Palladium(II)-Catalyzed Intramolecular 1,4-Oxyacyloxylation of Conjugated Dienes. A Stereocontrolled Route to Fused Six-Membered Lactones and Pyrans

Article abstract of DOI:10.1021/jo0357667

Stereocontrolled palladium(II)-catalyzed intramolecular 1,4-oxidations of dienyl acids and alcohols proceed under mild conditions to give fused δ-lactones and pyrans, respectively, in good yields. The stereo- and regioselectivity was affected by the presence of LiCl and solvent composition (HOAc/acetone). The products obtained were used for further functionalizations using copper(I)-mediated reactions. Stoichiometric reactions of preformed dibutylcyanocuprates with pyrans containing an allylic acetate gave cis- and trans-fused ring systems with high γ-selectivity and in high yields.

Full text of DOI:10.1021/jo0357667

P a lla d iu m (II)-Ca ta lyzed In tr a m olecu la r 1,4-Oxya cyloxyla tion of
Con ju ga ted Dien es. A Ster eocon tr olled Rou te to F u sed
Six-Mem ber ed La cton es a n d P yr a n s
Renzo C. Verboom, B. Anders Persson, and J an-E. Ba¨ckvall*
Department of Organic Chemistry, Arrhenius Laboratory, Stockholm University,
SE-106 91 Stockholm, Sweden
jeb@organ.su.se
Received December 3, 2003
Stereocontrolled palladium(II)-catalyzed intramolecular 1,4-oxidations of dienyl acids and alcohols
proceed under mild conditions to give fused δ-lactones and pyrans, respectively, in good yields.
The stereo- and regioselectivity was affected by the presence of LiCl and solvent composition (HOAc/
acetone). The products obtained were used for further functionalizations using copper(I)-mediated
reactions. Stoichiometric reactions of preformed dibutylcyanocuprates with pyrans containing an
allylic acetate gave cis- and trans-fused ring systems with high γ-selectivity and in high yields.
SCHEME 1
In tr od u ction
The preparation of lactones from alkenoic acids is an
important synthetic transformation that is commonly
achieved by the iodo- or selenolactonization reactions.1,2
Efficient methods for lactonization of alkenes, allenes,
and dienes via metal activation have also been devel-
oped.3-6
Palladium(II)-catalyzed 1,4-oxidation of conjugated
dienes has proven to be a useful tool in organic synthesis.7
Stereoselective inter- as well as intramolecular reactions
with a variety of nucleophiles have been developed.8,9 We
have previously reported on the efficient 1,4-acetoxylac-
tonization of 1,3-dienes giving five-membered lactones
with a dual stereocontrol (Scheme 1).5,6
Attempts to extend this lactonization reaction to six-
membered lactones were unsuccessful and led mainly to
1,4-diacetoxylation of the diene due to a competing
intermolecular reaction.5,10 Intramolecular 1,4-function-
alizations of 1,3-dienes having a hydroxyalkyl chain in
the 2-position of the diene have been developed in our
group during the past years.11 We were therefore inter-
ested in whether the corresponding 2-substituted 1,3-
dienes with a carboxylic nucleophile in the side chain
would be able to compete with the intermolecular reac-
tion, thereby providing six-membered lactones (eq 1).
In this paper, we report on intramolecular 1,4-oxida-
tions involving different nucleophiles (-COOH and -OH)
in the first step of the reaction. The δ-lactones and pyrans
* Corresponding author. Fax: +46 8 154908.
(1) Dowle, M. D.; Davies, D. I. Chem. Soc. Rev. 1979, 8, 171 and
references therein.
(2) Nicolaou, K. C.; Petasis, N. A. Selenium in Natural Products
Synthesis, CIS, Inc.: Philadelphia, 1994.
(3) For
a review on reactions of metal-activated alkenes with
heteroatom nucleophiles, see: Hegedus, L. S. In Comprehensive
Organic Synthesis, Vol. 3; Trost, B. M., Fleming, I., Eds.; Pergamon:
Oxford, 1991; pp 551-583.
(4) (a) Larock, R. C.; Harrison, L. W.; Hsu, M. H. J . Org. Chem.
1984, 49, 3662. (b) Pearson, A. J .; Kole, S. L.; Ray, T. J . Am. Chem.
Soc. 1984, 106, 6060. (c) Pearson, A. J .; Khan, M. N. I. J . Org. Chem.
1985, 50, 5276. (d) Pearson, A. J .; Ray, T. Tetrahedron 1985, 41, 5765.
(e) Ma, S.; Shi, Z. J . Org. Chem. 1998, 63, 6387. (f) Zenner, J . M.;
Larock, R. C. J . Org. Chem. 1999, 64, 7312.
(5) (a) Ba¨ckvall, J .-E.; Andersson, P. G.; Vågberg, J . O. Tetrahedron
Lett. 1989, 30, 137. (b) Ba¨ckvall, J .-E.; Granberg, K. L.; Andersson, P.
G.; Gatti, R.; Gogoll, A. J . Org. Chem. 1993, 58, 5445.
(6) This reaction has also been applied to the synthesis of the natural
products paeonilactone A and B: (a) Ro¨nn, M.; Andersson, P. G.;
Ba¨ckvall, J .-E. Acta Chem. Scand. 1998, 52, 524. (b) J onasson, C.;
Ro¨nn, M.; Ba¨ckvall, J .-E. J . Org. Chem. 2000, 65, 2122.
(7) (a) Ba¨ckvall, J . E. In Metal-catalyzed Cross-Coupling Reactions;
Stang, P., Diederich, F., Eds.; VCH: Weinheim, 1998; pp 339-385.
(b) Harrington, P. J . In Comprehensive Organometallic Chemistry II;
Abel, E. W., Stone, G. A., Wilkinson, G., Eds. (Hegedus, L. S., Vol.
Ed.); Pergamon: New York, 1995; Vol. 12, pp 797-904.
(8) (a) Ba¨ckvall, J .-E.; Bystro¨m, S. E.; Nordberg, R. E. J . Org. Chem.
1984, 49, 4619. (b) Ba¨ckvall, J .-E.; Nystro¨m, J . E.; Nordberg, R. E. J .
Am. Chem. Soc. 1985, 107, 3676. (c) Ba¨ckvall, J .-E.; Vågberg, J . O. J .
Org. Chem. 1988, 53, 5695.
(9) (a) Ba¨ckvall, J .-E.; Andersson, P. G. J . Am. Chem. Soc. 1990,
112, 3683. (b) Ba¨ckvall, J .-E.; Andersson, P. G. J . Org. Chem. 1991,
56, 2274. (c) Andersson, P. G.; Ba¨ckvall, J .-E. J . Am. Chem. Soc. 1992,
114, 8696. (d) Ba¨ckvall, J .-E.; Andersson, P. G. J . Am. Chem. Soc. 1992,
114, 6374. (e) Ba¨ckvall, J .-E.; Nilsson, Y. I. M.; Andersson, P. G.; Gatti,
R. G. P.; Wu, J . Tetrahedron Lett. 1994, 35, 5713. (f) Castan˜o, A. M.;
Ba¨ckvall, J .-E. J . Am. Chem. Soc. 1995, 117, 560. (g) Nilsson, Y. I. M.;
Gatti, R. G. P.; Andersson, P. G.; Ba¨ckvall, J .-E. Tetrahedron 1996,
52, 7511. (h) Castan˜o, A. M.; Persson, B. A.; Ba¨ckvall, J .-E. Chem. Eur.
