Pd(OAc)2/P(cC6H11) 3-catalyzed allylation of aryl halides with homoallyl alcohols via retro-allylation

Article abstract of DOI:10.1021/ja067372d

Allylations of aryl halides take place upon treatment of tertiary homoallyl alcohols with aryl halides in the presence of cesium carbonate and a palladium catalyst. The allylation reaction would consist of the following steps: (1) oxidative addition of ar

Full text of DOI:10.1021/ja067372d

Published on Web 03/21/2007
Pd(OAc)2/P(cC6H11)3-Catalyzed Allylation of Aryl Halides with
Homoallyl Alcohols via Retro-Allylation
Masayuki Iwasaki, Sayuri Hayashi, Koji Hirano, Hideki Yorimitsu,* and
Koichiro Oshima*
Contribution from the Department of Material Chemistry, Graduate School of Engineering,
Kyoto UniVersity, Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
Received October 13, 2006; E-mail: yori@orgrxn.mbox.media.kyoto-u.ac.jp; oshima@orgrxn.mbox.media.kyoto-u.ac.jp
Abstract: Allylations of aryl halides take place upon treatment of tertiary homoallyl alcohols with aryl halides
in the presence of cesium carbonate and a palladium catalyst. The allylation reaction would consist of the
following steps: (1) oxidative addition of aryl halide to palladium, (2) ligand exchange between the halide
and the homoallyl alcohol affording aryl(homoallyloxy)palladium, (3) retro-allylation of the palladium alkoxide
to generate σ-allyl(aryl)palladium with concomitant liberation of the relevant ketone, and (4) productive
reductive elimination. Since the retro-allylation step proceeds in a concerted fashion via a conformationally
regulated six-membered cyclic transition state, the allylation reactions are highly regio- and stereospecific
when homoallyl alcohols having a substituted allyl group are used. Whereas triarylphosphine is known to
serve as a ligand for the palladium-catalyzed allyl transfer reactions, tricyclohexylphosphine proves to
significantly expand the scopes of aryl halides to electron-rich aryl chlorides and of homoallyl alcohols to
cyclic homoallyl alcohols. The new arylative ring-opening reactions of cyclic homoallyl alcohols allow for
the synthesis of ketones having a branched or linear allylarene moiety at the remote terminus in regio- and
stereospecific manners.
1. Introduction
However, there are many issues to be resolved, which include
reaction efficiency and functional group compatibility.
The most critical problem is the regio- and stereoselectivity
of the allylation when substituted allylmetals are employed (eq
1).3b,e-i,4,5e,f,6 For instance, a cross-coupling reaction with a crotyl
metal reagent takes place competitively at the R- and γ-positions
of the crotyl group. In addition, the product coupled at the
R-position usually consists of a mixture of E and Z isomers. In
order that the cross-coupling allylation becomes a useful tool
for modern organic synthesis, such regio- and stereochemical
control of the allylation should be established.
Transition-metal-catalyzed cross-coupling reaction ranks as
one of the most important reactions in organic synthesis and
has been extensively investigated.1 One thus tends to think that
the cross-coupling strategy can construct arbitrary carbon-
carbon bonds by optimizing reaction conditions. However,
despite their seeming simplicity, the cross-coupling reactions
of aryl halides with allylmetals represent rare combinations
relative to those with arylmetals forming biaryls.2-6 In light of
the importance of allylation reactions in organic synthesis,7
further studies on the rare cross-coupling reactions are necessary.
(1) (a) Metal-Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P.
J., Eds.; Wiley-VCH: Weinheim, 1998. (b) Metal-Catalyzed Cross-
Coupling Reactions, 2nd ed.; de Meijere, A., Diederich, F., Eds.; Wiley-
VCH: Weinheim, 2004. (c) Cross-Coupling Reactions. A Practical Guide;
Miyaura, N., Ed.: Springer: Berlin, 2002. (d) Handbook of Organopal-
ladium Chemistry for Organic Synthesis; Negishi, E., Ed.; John Wiley &
Sons: New York, 2002.
(2) Nickel- or copper-catalyzed reactions with an allyl Grignard reagent: (a)
Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.; Kodama,
S.; Nakajima, I.; Minato, A.; Kumada, M. Bull. Chem. Soc. Jpn. 1976, 49,
1958-1969. (b) Commercon, A.; Normant, J. F.; Villieras, J. J. Organomet.
