column chromatography on
silica gel to give allylic carbonate 9a–i or 18.
3-Hydroxymethyl-3-(4-methylbenzyl)-5-vinyltetrahydrofuran (10b)
and (11b): Colorless oil, 176 mg, 95% yield. Mixture of rac-
(3R,5S)-10b and rac-(3S,5S)-11b, which were separated by column
chromatography.
rac-(3R,5S)-10b: Colorless oil. Rf = 0.31 (petroleum ether/diethyl
ether, 1:1). 1H NMR (300 MHz, CDCl3): δ = 1.45 (dd, J = 13.0,
8.3 Hz, 1 H, CH2), 1.64 (s, 1 H, OH), 2.03 (dd, J = 13.0, 7.5 Hz, 1
(E)-5-Benzyl-6-hydroxy-5-(hydroxymethyl)hex-2-en-1-yl
Methyl H, CH2), 2.33 (s, 3 H, CH3), 2.75 (d, J = 13.6 Hz, 1 H, ArCH2),
Carbonate (9a): Colorless oil, 926 mg, 67% yield. Rf = 0.48 (ethyl
acetate/petroleum ether, 4:1). 1H NMR (300 MHz, CDCl3): δ =
2.07 (d, J = 7.5 Hz, 2 H, CH2-CH=), 2.63 (s, 2 H, OH), 2.67 (s, 2
2.84 (d, J = 13.6 Hz, 1 H, ArCH2), 3.47 (br. s, 2 H, CH2OH), 3.64
(d, J = 9.0 Hz, 1 H, CH2O), 3.80 (d, J = 9.0 Hz, 1 H, CH2O), 4.40
(ddd, J = 8.3, 7.5, 6.4 Hz, 1 H, CH-CH=), 5.09 (d, J = 10.4 Hz, 1
H, PhCH2), 3.57 (br. s, 4 H, CH2OH), 3.80 (s, 3 H, CH3), 4.61 (d, H, CH=CH2), 5.24 (d, J = 17.1 Hz, 1 H, CH=CH2), 5.86 (ddd, J
Eur. J. Org. Chem. 2007, 2296–2309
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2305

A. Zawisza, B. Fenêt, D. Sinou
FULL PAPER
= 17.1, 10.4, 6.4 Hz, 1 H, CH=CH2), 7.10 (s, 4 H, Harom) ppm. 13
C
H, CH2O), 3.84 (d, J = 8.9 Hz, 1 H, CH2O), 4.44 (ddd, J = 8.3,
NMR (75 MHz, CDCl3): δ = 21.4, 39.8, 40.3, 50.0, 66.9, 75.5, 80.4, 7.5, 6.4 Hz, 1 H, CH-CH=), 5.10 (dd, J = 10.4, 1.1 Hz, 1 H,
116.0, 129.5, 130.4, 135.4, 136.4, 139.2 ppm. C15H20O2 (232.32):
calcd. C 77.55, H 8.68; found C 77.41, H 8.93.
CH=CH2), 5.25 (dd, J = 17.0, 1.1 Hz, 1 H, CH=CH2), 5.87 (ddd,
J = 17.0, 10.4, 6.4 Hz, 1 H, CH=CH2), 7.30–7.90 (m, 7 H, Harom
)
ppm. 13C NMR (75 MHz, CDCl3): δ = 40.3, 50.5, 65.6, 75.1, 80.4,
116.1, 125.9, 126.5, 128.0, 128.2, 128.8, 128.9, 132.6, 133.8, 136.23,
139.5 ppm. C18H20O2 (268.35): calcd. C 80.56, H 7.51; found C
80.29, H 7.46.
The separation of the enantiomers was performed by HPLC with
n-hexane/2-propanol (95:5) as the eluent: tR = 24.7 min and tR
=
33.3 min.
rac-(3S,5S)-11b: Colorless oil. Rf = 0.23 (petroleum ether/diethyl
ether, 1:1). 1H NMR (300 MHz, CDCl3): δ = 1.61 (dd, J = 12.6,
8.7 Hz, 1 H, CH2), 1.96 (dd, J = 12.6, 6.9 Hz, 1 H, CH2), 2.02 (br.
s, 1 H, OH), 2.32 (s, 3 H, CH3), 2.73 (d, J = 13.5 Hz, 1 H, ArCH2),
2.83 (d, J = 13.5 Hz, 1 H, ArCH2), 3.46 (s, 2 H, CH2OH), 3.69 (d,
J = 8.7 Hz, 1 H, CH2O), 3.75 (d, J = 8.7 Hz, 1 H, CH2O), 4.41
(ddd, J = 8.7, 6.9, 6.6 Hz, 1 H, CH-CH=), 5.10 (d, J = 10.4 Hz, 1
H, CH=CH2), 5.22 (d, J = 17.0 Hz, 1 H, CH=CH2), 5.87 (ddd, J
The separation of the enantiomers was performed by HPLC with
n-hexane/2-propanol (98:2) as the eluent: tR = 42.3 min and tR
=
44.7 min.