J . 1997, 3, 482. (i) Lo¨fstedt, J .; Franze´n, J .; Ba¨ckvall, J .-E. J . Org.
Chem. 2001, 66, 8015. (j) Dorange, I.; Lo¨fstedt, J .; Na¨rhi, K.; Franze´n,
J .; Ba¨ckvall, J .-E. Chem. Eur. J . 2003, 9, 577.
(10) The increased flexibility of the acid-functionalized tether
rendered the lactonization reaction too slow compared to the intermo-
lecular reaction.
(11) (a) Koroleva, E. B.; Ba¨ckvall, J .-E.; Andersson, P. G. Tetrahe-
dron Lett. 1995, 36, 5397. (b) Itami, K.; Palmgren, A.; Ba¨ckvall, J .-E.
Tetrahedron Lett. 1998, 39, 1223.
10.1021/jo0357667 CCC: $27.50 © 2004 American Chemical Society
Published on Web 04/02/2004
3102
J . Org. Chem. 2004, 69, 3102-3111

Intramolecular 1,4-Oxyacyloxylation of 1,3-Dienes
The palladium(II)-catalyzed oxidation of 1,3-dienes is
usually highly regioselective toward formation of 1,4-
addition product.5,7-9,18 Factors such as the electronic
nature of the first nucleophile and the conformation of
the (π-allyl)palladium intermediate have been shown to
be important for this selectivity.18 The choice of solvent
has also been demonstrated to affect the regioselectivity
in related cyclizations.19 To investigate if the latter factor
would also influence the regioselectivity in this system,
a short solvent study was made using 3a as a model
substrate.20 By varying the solvent composition from
100% HOAc to HOAc/acetone 1:6,21 a trend in regiose-
lectivity was observed. The best selectivity favoring
formation of the 1,4-addition product was obtained with
HOAc/acetone 1:4. Therefore, this solvent system was
used for all reactions.
obtained are highly stereodefined products and are
interesting intermediates for further functionalization
reactions. Transition-metal-catalyzed reactions of these
allylic substrates can lead to cis- or trans-fused hetero-
cyclic ring systems. Pd(0)-catalyzed hydrogenolysis and
Cu(I)-catalyzed SN2′ substitution reactions of the 1,4-
oxidation products provide access to stereodefined cis-
and trans-fused ring systems, with the concomitant
introduction of a hydrogen or an extra carbon substituent
at the bridgehead position.
Resu lts a n d Discu ssion
It is well documented that the role of the chloride ion
is to block the coordination of acetate to palladium and
thereby favor external attack of acetate.7 When the
reaction was carried out without added LiOAc and LiCl,
trans-product 9c was produced as a single isomer (entry
2).16,22 Thus, the internal acetate migration is more
selective toward 1,4-addition product than the external
attack by the acetate nucleophile (Figure 1, A). It is
known that this cis migration occurs via a σ-allyl
intermediate.7,8a,23 There would be release of strain in the
(σ-allyl)palladium intermediate B (Figure 1), which has
a more flexible double bond compared to the other
possible σ-allyl (with the double bond connected to the
bridgehead position). Thus, formation of intermediate B
would favor the 1,4-addition product.
Lactonization of the seven-membered ring 3b, in the
presence of LiOAc and LiCl, gave results similar to those
for the six-membered ring but with lower regioselectivity,
providing regioisomeric lactones 10a and 10b in a ratio
of 63:37 in 90% combined yield.16 When the reaction was
run in the absence of LiCl and with only 1 equiv of LiOAc,
the regioselectivity was much improved and 10a and 10b
were obtained in a ratio 91:9 in 98% combined yield
(entry 3). When the reaction was carried out without
added LiOAc and LiCl to obtain the trans-1,4-addition
product, the cis/trans selectivity was not so good, and a
mixture of four isomers of 10 (cis and trans; 1,2- and 1,4-
addition) was obtained with >90% overall cis selectivity.16
A lower trans selectivity for seven-membered rings
compared to six-membered rings has previously been
observed in the 1,4-diacetoxylation of dienes and was
explained by conformational differences in the (σ-allyl)-
palladium intermediates, with cis migration being un-
favored for the seven-membered ring.8a Upon addition of
2.5 mol % sulfuric acid, to slow the rate of the external
attack, and with p-benzoquinone as the stoichiometric
The requisite starting materials were prepared by a
palladium-catalyzed Negishi cross-coupling12a of the diene
triflates13 1a -c with the zinc reagents from ethyl 3-io-
dopropionate or ethyl 4-iodobutyrate, followed by either
hydrolysis or reduction. This afforded the corresponding
carboxylic acids 3a -c or alcohols 4a -c, respectively
(Scheme 2).
The corresponding aromatic derivatives 3d ,e were
prepared in a similar way (Scheme 3). Palladium-
catalyzed coupling of diene triflates 1a ,b with the zinc
derivative 5, obtained from the methyl ester of 2-bro-
mobenzoic acid and activated zinc,12b,c gave 2e,f, which
after hydrolysis afforded 3d ,e.
Triflate 1d was prepared from (R)-(-)-carvone and
then used to prepare diene acid 3f employing the
aforementioned procedure (Scheme 4). A direct pathway
to 4d 11b would be by reduction of ester 2e. Due to the
relative instability of 2e, another method was chosen. The
benzylic diene alcohol 4d was prepared instead by a
nickel-catalyzed cross-coupling14 of 2-cyclohexadienyl
diphenyl phosphate 615 with the Grignard reagent 7,
derived from (2-bromobenzyl)-tert-butyldimethylsilyl ether,
and subsequent hydrolysis of silyl ether 8 with TBAF
(Scheme 5).
A. P a lla d iu m (II)-Ca ta lyzed In tr a m olecu la r 1,4-
Dia cyloxyla tion Rea ction s. Palladium-catalyzed oxi-
dation of diene acid 3a in acetic acid/acetone 1:4 in the
presence of LiOAc and LiCl, using catalytic p-benzo-
quinone (BQ) and stoichiometric MnO2 as the oxidant,
afforded the fused lactone 9 in 90% yield and with a high
degree of stereocontrol in the addition across the diene
(Table 1, entry 1).16 Surprisingly, the regioselectivity was
poor, and a 75:25 mixture of 1,4- and 1,2-addition
products 9a and 9b was obtained.17
(12) (a) Tamaru, Y.; Ochiai, H.; Nakamura, T.; Yoshida, Z. Tetra-
hedron Lett. 1986, 27, 955. (b) Zhu, L.; Wehmeyer, R. M.; Rieke, R. D.
J . Org. Chem. 1991, 56, 1445. (c) Palmgren, A.; Thorarensen, A.;
Ba¨ckvall, J .-E. J . Org. Chem. 1998, 63, 3764.
(13) (a) McMurry, J . E.; Scott, W. J . Tetrahedron Lett. 1983, 24, 979.
(b) Karlstro¨m, A. S. E.; Ro¨nn, M.; Thorarensen, A.; Ba¨ckvall, J .-E. J .
Org. Chem. 1998, 63, 2517.
