Copper-catalyzed reaction of alkyl halides with cyclopentadienylmagnesium reagent

Article abstract of DOI:10.1021/ol800814k

(Chemical Equation Presented) Treatment of alkyl halides, including tertiary alkyl bromides, with cyclopentadienylmagnesium bromide in the presence of a catalytic amount of copper(II) triflate yielded the corresponding cyclopentadienylated products in high yields. The following hydrogenation of the products provided alkyl-substituted cyclopentanes.

Full text of DOI:10.1021/ol800814k

ORGANIC
LETTERS
2008
Vol. 10, No. 12
2545-2547
Copper-Catalyzed Reaction of Alkyl
Halides with
Cyclopentadienylmagnesium Reagent
Masahiro Sai, Hidenori Someya, Hideki Yorimitsu,* and Koichiro Oshima*
Department of Material Chemistry, Graduate School of Engineering, Kyoto UniVersity,
Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510, Japan
yori@orgrxn.mbox.media.kyoto-u.ac.jp; oshima@orgrxn.mbox.media.kyoto-u.ac.jp
Received April 10, 2008
ABSTRACT
Treatment of alkyl halides, including tertiary alkyl bromides, with cyclopentadienylmagnesium bromide in the presence of a catalytic amount
of copper(II) triflate yielded the corresponding cyclopentadienylated products in high yields. The following hydrogenation of the products
provided alkyl-substituted cyclopentanes.
Copper-catalyzed reactions of alkyl halides with organometallic
reagents are among the most useful carbon-carbon bond
forming reactions in organic synthesis.1 Whereas copper-
catalyzed reactions of primary alkyl halides have been well-
established, there are few examples of copper-catalyzed reac-
tions of secondary1d and tertiary alkyl halides with organometallic
reagents that create tertiary quaternary carbons.2 Here we report
such a rare example. The cyclopentadienyl Grignard reagent
proved to react with tertiary alkyl halides under copper catalysis
to afford the corresponding coupling products.
in high combined yield (Scheme 1).3 Initially formed 2a
would undergo isomerization into 3a and 3a′ because of the
high acidity of the hydrogen on the cyclopentadienyl ring.
In order to simplify the analysis of the products,4 the products
were subjected to hydrogenation with the aid of platinum
oxide in boiling acetic acid.5 Cyclopentyl-substituted product
4a was obtained in 85% overall yield.
The choice of solvent is crucial to attain high yield (Table
1). Bulky ethers such as diisopropyl ether and t-butyl methyl
Treatment of 2-methyl-2-bromodecane (1a) with cyclo-
pentadienylmagnesium bromide in the presence of a catalytic
amount of copper(II) triflate in diisopropyl ether afforded a
mixture of the corresponding coupling products 3a and 3a′
(3) General procedure: Copper(II) triflate (9.0 mg, 0.0025 mmol) was
placed in a 30 mL reaction flask under argon. A solution of cyclopentadi-
enylmagnesium bromide (0.86 M in t-butyl methyl ether, prepared from
cyclopentadiene and butylmagnesium bromide, 1.16 mL, 1.0 mmol) was
then added to the flask. Substrate 1a (118 mg, 0.50 mmol) in diisopropyl
ether (4.0 mL) was added. After being stirred for 3 h at 25 °C, the reaction
mixture was poured into a saturated ammonium chloride solution (10 mL).
The products were extracted with hexane (10 mL × 3). The combined
organic layer was dried over Na2SO4 and concentrated. Silica gel column
purification (hexane) of the crude product provided a mixture of 3a and
3a′ (105 mg, 0.47 mmol) in 95% combined yield. Platinum oxide (11 mg,
0.047 mmol) was placed in a 30 mL reaction flask. The flask was filled
with argon first, and then with hydrogen. The mixture of 3a and 3a′ (105
mg, 0.47 mmol) in acetic acid (10 mL) was added, and the resulting mixture
was heated for 12 h. After being cooled to room temperature, the mixture
was filtered through a pad of Celite. After evaporation, the crude product
was chromatographed on silica gel (hexane) to afford 4a (96 mg, 0.43 mmol)
in 85% overall yield.
(1) (a) Lipshutz, B. H.; Sengupta, S. Org. React. 1992, 41, 149–631.
(b) Terao, J.; Ikumi, A.; Kuniyasu, H.; Kambe, N. J. Am. Chem. Soc. 2003,
125, 5646–5647. (c) Terao, J.; Todo, H.; Begum, S. A.; Kuniyasu, H.;
Kambe, N. Angew. Chem., Int. Ed. 2007, 46, 2086–2089. (d) Burns, D. H.;
Miller, J. D.; Chan, H. K.; Delaney, M. O. J. Am. Chem. Soc. 1997, 119,
2125–2133. (e) Cahiez, G.; Chaboche, C.; Jezequel, M. Tetrahedron 2000,
56, 2733–2737. (f) Herber, C.; Breit, B. Eur. J. Org. Chem. 2007, 3512–
3519.
(2) Cobalt and silver are known to catalyze the reactions of tertiary alkyl
halides with allyl- or benzylmagnesium reagents: (a) Tsuji, T.; Yorimitsu,
H.; Oshima, K. Angew. Chem., Int. Ed. 2002, 41, 4137–4139. (b) Ohmiya,
H.; Yorimitsu, H.; Oshima, K. Chem.—Eur. J. 2004, 10, 5640–5648. (c)
Someya, H.; Ohmiya, H.; Yorimitsu, H.; Oshima, K. Org. Lett. 2008, 10,
969–971.
(4) Products 3a and 3a′ underwent smooth dimerization by the
Diels-Alder reaction even at room temperature overnight. The following
hydrogenation should be performed immediately.
10.1021/ol800814k CCC: $40.75
Published on Web 05/16/2008
2008 American Chemical Society

