Tandem intramolecular carbolithiation-lithium/zinc transmetallation and applications to carbon-carbon bond-forming reactions

Article abstract of DOI:10.1002/ejoc.200400349

Lithium/zinc transmetallation with the cyclic organolithium intermediate 3 (prepared by intramolecular carbolithiation of the initially formed organolithium 2) gives the corresponding organozinc intermediate 5. Copper- or palladium-promoted S_N2

Full text of DOI:10.1002/ejoc.200400349

FULL PAPER
Tandem Intramolecular Carbolithiation-Lithium/Zinc Transmetallation and
Applications to Carbon؊Carbon Bond-Forming Reactions
Miguel Yus*[a] and Rosa Ortiz[a]
Dedicated to Professor Armin de Meijere on the occasion of his 65th birthday
Keywords: Alkylation and acylation / Intramolecular carbolithiation / LithiumϪzinc transmetallation / Michael reaction /
Negishi reaction
Lithium/zinc transmetallation with the cyclic organolithium
intermediate 3 (prepared by intramolecular carbolithiation of
the initially formed organolithium 2) gives the corresponding
organozinc intermediate 5. Copper- or palladium-promoted
acylation, and conjugate addition to α,β-unsaturated car-
bonyl compounds, afford (after hydrolysis) the expected com-
pounds 7−15, which are not accessible directly from the or-
ganolithium precursor 3 even with transition metal catalysis.
SN2Ј reactions between compound 5 and allylic or propar- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
gylic halides, as well as arylation, vinylation, benzylation,
Germany, 2004)
Introduction
heterocyclic compounds,[7] (c) generation of polylithium
synthons, mainly by halogen-lithium exchange from polych-
lorinated materials,[8] and (d) activation of other metals[9]
such as nickel, and their use in reduction reactions.[10] In
some cases, when the organolithium intermediate is too un-
stable, it is necessary to perform the lithiation in the pres-
ence of the electrophile (Barbier-type reaction con-
ditions)[11] in order to avoid its decomposition. A very re-
cent application of the arene-catalyzed lithiation was the
generation of an unsaturated organolithium compound 2,
which can undergo intramolecular carbolithiation[12] to
yield a new organolithium compound 3. Further treatment
of this intermediate with typical electrophiles, such as car-
bonyl compounds, affords the expected compounds 4.[13]
However, other processes such as SN2Ј reactions, arylation,
acylation, or conjugate addition are not possible, either
with no reaction taking place or with the production of
mixtures of compounds being observed. For these reasons
we considered the possibility of transforming the intermedi-
ate 3 into an organozinc compound 5[14] in order to study
such reactions and to produce a new family of cyclopen-
tane-derived compounds of type 6 (Scheme 1). Thus, in this
paper we combine intramolecular carbolithiation with a
lithium/zinc transmetallation to extend the reactivity of in-
termediate 3.[15]
Organolithium compounds are very useful intermediates
in synthetic organic chemistry, since because of the high
polarity of the carbon-lithium bond they are potential car-
banions capable of reacting with different electrophiles un-
der mild reaction conditions (low temperatures).[1] A special
class of organolithium intermediates are those bearing a
functionality,[2] as they are able to transfer the functionality
to the electrophilic reagent in their reactions with electro-
philes, so polyfunctionalized molecules can be prepared in
only one synthetic operation. One problem associated with
the generation of very reactive organolithium intermediates
is that the lithiation step should be carried out at low tem-
perature in order to avoid decomposition of the carbanionic
intermediate. For that purpose, we have over the last few
years been developing a methodology consisting of the use
of lithium powder and a catalytic amount of an arene, with
the most used electron-transfer agents being naphthalene
and 4,4Ј-di-tert-butylbiphenyl (DTBB).[3,4] We have recently
introduced a polymer-supported version of this arene-cata-
lyzed lithiation, which allows us to reuse the polymer sev-
eral times without losing any efficiency.[5] In our group we
have used this methodology for: (a) generation of organoli-
thium compounds starting from nonhalogenated materi-
als,[6] (b) preparation of functionalized organolithium com-
pounds by carbon-heteroatom bond cleavage,[2] including
Results and Discussion
[a]
Once intermediate 3 had been generated by DTBB-cata-
lyzed lithiation of 6-chlorohex-1-ene (1),[13] the excess of
lithium powder was filtered off, and the resulting solution
containing the intermediate 3 was added at 0 °C to a solu-
´
´
Departamento de Quımica Organica, Facultad de Ciencias, and
´
´
Instituto de Sıntesis Organica (ISO), Universidad de Alicante,
Apdo. 99, 03080 Alicante, Spain
Fax: (internat.) ϩ34-965-903549
E-mail: yus@ua.es
Eur. J. Org. Chem. 2004, 3833Ϫ3841
DOI: 10.1002/ejoc.200400349
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3833

M. Yus, R. Ortiz
FULL PAPER
Scheme 1
tion of zinc bromide (1.1 equiv.). After 15 min, copper()
cyanide (1.1 equiv.) was added at the same temperature to
the resulting solution of compound 5, and the mixture was
then treated with an allylic chloride or bromide, giving,
after hydrolysis with 2  hydrochloric acid, the correspond-
ing product 7, as the outcome of a clean SN2Ј process
(Scheme 2 and Scheme 3, Table 1, entries 1Ϫ3). The corre-
sponding SN2 products, which are the only ones obtained
on direct treatment of intermediate 3 with the same electro-
philes,[16] were never observed (GLC-MS) in the reaction
crude mixtures.
