Synthesis of Aromatic Bisabolene Natural Products via Palladium-Catalyzed Cross-Couplings of Organozine Reagents

Article abstract of DOI:10.1021/jo035778s

Aromatic bisabolene derivatives were prepared by two methods involving cross-coupling of organozinc reagents. The first synthesis of (±)-glandulone A (10), as well as syntheses of (± )-curcuhydroquinone (8) and (±)-curcuquinone (9), were accomplished via coupling of a secondary alkyl zinc reagent (1,5-dimethyl-4-hexenylzinc halide, 18) to protected bromohydroquinones using Pd(dppf)Cl₂ as catalyst. Coupling of arylzinc halides with alkenyl triflate 16 using Pd(PPh ₃)₄ catalyst provided a number of bisabolene derivatives and led to syntheses of dehydro-α-curcumene (2), (±)-curcuphenol (3), and (±)-elvirol (13). A high-yield synthesis of the (±)-heliannuol D precursor 29 is also reported using this method.

Full text of DOI:10.1021/jo035778s

Syn th esis of Ar om a tic Bisa bolen e Na tu r a l P r od u cts via
P a lla d iu m -Ca ta lyzed Cr oss-Cou p lin gs of Or ga n ozin c Rea gen ts†
J ames R. Vyvyan,*,‡ Celeste Loitz, Ryan E. Looper, Cheryl S. Mattingly,
Emily A. Peterson, and Steven T. Staben
Department of Chemistry, Western Washington University, Bellingham, Washington 98225-9150
vyvyan@chem.wwu.edu
Received December 4, 2003
Aromatic bisabolene derivatives were prepared by two methods involving cross-coupling of
organozinc reagents. The first synthesis of (()-glandulone A (10), as well as syntheses of
(()-curcuhydroquinone (8) and (()-curcuquinone (9), were accomplished via coupling of a secondary
alkyl zinc reagent (1,5-dimethyl-4-hexenylzinc halide, 18) to protected bromohydroquinones using
Pd(dppf)Cl2 as catalyst. Coupling of arylzinc halides with alkenyl triflate 16 using Pd(PPh3)4 catalyst
provided a number of bisabolene derivatives and led to syntheses of dehydro-R-curcumene (2), (()-
curcuphenol (3), and (()-elvirol (13). A high-yield synthesis of the (()-heliannuol D precursor 29
is also reported using this method.
In tr od u ction
cumene (1a )3 and dehydro-R-curcumene (2),4 aromatic
bisabolenes are components of many plant essential oils.
Some aromatic bisabolenes, such as (+)-nuciferal (1b)5
and (+)-turmerone (5a ),6 possess side chains that are
more highly oxidized than those present in curcumene
and dehydrocurcumene. Phenolic aromatic bisabolenes
include (-)-curcuphenol (3),7 (+)-xanthorrhizol (4),8 tur-
meronol B (5b),9 allylic alcohols 6 and 7,10 and the
rearranged bisabolene elvirol (13).11 More highly oxidized
Aromatic bisabolene natural products have been popu-
lar synthetic targets for 30 years1 and continue to be a
proving ground for the development of synthetic meth-
ods.2 Typified by the parent hydrocarbons (+)-R-cur-
† Dedicated to Professor Stephen K. Taylor on the occasion of his
60th birthday.
‡ Henry Dreyfus Teacher-Scholar 2003
(1) (a) Heathcock, C. H. In The Total Synthesis of Natural Products;
ApSimon, J . W., Ed.; Wiley: New York, 1973; Vol. 2, p 197. (b)
Heathcock, C. H.; Graham, S. L.; Pirrung, M. C.; Plavac, F.; White, C.
T. In The Total Synthesis of Natural Products; ApSimon, J . W., Ed.;
Wiley and Sons: New York, 1981; Vol. 5, p 35. (c) Pirrung, M. C.;
Morehead, A. T. In The Total Synthesis of Natural Products; Goldsmith,
D., Ed.; Wiley and Sons: New York, 1997; Vol. 10, p 29.
(3) (a) Honwad, V. K.; Rao, A. S. Tetrahedron 1965, 21, 2593-2604.
(b) Damodaran, N. P.; Dev, S. Tetrahedron 1965, 21, 4113-4122.
(4) Tomita, B.; Hirose, Y.; Nakatsuka, T. Mokuzai Gakkaishi 1969,
15, 46.
(5) Sakai, T.; Nishimura, K.; Hirose, Y. Bull Chem. Soc. J pn. 1965,
38, 381-387.
(2) Selected recent examples of aromatic bisabolene synthesis: (a)
Meyers, A. I.; Stoianova, D. J . Org. Chem. 1997, 62, 5219-5221. (b)
Kimachi, T.; Takemoto, Y. J . Org. Chem. 2001, 66, 2700-2704. (c)
Fuganti, C.; Serra, S. J . Chem. Soc., Perkin Trans. 1 2000, 3758-3764.
(d) Fuganti, C.; Serra, S.; Dulio, A. J . Chem. Soc., Perkin Trans. 1 1999,
279-282. (e) Fuganti, C.; Serra, S. Synlett 1998, 1252-1254. (f)
Sugahara, T.; Ogasawara, K. Tetrahedron: Asymmetry 1998, 9, 2215-
2217. (g) Nagumo, S.; Irie, S.; Hayashi, K.; Akita, H. Heterocycles 1996,
43, 1175-1178. (h) Ono, M.; Ogura, Y.; Hatogai, K.; Akita, H.
Tetrahedron: Asymmetry 1995, 6, 1829-1832. (i) Ono, M.; Yamamoto,
Y.; Akita, H. Chem. Pharm. Bull. 1995, 43, 553-558. (j) Ono, M.;
Ogura, Y.; Hatogai, K.; Akita, H. Chem. Pharm. Bull. 2001, 49, 1581-
1585. (k) Ono, M.; Suzuki, K.; Tanikawa, S.; Akita, H. Tetrahedron:
Asymmetry 2001, 12, 2597-2604. (l) Sharma, M. L.; Chand, T. Indian
J . Chem. 1997, 36B, 553-556. (m) Sharma, M. L.; Chand, T. Tetra-
hedron Lett. 1996, 37, 2279-2280. (n) Kad, G. L.; Khurana, A.; Singh,
V.; Singh, J . J . Chem. Res., Synop. 1999, 164-165. (o) Takabatake,
K.; Nishi, I.; Shindo, M.; Shishido, K. J . Chem. Soc., Perkin Trans. 1
2000, 1807-1808. (p) Sato, K.; Bando, T.; Shindo, M.; Shishido, K.
Heterocycles 1999, 50, 11-15. (q) Shishido, K.; Bando, T. J . Mol. Catal.
B: Enzym. 1998, 5, 183-186. (r) Tanaka, K.; Nuruzzaman, M.;
Yoshida, M.; Asakawa, N.; Yang, X.-S.; Tsubaki, K.; Fuji, K. Chem.
Pharm. Bull. 1999, 47, 1053-1055. (s) Kimachi, T.; Takemoto, Y. J .
Org. Chem. 2001, 66, 2700-2704. (t) Ho, T.-L.; Ho, M.-F. J . Chin.
Chem. Soc. 2001, 48, 879-881. (u) Hagiwara, H.; Okabe, T.; Ono, H.;
Kamat, V. P.; Hoshi, T.; Suzuki, T.; Ando, M. J . Chem. Soc., Perkin
Trans. 1 2002, 895-900. (v) Li, A.; Yue, G.; Li, Y.; Pan, X.; Yang, T.-
K. Tetrahedron: Asymmetry 2003, 14, 75-78. (w) Singh, V.; Khurana,
A.; Kaur, I.; Sapehiyia, V.; Kad, G. L.; Singh, J . J . Chem. Soc., Perkin
Trans. 1 2002, 1766-1768. (x) Rowe, B. J .; Spilling, C. D. J . Org. Chem.
2003, 68, 9502-9505.
(6) Honwad, V. K.; Rao, A. S. Tetrahedron 1964, 2921-2925.
(7) (a) McEnroe, F. J .; Fenical, W. Tetrahedron 1978, 34, 1661-
1664. (b) Fusetani, N.; Sugano, M.; Matsunaga, S.; Hashimoto, K.