Chem. 1977, 128, 1-11. (c) Blanchette, M. A.; Malamas, M. S.; Nantz,
M. H.; Roberts, J. C.; Somfai, P.; Whritenour, D. C.; Masamune, S.;
Kageyama, M.; Tamura, T. J. Org. Chem. 1989, 54, 2817-2825.
(3) Palladium-catalyzed reactions with allylstannanes: (a) Kosugi, M.; Sasaza-
wa, K.; Shimizu, Y.; Migita, T. Chem. Lett. 1977, 301-302. (b) Godschalx,
J.; Stille, J. K. Tetrahedron Lett. 1980, 21, 2599-2602. (c) Scott, W. J.;
Crisp, G. T.; Stille, J. K. J. Am. Chem. Soc. 1984, 106, 4630-4632. (d)
Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033-3040. (e)
Obora, Y.; Tsuji, Y.; Kobayashi, M.; Kawamura, T. J. Org. Chem. 1995,
60, 4647-4649. (f) Takemura, S.; Hirayama, A.; Tokunaga, J.; Kawamura,
F.; Inagaki, K.; Hashimoto, K.; Nakata, M. Tetrahedron Lett. 1999, 40,
7501-7505. (g) Trost, B. M.; Keinan, E. Tetrahedron Lett. 1980, 21, 2595-
2598. (h) Me´ndez, M.; Cuerva, J. M.; Go´mez-Bengoa, E.; Ca´rdenas, D. J.;
Echavarren, A. M. Eur. J. Org. Chem. 2002, 3620-3628. (i) Goliaszewski,
A.; Schwartz, J. Tetrahedron 1985, 41, 5779-5789.
As the pioneering solution to the problem, Hatanaka and
Hiyama developed regioselective cross-coupling reactions of aryl
halides with substituted allylfluorosilanes.4 Monodentate triph-
(4) Palladium-catalyzed reactions with allylfluorosilanes: (a) Hatanaka, Y.;
Ebina, Y.; Hiyama, T. J. Am. Chem. Soc. 1991, 113, 7075-7076. (b)
Hatanaka, Y.; Goda, K.; Hiyama, T. Tetrahedron Lett. 1994, 35, 1279-
1282. (c) Hatanaka, Y.; Goda, K.; Hiyama, T. Tetrahedron Lett. 1994, 35,
6511-6514. (d) Hatanaka, Y. J. Synth. Org. Chem. Jpn. 1995, 53, 581-
592. (e) Hiyama, T.; Matsuhashi, H.; Fujita, A.; Tanaka, M.; Hirabayashi,
K.; Shimizu, M.; Mori, A. Organometallics 1996, 15, 5762-5765. (f)
Hiyama, T.; Hatanaka, Y. Pure Appl. Chem. 1994, 66, 1471-1478.
9
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J. AM. CHEM. SOC. 2007, 129, 4463-4469
4463

A R T I C L E S
Scheme 1
Iwasaki et al.
Scheme 2
enylphosphine led to γ-selectivity,4a and bidentate 1,3-bis-
(diphenylphosphino)propane, to R.4c However, the excellent
example highlights the difficulty in achieving the cross-coupling
allylation from the viewpoint of modern organic synthesis.
Specifically, the reactions required heating in sealed tubes and
the use of relatively labile allylfluorosilanes and lacked universal
stereochemical control of the (E)- and (Z)-R-products. A
regiocontrolled coupling reaction of tributylcrotylstannane with
1-iodonaphthalene was reported.3e Use of triphenylarsine as a
ligand provided the corresponding (E)-R-product, whereas
triphenylphosphine yielded the γ-product.8 Unfortunately, the
generality and the efficiency of the reaction are unsatisfactory,
and no procedure to obtain (Z)-R-product was disclosed. Very
recently, a γ-selective cross-coupling reaction with potassium
(E)-crotyltrifluoroborate was reported, wherein no R-selectivity
was attained.5e,f,9
The γ-selectivity observed in the reactions of crotylfluorosi-
lanes and of crotyltrifluoroborate was explained by the following
hypotheses (Scheme 1):4a,5e (1) the transmetalations between
the crotylmetals and arylpalladium halides proceed in an SE2′
process,10 and (2) aryl(1-methyl-2-propenyl)palladiums, a σ-al-
lylpalladium11 formed by the transmetalations, predominantly
undergo rapid reductive elimination of 1-methyl-2-propenylare-
nes without suffering from conceivable σ-π interconversion
that can lead to the R-product. The hypotheses clearly suggest
that one should simply prepare and use the corresponding well-
defined allyl metals to obtain the desired products selectively.