(14) Karlstro¨m, A. S. E.; Itami, K.; Ba¨ckvall, J .-E. J . Org. Chem.
1999, 64, 1745.
(15) Blotny, G.; Pollack, R. M. Synthesis 1988, 109.
(17) This is one of the rare exceptions to the very high 1,4-
regioselectivity usually obtained in the palladium-catalyzed oxidations
of conjugated dienes; see refs 5b and 11a.
(18) (a) Szabo´, K. J . J . Am. Chem. Soc. 1996, 118, 7818. (b) Szabo´,
K. J . Chem. Eur. J . 1997, 3, 592.
(19) Andersson, P. G.; Aranyos, A. Tetrahedron Lett. 1994, 35, 4441.
(20) Control experiments showed that no allylic transposition in the
products occurred under the reaction conditions; see: Overman, L. E.
Angew. Chem., Int. Ed. Engl. 1984, 23, 579.
(16) The relative configuration of compounds 9a , 10a , 11a , 12, 13a ,
16a , and 18a were unambiguously assigned by NOE experiments. On
the basis of these data, the relative stereochemistry of the remaining
compounds (9b,c, 10b, 11b,c, 13b,c, 16b, and 18b) were readily
assigned from their 1H NMR spectra.
(21) This corresponds to 7.5 equiv of HOAc to substrate.
(22) For
a mechanistic discussion, and an explanation of the
stereoselectivity, see refs 5b and 8a.
(23) Grennberg, H.; Langer, V.; Ba¨ckvall, J .-E. J . Chem. Soc., Chem.
Commun. 1991, 1190.
J . Org. Chem, Vol. 69, No. 9, 2004 3103

Verboom et al.
SCHEME 2a
a
Reagents and conditions: (a) LDA, -78 °C, then PhNTf2; (b) IZn(CH2)m+1CO2Et, 5% Pd(PPh3)4, benzene-DMA, 60 °C; (c) LiOH,
THF-H2O 4:1, rt; (d) LiAlH4, Et2O, 0 °C f rt.
SCHEME 3a
However, a significant amount of hydrolyzed product 11b
was also formed under the reaction conditions. This is
not a crucial problem, as the alcohol easily can be
transformed into the acetate 11a . Hydrolysis did not
occur when the reaction was performed without LiOAc
and LiCl, and the trans product 11c16 was isolated as a
single isomer in 47% yield (entry 5). Substrate 3d is
slightly unstable and aromatizes easily during the reac-
tion, which accounts for the low yields. The seven-
membered aromatic analogue 3e gave the cis-1,4-addition
product 12 only and in 63% yield when the reaction was
run chloride-free and with a 2 M LiOAc concentration
(entry 6).
Applying the chloride- and acetate-free conditions to
substrate 3c, with a longer carbon chain, led to no ring-
closed product, but instead, the diacetate was formed.
This shows that the formation of a seven-membered
lactone ring by intramolecular attack of the carboxylic
acid on the diene is slower than intermolecular attack
by acetate.
a
Reagents and conditions: (a) 5, 5% Pd(PPh3)4, THF, 55 °C;
(b) NaOH, MeOH-H2O 4:1, reflux.
SCHEME 4a
Carboxylic acids other than acetic acid can also be used
as the external nucleophile, as is illustrated in entries 7
and 8. Cyclization of substrate 3a in the presence of 1
equiv of benzoic acid and 4 equiv of lithium benzoate and
a catalytic amount of LiCl in acetone resulted in the
formation of cis-1,4-product 13a , together with a small
amount of the corresponding cis-1,2-product 13b (ratio
81:19, 58% yield). The use of 5 equiv of benzoic acid in
the absence of any lithium salts afforded the trans-1,4-
product 13c as the only isomer in 56% yield.
a
Reagents and conditions: (a) LDA, -78 °C, then PhNTf2; (b)
IZn(CH2)2CO2Et, 5% Pd(PPh3)4, benzene-DMA, 60 °C; (c) LiOH,
THF-H2O 4:1, rt.
SCHEME 5a
Cyclization of the carvone derivative 3f gave a complex
mixture of isomers and aromatized byproducts from
which lactone 14 was isolated in 23% yield (Scheme 6).16
It is interesting to note, however, that the cis-1,4-addition
occurs on the same face as that of the isopropenyl group,
giving an all-cis relative configuration of the substituents
on the cyclohexenyl ring. This indicates that palladium
is primarily coordinating to the less sterically hindered
face of the diene. Carrying out the reaction under
chloride- and acetate-free conditions gave lactone 14 in
a mixture with (at least) three isomers in 11% combined
yield.
a
Reagents and conditions: (a) 7, NiCl2(dppe), Et2O, 0 °C; (b)
TBAF, THF, rt.
oxidant, slightly improved results were obtained. A
mixture of only three isomers was isolated, containing
not more than 30% of the trans-1,4-addition product.
In contrast to substrates 3a and 3b, the aromatic
derivative 3d gave a completely regioselective cis addition
with formation of the 1,4-addition product only (entry 4).
Interestingly, when 3a was cyclized without LiOAc but
with an excess of LiCl (2.0 equiv), a complex mixture of
3104 J . Org. Chem., Vol. 69, No. 9, 2004

Intramolecular 1,4-Oxyacyloxylation of 1,3-Dienes
TABLE 1. In tr a m olecu la r 1,4-Oxid a tion s w ith Ca r boxylic Acid sa
a
All reactions were performed on a 100 mg scale. Reaction conditions: the substrate was dissolved in 0.5 mL of HOAc/acetone 1:4 and
added during 12 h to a solution of Pd(OAc)2 (5 mol %), BQ (20-25 mol %), LiOAc and LiCl (if necessary), and MnO2 (1.2 equiv) in 1.5 mL
b
of HOAc/ acetone 1:4 at rt. After complete addition, the reaction mixture was stirred for an additional time. Addition time of the substrate
d
and additional stirring time. c Isolated yields. Determined by 1H NMR spectroscopy. e Reaction was performed at 40 °C. The substrate
g
was added at once. f With 10 mol % Pd(OAc)2 and 2 equiv of BQ instead of MnO2. With 1 equiv of PhCO2H and 4 equiv of PhCO2Li in
h
3 mL of acetone. With 5 equiv of PhCO2H in 3 mL of acetone.
isomers was obtained where the main product came from
external attack by acetate. None of the expected allylic
chloride from external nucleophilic attack by chloride5b,8b
on the (π-allyl)palladium intermediate was observed. The
same result was also obtained with the seven-membered
ring 3b.
J . Org. Chem, Vol. 69, No. 9, 2004 3105

Verboom et al.
The aromatic six-membered ring analogue 4d 11b cy-
clized in 90% yield to selectively give the 1,4-cis-addition
product 18a (cis/trans ) 88:12) with LiCl and 2.5 M
LiOAc (entry 5). Under chloride- and acetate-free condi-
tions, 4d cyclized in 80% yield to predominantly give 1,4-
trans-addition product 18b (cis/trans ) 20:80) (entry 6).
In both cases only the 1,4-oxidation product was ob-
served.
