Zirconocene-mediated and/or catalyzed unprecedented coupling reactions of alkoxymethyl-substituted styrene derivatives

Article abstract of DOI:10.1021/jo0502293

Reactions of o-(alkoxymethyl)styrene derivatives with a stoichiometric amount of zirconocenebutene complex (zirconocene equivalent, "Cp ₂Zr") brought about an insertion of the zirconocene species into a benzylic carbon-oxygen bond. The oxidative insertion of Cp₂Zr to the benzylic carbon-oxygen bond is a result of sequential reactions: (i) formation of zirconacyclopropane by the ligand exchange with o-(alkoxymethyl)styrene, (ii) elimination of the alkoxy group through an aromatic conjugate system giving metalated o-quinodimethane species, and (iii) transfer of zirconium metal to the benzylic position. Through use of a catalytic amount of "Cp₂Zr", however, unprecedented homo-coupling reactions (dimerization) of o-(alkoxymethyl)styrene derivatives occurred to give a tetracyclic compound. On the other hand, reactions of o-(1-alkoxyisopropyl) styrene derivatives gave rise to the analogous tetracyclic compounds regardless of the amount of "Cp₂Zr" (stoichiometric or catalytic). Heterocoupling product between o-(1-alkoxyisopropyl)styrene and styrene congeners was obtained in high cis stereo- and regioselectivity by treating o-(1-alkoxyisopropyl)styrene derivatives with "Cp₂Zr" in the presence of an excess amount of styrene derivatives.

Full text of DOI:10.1021/jo0502293

Zirconocene-Mediated and/or Catalyzed Unprecedented Coupling
Reactions of Alkoxymethyl-Substituted Styrene Derivatives
Yutaka Ikeuchi,†,‡ Takeo Taguchi,‡ and Yuji Hanzawa*,§
Sankyo Co., Ltd., 1-12-1 Shinomiya, Hiratsuka-shi, Kanagawa 254-8560, Japan, Tokyo University of
Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji-shi, Tokyo 192-0392, Japan, and Showa
Pharmaceutical University, 3-3165 Higashi-tamagawagakuen, Machida-shi, Tokyo 194-8543, Japan
hanzaway@ac.shoyaku.ac.jp
Received February 5, 2005
Reactions of o-(alkoxymethyl)styrene derivatives with a stoichiometric amount of zirconocene-
butene complex (zirconocene equivalent, “Cp2Zr”) brought about an insertion of the zirconocene
species into a benzylic carbon-oxygen bond. The oxidative insertion of Cp2Zr to the benzylic carbon-
oxygen bond is a result of sequential reactions: (i) formation of zirconacyclopropane by the ligand
exchange with o-(alkoxymethyl)styrene, (ii) elimination of the alkoxy group through an aromatic
conjugate system giving metalated o-quinodimethane species, and (iii) transfer of zirconium metal
to the benzylic position. Through use of a catalytic amount of “Cp2Zr”, however, unprecedented
homo-coupling reactions (dimerization) of o-(alkoxymethyl)styrene derivatives occurred to give a
tetracyclic compound. On the other hand, reactions of o-(1-alkoxyisopropyl)styrene derivatives gave
rise to the analogous tetracyclic compounds regardless of the amount of “Cp2Zr” (stoichiometric or
catalytic). Heterocoupling product between o-(1-alkoxyisopropyl)styrene and styrene congeners was
obtained in high cis stereo- and regioselectivity by treating o-(1-alkoxyisopropyl)styrene derivatives
with “Cp2Zr” in the presence of an excess amount of styrene derivatives.
Introduction
tuted styrene derivatives 4, which possess a reactive
olefin site to “Cp2Zr” and a leaving alkoxy group through
the aromatic π-conjugated system. Preliminary examina-
tion of the reactions of o-, m-, or p-alkoxymethyl-
substituted styrene derivatives 4 toward “Cp2Zr” showed
a remarkable difference in reactivity.4
Easy preparation and versatile reactivity of zir-
conocene-butene complex 1 (“Cp2Zr”, Cp ) cyclopenta-
dienyl)1 attracted synthetic organic chemists to the use
of “Cp2Zr” as a zirconocene equivalent for the study of
new carbon-carbon bond formation.2 During the course
of our studies of “Cp2Zr”-mediated carbon-carbon bond
formation reactions, we reported an efficient generation
of allylic zirconocene 3 species from allylic ethers through
â-alkoxy elimination of the zirconacyclopropane inter-
mediate 2.3 On the basis of the formation of allylic
zirconocene 3, we were tempted to examine “Cp2Zr”-
catalyzed or -mediated reactions of alkoxymethyl-substi-
† Sankyo Co., Ltd..