reagent in THF or diethyl ether was far less reactive.
Attempts to prepare the reagent in diisopropyl ether failed,
resulting in incomplete deprotonation.
Scheme 1. Copper-Catalyzed Cyclopentadienylation of Tertiary
Alkyl Bromide 1a Followed by Hydrogenation
A variety of copper salts showed the catalytic activity
(Table 1, entries 1 and 9-15). Copper(II) fluoride is an
alternative catalyst, albeit with lower efficiency (entry 9).
Copper(II) chloride was less efficient (entry 10). Not only
copper(II) halides but also copper(I) halides exhibited modest
catalytic activity (entries 11-13). Other copper salts such
as copper(I) acetate and cyanide exhibited low catalytic
activity (entries 14 and 15). Silver(I) nitrate, which was
effective in the cross-coupling reaction of tertiary alkyl
halides with allyl or benzyl Grignard reagent,2c was less
effective than copper(II) triflate (entry 17).
A variety of alkyl halides were subjected to the cyclo-
pentadienylation (Table 2). Not only alkyl bromide 1a but
ether were suitable solvents (entries 1 and 2). Toluene that
had no heteroatoms was comparable to diisopropyl ether
(entry 3). The reactions in widely used diethyl ether, THF,
Table 2. Copper-Catalyzed Cyclopentadienylation of Alkyl
Halides Followed by Hydrogenation
Table 1. Solvent Effect and Catalyst Screening
entry
solvent
i-Pr2O
t-BuOMe
toluene
catalyst
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
combined yield/%a
1
2
3
96 (95)b
68
90
4
diethyl ether Cu(OTf)2
16
5
6
7
8
dioxane
THF
c-C5H11OMe
Bu2O
i-Pr2O
i-Pr2O
i-Pr2O
i-Pr2O
i-Pr2O
i-Pr2O
i-Pr2O
i-Pr2O
i-Pr2O
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
Cu(OTf)2
CuF2
CuCl2
CuCl
CuBr
CuI
CuOAc
CuCN
CuOTf•0.5 C6H6
AgNO3
12
15
13
22
77
59
44
57
31
30
26
27
9
10
11
12
13
14
15
16
17
26
a Performed at reflux for 6 h. b Performed for 6 h. c Determined by 1H
NMR analysis. Starting material 1g was recovered in 67% yield.
a NMR yield. b Isolated yield.
and dioxane were sluggish (entries 4-6). Cyclopentyl methyl
ether and dibutyl ether also failed to serve as the solvent
(entries 7 and 8). Thus, less coordinating solvents afforded
higher combined yields of 3a and 3a′.
It is worth noting that cyclopentadienylmagnesium bro-
mide should be prepared by deprotonation of cyclopentadiene
with butylmagnesium bromide in t-butyl methyl ether. The
also the corresponding chloride 1a-Cl reacted smoothly with
CpMgBr (entry 1). The reactions of 1-haloadamantane
(5) The hydrogenation is not a trivial reaction because of the steric
hindrance of the tertiary alkyl group. Initial attempts to reduce the mixture
of 3a and 3a′ in other solvents such as isopropyl alcohol and formic acid
under 0.1 MPa of hydrogen failed to attain full conversion.
2546
Org. Lett., Vol. 10, No. 12, 2008