Scheme 2. (i) ZnBr2, THF, 0 °C, 15 min; (ii) CuCN·2LiCl, THF, 0
°C, 15 min; (iii) RCHϭCHCH2X (X ϭ Cl, Br), 0 °C, 2 h; (iv) 2 
HCl; (v) RCϵCCH2Cl
An SN2Ј process was also the only one observed when
propargyl chlorides were used, compounds 8 being isolated
under the same reaction conditions (Schemes 2 and 3,
Table 1, entries 4 and 5). In the case of 1,4-dichlorobut-2-
yne as electrophile (1:0.5 molar ratio), the obtained allene
8c underwent a second SN2Ј addition to give the corre-
sponding 1,3-diene 9[17] (Scheme 2 and Scheme 4, Table 1,
entry 6). The same result was obtained with use of a stoi-
chiometric amount of the electrophile, the excess of the
starting compound being isolated unchanged after workup.
On the other hand, intermediate 3 also mainly gives acety-
Scheme 3. Structures of compounds 7Ϫ15
lene derivatives through SN2 reactions when propargyl chlo- pected coupling products 10 (Scheme 3 and Scheme 5,
rides are used as electrophiles.[18,19]
Table 1, entries 7 and 9Ϫ11). No significant difference in
We next studied the palladium-catalyzed arylation of the yield was observed when phenyl iodide was used instead
zinc intermediate 5, the so-called Negishi-type reac- of phenyl bromide (Table 1, entries 7 and 8). Brominated
tion.[20,21] Thus, once compound 5 had been generated as heterocycles were also suitable electrophiles for the Negishi-
shown above, it was treated with a catalytic amount (5 type reaction, and the expected coupling products 10 were
mol %) of the complex of palladium() acetate and tri-tert- easily obtained under similar reaction conditions (Scheme 3
butylphosphane in THF at room temperature, and the cor- and Table 1, entries 12Ϫ15). Arylation of the lithium inter-
responding aryl bromide was then added, the resulting mix- mediate 3 also failed here, even in the presence of the pal-
ture being heated at reflux to give, after hydrolysis, the ex- ladium catalyst, so the presence of both the zinc and the
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Eur. J. Org. Chem. 2004, 3833Ϫ3841

Tandem Intramolecular Carbolithiation-Lithium/Zinc Transmetallation
FULL PAPER
Table 1. Preparation of compounds 7Ϫ15
Electrophile
E
Additive
(equiv.)
Reaction conditions
Product[a]
No.
Entry
T (°C)
time (h)
Yield (%)[b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
(E)-PhCHϭCHCH2Cl
geranyl chloride
(E)-BrCH2CHϭCHCH2Br
PhCϵCCH2Cl
C5H11CϵCCH2Cl
ClCH2CϵCCH2Cl
PhBr
CuCN·2LiCl (1.1)
0
0
0
0
0
2
2
2
2
2
2
6
6
6
6
6
6
6
6
6
6
6
6
6
6
3
3
3
3
3
3
3
3
3
3
3
7a
7b
54
53
66
45
61
59[c]
46
53
52
60
62
46
66
48
53
39
56
44
46
30
54
74
82
60
54
61
45
63
62
66
31[e]
CuCN·2LiCl (1.1)
CuCN·2LiCl (1.1)
7c
CuCN·2LiCl (1.1)
8a
CuCN·2LiCl (1.1)
8b
CuCN·2LiCl (1.1)
0
9
Pd(OAc)2(PtBu3)2 (0.05)
Pd(OAc)2(PtBu3)2 (0.05)
Pd(OAc)2(PtBu3)2 (0.05)