‡ Tokyo University of Pharmacy and Life Science.
§ Showa Pharmaceutical University.
(1) Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett.
1986, 27, 2829.
(2) For recent reviews, see: (a) Marek, I., Ed. Titanium and
Zirconium in Organic Synthesis, Wiley-VCH: Weinheim, Germany,
2002. (b) Suzuki, K.; Wipf, P., Eds.; Recent advances in the chemistry
of zirconocenes. In Symposium-in print Tetrahedron 2004, 60, 1267.
(3) For review, see: Hanzawa, Y.; Ito, H.; Taguchi, T. Synlett 1995,
299.
In this paper, we disclose a full account of the
“Cp2Zr”-mediated or -catalyzed reactions of o-, m-, and
(4) Hanzawa, Y.; Ikeuchi, Y.; Nakamura, T.; Taguchi, T. Tetrahedron
Lett. 1995, 36, 6503.
10.1021/jo0502293 CCC: $30.25 © 2005 American Chemical Society
Published on Web 04/16/2005
4354
J. Org. Chem. 2005, 70, 4354-4359

Zirconocene-Mediated Unprecedented Coupling Reactions
reaction of meta-substituted isomer m-4 with an equiva-
lent amount of “Cp2Zr”, however, butene-coupling product
13 was obtained as the sole product as in the case of the
styrene-“Cp2Zr” reaction.
These results indicate that the insertion of zirconocene
into the benzylic carbon-oxygen bond took place in the
reactions of o- and p-4 and not in the reaction of m-4,
and thus, the importance of the π-conjugation is obvious.
It is also obvious that benzylic zirconocene species is
formed prior to the addition of the second “Cp2Zr” in the
reactions of o- and p-4. Thus, benzylzirconocene species
16, for example, would be formed through (i) the ligand
exchange of the first equivalent of “Cp2Zr” with a double
bond of o-4a giving a zirconacyclopropane derivative 14,
(ii) the elimination of the alkoxy group in 14 through the
aromatic π-system to generate o-quinodimethane inter-
mediate 15,7 and (iii) the transfer of the Cp2Zr moiety to
a benzylic position (Figure 2). The described processes
(i-iii) explain the formation of 10 (X ) H or D) in the
reaction of o-4a with 2 equiv of “Cp2Zr” or the formation
of 13.
Formation of Homocoupling Products (Dimer-
ization). The reaction of o-(1-alkoxyisopropyl)styrene
17a, which is a dimethyl-substituted analogue of o-4a,
with an equivalent amount of “Cp2Zr” afforded an unex-
pected homocoupling product 19a as a mixture of trans/
cis isomers8 (ratio ) 3.0/1). In addition, reduced product
18 was not detected (Scheme 2 and Table 1).9 No
deuterium was incorporated into 19a by DCl-D2O work-
up. The homocoupling reactions were affected by the
substituent, and thus p-methoxy-substituted styrene
derivative 17c gave a complex mixture (entry 3). It is
worth mentioning that the reaction of the fluorine-
substituted isomer 17d with “Cp2Zr” (1 equiv) gave a
corresponding homocoupling product 19c in a 29% yield
(trans/cis ) 2.5) together with 20 (X ) H) in a 50% yield
as a single cis-stereoisomer (entry 4).8 The incorporation
of one deuterium atom into 20 (X ) D) by DCl-D2O
workup indicates that the coupled product 20 is gener-
FIGURE 1. Regio- and stereoselective formation of 6.5
p-alkoxymethyl-substituted styrene derivatives 4 and the
unprecedented formation of homo- and heterocoupling
products.
The reaction of styrene (5a) with “Cp2Zr” has been
reported to give regio- and stereoselectivily zirconacyclo-
pentane intermediate 6, which is converted to styrene-
butene coupled product 7 in good yields by acid treatment
(Figure 1).5,6 In this coupling reaction, it is worth noting
that the formation of the styrene-styrene homocoupling
(dimerization) products has been reported to be less than
10% under thermodynamically equilibrated conditions.
