Synthesis of Farnesol Analogues through Cu(I)-Mediated Displacements of Allylic THP Ethers by Grignard Reagents

Article abstract of DOI:10.1021/jo990161p

The synthesis of a family of farnesol analogues, incorporating aromatic rings, has been achieved in high yields through the development of a regioselective coupling of allylic tetrahydropyranyl ethers with organometallic reagents. The allylic THP group is displaced readily by Grignard reagents in the presence of Cu(I) halides but is stable in the absence of added copper. Thus, an allylic THP group can fulfill its traditional role as a protecting group or serve as a leaving group depending on reaction conditions. An improved synthesis of (2E,6E)-10,11-dihydrofarnesol also has been accomplished using this methodology, and some preliminary studies on the reactivity and regioselectivity of THP ether displacements were conducted. The farnesol analogues reported herein may be useful probes of the importance of nonbonding interactions in enzymatic recognition of the farnesyl chain and allow development of more potent competitive inhibitors of enzymes such as farnesyl protein transferase.

Full text of DOI:10.1021/jo990161p

J . Org. Chem. 1999, 64, 4821-4829
4821
Syn th esis of F a r n esol An a logu es th r ou gh Cu (I)-Med ia ted
Disp la cem en ts of Allylic THP Eth er s by Gr ign a r d Rea gen ts
Mark F. Mechelke and David F. Wiemer*
Department of Chemistry, University of Iowa, Iowa City, Iowa 52242-1294
Received J anuary 29, 1999
The synthesis of a family of farnesol analogues, incorporating aromatic rings, has been achieved
in high yields through the development of a regioselective coupling of allylic tetrahydropyranyl
ethers with organometallic reagents. The allylic THP group is displaced readily by Grignard reagents
in the presence of Cu(I) halides but is stable in the absence of added copper. Thus, an allylic THP
group can fulfill its traditional role as a protecting group or serve as a leaving group depending on
reaction conditions. An improved synthesis of (2E,6E)-10,11-dihydrofarnesol also has been
accomplished using this methodology, and some preliminary studies on the reactivity and
regioselectivity of THP ether displacements were conducted. The farnesol analogues reported herein
may be useful probes of the importance of nonbonding interactions in enzymatic recognition of the
farnesyl chain and allow development of more potent competitive inhibitors of enzymes such as
farnesyl protein transferase.
The family of GTP-binding proteins known as RAS
plays an essential role in signal transduction pathways
that regulate cell proliferation,1-4 and mutations in RAS
proteins are associated with approximately 30% of all
human cancers.1 Because a metabolic farnesylation reac-
tion, catalyzed by the enzyme farnesyl protein trans-
ferase (FPTase), is essential for RAS-induced cellular
transformations, an intense interest in farnesyl pyro-
phosphate analogues as potential chemotherapeutic agents
has arisen.5-7 However, farnesyl pyrophosphate is a
substrate for many other enzymes, perhaps most notably
squalene synthase, which suggests that selective inhibi-
tion of FPTase by terpene analogues is not a trivial goal.
Most research in this area has focused on replacing
the biologically labile diphosphate “head” of farnesyl
pyrophosphate with a more stable bioisosteric moiety.8-13
Recent evidence suggests that modifications of the hy-
drophobic farnesyl “tail” might enhance the binding of
farnesyl pyrophosphate analogues. For example, photo-
active farnesyl pyrophosphate mimetics that incorporate
stable ether-linked benzophenones into the terpenoid
chain14 gave a slight increase (1.5-fold) in the binding
affinity for FPTase. In addition, the publication of a
crystal structure for FPTase15 revealed a hydrophobic
pocket lined with aromatic amino acid residues that
presumably accepts the terpenoid chain. These data
support the design of novel, aromatic farnesyl “tails”,
compounds that may further illuminate the importance
of nonbonding interactions in enzymatic recognition of
the farnesyl chain.16 Synthesis of such compounds could
be approached through displacement of an allylic leaving
group by an appropriate nucleophile, but constructing
farnesol analogues (e.g., 1) via this strategy would require
reaction at one allylic position of a geraniol derivative
(2) in the presence of a second allylic functional group
that also might be displaced. One solution to this
problem, based on an interesting Cu(I)-mediated dis-
placement of allylic tetrahydropyranyl (THP) ethers by
Grignard reagents, is the subject of this report.
(1) Barbacid, M. Annu. Rev. Biochem. 1987, 56, 779-827.
(2) Lowy, D. R.; Willumsen, B. M. Annu. Rev. Biochem. 1993, 62,
851-891.
(3) Bos, J . L. Cancer Res. 1989, 49, 4682-4689.
(4) Chang, E. H.; Furth, M. E.; Scolnick, E. M.; Lowy, D. R. Nature
1982, 297, 479-483.
Compounds of the general structure 2 are readily
available through oxidation of geraniol derivatives with
selenium dioxide.17 For example, oxidation of geranyl
acetate (3) with SeO2 gives alcohol 4, and this compound
(5) Willumsen, B. M.; Norris, K.; Papageorge, A. G.; Hubbert, N.
L.; Lowy, D. R. EMBO J . 1984, 3, 2581-2585.
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S. S.; Manne, V. J . Med. Chem. 1995, 38, 2906-2921.
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L. S. Biochemistry 1998, 37, 9612-9618.
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Lawrence, R. M.; Chen, Y.; Sulsky, R. B.; Ciosek, C. P., J r.; Harrity,
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A. J . Med. Chem. 1995, 38, 2596-2605.
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Anthony, N. J .; Gibbs, J . B. Biochemistry 1992, 31, 3800-3807.
(12) Valentijn, A. R. P. M.; van den Berg, O.; van der Marel, G. A.;
Cohen, L. H.; van Boom, J . H. Tetrahedron 1995, 51, 2099-2108.
(13) Holstein, S. A.; Cermak, D. M.; Wiemer, D. F.; Lewis, K.; Hohl,
R. J . Bioorganic & Medicinal Chemistry 1998, 6, 687-694.
(16) For syntheses of other modified farnesols, see: Gibbs, R. A.;
Krishnan, V. Tetrahedron Lett. 1994, 35, 2509-2512. (b) Gibbs, R. A.;
Krishnan, V.; Dolence, J . M.; Poulter, C. D. J . Org. Chem. 1995, 60,
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Gibbs, R. A. Tetrahedron Lett. 1998, 39, 3991-3994.
(17) SeO2 oxidation of geraniol protected with THP, TBDPS, or
benzyl groups gave modest yields, while oxidation of geranyl acetate
gave >55% yield. For the oxidation procedure cf: Sharpless, K. B.;
Umbreit, M. A. J . Am. Chem. Soc. 1977, 99, 5526-5528.