In spite of the intelligible idea, preparation of allyl metals having
an arbitrary substitution pattern is generally difficult. Moreover,
there remains a possibility that the transmetalation would pro-
ceed unexpectedly in an SE2 fashion, which can heavily depend
on the structure and electronic factors of allyl metals used.10
We have recently communicated the use of homoallyl
alcohols as the allyl sources in the palladium-catalyzed allyla-
tions of organic halides instead of allyl metal reagents.12 Scheme
2 illustrates our proposed mechanism. After oxidative addition
yielding A (step 1), ligand exchange with homoallyl alcohol 1
would take place to afford alkoxy(aryl)palladium B (step 2).
Retro-allylation reaction of B,13-15 the key step of our strategy,
occurred, providing σ-allyl(aryl)palladium C (step 3). Since the
retro-allylation proceeds in a concerted fashion via a confor-
mationally regulated six-membered cyclic transition state and
the reductive elimination from C (step 4) is faster than the
isomerization of C to π-allyl(aryl)palladium (see Scheme 1),
the stereo- and regiochemical information of homoallyl alcohol
1 is transferred to C and then to the allylated product 3. In
contrast to allyl metals, homoallyl alcohols are not sensitive to
(12) Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc.
2006, 128, 2210-2211.
(5) Palladium-catalyzed reactions with allylboron reagents: (a) Kalinin, V. N.;
Denisov, F. S.; Bubnov, Y. N. MendeleeV Commun. 1996, 6, 206-207.
(b) Fu¨rstner, A.; Siedel, G. Synlett 1998, 161-162. (c) Occhiato, E. G.;
Trabocchi, A.; Guarna, A. J. Org. Chem. 2001, 66, 2459-2465. (d) Kotha,
S.; Behera, M.; Shah, V. R. Synlett 2005, 1877-1880. (e) Yamamoto, Y.;
Takada, S.; Miyaura, N. Chem. Lett. 2006, 35, 704-705. (f) Yamamoto,
Y.; Takada, S.; Miyaura, N. Chem. Lett. 2006, 35, 1368-1369.
(6) Palladium-catalyzed reactions with allylindiums: (a) Lee, P. H.; Sung, S.-
Y.; Lee, K. Org. Lett. 2001, 3, 3201-3204. (b) Lee, K.; Lee, J.; Lee, P. H.
J. Org. Chem. 2002, 67, 8265-8268.
(13) Zirconium-mediated reactions: (a) Fujita, K.; Yorimitsu, H.; Oshima, K.
Chem. Rec. 2004, 4, 110-119. (b) Fujita, K.; Yorimitsu, H.; Shinokubo,
H.; Oshima, K. J. Org. Chem. 2004, 69, 3302-3307. Gallium-mediated
reactions: (c) Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima, K. Org.
Lett. 2005, 7, 3577-3579. (d) Hayashi, S.; Hirano, K.; Yorimitsu, H.;
Oshima, K. J. Organomet. Chem. 2007, 692, 505-513. Rhodium-catalyzed
reactions: (e) Takada, Y.; Hayashi, S.; Hirano, K.; Yorimitsu, H.; Oshima,
K. Org. Lett. 2006, 8, 2515-2517.
(14) Retro-allylations from lithium, magnesium, tin, and zinc alkoxides were
observed: (a) Benkeser, R. A.; Siklosi, M. P.; Mozdzen, E. C. J. Am. Chem.
Soc. 1978, 100, 2134-2139. (b) Gerard, F.; Miginiac, P. Bull. Chim. Soc.
Fr. 1974, 2527-2533. (c) Jones, P.; Knochel, P. J. Org. Chem. 1999, 64,
186-195. (d) Peruzzo, V.; Tagliavini, G. J. Organomet. Chem. 1978, 162,
37-44. (e) Yanagisawa, A.; Aoki, T.; Arai, T. Synlett 2006, 2071-2074.
Ruthenium-catalyzed deallylation was reported: (e) Kondo, T.; Kodoi, K.;
Nishinaga, E.; Okada, T.; Morisaki, Y.; Watanabe, Y.; Mitsudo, T. J. Am.
Chem. Soc. 1998, 120, 5587-5588. Rhodium-catalyzed deallylation was
reported: (f) Zhao, P.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 9642-9643.
(15) Palladium-catalyzed reactions of organic halides with tertiary alcohols via
â-carbon elimination were reported. Arylation with arylmethanols: (a)
Terao, Y.; Wakui, H.; Satoh, T.; Miura, M.; Nomura, M. J. Am. Chem.