Pd(OAc)2(PtBu3)2 (0.05)
Pd(OAc)2(PtBu3)2 (0.05)
Pd(OAc)2(PtBu3)2 (0.05)
Pd(OAc)2(PtBu3)2 (0.05)
Pd(OAc)2(PtBu3)2 (0.05)
Pd(OAc)2(PtBu3)2 (0.05)
Pd(OAc)2(PtBu3)2 (0.05)
Pd(OAc)2(PtBu3)2 (0.05)
Pd(OAc)2(PtBu3)2 (0.05)
Pd(OAc)2(PtBu3)2 (0.05)
Pd(OAc)2(PtBu3)2 (0.05)
PdCl2(PPh3)2 (0.05)
PdCl2(PPh3)2 (0.05)
PdCl2(PPh3)2 (0.05)
PdCl2(PPh3)2 (0.05)
PdCl2(PPh3)2 (0.05)
PdCl2(PPh3)2 (0.05)
PdCl2(PPh3)2 (0.05)
CuCN·2LiCl (1.1)[d]
CuCN·2LiCl (1.1)[d]
CuCN·2LiCl (1.1)[d]
CuCN·2LiCl (1.1)[d]
65
65
65
65
65
65
65
65
65
65
65
65
65
65
0
0
0
0
0
0
0
0
0
10a
10a
10b
10c
10d
10e
10f
10g
10h
11a
12
PhI
4-MeC6H4Br
4-MeOC6H4Br
4-O2NC6H4Br
2-bromothiophene
3-bromothiophene
2-bromopyridine
3-bromopyridine
(E)-PhCHϭCHBr
CH2ϭCPhBr
PhCH2Br
13a
13b
13c
14a
14b
14c
14d
14e
14f
14g
15a
15b
15c
15d
4-tBuC6H4CH2Br
4-FC6H4CH2Br
BuCOCl
tBuCOCl
c-C6H11COCl
PhCOCl
4-tBuC6H4COCl
4-MeOC6H4COCl
4-O2NC6H4COCl
CH2ϭCHCOMe
cyclopent-2-enone
cyclohex-2-enone
(E)-MeCHϭCMeCOMe
0
0
[a] All products were Ͼ95% pure (GLC and/or 1H NMR). [b] Isolated yield after column chromatography (silica gel, hexane/ethyl acetate)
based on 6-chlorohex-1-ene (1) used as starting material for the generation of intermediates 3 and 5. [c] Only 0.5 equiv. of the electrophile
[d]
[e]
1
were used. BF3·OEt2 (1.1 equiv.) was also used as additive. A ca. 1:1 mixture of diastereomers was obtained (300 MHz H NMR).
Scheme 4
palladium components is necessary for the reaction to
take place.[21]
Scheme 5. (i) Pd(OAc)2(PtBu3)2 (5%), THF, room temp., 10 min;
(ii) ArX (X ϭ Br, I), THF reflux, 6 h; (iii) 2  HCl; (iv) BrR1Cϭ
CHR2, THF reflux, 6 h; (v) ArCH2Br, THF reflux, 6 h; (vi)
PdCl2(PPh3)2, THF, 0 °C, 15 min; (vii) RCOCl, 0 °C to room
temp., 2 h
When a vinyl bromide was used under the same reaction
conditions as employed for the Negishi reaction, the ex-
pected coupling products 11 were obtained (Schemes 3 and
5, Table 1, entry 16). With treatment with α-bromostyrene,
however, the initially formed olefin 11b underwent spon-
taneous isomerization under the reaction conditions, giving
the corresponding product 12 (Scheme 3 and Table 1, en-
try 17).
Palladium-promoted benzylation of the zinc intermediate
5 under the same reaction conditions as described above for
the Negishi-type reaction gave the expected coupling prod-
ucts 13 (Schemes 3 and 5, and Table 1, entries 18Ϫ20). It is
noteworthy that significant amounts of the corresponding
dimers (dibenzylic products), resulting from self-coupling
of the electrophile used, were obtained in these cases. These
dimers were the only reaction products isolated for α-substi-
Eur. J. Org. Chem. 2004, 3833Ϫ3841
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M. Yus, R. Ortiz
FULL PAPER
tuted benzylic bromides, such as α-methyl- and α-phe-
nylbenzyl bromides, as well as for fluorenyl bromide.