10.1021/jo990161p CCC: $18.00 © 1999 American Chemical Society
Published on Web 06/06/1999

4822 J . Org. Chem., Vol. 64, No. 13, 1999
Mechelke and Wiemer
Ta ble 1. Cu (I)-Med ia ted Cou p lin g of Allylic THP Eth er s
w ith Ar yl Gr ign a r d Rea gen ts
has been converted to the corresponding bromide 5 by
reaction with N-bromosuccinimide and dimethyl sulfide.18
Unfortunately, reaction of compound 5 with phenylmag-
nesium bromide in the presence of copper(I) iodide gave
primarily the diaryl compound 6. In an effort to circum-
vent the double displacement, the related compound 9
was prepared by reaction of the geranyl THP ether 7 with
SeO2 to afford alcohol 8 and subsequent reaction with
acetic anhydride. Surprisingly, reaction of compound 9
with C6H5MgBr and Cu(I)I also gave compound 6 as the
major product, suggesting that under these conditions
displacement of an allylic THP ether may be as facile as
the displacement of an allylic acetate or bromide.19,20
Displacement of allylic THP ethers ultimately allowed
the regioselective synthesis of a series of aromatic far-
nesol analogues. One appropriate substrate for the
displacement was prepared by conversion of THP ether
1021 to alcohol 11 by reduction with LiAlH4 or by basic
hydrolysis. A parallel reaction series was used to convert
prenyl acetate (12) to the known alcohol 13 and then to
the desired THP ethers 14 and 15.22 Compounds 11 and
15 were examined in Grignard coupling reactions with
several different organometallic species without attempt-
ing protection of the free hydroxyl group. Instead, an
excess of the Grignard reagent was employed, presum-
ably leading to formation of a C-1 alkoxide in situ. In all
cases, efficient coupling was observed under these condi-
tions (Table 1). When compound 11 was treated with an
excess of the reagents derived from bromobenzene or
m-bromotoluene, the coupled products 16 and 17 were
obtained in high yields. With the TBDMS-protected
m-bromophenol, coupling also proceeded smoothly, and
treatment of the initial product with TBAF gave phenol
18 in 92% overall yield. Coupling of the smaller THP
ether 15 with larger naphthyl and biphenyl reagents was
examined to obtain coupled products approximating the
length of the farnesyl chain. In this series, the desired
compounds (19, 21, and 23) were always the major
reaction products, and each was obtained in good yield,
but in all three cases, a small amount of SN2′ coupling
(∼5:1 ratio of SN2/SN2′) was observed (compounds 20, 22,
and 24). The SN2 and SN2′ products were readily sepa-
rable by column chromatography and easily identified by
1
their H NMR spectra.
In a similar manner, the reaction of the Grignard
reagents derived from aryl bromides 25 and 28 with THP
ether 15 was expected to afford the biphenyl derivative
26 and the benzophenone derivative 31. To prepare the
requisite Grignard reagents, commercially available 3-bro-
mobenzaldehyde (32) was treated with phenylmagnesium
bromide, and the resulting alcohol was treated with PDC
to afford the known23 3-bromobenzophenone (33) in 89%
yield. Protection of the carbonyl group with ethylene
glycol afforded ketal 28, while reduction with NaBH4 in
trifluoroacetic acid24 provided the desired bromide 25.
(18) Dauben, W. G.; Saugier, R. K.; Fleischhauer, I. J . Org. Chem.
1985, 50, 3767-3774.
(19) For earlier examples of THP ether displacements see: (a)
Katzenellenbogen, J . A.; Corey, E. J . J . Org. Chem. 1972, 37, 1441-
1442. (b) Claesson, A.; Ta¨mnefors, I.; Olsson, L.-I. Tetrahedron Lett.
1975, 1509-1512.
(20) Displacements of allylic ethers by Grignard reagents have been
observed: (a) Normant, J . F.; Commercon, A.; Gendreau, Y.; Bourgain,
M.; Villieras, J . Bull. Soc. Chim. Fr. 1979, 309-314. (b) Normant, J .
F.; Commercon, A.; Bourgain, M.; Villieras, J . Tetrahedron Lett. 1975,
44, 3833-3836. (c) Commercon, A.; Bourgain, M.; Delaumeny, M.;
Normant, J . F.; Villieras, J . Tetrahedron Lett. 1975, 44, 3837-3840.
(21) Marshall, J . A.; Andrews, R. C. J . Org. Chem. 1985, 50, 1602-
1606.
(23) Wagner, P. J .; Sedon, J . H.; Gudmundsdottir, A. J . Am. Chem.
Soc. 1996, 118, 746-754.
(24) (a) Gribble, G. W.; Leese, R. M. Synthesis 1977, 172-176. (b)
Gribble, G. W.; Kelly, W. J .; Emery, S. E. Synthesis 1978, 763-765.
(22) Borcherding, D. R.; Narayanan, S.; Hasobe, M.; McKee, J . G.;
Keller, B. T.; Borchardt, R. T. J . Med. Chem. 1988, 31, 1729-1738.

Cu(I)-Mediated Displacements of Allylic THP Ethers
J . Org. Chem., Vol. 64, No. 13, 1999 4823
ments that we observed with the aryl reagents suggested
that allylic THP ethers are more readily displaced than
the corresponding methyl and ethyl ethers. Parallel
reactions showed that the THP derivative of geraniol (35)
undergoes copper-mediated Grignard displacement at
least 10-fold faster than the corresponding methyl or
phenyl ethers (37 and 38, respectively). Compound 35
gave the coupled product 36 in 92% yield after 1.5 h,
while after 17 h the same product was obtained in 20%
and 55% yields from the methyl (37) and phenyl ethers
(38), respectively. The ethoxyethyl ether 39 also was
displaced more rapidly than the methyl and phenyl
ethers, giving the coupled product in 80% yield after 17
h and demonstrating the importance of the acetal func-
tionality in the coupling reaction. However, a comparison
Treatment of THP ether 15 with an excess of the
Grignard reagent derived from bromide 25 provided the
desired product 26 in moderate yield along with a small
amount of the SN2′ product 27. Reaction of THP ether
15 with the Grignard reagent derived from bromide 28,
followed by deprotection of the resulting ketal 29 by
treatment with PPTS, gave ketone 31. Once again, a
small amount of the SN2′ product 30 was observed in the
coupling reaction.
Observation of small amounts of SN2′ products in all
five reactions attempted with THP ether 15 might be
explained by complexation of the organometallic reagent
with the intermediate alkoxide, followed by intramolecu-
lar delivery of the aryl group.25 However, when allylic
alcohol 15 was protected with a TBDMS group (34), the
SN2′ product was still observed albeit in diminished
amounts. Thus, it may be that there is still complexation
of the acetal protecting groups suggests that the THP
ether is the more proficient leaving group. Finally,
reaction of the THP ether 35 proved more facile than
reaction of the phenyl ether 38, despite the difference in
stability of the corresponding anions.
One explanation for the reactivity of the THP group
may involve metal coordination catalysis. It is possible
that the acetal oxygens chelate with an organocopper
species, delivering the nucleophile directly to the allylic
site of SN2 substitution. Research performed on 2-(allyl-
oxy)benzothiazoles demonstrated that copper(I) π com-
plexes can be used to direct nucleophilic organocopper
substitution reactions.26 Alternatively, bidentate coordi-
nation of the acetal oxygens could result in activation of
the THP as a leaving group. This hypothesis also has
some literature precedence, in that THP ethers have been
cleanly deprotected by treatment with magnesium bro-
mide in ether,27 and a similar process has been shown to
facilitate the cleavage of MEM ethers.28 While it is
difficult to distinguish between these possibilities, CuI
does accelerate displacement of the THP group signifi-
cantly relative to reactions attempted in the presence of
MgBr2 alone. As noted above, treatment of THP ether
35 with phenylmagnesium bromide gives complete reac-
tion within 90 min at room temperature in the presence
of CuI. In the absence of CuI, no coupling was observed
at room temperature even in the presence of added MgBr2
(1.5 equiv). Even at elevated temperatures (50 °C), only
small amounts of the coupled product were observed in
the MgBr2 reactions. Thus, it seems likely that a copper
complex is involved in this transformation rather than
simple Lewis acid activation of the THP ether. However,
in the CuI-mediated reactions of THP ethers 40, 43, and
and delivery in the more crowded TBDMS ether or that
the longer terpenoid chain of compound 11 provides
sufficient steric hindrance to minimize SN2′ coupling in
that series, while the smaller prenyl THP ether 15 lacks
the steric bulk to completely inhibit SN2′ reaction.
Displacements of ethers have some precedence in
reports by Katzenellenbogen and Corey,19a Claesson,19b
and Normant.20 Even so, the THP displacements sum-
marized above appear to be particularly facile. For
example, treatment of the geranyl THP ether 35 with
excess phenylmagnesium bromide in the absence of
copper(I) salt gave no detectable coupling, demonstrating
that allylic THP ethers are stable to Grignard reagents.