rac-(3S,5S)-11d: Colorless oil. Rf = 0.69 (ethyl acetate/petroleum
ether, 2:1). 1H NMR (300 MHz, CDCl3): δ = 1.69 (dd, J = 12.8,
8.7 Hz, 1 H, CH2), 1.86 (s, 1 H, OH), 1.98 (dd, J = 12.8, 7.1 Hz, 1
H, CH2), 2.92 (d, J = 13.4 Hz, 1 H, ArCH2), 3.03 (d, J = 13.4 Hz,
1 H, ArCH2), 3.49 (br. s, 2 H, CH2OH), 3.72 (d, J = 8.9 Hz, 1 H,
CH2O), 3.82 (d, J = 8.9 Hz, 1 H, CH2O), 4.41 (ddd, J = 8.7, 7.1,
6.4 Hz, 1 H, CH-CH=), 5.11 (d, J = 10.4 Hz, 1 H, CH=CH2), 5.24
(d, J = 17.0 Hz, 1 H, CH=CH2), 5.86 (ddd, J = 17.0, 10.4, 6.4 Hz, 1
H, CH=CH2), 7.20–7.90 (m, 7 H, Harom) ppm. 13C NMR (75 MHz,
CDCl3): δ = 41.0, 50.5, 65.5, 75.0, 80.3, 115.8, 125.9, 126.5, 128.0,
128.1, 128.2, 128.8, 128.9, 132.6, 133.8, 136.3, 139.5 ppm. HRMS
(EI): calcd. for C18H20O2 [M]+· 268.1463; found 268.1463.
= 17.0, 10.4, 6.6 Hz, 1 H, CH=CH2), 7.09 (s, 4 H, Harom) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 21.4, 40.5, 40.9, 50.3, 65.5, 75.0, 80.3,
115.7, 129.4, 130.2, 135.5, 136.3, 139.5 ppm. HRMS (EI): calcd.
for C15H20O2 [M]+· 232.1463; found 232.1467.
The separation of the enantiomers was performed by HPLC with
n-hexane/2-propanol (95:5) as the eluent: tR = 23.2 min and tR
=
25.1 min.
3-Hydroxymethyl-3-(2-methylbenzyl)-5-vinyltetrahydrofuran (10c)
and (11c): Colorless oil, 175 mg, 94% yield. Mixture of rac-(3R,5S)-
10c and rac-(3S,5S)-11c, which were separated by column
chromatography.
The separation of the enantiomers was performed by HPLC with
n-hexane/2-propanol (98:2) as the eluent: tR = 84.6 min and tR
=
88.6 min.
3-[(E)-Cinnamyl]-3-hydroxymethyl-5-vinyltetrahydrofuran (10e) and
(11e): Colorless oil, 191 mg, 98% yield. Mixture of rac-(3R,5S)-10e
and of rac-(3S,5S)-11e, which were separated by column
chromatography.
rac-(3R,5S)-10c: Colorless oil. Rf = 0.27 (petroleum ether/diethyl
ether, 1:1). 1H NMR (300 MHz, CDCl3): δ = 1.55 (dd, J = 12.8,
7.9 Hz, 1 H, CH2), 1.58 (s, 1 H, OH), 2.03 (dd, J = 12.8, 7.7 Hz, 1
H, CH2), 2.36 (s, 3 H, CH3), 2.87 (s, 2 H, ArCH2), 3.48–3.60 (m,
2 H, CH2OH), 3.60 (d, J = 9.0 Hz, 1 H, CH2O), 3.80 (d, J = 9.0 Hz,
1 H, CH2O), 4.37 (ddd, J = 7.9, 7.7, 6.4 Hz, 1 H, CH-CH=), 5.09
(dd, J = 10.4, 1.1 Hz, 1 H, CH=CH2), 5.23 (dd, J = 17.2, 1.1 Hz,
1 H, CH=CH2), 5.87 (ddd, J = 17.2, 10.4, 6.4 Hz, 1 H, CH=CH2),
7.08–7.20 (m, 4 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ =
20.6, 35.9, 40.1, 50.6, 67.6, 74.7, 80.4, 115.9, 126.2, 126.9, 131.1,
131.3, 137.5, 139.3 ppm. HRMS (ESI): calcd. for C15H21O2 [M +
H]+ 233.1542; found 233.1545.
rac-(3R,5S)-10e: Colorless oil. Rf = 0.27 (petroleum ether/diethyl
ether, 1:1). 1H NMR (300 MHz, CDCl3): δ = 1.53 (dd, J = 12.8,
8.3 Hz, 1 H, CH2), 1.69 (s, 1 H, OH), 2.01 (dd, J = 12.8, 7.5 Hz, 1
H, CH2), 2.40 (ddd, J = 13.9, 7.7, 1.1 Hz, 1 H, CH2-CH=), 2.48
(ddd, J = 13.9, 7.7, 1.1 Hz, 1 H, CH2-CH=), 3.58 (s, 2 H, CH2OH),
3.59 (d, J = 9.0 Hz, 1 H, CH2O), 3.88 (d, J = 9.0 Hz, 1 H, CH2O),
4.38 (ddd, J = 8.3, 7.4, 6.4 Hz, 1 H, CH-CH=), 5.11 (ddd, J = 10.4,
1.5, 1.5 Hz, 1 H, CH=CH2), 5.25 (ddd, J = 17.1, 1.5, 1.5 Hz, 1 H,
CH=CH2), 5.88 (ddd, J = 17.1, 10.4, 6.4 Hz, 1 H, CH=CH2), 6.22
(ddd, J = 15.8, 7.5, 7.5 Hz, 1 H, CH2-CH=), 6.50 (d, J = 15.8 Hz,
1 H, C6H5CH=CH), 7.18–7.38 (m, 5 H, Harom) ppm. 13C NMR
(75 MHz, CDCl3): δ = 38.5, 40.5, 49.5, 67.9, 75.4, 80.5, 116.1,
126.5, 127.4, 127.7, 128.9, 133.5, 137.6, 138.9 ppm. HRMS (ESI):
calcd. for C16H21O2 [M + H]+ 245.1542; found 245.1545.