We next studied the palladium-catalyzed acylation of in-
termediate 5 with different alkyl and aryl acyl chlorides at
temperatures ranging between 0 °C and room temperature,
in order to prepare the expected ketones 14 (Schemes 3 and
5, and Table 1, entries 21Ϫ27). In this case the palladium()
chloride/triphenylphosphane (5%) complex was active en-
ough for the reaction to take place. In no case the corre-
Experimental Section
General: All reactions were carried out under argon. FT-IR spectra
were obtained with a Nicolet Impact 400D spectrophotometer. H
1
and 13C NMR spectra were recorded at 300 and 75 MHz, respec-
tively, on a Bruker AC 300 instrument in CDCl3 as solvent and
with TMS as internal standard; chemical shifts (δ) are given in
ppm, and coupling constants (J) are given in Hz. Low-resolution
mass spectra (EI) were obtained at 70 eV with an Agilent 5973
Network spectrometer, fragment ions in m/z with relative intensities
sponding alcohol resulting from over-addition to the ketone (%) in parentheses. High-resolution mass spectra were obtained by
the service at the University of Alicante on a Finnigan MAT 95 S
apparatus. The purities of volatile products and chromatographic
analyses (GLC) were determined on an Agilent 6890 Series instru-
ment equipped with a flame ionization detector and a 30 m capil-
lary column (0.32 mm diam., 0.25 µm film thickness), with nitrogen
(2 mL/min) as carrier gas, Tinjector ϭ 275 °C, Tdetector ϭ 300 °C,
Tcolumn ϭ 60 °C (3 min) and 60Ϫ270 °C (15 °C/min). Thin layer
chromatography (TLC) was carried out on Merck plastic sheets
coated with 60 F254 silica gel. Column chromatography was carried
out on Merck 63Ϫ200 µm silica gel. All starting materials and sol-
14 was detected. As is well known, this is the normal pro-
cess when an alkyllithium, such as compound 3, is treated
with an acyl chloride, even under favorable stoichiometric
conditions.[22]
In the final part of this study we investigated reactions
between intermediate 5 and α,β-unsaturated ketones.[23] In
this case it was not only necessary to use a stoichiometric
amount of copper() cyanide to activate the organometallic
reagent, but we also needed to activate the carbonyl com-
pound with the boron trifluoride/diethyl ether complex.[24] vents were commercially available (Acros, Aldrich, Fluka) and were
used as the best grade without further purification. Lithium pow-
der was prepared from commercially available lithium granules
(99%, high sodium content, Aldrich) as already reported by us.[26]
Zinc bromide was dried with a heating gun under reduced pressure
(0.1 Torr) for 15 h before use. 3-Phenylpropargyl chloride was pre-
pared by the reported procedure.[27]
Under these reaction conditions the expected 1,4-addition
products 15 were isolated (Scheme 3 and Scheme 6, Table 1,
entries 28Ϫ31) without any contamination with the corre-
sponding 1,2-addition adducts, which were the main prod-
ucts when intermediate 3 was used in the absence of the
copper and boron partners.[25]
SN2Ј Reactions between Intermediate 5 and Allylic and Propargylic
Halides. Isolation of Compounds 7؊9. General Procedure: 6-Chlo-
rohex-1-ene (0.138 mL, 1.0 mmol) was added at Ϫ30 °C under an
argon atmosphere to a stirred green suspension of lithium powder
(40 mg, 5.8 mmol) and DTBB (13.3 mg, 0.05 mmol) in THF
(4 mL). The color disappeared after the substrate addition, the re-
action mixture was stirred until the green color was regenerated
(40 min), and the excess lithium was then filtered off under inert
conditions. The resulting solution was added at 0 °C to a solution
of zinc bromide (260 mg, 1.1 mmol) in THF (5 mL) and the color
of the mixture changed to brown. A solution of CuCN·2LiCl [pre-
pared by dissolving copper() cyanide (100 mg, 1.1 mmol) and lith-
ium chloride (93 mg, 2.2 mmol) in THF (5 mL)] was added to the
resulting mixture, which then turned black. The solution was
stirred for 10 min at 0 °C and the corresponding allylic or propar-
gylic halide (1.1 mmol) was added. After 2 h stirring, the reaction
mixture was hydrolyzed with water (10 mL), acidified (2  HCl,
10 mL), and extracted with ethyl acetate (3 ϫ 20 mL). The organic
layer was washed with saturated NH4Cl solution (2 ϫ 15 mL) and
Scheme 6. (i) CuCN·2LiCl, THF,
0 °C, 15 min; (ii) E ϭ
R1CHCR2COR3, BF3·OEt2, THF, 0 °C; (iii) HCl/H2O
Conclusion
Lithium/zinc transmetallation, after intramolecular car-
bolithiation, allows the reactivity of the corresponding cyc-
lic organolithium intermediates to be expanded, to afford
new reactions not possible through lithium chemistry alone,
including SN2Ј reactions, arylation, vinylation, benzylation, dried over MgSO4, and the solvents were evaporated (15 Torr) to
yield a residue, which was purified by column chromatography (sil-
ica gel, hexane) to give compounds 7Ϫ9. Structures and yields are
given in Scheme 3 and Table 1; physical, spectroscopic and analyti-
cal data follow.
acylation, and conjugate addition. In all these processes the
organozinc reagent 5 is activated with a transition metal
such as copper or palladium. It is noteworthy that all yields
given in this paper are relative to the starting chlorinated
material 1, and so include the processes of (a) lithiation, (b)
carbolithiation, (c) lithium-zinc transmetallation, (d) tran-
sition metal-promoted coupling, and (e) final hydrolysis,
suggesting that they can be considered rather good, this
route being convenient for the generation of cyclopentane
derivatives. In all cases variable amounts of methylcyclo-
pentane, the result of metal-hydrogen exchange from inter-
mediates 3 and/or 5, are obtained as by-product (GLC), this
compound being easily removable thanks to its high vola-
tility.