Results and Discussion
Generation of Benzylzirconocene Intermediates.
The reactions of o-(benzyloxymethyl)styrene derivatives
(o-4a-c) with a stoichiometric amount of “Cp2Zr” in THF
at room temperature gave o-methylstyrene compounds
8a-c or the monodeuteriomethyl congener of 8a after
acidic workup (HCl-H2O or DCl-D2O) in good yields
(Scheme 1). To our surprise, butene-coupling product 9
could not be detected in the reaction media. The double
bond of o-4a is indispensable because the reaction of
dibenzyl ether with “Cp2Zr” under the same conditions
did not afford any products except the recovered starting
material. Through use of 2 equiv of “Cp2Zr”, o-4a afforded
butene-coupling compound 10a (X ) H) in a 79% yield,
and three deuterium atoms were incorporated into 10a
(X ) D) by DCl-D2O workup. The reaction of p-(benzyl-
oxymethyl)styrene (p-4) with “Cp2Zr” indicated similar
reactivity to that of o-4a. Thus, the formation of p-
methylstyrene (11) or butene-coupling product 12 de-
pended on the amount of “Cp2Zr” employed. In the
SCHEME 1
J. Org. Chem, Vol. 70, No. 11, 2005 4355

Ikeuchi et al.
FIGURE 2. “Cp2Zr”-mediated reaction pathway.
SCHEME 2
SCHEME 3
a Isolated yields. bn-BuLi (1/3 equiv) was added before hydrolytic
workup.
TABLE 1. Formation of 19a
compared to 20 (28%) (entry 5), and thus the homocou-
pling reaction could be suggested to proceed with 20 (X
) ZrCp2(OMe)) as a key intermediate.
The lack of deuterium introduction into 19 by the acidic
workup with DCl-D2O suggests that dimeric product 19
was not generated as an organometallic compound in the
reaction media. A half equivalent of “Cp2Zr” to 17a was
sufficient (84% yield) for the formation of 19a (Scheme
% yieldb of
% yieldb
entry
17
17a: R ) H;
17b: R ) H; R1 ) CH3
19 (trans/cis)
of 20
1
3). The use of /3 equiv of “Cp2Zr”, however, indicated a
1
19a: 83 (3.0)
19a: 78
-
-
formation of 19a in a lower yield (62%) with considerable
recovery of 17a (31%), and the addition of n-BuLi (1/3
equiv) to the reaction mixture prior to the hydrolytic
workup increased the yield of 19a (75%). Thus, the
homocoupling process is a catalytic process with respect
to “Cp2Zr”.
2
3
17c: R ) CH3O; R1 ) CH3 complex mixture
4c
5d
17d: R ) F; R1 ) CH3
17d: R ) F; R1 ) CH3
19c: 29 (2.5)
19c: 53
50
28
a Reaction conditions: 17 (0.5 mmol), “Cp2Zr” (1.05 equiv), THF,
rt. b Isolated yields. c 6.5 h of reaction time. d 97 h of reaction time.
The reactions of o-(alkoxymethyl)styrene derivatives
with a catalytic amount of Cp2ZrCl2 (10 mol %) in the
presence of 3 equiv of n-BuMgCl in THF at refluxing
temperature10 are summarized in Table 2. Under the
catalytic conditions, improved yields of dimers 19 were
observed in comparison to those under the stoichiometric
conditions (entries 4-7). It is interesting to note that the
styrene derivatives o-4, which did not give dimerization
products under the stoichiometric conditions, gave dimer-
ization products 19 under the catalytic conditions (entries
1 and 3). In contrast to the result of the reaction of o-4,
p-(benzyloxymethyl)styrene (p-4) resulted in polymeri-
zation under catalytic conditions.
The catalytic process for the formation of 19 consisted
of the prior formation of zirconacyclopropane 14′ and the
formation of dialkoxyzirconocene, which regenerated
“Cp2Zr” through the reaction with Grignard reagent, and
the dimerization product 19 was expelled from the
catalytic cycle as shown in Figure 3.
ated as a zirconocene species in the reaction media. The
prolonged reaction of 17d (97 h) with an equivalent
amount of “Cp2Zr” increased the ratio of 19c (53%)
(5) Swanson, D. R.; Rousset, C. J.; Negishi, E.; Takahashi, T.; Seki,
T.; Saburi, M.; Uchida, Y. J. Org. Chem. 1989, 54, 3521.