Parallel reactions also were performed in the presence
of catalytic and excess Cu(I)I. In both cases, nearly
quantitative yields of the desired coupled product 36 were
obtained, although the reaction proceeds more slowly in
the presence of catalytic CuI (17 h for 0.1 equiv vs 1.5 h
for 1.5 equiv).
While Normant and co-workers observed facile dis-
placement of allylic methyl and ethyl ethers by alkyl-
copper species, they were unable to obtain comparable
results with arylcopper reagents.20 The facile displace-
(26) Calo, V.; Lopez, L.; Pesce, G.; Calianno, A. J . Org. Chem. 1982,
47, 4482-4485.
(27) Kim, S.; Park, J . H. Tetrahedron Lett. 1987, 28, 439-440.
(28) Corey, E. J .; Gras, J .-L.; Ulrich, P. Tetrahedron Lett. 1976, 809-
812.
(25) (a) Eisch, J . J .; Merkley, J . H. J . Am. Chem. Soc. 1979, 101,
1148-1155. (b) Eisch, J . J . J . Organomet. Chem. 1980, 200, 101-117.
(c) Eisch, J . J .; Merkley, J . H.; Galle, J . E. J . Org. Chem. 1979, 44,
587-593.

4824 J . Org. Chem., Vol. 64, No. 13, 1999
Mechelke and Wiemer
Ta ble 2. Regioselectivity in Cu (I)-Med ia ted
Disp la cem en ts of Allylic THP Eth er s w ith C6H5MgBr
The regioselectivity of the THP coupling reactions is
particularly noteworthy. In contrast to the results de-
scribed above, when allylic bromide 49 (readily available
from alcohol 48) is treated with isoamylmagnesium
bromide in the presence of copper(I) iodide, either at 25
°C or at -78 °C, a 1.9/1.0 ratio of SN2′(51)/SN2(50)
products was observed. Because no SN2′ substitution was
46 with phenylmagnesium bromide, the ether’s steric
environment appears to dictate the SN2/SN2′ ratio (Table
2). Because only SN2 products might be expected if
complexation and delivery were involved, observation of
the SN2′ products makes it more difficult to determine
the precise nature of this CuI-mediated displacement.
In theory, coupling of the allylic THP ether 11 with
isoamylmagnesium bromide would allow a regiospecific
synthesis of (2E,6E)-10,11-dihydrofarnesol (47),29 a com-
pound with a saturated terpenoid tail that could serve
as a negative control in studies of enzyme binding.30
observed in the coupling of isoamylmagnesium bromide
with the analogous THP ether 11, these results suggested
that allylic THP ethers are displaced with regioselectivity
not found in the corresponding allylic bromides. A set of
parallel reactions was performed with n-butylmagnesium
and several pairs of THP ethers and the corresponding
bromides (compounds 35 and 54, 40 and 57, 43 and 60,
and 46 and 61), and consistently high regioselectivity was
observed with the THP ethers (Table 3). In three of the
four cases, the THP ethers provided greater than 50:1
ratios of SN2/SN2′ products, while the allylic bromides
exhibited a much greater proportion of SN2′ substitution.
The only exception to this trend was in the case of the
secondary THP ether 46, which gave almost exclusively
the SN2′ coupling product 55. However, even in this case
displacement of the THP ether was more selective (>50:1
SN2′ to SN2) than displacement of the corresponding
bromide (1.5:1.0 SN2′ to SN2). While the basis for this
enhanced regioselectivity is not yet clear, this regiose-
lectivity can be very advantageous as shown in the
synthesis of (E,E)-10,11-dihydrofarnesol. Further inves-
tigation into the mechanism of Cu(I)-mediated Grignard
coupling of THP ethers might lead to a better under-
standing of this interesting observation.
In conclusion, displacement of THP ethers in Cu(I)-
mediated Grignard reactions is an effective strategy for
coupling aromatic and alkyl compounds with allylic
alcohols. Allylic THP ethers can be synthesized in nearly
quantitative yields from the corresponding alcohols and
are much more stable than the corresponding allylic
halides. This stability allows THP ethers to be viewed
as both protecting groups and reactive centers. Both the
ease of displacements observed with allylic THP ethers
and the enhanced regioselectivity observed for allylic
THP ethers versus the corresponding allylic bromides
make this coupling reaction a useful and versatile
process. Finally, this reaction has allowed preparation
of a family of farnesol analogues incorporating aromatic
rings as well as (2E,6E)-10,11-dihydrofarnesol, com-
pounds which should be of use as probes of metabolic
processes based on farnesyl pyrophosphate.33,34
Initial attempts at performing this coupling reaction
under the conditions used in the aryl Grignard cases
failed to provide any of the coupled product, perhaps
because of the lower thermal stability of alkylcopper
species and their tendency to undergo â-elimination.31,32
When this coupling reaction was repeated at lower
temperature in the presence of the more soluble Cu(I)-
Br,20a the desired coupling was obtained. For example,
when THP ether 11 was added to a suspension of
isoamylmagnesium bromide and CuBr at -35 °C, and
the temperature was gradually allowed to warm to -10
°C, the desired product 47 was obtained in 81% yield.
None of the SN2′ substitution product was observed in
the coupling reaction. Thus, (E,E)-10,11-dihydrofarnesol
(47) was prepared in four steps from geranyl acetate (3)
with an overall yield of 45%.
(29) (a) Eidem, A.; Buchecker, R.; Kjosen, H.; Liaaen-J ensen, S. Acta
Chem. Scand. B 1975, 29, 1015-1023. (b) Washburn, W. N.; Kow, R.
Tetrahedron Lett. 1977, 1555-1558. (c) Biller, S. A. U.S. Patent, Patent
Number 5,212,164, May 18, 1993. (d) Zhang, H.; Chen, J .; J iang, J .
Yingyong Huaxue 1993, 10, 104-106. (e) Mechelke, M. F.; Wiemer, D.
F. Tetrahedron Lett. 1998, 39, 9609-9612.
(30) Hohl, R. J .; Lewis, K. A.; Cermak, D. M.; Wiemer, D. F. Lipids
1998, 33, 39-46.
(31) Costa, G.; Camus, A.; Gatti, L.; Marsich, N. J . Organomet.
Chem. 1966, 5, 568-572.
(33) Westfall, D.; Aboushadi, N.; Shackelford, J . E.; Krisans, S. K.
Biochem. Biophys. Res. Commun. 1997, 230, 562-568.
(32) Tamura, M.; Kochi, J . J . Am. Chem. Soc. 1971, 93, 1485-1487.

Cu(I)-Mediated Displacements of Allylic THP Ethers
J . Org. Chem., Vol. 64, No. 13, 1999 4825
Ta ble 3. Regioselectivity in Cu (I)-Med ia ted
Disp la cem en ts of Allylic THP Eth er s a n d Allyl Br om id es
in Rea ction s w ith n -Bu MgBr
and the aqueous phase was extracted with ether. The com-
bined organic extract were concentrated under vacuum to
provide a mixture of the desired alcohol 4 and the correspond-
ing aldehyde. The mixture was dissolved in ice-cold methanol
(70 mL), and NaBH4 powder (1.40 g, 37.0 mmol) was added
slowly over 0.5 h. After the mixture was stirred for an
additional hour, the resulting suspension was quenched by
addition of saturated NH4Cl and extracted with ether and the
combined organic extracts were concentrated under vacuum.
Purification of the resulting liquid by flash column chroma-
tography (60:40 hexanes/ethyl acetate) afforded alcohol 417,35
as a light yellow oil (4.18 g, 53%): 1H NMR δ 5.37 (tq, 1H, J
) 7.0, 1.1 Hz), 5.34 (tq, 1H, J ) 7.0, 1.0 Hz), 4.58 (d, 2H, J )
7.0 Hz), 3.97 (s, 2H), 2.31 (br s, 1H), 2.22-2.06 (m, 4H), 2.05
(s, 3H), 1.71 (s, 3H), 1.66 (s, 3H).