rac-(3S,5S)-11c: Colorless oil. Rf = 0.19 (petroleum ether/diethyl
ether, 1:1). 1H NMR (300 MHz, CDCl3): δ = 1.61 (dd, J = 12.8,
8.7 Hz, 1 H, CH2), 2.04 (dd, J = 12.8, 7.0 Hz, 1 H, CH2), 2.16 (s,
1 H, OH), 2.33 (s, 3 H, CH3), 2.81 (d, J = 13.9 Hz, 1 H, ArCH2),
2.84 (d, J = 13.9 Hz, 1 H, ArCH2), 3.54 (s, 2 H, CH2OH), 3.68 (d,
J = 8.9 Hz, 1 H, CH2O), 3.72 (d, J = 8.9 Hz, 1 H, CH2O), 4.42
(ddd, J = 8.7, 7.0, 6.6 Hz, 1 H, CH-CH=), 5.05 (d, J = 10.4 Hz, 1
H, CH=CH2), 5.20 (d, J = 17.1 Hz, 1 H, CH=CH2), 5.79 (ddd, J
rac-(3S,5S)-11e: Colorless oil. Rf = 0.18 (petroleum ether/diethyl
ether, 1:1). 1H NMR (300 MHz, CDCl3): δ = 1.60 (dd, J = 12.8,
8.6 Hz, 1 H, CH2), 1.80 (s, 1 H, OH), 2.08 (dd, J = 12.8, 7.0 Hz, 1
H, CH2), 2.44 (ddd, J = 14.1, 7.7, 0.8 Hz, 1 H, CH2-CH=), 2.58
(ddd, J = 14.1, 7.7, 0.8 Hz, 1 H, CH2-CH=), 3.63 (s, 2 H, CH2O),
3.76 (s, 2 H, CH2OH), 4.43 (ddd, J = 8.6, 7.0, 6.4 Hz, 1 H, CH-
CH=), 5.14 (d, J = 10.4 Hz, 1 H, CH=CH2), 5.27 (d, J = 17.0 Hz,
1 H, CH=CH2), 5.90 (ddd, J = 17.0, 10.4, 6.4 Hz, 1 H, CH=CH2),
6.21 (ddd, J = 15.8, 7.5, 7.5 Hz, 1 H, CH2-CH=), 6.50 (d, J =
15.8 Hz, 1 H, C6H5CH=CH), 7.20–7.40 (m, 5 H, Harom) ppm. 13C
NMR (75 MHz, CDCl3): δ = 39.4, 40.8, 49.7, 67.0, 75.1, 80.5,
115.9, 126.5, 126.7, 127.7, 128.9, 133.4, 137.6, 139.2 ppm. HRMS
(EI): calcd. for C16H21O2 [M]+· 244.1463; found 244.1479.
= 17.1, 10.4, 6.6 Hz, 1 H, CH=CH2), 7.05–7.18 (m, 4 H, Harom
)
ppm. 13C NMR (75 MHz, CDCl3): δ = 20.6, 36.4, 40.4, 50.8, 66.4,
74.0, 80.1, 115.7, 126.1, 126.9, 131.1, 131.2, 136.9, 137.4, 139.5
ppm. HRMS (ESI): calcd. for C15H21O2 [M + H]+ 233.1542; found
233.1545.
3-Hydroxymethyl-3-(2-naphtylmethyl)-5-vinyltetrahydrofuran (10d)
and (11d): Colorless oil, 201 mg, 94% yield. Mixture of rac-
(3R,5S)-10d and rac-(3S,5S)-11d, which were separated by column
chromatography.
rac-(3R,5S)-10d: Colorless oil. Rf = 0.74 (ethyl acetate/petroleum
ether, 2:1). 1H NMR (300 MHz, CDCl3): δ = 1.48 (dd, J = 12.8,
8.3 Hz, 1 H, CH2), 1.57 (s, 1 H, OH), 2.13 (dd, J = 12.8, 7.5 Hz, 1 3-Ethyl-3-hydroxymethyl-5-vinyltetrahydrofuran (10f) and (11f):
H, CH2), 2.96 (d, J = 13.4 Hz, 1 H, ArCH2), 3.05 (d, J = 13.4 Hz, Colorless oil, 113.7 mg, 91% yield. Mixture of rac-(3R,5S)-10f and
1 H, ArCH2), 3.46–3.55 (m, 2 H, CH2OH), 3.72 (d, J = 8.9 Hz, 1
rac-(3S,5S)-11f, which were separated by column chromatography.