(6) Besides the reactivity of styrene with a stoichiometric amount
of 1, the efficient alkylation reaction of the styrene double bond has
been reported by treatment with a catalytic amount of Cp2ZrCl2 in
the presence of Grignard reagent (3 equiv) and alkyl halides or
tosylates. (a) Cesati, R. C., III; Armas, J.; Hoveyda, A. H. Org. Lett.
2002, 4, 395. (b) Armas, J.; Hoveyda, A. H. Org. Lett. 2001, 3, 2097.
(c) Armas, J.; Kolis, S. P.; Hoveyda, A. H. J. Am. Chem. Soc. 2000,
122, 5977. (d) Terao, J.; Torii, K.; Saito, K.; Kambe, N.; Baba, A.;
Sonoda, N. Angew. Chem., Int. Ed. 1998, 37, 2653. (e) Terao, J.;
Watanabe, T.; Saito, K.; Kambe, N.; Sonoda, N. Tetrahedron Lett. 1998,
39, 9201. (f) Swanson, D. R.; Rousset, C. J.; Negishi, E.; Takahashi,
T.; Seki, T.; Saburi, M.; Uchida, Y. J. Org. Chem. 1989, 54, 3521.
(7) The generation of o-quinodimethane intermediates from o-
alkoxymethylstyrene and its related compounds through the elimina-
tion of an alkoxyl group has been reported. (a) Hirao, A.; Negishi, Y.;
Hayashi, M.; Sako, K.; Ryu, W.; Loykulnant, S.; Matsuo, A.; Sugiyama,
K. Macromol. Chem. Phys. 2001, 202, 3590. (b) Hirao, A.; Kitamura,
K.; Takenaka, K.; Nakahama, S. Macromolecules 1993, 26, 4995. (c)
Ishizone, T.; Kato, R.; Ishino, Y.; Hirao, A.; Nakahama, S. Macromol-
ecules 1991, 24, 1449. See also: (d) Moss, R. J.; Rickborn, B. J. Org.
Chem. 1986, 51, 1992. (e) Moss, R. J.; White, R.; Rickborn, B. J. Org.
Chem. 1985, 50, 5132. (f) Moss, R. J.; Rickborn, B. J. Org. Chem. 1984,
49, 3694. (g) Tuschka, T.; Naito, K.; Rickborn, B. J. Org. Chem. 1983,
48, 70.
(8) Structure was determined by X-ray analysis.
(9) Although dimer 19a was obtained in a lower yield, using methyl
ether 17b, than benzyl ether 17a, for easy preparation of substrates,
methyl ether derivatives were prepared for the other substrates. See
the Supporting Information.
(10) It was essential to heat the reaction mixture to reflux to bring
about an efficient formation of 19.
4356 J. Org. Chem., Vol. 70, No. 11, 2005

Zirconocene-Mediated Unprecedented Coupling Reactions
TABLE 2. Formation of 19 from o-4 or 17 under
TABLE 3. Heterocoupling Reactions of 17b with
Styrene Derivativesa
Catalytic Conditionsa
% yieldb of
19 (trans/cis)
entry
o-4 or 17
1
2
3
4
5
6
7
o-4a
o-4b
o-4c
17a
17b
17c
17d
19d: 57 (1.3)
19e: nd
19f: 52 (2.1)
19a: 89 (2.8)
19a: 81 (3.0)
19b: 55 (2.4)
19c: 44c (1.4)
a Reaction conditions: o-4 or 17 (0.5 mmol), Cp2ZrCl2 (10 mol
%), n-BuMgCl (3 equiv), THF, reflux. b Isolated yields. c Coupled
product 20 was also obtained in a 34% yield.
a Reaction conditions: 17b (0.5 mmol), 5 (3 equiv), “Cp2Zr” (1.2
equiv), THF, rt. b Isolated yields. The yields of 19 are shown in
parentheses. c 1 equiv of 5a was used. d Reaction conditions:
Cp2ZrCl2 (10 mol %), n-BuMgCl (3 equiv), THF, reflux.
FIGURE 3. Catalytic cycle for the formation of 19.
FIGURE 4. Regio- and stereoselective formation of 22 by
Negishi et al.