3,7-Dim eth yl-8-[(tetr a h yd r o-2H-p yr a n -2-yl)oxy]-2E,6E-
octa d ien -1-ol (11). To a solution of alcohol 4 (1.95 g, 9.2
mmol) in dichloromethane (40 mL) at 0 °C was added dropwise
3,4-dihydro-2H-pyran (DHP) (2.1 mL, 23.0 mmol) followed by
p-TsOH (28 mg, 0.1 mmol). After the reaction mixture was
allowed to stir for 3 h, the resulting suspension was washed
with saturated NaHCO3 and extracted with ether and the
combined organic extracts were concentrated under vacuum
to afford acetate 10.21 The residue was dissolved in MeOH (50
mL), and potassium carbonate (5.3 g, 38.4 mmol) was added
in one portion. After the mixture was vigorously stirred for
1.5 h, the mixture was treated with saturated NH4Cl, extracted
with ether, and the combined organic extracts were concen-
trated under vacuum. The resulting liquid was purified by
flash column chromatography (60:40 hexanes/ethyl acetate) to
1
provide THP ether 11 (2.34 g, 9.2 mmol) as a clear oil with H
and 13C NMR spectra comparable to reported data.21
4-Acetoxy-2-m eth yl-2E-bu ten -1-ol (13). Prenyl acetate
(5.72 g, 44.7 mmol) in CH2Cl2 was treated with 70% tert-butyl
hydroperoxide (20.0 mL, 140 mmol), SeO2 (2.14 g, 19.3 mmol),
and 4-hydroxybenzoic acid (642 mg, 4.65 mmol) at room
temperature for 23 h using the general SeO2 oxidation
procedure described above for alcohol 4. Standard workup,
including treatment with NaBH4 (1.60 g, 42.3 mmol), and
purification of the resulting liquid by flash column chroma-
tography (60:40 hexanes/ethyl acetate) afforded alcohol 1336
as a light yellow oil (2.22 g, 35%): 1H NMR δ 5.62 (tq, 1H, J
) 7.1, 1.4 Hz), 4.64 (d, 2H, J ) 7.0 Hz), 4.04 (s, 2H), 3.27 (br
s, 1H), 2.05 (s, 3H), 1.72 (s, 3H); 13C NMR δ 171.0, 140.7, 117.9,
66.9, 60.7, 20.6, 13.5.
4-[(Tetr a h yd r o-2H-p yr a n -2-yl)oxy]-3-m eth yl-2E-bu ten -
1-ol (15). To a stirred solution of alcohol 13 (1.10 g, 7.63 mmol)
in CH2Cl2 (20 mL) at 0 °C were added DHP (1.8 mL, 19.8
mmol) and pTsOH (14.5 mg, 0.08 mmol). The mixture was
stirred for 3 h, and the resulting suspension was washed with
saturated NaHCO3 and extracted with ether. After evaporation
of solvent, the resulting liquid was dissolved in MeOH (40 mL),
and K2CO3 (4.21 g, 30.5 mmol) was added in one portion. After
being stirred for 2 h, the mixture was neutralized by addition
of saturated NH4Cl and extracted with ether. The combined
organic extracts were concentrated in vacuo and purified by
column chromatography (60:40 hexanes/ethyl acetate) to afford
THP ether 1522,37 (1.39 g, 98%) as a clear oil: 1H NMR δ 5.68
(tq, 1H, J ) 6.7, 1.4 Hz), 4.63 (dd, 1H, J ) 3.2, 3.2 Hz), 4.19
(d, 2H, J ) 6.6 Hz), 4.12 (d, 1H, J ) 12.3 Hz), 3.91-3.83 (m,
Exp er im en ta l Section
Tetrahydrofuran (THF) was distilled from sodium/benzo-
phenone immediately prior to use, while dichloromethane,
toluene, and pyridine were freshly distilled from calcium
hydride. All reactions in these solvents were conducted in oven-
dried glassware under a positive pressure of nitrogen. Column
chromatography was performed on silica gel (40 µm). NMR
spectra (1H NMR at 300 MHz and 13C NMR at 75 MHz) were
recorded with CDCl3 as solvent and residual CHCl3 or tetra-
methylsilane as internal standards. High-resolution mass
spectra were obtained on reversed geometry mass spectrom-
eters at the University of Iowa Mass Spectrometry Facility.
Elemental analyses were performed by Atlantic Microlab, Inc.
(Norcross, GA).
8-Acetoxy-2,6-d im eth yl-2E,6E-octa d ien -1-ol (4). In a
typical procedure,17 20.0 mL (146 mmol) of 70% tert-butyl
hydroperoxide was added to a suspension of SeO2 (1.84 g, 16.6
mmol) and 4-hydroxybenzoic acid (550 mg, 3.98 mmol) in 50
mL of CH2Cl2. The reaction mixture was then treated with a
solution of geranyl acetate (8.0 mL, 37.4 mmol) in CH2Cl2 (10
mL) via cannula and stirred at room temperature for 18 h.
The resulting suspension was washed with saturated NaHCO3,
1H), 3.87 (d, 1H, J ) 12.3 Hz), 3.56-3.47 (m, 1H), 2.47 (br s,
13
1H), 1.92-1.71 (m, 2H), 1.70 (s, 3H), 1.69-1.40 (m, 4H);
C
NMR δ 134.9, 125.8, 97.6, 71.9, 61.9, 58.7, 30.4, 25.3, 19.2,
13.9; HRMS calcd for C10H18O3 (M + Li)+ 193.1416, found
193.1414.
3,7-Dim eth yl-8-p h en yl-2E,6E-octa d ien -1-ol (16). Com-
mercially available phenylmagnesium bromide (3.8 mL of a 3
(35) Sato, K.; Inoue, S.; Onishi, A.; Uchida, N.; Minowa, N. J . Chem.
Soc., Perkin Trans. 1 1981, 761-769.
(36) Masaki, Y.; Hashimoto, K.; Kaji, K. Tetrahedron Lett. 1978,
4539-4542.
(37) Watanabe, H.; Hatakeyama, S.; Tazumi, K.; Takano, S.; Ma-
suda, S.; Okano, T.; Kobayashi, T.; Kubodera, N. Chem. Pharm. Bull.
1996, 44, 2280-2286.
(34) Crick, D. C.; Andres, D. A.; Waechter, C. J . Biochem. Biophys.
Res. Commun. 1995, 211, 590-599.

4826 J . Org. Chem., Vol. 64, No. 13, 1999
Mechelke and Wiemer
M solution, 11.4 mmol) was added dropwise to a mixture of
THP ether 11 (269 mg, 1.06 mmol) and copper(I) iodide (988
mg, 5.19 mmol) stirring at room temperature in THF (20 mL).
The resulting mixture was heated to 50 °C and allowed to stir
for 4 h. The reaction was then quenched by addition of
saturated NH4Cl and extracted with ether. Concentration of
the combined extracts in vacuo provided a yellow oil, which
upon purification by flash column chromatography (60:40
hexanes/ethyl acetate) afforded compound 16 as a pale yellow
oil (197 mg, 81%): 1H NMR δ 7.28-7.12 (m, 5H), 5.39 (tq, 1H,
J ) 6.9, 1.1 Hz), 5.22 (tq, 1H, J ) 7.0, 1.2 Hz), 4.10 (d, 2H, J
) 6.9 Hz), 3.26 (s, 2H), 2.19-2.03 (m, 4H), 1.65 (s, 3H), 1.52
(s, 3H); 13C NMR δ 140.2, 138.8, 134.5, 128.6 (2C), 128.0 (2C),
127.7, 125.7, 123.6, 59.0, 46.0, 39.3, 26.1, 16.0, 15.6. Anal.