Experentia 1987, 43, 1234-1235. (c) Wright, A. E.; Pomponi, S. A.;
McConnell, O. J .; Kohmoto, S.; McCarthy, P. J . J . Nat. Prod. 1987,
50, 976-978. (d) Miller, S. L.; Tinto, W. F.; McLean, S.; Reynolds, W.
F.; Yu, M. J . Nat. Prod. 1995, 58, 1116-1119. (e) D’Armas, H. T.;
Mootoo, B. S.; Reynolds, W. F. J . Nat. Prod. 2000, 63, 1593-1595. (f)
El Sayed, K. A.; Yousaf, M.; Harmann, M. T.; Avery, M. A.; Kelly, M.;
Wipf, P. J . Nat. Prod. 2002, 65, 1547-1553.
(8) (a) Rimpler, H.; Hansel, R.; Kochendorfer, L. Z. Naturforsch.
1970, 25, 995; Chem. Abstr. 1971, 74, 13288c. (b) Aguilar, M. I.;
Delgado, G.; Bye, R.; Linares, E. Phytochemistry 1993, 33, 1161-1163.
(c) Manguro, L. O. A.; Mukonyi, K. M.; Githiomi, J . K. Planta Med.
1996, 62, 84-85. (d) Mata, R.; Mart´ınez, E.; Bye, R.; Morales, G.; Singh,
M. P.; J anso, J . E.; Maiese, W. M.; Timmermann, B. J . Nat. Prod. 2001,
64, 911-914. (e) Lee, S. K.; Hong, C.-H.; Huh, S.-K.; Kim, S.-S.; Oh,
O.-J .; Min, H.-Y.; Park, K.-K.; Chung, W.-Y.; Hwang, J .-K. J . Environ.
Pathol. Toxicol. 2002, 21, 141-148. (f) Hwang, J .-K.; Shim, J .-S.; Baek,
N.-I.; Pyun, Y.-R. Planta Med. 2000, 66, 196-197. (g) Aguilar, M. I.;
Delgado, G.; Hernanadez, M.; Villarreal, M. L. Nat. Prod. Lett. 2001,
15, 93-101.
(9) Imai, S.; Morikiyo, M.; Furihata, K.; Hayakana, Y.; Seto, H.
Agric. Biol. Chem. 1990, 54, 2367.
(10) Butler, M. S.; Capon, R. J .; Nadeson, R.; Beveridge, A. A. J .
Nat. Prod. 1991, 54, 619-623.
(11) (a) Bohlmann, F.; Grenz, M. Tetrahedron Lett. 1969, 1005-
1006. (b) Bohlmann, F.; Ko¨rnig, D. Chem. Ber. 1974, 107, 1777-1779.
(c) Dennison, N. R.; Mirrington, R. N.; Stuart, A. D. Aust. J . Chem.
1975, 28, 1339-1343.
10.1021/jo035778s CCC: $27.50 © 2004 American Chemical Society
Published on Web 03/06/2004
J . Org. Chem. 2004, 69, 2461-2468
2461

Vyvyan et al.
aromatic bisabolenes include (-)-curcuhydroquinone (8),7
(-)-curcuquinone (9),7 and glandulone A (10).12 It is
interesting to note that both enantiomers of curcuphenol
are naturally occurring: (-)-curcuphenol (3) is produced
by terrestrial plants and soft corals and (+)-curcuphenol
(ent-3) is isolated from marine sponges.7,10,13 (-)-Cur-
cuphenol (3) has antibiotic activity,7a while (+)-curcuphen-
ol (ent-3) exhibits cytotoxicity against murine and human
tumors7c,14 and inhibits H,K-ATPase.7b Xanthorrhizol (4)
and its derivatives display antifungal and antitumor
properties as well as inhibition of COX-2.8
SCHEME 1
logues. More specifically, we desired an approach that
would permit the use of a common aromatic unit that
could be coupled to varying side chains to allow the
preparation of the heliannuols and related compounds
in a divergent manner. Thus, we envisioned two distinct
ways to assemble the bisabolene skeleton by attaching
the 6-methyl-5-heptenyl side chain to the aromatic core
via Pd-catalyzed couplings of organozinc reagents (Scheme
1).19 The first involved the attachment of secondary
organozinc halide 14 to aryl bromide 15. The second
strategy utilized coupling alkenyl triflate 16 to arylzinc
halide 17.20 Herein we report our results from both types
of couplings and elaboration of the products thus obtained
to produce natural products 2, 3, 8-10, and 13. We also
report an improved preparation of 29, a key intermediate
in the synthesis of heliannuol D (12).15a
Resu lts a n d Discu ssion
We first examined the reactions of secondary alkylzinc
reagents 14 because it provided the most direct route to
the desired bisabolene skeleton via formation of an sp2-
sp3 C-C bond. The alkylzinc reagents employed in the
first part of the study were prepared by reaction of the
corresponding halides 18 with Rieke zinc in tetrahydro-
furan (Scheme 2). The bromide 18a generally gave a
cleaner conversion to the organozinc reagent 14a as
determined by GC analysis. Iodide 18b produced a
significant amount of 2,6,7,11-tetramethyl-2,10-dodeca-
We became interested in the preparation of function-
alized aromatic bisabolenes as part of our continuing
program targeting the total synthesis of the helian-
nuols.15 Exemplified by heliannuols A and D (11 and 12,
respectively), the heliannuols are a novel family of twelve
allelochemicals16 isolated from the sunflower Helianthus
annuus.17 The unusual benzoxocane and benzoxepane
structures of the heliannuols have attracted significant
attention from synthetic chemists.15,18 The biosynthesis
of the heliannuols is thought to involve 8 or 9 as an
intermediate.17b,e
(17) (a) Mac´ıas, F. A.; Varela, R. M.; Torres, A.; Molinillo, J . M. G.;
Fronczek, F. R. Tetrahedron Lett. 1993, 34, 1999-2002. (b) Mac´ıas, F.
A.; Molinillo, J . M. G.; Varela, R. M.; Torres, A.; Fronczek, F. R. J .
Org. Chem. 1994, 59, 8261-8266. (c) Mac´ıas, F. A.; Varela, R. M.;
Torres, A.; Molinillo, J . M. G. Tetrahedron Lett. 1999, 40, 4725-4728.
(d) Mac´ıas, F. A.; Varela, R. M.; Torres, A.; Molinillo, J . M. G. J . Nat.
Prod. 1999, 62, 1636-1639. (e) Mac´ıas, F. A.; Varela, R. M.; Torres,
A.; Molinillo, J . M. G. J . Chem. Ecol. 2000, 26, 2173-2185. (f) Mac´ıas,
F. A.; Torres, A.; Galindo, J . L. G.; Varela, R. M.; AÄ lvarez, J . A.;
Molinillo, J . M. G. Phytochemistry 2002, 61, 687-692.
(18) (a) Takabatake, K.; Nishi, I.; Shindo, M.; Shishido, K. J . Chem.
Soc., Perkin Trans. 1 2000, 1807-1808. (b) Sato, K.; Yoshimura, T.;
Shindo, M.; Shishido, K. J . Org. Chem. 2001, 66, 309-314. (c) Tuhina,
K.; Bhowmik, D. R.; Venkateswaran, R. V. Chem. Commun. 2002, 634-
635. (d) Kishkuku, H.; Shindo, M.; Shishido, K. Chem. Commun. 2003,
350-351. (e) Doi, F.; Ogamino, T.; Sugai, T.; Nishiyama, S. Synlett
2003, 411-413. (f) Doi, F.; Ogamino, T.; Sugai, T.; Nishiyama, S.
Tetrahedron Lett. 2003, 44, 4877-4880. (g) Mac´ıas, F. A.; Chinchilla,
D.; Molinillo, J . M. G.; Marin, D.; Varela, R. M.; Torres, A. Tetrahedron
2003, 59, 1679-1683. (h) Kamei, T.; Shindo, M.; Shishido, K. Tetra-
hedron Lett. 2003, 44, 8505-8507.
We sought short, efficient methods for preparing the
aromatic bisabolene skeleton that would be useful in the
synthesis of the heliannuols as well as unnatural ana-
(12) Spring, O.; Rodon, U.; Mac´ıas, F. A. Phytochemistry 1992, 31,
1541-1544.
(13) Harrison, B.; Crews, P. J . Org. Chem. 1997, 62, 2646-2648.