2306
www.eurjoc.org
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2296–2309

Selectivity of the Palladium-Catalyzed Formation of Cyclic Ethers
FULL PAPER
rac-(3R,5S)-10f: Colorless oil. Rf = 0.30 (petroleum ether/diethyl
ether, 1:1). H NMR (300 MHz, CDCl3): δ = 0.92 (t, J = 7.5 Hz,
CH2OH), 3.69–3.81 (m, 2 H, CH2OH, CH-CH=), 3.88 (dd, J =
11.5, 2.5 Hz, 1 H, CH2O), 5.10 (br. d, J = 10.6 Hz, 1 H, CH=CH2),
1
3 H, CH3), 1.48 (dd, J = 12.6, 8.5 Hz, 1 H, CH2), 1.54 (q, J = 5.23 (br. d, J = 17.1 Hz, 1 H, CH=CH2), 5.84 (ddd, J = 17.1, 10.6,
7.5 Hz, 2 H, CH3CH2), 1.62 (s, 1 H, OH), 1.88 (dd, J = 12.6,
5.5 Hz, 1 H, CH=CH2), 7.10–7.40 (m, 5 H, Harom) ppm. 13C NMR
7.4 Hz, 1 H, CH2), 3.46 (d, J = 8.9 Hz, 1 H, CH2O), 3.54 (s, 2 H, (75 MHz, CDCl3): δ = 28.1, 30.2, 38.2, 41.7, 63.3, 73.2, 78.9, 115.4,
CH2OH), 3.85 (d, J = 8.9 Hz, 1 H, CH2O), 4.32 (ddd, J = 8.5,
7.4, 6.4 Hz, 1 H, CH-CH=), 5.12 (ddd, J = 10.4, 1.5, 1.1 Hz, 1 H,
CH=CH2), 5.24 (ddd, J = 17.0, 1.5, 1.1 Hz, 1 H, CH=CH2), 5.88
(ddd, J = 17.0, 10.4, 6.4 Hz, 1 H, CH=CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 9.5, 27.2, 40.5, 49.1, 67.3, 75.7, 80.6, 116.1,
139.1 ppm. HRMS (ESI): calcd. for C9H17O2 [M + H]+ 157.1229;
found 157.1227.
126.7, 128.5, 130.8, 137.5, 139.2 ppm. HRMS (ESI): calcd. for
C15H21O2 [M + H]+ 233.1541; found 233.1544.
The separation of the enantiomers was performed by HPLC with
n-hexane/2-propanol (95:5) as the eluent: tR = 28.4 min and tR
=
29.5 min.
rac-(3R,6S)-11h: Colorless oil. Rf = 0.44 (petroleum ether/diethyl
ether, 1:1). 1H NMR (500 MHz, CDCl3): δ = 1.38–1.48 (m, 1 H,
CH2), 1.53–1.71 (m, 3 H, CH2, OH), 1.72–1.89 (m, 1 H, CH2), 2.84
(d, J = 13.4 Hz, 1 H, C6H5CH2), 2.98 (d, J = 13.4 Hz, 1 H,
C6H5CH2), 3.25 (d, J = 11.0 Hz, 1 H, CH2OH), 3.30 (d, J =
11.0 Hz, 1 H, CH2OH), 3.36 (d, J = 11.5 Hz, 1 H, CH2O), 3.78–
3.87 (m, 2 H, CH2O, CH-CH=), 5.18 (br. d, J = 10.6 Hz, 1 H,
CH=CH2), 5.32 (br. d, J = 17.3 Hz, 1 H, CH=CH2), 5.97 (ddd, J
rac-(3S,5S)-11f: Colorless oil. Rf = 0.25 (petroleum ether/diethyl
1
ether, 1:1). H NMR (300 MHz, CDCl3): δ = 0.90 (t, J = 7.5 Hz,
3 H, CH3), 1.46 (dd, J = 12.6, 8.5 Hz, 1 H, CH2), 1.54 (q, J =
7.5 Hz, 2 H, CH3CH2), 1.76 (s, 1 H, OH), 1.99 (dd, J = 12.6,
6.8 Hz, 1 H, CH2), 3.58 (s, 2 H, CH2OH), 3.61 (d, J = 8.9 Hz, 1
H, CH2O), 3.71 (d, J = 8.9 Hz, 1 H, CH2O), 4.39 (ddd, J = 8.5,
6.8, 6.4 Hz, 1 H, CH-CH=), 5.09 (ddd, J = 10.4, 1.5, 1.1 Hz, 1 H,
CH=CH2), 5.23 (ddd, J = 17.0, 1.5, 1.1 Hz, 1 H, CH=CH2), 5.86
(ddd, J = 17.0, 10.4, 6.4 Hz, 1 H, CH=CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 9.6, 27.9, 40.8, 49.4, 66.3, 75.3, 80.5, 115.6,
139.4 ppm. HRMS (ESI): calcd. for C9H17O2 [M + H]+ 157.1229;
found 157.1228.
= 17.3, 10.6, 5.5 Hz, 1 H, CH=CH2), 7.15–7.35 (m, 5 H, Harom
)
ppm. 13C NMR (75 MHz, CDCl3): δ = 27.6, 29.1, 36.6, 38.7, 67.4,
73.3, 79.1, 115.6, 126.5, 128.6, 130.9, 138.7, 139.5 ppm. HRMS
(ESI): calcd. for C15H21O2 [M + H]+ 233.1541; found 233.1543.
The separation of the enantiomers was performed by HPLC with
n-hexane/2-propanol (95:5) as the eluent: tR = 23.9 min and tR
=
3-Cyclohexylmethyl-3-hydroxymethyl-5-vinyltetrahydrofuran (10g)
and (11g): Colorless oil, 170 mg, 95% yield. Mixture of rac-
(3R,5S)-10g and rac-(3S,5S)-11g, which were separated by column
chromatography.