Calcd for C16H22O: C, 83.42; H, 9.63. Found: C, 83.40; H, 9.59.
1-[8′-Hydr oxy-2′,6′-dim eth yl-2′E,6′E-octadien yl]-3-m eth -
ylben zen e (17). Ground Mg0 turnings (2.0 g, 82.3 mmol) were
placed in a flame-dried, 100 mL, three-necked flask followed
by the addition of THF (30 mL) and a crystal of iodine. The
mixture was gradually heated to reflux as 3-bromotoluene (6.0
mL, 49.5 mmol) was added dropwise via cannula. When
Grignard reagent formation was evident (0.5 h), the reaction
mixture was allowed to cool to ∼40 °C. Copper(I) iodide (4.13
g, 21.7 mmol) was subsequently added in one portion followed
by the addition of THP ether 11 (1.09 g, 42.8 mmol) in THF
(10 mL). The resulting suspension was heated at 50 °C until
the reaction was complete by TLC analysis (1 h). The mixture
was quenched by addition of saturated NH 4Cl and extracted
with ether to afford, after purification by column chromatog-
raphy (60:40 hexanes/ethyl acetate), the product 17 as a yellow
oil (951 mg, 91%).
3-(8′-H yd r oxy-2′,6′-d im et h yl-2′E,6′E-oct a d ien yl)p h e-
n ol (18). In the same manner described above for compound
17, THP ether 11 (1.20 g, 4.74 mmol) was treated with the
Grignard reagent prepared from the known38 TBDMS-protect-
ed derivative of 3-bromophenol (8.17 g, 28.5 mmol). After the
mixture was stirred for 3 h at 50 °C and standard workup,
the resulting yellow oil was dissolved in THF (20 mL), treated
with tetrabutylammonium fluoride (15.0 mL of a 1 M solution
in THF, 15.0 mmol), and allowed to stir at room temperature
for 2 h. The solution was then washed with saturated NH4Cl
and extracted with ether. The combined extracts were con-
centrated in vacuo and purified by flash column chromatog-
raphy (60:40 hexanes/ethyl acetate) to afford phenol 18 (1.07
g, 92%).
1-(4′-Hyd r oxy-2′-m eth yl-2′E-bu ten yl)n a p h th a len e (19).
Ground Mg0 turnings (2.58 g, 106 mmol) were placed in a
flame-dried, 250 mL, three-necked round-bottom flask followed
by addition of THF (100 mL) and a crystal of iodine. The
mixture was gradually heated to reflux as commercially
available 1-bromonaphthalene (9.8 mL, 70.8 mmol) was added
dropwise via cannula. When Grignard reagent formation was
evident (1 h), the reaction mixture was allowed to cool to ∼40
°C. CuI (6.0 g, 31.5 mmol) was subsequently added in one
portion followed by the addition of THP ether 15 (1.32 g, 7.08
mmol) in THF (10 mL). The resulting suspension was heated
to 50 °C and allowed to stir for 3 h. After the reaction was
cooled to room temperature, the reaction was quenched by
addition of saturated NH4Cl and extracted with ether and the
combined organic extracts were concentrated in vacuo. Puri-
fication by column chromatography on silica gel (60:40 hex-
anes/ethyl acetate) afforded both the SN2 product 19 (1.03 g,
69%) and the SN2′ product 20 (181 mg, 12%) as yellow oils.
6.8 Hz), 4.12-3.93 (m, 2H), 1.92 (br s, 1H), 1.63 (s, 3H); 13C
NMR δ 144.9, 135.8, 134.0, 132.3, 128.8, 127.4, 126.0, 125.5,
125.3, 124.3, 123.2, 112.7, 64.0, 49.9, 21.9; HRMS calcd for
C
15H16O (M + Na)+ 235.1099, found 235.1084.
2-(4′-Hyd r oxy-2′-m eth yl-2′E-bu ten yl)n a p h th a len e (21).
THP ether 15 (655 mg, 3.52 mmol) was treated with CuI (2.66
g, 14.0 mmol) and the Grignard reagent prepared from
commercially available 2-bromonaphthalene (4.70 g, 22.7
mmol), using the procedure described above for compound 19.
After the mixture was stirred for 1 h at 50 °C, the reaction
mixture was quenched by addition of saturated NH4Cl and
extracted with ether and the combined organic extracts were
concentrated under vacuum. The resulting yellow oil was
purified by flash column chromatography (60:40 hexanes/ethyl
acetate) to afford both the SN2 product 21 (562 mg, 75%) and
the SN2′ product 22 (116 mg, 16%).
4-(4′-Bip h en yl)-3-m eth yl-2E-bu ten -1-ol (23). THP ether
15 (1.14 g, 6.12 mmol) was treated with CuI (1.30 g, 6.83 mmol)
and the Grignard reagent prepared from commercially avail-
able 4-bromobiphenyl (9.10 g, 39.0 mmol) using the procedure
described above for compound 19. After the mixture was
stirred for 4 h at 50 °C, the reaction mixture was quenched
by addition of saturated NH4Cl and extracted with ether and
the combined organic extracts were concentrated under vacuum.
Purification by flash column chromatography (60:40 hexanes/
ethyl acetate) afforded both the SN2 product 23 (1.12 g, 77%)
and the SN2′ product 24 (220 mg, 15%) as white solids.
3-Br om oben zop h en on e (33). 3-Bromobenzaldehyde (5.50
g, 29.7 mmol) was dissolved in THF (30 mL) and treated with
phenylmagnesium bromide (15.0 mL of a 2 M solution in THF,
30.0 mmol). After the mixture was stirred for 1 h, the reaction
mixture was quenched by addition of saturated NH4Cl and
extracted with ether. Concentration of the ethereal extracts
under vacuum afforded an oil, which was dissolved im-
mediately in CH2Cl2 (60 mL). PDC (15.5 g, 41.2 mmol) and
molecular sieve powder (2 g) were subsequently added to the
solution, and the resulting dark brown mixture was allowed
to stir for 3 h at room temperature. Filtration of the reaction
mixture through a thin layer of silica gel, concentration of the
filtrate under vacuum, and purification by flash column
chromatography (90:10 toluene/hexanes) afforded 3-bromoben-
zophenone23 (33) as a white solid (6.87 g, 89%). Both 1H and
13C NMR spectra agreed with literature data.
1-Br om o-3-ben zylben zen e (25). Excess NaBH4 pellets
(∼2.4 g, 63.5 mmol) were added slowly (1 pellet/ 5 min) to
trifluoroacetic acid (30 mL) stirring at 0 °C. After the NaBH4
addition was complete (∼30 min), a solution of 3-bromoben-
zophenone (2.04 g, 7.83 mmol) in CH2Cl2 (15 mL) was added
dropwise via cannula, and the solution turned from clear to
yellow to cloudy white upon ketone addition. After the mixture
was stirred for 21 h, the reaction mixture was diluted with
distilled water (20 mL) and adjusted to pH ∼10 by addition of
solid NaOH. Extraction with ether, concentration under
vacuum, and purification by column chromatography (80:20
toluene/hexanes) afforded the desired aryl bromide 25 (1.51
g, 78%): 1H NMR δ 7.31-7.03 (m, 9H), 3.86 (s, 2H); 13C NMR
δ 143.3, 140.0, 131.8, 129.9, 129.1, 128.8 (2C), 128.5 (2C),
127.5, 126.3, 122.5, 41.4. Anal. Calcd for C13H9Br: C, 63.41;
H, 4.51. Found: C, 63.35; H, 4.55.