(14) Chen, C.-Y.; Shen, Y.-C.; Chen, Y.-J .; Sheu, J .-H.; Duh, C.-Y.
J . Nat. Prod. 1999, 62, 573-576.
(15) (a) Vyvyan, J . R.; Looper, R. E. Tetrahedron Lett. 2000, 41,
1151-1154. (b) J . R. Vyvyan; R. E. Looper; S. T. Staben, Division of
Organic Chemistry Proceedings, 225th National ACS Meeting, March
23-27, 2003, New Orleans, LA. ORGN659. (c) J . R. Vyvyan; J . M.
Oaksmith; B. W. Parks, Division of Organic Chemistry Proceedings,
223rd National ACS Meeting, April 7-11, 2002, Orlando, FL. ORGN435.
(16) Vyvyan, J . R. Tetrahedron 2002, 58, 1631-1646.
(19) (a) Knochel, P.; Millot, N.; Rodriguez, A. L.; Tucker, C. E. Org.
React. 2001, 58, 417-732. (b) Negishi, E.-I. In Organozinc Reagents:
A Practical Approach; Knochel, P., J ones, P. Eds.; Oxford: New York,
1999; Chapter 11. (c) Erdik, E. Organozinc Reagents in Organic
Synthesis; CRC Press: Boca Raton, 1996; pp 274-344.
(20) McCague, R. Tetrahedron Lett. 1987, 28, 701-702.
2462 J . Org. Chem., Vol. 69, No. 7, 2004

Aromatic Bisabolenes via Organozinc Cross-Couplings
TABLE 1. Olefin Cr oss Meta th esis of 20a w ith
Meth a cr olein
SCHEME 2
yield (%)a
equiv
of 22
equiv
of 23
temp
(°C)
time
(h)
entry
21
24
1
2
3
1.0
5.0
1.2
0.02
0.02
0.02
41
41
23
19
18
18
52
25
3
0
32
37b
a
b
Isolated yield of purified material. 62% recovered 20a .
stoichiometric oxidant25 improved the yield of crude
product considerably but gave a mixture of 10 and the
corresponding allylic alcohol in a 3:1 ratio as determined
by 1H NMR analysis. The crude product was oxidized
directly with PDC to yield (()-glandulone A (10) in 41%
yield for the two steps after chromatographic purification.
The IR, UV-vis, and 1H and 13C NMR spectra of our
synthetic 10 matched the data reported for natural
glandulone A.12
In an attempt to improve the overall yield of 10, we
reversed the order of the allylic oxidation and the
conversion to the quinone. Dimethyl ether 20a was
oxidized with SeO2 to produce the corresponding (E)-R,â-
unsaturated aldehyde 21 in modest yield, and the sub-
sequent oxidation of 21 with ceric ammonium nitrate
produced 10 in excellent yield (Scheme 2). Still frustrated
by the low yield of 21 via the SeO2 oxidation, however,
we examined the olefin cross metathesis of 20a with
methacrolein (22) using Grubbs’ second generation cata-
lyst (23). Using the reported conditions,26 21 was pro-
duced along with the corresponding Z-isomer 24 in a 2:1
ratio (Table 1, entry 1). Using excess 22 at reflux resulted
in a higher E:Z product ratio (entry 2). Running the cross
metathesis at room temperature resulted in exclusive
formation of E-isomer 21, but at the expense of overall
conversion (entry 3). Attempts to perform the olefin cross
metathesis reaction on quinone 9 were unsuccessful.
Thus the first synthesis of (()-glandulone A (10) was
accomplished in three steps from 18 (via 21) in 41%
overall yield.
diene21 during the reaction with activated zinc, thereby
reducing the amount of 14b available for subsequent
coupling. The alkylzinc halides 14 were coupled to aryl
bromides 19a and 19b using Pd(dppf)Cl2 as catalyst to
produce aromatic bisabolenes 20a and 20b in good yield
(Scheme 2). In both cases use of alkylzinc reagent 14b
instead of 14a resulted in a slightly lower yield (8% on
average) of 20 from the coupling reaction.
Despite reports to the contrary,22 cleavage of the
methyl ethers in 20a with boron tribromide was unsuc-
cessful in our hands, yielding a mixture of mono-depro-
tected compounds and side products arising from Friedel-
Crafts-type alkylation of the trisubstituted olefin of the
side chain.2a,i,23 Methoxymethyl protected 20b, on the
other hand, was easily deprotected under acidic condi-
tions to provide (()-curcuhydroquinone (8) in excellent
yield. Hydroquinone 8 was prone to air oxidation, how-
ever, leading us to convert both 20a and 20b to (()-
curcuquinone (9) through oxidative deprotection with
ceric ammonium nitrate (CAN)24 (Scheme 2). Allylic
oxidation of 9 to install the R,â-unsaturated aldehyde of
glandulone A (10) proved somewhat problematic. Reac-
tion of 9 with a stoichiometric amount of selenium dioxide
gave very low yields (12-15%) of 10. Use of catalytic
amounts of SeO2 with tert-butylhydroperoxide as the
Although the secondary alkylzinc route to functional-
ized aromatic bisabolenes described above was successful,
preparing large quantities of the alkylzinc reagents 14
presented some difficulties, including variation in the
reactivity of the Rieke zinc from batch to batch and
removal of the naphthalene used in the preparation of
the Rieke zinc.27
(21) Characterization data for 2,6,7,11-tetramethyl-2,10-dodecadiene
(mixture of diastereomers). IR (neat, NaCl plates): 1642, 1454, 1378,
908, and 735 cm-1 1H NMR (CDCl3, 300 MHz): δ 5.10 (m, 2H), 1.95
.
(m, 4H), 1.68 (br s, 6H), 1.60 (br s, 6H), 1.5-0.9 (overlapping m, 6H),
0.82 (d, J ) 6.5, 3H), and 0.76 (d, J ) 6.5, 3H). 13C NMR (CDCl3, 75
MHz): δ 131.0, 125.1, 125.09, 37.1, 36.2, 35.0, 33.0, 31.6, 26.2, 26.1,
25.7, 17.6, 16.3, and 14.3. LRMS (EI): m/z (rel int) 222 (5, M+), 137
(5), 123 (5), 109 (60), 95 (20), 82 (95), 69(95), 55 (50), and 41 (100).
(22) Sa´nchez, I. H.; Lemini, C.; J oseph-Nathan, P. J . Org. Chem.
1981, 46, 4666-4667.
We then turned our attention to the palladium-
catalyzed coupling of arylzinc species (cf. 17) to alkenyl
triflate 16.28 We optimized the coupling reaction condi-
tions using commercially available 4-methylphenylzinc
(23) Feutrill, G. I.; Mirrington, R. N. Aust. J . Chem. 1972, 25, 1719-
(25) Umbreit, M. A.; Sharpless, K. B. J . Am. Chem. Soc. 1977, 99,
1729.
5526-5528.
(24) J acob, P., III; Callery, P. S.; Shulgin, A. T.; Castagnoli, N. J .
Org. Chem. 1976, 41, 3627-3629.
(26) Chatterjee, A. K.; Grubbs, R. H. Angew. Chem., Int. Ed. 2002,
41, 3172-3174.
J . Org. Chem, Vol. 69, No. 7, 2004 2463

Vyvyan et al.