25.4 min.
3-Benzyl-3-hydroxymethyl-7-vinyloxepan (10i) and (11i): Colorless
oil, 120 mg, 61% yield. Mixture of rac-(3R,7S)-10i and rac-(3S,7S)-
11i, which were separated by column chromatography.
rac-(3R,5S)-10g: Colorless oil. Rf = 0.37 (petroleum ether/diethyl
ether, 1:1). 1H NMR (300 MHz, CDCl3): δ = 0.82–1.46 (m, 6 H,
C6H11), 1.38 (d, J = 5.5 Hz, 2 H, CH2C6H11), 1.57 (dd, J = 12.8,
7.9 Hz, 1 H, CH2), 1.60–1.68 (m, 6 H, C6H11, OH), 1.90 (dd, J =
12.8, 7.7 Hz, 1 H, CH2), 3.39 (d, J = 9.0 Hz, 1 H, CH2O), 3.54 (s,
2 H, CH2OH), 3.89 (d, J = 9.0 Hz, 1 H, CH2O), 4.32 (ddd, J =
7.9, 7.7, 6.4 Hz, 1 H, CH-CH=), 5.10 (ddd, J = 10.4, 1.3, 1.3 Hz,
1 H, CH=CH2), 5.24 (ddd, J = 17.0, 1.3, 1.3 Hz, 1 H, CH=CH2),
5.88 (ddd, J = 17.0, 10.4, 6.4 Hz, 1 H, CH=CH2) ppm. 13C NMR
(75 MHz, CDCl3): δ = 26.6, 26.8, 34.9, 35.4, 35.5, 41.8, 42.6, 48.8,
67.8, 76.7, 80.6, 116.1, 139.1 ppm. C14H24O2 (224.34): calcd. C
74.95, H 10.78; found C 74.62, H 10.89.
rac-(3S,7S)-10i: Colorless oil. Rf = 0.87 (petroleum ether/diethyl
ether, 1:1). 1H NMR (500 MHz, CDCl3): δ = 1.35–1.76 (m, 5 H,
CH2), 1.81–1.97 (m, 1 H, CH2), 2.28 (s, 1 H, OH), 2.48 (d, J =
13.2 Hz, 1 H, C6H5CH2), 2.64 (d, J = 13.2 Hz, 1 H, C6H5CH2),
3.40 (d, J = 10.9 Hz, 1 H, CH2OH), 3.44 (d, J = 12.8 Hz, 1 H,
CH2O), 3.52 (d, J = 10.9 Hz, 1 H, CH2OH), 3.90 (d, J = 12.8 Hz,
1 H, CH2O), 3.95–4.05 (m, 1 H, CH-CH=), 5.09 (br. d, J =
10.6 Hz, 1 H, CH=CH2), 5.20 (br. d, J = 17.3 Hz, 1 H, CH=CH2),
5.85 (ddd, J = 17.3, 10.6, 5.3 Hz, 1 H, CH=CH2), 7.15–7.35 (m, 5
H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.8, 34.0, 36.9,
40.1, 43.9, 67.9, 74.2, 82.6, 114.6, 126.5, 128.4, 130.9, 138.1, 139.9
ppm. C16H22O2 (246.34): calcd. C 78.01, H 9.00; found C 77.86, H
8.91.
rac-(3S,5S)-11g: Colorless oil. Rf = 0.27 (petroleum ether/diethyl
ether, 1:1). 1H NMR (300 MHz, CDCl3): δ = 0.80–1.40 (m, 8 H,
The separation of the enantiomers was performed by HPLC with
C6H11, CH2C6H11), 1.46 (dd, J = 12.8, 8.9 Hz, 1 H, CH2), 1.55– n-hexane/2-propanol (95:5) as the eluent: tR = 26.1 min and tR
=
1.75 (m, 5 H, C6H11), 1.96 (s, 1 H, OH), 2.10 (dd, J = 12.8, 6.8 Hz,
1 H, CH2), 3.55 (d, J = 8.9 Hz, 1 H, CH2O), 3.58 (s, 2 H, CH2OH),
3.76 (d, J = 8.9 Hz, 1 H, CH2O), 4.40 (ddd, J = 8.9, 6.8, 6.4 Hz, 1
H, CH-CH=), 5.09 (ddd, J = 10.4, 1.3, 1.3 Hz, 1 H, CH=CH2),
5.22 (ddd, J = 17.0, 1.3, 1.3 Hz, 1 H, CH=CH2), 5.84 (ddd, J =
17.0, 10.4, 6.4 Hz, 1 H, CH=CH2) ppm. 13C NMR (75 MHz,
CDCl3): δ = 26.6, 26.8, 34.8, 35.3, 35.4, 42.3, 43.1, 49.2, 66.5, 76.0,
80.1, 115.5, 139.5 ppm. HRMS (ESI): calcd. for C14H25O2 [M +
H]+ 225.1855; found 225.1855.