The stereoselectivity for the intramolecular alkoxy-
acyloxylation reactions was slightly lower compared to
the analogous diacyloxylation reactions (vide supra) as
all products (except for the seven-membered rings) were
obtained together with small amounts of the other
stereoisomer. A possible explanation could be that the
methylene hydrogen atoms next to the oxygen interfere
with palladium and thereby hinder the cis migration. The
external attack, leading to the cis product, would then
compete with the retarded cis migration and give the
unwanted stereoisomer. This, on the other hand, would
not explain why the trans product is formed even in the
presence of LiCl, which usually efficiently blocks the cis
migration.
F IGURE 1.
SCHEME 6. Cycliza tion of Ca r von e Der iva tive 3f
C. Attem p ted P a lla d iu m (II)-Ca ta lyzed 1,4-Am i-
d oa cetoxyla tion Rea ction s. Amides 19 and 20 were
prepared in a few steps from dienyl alcohol 4b (Scheme
7). Mesylation of alcohol 4b followed by reaction with
sodium tosylamide gave tosylamide 19. Mesylation of 4b
followed by Gabriel synthesis gave the primary amine,
which was acylated with benzylchloroformate to give
carbamate 20. Substrates 19 and 20 were subjected to
the oxidation conditions as used for the alcohols, but the
ring-closed products 21 and 22 were not formed (Scheme
7). Instead, products from intermolecular attack were
observed, indicating that amides are very weak nucleo-
philes and cannot compete with acetate in this reaction.
This result is surprising when compared to earlier related
work on 1,4-oxidation reactions: with an amide func-
tionality on a tether in the 5-position of the 1,3-diene,
the ring-closed products could be obtained in usually
more than 85% yield using the same reaction conditions.9a
In those reactions, five-membered rings were formed,
however, with the nucleophile in closer proximity to the
diene. In the reaction discussed here, the formation of
the diacetate products when using amide nucleophiles
is remarkable, since only traces of these products are
formed in the oxidation reactions with carboxylic acids
and alcohols forming six-membered rings (vide supra).
D. Syn th etic Ap p lica tion s: P a lla d iu m (0)-Ca ta -
lyzed Hyd r ogen olysis Rea ction s. The stereodefined
allylic products, obtained by intramolecular 1,4-oxidation
reactions as shown before, are interesting substrates from
a synthetic point of view. Tsuji et al. have reported on
the Pd(0)-catalyzed hydrogenolysis of allylic formate or
acetate esters24 and applied this to the synthesis of cis-
or trans-fused hydrindan and decalin systems, as well
as the synthesis of steroids.25 The reaction is usually
highly regio- and stereospecific. Formation of a (π-allyl)-
palladium formate complex from a formate ester proceeds
with inversion of configuration. After rearrangement to
a (σ-allyl)palladium formate complex, a concerted process
B. P a lla d iu m (II)-Ca ta lyzed In tr a m olecu la r 1,4-
Alk oxya cyloxyla tion Rea ction s. Intramolecular 1,4-
oxidation reactions, with a hydroxyalkyl chain in the
2-position of a 1,3-diene, have recently been reported.11
The oxidation of diene alcohol 4a 11a was difficult to
reproduce, and the previously published results could not
be obtained. The reaction proved sensitive to the acetate
concentration, and both 15a and 15b were formed with
small amounts of the other diastereomer. For that reason,
stoichiometric BQ was used as the oxidant instead of
MnO2, thereby avoiding the formation of Mn(OAc)2 under
the acetate-free reaction conditions that are necessary
for the trans products. To obtain cis-addition product 15a ,
a high acetate concentration was needed, and running
the reaction with LiCl and 3 M LiOAc afforded 15a as
the major product (cis/trans ) 80:20) (Table 2, entry 1).
In the absence of chloride and acetate, trans-addition
product 15b was obtained in good selectivity (cis/trans
) 5:95) (entry 2). For these reactions, the use of HOAc
as the solvent proved superior to mixtures of HOAc and
acetone.
Diene alcohol 4c reacted much slower than 4a . Without
added LiOAc, a very slow reaction (reaction time 3 days)
gave regioisomers 16a and 16b in a ratio 46:54 (entry
3). Acetic acid/acetone 1:4 had to be used as the solvent
here to obtain the best selectivity toward 1,4-addition
product. The addition of chloride and acetate did not lead
to the formation of the 1,4-cis-addition product, and the
diacetate was isolated instead. In the presence of a
catalytic amount of LiCl and without LiOAc, small
amounts of the diacetate and the Diels-Alder product
were observed.
Oxidation of the seven-membered ring 4b gave com-
pound 17 in 69% yield with high stereoselectivity (>98%
1,4-cis-addition) when the reaction was run with 2 M
LiOAc, at 40 °C. The seven-membered ring substrate 4b
gave cis addition over the diene even at lower concentra-
tions of LiOAc (cf. lactone 10a , entry 3 in Table 1), but
the high concentration was needed to suppress formation
of the 1,2-oxidation product (entry 4).
(24) Tsuji, J .; Yamakawa, T. Tetrahedron Lett. 1979, 613.
(25) (a) Mandai, T.; Matsumoto, T.; Kawada, M.; Tsuji, J . J . Org.
Chem. 1992, 57, 1326. (b) Mandai, T.; Matsumoto, T.; Kawada, M.;
Tsuji, J . Tetrahedron 1993, 49, 5483.
3106 J . Org. Chem., Vol. 69, No. 9, 2004

Intramolecular 1,4-Oxyacyloxylation of 1,3-Dienes
TABLE 2. In tr a m olecu la r 1,4-Oxid a tion s w ith Alcoh olsa
a
All reactions were performed on a 100 mg scale. Reaction conditions: the substrate was dissolved in 0.5 mL of HOAc and added
during 8 h to a solution of Pd(OAc)2 (10 mol %), BQ (2 equiv), and LiOAc and LiCl (if necessary) in 2.5 mL of HOAc at rt. After complete
b
addition, the reaction mixture was stirred for an additional time. Addition time of the substrate and additional stirring time. c Isolated
d
yields. Determined by 1H NMR spectroscopy. e In 2.5 mL of HOAc/acetone 1:4. f Reaction was performed at 40 °C. The substrate was
added at once.
SCHEME 7. Attem p ted 1,4-Oxid a tion Rea ction s
w ith Dien yl Am id esa
and gives the final product with overall inversion. The
same reaction can be done with an allylic acetate ester
if formic acid is employed as the reducing agent. The use
of an allylic formate ester or formic acid as the hydride
source is essential for the high regioselectivity. Another
factor influencing the regioselectivity is the choice of the
ligand, where the use of tri-n-butylphosphine is reported
to be superior to other phosphines.
In initial experiments, allylic lactone 9c was used with
ammonium formate as the reducing agent in refluxing
THF. We found that 1 equiv of tri-n-butylphosphine, as
reported by Tsuji, did not reduce Pd(OAc)2 to render the
active catalyst, and 4 equiv of phosphine was needed.
Under these conditions, the desired trans-fused product
a
Reagents and conditions: (a) MsCl, Et3N, CH2Cl2, 0 °C, then
rt; (b) TsNHNa, DMF, rt; (c) potassium phthalimide, KI, DMF,
rt; (d) H2NNH2, EtOH, rt then 40 °C; (e) BnCO2Cl, NaOH, THF-
H2O 2:1, 0 °C, then rt.