TABLE 2. P a lla d iu m -Ca ta lyzed Cou p lin gs of Ar ylzin c
Ha lid es w ith Alk en yl Tr ifla te 16
SCHEME 3
2-methoxymethoxy-4-methylphenylzinc reagents all re-
acted with triflate 16 under the optimized conditions to
produce cross-coupled products 25-28, respectively, in
moderate to good yields (Table 2, entries 5-8). This
coupling strategy was also employed in the preparation
of benzyl ether 29 in an impressive 94% yield (entry 9),
considerably higher than was achieved previously in our
synthesis of (()-heliannuol D (12).15
The arylzinc reagent required for the synthesis of 29
was prepared from 4-bromo-2-methylanisole (30) (Scheme
3).15 Bromide 30 was converted to the aryllithium species
followed by reaction with triisopropylborate and oxidation
of the resulting boronate ester with tert-butylhydroper-
oxide, which gave 3-methyl-4-methoxyphenol (31) in
nearly quantitative yield. We have found the use of tert-
butylhydroperoxide in aqueous ammonium chloride solu-
tion for this transformation to be superior to acidic
hydrogen peroxide in some cases.30 Phenol 31 was then
brominated at the less-hindered ortho position and
protected as the benzyl ether to provide 33. Lithium-
halogen exchange on 33 with tert-butyllithium followed
by transmetalation with zinc chloride provided the aryl-
zinc species for the cross-coupling with triflate 16 to yield
29 (Table 2, entry 9).
a
4-Methylphenylzinc iodide (entries 1-4), phenylzinc iodide
(entry 5), and 2-methoxyphenylzinc bromide (entry 6) were
purchased from Aldrich as 0.5 M solutions in THF. 2-Benzylox-
yphenylzinc bromide (entry 7), 2-methoxymethoxy-4-methylphenyl
zinc chloride (entry 8), and 2-benzyloxy-4-methoxy-3-methylphe-
nylzinc halide (entry 9) were prepared by reaction of the corre-
sponding aryl bromide (entries 7 and 9) or arene (entry 8) with
tert-butyllithium followed by transmetalation with zinc chloride
The conjugated olefin in dienes such as 2 and 25-29
can be selectively reduced using lithium or sodium in
liquid ammonia.7a,22 We have found it more efficient and
convenient, however, to submit the crude product mixture
from the cross-coupling reaction directly to the dissolving
metal reduction rather than purify and characterize the
dienes. This process is illustrated with syntheses of
curcuphenol (3) and elvirol (13) (Scheme 4). Directed
metalation of MOM-protected m-cresol 34,31,32 trans-
metalation with zinc chloride, palladium-catalyzed coup-
ling of the arylzinc species to triflate 16, and dissolving
metal reduction of the crude coupling product provided
35 in 91% overall yield. Hydrolysis of the methoxymethyl
ether group gave (()-curcuphenol (3) in excellent yield.
Aryl bromide 36 was subjected to a similar sequence of
reactions to produce (()-elvirol (13) in 86% overall yield.
b
(see Experimental Section). Isolated yield.
iodide as a test substrate to produce dehydro-R-cur-
cumene (2) (Table 2, entries 1-4). Higher yields of 2 were
obtained when 16 was used in slight excess (compare
entry 1 to entry 4 and entry 2 to entry 3). Reducing the
amount of palladium catalyst to 5 mol % lowered product
yield only slightly (compare entries 3 and 4). Use of the
nonaflate29 corresponding to 16 in the cross-coupling
reaction resulted in a shorter reaction time but a com-
parable isolated yield of the cross-coupled product. Phen-
ylzinc, 2-methoxyphenylzinc, 2-benzyloxyphenylzinc and
(27) It is also possible to prepare Rieke zinc with substoichiometric
amounts of naphthalene as electron carrier: Rieke, R. D.; Hanson, M.
V. In Organozinc Reagents: A Practical Approach; Knochel, P., J ones,
P. Eds.; Oxford: New York, 1999; Chapter 2. Since this portion of the
work was completed, highly active Rieke zinc has become commercially
available.
(28) (a) Kamikubo, T.; Ogasawara, K. Chem. Commun. 1996, 1679-
1680. (b) Miller, M. W.; J ohnson, C. R. J . Org. Chem. 1997, 62, 1582-
1583. (c) Graham, A. E.; Taylor, R. J . K. J . Chem. Soc., Perkin Trans.
1 1997, 1087-1089.
(29) (a) Ritter, K. Synthesis 1993, 735-762. (b) Zimmer, R.; Webel,
M.; Reissig, H.-U. J . Prakt. Chem. 1998, 340, 274-277. (c) Cleve, A.;
Fritzmeier, K.-H.; Heinrich, N.; Klar, U.; Mu¨ller-Fahrnow, A.; Neef,
G.; Ottow, E.; Schwede, W. Tetrahedron 1996, 52, 1529-1542.
(30) (a) Hawthorne, M. F. J . Org. Chem. 1957, 22, 1001. (b) Simon,
J .; Salzbrunn, S.; Surya Prakash, G. K.; Petasis, N. A.; Olah, G. A. J .
Org. Chem. 2001, 66, 633-634.
(31) Snieckus, V. Chem. Rev. 1990, 90, 879-933.
(32) Ronald, R. C.; Winkle, M. R. Tetrahedron 1983, 39, 2031-2042.
2464 J . Org. Chem., Vol. 69, No. 7, 2004

Aromatic Bisabolenes via Organozinc Cross-Couplings
give 20a as a colorless oil (1.70 g, 81%). Rf ) 0.2 in 30:1
hexanes/ethyl acetate. IR (neat, NaCl plates): 1652, 1466,
1207, 1049, and 860 cm-1. 1H NMR (CDCl3, 300 MHz): δ 6.68
(s, 1H), 6.67 (s, 1H), 5.12 (t septets, J ) 7.1, 1.3, 1H), 3.78 (s,
3H), 3.76 (s, 3H), 3.14 (sextet, J ) 7.1, 1H), 2.20 (s, 3H), 1.91
(m, 2H), 1.66 (br s, 3H), 1.70-1.49 (m, 2H), 1.54 (br s, 3H),
and 1.18 (d, J ) 7.0, 3H). 13C NMR (CDCl3, 75 MHz): δ 151.8,
150.8, 133.9, 131.1, 124.8, 124.1, 114.3, 109.7, 56.3, 56.1, 37.3,
31.8, 26.3, 25.7, 21.2, 17.6, and 16.0. LRMS (EI): m/z (rel int)
262 (81, M+), 192 (14), 180 (34), and 170 (100).
SCHEME 4
2,5-Bis(m eth oxym eth oxy)-4-(1,5-d im eth ylh ex-4-en yl)-
tolu en e (20b).2i,34 Following the procedure used above for the
preparation of 20a , bromide 18a (2.87 g, 15.0 mmol), aryl
bromide 19b (2.33 g, 8.00 mmol), and Pd(dppf)Cl2 (0.65 g, 0.80
mmol, 10 mol %) yielded 20b as a colorless oil (2.04 g, 79%)
after purification by MPLC (12:1 hexanes/ethyl acetate). Rf )
0.3 in 19:1 hexanes/ethyl acetate. IR (neat, NaCl plates): 1503,
1
1450, 1185, 1148, 1080, and 1012 cm-1. H NMR (CDCl3, 300
MHz): δ 6.93 (s, 2H), 5.16 (obscured m, 1H) 5.16 (s, 2H), 5.14
(s, 2H) 3.53 (s, 6H), 3.21 (sextet, J ) 7.1, 1H), 2.26 (s, 3H),
1.97 (m, 2H), 1.71 (br s, 3H), 1.75-1.55 (m, 2H), 1.58 (br s,
3H), and 1.24 (d, J ) 7.0, 3H). 13C NMR (CDCl3, 75 MHz): δ
150.7, 149.6, 135.1, 131.2, 125.6, 124.9, 117.5, 113.8, 95.6, 95.4,
56.0, 56.0, 37.4, 32.0, 26.4, 25.8, 21.4, 17.7, and 16.3. LRMS
(EI): m/z (rel int) 322 (14, M+), 195 (37), 151 (13), and 45 (100).
Gla n d u lon e A (10) via SeO2 Oxid a tion of Cu r cu qu in -
on e (9). tert-Butylhydroperoxide (90% solution, 0.35 mL, 3.6
equiv) was added to a solution of 9 (200 mg, 0.861 mmol), SeO2
(10 mg, 0.086 mmol), and salicylic acid (12 mg, 0.086 mmol)
in CH2Cl2 (20 mL). The mixture was refluxed for 2.5 h and
then diluted with CHCl3. The solution was washed (Na2CO3,
brine), dried (Na2SO4), and concentrated. The residue was then
dissolved in CH2Cl2 (20 mL), pyridinium dichromate (324 mg,
0.861 mmol) was added, and the mixture was stirred for 2 h.
Con clu sion s
The assembly of the aromatic bisabolene skeleton was
accomplished using two complementary strategies in-
volving the cross-coupling of organozinc derivatives.