1-Be n zyl-3-(4′-h yd r oxy-2′-m e t h yl-2′E -b u t e n yl)b e n -
zen e (26). According to the procedure described above for
compound 19, THP ether 15 (190 mg, 1.02 mmol) was treated
with CuI (305 mg, 1.61 mmol) and the Grignard reagent
prepared from aryl bromide 25 (1.32 g, 5.35 mmol). After the
mixture was stirred for 2 h at 50 °C, standard workup and
purification of the resulting oil by flash column chromatogra-
phy (60:40 hexanes/ethyl acetate) afforded both the SN2
coupled product 26 (158 mg, 61%) and the SN2′ product 27 (31
mg, 12%).
For compound 19: 1H NMR δ 8.08-7.22 (m, 7H), 5.33 (tq,
1H, J ) 6.8, 1.4 Hz), 4.08 (d, 2H, J ) 6.8 Hz), 3.74 (s, 2H),
1.66 (s, 3H); 13C NMR δ 138.1, 135.2, 133.8, 132.3, 128.6, 127.2,
127.0, 125.7, 125.5, 125.4, 125.4, 124.1, 59.2, 42.6, 16.6. Anal.
Calcd for C15H16O: C, 84.86; H, 7.60. Found: C, 84.60; H, 7.56.
For compound 20: 1H NMR δ 8.14 (d, 1H, J ) 8.0 Hz), 7.83
(dd, 1H, J ) 7.4, 2.0 Hz), 7.72 (dd, 1H, J ) 7.5, 1.9 Hz), 7.52-
7.34 (m, 4H), 5.09 (s, 1H), 5.02 (s, 1H), 4.30 (dd, 1H, J ) 6.8,
3-Br om oben zop h en on e a ceta l (28). Benzophenone 33
(2.22 g, 8.51 mmol) was added to a mixture of toluene (20 mL),
ethylene glycol (3.1 mL, 55.6 mmol), and pTsOH (245 mg, 1.29
mmol) stirring in a 100 mL round-bottom flask. The flask was
fitted with a Dean-Stark trap, and the reaction mixture was
heated to reflux. After 16 h, the reaction was diluted with
(38) Bosse, F.; Tunoori, A. R.; Maier, M. E. Tetrahedron 1997, 53,
9159-9168.

Cu(I)-Mediated Displacements of Allylic THP Ethers
J . Org. Chem., Vol. 64, No. 13, 1999 4827
water and extracted with ether. TLC analysis (90:10 toluene/
hexanes) of the concentrated organic fractions showed a
mixture of desired ketal 28 (Rf ) 0.53, stains pink with iodine)
and starting material 33 (Rf ) 0.45, stains yellow with iodine).
These two compounds were not readily separated by column
chromatography (90:10 toluene/hexanes), but some fractions
of the pure ketal 28 could be isolated (1.31 g, 51%): 1H NMR
δ 7.70 (dd, 1H, J ) 1.9, 1.9 Hz), 7.52-7.25 (m, 7H), 7.16 (dd,
1H, J ) 7.9, 7.9 Hz), 4.03 (s, 4H); 13C NMR δ 144.6, 141.5,
131.1, 129.7, 129.1, 128.2 (2C), 128.2, 125.9 (2C), 124.8, 122.3,
108.6, 64.9 (2C). Anal. Calcd for C15H13BrO2: C, 59.21; H, 4.31.
Found: C, 59.10; H, 4.24.
Keta l 29. According to the procedure described above for
compound 19, THP ether 15 (166 mg, 0.89 mmol) was treated
with CuI (255 mg, 1.34 mmol) and the Grignard reagent
prepared from aryl bromide 28 (1.51 g, 4.97 mmol). After the
mixture was stirred for 4 h at 50 °C, standard workup and
purification of the resulting oil by column chromatography on
silica gel (60:40 hexanes/ethyl acetate) afforded both the SN2
coupled product 29 (148 mg, 54%) and the SN2′ product 30 (29
mg, 10%).
3-(4′-H yd r oxy-2′-m et h yl-2′E-b u t en yl) b en zop h en on e
(31). Alcohol 29 (93 mg, 0.30 mmol) was dissolved in acetone
(10 mL) and treated with PPTS (26 mg, 0.10 mmol). The
resulting suspension was heated to reflux and stirred for 23
h. The reaction mixture was then diluted with NaHCO3 and
extracted with ether and the combined organic extracts were
concentrated in vacuo. Final purification by flash column
chromatography (60:40 hexanes/ethyl acetate) afforded the
desired benzophenone 31 as a clear oil (70 mg, 88%): 1H NMR
δ 7.82-7.75 (m, 2H), 7.66-7.34 (m, 7H), 5.49 (tq, 1H, J ) 6.8,
1.2 Hz), 4.16 (d, 2H, J ) 6.7 Hz), 3.37 (s, 2H), 2.05 (br s, 1H),
1.61 (s, 3H); 13C NMR δ 196.8, 139.7, 137.5, 137.4 (2C), 133.0,
132.3, 130.3, 129.9 (2C), 128.1 (3C), 128.1, 126.0, 59.0, 45.6,
16.0; HRMS calcd for C18H18O2 (M + Na)+ 289.1188, found
289.1194.
Effects of Cu I on THP Eth er Su bstitu tion 3,7-Di-
m eth yl-1-p h en yl-2E,6E-octa d ien e (36). Absence of CuI: To
a solution of THP ether 3514 (272 mg, 1.14 mmol) in THF (10
mL) was added phenylmagnesium bromide (1.8 mL of a 3 M
solution, 5.40 mmol). No coupled product was observed after
17 h at 50 °C.
Catalytic CuI: To a solution of THP ether 35 (252 mg, 1.06
mmol) in THF (10 mL) was added CuI (20.1 mg, 0.106 mmol)
and phenylmagnesium bromide (1.8 mL of a 3 M solution, 5.40
mmol). The reaction mixture was stirred at 50 °C and product
formation was monitored by TLC analysis. After the mixture
was stirred for 17 h, the reaction appeared to be complete. The
resulting mixture was quenched by addition of saturated NH4-
Cl and extracted with ether and combined organic extracts
were concentrated under vacuum. Purification of the residue
by flash column chromatography (95:5 hexanes/toluene) af-
forded the product 3639 (211 mg, 93%) as a clear oil. Both 1H
and 13C NMR were identical to literature values.39
Excess CuI: To a solution of THP ether 35 (247 mg, 1.04
mmol) in THF (10 mL) was added CuI (300 mg, 1.58 mmol)
and phenylmagnesium bromide (1.8 mL of a 3 M solution, 5.40
mmol). After the mixture was stirred for 1.5 h, the reaction
was observed to be complete by TLC analysis. The mixture
was then quenched by addition of saturated NH4Cl and
extracted with ether and the combined organic extracts were
concentrated in vacuo. The resulting oil was purified by column
chromatography to afford the coupled product 36 (204 mg,
92%).
1.10 mmol), ethoxyethyl (39,42 264 mg, 1.17 mmol), and THP
(35,14 247 mg, 1.04 mmol) ether derivatives of geraniol were
dissolved in THF (10 mL) and treated with excess CuI (1.5
equiv) and phenylmagnesium bromide (5.0 equiv). All four
flasks were heated to 50 °C, and the reaction mixtures were
monitored by TLC analysis. After 1.5 h, THP ether 35
appeared to be completely converted to the coupled product
36. This reaction was quenched by addition of saturated NH4-
Cl and extracted with ether and the combined extracts were
concentrated in vacuo to afford after purification by column
chromatography (95:5 hexanes/toluene) the coupled product
36 (204 mg, 92%). The other three ethers were allowed to stir
for 17 h at 50 °C. Upon standard workup and purification by
column chromatography, methyl ether 37 afforded a 20% yield
of coupled product (64 mg), phenyl ether 38 gave a 55% yield
of product (131 mg), and ethoxyethyl ether 39 provided an 80%
yield of the coupled product 36 (199 mg).