Formation of Heterocoupling Products. Although
the mechanism for the Cp2ZrCl2-catalyzed or “Cp2Zr”-
mediated homocoupling formation of 19, which will be
discussed later, is still unclear, it may be of interest to
investigate the possibility for the heterocoupling reaction
of 17 with other olefins. Attempts to obtain such hetero-
coupling products would contribute to the understanding
of the reaction mechanisms for the formation of 19. The
results of the reaction of 17 with styrene (5a) as a
heterocoupling partner are shown in Table 3. Thus, in
the “Cp2Zr”-mediated reaction of 17b with 1 equiv of
styrene (5a), heterointermolecular coupling product 21a
was obtained in a 56% yield as a single cis-stereoisomer8
along with homodimer 19a (21% yield), and neither
styrene (5a)-butene nor styrene-styrene coupling prod-
uct (see, Figure 1) was obtained. Use of 3 equiv of styrene
(5a) increased the yield of 21a to 85% (entry 2). Treat-
ment of the reaction mixture with DCl/D2O afforded the
monodeuteriomethyl compound of 21a in an excellent
deuterium content (>95% D, 79% yield). The intermo-
lecular heterocoupling reaction of 17 was restricted to a
styrene double bond, without a substituent on the double
bond, as a coupling partner (Table 3). All other examined
unsaturated compounds, such as maleic anhydride, 3,4-
SCHEME 4
dihydrofuran, phenylacetylene, diphenylacetylene, cis- or
trans-stilbene, and R- or â-methylstyrene, did not give a
heterocoupling product but gave the homocoupling prod-
uct 19. It should be noted that the “Cp2Zr”-mediated
reaction of o-benzyloxymethystyrene (o-4a) with styrene
(5a) gave a reduced product 8a as the sole product (entry
8). The heterointermolecular coupling reaction of 17b
with styrene (5a) was also carried out under the same
catalytic conditions with a similar efficiency to the
stoichiometric conditions (entry 3).
Mechanistic Consideration of Coupling Reac-
tions. Concerning the “Cp2Zr”-mediated styrene-sty-
rene homocoupling reaction, the reaction of Cp2Zr-
(CH2CH2Ph)2 with styrene has been reported to give
trans-2,5-diphenylzirconacyclopenatane intermediate 22.5
The stereo- and regioselective formation of 22 was ex-
J. Org. Chem, Vol. 70, No. 11, 2005 4357

Ikeuchi et al.
FIGURE 5. Supposed intermediates.
SCHEME 5
in the insertion of zirconocene into a benzylic carbon-
oxygen bond. Reactions of o-(1-alkoxyisopropyl)styrene
derivatives with a stiochiometric and/or a catalytic
amount of “Cp2Zr” (Cp2ZrCl2 (10 mol %)) in the presence
of 3 equiv of n-BuMgBr cause dimerization reactions as
a major product. The catalytic process turned out to be
efficient also for the dimerization of o-(alkoxymethyl)-
styrene, which yields benzylzirconocene species under the
stoichiometric conditions. Heterocoupling reactions of
o-(1-alkoxyisopropyl)styrene derivatives with styrene
have been brought about in high cis-stereoselectivity.
Although the precise reaction mechanism for the de-
scribed formation of homo- and heterocoupling products
has yet to be elucidated, the intramolecular Diels-Alder
reaction is supposed to be involved at this point in time.