Secondary alkylzinc halides 14 react with aryl bromides
19 using Pd(dppf)Cl2 as catalyst to produce the cross-
coupled product 20 in good yield. The side chain of
bisabolene derivative 20 was elaborated through sele-
nium dioxide oxidation and alkene cross metathesis to
yield (()-glandulone A (10) in high overall yield via the
natural products (()-curcuhydroquinone (8) and (()-
curcuquinone (9). Arylzinc halides react with alkenyl
triflate 16 using Pd(PPh3)4 as catalyst to produce cross-
coupled products in good to excellent yields. These
styrene derivatives may be purified and characterized or
subjected to dissolving metal reduction to saturate the
conjugated olefin in the side chain. The natural products
(()-curcuphenol (3) and (()-elvirol (13) were prepared
by the latter protocol.
The mixture was then passed through
a plug of silica,
concentrated, and purified by radial chromatography (12:1
hexanes/ethyl acetate) to yield 10 (87 mg, 41%) as a yellow
oil.
Via CAN Oxid a tion of Ald eh yd e 21. A solution of ceric
ammonium nitrate (1.10 g, 2.00 mmol dissolved in 5 mL water)
was added dropwise to a solution of aldehyde 21 (276 mg, 1.00
mmol) in acetonitrile (5 mL). After the addition was complete,
the mixture was stirred an additional 5 min before transferring
the solution to a separatory funnel. The solution was extracted
with CH2Cl2, and the organic phase was dried over Na2SO4.
Solvent removal yielded spectroscopically pure 10 (224 mg,
91%) as a yellow oil. Rf ) 0.42 in 6:1 hexanes/ethyl acetate.
UV-vis: λmax 232 nm (log ꢀ ) 4.53), 252, and 262 (sh). IR (neat,
NaCl plates): 2922, 2852, 2710, 1719, 1682, 1650, and 1611
Exp er im en ta l Section 33
4-(1,5-Dim eth yl-4-h exen yl)-2,5-dim eth oxytolu en e (20a).22
A 50-mL centrifuge tube was charged with naphthalene (7.69
g, 60.0 mmol) and lithium wire (0.42 g, 60 mmol) that was
hammered flat and rinsed free of mineral oil in hexanes. After
an argon atmosphere was established, THF (5 mL) was added,
and a dark green color was established. After disappearance
of the Li (approx 2 h), ZnCl2 (1.0 M in ether, 30 mL, 30 mmol)
was slowly added. The mixture was then stirred for 1 h and
centrifuged. The supernatant was withdrawn via syringe, and
a fresh portion of dry THF (10 mL) was added. The mixture
was stirred for 10 min and centrifuged, and the supernatant
was withdrawn. Bromide 18a (2.87 g, 15.0 mmol) in THF (10
mL) was added to the zinc particulate, and the mixture was
stirred overnight. The zinc insertion was checked by GC
analysis,27 which showed disappearance of the halide and
appearance of the corresponding alkane. When the halide was
consumed, the solution was transferred via cannula to a flask
containing a solution of 19a (1.86 g, 8.00 mmol) and Pd(dppf)-
Cl2 (0.65 g, 0.80 mmol, 10 mol %) in THF (20 mL). The mixture
was heated to reflux, and after 24 h the mixture was cooled,
diluted with ether (100 mL), washed (10% HCl, sat. NaHCO3,
brine), and dried (MgSO4). After solvent removal, the resulting
residue was purified by MPLC (19:1 hexanes/ethyl acetate) to
1
cm-1. H NMR (CDCl3, 300 MHz): δ 9.40 (s, 1H), 6.61 (q, J )
1.5, 1H), 6.54 (d, J ) 0.9, 1H), 6.45 (app. tq, J ) 7.3, 1.3, 1H),
2.97 (sextet, J ) 6.8, 1H), 2.34 (app qd, J ) 7.3, 1.1, 2H), 2.05
(d, J ) 1.5, 3H), 1.8-1.5 (m, 2H), 1.72 (d, J ) 1.1, 3H), and
1.18 (d, J ) 6.8, 3H). 13C NMR (CDCl3, 75 MHz): δ 195.1,
188.2, 187.2, 153.3, 153.1, 145.4, 139.8, 133.7, 131.4, 34.4, 31.3,
26.8, 19.1, 15.4, and 9.2. Anal. Calcd for C15 H18O3: C, 73.15;
H, 7.37. Found: C, 72.83; H, 7.17.
(E)-6-(2,5-Dim eth oxy-4-m eth ylp h en yl)-2-m eth yl-2-h ep -
ten a l (21) a n d (Z)-6-(2,5-Dim eth oxy-4-m eth ylp h en yl)-2-
m eth yl-2-h ep ten a l (24) via Cr oss Meta th esis of 20a .
Grubbs’ catalyst 23 (25 mg, 0.03 mmol, 2 mol %) was placed
in a 25-mL two-necked flask fitted with a condenser under
argon. Dry CH2Cl2 (5 mL) was added, followed by 20a (394
mg, 1.50 mmol) and freshly distilled methacrolein (105 mg,
1.50 mmol). The mixture was refluxed overnight, concentrated
on a rotary evaporator, and passed through a small silica plug
(12:1 hexanes/ethyl acetate). The filtrate was concentrated and
purified by MPLC (19:1 hexanes/ethyl acetate) to yield 21 (218
mg, 52%) and 24 (103 mg, 25%) as yellow oils. Da ta for 21.
(33) General experimental procedures may be found in Supporting
Information.
(34) Ono, M.; Yamamoto, Y.; Todoriki, R.; Akita, H. Heterocycles
1994, 37, 181-185.
J . Org. Chem, Vol. 69, No. 7, 2004 2465

Vyvyan et al.
IR (neat, NaCl plates): 2830, 2710, 1685, 1642, 1505, 1466,
1H), 7.12 (dd, J ) 7.4, 1.8, 1H), 6.90 (td, J ) 7.4, 1.0, 1H),
6.86 (br d, J ) 8.0, 1H), 5.12 (overlapping m, 2H), 5.00 (d, J )
2.0, 1H), 3.81 (s, 3H), 2.49 (t, J ) 7.4, 2H), 2.03 [br dt (app q),
J ) 7.3, 2H], 1.66 (br s, 3H), and 1.53 (br s, 3H). 13C NMR
(CDCl3, 75 MHz): δ 156.5, 149.0, 132.1, 131.4, 130.2, 128.2,
124.2, 120.4, 114.0, 110.5, 55.4, 36.3, 26.8, 25.7, and 17.6. Anal.
Calcd for C15 H20O: C, 83.29; H, 9.32. Found: C, 83.13; H,
9.53.
1
1400, 1209, 1049 and 861 cm-1. H NMR (CDCl3, 300 MHz):
δ 9.35 (s, 1H), 6.68 (s, 1H), 6.65 (s, 1H), 6.47 (app td, J ) 7.3,
1.5, 1H), 3.79 (s, 3H), 3.75 (s, 3H), 3.19 (sextet, J ) 6.8, 1H),
2.27 (m, 2H), 2.21 (s, 3H), 1.77 (m, 2H), 1.66 (br s, 3H), and
1.23 (d, J ) 6.8, 3H). 13C NMR (CDCl3, 75 MHz): δ 195.4,
155.3, 151.8, 150.8, 139.1, 132.4, 124.8, 114.1, 109.7, 56.2, 56.1,
35.8, 31.9, 27.3, 21.1, 16.1 and 9.1. LRMS (EI): m/z (rel int)
276 (45, M+), 192 (15), and 179 (100). Anal. Calcd for C17
H24O3: C, 73.88; H, 8.75. Found: C, 73.85; H, 9.04. Da ta for
24. IR (neat, NaCl plates): 2852, 1676, 1503, 1208, and 1047
cm-1. 1H NMR (CDCl3, 300 MHz): δ 9.90 (s, 1H), 6.66 (s, 1H),
6.61 (s, 1H), 6.47 (app tq, J ) 8.2, 1.5, 1H), 3.78 (s, 3H), 3.72
(s, 3H), 3.19 (sextet, J ) 6.7, 1H), 2.40 (m, 2H), 2.20 (s, 3H),
1.75 (m, 2H), 1.72 (q, J ) 1.2, 3H), and 1.22 (d, J ) 7.0, 3H).
13C NMR (CDCl3, 75 MHz): δ 191.3, 151.9, 150.7, 150.0, 135.8,
132.2, 124.8, 114.1, 109.6, 56.2, 56.1, 37.2, 31.6, 25.0, 21.4, 16.4
and 16.1. Anal. Calcd for C17 H24O3: C, 73.88; H, 8.75. Found:
C, 73.68; H, 8.71.