1-P h en yl-2E-octen e (41) a n d 3-p h en yl-1-octen e (42). A
solution of known43 THP ether 40 (414 mg, 1.95 mmol) in THF
(10 mL) was treated with phenylmagnesium chloride (5 mL
of a 2 M solution, 10 mmol) in the presence of CuI (581 mg,
3.05 mmol). The reaction mixture was heated to 50 °C and
monitored by TLC analysis. After 3 h, the reaction was
quenched by addition of saturated NH4Cl and extracted with
hexanes and the combined organic extracts were concentrated
under vacuum. Purification by column chromatography (hex-
anes) afforded a mixture of the SN2 coupled product 4144 and
trace amounts of the SN2′ product 4244 (314 mg, 85%, >50:1
1
ratio of SN2/SN2′ as observed by H NMR).
1-P h en yl-2Z-h exen e (44) a n d 3-P h en yl-1-h exen e (45).
A solution of THP ether 4345 (538 mg, 2.93 mmol) in THF (10
mL) was treated with phenylmagnesium chloride (7.5 mL of
a 2 M solution, 15 mmol) in the presence of CuI (841 mg, 4.42
mmol). The reaction mixture was heated to 50 °C and
monitored by TLC analysis. After 3 h, standard workup and
purification by column chromatography (hexanes) afforded a
mixture of the SN2 product 4446 and the SN2′ product 4547 (418
mg, 89%, 7.3:1.0 ratio of SN2/SN2′ as observed by 1H NMR).
3-P h en yl-1-octen e (42) a n d E/Z-1-P h en yl-2-octen e (41).
A solution of THP ether 4648 (505 mg, 2.38 mmol) in THF (10
mL) was treated with phenylmagnesium chloride (6 mL of a 2
M solution, 12 mmol) in the presence of CuI (692 mg, 3.64
mmol). The reaction mixture was heated to 50 °C and
monitored by TLC analysis. After 3 h, standard workup and
purification by column chromatography (hexanes) afforded a
mixture of the SN2 product 4244 and the cis/trans isomers of
the SN2′ product 4144 (425 mg, 95%, 11.5:1.0 ratio of SN2′/SN2
products; the SN2′ product 41 is in a 1.2:1.0 ratio of cis/trans
isomers as observed by 1H NMR). Data for olefins E-41 and
42 agreed with that reported above.
3,7,11-Tr im eth yl-2E,6E-d od eca d ien -1-ol (47). Ground
Mg0 turnings (702 mg, 28.9 mmol) were placed in a flame-
dried, 100 mL three-necked flask followed by addition of THF
(20 mL) and a crystal of iodine. Commercially available
3-methyl-1-bromobutane (2.40 mL, 20.0 mmol) in 10 mL of
THF was added dropwise via cannula, and formation of the
Grignard reagent was observed by the disappearance of Mg0.
THP ether 11 (499 mg, 1.96 mmol) was dissolved in THF (10
mL) in a second 100 mL flask and cooled to -35 °C. Addition
of CuBr (501 mg, 3.49 mmol) in one portion to the THP ether
solution was followed by dropwise addition of the freshly
prepared Grignard reagent via cannula. The resulting mixture
(42) Still, W. C.; McDonald, J . H.; Collum, D. B.; Mitra, A.
Tetrahedron Lett. 1979, 593-594.
Com p a r ison of Eth er Disp la cem en t: 3,7-Dim eth yl-1-
p h en yl-2E,6E-octa d ien e (36). In a parallel set of reactions,
the methyl (37,40 247 mg, 1.47 mmol), phenyl (38,41 254 mg,
(43) Porter, N. A.; Ziegler, C. B., J r.; Khouri, F. F.; Roberts, D. H.
J . Org. Chem. 1985, 50, 2252-2258.
(44) Mizojiri, R.; Kobayashi, Y. J . Chem. Soc., Perkin Trans. 1 1995,
2073-2075.
(45) Kantam, M. L.; Santhi, P. L. Synth. Commun. 1993, 23, 2225-
(39) Ba¨ckvall, J .-E.; Persson, E. S. M.; Bombrun, A. J . Org. Chem.
1994, 59, 4126-4130.
2228.
(46) Tsuchimoto, T.; Tobita, K.; Hiyama, T.; Fukuzawa, S.-I. J . Org.
Chem. 1997, 62, 6997-7005.
(40) Burk, R. M.; Gac, T. S.; Roof, M. B. Tetrahedron Lett. 1994, 35,
8111-8112.
(47) Flemming, S.; Kabbara, J .; Nickisch, K.; Westermann, J .; Mohr,
J . Synlett 1995, 183-185.
(41) Goux, C.; Massacret, M.; Lhoste, P.; Sinou, D. Organometallics
1995, 14, 4585-4593.
(48) Maiti, G.; Roy, S. C. J . Org. Chem. 1996, 61, 6038-6039.

4828 J . Org. Chem., Vol. 64, No. 13, 1999
Mechelke and Wiemer
was stirred at -35 °C for 1 h and then allowed to warm
gradually to -10 °C. After the mixture was stirred for 48 h,
the resulting dark brown suspension was quenched by addition
of NH4Cl and extracted with ether and the combined organic
extracts were concentrated in vacuo. Final purification by
column chromatography (70:30 hexanes/ethyl acetate) afforded
(2E,6E)-10,11-dihydrofarnesol 4729c as a clear oil (355 mg,
81%): 1H NMR δ 5.40 (tq, 1H, J ) 6.9, 1.3 Hz), 5.10 (tq, 1H,
J ) 6.8, 1.3 Hz), 4.12 (d, 2H, J ) 6.8 Hz), 2.37 (br s, 1H), 2.16-
1.99 (m, 4H), 1.94 (t, 2H, J ) 7.3 Hz), 1.67 (s, 3H), 1.58 (s,
3H), 1.57-1.11 (m, 5H), 0.87 (d, 6H, J ) 6.5 Hz); 13C NMR δ
139.1, 135.5, 123.5, 123.4, 59.0, 39.8, 39.5, 38.5, 27.7, 26.2, 25.6,
22.5 (2C), 16.1, 15.7.
In a parallel reaction, a solution of geranyl bromide 54 (0.22
mL, 1.11 mmol) in THF (10 mL) was cooled to -30 °C and
treated with CuBr (260 mg, 1.81 mmol) and n-butylmagnesium
chloride (3.3 mL of a 2 M solution in THF, 6.6 mmol) under
the same reaction conditions described above. After 1 h, the
reaction mixture was allowed to warm to -10 °C and left to
stir overnight (17 h). The resulting suspension was quenched
by addition of NH4Cl and extracted with ether the combined
organic extracts were and then purified by column concen-
trated in vacuo chromatography (hexanes) to afford a 6.3:1.0
mixture of SN2(52)/SN2′(53) products as measured by 1H NMR
(223 mg, 100%).
6E-Dod ecen e (55) a n d 3-n -Bu tyl-1-octen e (56). In a set
of reactions similar to those described in the general procedure
above, THP ether 4043 (521 mg, 2.46 mmol) in THF (10 mL)
at -30 °C was treated with CuBr (582 mg, 4.05 mmol) and
n-butylmagnesium chloride (7.6 mL of a 2 M solution in THF,
15.2 mmol). After the mixture was stirred for 2 h, the reaction
mixture was quenched and the products were purified under
standard conditions to afford a >50:1 mixture of SN2(55)/SN2′-
(56) substitution products as determined by 1H NMR analy-
sis53,54 (366 mg, 89%).