Soc. 2001, 123, 10407-10408. Via ring opening of cyclobutanols: (b)
Nishimura, T.; Uemura, S. J. Am. Chem. Soc. 1999, 121, 11010-11011.
(c) Larock, R. C.; Reddy, C. K. Org. Lett. 2000, 2, 3325-3327.
Alkynylation with propargylic alcohols: (d) Chow, H.-F.; Wan, C.-W.;
Low, K.-H.; Yeung, Y.-Y. J. Org. Chem. 2001, 66, 1910-1913.
(7) (a) Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207-2293. (b)
Denmark, S. E.; Fu, J. Chem. ReV. 2003, 103, 2763-2793.
(8) Ligand effect on the regiochemistry of such couplings is discussed in
detail: (a) Kurosawa, H.; Shiba, K.; Hirako, K.; Kakiuchi, K.; Ikeda, I. J.
Chem. Soc., Chem. Commun. 1994, 1099-1100. (b) Kurosawa, H.; Shiba,
K.; Hirako, K.; Ikeda, I. Inorg. Chim. Acta 1996, 250, 149-154. (c)
Kurosawa, H.; Ogoshi, S. Bull. Chem. Soc. Jpn. 1998, 71, 973-984.
(9) γ-Selective Pd-catalyzed reactions of allylboronic acids with iodoarenes
have been reported very recently. However, a different mechanism which
includes a carbopalladation process is believed to operate in the reactions.
Sebelius, S.; Olsson, V. J.; Wallner, O. A.; Szabo´, K. J. J. Am. Chem. Soc.
2006, 128, 8150-8151.
(10) (a) Naruta, Y.; Nishigaichi, Y.; Maruyama, K. Tetrahedron 1989, 45, 1067-
1078. (b) Roberts, R. M. G. J. Organomet. Chem. 1969, 18, 307-319.
(11) Chemistry of σ-allylpalladiums: (a) Numata, S.; Okawara, R.; Kurosawa,
H. Inorg. Chem. 1977, 16, 1737-1741. (b) Solin, N.; Kjellgren, J.; Szabo´,
K. J. J. Am. Chem. Soc. 2004, 126, 7026-7033. (c) Garc´ıa-Iglesias, M.;
Bun˜uel, E.; Ca´rdenas, D. J. Organometallics 2006, 25, 3611-3618.
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Palladium-Catalyzed Retro-Allylation
A R T I C L E S
Table 1. Pd(OAc)2/PCy3-Catalyzed Methallylation of Aryl Halides
2 with Homoallyl Alcohol 1a via Retro-Allylationa
air and moisture. Any homoallyl alcohols are practically
available, which would in principle allow for introducing allyl
groups of various substitution patterns.
Despite the potential utility of our strategy, we noticed that
the scope of our allylation reaction is limited. Specifically, some
aryl bromides and most aryl chlorides did not undergo smooth
allylation under the standard conditions. In addition, cyclic
homoallyl alcohols are not good substrates, probably because
they are so rigid that the interaction between the palladium
center and the double bond is insufficient at the transition state
of the palladium-mediated retro-allylation. The uniqueness of
our allylation reaction promoted us to overcome these limita-
tions. Here we report a much more efficient protocol. The
improved protocol, which utilizes tricyclohexylphosphine as a
ligand, now allows us to use a wider variety of aryl halides as
well as to perform arylative ring-opening reactions of unstrained
cyclic homoallyl alcohols.
2. Results and Discussion
2.1. Scope of Organic Halides and Ligand Effect. In the
previous report,12 we performed the reactions in most cases
under the catalysis of 5 mol % of palladium acetate and 20
mol % of triarylphosphine. After screening of catalysts,16 we
found that a combination of 5 mol % of palladium acetate and
10 mol % of tricyclohexylphosphine proved to be the best
catalyst. Treatment of 1-chloronaphthalene (2a) with 1a17 in
the presence of cesium carbonate and the Pd(OAc)2/tri(p-tolyl)-
phosphine (1:4 molar ratio) catalyst in refluxing toluene afforded
1-methallylnaphthalene (3a) in only 6% yield (Table 1, entry
1). On the other hand, the use of tricyclohexylphosphine18 (Pd-
(OAc)2/PCy3 ) 1:2) dramatically enhanced the catalytic activity
(entry 2). It is worth noting that the Pd(OAc)2/PCy3 ratio is
important to attain high yields. Use of a 1:4 ratio resulted in a
very poor yield (6%) and recovery of 72% of 2a. Tricyclo-
hexylphosphine also promoted the methallylations of 4-bromo-
biphenyl (2b) and 2-bromonaphthalene (2c), wherein P(p-tol)3
failed to serve to attain satisfactory yields (entries 3-6). The
bulkier PCy3 would increase steric hindrance around the
palladium center of the alkoxy(aryl)palladium B. PCy3 would
thus prevent the vacant coordination site that is responsible for
the indispensable interaction with the double bond of 1a from
being occupied through the coordination of an additional PCy3
and/or the dimerization of the palladium complex.19 2-Bro-
mopyridine (2d) was converted to 2-methallylpyridine (3d) in
moderate yield, the remainder being 2d untouched (entry 7).