plained to be a result of the favorable thermodynamic
effect of benzylic and/or agostic interaction of the R-phen-
yl group to Zr (Figure 4). Treatment of 17b with Cp2Zr-
(CH2CH2Ph)2 under identical conditions afforded 19a and
21a, and a product derived from 2-[2-(methoxyisopropyl)-
phenyl]-5-phenylzirconacyclopentane 23, which corre-
sponds to 22 could not be obtained (Scheme 4). At this
point in time, either one of the intermediates, zircona-
cyclopentane 24 or o-quinodimethane intermediate 25,
could be involved as a key intermediate for the formation
of 19 or 21 (Figure 5). It is interesting to note that the
reaction of o-tert-butylstyrene (26) with an equivalent
amount of “Cp2Zr” gave o-tert-butylethylbenzene (59%)
along with the recovered 26 (35%) (Scheme 5). Further-
more, the reaction of Cp2Zr(CH2CH2Ph)2 with o-tert-
butylstyrene (26) ended with a recovery of 26. These
observations imply that a ligand exchange would be
possible in the reaction of o-tert-butylstyrene (26) with
“Cp2Zr” giving 26-zirconocene complex, which did not
react with butene. It is also obvious that 26 did not couple
with styrene-zirconocene complex, and thus, the par-
ticipation of the alkoxy group in o-4 or 17 plays a
significant role in the reaction with “Cp2Zr”. It should
also be noted that the stereochemistry of heterocoupling
products 21 or the supposed intermediate 20d (R ) F)
for homocoupling (see, Scheme 2) is cis while the stere-
ochemistry of homodimer 19 itself is a mixture of cis and
trans isomers. Thus, the stereochemical outcome of
homodimer 19 would suggest that once formed cis ster-
eochemistry in 20 does not last through the reaction.11
Experimental Section
Typical Procedure for Generation and Butene-Coup-
ling Reactions of Benzylzirconocene Intermediates. To
a solution of Cp2ZrCl2 (153 mg, 0.53 mmol) in THF (5 mL) was
added n-BuLi (1.6 M solution in n-hexane, 0.66 mL, 1.05 mmol)
at -78 °C and the mixture was stirred for 1 h at the same
temperature. To this solution was added a solution of o-4a (112
mg, 0.50 mmol) in THF (2 mL) with gradual warming to room
temperature, and the solution was stirred for 3 h. To this
reaction mixture was added 1 M HCl (aq), extracting with
ether. The organic layer was washed with brine and dried over
anhydrous MgSO4, and the filtrate was concentrated to dry-
ness. The residue was purified by flash chromatography (n-
hexane) to give 8a (52 mg, 88%).
1-Methy-2-vinylbenzene (8a): The structure was con-
firmed by comparison of spectral data from a commercially
available sample.
1-Methyl-2-(3-methylpentyl)benzene (10): This product
was prepared from o-4a (112 mg, 0.50 mmol), Cp2ZrCl2 (307
mg, 1.05 mmol), and n-BuLi (1.6 M, 1.31 mL, 2.10 mmol)
according to the typical procedure. Colorless oil. IR (neat) 2961,
2928, 2873, 1906, 1605, 1493, 739 cm-1. 1H NMR (CDCl3, 300
MHz) δ 7.25-7.13 (4H, m), 2.78-2.56 (2H, m), 2.37 (3H, s),
1.66-1.25 (5H, m), 1.02 (3H, d, J ) 6.1 Hz), 0.96 (3H, t, J )
7.2 Hz). 13C NMR (CDCl3, 75.5 MHz) δ 141.4, 135.7, 130.1,
128.7, 125.9, 125.7, 37.3, 34.7, 30.9, 29.4, 19.23, 19.19, 11.4.
EI-MS (m/z) 176 (M+).
Typical Procedure for Homocoupling Reactions un-
der Catalytic Conditions. To a solution of 17b (88 mg, 0.50
mmol) and Cp2ZrCl2 (14.6 mg, 0.05 mmol) in THF (5.2 mL)
was added n-BuMgCl (0.84 M solution in THF, 1.79 mL, 1.50
mmol) at room temperature and the mixture was refluxed for
5 h. To this reaction mixture was added by 1 M HCl (aq) at 0
°C, extracting with ether. The organic layer was washed with
brine and dried over anhydrous MgSO4, and the filtrate was
concentrated to dryness. The residue was purified by flash
chromatography (n-hexane) to give 19a (59 mg, 81%) as a
Conclusions
In conclusion, we found unexpected and unprecedented
reactions of “Cp2Zr” with (alkoxymethyl)styrene deriva-
tives. Reactions of o- or p-(alkoxymethyl)styrene deriva-
tives with a stoichiometric amount of “Cp2Zr” resulted
(11) It is known that the formation of 19d by intramolecular Diels-
Alder reaction of o-quinodimethane intermediate is generated from a
sulfone derivative. Thus, the formation of 19 from 21 might have
occurred via a similar pathway. See: Levy, L. A.; Sashikumar, V. P.