3,7,11-Tr im eth yl-2E,6E-dodecadien yl Ben zyl Eth er (50)
an d 6-Isoam yl-3,7-dim eth yl-2E,7-octadien yl Ben zyl Eth er
(51). Alcohol 4849 (510 mg, 1.96 mmol) in THF (20 mL) at 0
°C was treated with pyridine (0.05 mL, 0.62 mmol) and PBr3
(0.10 mL, 1.05 mmol). The resulting suspension was stirred
for 1 h and then washed with NaHCO3. Extraction with ether,
treatment with MgSO4, and filtration through Celite afforded
bromide 4950 as a yellow oil. The Grignard reagent derived
from 3-methyl-1-bromobutane (1.0 mL, 8.35 mmol) was then
prepared in the typical manner, using Mg0 turnings (206 mg,
8.47 mmol) and a crystal of iodine. CuI (50.2 mg, 0.26 mmol)
was added in one portion to bromide 49, stirring at room
temperature in THF (10 mL) followed by immediate addition
of the freshly prepared Grignard reagent. After the mixture
was stirred for 5 h, the resulting mixture was quenched by
addition of NH4Cl and extracted with ether and the organic
extracts were concentrated in vacuo. Purification by column
chromatography (90:10 hexanes/ethyl acetate) afforded a
mixture of the SN2 (50)51 and SN2′ (51) substitution products
Bromide 5755 (527 mg, 2.76 mmol) was treated with n-
BuMgCl reaction conditions as described above for THP ether
40. After the mixture was stirred for 2 h at -30 °C, standard
workup and purification provided a 3.3:1.0 mixture of SN2-
(55)/SN2′(56) products (385 mg, 83%).
4-Decen e (58) a n d 3-n -P r op yl-1-h ep ten e (59). Following
the general procedure described above, THP ether 4345 (626
mg, 3.40 mmol) in 10 mL THF at -30 °C was treated with
CuBr (723 mg, 5.04 mmol) and n-BuMgCl (9.0 mL of a 2 M
solution in THF, 18.0 mmol). After 1 h, the reaction mixture
was allowed to warm to -10 °C and then stirred for an
additional 24 h. Standard workup and purification provided
a >50:1 ratio of SN2 (58)/SN2′ (59) products as measured by
1H NMR analysis56 (302 mg, 64%). On the basis of 1H and 13C
NMR data, alkene 58 was a 1:1 mixture of cis/trans isomers.
Bromide 6058 (518 mg, 3.18 mmol) was subjected to reaction
conditions as described above for THP ether 43. The reaction
mixture was stirred for 7 h and then purified using standard
procedures. A 2.6:1 ratio of SN2/SN2′ products (58:59) was
1
in a 1.0:1.9 ratio as determined by H NMR (346 mg, 56%).
For the SN2 product 50: 1H NMR δ 7.35-7.21 (m, 5H), 5.39
(tq, 1H, J ) 6.8, 1.3 Hz), 5.10 (tq, 1H, J ) 6.7, 1.1 Hz), 4.48 (s,
2H), 4.01 (d, 2H, J ) 6.6 Hz), 2.15-1.89 (m, 6H), 1.63 (s, 3H),
1.58 (s, 3H), 1.57-1.10 (m, 5H), 0.85 (d, 6H, J ) 6.6 Hz).
For SN2′ product 51: 1H NMR (selected) δ 4.75-4.73 (m,
1H), 4.67-4.65 (m, 1H), 1.62 (s, 3H), 0.86 (d, 6H, J ) 6.5 Hz).
The same reaction was also performed at -78 °C, and
similar results were obtained (1.0:2.0 of 50:51, 205 mg, 27%).
Gen er a l P r oced u r e for n -Bu tylm a gn esiu m Br om id e
Ad d ition to Allylic Br om id es a n d THP Eth er s. 2,6-
d im et h yl-2E,6E-d od eca d ien e (52) a n d 3-n -Bu t yl-3,7-d i-
m eth yl-1,6E-octa d ien e (53). THP ether 35 (288 mg, 1.21
mmol) was dissolved in THF (10 mL), the solution was cooled
to -30 °C and treated with CuBr (261 mg, 1.82 mmol) and
n-butylmagnesium chloride (3.3 mL of a 2 M solution in THF,
6.6 mmol). After the mixture was stirred for 1 h, the reaction
mixture was allowed to gradually warm to -10 °C and then
stirred for an additional 42 h. The resulting suspension was
quenched by addition of NH4Cl and extracted with ether and
the combined extracts were concentrated in vacuo and then
purified by column chromatography (hexanes) to afford a >50:1
mixture of SN2(52)/SN2′(53) coupled products as determined
1
observed by H NMR (210 mg, 47%), and only trace amounts
of isomerized trans SN2 product could be detected.
6-Dod ecen e (55) a n d 3-n -Bu tyl-1-octen e (56) fr om
Eth er 46 a n d Br om id e 61. THP ether 4648 (631 mg, 2.98
mmol) was treated with CuBr (660 mg, 4.60 mmol) and
n-BuMgCl (7.5 mL of a 2 M solution in THF, 15 mmol) at -30
°C in THF (10 mL). After 1 h, the reaction mixture was allowed
to warm gradually to -10 °C and then stirred for an additional
24 h. Standard workup and purification provided a >50:1 ratio
of SN2′/SN2 products (55:56) as determined by 1H NMR
analysis (333 mg, 67%). Data for olefins E-55 and 56 agreed
with that reported above.
The bromide 6159 (620 mg, 3.25 mmol) was subjected to
similar conditions as THP ether 46, and workup of the
resulting suspension afforded a 1.5:1.0 mixture of SN2′/SN2 (55:
56) products (375 mg, 69%). In the SN2′ products from both
the THP ether and bromide, small amounts of the cis isomer
could be observed in the 13C NMR spectra, but it was not
1
by H NMR analysis (130 mg, 56%).
For the SN2 product 52: 1H NMR spectrum agreed with
literature data;20a,57 13C NMR δ 134.7, 131.1, 124.9, 124.5, 39.8,
31.6, 29.6, 27.9, 26.8, 25.7, 22.7, 17.6, 15.9, 14.1.
For the SN2′ product 53: 1H NMR spectrum agreed with
literature data;52,57 13C NMR (selected) δ 147.5, 125.2, 111.3,
40.8, 40.6, 39.4, 26.3, 23.6, 22.9, 22.6, 17.5, 14.1.
possible to determine this ratio by H NMR.
1
Ack n ow led gm en t. We thank J ohn B. MacMillan for
his experimental assistance. Financial support from the
Roy J . Carver Charitable Trust and from the University
(49) (a) Altman, L. J .; Ash, L.; Marson, S. Synthesis 1974, 129-
131. (b) Masaki, Y.; Iwata, I.; Mukai, I.; Oda, H.; Nagashima, H. Chem.
Lett. 1989, 659-662.
(50) Masaki, Y.; Hashimoto, K.; Iwai, H.; Kaji, K. Chem. Lett. 1978,
1203-1204.
(55) Nakanishi, S.; Yamamoto, T.; Furukawa, N.; Otsuji, Y. Syn-
thesis 1994, 609-612.
(56) Suzuki, N.; Kondakov, D. Y.; Takahashi, T. J . Am. Chem. Soc.
1993, 115, 8485-8486.
(57) Ba¨ckvall, J . E.; Sellen, M.; Grant, B. J . Am. Chem. Soc. 1990,
(51) Miyakoshi, T.; Takazawa, H.; Hagimoto, M. Yukagaku 1990,
39, 83-89.
(52) Yanagisawa, A.; Nomura, N.; Yamamoto, H. Tetrahedron 1994,
50, 6017-6028.
112, 6615-6621.
(53) Maeda, K.; Shinokubo, H.; Oshima, K. J . Org. Chem. 1996, 61,
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Cu(I)-Mediated Displacements of Allylic THP Ethers
J . Org. Chem., Vol. 64, No. 13, 1999 4829
27, 29, 30, E- and Z-41, 42, 44, 45, E- and Z-55, 56, E- and
Z-58). This material is available free of charge via the Internet
at http://pubs.acs.org.
of Iowa in the form of an Iowa Fellowship to M.F.M. is
gratefully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: The product char-
acterization data for 20 compounds (17, 18, 21, 22, 23, 24, 26,
J O990161P