Electron-deficient aryl chloride 2e smoothly underwent the
methallylation reaction (entry 8). Although the reaction of
electron-rich p-bromoanisole (2f) with P(p-tol)3 resulted in a
lower yield of coupling product 3f, PCy3 is the better ligand
(entries 9 and 10). The reactions of electron-rich, much less
reactive p-chloroanisole (2g) and p-bromo-N,N-dimethylaniline
(2h) proceeded smoothly with the aid of PCy3 (entries 11 and
12). Tri(tert-butyl)phosphine was also a highly effective ligand
a A mixture of Pd(OAc)2 (0.025 mmol), phosphine (0.10 mmol for P(p-
tol)3 and PPh3, 0.050 mmol for PCy3 and (R)-MONOPHOS, 0.025 mmol
for PtBu3), Cs2CO3 (0.72 mmol), 1a (0.60 mmol), and 2 (0.50 mmol) was
boiled in toluene (3.0 mL). b Isolated yields. Yields determined by 1H NMR
are in parentheses. c As a byproduct, 2-methallylnaphthalene was obtained
in 8% yield. d 0.050 mmol of PtBu3 was used. e 74% of 2h was recovered.
f (R)-MONOPHOS, a monodentate phosphoramidite ligand, [(R)-(binaph-
thoxy)]PNMe2. See reference 20. g Alcohol 1a (1.0 mmol) and Cs2CO3 (1.2
mmol) were used.
(entry 13). In this case, a catalyst prepared from equimolar
amounts of Pd(OAc)2 and PtBu3 was essential to attain high
catalytic activity; otherwise the yields were poor (entry 14). Thus
electron-rich trialkylphosphines have significantly expanded the
scope of organic halides. Attempted methallylations of alkenyl
halides resulted in poor to fair yields. The highest yield was
observed when R-bromostyrene (2i) reacted with the aid of (R)-
MONOPHOS ligand20 (entry 15). Tricyclohexylphosphine did
not work well in the reaction of 2i (entry 16).
2.2. Homoallyl Alcohols as Regio- and Stereospecific Allyl
Donors. Homoallyl alcohol 1b effected allylation of 2j to yield
1-allylnaphthalene (3i) in excellent yield (eq 2, Np ) 1-naphthyl
hereafter). The reaction of 1b implies the generality of the allyl
(16) The results of the ligand screening experiments are in the Supporting
Information.
(17) The preparations of homoallyl alcohols 1, 6, and 8 are described in the
Supporting Information in detail.
(18) (a) Reddy, N. P.; Tanaka, M. Tetrahedron Lett. 1997, 38, 4807-4810. (b)
Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176-4211. (c)
Grushin, V. V.; Alper, H. Chem. ReV. 1994, 94, 1047-1062.
(19) (a) Roy, A. H.; Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 1232-1233.
(b) Roy, A. H.; Hartwig, J. F. Organometallics 2004, 23, 1533-1541.
transfer reaction in the Pd(OAc)2/PCy3 system. We thus
examined the scope of homoallyl alcohols, focusing on the
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A R T I C L E S
Iwasaki et al.
Table 2. Regiospecific Allylation of 1-Halonaphthalene with Homoallyl Alcohols 1a
a The reactions were performed under the conditions in Table 1, entry 1. b The yields obtained by using P(p-tol)3 are in parentheses. The yields in
parentheses were reported in the previous communication. See ref 12. c Substrate 1e (1.0 mmol) and Cs2CO3 (1.2 mmol) were used. More than 30% of
naphthalene was obtained.
Scheme 3
feasibility of regio- and stereocontrolled allylation in the present
catalyst system.