27.6 min.
rac-(3R,7S)-11i: Colorless oil. Rf = 0.45 (petroleum ether/diethyl
ether, 1:1). 1H NMR (500 MHz, CDCl3): δ = 1.30–1.95 (m, 7 H,
CH2, OH), 2.50 (d, J = 13.2 Hz, 1 H, C6H5CH2), 2.76 (d, J =
13.2 Hz, 1 H, C6H5CH2), 3.32 (d, J = 11.0 Hz, 1 H, CH2OH), 3.54
(d, J = 12.8 Hz, 1 H, CH2O), 3.56 (d, J = 11.0 Hz, 1 H, CH2OH),
3.60 (d, J = 12.8 Hz, 1 H, CH2O), 4.10–4.19 (m, 1 H, CH-CH=),
5.10 (br. d, J = 10.6 Hz, 1 H, CH=CH2), 5.24 (br. d, J = 17.3 Hz,
1 H, CH=CH2), 5.88 (ddd, J = 17.3, 10.6, 4.7 Hz, 1 H, CH=CH2),
7.15–7.20 (m, 5 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ =
21.1, 35.3, 36.5, 41.1, 43.9, 65.9, 70.1, 80.0, 114.4, 126.5, 128.4,
131.0, 138.4, 139.8 ppm. C16H22O2 (246.34): calcd. C 78.01, H 9.00;
found C 77.96, H 8.95.
3-Benzyl-3-hydroxymethyl-6-vinyltetrahydro-2H-pyran (10h) and
(11h): Colorless oil, 156 mg, 84% yield. Mixture of rac-(3S,6S)-10h
and rac-(3R,6S)-11h, which were separated by column chromatog-
raphy.
The separation of the enantiomers was performed by HPLC with
rac-(3S,6S)-10h: Colorless oil. Rf = 0.55 (petroleum ether/diethyl
ether, 1:1). 1H NMR (500 MHz, CDCl3): δ = 1.43–1.59 (m, 3 H,
CH2), 1.63–1.72 (m, 1 H, CH2), 1.84 (s, 1 H, OH), 2.41 (d, J =
13.2 Hz, 1 H, C6H5CH2), 2.63 (d, J = 13.2 Hz, 1 H, C6H5CH2),
n-hexane/2-propanol (95:5) as the eluent: tR = 22.1 min and tR
=
28.4 min.
Preparation of 3-Benzyl-6-vinyltetrahydro-2H-pyran-3-yl]methyl 3,5-
3.31 (d, J = 11.5 Hz, 1 H, CH2O), 3.50 (d, J = 10.9 Hz, 1 H, Dinitrobenzoates (19) and (20): A solution of compound 10h or 11h
Eur. J. Org. Chem. 2007, 2296–2309
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2307

A. Zawisza, B. Fenêt, D. Sinou
FULL PAPER
(23.2 mg, 0.1 mmol) in pyridine (2 mL), cooled to 0 °C, was treated
troleum ether/diethyl ether, 1:1). 1H NMR (300 MHz, CDCl3): δ =
with 3,5-dinitrobenzoyl chloride (46 mg, 2 mmol). After 12 h at 1.25 (s, 3 H, CH3), 1.67–1.75 (m, 2 H, CH2), 1.88–1.96 (m, 2 H,
room temp., the reaction mixture was quenched with water (5 mL)
and extracted with CH2Cl2 (2ϫ5 mL). The combined organic
phases were dried with Na2SO4 and concentrated under reduced
pressure to give a residue that was purified by column chromatog-
raphy on silica gel to give the corresponding dinitrobenzoate 19 or
20.
CH2), 2.26 (s, 3 H, CH3), 2.49 (s, 2 H, CH2Ar), 3.82 (br. d, J =
8.1 Hz, 2 H, CH2O), 3.93 (br. d, J = 8.1 Hz, 2 H, CH2O), 6.90–
7.12 (m, 5 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 20.6,
25.5, 28.6, 32.3, 34.4, 37.2, 73.4, 94.8, 126.0, 127.1, 131.1, 131.4,
134.9, 136.9 ppm. C15H20O2 (232.32): calcd. C 77.55, H 8.69; found
C 77.39, H 8.84.
rac-(3S,6S)-19: Colorless solid. M.p. 88–90 °C. 37.5 mg, 88% yield.
Rf = 0.83 (petroleum ether/diethyl ether, 1:1). 1H NMR (500 MHz,
1-Methyl-4-naphtylmethyl-2,6-dioxobicyclo[2.2.2]octane (21d): Col-
orless solid. M.p. 111–112 °C. 81.2 mg, 78% yield. Rf = 0.56 (petro-
CDCl3): δ = 1.40–1.85 (m, 4 H, CH2), 2.53 (d, J = 13.5 Hz, 1 H, leum ether/diethyl ether, 1:1). 1H NMR (300 MHz, CDCl3): δ =
C6H5CH2), 2.64 (d, J = 13.5 Hz, 1 H, C6H5CH2), 3.41 (d, J =
1.25 (s, 3 H, CH3), 1.67–1.78 (m, 2 H, CH2), 1.87–1.97 (m, 2 H,
11.7 Hz, 1 H, CH2O), 3.70–3.78 (m, 1 H, CH-CH=), 3.92 (br. d, J CH2), 2.60 (s, 2 H, CH2Ar), 3.83 (br. d, J = 8.1 Hz, 2 H, CH2O),
= 11.7 Hz, 1 H, CH2O), 4.37 (d, J = 11.3 Hz, 1 H, CH2OCO), 4.43
(d, J = 11.3 Hz, 1 H, CH2OCO), 5.04 (br. d, J = 10.6 Hz, 1 H,
3.96 (br. d, J = 8.1 Hz, 2 H, CH2O), 7.10–7.90 (m, 7 H, Harom
)
ppm. 13C NMR (75 MHz, CDCl3): δ = 25.5, 28.3, 32.2, 33.6, 41.1,
CH=CH2), 5.16 (br. d, J = 17.3 Hz, 1 H, CH=CH2), 5.78 (ddd, J 73.4, 95.1, 126.0, 126.6, 127.9, 128.0, 128.2, 128.7, 128.8, 132.6,
= 17.3, 10.7, 5.5 Hz, 1 H, CH=CH2), 6.95–7.20 (m, 5 H, Harom), 133.7, 134.0 ppm. C18H20O2 (268.35): calcd. C 80.56, H 7.53; found
8.91 (s, 2 H, Harom), 9.14 (s, 1 H, Harom) ppm. 13C NMR (75 MHz, C 80.60, H 7.70.