(E)-6-(2,5-Dim eth oxy-4-m eth ylp h en yl)-2-m eth yl-2-h ep -
ten a l (21) via SeO2 Oxid a tion of 20a . A mixture of alkene
20a (122 mg, 0.465 mmol) and SeO2 (102 mg, 0.919 mmol) in
ethanol (25 mL) was heated to reflux for 2 days. At that time
a small amount of NaHSO3 was added, and the solvent was
removed by evaporation. The residue was dissolved in CH2-
Cl2, washed with 10% HCl and brine, dried over Na2SO4, and
concentrated. Purification by radial chromatography (9:1 hex-
anes/ethyl acetate) gave 21 (70 mg, 55%) as a yellow oil.
Gen er a l P r oced u r e for Rea ction of Ar ylzin c Rea gen ts
w ith Alk en yl Tr ifla te 16. 4-(5-Meth yl-1-m eth ylen e-4-
h exen yl)tolu en e (d eh yd r o-R-cu r cu m en e) (2, Ta ble 2,
en tr y 4).35 Triflate 16 (0.515 g, 1.99 mmol) was added to a
mixture of Pd(PPh3)4 (0.118 g, 0.102 mmol, 10 mol %) in THF
(20 mL) under argon. 4-Methylphenylzinc iodide (2.0 mL, 0.5
M in THF, 1.0 mmol) was added, and the solution was heated
at reflux for 6 h. The solution was then cooled and partitioned
between hexanes and water. The layers were separated, and
the aqueous phase was extracted with ether. The combined
organic layers were washed (3 M NaOH, brine), dried (Na2-
SO4), and concentrated. Radial chromatography (hexanes)
provided 2 (0.172 g, 86%) as a pale yellow oil. 1H NMR (CDCl3,
300 MHz): δ 7.31 (app d, J ) 8.0, 1H), 7.13 (app d, J ) 8.0,
1H), 5.25 (d, J ) 1.4, 1H), 5.12 (t septets, J ) 7.0, 1.4, 1H),
5.01 (br q, J ) 1.4, 1H), 2.50 (t, J ) 7.5, 2H), 2.35 (s, 3H), 2.13
[br dt (app q), J ) 7.5, 2H], 1.67 (br s, 3H), and 1.55 (br s,
3H). 13C NMR (CDCl3, 75 MHz): δ 148.1, 138.3, 136.9, 131.7,
128.9, 125.9, 123.9, 111.4, 35.4, 27.0, 25.7, 21.1, and 17.7.
6-Meth yl-2-p h en yl-1,5-h ep ta d ien e (25).36 The general
procedure for the preparation of 2 was followed. Triflate 16
(0.777 g, 3.01 mmol), Pd(PPh3)4 (0.120 g, 0.104 mmol, 5 mol
%) and phenylzinc iodide (4.0 mL, 0.5 M in THF, 2.0 mmol)
yielded 25 (0.252 g, 68%) as a pale yellow oil after purification
by radial chromatography. 1H NMR (CDCl3, 300 MHz): δ 7.5-
7.2 (m, 5H), 5.28 (d, J ) 1.4, 1H), 5.12 (m, 1H), 5.06 (q, J )
1.4, 1H), 2.52 (t, J ) 7.5, 2H), 2.13 [br dt (app q), J ) 7.3, 2H],
1.68 (br s, 3H), and 1.55 (br s, 3H). 13C NMR (CDCl3, 75
MHz): δ 148.3, 141.3, 131.8, 128.2, 127.2, 126.1, 123.8, 112.2,
35.4, 26.9, 25.7, and 17.7.
1-Ben zyloxy-2-(5-m eth yl-1-m eth ylen e-4-h exen yl)-ben -
zen e (27). 2-Benzyloxyphenylzinc bromide was prepared by
adding an ethereal solution of benzyl 2-bromophenyl ether37
(1.43 g, 5.43 mmol) to a cold (-78 °C) solution of t-BuLi (7.0
mL, 1.7 M in pentane, 11.9 mmol) in ether (5 mL). The solution
was warmed to 0 °C over 1 h and then recooled to -78 °C. A
solution of anhydrous ZnCl2 (5.7 mL, 1.0 M in THF, 5.7 mmol)
was added, and the resulting solution was stirred 1 h as it
warmed to room temperature. In a separate flask, triflate 16
(2.47 g, 9.55 mmol) was added to a mixture of Pd(PPh3)4 (0.356
g, 0.308 mmol) in THF (25 mL). The arylzinc reagent prepared
above was then cannulated into this flask and the mixture
heated to reflux for 2 h, stirred overnight at room temperature,
and heated to reflux again for 5 h. The reaction mixture was
partitioned between hexanes and 10% HCl solution. The layers
were separated, and the aqueous phase was extracted with
hexanes three times. The combined organic layers were
washed with water and brine, dried over Na2SO4, and con-
centrated. Purification by radial chromatography (gradient
elution, hexanes to 12:1 hexanes/ethyl acetate) gave 27 (1.00
g, 63%) as a colorless oil. IR (neat, NaCl plates): 3069, 3030,
1627, 1596, 1578, 1488, 1232, 1020, 899, 749, and 694 cm-1
.
1H NMR (CDCl3, 300 MHz): δ 7.38 (m, 5H), 7.18 (m, 2H), 6.91
(br t, J ) 7.5, 2H), 6.86 (br d, J ) 8.0, 1H), 5.14 (m, 1H), 5.08
(s, 2H), 5.04 (d, J ) 2.0, 1H), 2.53 (t, J ) 7.5, 2H), 2.03 [br dt
(app q), J ) 7.5, 2H], 1.64 (d, J ) 1.0, 3H), and 1.50 (br s, 3H).
13C NMR (CDCl3, 75 MHz): δ 155.6, 148.7, 137.3, 132.6, 131.4,
130.3, 129.5, 128.4, 127.7, 127.1, 124.2, 120.8, 114.2, 112.3,
70.2, 36.4, 26.8, 25.7, and 17.6. Anal. Calcd for C21 H24O: C,
86.26; H, 8.27. Found: C, 86.12; H, 8.38.
2-Meth oxym eth oxy-4-m eth yl-1-(5-m eth yl-1-m eth ylen e-
4-h exen yl)-ben zen e (28). The procedure used for the prepa-
ration of 2 was followed. The arylzinc reagent was prepared
from methoxymethyl ether 3432 (0.832 g, 5.46 mmol), t-BuLi
(3.53 mL, 1.7 M in pentane, 6.00 mmol), and anhydrous ZnCl2
(0.774 g, 5.46 mmol dissolved in dry THF). The resulting
solution was added to a mixture of triflate 16 (2.25 g, 8.19
mmol) and Pd(PPh3)4 (0.314 g, 0.273 mmol, 5 mol %) in THF
(30 mL). The mixture was heated to reflux for 2 h and worked
up as described above to give 28 (1.28 g, 90%) as a colorless
oil after flash chromatography (50:1 hexanes/ethyl acetate).
IR (neat, NaCl plates): 3069, 3030, 1611, 1569, 1503, 1154,
1073, 1016, 926, 898, and 818 cm-1 1H NMR (CDCl3, 300
.
MHz): δ 7.00 (d, J ) 7.6, 1H), 6.98 (br s, 1H), 6.76 (br d, J )
7.6, 1H), 5.15 (s, 2H), 5.11 (m, 1H), 5.08 (m, 1H), 4.98 (d, J )
2.0, 1H), 3.47 (s, 3H), 2.48 (t, J ) 8.0, 2H), 2.33 (s, 3H), 2.03
[br dt (app q), J ) 7.5, 2H], 1.66 (br s, 3H), and 1.53 (br s,
3H). 13C NMR (CDCl3, 75 MHz): δ 154.2, 148.8, 138.5, 131.6,
130.3, 130.2, 124.5, 122.7, 115.6, 114.2, 94.8, 56.4, 37.1, 27.3,
26.1, 21.8, and 18.1. LRMS (EI): m/z (rel int) 260 (5, M+), 217
(65), 185 (53), 173 (16), 159 (30), 145 (45), 69 (43), and 45 (100).