4-Cyclopentyl-3-phenyl-1-butene (7a): Rf ϭ 0.69 (hexane). IR (film):
1
ν˜ ϭ 3080, 3061, 3026 (CϭCH), 1636, 1600, 1492 cmϪ1 (CϭC). H
NMR (300 MHz, CDCl3): δ ϭ 1.31 (m, 11 H, 5 ϫ CH2, CH), 3.29
(m, 1 H, CHCHϭ), 5.01 (m, 2 H, CH2ϭ), 5.95 (ddd, J ϭ 7.7, 10.2,
17.1 Hz, 1 H, CHϭ), 7.23 (m, 5 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 25.1, 25.2, 32.6, 32.7 (4 ϫ CH2), 37.6 (CH), 42.1
(CHCH2CH), 49.0 (CHCHϭ), 113.6 (CH2ϭ), 126.0, 127.6, 128.4,
144.8 (ArC), 142.7 (CHϭ) ppm. GC-LRMS: m/z (%) ϭ 201 (1.0)
[Mϩ ϩ1], 200 (6.0) [Mϩ], 118 (36), 117 (100), 115 (29), 104 (14),
91 (16), 55 (14). HRMS for C15H20: calcd. 200.1565; found
200.1574 [Mϩ].
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Tandem Intramolecular Carbolithiation-Lithium/Zinc Transmetallation
FULL PAPER
3-(Cyclopentylmethyl)-3,7-dimethylocta-1,6-diene (7b): Rf ϭ 0.81
(38), 84 (30), 83 (35), 82 (99), 81 (43), 80 (19), 79 (54), 77 (26), 69
(hexane). IR (film): ν˜ ϭ 3080, 3056 (CϭCH), 1636 cmϪ1 (CϭC). (54), 68 (28), 67 (100), 66 (20), 65 (15), 55 (31), 53 (25). HRMS for
1H NMR (300 MHz, CDCl3): δ ϭ 0.98 (s, 3 H, CH2CCH3), 1.02
(m, 2 H, CH2), 1.29 (m, 2 H, CH2), 1.49 (m with s at 1.58, 9 H,
CH3CCH3, 3 ϫ CH2), 1.85 (m with s at 1.67, 8 H, CH3CCH3, 2
ϫ CH2, CH), 4.88 (dd, J ϭ 1.4, 17.5 Hz, 1 H, CHHϭ), 4.95 (dd,
J ϭ 1.4, 10.8 Hz, 1 H, CHHϭ), 5.08 [def. t, J ϭ 7.1 Hz, 1 H,
(CH3)2CϭCH], 5.73 (dd, J ϭ 10.8, 17.5 Hz, 1 H, CH2ϭCH) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 17.6, 22.7 [(CH3)2Cϭ], 22.9, 25.1
(3 ϫ CH2), 25.7 (CH3CHCH2), 35.0, 35.1 (2 ϫ CH2), 36.5
(CH2CHCH2), 40.1 (CH2CCH3), 41.6, 47.8 (2 ϫ CH2), 111.1 (ϭ
CH2), 125.2 [(CH3)2CϭCH], 130.9 [(CH3)2CϭCH], 148.0 (CH2ϭ
CH) ppm. GC-LRMS: m/z (%) ϭ 220 (3.0) [Mϩ], 138 (13), 137
(12), 109 (70), 96 (13), 95 (83), 83 (43), 82 (61), 81 (69), 79 (10), 70
(12), 69 (100), 68 (21), 67 (52), 55 (78), 53 (16). HRMS for C16H28:
calcd. 220.2191; found 220.2199 [Mϩ].
C16H26: calcd. 218.2035; found 218.2035 [Mϩ].
Arylation, Vinylation, and Benzylation of Intermediate 5. Isolation
of Compounds 10؊13. General Procedure: 6-Chlorohex-1-ene
(0.138 mL, 1.0 mmol) was added at Ϫ30 °C under an argon atmos-
phere to a stirred green suspension of lithium powder (40 mg,
5.8 mmol) and DTBB (13.3 mg, 0.05 mmol) in THF (4 mL). The
color disappeared after the substrate addition, the reaction mixture
was stirred until the green color was regenerated (40 min), and the
lithium excess was then filtered off under inert conditions. The re-
sulting solution was added at room temperature to a solution of
zinc bromide (260 mg, 1.1 mmol) in THF (5 mL), and the color of
the mixture changed to brown. A solution of Pd(OAc)2(PtBu3)2
[prepared by dissolving palladium() acetate (11.3 mg, 0.05 mmol)
and tri-tert-butylphosphane (22 mg, 0.1 mmol) in THF (7 mL)] was
added to the resulting mixture, and the corresponding aryl halide
(1.1 mmol) was then added. The mixture was heated at reflux for
6 h and was then hydrolyzed with water (10 mL), acidified (2 
HCl, 10 mL) and extracted with ethyl acetate (3 ϫ 20 mL). The
organic layer was washed with saturated NH4Cl solution (2 ϫ
15 mL) and dried over MgSO4. The solvents were evaporated
(15 Torr) to yield a residue, which was purified by column chroma-
tography (silica gel, hexane/ethyl acetate) to give compounds
10Ϫ13. Structures and yields are given in Scheme 3 and Table 1;
physical, spectroscopic and analytical data follow.
4-Bromo-3-(cyclopentylmethyl)-1-butene (7c): Rf ϭ 0.67 (hexane).