2.2.1. Regiocontrol. To justify our idea depicted in Scheme
2, we prepared a variety of homoallyl alcohols having unsym-
metrically substituted allyl moieties that are to be transferred.17
As the data summarized in Table 2 clearly show, the reactions
with the homoallyl alcohols indeed proceeded with high
regiospecificity. In the reaction of 1c (entry 1), the carbon-
carbon bond formation took place at the terminal olefinic carbon
of 1c to provide trisubstituted alkene 3j exclusively. No
regioisomer 3k was detected. Notably the 3j/3k selectivity
obtained by using PCy3 was much better than that obtained by
using P(p-tol)3.12 By changing P(p-tol)3 to PCy3, increasing the
contrast, the substituents at the allylic positions had little
steric bulk around the palladium would accelerate the rate of
the reductive elimination,19 thereby avoiding undesirable
isomerization of the initially formed σ-allylpalladium
(Scheme 1). The formation of linear coupling product 3l
predominated over that of branched 3m in the reaction of 1d
(entry 2). In contrast, the use of 1e led to the opposite
regioselectivity (entry 3). The regiospecificity is highly sug-
gestive of the retro-allylation of B followed by rapid reductive
elimination (Scheme 2).
It is worth noting that alcohol 1f, the stereoisomer of 1e,
resisted the transformation (entry 4). The substituent R6, located
at the trans position to the hydroxylated moiety, would retard
the reaction. We are tempted to assume that, on the transition
state of the retro-allylation reaction, R6 and one of the ligands
on the palladium of square planer geometry would create so
strong a repulsion that the palladium could not approach the
carbon-carbon double bond (Scheme 3).
effect on the efficiency. These facts strongly suggest that the
reactions proceed via a retro-allylation process. From a mecha-
nistic point of view, our carbon-carbon bond cleavage is
completely different from the palladium-catalyzed â-carbon
elimination.15
2.2.2. Stereocontrol of R-Products. Although the reactions
of 1d selectively yielded the linear coupling product 3l, 3l
consisted of a 63:37 mixture of (E)- and (Z) isomers (Table 2,
entry 2). We thus designed diastereomerically pure 1g, having
tert-butyl and methyl groups at the oxygenated carbon
(Table 3). To our delight, 1g realized stereospecific synthesis
of (E)- and (Z)-3l. Treatment of 2j with threo-1g21 under the
Pd(OAc)2/PCy3 catalysis afforded (E)-3l stereoselectively (entry
1). On the other hand, formation of (Z)-3l predominated over
that of (E)-3l in the reaction of erythro-1g (entry 2). Electron-
rich aryl chloride 2g as well as electron-deficient 2e also
participated in stereospecific allylations (entries 3-6). The
formations of (Z)-3 from erythro-1g were always exclusive when
PCy3 was used.
The substituents on the carbon-carbon double bonds proved
to influence the efficiency of the allyl transfer reaction. In
(20) van den Berg, M.; Minnaard, A. J.; Schudde, E. P.; van Esch, J.; de Vries,
A. H. M.; de Vries, J. G.; Feringa, B. L. J. Am. Chem. Soc. 2000, 122,
11539-11540.
(21) For the erythro/threo nomenclature, see: Noyori, R.; Nishida, I.; Sakata,
J. J. Am. Chem. Soc. 1981, 103, 2106-2108.
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4466 J. AM. CHEM. SOC. VOL. 129, NO. 14, 2007

Palladium-Catalyzed Retro-Allylation
A R T I C L E S
Table 3. Stereospecific Allylation of 2 with Diastereomerically
Pure Homoallyl Alcohols 1g-1ia
Scheme 4
Scheme 5
synthesis of silyl enolate (E)-3t also highlights the utility of
the retro-allylation strategy (entry 9). Although 1i consisted
of the erythro and threo isomers in a ratio of 9:1, a slight
excess (1.2 equiv) of 1i allowed for the exclusive formation of
(E)-3t.
2.3. Arylative Ring-Opening Reactions of Cyclic Homoal-
lyl Alcohols. The allylation reactions mentioned so far are allyl
transfer reactions from acyclic homoallyl alcohols 1a-1i, which
inherently accompany the loss of the corresponding ketone. We
next considered cyclic homoallyl alcohols as substrates. Properly
designed homoallyl alcohols can be transformed into σ-allyl-
(aryl)palladium intermediates that have an intramolecular keto
group. The reactions of such homoallyl alcohols proceed without
loss of any carbon units.