CDCl3): δ = 27.9, 30.8, 37.2, 43.1, 67.6, 73.2, 78.9, 115.9, 126.9,
1-Methyl-4-[(E)-2-phenylvinyl]-2,6-dioxobicyclo[2.2.2]octane (21e):
Colorless oil, 18.5 mg, 19% yield. Rf = 0.58 (petroleum ether/di-
128.8, 129.6, 130.4, 138.7, 134.2, 136.6, 149.0, 139.2, 162.7 ppm.
HRMS (ESI): calcd. for C22H23O7N2 [M + H]+ 427.1505; found
427.1507.
ethyl ether, 1:1). 1H NMR (300 MHz, CDCl3): δ = 1.30 (s, 3 H,
CH3), 1.72–1.82 (m, 2 H, CH2), 1.96–2.04 (m, 2 H, CH2), 2.07 (d,
J = 7.7 Hz, 2 H, CH2-CH=), 3.85 (br. d, J = 7.2 Hz, 2 H, CH2O),
3.88 (br. d, J = 7.2 Hz, 2 H, CH2O), 6.07 (dt, J = 15.6, 7.7 Hz, 1
H, =CH-CH2), 6.40 (d, J = 15.6 Hz, 1 H, C6H5CH=), 7.20–7.38
(m, 5 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ = 25.5, 28.5,
rac-(3R,6S)-20: Colorless oil, 38.3 mg, 90% yield. Rf = 0.83 (petro-
leum ether/diethyl ether, 1:1). 1H NMR (500 MHz, CDCl3): δ =
1.40–1.80 (m, 4 H, CH2), 2.85 (d, J = 13.7 Hz, 1 H, C6H5CH2),
3.04 (d, J = 13.7 Hz, 1 H, C6H5CH2), 3.39 (d, J = 11.7 Hz, 1 H,
CH2O), 3.78–3.85 (m, 1 H, CH-CH=), 3.98 (br. d, J = 11.7 Hz, 1 32.4, 33.2, 37.8, 73.3, 95.1, 124.3, 126.5, 127.8, 129.0, 133.7, 137.4
H, CH2O), 4.03 (d, J = 11.4 Hz, 1 H, CH2OCO), 4.10 (d, J = ppm. HRMS (ESI): calcd. for C16H21O2 [M + H]+ 245.1542; found
11.4 Hz, 1 H, CH2OCO), 5.15 (br. d, J = 10.6 Hz, 1 H, CH=CH2),
5.30 (br. d, J = 17.3 Hz, 1 H, CH=CH2), 5.90 (ddd, J = 17.3, 10.6,
5.5 Hz, 1 H, CH=CH2), 7.09–7.19 (m, 5 H, Harom), 8.93 (s, 2 H,
Harom), 9.17 (s, 1 H, Harom) ppm. HRMS (ESI): calcd. for
C22H23O7N2 [M + H]+ 427.1505; found 427.1507.
Typical Procedure for the PdII-Catalyzed Cyclization Reaction: A
solution of PdCl2(CH3CN)2 (5.2 mg, 0.02 mmol) in THF (3 mL)
was added to a solution of alcohol 8 or 17 (0.4 mmol) in THF
(3 mL) at room temp. under an argon atmosphere. The mixture was
stirred at room temp. for 24 h. The solvent was evaporated, and
the residue was purified by column chromatography on silica gel
with petroleum ether/ethyl acetate as the eluent to afford com-
pounds 10, 11, and 21.
245.1543.
4-Ethyl-1-methyl-2,6-dioxobicyclo[2.2.2]octane (21f): Colorless oil,
28.7 mg, 46% yield. Rf = 0.78 (petroleum ether/diethyl ether, 1:1).
1H NMR (300 MHz, CDCl3): δ = 0.80 (t, J = 7.9 Hz, 3 H, CH3),
1.17 (q, J = 7.9 Hz, 2 H, CH2CH3), 1.28 (s, 3 H, CH3), 1.62–1.70
(m, 2 H, CH2), 1.94–2.00 (m, 2 H, CH2), 3.77 (br. d, J = 9.6 Hz, 2
H, CH2O), 3.79 (br. d, J = 9.6 Hz, 2 H, CH2O) ppm. 13C NMR
(75 MHz, CDCl3): δ = 7.9, 25.5, 26.6, 27.7, 32.3, 32.3, 73.42, 94.7
ppm. HRMS (ESI): calcd. for C9H15O2 [M – H]+ 155.1072; found
155.1075.