1
23 was obtained in only 35% yield (according H NMR)
together with products formed from opening of the
lactone ring (Scheme 8). Since the two leaving groups
apparently show similar reactivity, it was necessary to
discriminate between them, and we planned to prepare
the formate ester. However, during hydrolysis of the
allylic acetate, the lactone was hydrolyzed too. Relacton-
takes place with decarboxylation and hydride transfer
to the most substituted side of the allyl system. The
hydride attack comes from the same side as palladium
J . Org. Chem, Vol. 69, No. 9, 2004 3107

Verboom et al.
SCHEME 8. P d (0)-Ca ta lyzed Hyd r ogen olysis
Rea ction on La cton e
SCHEME 11. Cop p er (I)-Med ia ted Su bstitu tion
Rea ction s on Aceta tes 18a ,ba
SCHEME 9a
a
Reagents and conditions: (a) n-Bu2Cu(CN)(MgBr)2, Et2O, 0 °C.
a
Reagents and conditions: (a) K2CO3, MeOH, rt; (b) HCO2H,
and the addition time of the Grignard reagent, the
Ac2O, pyridine, 0 °C, then rt.
reaction can be directed to either R- or γ-product26 (eq
2).
SCHEME 10a
a
Reagents and conditions: (a) K2CO3, MeOH, rt; (b) HCO2H,
The reaction proceeds by γ-selective oxidative addition
of the allylic acetate to the copper species with inversion
of configuration, followed by a reductive elimination.
Dependent on the reaction conditions, the reductive
elimination can be either fast (formation of γ-product)
or slow (formation of R-product). In this step, the config-
uration is retained, and the overall process hence takes
place with inversion of the configuration. A regioselective
γ-substitution reaction is most interesting with respect
to our substrates, since it will give similar cis- or trans-
fused ring systems as discussed before, but with an extra
carbon substituent at the bridgehead position, thus
generating highly defined chiral quaternary centers.
Therefore, stoichiometric reactions with a preformed
dialkyl cyanocuprate in ether at 0 °C should give the
γ-product selectively.27 Indeed, applying these conditions
to allylic pyrans 18a ,b selectively gave the γ-products,
and 28a ,b were obtained in high isolated yields (Scheme
11).
Thus, a two-step reaction sequence applied to dienyl
alcohols as demonstrated here gives easy access to fused
ring systems with a highly defined configuration. The
control of the stereoselectivity in the palladium-catalyzed
oxidation reaction and the overall inversion in the copper-
mediated SN2′ substitution reaction makes the synthesis
of these ring systems possible with predictable stereo-
chemistry. Allylic cis-acetates will lead to the cis-fused
ring systems, while trans-acetates will lead to the trans-
fused ring systems.
Ac2O, pyridine, 0 °C, then rt.
ization proved difficult and the formate ester could not
be obtained.
We turned our attention to the allylic pyrans instead,
which contain only one good leaving group (Scheme 9).
Applying the same reaction conditions as before to pyran
15b resulted in clean formation of the undesired product
diene 24, probably formed by â-hydride elimination from
the more stable intermediate (σ-allyl)palladium complex
with palladium attached to the higher substituted carbon.
The more reactive formate ester 25 was then prepared
and used as the substrate in THF at room temperature.
Once more, the formation of diene 24 was observed.
Finally, the aromatic analogue 26, prepared from 18b,
was subjected to the hydrogenolysis reaction. Unfortu-
nately, formate ester 27 afforded the wrong regioisomer,
olefin 27, having the double bond conjugated with the
aromatic ring (Scheme 10). This result indicates that the
reaction also in this case proceeds via the more stable
(σ-allyl)palladium complex, from which the hydride will
be delivered to the least substituted side of the allyl
system.
E. Syn th etic Ap p lica tion s: Cop p er (I)-Med ia ted
Su bstitu tion Rea ction s. Another way to functionalize
the products from the 1,4-oxidation reactions discussed
here is by organocopper SN2′-substitution reactions using
Grignard reagents. This type of reaction has previously
been studied in our group.26 By careful choice of the
copper(I) catalyst, the reaction temperature, the solvent,
The stoichiometric reactions of a dialkylcyanocuprate
with allylic lactone 9c gave products formed by opening
of the lactone ring. A leaving group more reactive than
(26) (a) Ba¨ckvall, J .-E.; Selle´n, M. J . Chem. Soc., Chem. Commun.
1987, 827. (b) Ba¨ckvall, J .-E.; Selle´n, M.; Grant, B. J . Am. Chem. Soc.
1990, 112, 6615. (c) Persson, E. S. M.; van Klaveren, M.; Grove, D.
M.; Ba¨ckvall, J .-E.; van Koten, G. Chem. Eur. J . 1995, 1, 351.
(27) Persson, E. S: M.; Ba¨ckvall, J .-E. Acta Chem. Scand. 1995, 49,
899.
3108 J . Org. Chem., Vol. 69, No. 9, 2004

Intramolecular 1,4-Oxyacyloxylation of 1,3-Dienes
cannula to a solution of 1a (0.228 g, 1.0 mmol) and Pd(PPh3)4
(57 mg, 0.05 mmol) in 6 mL of THF. The mixture was heated
and kept at 55 °C for 16 h. A saturated solution of NH4Cl was
added, and the aqueous phase was extracted with Et2O (×3).
The combined organic phases were washed with brine and
dried (MgSO4). After evaporation of the solvent, the residue
was chromatographed (pentane (200 mL) and then pentane/
Et2O 9:1) to give 0.139 g (65%) of the title compound as a
the lactone ring is obviously needed. However, the
replacement of acetate by a better leaving group was
impossible due to problems with the hydrolysis and
subsequent cyclization of 9c.
Con clu sion s
1
We have synthesized a number of bicyclic ring systems
by intramolecular palladium(II)-catalyzed 1,4-oxidation
reactions of 1,3-dienes having a side chain, with a
carboxylic or alcoholic nucleophile, in the 2-position of
the diene. The δ-lactones and pyrans, respectively, were
obtained in good yields, and both the cis- and trans-
diastereomers could be obtained selectively by the pres-
ence or absence of catalytic amounts of LiCl. Six-
membered rings can be formed efficiently by this method,
but the formation of seven-membered rings is too slow
to compete with the formation of the diacetate products.
We have also shown that the regioselectivity for the
oxidation of the dienyl carboxylic acids was affected by
the solvent composition, with acetic acid/acetone 1:4
leading to mostly 1,4-oxidation product.
Furthermore, we have tried to use the products from
the intramolecular oxidation reactions in transition
metal-catalyzed functionalization reactions. The sub-
strates were not easily compatible with a palladium(0)-
catalyzed hydrogenolysis reaction and gave ring-opened
products or wrong regioisomers instead of the expected
cis- or trans-fused ring systems. On the other hand,
stereo- and regioselective organocopper reactions of the
allylic acetate provided access to the cis- and trans-fused
ring systems via an anti SN2′-substitution of the allylic
acetate by an alkyl group. The products were obtained
in high yields.
colorless oil. H NMR δ: 7.75 (dd, J ) 7.7, 1.5 Hz, 1H), 7.44
(ddd, J ) 7.6, 7.6, 1.5 Hz, 1H), 7.31 (ddd, J ) 7.6, 7.6, 1.4 Hz,
1H), 7.27 (dd, J ) 7.6, 1.4 Hz, 1H), 5.90 (m, 2H), 5.79 (m, 1H),
3.82(s, 3H), 2.32 (m, 2H), 2.21 (m, 2H). 13C NMR δ: 169.0,
142.6, 137.3, 131.4, 129.9, 129.6, 129.5, 127.2, 126.8, 125.8,
123.6, 51.9, 22.7, 21.8. MS m/z: 214 (M+, 30), 182 (37), 181
(100), 153 (30). IR (neat): 2928, 1728, 1600, 1450, 1382, 1278,
1122, 965 cm-1
.