J. Org. Chem. 1985, 50, 1760.
4358 J. Org. Chem., Vol. 70, No. 11, 2005

Zirconocene-Mediated Unprecedented Coupling Reactions
mixture of trans/cis ) 3.0. Recrystallization from EtOH gave
trans-19a as a single isomer.
dryness. The residue was purified by flash chromatography
(n-hexane), and further purification was carried out by MPLC
(n-hexane) to give 21a (106 mg, 85%).
trans-6,6,12,12-Tetramethyl-4b,5,6,10b,11,12-hexahy-
drochrysene (trans-19a): Colorless crystalline solid. Mp
(EtOH) 169.5-172.0 °C. IR (KBr) 2955, 2905, 2854, 1485, 1344,
1,1,4-Trimethyl-3-phenyl-1,2,3,4-tetrahydronaphtha-
lene (21a): Colorless crystalline solid. Mp (ether) 75.4-76.4
1
755, 743 cm-1. H NMR (CDCl3, 400 MHz) δ 7.46-7.18 (8H,
°C. IR (KBr) 2962, 2931, 1487, 1452, 1040, 763, 751, 699 cm-1
.
1H NMR (CDCl3, 400 MHz) δ 7.37-7.31 (3H, m), 7.26-6.97
(6H, m), 3.38 (1H, ddd, J ) 13.6, 4.8, 1.9 Hz), 3.09 (1H, dq, J
) 7.2, 4.8 Hz), 2.25 (1H, dd, 13.6, 13.0 Hz), 1.73 (1H, dd, J )
13.0, 1.9 Hz), 1.44 (3H, s), 1.31 (3H, s), 0.87 (3H, d, J ) 7.2
Hz). 13C NMR (CDCl3, 100 MHz) δ 144.8, 144.4, 142.1, 129.2,
128.2, 127.8, 126.9, 126.2, 126.0, 125.6, 40.4, 39.4, 37.2, 35.2,
32.7, 32.3, 18.1. EI-MS (m/z) 250 (M+). Anal. Calcd for C19H22:
C, 91.14; H, 8.86. Found: C, 91.25; H, 8.46.
m), 2.88 (2H, dd, J ) 11.0, 1.0 Hz), 2.44 (2H, dd, J ) 12.5, 1.0
Hz), 1.71 (2H, dd, J ) 12.5, 11.1 Hz), 1.44 (12H, s). 13C NMR
(CDCl3, 100 MHz) δ 145.8, 138.9, 127.0, 126.1, 125.6, 125.4,
44.0, 38.6, 35.3, 33.1, 32.6. EI-MS (m/z) 290 (M+). Anal. Calcd
for C22H26: C, 90.73; H, 9.27. Found: C, 91.03; H, 9.23.
cis-6,6,12,12-Tetramethyl-4b,5,6,10b,11,12-hexahydro-
chrysene (cis-19a): Colorless crystalline solid. Mp (ether)
161.4-163.4 °C. 1H NMR (CDCl3, 400 MHz) δ 7.43-7.15 (8H,
m), 3.25 (2H, dd, J ) 13.1, 4.2 Hz), 1.99 (2H, br t, J ) 13.1
Hz), 1.69 (2H, dd, J ) 14.2, 4.2 Hz), 1.40 (6H, s), 1.35 (6H, s).
13C NMR (CDCl3, 100 MHz) δ 145.0, 140.0, 129.5, 126.4, 125.7,
125.3, 43.4, 35.3, 34.8, 31.3, 30.3.
Typical Procedure for Heterocoupling Reactions. To
a solution of Cp2ZrCl2 (175 mg, 0.60 mmol) in THF (5 mL) was
added n-BuLi (1.6 M solution in n-hexane, 0.75 mL, 1.20 mmol)
at -78 °C with 1 h of stirring at the same temperature. To
this solution was added a solution of 17b (112 mg, 0.50 mmol)
and 5a (156 mg, 1.50 mmol) in THF (2 mL), which was
gradually warmed to room temperature and stirred for 3 h.
To this reaction mixture was added 1 M HCl (aq), extracting
with ether. The organic layer was washed with brine and dried
over anhydrous MgSO4, and the filtrate was concentrated to
Acknowledgment. We thank Dr. M. Shiro (Rigaku
Corporation) and Mr. H. Fukaya (TUPLS) for X-ray
analyses. We also acknowledge Professor T. Takahashi
of Hokkaido University for valuable information.
Supporting Information Available: Experimental pro-
cedures and characterization data for products and starting
materials, and X-ray data of 19a-c,f, 20, and 21a in CIF
format. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0502293
J. Org. Chem, Vol. 70, No. 11, 2005 4359