To begin with, cycloheptenol 6a was prepared in four steps.17
The synthesis consisted of (1) nucleophilic addition of 4-pen-
tenylmagnesium bromide to pivalaldehyde, (2) oxidation
with pyridinium chlorochromate, (3) nucleophilic allylation of
the resulting ketone, and (4) ruthenium-catalyzed ring
closing metathesis (Scheme 5). Each step was facile and
robust, and thus endocyclic homoallyl alcohol 6a was readily
accessible.
a The reactions were performed under the conditions in Table 1, entry
1. b The yields obtained by using P(p-tol)3 and the corresponding aryl
bromides are in parentheses. The yields in parentheses were reported in ref
12. c The branched product was contaminated with ethyl p-[(E)-1-methyl-
1-propenyl]benzoate. d The alcohol 1i used was a 9:1 mixture of erythro-
1i and threo-1i.
We rationalize the mechanism of the stereospecific allyl
transfer reaction as follows (Scheme 4). Upon the retro-allylation
reaction of threo-1g, a chairlike transition state 4a that locates
the tert-butyl group at the equatorial position would be
most stable among possible transition states including another
chairlike transition state 4b and twist-boat transition states,
on the basis of the conventional conformational analysis.
Formation of aryl[(E)-crotyl]palladium (E)-5 is thus favored.
The intermediate probably undergoes reductive elimination
so rapidly that its isomerization into π-allylpalladium and any
other isomers is negligible. A similar explanation is applic-
able to the reaction of erythro-1g, where a chairlike transi-
tion state having the tert-butyl group at the equatorial position
and the two methyl groups at the axial positions would be
preferred.
Cycloheptenol 6a was subjected to the palladium-catalyzed
reactions with various aryl bromides (Table 4). The arylative
ring-opening reactions were regiospecific, providing terminal
unsaturation. The reactions required a higher temperature in
refluxing xylene. The more restricted conformation of 6a,
compared to that of acyclic homoallyl alcohols such as 1a,
would cause weaker interaction between the palladium and the
double bond in the corresponding palladium alkoxide (Figure
1). Tricyclohexylphosphine, three equimolar amounts to pal-
ladium, was the best ligand, and triphenylphosphine did not
serve (entry 5). The tert-butyl group of 6a was essential to attain
The allyl transfer reaction was applied to stereospecific
synthesis of vinyl ether 3r starting from diastereomerically
pure 1h (Table 3, entries 7 and 8). Highly stereoselective
9
J. AM. CHEM. SOC. VOL. 129, NO. 14, 2007 4467

A R T I C L E S
Iwasaki et al.
Table 4. Arylative Ring-Opening Reactions of
1-tert-Butyl-3-cyclohepten-1-ol (6a)a
Scheme 6
Table 5. Arylative Ring-opening Reactions of erythro- and
threo-2-Isopropenyl-1-methylcyclohexanol (8a)a
entry
erythro/threo-8a
2
9
yield/% (E/Z)
1
2
3
4
5
6
7
8
erythro
erythro
erythro
erythro
erythro
erythro
threo
2k
2o
2p
2f
2m
2n
2k
2n
9a
9b
9c
9d
9e
9f
76 (<1:99)
54 (<1:99)
81 (<1:99)
61b (<1:99)
64 (<5:95)
84 (<5:95)
86 (>99:1)
71 (>95:5)
9a
9f
threo
a Pd(OAc)2 (0.025 mmol), PCy3 (0.075 mmol), Cs2CO3 (0.60
mmol), 8a (0.50 mmol), and 2 (0.60 mmol) were used. b Performed for
22 h.
a Pd(OAc)2 (0.025 mmol), PCy3 (0.075 mmol), Cs2CO3 (0.72 mmol),
6a (0.60 mmol), and 2 (0.50 mmol) were used. b PPh3 (0.10 mmol) was
used instead of PCy3 (0.075 mmol).
Scheme 7
Figure 1. One of the possible modes of interaction between the palladium
and the double bond of 6a.
of the resulting carbonyl group (Scheme 6). The methylation
provided a mixture of erythro-8a and threo-8a in a ratio of 10:
1, which was (4) chromatographed on silica gel to isolate each
isomer.
satisfactory yields. The reaction of the isopropyl analogue 6b
furnished the corresponding product in only 20% yield (eq 3).
Cyclohexenol 6c underwent the ring-opening, wherein PPh3 was
exceptionally the better ligand (eq 4).
Both of the isomers 8a underwent smooth ring-opening with
excellent regio- and stereospecificity (Table 5). The reactions
represent novel synthesis of ketones involving extremely remote
arylation. The high stereoselectivity would stem from bicyclic,
decalin-like transition states 10 (Scheme 7).