3-(2-Cycloh exa d ien yl)p r op a n oic Acid (3a ). Ethyl ester
2a (2.25 g, 12.5 mmol) was dissolved in 125 mL of THF-H2O
4:1. LiOH (900 mg, 37.5 mmol) was added, and the mixture
was stirred at ambient temperature overnight. THF was
removed in vacuo, and the aqueous phase was washed once
with pentane/Et2O. After acidification (concd HCl), the aqueous
phase was extracted with EtOAc (×4) and the combined
organic phases were dried (Na2SO4). After evaporation of the
solvents, the residue was chromatographed through a short
silica column (pentane/Et2O 1:1) to give 1.88 g (99%) of 3a as
a colorless oil. 1H NMR δ: 5.88-5.77 (m, 2H), 5.52 (m, 1H),
2.51-2.43 (m, 2H), 2.39-2.31 (m, 2H), 2.10 (m, 4H). 13C NMR
δ: 179.6, 133.9, 127.4, 126.4, 120.8, 33.1, 30.3, 22.2 (2C). MS
m/z: 152 (M+, 27), 134 (22), 91 (100), 77 (31). IR (neat): 2937,
1735, 1497, 1207, 1044, 985, 744 cm-1
.
2-(2-Cycloh exa d ien yl)ben zoic Acid (3d ). Hydrolysis of
diene 2e in MeOH-H2O 4:1 with NaOH (3 equiv) and heating
the mixture at reflux temperature gave 3d as a colorless oil
1
in 80% yield. H NMR δ: 7.91 (dd, J ) 7.7, 1.4 Hz, 1H), 7.50
(ddd, J ) 7.6, 7.6, 1.4 Hz, 1H), 7.35 (ddd, J ) 7.6, 7.6, 1.3 Hz,
1H), 7.30 (dd, J ) 7.6, 1.3 Hz, 1H), 5.96 (m, 1H), 5.89 (m, 1H),
5.80 (m, 1H), 2.33 (m, 2H), 2.22 (m, 2H). 13C NMR δ: 173.4,
143.7, 137.3, 132.3, 130.5, 130.2, 130.0, 127.1, 126.9, 126.0,
123.9, 22.7, 21.7. MS m/z: 200 (M+, 13), 172 (100), 144 (82),
116 (29).
The combination of a stereoselective intramolecular
1,4-oxidation reaction and either hydrogenolysis or SN2′-
substitution reaction should be useful for obtaining cis-
or trans-fused ring systems. The presence of such struc-
tures in nature makes the reactions discussed in this
paper potentially useful in organic synthesis.
3-(2-Cycloh exa d ien yl)p r op a n ol (4a ). LiAlH4 (1.33 g, 35.0
mmol) was suspended in 30 mL of Et2O and cooled to 0 °C.
Ethyl ester 2a (3.0 g, 16.7 mmol) was dissolved in 25 mL of
Et2O and added dropwise to the suspension. The solution was
stirred for 45 min at 0 °C and then at rt for 1 h. A saturated
Na2SO4 solution was carefully added to quench the reaction.
Et2O was added, and the phases were separated. The aqueous
phase was extracted with Et2O (×2), and the combined organic
phases were washed with H2O and brine and then dried
(MgSO4). After evaporation of the solvent, the residue was
chromatographed (pentane/ Et2O 1:1) to give 2.22 g (97%) of
4a as a colorless oil. 1H NMR δ: 5.88-5.76 (m, 2H), 5.54-
5.49 (m, 1H), 3.67-3.62 (t, J ) 6.6 Hz, 2H), 2.15-2.06 (m, 6H),
1.75-1.62 (m, 2H), 1.43 (br s, 1H). 13C NMR δ: 135.4, 127.2,
127.1, 120.7, 62.7, 32.0, 31.3, 22.5, 22.4.
2-(2-Cycloh exa d ien yl)ben zyl Alcoh ol (4d ). Silyl ether 814
(1.49 g, 4.97 mmol) was dissolved in 5 mL of THF and added
to a solution of TBAF (3.13 g, 9.93 mmol) in 20 mL of THF
under argon. The reaction was complete in 10 min. The solvent
was evaporated, Et2O was added, and the organic phase was
washed with H2O (×2) and brine and dried (MgSO4). The
solvent was carefully evaporated at reduced pressure and
without heating. The residue was chromatographed (pentane/
Et2O 2:1) to give 745 mg (81%) of 4d as a colorless oil. 1H NMR
δ: 7.47-7.43 (m, 1H), 7.33-7.23 (m, 2H), 7.19-7.15 (m, 1H),
6.02-5.90 (m, 2H), 5.80-5.75 (m, 1H), 4.69 (d, J ) 4.8 Hz,
2H), 2.37-2.28 (m, 2H), 2.27-2.18 (m, 2H), 1.73 (br s, 1H).
13C NMR δ: 141.3, 138.2, 136.2, 128.9, 128.3, 127.8, 127.5,
127.4, 127.0, 125.3, 63.4, 22.7, 21.9.
Exp er im en ta l Section
3-(2-Cycloh exa d ien yl)p r op a n oic Acid Eth yl Ester (2a ).
Following a literature procedure,12a triflate 1a (3.33 g, 14.6
mmol) was allowed to react with Pd(PPh3)4 (843 mg, 0.73
mmol) and the zinc reagent (prepared from ethyl-3-iodopro-
pionate (5.00 g, 21.9 mmol) and Zn(Cu) couple28 (2.40 g, 36.7
mmol)) in 135 mL of benzene and 10 mL of DMA at 60 °C,
and the reaction was stirred overnight. The mixture was cooled
to rt and poured into a saturated solution of NH4Cl (100 mL).
The phases were separated, and the aqueous phase was
extracted with ether (×3). The combined organic phases were
washed with brine, dried (MgSO4), and evaporated. Column
chromatography (pentane/Et2O 95:5) gave 2.25 g (86%) of 2a
as a colorless oil. 1H NMR δ: 5.86-5.77 (m, 2H), 5.51-5.46
(m, 1H), 4.12 (q, J ) 7.1 Hz, 2H), 2.43-2.28 (m, 4H), 2.08 (m,
4H), 1.24 (t, J ) 7.1 Hz, 3H). 13C NMR δ: 173.4, 134.4, 127.3,
126.7, 120.8, 60.4, 33.6, 30.8, 22.4 (2C), 14.4. MS m/z; 180 (M+,
24), 134 (24), 105 (34), 91 (100), 77 (23). IR (neat): 2824, 1735,
1439, 1372, 1288, 1176, 1042, 941, 809, 745 cm-1
.
2-(2-Cycloh exa d ien yl)ben zoic Acid Meth yl Ester (2e).