Anal. Calcd for C17H24O2: C, 78.42; H, 9.29. Found: C, 78.05;
H, 9.61.
4-Ben zyloxy-2-m eth yl-5-(5-m eth yl-1-m eth ylen e-4-h ex-
en yl)a n isole (29). The procedure used for the preparation of
27 was followed. The arylzinc reagent was prepared from
bromide 33 (1.69 g, 5.50 mmol), tert-BuLi (7.0 mL, 1.7 M in
pentane, 11.9 mmol), and anhydrous ZnCl2 (5.5 mL, 1.0 M in
THF, 5.5 mmol). The resulting solution was added to a mixture
of triflate 16 (2.58 g, 10.0 mmol) and Pd(PPh3)4 (0.326 g, 0.282
mmol) in THF (25 mL). The mixture was heated to reflux for
2-(5-Meth yl-1-m eth ylen e-4-h exen yl)a n isole (26). The
general procedure for the preparation of 2 was followed.
Triflate 16 (1.89 g, 7.31 mmol), Pd(PPh3)4 (0.339 g, 0.293
mmol), and 2-methoxyphenylzinc bromide (10.0 mL, 0.5 M in
THF, 5.00 mmol) yielded 26 (0.920 g, 85%) as a colorless oil
after purification by radial chromatography. IR (neat, NaCl
plates): 3074, 1629, 1596, 1576, 1489, 1240, 1029, 897, and
750 cm-1. 1H NMR (CDCl3, 300 MHz): δ 7.24 (td, J ) 8.0, 1.8,
(35) (a) Mori, K. Agric. Biol. Chem. 1972, 36, 503-505. (b) Vig, O.
P.; Bari, S. S.; Sharma, S. D.; Rana, S. S. Indian J . Chem. 1977, 15B,
1076-1077. (c) Bellesia, F.; Ghelfi, F.; Pagnoni, U. M.; Pinetti, A. Gazz.
Chim. Ital. 1992, 122, 437-439.
(36) Khrimayan, A. P.; Makaryan, G. M.; Badanyan, S. O. Arm.
Khim. Zh. 1986, 39, 574-580; Chem. Abstr. 108, 5609.
(37) Dalby, K. N.; Kirby, A. J .; Hollfelder, F. J . Chem. Soc., Perkin
Trans. 2 1993, 1269-1281.
2466 J . Org. Chem., Vol. 69, No. 7, 2004

Aromatic Bisabolenes via Organozinc Cross-Couplings
12 h and worked-up as described above to give 29 (1.75 g, 94%)
as a light brown oil that was spectroscopically pure and used
in subsequent reactions. An analytical sample was prepared
by flash chromatography (19:1 hexanes/ethyl acetate). 1H NMR
(CDCl3, 300 MHz): δ 7.37 (m, 5H), 6.75 (br s, 1H), 6.65 (br s,
1H), 5.13, (d, J ) 2.0, 1H), 5.08 (obscured m, 1H), 5.05 (d, J )
2.0, 1H), 5.00 (s, 2H), 3.80 (s, 3H), 2.53 (t, J ) 7.5, 2H), 2.19
(s, 3H), 2.05 (m, 2H), 1.65 (br s, 3H), and 1.51 (s, 3H). 13C NMR
(CDCl3, 75 MHz): δ 151.8, 149.3, 148.8, 137.6, 131.3, 130.7,
128.4, 127.6, 127.2, 126.0, 124.3, 116.5, 113.9, 112.5, 71.5, 55.9,
36.5, 26.8, 25.7, 17.7, and 16.1. Anal. Calcd for C23H28O2: C,
82.10; H, 8.39. Found: C, 81.84; H, 8.23.
(CDCl3, 75 MHz): δ 152.0, 145.8, 128.1, 117.9, 113.3, 105.8,
56.0, and 16.0. Anal. Calcd for C8H9BrO2: C, 44.27; H, 4.18.
Found: C, 44.27; H, 4.17.
5-Br om o-4-ben zyloxy-2-m eth yla n isole (33). Sodium hy-
dride (60% dispersion in mineral oil, 3.3 g, 0.082 mol hydride)
was washed thrice with hexanes and slurried in dry THF (60
mL). The flask was cooled in an ice bath, and phenol 32 (16.2
g, 0.074 mol) was added via addition funnel as a solution in
THF. Benzyl bromide (9.0 mL, 13 g, 0.076 mol) was then
dissolved in THF (15 mL) and added via addition funnel. When
the addition was complete, the cooling bath was removed. The
mixture was stirred 2 h before dry DMF (25 mL) was added
and the reaction was stirred overnight. The reaction mixture
was quenched by the addition of sat. NH4Cl solution and
diluted with ether. The layers were separated, and the aqueous
layer was extracted with ether. The combined organic layers
were washed with 10% NaOH solution (2×) and sat. LiCl
solution before drying over MgSO4. Solvent removal gave a
light brown oil that was purified by Kugelrohr distillation (bp
170-180 °C at 0.1 mmHg) to yield 33 (22.2 g, 97%) as an oil
that solidified on standing. An analytical sample was recrys-
tallized (mp 43-45 °C) from light petroleum ether. IR (film
deposited from CH2Cl2): 1208, 1028, 852, 789, 730, and 695
4-Meth oxy-3-m eth ylp h en ol (31).38 4-Bromo-2-methylani-
sole (30)39 (20.2 g, 0.100 mol) was charged to a dry 500-mL
three-necked flask equipped with an efficient reflux condenser
and a large magnetic stir bar. The vessel was placed under
argon and dry ether (200 mL) was added via syringe. Lithium
wire (1.62 g, 0.233 mol) was cut into ∼1 cm pieces, hammered
flat, rinsed with hexanes to remove mineral oil, and added to
the reaction flask under a positive flow of argon. The reaction
mixture began to spontaneously reflux. Reflux was maintained
with a heating mantle until the lithium was nearly consumed.
A small (0.7 mL) aliquot was removed via syringe, quenched
with saturated NH4Cl solution, and extracted with ether (2
mL), and the ether layer was passed through a plug of
anhydrous MgSO4. Analysis by GC indicated 97% 2-methyl-
anisole (from protonation of the aryllithium species) and 3%
30. The flask was cooled with a dry ice/2-propanol bath,
triisopropylborate (30 mL, 0.130 mol) was added via syringe,
and the mixture was allowed to warm to room temperature.
A large amount of white solid formed. The reaction mixture
was transferred to a 1-L Erlenmeyer flask with the aid of
additional ether. At this point the remaining pieces of lithium
were carefully removed and quenched with ethanol. tert-
Butylhydroperoxide (90% solution, 15 mL) was added CAU-
TIOUSLY with vigorous stirring, followed by saturated NH4Cl
solution (∼100 mL). Two clear layers formed during this
process. The light brown mixture was transferred to a sepa-
ratory funnel, and the aqueous phase was acidified (pH ∼4)
with 10% HCl. The layers were separated, and the aqueous
phase was extracted with ether (100 mL). The combined ether
layers were washed [sat. NaHSO3, sat. NaHCO3 (CAUTION-
frothing!), and brine] and dried over anhydrous Na2SO4.
Removal of solvent gave 31 (15.9 g, 115% crude mass recovery)
as a light brown oil. The crude phenol was >95% pure by GC
analysis (the main contaminant was tert-butyl alcohol) and
was used without further purification. IR (neat, NaCl plates):
1
cm-1. H NMR (CDCl3, 300 MHz): δ 7.46 (br d, J ) 7.5, 2H),
7.35 (m, 3H), 6.98 (s, 1H), 6.77 (s, 1H), 5.03 (s, 2H), 3.74 (s,
3H), and 2.13 (s, 3H). 13C NMR (CDCl3, 75 MHz): δ 152.6,
148.8, 136.9, 128.4, 127.8, 127.2, 126.7, 117.7, 115.1, 109.3,
72.0, 55.9 and 16.2. Anal. Calcd for C15H15BrO2: C, 58.65; H,
4.92. Found: C, 58.81; H, 5.10.
4-(1,5-Dim et h yl-4-h exen yl)-3-m et h oxym et h oxy-t olu -
en e (35).2f,i,j t-BuLi (2.78 mL, 1.4 M in pentane, 4.00 mmol)
was added over 10 min to a cold (-78 °C) solution of 3432 (609
mg, 4.00 mmol) in THF (10 mL). After 1 h, anhydrous ZnCl2
(4.0 mL, 1.0 M in Et2O, 4.0 mmol) was added, and the mixture
was warmed to room temperature over 0.5 h. The arylzinc
species was then transferred via cannula to a solution of
triflate 16 (516 mg, 1.99 mmol) and Pd(PPh3)4 (115 mg, 0.10
mmol, 5 mol %) in THF (10 mL). The mixture was refluxed
for 24 h, cooled, and diluted with hexanes (100 mL). The
mixture was passed through silica (1 × 0.5 in.) with hexanes
and concentrated to yield crude 28 that was used directly in
the next step.