Alcohol 8b having a vinyl group underwent stereospe-
cific ring-opening. In the reaction of erythro-8b (eq 5),
slightly lower yet still satisfactory stereoselectivity was ob-
served, compared to the reaction of erythro-8a (Table 5,
entry 1). The stereoselectivity was perfect in the reaction
of threo-8b albeit the conversion of threo-8b was low even
with an increasing amount of the catalyst (eq 6). Synthesis of
butyl ketone (Z)-9h was also successful starting from erythro-
8c (eq 7).
We next prepared erythro- and threo-2-isopropenyl-1-meth-
ylcyclohexanol (8a).17,21 Homoallyl alcohol 8a was synthesized
in four steps: (1) the reaction of cyclohexene oxide with di-
(isopropenyl)cuprate, (2) oxidation by PCC, and (3) methylation
9
4468 J. AM. CHEM. SOC. VOL. 129, NO. 14, 2007

Palladium-Catalyzed Retro-Allylation
A R T I C L E S
4. Experimental Section
4.1. Typical Procedure for Pd(OAc)2/PCy3-Catalyzed Allylation
of Aryl Halides with Homoallyl Alcohol 1a: The reaction of entry 2
in Table 1 is representative. Cesium carbonate (0.23 g, 0.72 mmol)
was placed in a 30-mL two-necked reaction flask equipped with a
Dimroth condenser. The cesium carbonate was dried in vacuo with
heating with a hair dryer for 2 min. Palladium acetate (5.6 mg, 0.025
mmol) was added in the reaction flask. The flask was then filled with
argon by using the standard Schlenk technique. Tricyclohexylphosphine
(0.50 M in toluene, 0.10 mL, 0.050 mmol) and toluene (1.0 mL) were
added, and the resulting mixture was stirred for 10 min at room
temperature. Toluene (2.0 mL), homoallyl alcohol 1a (0.10 g, 0.60
mmol), and 1-chloronaphthalene (2a, 0.081 g, 0.50 mmol) were
sequentially added at ambient temperature. The resulting mixture was
heated at reflux for 12 h. After the mixture was cooled to room
temperature, water (20 mL) was added. The product was extracted with
hexane (20 mL × 3). The combined organic layer was dried over
sodium sulfate and concentrated in vacuo. Silica gel column purification
with hexane as an eluent gave 1-methallylnaphthalene (3a, 0.072 g,
0.40 mmol) in 79% yield.
4.2. Arylative Ring-Opening Reactions of Cyclic Homoallyl
Alcohols: Palladium acetate (5.6 mg, 0.025 mmol), tricyclohexylphos-
phine (21 mg, 0.075 mmol), and cesium carbonate (235 mg, 0.72 mmol)
were placed in a 30-mL reaction flask under argon. Xylene (5 mL)
was added, and the whole mixture was stirred for 10 min to prepare
the palladium catalyst. Substrates 6a (101 mg, 0.60 mmol) and 2k
(0.069 mL, 0.50 mmol) were added to the mixture. The mixture was
heated at reflux for 12 h. After the mixture was allowed to cool to
ambient temperature, the product was extracted with ethyl acetate (10
mL × 3). The combined organic layer was washed with brine, dried
over Na2SO4, and concentrated in vacuo to leave a yellow oil. Puri-
fication by silica gel column chromatography (hexane/ethyl acetate )
30:1) provided ketone 7a (109 mg, 0.402 mmol) in 80% isolated yield.
3. Conclusion
Compared to the previous catalyst, the combination of
palladium acetate and tricyclohexylphosphine proved to be much
more effective for the palladium-catalyzed allylation of aryl
halides with homoallyl alcohols. The scope of aryl halides has
become wider, and most aryl halides including electron-rich aryl
chlorides could participate. Moreover, the Pd(OAc)2/PCy3-
catalyzed retro-allylation strategy is powerful enough to be
applicable to arylative ring-opening reactions of cyclic homoallyl
alcohols. The arylative ring-opening now allows for the regio-
and stereospecific synthesis of ketones having a branched or
linear allylarene unit at the remote terminus.
Acknowledgment. This work was supported by Grants-in-
Aid for Scientific Research from the Ministry of Education,
Culture, Sports, Science and Technology, Government of Japan.
K.H. thanks JSPS for financial support.
The retro-allylation system will be applicable to other
transformations catalyzed by other transition metals, in which
generation of the regio- and stereochemically defined σ-allyl
complexes is important. In light of the importance of allylation
reactions, retro-allylation can play key roles in developing highly
selective organic reactions.
Supporting Information Available: Experimental details
and characterization data for new compounds (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
JA067372D
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