The organozinc reagent 5 (1.5 mmol, 6 mL THF) from
2-bromobenzoic acid methyl ester12b was transferred via a
Com p ou n d 9a . Gen er a l P r oced u r e for P a lla d iu m (II)-
(28) Smith, R. D.; Simmons, H. E. Organic Syntheses; Wiley: New
York, 1973; Collect. Vol. V, p 855.
Ca ta lyzed 1,4-Dia cyloxyla tion . To a solution of Pd(OAc)2
J . Org. Chem, Vol. 69, No. 9, 2004 3109

Verboom et al.
(7.4 mg, 0.033 mmol), p-benzoquinone (17.8 mg, 0.164 mmol),
MnO2 (68.7 mg, 0.79 mmol), LiCl (5.6 mg, 0.132 mmol), and
LiOAc‚2H2O (134 mg, 1.32 mmol) in 1.5 mL of HOAc/acetone
1:4 was added diene acid 3a (100 mg, 0.66 mmol) in 0.5 mL of
HOAc/acetone 1:4 over 12 h. After additional stirring for 24
h, saturated NaHCO3 (aq) was added, and the aqueous phase
was extracted with Et2O (×4). The combined organic phases
were washed with brine and dried (MgSO4), and the solvent
was evaporated. Column chromatography (pentane/Et2O 1:3)
gave 125 mg (90%) of lactones 9a and 9b in a 75:25 ratio.
White solid. Mp: 90-91 °C. 1H NMR δ: 5.75 (m, 1H), 5.18
(m, 1H), 4.75 (m, 1H), 2.72-2.47 (m, 4H), 2.06 (m, 1H), 2.03
(s, 3H), 2.00-1.86 (m, 2H), 1.78 (m, 1H). 13C NMR δ: 171.6,
170.5, 136.9, 123.2, 75.2, 66.2, 29.7, 25.4, 25.3, 24.5, 21.2. MS
m/z: 211 ([M + H]+, 0.8), 168 (100), 150 (27), 122 (36), 108
(37), 95 (69), 79 (41). IR (KBr): 2922, 1731, 1435, 1363, 1241,
1021 cm-1. Anal. Calcd for C11H14O4: C, 62.85; H, 6.71.
Found: C, 63.05; H, 6.88.
Com p ou n d 9b. Colorless oil. 1H NMR δ: 6.00 (ddd, J )
9.8, 4.5, 2.9 Hz, 1H), 5.58 (ddd, J ) 9.8, 2.5, 1.8 Hz, 1H), 4.94
(dd, J ) 11.2, 3.6 Hz, 1H), 2.60 (dd, J ) 9.6, 1.3 Hz, 1H), 2.58
(d, J ) 9.6 Hz, 1H), 2.34-2.08 (m, 4H), 2.09 (s, 3H), 1.98 (m,
1H), 1.87 (m, 1H). 13C NMR δ: 176.3, 170.3, 133.5, 127.5, 82.3,
74.8, 31.8, 29.1, 24.3, 23.9, 21.2. MS m/z: 210 (M+, 1.5), 167
(5), 139 (26), 124 (100), 96 (62), 81 (32).
1H and 13C NMR data were in agreement with those reported
in the literature.11b
Com p ou n d 16a . Using the same procedure and amounts
as for 15b, but with 72 h of additional stirring time, pyrans
16a and 16b were isolated in a 46:54 ratio in 70% yield. The
products were separated by column chromatography (pentane/
Et2O 2:1). Colorless oil. 1H NMR δ: 5.24-5.21 (m, 1H), 5.14-
5.09 (q, J ) 2.4 Hz, 1H), 3.99-3.93 (m, 1H), 3.88-3.82 (app t,
J ) 7.2 Hz, 1H), 3.54-3.47 (dt, J ) 11.6, 3.2 Hz, 1H), 2.33-
2.26 (m, 1H), 2.23-2.12 (m, 1H), 2.05 (s, 3H), 1.86-1.80 (dd,
J ) 13.2, 6.0 Hz, 1H), 1.76-1.61 (m, 2H), 1.50-1.43 (dd, J )
13.2, 8.8 Hz, 1H), 0.96 (s, 3H), 0.89 (s, 3H). 13C NMR δ: 171.1,
138.5, 120.8, 76.7, 73.3, 68.0, 41.7, 34.9, 31.1, 28.0, 27.9, 21.2,
20.7.
1
Com p ou n d 16b. Colorless oil. H NMR δ: 5.83-5.79 (dd,
J ) 10.0, 1.2 Hz, 1H), 5.64-5.60 (d, J ) 10.0 Hz, 1H), 3.85-
3.76 (m, 2H), 3.44-3.37 (ddd, J ) 11.2, 9.6, 3.2 Hz, 1H), 2.55-
2.48 (dddd, J ) 12.8, 4.8, 4.0, 1.6 Hz, 1H), 1.94 (s, 3H), 1.83-
1.73 (m, 3H), 1.65-1.47 (m, 2H), 1.07 (s, 3H), 1.00 (s, 3H). 13
C
NMR δ: 169.9, 142.2, 124.4, 76.1, 75.6, 66.2, 37.2, 33.0, 32.0,
31.2, 30.2, 23.5, 22.2.
Com p ou n d 17. Following the general procedure, 4b was
allowed to react in the presence of 2 M LiOAc‚2H2O but
without added LiCl. The substrate was added at once, and the
reaction was stirred at 40 °C for 36 h. Chromatography
(pentane/Et2O 2:1) gave 17 as a colorless oil.1H NMR δ: 5.42-
5.34 (m, 2H), 4.02-3.89 (m, 2H), 3.54-3.43 (m, 1H), 2.40-
2.28 (m, 1H), 2.20-2.09 (m, 1H), 2.05 (s, 3H), 1.96-1.80 (m,
4H), 1.74-1.56 (m, 4H). 13C NMR δ: 170.6, 141.5, 125.0, 79.1,
72.6, 65.4, 32.5, 31.9, 30.0, 25.2, 21.7, 21.5.
Com p ou n d 13a . To a solution of Pd(OAc)2 (7.4 mg, 0.033
mmol), p-benzoquinone (17.8 mg, 0.164 mmol), MnO2 (68.7 mg,
0.79 mmol), LiCl (5.6 mg, 0.132 mmol), benzoic acid (80.3 mg,
0.66 mmol), and PhCO2Li (337 mg, 2.63 mmol) in 2.5 mL of
acetone was added diene acid 3a (100 mg, 0.66 mmol) in 0.5
mL of acetone over 12 h. After additional stirring for 48 h and
workup, chromatography (pentane/Et2O 1:3) gave an insepa-
rable mixture of two isomers 13a and 13b (81:19) in 58% yield.
A pure sample of 13a was obtained by recrystallization from
Com p ou n d 25. Allylic acetate 15b (970 mg, 4.95 mmol) was
dissolved in MeOH (10 mL), and K2CO3 (68.4 mg, 0.49 mmol)
was added. The solution was stirred at rt for 3 h. After
evaporation of the solvent, column chromatography (pentane/
Et2O 1:3) gave 623 mg (82%) of the corresponding alcohol as
a colorless oil.