required a higher temperature and a prolonged reaction time
(entries 2 and 3). Gratifyingly, a phenylsulfanyl group as
well as a methoxyl group was compatible without deactivat-
ing the copper catalyst (entries 4 and 5). Unfortunately, the
following hydrogenation of 3d and 3d′ proceeded inef-
ficiently, although the reaction conditions were not optimized
for the sulfur-containing substrate. The reaction of secondary
alkyl halides were moderate (entries 6 and 7). The reaction
of primary alkyl bromide 1g was sluggish (entry 8).
Interestingly, tertiary alkyl fluoride 1h participated in the
cyclopentadienylation (entry 9).
Scheme 3. Stoichiometric Reactions
The copper-catalyzed reaction of 1a with pentamethylcy-
clopentadienylmagnesium bromide in refluxing diisopropyl
ether afforded the corresponding coupling product 5 in 41%
yield (Scheme 2). This reaction provides a rare example of
in a high combined yield of 86%. Hence, the copper reagent
that is active for this reaction might be [Cp3Cu]MgBr6 or a
more complex cuprate.7
In summary, Cu(OTf)2 proved to efficiently catalyze the
reaction of tertiary alkyl halides with cyclopentadienyl
Grignard reagent. Including the following hydrogenation of
the cyclopentadienyl ring with hydrogen under Pt2O catalysis,
the overall transformation represents formal cyclopentylation
of tertiary alkyl halides.
Scheme 2
.
Copper-Catalyzed Pentamethylcyclopentadienylation
of Tertiary Alkyl Bromide 1a
Acknowledgment. This work was supported by Grants-
in-Aid for Scientific Research and COE and Global COE
Research Programs from JSPS.
construction of two adjacent quaternary carbon centers.
To gain information about the reaction mechanism, the
reactions of 1a with stoichiometric copper reagents were
examined with varying amounts of CpMgBr (Scheme 3).
Treatment of 1a (0.50 mmol) with a copper complex,
prepared from 0.50 mmol of Cu(OTf)2 and 0.50 mmol of
CpMgBr, did not provide 3a and 3a′ with complete recovery
of 1a. Most of 1a remained unchanged when 1a was treated
with a copper reagent, prepared from 0.50 mmol of Cu(OTf)2
and 1.0 mmol of CpMgBr. A reagent generated from 0.50
mmol of Cu(OTf)2 and 1.5 mmol of CpMgBr dramatically
changed the outcome. The desired products were obtained
Supporting Information Available: Characterization data
of the products. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL800814K
(6) No dicyclopentadienyl (Cp-Cp) was formed upon treatment of
Cu(OTf)2 with 2 equiv of CpMgBr in the absence of organic halide. This
fact indicates that the active copper species in the reaction mixture is not
CuI or Cu0 species but CuII.
(7) We examined some experiments to assess the intermediacy of alkyl
radicals in the reaction, which failed to support the intermediacy. Investiga-
tions to reveal the reaction mechanism are underway.
Org. Lett., Vol. 10, No. 12, 2008
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