4-Cyclohexylmethyl-1-methyl-2,6-dioxobicyclo[2.2.2]octane (21g):
Colorless oil, 53.8 mg, 60% yield. Rf = 0.85 (petroleum ether/di-
ethyl ether, 1:1). 1H NMR (300 MHz, CDCl3): δ = 0.82–1.35 (m, 6
H, C6H11), 0.98 (d, J = 5.5 Hz, 2 H, C6H11CH2), 1.27 (s, 3 H,
CH3), 1.54–1.75 (m, 7 H, CH2, C6H11), 1.93–2.02 (m, 2 H, CH2),
3.77–3.85 (m, 4 H, CH2O) ppm. 13C NMR (75 MHz, CDCl3): δ =
4-Benzyl-1-methyl-2,6-dioxobicyclo[2.2.2]octane (21a): Colorless so-
lid. M.p. 78–80 °C. 59.3 mg, 68% yield. Rf = 0.52 (petroleum ether/
1
diethyl ether, 1:1). H NMR (300 MHz, CDCl3): δ = 1.25 (s, 3 H,
CH3), 1.60–1.70 (m, 2 H, CH2), 1.85–1.96 (m, 2 H, CH2), 2.45 (s, 25.5, 26.4, 28.7, 32.4, 32.7, 33.3, 35.8, 42.1, 73.7, 94.7 ppm. HRMS
2 H, CH2C6H5), 3.78 (br. d, J = 8.1 Hz, 2 H, CH2O), 3.89 (br. d,
J = 8.1 Hz, 2 H, CH2O), 6.97–7.33 (m, 5 H, Harom) ppm. 13C NMR
(75 MHz, CDCl3): δ = 25.5, 28.3, 32.2, 33.2, 41.0, 73.3, 95.1, 127.0,
128.7, 130.3, 136.3 ppm. C14H18O2 (218.29): calcd. C 77.03, H 8.31;
found C 77.15, H 8.35.
(ESI): calcd. for C14H25O2 [M + H]+ 225.1855; found 225.1853.
1-Benzyl-5-methyl-6,9-dioxabicyclo[3.2.1]nonane (21h): Colorless
solid. M.p. 59–61 °C. 21.3 mg, 23% yield. Rf = 0.82 (petroleum
1
ether/diethyl ether, 1:1). H NMR (300 MHz, CDCl3): δ = 1.25 (s,
3 H, CH3), 1.48–1.90 (m, 6 H, CH2), 2.45 (s, 2 H, CH2C6H5), 3.77
1-Methyl-4-(4-methylbenzyl)-2,6-dioxobicyclo[2.2.2]octane
(21b): (br. d, J = 8.1 Hz, 2 H, CH2O), 3.89 (br. d, J = 8.1 Hz, 2 H, CH2O),
Colorless solid. M.p. 68–69 °C. 56.7 mg, 61% yield. Rf = 0.73 (pe- 6.95–7.30 (m, 5 H, Harom) ppm. 13C NMR (75 MHz, CDCl3): δ =
troleum ether/diethyl ether, 1:1). 1H NMR (300 MHz, CDCl3): δ =
1.25 (s, 3 H, CH3), 1.57–1.72 (m, 2 H, CH2), 1.88–1.97 (m, 2 H,
CH2), 2.34 (s, 3 H, CH3), 2.42 (s, 2 H, CH2Ar), 3.78 (br. d, J =
8.1 Hz, 2 H, CH2O), 3.90 (br. d, J = 8.1 Hz, 2 H, CH2O), 6.92 (d,
28.1, 28.1, 29.9, 31.7, 33.4, 41.0, 73.2, 96.8, 126.9, 128.6, 130.3,
136.4 ppm. HRMS (ESI): calcd. for C15H21O2 [M + H]+ 233.1542;
found 233.1542.
Supporting Information (see also the footnote on the first page of
this article): Preparation and spectroscopic data for compounds
3a–b, 4a–c, 5a–c, 13, and 14. Spectroscopic data for compounds
J = 7.9 Hz, 2 H, Harom), 7.10 (d, J = 7.9 Hz, 2 H, Harom) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 21.4, 25.5, 28.2, 32.2, 33.2, 40.5, 73.3,
95.1, 129.3, 130.2 ppm. C15H20O2 (232.32): calcd. C 77.55, H 8.69;
found C 77.37, H 8.77.
1
6b, 6d, 6f–i, 7b–i, 8b–i, 9b–i, and 15–18. Copies of H spectra for
compounds 10a–i and 11a–i, 1H and 13C spectra for compounds
1-Methyl-4-(4-methylbenzyl)-2,6-dioxobicyclo[2.2.2]octane
(21c): 21a–h, and NOESY 1D and 2D for compounds 10a, 11a, 10i, 11i,
Colorless solid. M.p. 46–47 °C. 69.7 mg, 75% yield. Rf = 0.80 (pe- 19, and 20.
2308
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© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2007, 2296–2309

Selectivity of the Palladium-Catalyzed Formation of Cyclic Ethers
FULL PAPER
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Received: November 27, 2006
Published Online: March 16, 2007
Eur. J. Org. Chem. 2007, 2296–2309
© 2007 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2309