1
pentane/Et2O. H NMR δ: 8.07-8.02 (m, 2H), 7.60-7.53 (m,
1H), 7.48-7.41 (m, 2H), 5.93-5.88 (m, 1H), 5.51-5.445 (m,
1H), 4.86-4.79 (m, 1H), 2.79-2.51 (m, 4H), 2.23-2.03 (m, 3H),
1.97-1.85 (m, 1H). 13C NMR δ: 171.9, 166.2, 137.4, 133.2,
130.3, 129.8, 128.5, 123.5, 75.5, 66.9, 29.9, 25.7, 25.6, 24.9.
Anal. Calcd for C16H16O4: C, 70.57; H, 5.92. Found: C, 70.34;
A solution of formic acid (1.16 mL, 29.6 mmol) and acetic
anhydride (2.79 mL, 29.6 mmol) was stirred for 15 min and
then cooled to 0 °C. The allylic alcohol (228 mg, 1.48 mmol),
dissolved in pyridine (3.59 mL, 44.4 mmol), was slowly added,
and the solution was stirred for 2 h at rt. Et2O was added,
and the solution was washed with water (×2) and aqueous
NaHCO3 (×2). The organic phase was dried (MgSO4) and
evaporated. Column chromatography (pentane/Et2O 85:15)
gave 238 mg (88%) of the allylic formate ester 25 as a colorless
oil. 1H NMR δ: 8.05 (s, 1H), 5.47-5.41 (m, 2H), 4.02-3.94 (m,
1H), 3.92-3.85 (m, 1H), 3.61-3.51 (dt, J ) 11.4, 3.3 Hz, 1H),
2.39-2.30 (m, 1H), 2.30-2.17 (m, 1H), 2.17-2.04 (m, 2H),
1.83-1.64 (m, 2H), 1.62-1.53 (m, 2H). 13C NMR δ: 160.9,
141.6, 121.0, 73.9, 69.6, 68.1, 31.7, 28.1, 27.1, 26.6.
1
H, 5.95. Com p ou n d 13b. H NMR (distinguishable peaks in
mixture of isomers) δ: 5.83-5.77 (m, 1H), 5.24-5.17 (m, 1H),
4.79-4.72 (m, 1H).
Com p ou n d 13c. To a solution of Pd(OAc)2 (7.4 mg, 0.033
mmol), p-benzoquinone (14.2 mg, 0.132 mmol), MnO2 (68.7 mg,
0.79 mmol), and benzoic acid (400 mg, 3.29 mmol) in 2.5 mL
of acetone was added diene acid 3a (100 mg, 0.66 mmol) in
0.5 mL of acetone over 12 h. After additional stirring for 12 h
and workup, chromatography (pentane/Et2O 1:3) gave 13c as
a colorless oil in 56% yield. 1H NMR δ: 8.05-8.00 (m, 2H),
7.59-7.53 (m, 1H), 7.47-7.40 (m, 2H), 5.85-5.81 (m, 1H),
5.66-5.57 (m, 1H), 4.95-4.87 (m, 1H), 2.79-2.47 (m, 4H),
2.41-2.26 (m, 2H), 1.96-1.69 (m, 2H). 13C NMR δ: 171.9,
166.1, 135.9, 133.2, 130.2, 129.7, 128.5, 125.3, 75.2, 69.5, 29.9,
27.4, 26.3, 25.5.
Com p ou n d 28a . Gen er a l P r oced u r e for Cr oss-Cou -
p lin g Rea ction s w ith P r efor m ed Dibu tylcu p r a tes. n-
BuMgBr (1.05 mL, 0.45 M in Et2O, 0.471 mmol) was added
dropwise to a slurry of CuCN (22 mg, 0.246 mmol) in Et2O
(1.5 mL) at -30 °C. The reaction mixture was stirred for 2 h
while the temperature was allowed to rise to 0 °C. Allylic
acetate 18a (cis/trans 86:14; 50 mg, 0.205 mmol) was dissolved
in Et2O (1.0 mL) and added to the cuprate at 0 °C. The reaction
mixture was stirred at that temperature for 2 h and then
quenched with NH4Cl. The two layers were separated, and the
aqueous phase was extracted with Et2O (×3). The combined
organic layers were washed with brine, dried (MgSO4), and
evaporated. Column chromatography (pentane/Et2O 2:1) gave
44.6 mg (90%) of an inseparable mixture of compounds 28a
Com p ou n d 15a . Gen er a l P r oced u r e for P a lla d iu m (II)-
Ca ta lyzed 1,4-Alk oxya cyloxyla tion Rea ction s. To a solu-
tion of Pd(OAc)2 (16.3 mg, 0.072 mmol), p-benzoquinone (156.5
mg, 1.45 mmol), LiCl (9.2 mg, 0.217 mmol), and LiOAc‚2H2O
(765 mg, 7.5 mmol) in 2.0 mL of HOAc was added diene alcohol
4a (100 mg, 0.725 mmol) in 0.5 mL of HOAc over 8 h. After
additional stirring for 12 h, brine was added, and the aqueous
phase was extracted with Et2O (×3). The combined organic
phases were washed with cold 2 M NaOH and brine. After
drying (MgSO4) and evaporation of the solvent, the residue
was chromatographed (pentane/Et2O 2:1) to give 60 mg (42%)
1
and 28b in a 86:14 ratio as a colorless oil. H NMR δ: 7.35-
7.31 (dd, J ) 7.8, 1.5 Hz, 1H), 7.26-7.20 (m, 1H), 7.16-7.09
(ddd, J ) 7.8, 1.5 Hz, 1H), 6.98-6.94 (m, 1H), 5.76-5.65 (m,
2H), 4.81-4.78 (d, J ) 3.6 Hz, 2H), 4.02-3.98 (app t, J ) 4.8
Hz, 1H), 2.29-2.16 (m, 1H), 2.11-1.85 (m, 4H), 1.66-1.55
(ddd, J ) 14.4, 12.3, 4.2 Hz, 1H), 1.28-1.12 (m, 3H), 1.06-
0.94 (m, 1H), 0.86-0.81 (t, J ) 7.2 Hz, 3H). 13C NMR δ: 140.4,
1
of pyrans 15a and 15b in an 80:20 ratio. The H and 13C NMR
data were in agreement with those reported in the literature.11b
Com p ou n d 15b. Using the same procedure and amounts
as for 15a , but without added LiCl and LiOAc‚2H2O, pyrans
15a and 15b were isolated in a 5:95 ratio in 56% yield. The
3110 J . Org. Chem., Vol. 69, No. 9, 2004

Intramolecular 1,4-Oxyacyloxylation of 1,3-Dienes
134.5, 134.1, 127.1, 127.0, 125.5, 125.3, 124.2, 74.4, 66.4, 40.9,
40.7, 26.7, 24.2, 23.5, 22.0, 14.1.
Su p p or tin g In for m a tion Ava ila ble: Additional experi-
mental and characterization data for starting material syn-
thesis; reactions following general procedures; 1H and 13C NMR
spectra of compounds 1c,d , 2a -g, 3a -f, 4b,c, 9b-c, 11a -c,
13c, 14, 16a ,b, 17, 18a , 19, 20, 25, and 28a ,b. This material
is available free of charge via the Internet at http://pubs.acs.org.
Ackn owledgm en t. Financial support from the Swed-
ish Research Council and the Swedish Research Council
for Engineering Sciences is gratefully acknowledged.
J O0357667
J . Org. Chem, Vol. 69, No. 9, 2004 3111