IR (film): ν˜ ϭ 3076 (CϭCH), 1641 cmϪ1 (CϭC). 1H NMR
(300 MHz, CDCl3): δ ϭ 1.46 (m, 11 H, 5 ϫ CH2, CH2CHCH2),
2.41 (m, 1 H, CHCH2Br), 3.35 (d, J ϭ 2.8 Hz, 1 H, BrCHH), 3.37
(d, J ϭ 2.3 Hz, 1 H, BrCHH), 5.10 (m, 2 H, CH2ϭ), 5.62 (m, 1 H,
CHϭ) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 25.06, 25.09, 32.1,
33.1 (4 ϫ CH2), 37.3 (CH2CHCH2), 38.6, 39.5 (2 ϫ CH2), 44.9
(CHCH2Br), 116.5 (CH2ϭ), 139.8 (CHϭ) ppm. GC-LRMS: m/z
(%) ϭ 189 (1.3) [Mϩ Ϫ (CHϭCH2)], 137 (12), 123 (19), 109 (11),
95 (33), 83 (55), 82 (68), 81 (68), 79 (15), 69 (28), 68 (19), 67 (87),
55 (100), 54 (46), 53 (37). HRMS for C8H12Br: calcd. 189.0279;
found 189.0067 [Mϩ Ϫ (CHϭCH2)].
(Cyclopentylmethyl)benzene (10a):[28] Rf ϭ 0.62 (hexane). IR (film):
ν˜ ϭ 3084, 3062, 3026 (ArCϪH), 1603, 1495 cmϪ1 (ArCϪC). 1H
NMR (300 MHz, CDCl3): δ ϭ 1.19 (m, 2 H, CH2), 1.60 (m, 6 H,
3 ϫ CH2), 2.08 (def. sept, J ϭ 7.6 Hz, 1 H, CH), 2.60 (d, J ϭ
7.3 Hz, 2 H, ArCH2), 7.21 (m, 5 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 24.9, 32.4 (4 ϫ CH2), 42.0 (CH), 42.1
(CH2), 125.5, 128.1, 128.8, 142.4 (ArC) ppm. GC-LRMS: m/z
(%) ϭ 161 (2.9) [Mϩ ϩ 1], 160 (20.2) [Mϩ], 92 (100), 91 (52), 69
(19), 65 (10). HRMS for C12H16: calcd. 160.1252; found 160.1260
[Mϩ].
4-Cyclopentyl-3-phenyl-1,2-butadiene (8a): Rf ϭ 0.70 (hexane). IR
(film): ν˜ ϭ 3059, 3027 (CϭCϭCϪH), 1940 cmϪ1 (CϭCϭC). 1H
NMR (300 MHz, CDCl3): δ ϭ 1.22 (m, 2 H, CH2), 1.56 (m, 4 H,
2 ϫ CH2), 1.81 (m, 2 H, CH2), 2.10 (sept, J ϭ 7.6 Hz, 1 H, CH),
2.41 (t, J ϭ 3.2 Hz, 1 H, CHHCϭCϭ), 2.43 (t, J ϭ 3.5 Hz, 1 H,
CHHCϭCϭ), 5.04 (d, J ϭ 3.0 Hz, 1 H, CHHϭ), 5.05 (d, J ϭ
3.1 Hz, 1 H, CHHϭ), 7.18 (t, J ϭ 7.3 Hz, 1 H, ArH), 7.30 (m, 2
H, ArH), 7.40 (d, J ϭ 7.6 Hz, 2 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 25.2, 32.7, 36.4 (5 ϫ CH2), 38.2 (CH), 77.6 (CH2ϭ),
104.6 (CH2ϭCϭC), 126.0, 126.5, 128.3, 136.6 (ArC), 209.2 (CH2ϭ
CϭC) ppm. GC-LRMS: m/z (%) ϭ 199 (0.7) [Mϩ ϩ1], 198 (4.1)
[Mϩ], 131 (14), 130 (100), 129 (72), 128 (28), 127 (11), 115 (49), 91
(11). HRMS for C15H18: calcd. 198.1409; found 198.1406 [Mϩ].
p-(Cyclopentylmethyl)toluene (10b): Rf ϭ 0.71 (hexane). IR (film):
1
ν˜ ϭ 3047, 3018, 3003 (ArCϪH), 1514 cmϪ1 (ArCϪC). H NMR
(300 MHz, CDCl3): δ ϭ 1.17 (m, 2 H, CH2), 1.59 (m, 6 H, 3 ϫ
CH2), 2.05 (sept, J ϭ 7.6 Hz, 1 H, CHCH2), 2.30 (s, 3 H, CH3),
2.55 (d, J ϭ 7.5 Hz, 2 H, ArCH2), 7.06 (m, 4 H, ArH) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ 21.0 (CH3), 24.9, 32.4, 41.6 (5 ϫ
CH2), 42.1 (CHCH2), 128.6, 128.8, 134.8, 139.3 (ArC) ppm. GC-
LRMS: m/z (%) ϭ 175 (2.6) [Mϩ ϩ1], 174 (26.8) [Mϩ], 106 (86),
105 (100), 91 (23). HRMS for C13H18: calcd. 174.1409; found
174.1406 [Mϩ].