Ammonia (∼15 mL) was condensed into a two-necked flask
fitted with a dry ice coldfinger condenser and cooled in a dry
ice/i-PrOH bath. Dry ether (10 mL) was then added followed
by lithium wire (42 mg, 6.0 mmol) cut into small pieces. A dark
blue color was established, and the crude 28 prepared above
was added as a solution in ether (2 mL). The mixture was
stirred for 0.5 h before NH4Cl (1.5 g) was added in small
portions to discharge the blue color. The ammonia was allowed
to evaporate, and the residue was diluted with ether, washed
with brine, dried (Na2SO4), and concentrated. Flash chroma-
tography (9:1 hexanes/ethyl acetate) gave 35 (0.480 g, 91%
from 16) as a colorless oil. IR (neat, NaCl plates): 1649, 1502,
1
3294 (br), 949, 861, 802, 751 and 721 cm-1. H NMR (CDCl3,
300 MHz): δ 6.69 (d, J ) 8.5, 1H), 6.66 (d, J ) 3.0, 1H), 6.61
(dd, J ) 8.5, 3.0, 1H), 4.29 (s, OH), 3.78 (s, 3H), and 2.19 (s,
3H). 13C NMR (CDCl3, 75 MHz): δ 151.8, 148.9, 128.0, 118.0,
112.6, 111.6, 56.1, and 16.1.
2-Br om o-4-m eth oxy-5-m eth ylp h en ol (32). The crude
phenol 31 prepared above was dissolved in CHCl3 (125 mL),
and the solution was cooled in an ice bath. Bromine (5.0 mL,
16 g, 0.10 mol) was dissolved in CHCl3 (75 mL) and added via
an addition funnel over 3 h. The reaction was quenched with
sat. NaHSO3 solution and transferred to a separatory funnel.
The layers were separated, and the aqueous phase was
extracted with CH2Cl2. The combined organic layers were
washed (water, sat. NaHCO3, brine), dried (Na2SO4), and
concentrated to yield 32 (20.1 g, 93%) as a tan solid of sufficient
purity to be used in subsequent reactions. An analytical sample
was recrystallized (mp 76-78 °C) from light petroleum ether.
IR (film deposited from CDCl3): 3140 (br), 1200, 859, 824, 787,
and 728 cm-1. 1H NMR (CDCl3, 300 MHz): δ 6.86 (s, 1H), 6.82
(s, 1H), 5.11 (s, OH), 3.76 (s, 3H), and 2.14 (s, 3H). 13C NMR
1150, 1073, 1017, 923, and 808 cm-1 1H NMR (CDCl3, 300
.
MHz): δ 7.06 (d, J ) 7.7, 1H), 6.88 (s, 1H), 6.79 (d, J ) 7.7,
1H), 5.17 (s, 2H), 5.12 (t septets, J ) 7.1, 1.3, 1H), 3.49 (s,
3H), 3.16 (sextet, J ) 7.0, 1H), 2.31 (s, 3H), 1.91 (app. septet,
J ) 7.0, 2H), 1.7-1.4 (m, 2H), 1.66 (s, 3H), 1.57 (br s, 3H),
and 1.19 (d, J ) 7.1, 3H). 13C NMR (CDCl3, 75 MHz): δ 154.5,
136.3, 133.4, 131.1, 126.7, 124.8, 124.5, 114.8, 94.5, 55.9, 37.3,
31.5, 26.3, 25.7, 21.27, 21.21, and 17.6. Anal. Calcd for
C
17H26O2: C, 77.82; H, 9.99. Found: C, 77.62; H, 9.99.
2-(1,5-Dim eth yl-4-h exen yl)-4-m eth ylp h en ol [(()-Elvi-
r ol] (13).2k,v,w,11b,c t-BuLi (6.12 mL, 1.7 M in pentane, 10.4
mmol) was added over 10 min to a cold (-78 °C) solution of
36 (1.37 g, 4.94 mmol) in THF (10 mL). After 1 h, anhydrous
ZnCl2 (5.9 mL, 1.0 M in ether, 5.9 mmol) was added, and the
mixture was warmed to room temperature. The solution was
then transferred via cannula to a solution of alkenyl triflate
16 (1.53 g, 5.93 mmol) and Pd(PPh3)4 (285 mg, 0.250 mmol, 5
mol %) in THF (10 mL). The mixture was refluxed for 24 h,
(38) (a) Rathore, R.; Kochi, J . K. J . Org. Chem. 1995, 60, 7479-
7490. (b) Hauser, F. M.; Ganguly, D. J . Org. Chem. 2000, 65, 1842-
1849.
(39) Carren˜o, M. C.; Garcia Ruano, J . L.; Sanz, G.; Toledo, M. A.;
Urbano, A. J . Org. Chem. 1995, 60, 5328-5331.
J . Org. Chem, Vol. 69, No. 7, 2004 2467

Vyvyan et al.
cooled, and diluted with hexanes (100 mL). The mixture was
washed (10% HCl, brine), dried (Na2SO4), and concentrated.
The residue was passed through a silica plug with hexanes
and concentrated to give a yellow oil (1.74 g, >100%) that was
used directly in the next step.
127.0, 124.6, 115.3, 37.2, 31.6, 26.1, 25.7, 21.0, 20.7, and 17.6.
Anal. Calcd for C15H22O: C, 82.52; H, 10.16. Found: C, 82.61;
H, 10.26.
Ack n ow led gm en t. J .R.V. and C.S.M. are grateful
to Professor Stephen K. Taylor, Hope College, Holland,
MI for allowing us to conduct preliminary investigations
in his laboratory during a Camille and Henry Dreyfus
postdoctoral fellowship. We thank the National Science
Foundation (CHE-0094378), The Camille and Henry
Dreyfus Foundation, Research Corporation, the Western
Washington University Bureau of Faculty Research and
the donors of the Petroleum Research Fund, adminis-
tered by the American Chemical Society, for partial
support of this research.
Ammonia (∼30 mL) was condensed into a two-necked flask
fitted with a dry ice condenser and cooled in a dry ice/i-PrOH
bath. Ether (30 mL) was added followed by lithium wire (225
mg, 32.4 mmol) cut in small pieces. A dark blue color was
established, and the aforementioned crude alkene was added
as a solution in ether. The mixture was stirred for 1.5 h before
NH4Cl (3g) was added in small portions to discharge the blue
color. The mixture was diluted with ether, washed with brine,
dried (Na2SO4), and concentrated. Purification by flash chro-
matography (3:1 hexanes/ethyl acetate) gave (()-elvirol (13)
(0.920 g, 86% from 36) as a colorless oil. IR (neat): 3441 (br),
1
1609, 1258, 1200, and 810 cm-1. H NMR (CDCl3, 300 MHz):
Su p p or tin g In for m a tion Ava ila ble: Experimental pro-
cedures and characterization data for 3, 8, 9, 18a , 18b, 19b,
and 36. This material is available free of charge via the
Internet at http://pubs.acs.org.
δ 6.95 (d, J ) 1.8, 1H), 6.84 (dd, J ) 8.1, 1.8, 1H), 6.64 (d, J
) 8.1, 1H), 5.13 (t septets, J ) 7.1, 1.3, 1H), 4.68 (s, 1H), 2.98
(sextet, J ) 7.0, 1H), 2.26 (s, 3H), 1.94 (m, 2H), 1.69 (s, 3H),
1.65 (m, 2H), 1.51 (br s, 3H), and 1.23 (d, J ) 7.0, 3H). 13C
NMR (CDCl3, 75 MHz): δ 150.7, 132.8, 132.0, 130.0, 127.6,
J O035778S
2468 J . Org. Chem., Vol. 69, No. 7, 2004