3-(Cyclopentylmethyl)-1,2-octadiene (8b): Rf ϭ 0.88 (hexane). IR
1
(film): ν˜ ϭ 3046 (CϭCϭCϪH), 1957 cmϪ1 (CϭCϭC). H NMR
(300 MHz, CDCl3): δ ϭ 0.89 (t, J ϭ 6.6 Hz, 3 H, CH3), 1.56 (m,
19 H, 9 ϫ CH2, CH), 4.62 (m, 2 H, ϭCH2) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 14.1 (CH3), 22.6, 25.3, 27.3, 31.6, 32.2, 32.7,
39.1 (9 ϫ CH2), 38.1 (CH), 74.8 (CϭCϭCH2), 102.9 (CϭCϭCH2),
206.3 (CϭCϭCH2) ppm. GC-LRMS: m/z (%) ϭ 192 (0.7) [Mϩ],
121 (43), 109 (15), 107 (24), 95 (42), 94 (18), 93 (35), 91 (18), 82
(12), 81 (34), 80 (14), 79 (39), 77 (16), 69 (31), 68 (100), 67 (69), 55
(23), 53 (14). HRMS for C14H24: calcd. 192.1878; found 192.1860
[Mϩ].
p-(Cyclopentylmethyl)anisole (10c):[29] Rf ϭ 0.26 (hexane). IR
(film): ν˜ ϭ 3060, 3030 (ArCϪH), 1612, 1583, 1512 (ArCϪC), 1246,
1
1040 cmϪ1 (CϪO). H NMR (300 MHz, CDCl3): δ ϭ 1.17 (m, 2
H, CH2), 1.53 (m, 2 H, CH2), 1.67 (m, 4 H, 2 ϫ CH2), 2.04 (def.
sept, J ϭ 7.5 Hz, 1 H, CH2CH), 2.54 (d, J ϭ 7.5 Hz, 2 H, ArCH2),
3.78 (s, 3 H, OCH3), 6.81 (d, J ϭ 8.6 Hz, 2 H, 2 ϫ ArH), 7.08 (d,
J ϭ 8.4 Hz, 2 H, 2 ϫ ArH) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 24.9, 32.4 (4 ϫ CH2), 41.1 (ArCH2), 42.2 (CH), 55.2 (CH3),
113.5, 129.6, 134.5, 157.5 (6 ϫ ArC) ppm. GC-LRMS: m/z (%) ϭ
191 (1.2) [Mϩ ϩ 1], 190 (8.6) [Mϩ], 122 (13), 121 (100).
2,3-Bis(cyclopentylmethyl)-1,3-butadiene (9):[17] Rf ϭ 0.85 (hexane).
1
IR (film): ν˜ ϭ 3088 (CϭCH), 1629, 1592 cmϪ1 (CϭC). H NMR
(300 MHz, CDCl3): δ ϭ 1.13, 1.60, 1.98 (3 m, 18 H, 8 ϫ CH2, 2
ϫ CH), 2.22 (d, J ϭ 7.3 Hz, 4 H, 2 ϫ CH2Cϭ), 4.88 (s, 2 H, ϭ
CH2), 5.03 (s, 2 H, ϭCH2) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 1-(Cyclopentylmethyl)-p-nitrobenzene (10d):[30] Rf ϭ 0.35 (hexane).
25.1, 32.5, 40.9 (10 ϫ CH2), 38.4 (2 ϫ CH), 112.0 (2 ϫ ϭCH2), IR (film): ν˜ ϭ 3103, 3077, 3048 (CϭCH), 1597 (CϭC), 1517, 1345
147.7 (2 ϫ CϭCH2) ppm. GC-LRMS: m/z (%) ϭ 219 (1.2) [Mϩ cmϪ1 (NO2). 1H NMR (300 MHz, CDCl3): δ ϭ 1.20 (m, 2 H, CH2),
ϩ1], 218 (5.5) [Mϩ], 150 (30), 149 (44), 136 (28), 135 (83), 121 (48), 1.63 (m, 6 H, 3 ϫ CH2), 2.10 (def. sept, J ϭ 7.7 Hz, 1 H, CH),
109 (16), 108 (53), 107 (91), 104 (13), 95 (33), 94 (23), 93 (55), 91
2.72 (d, J ϭ 7.5 Hz, 2 H, ArCH2), 7.32 (d, J ϭ 8.7 Hz, 2 H, ArH),
Eur. J. Org. Chem. 2004, 3833Ϫ3841
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3837

M. Yus, R. Ortiz
8.13 (d, J ϭ 8.7 Hz, 2 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): CDCl3): δ ϭ 15.9 (CH3), 25.4, 33.6 (4 ϫ CH2), 39.7 (CH), 125.5,
FULL PAPER
δ ϭ 24.8, 32.4, 41.6 (5 ϫ CH2), 41.9 (CH), 123.4, 129.4, 146.1,
126.3, 128.1, 143.9 (ArC), 133.1 (Cϭ), 134.2 (CHϭ) ppm. GC-
150.3 (ArC) ppm. GC-LRMS: m/z (%) ϭ 206 (0.77) [Mϩ ϩ1], 205 LRMS: m/z (%) ϭ 186 (42.8) [Mϩ], 171 (29), 157 (18), 144 (18),
(5.62) [Mϩ], 137 (100), 115 (10), 107 (17), 91 (11), 90 (13), 69 (40). 143 (55), 142 (15), 141 (19), 130 (19), 129 (90), 128 (61), 127 (16),
HRMS for C12H15NO2: calcd. 205.1103; found 205.1110 [Mϩ].
119 (12), 118 (100), 117 (36), 115 (37), 105 (33), 103 (15), 91 (41),
78 (10), 77 (21), 51 (11). HRMS for C14H18: calcd. 186.1409; found
186.1404 [Mϩ].
2-(Cyclopentylmethyl)thiophene (10e):[31] Rf ϭ 0.66 (hexane). IR
1
(film): ν˜ ϭ 3106, 3070, 3045 cmϪ1 (ArCϪH). H NMR (300 MHz,
(2-Cyclopentylethyl)benzene (13a):[35] Rf ϭ 0.75 (hexane). IR (film):
ν˜ ϭ 3085, 3062, 3026 (ArCϪH), 1603, 1496 cmϪ1 (ArCϪC). 1H
NMR (300 MHz, CDCl3): δ ϭ 1.15 (m, 2 H, CH2), 1.57 (m, 6 H,
3 ϫ CH2), 1.78 (m, 4 H, 2 ϫ CH2), 2.61 (t, J ϭ 7.9 Hz, 2 H,
PhCH2), 7.16, 7.27 (2m, 3H and 2H respectively, ArH) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ 25.2, 32.6, 35.1, 38.1 (6 ϫ CH2), 39.6
(CHCH2), 125.5, 128.2, 128.3, 143.1 (ArC) ppm. GC-LRMS: m/z
(%) ϭ 174 (16.9) [Mϩ], 92 (100), 91 (43), 83 (11), 55 (19). HRMS
for C13H18: calcd. 174.1409; found 174.1406 [Mϩ].
CDCl3): δ ϭ 1.24 (m, 2 H, CH2), 1.57 (m, 4 H, 2 ϫ CH2), 1.78
(m, 2 H, CH2), 2.14 (sept, J ϭ 7.6 Hz, 1 H, CH), 2.81 (d, J ϭ
7.3 Hz, 2 H, ArCH2), 6.77 (d, J ϭ 3.4 Hz, 1 H, ArH), 6.91 (dd,
J ϭ 3.4, 5.1 Hz, 1 H, ArH), 7.10 (m, 1 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 25.1, 32.4, 36.1 (5 ϫ CH2), 42.1 (CH),
122.8, 124.3, 126.5, 145.2 (4 ϫ ArC) ppm. GC-LRMS: m/z (%) ϭ
167 (3.2) [Mϩ ϩ1], 166 (24.5) [Mϩ], 98 (60), 97 (100), 69 (10).
3-(Cyclopentylmethyl)thiophene (10f): Rf ϭ 0.81 (hexane). IR (film):
1
ν˜ ϭ 3104, 3072, 3048, 1536 cmϪ1 (ArCϪH). H NMR (300 MHz,
1-tert-Butyl-4-(cyclopentylethyl)benzene (13b): Rf ϭ 0.76 (hexane).
IR (film): ν˜ ϭ 3091, 3054, 3022 cmϪ1 (ArCϪH). 1H NMR
(300 MHz, CDCl3): δ ϭ 1.13 (m, 2 H, CH2), 1.31 (s, 9 H, 3 ϫ
CH3), 1.57 (m, 6 H, 3 ϫ CH2), 1.80 (m, 3 H, CH, CH2), 2.59 (t,
J ϭ 8.0 Hz, 2 H, ArCH2), 7.12 (d, J ϭ 8.1 Hz, 2 H, 2 ϫ ArH),
7.29 (d, J ϭ 8.3 Hz, 2 H, 2 ϫ ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 25.2 (CH2), 31.4 (3 ϫ CH3), 32.6 (CH2), 34.3
[C(CH3)3], 34.6, 38.1 (2 ϫ CH2), 39.7 (CH), 125.1, 128.0, 140.0,
148.2 (6 ϫ ArC) ppm. GC-LRMS: m/z (%) ϭ 230 (12.6) [Mϩ], 216
(17), 215 (100), 147 (11), 117 (16), 91 (10), 55 (17). HRMS for
C17H26: calcd. 230.2035; found 230.2010 [Mϩ].
CDCl3): δ ϭ 1.17 (m, 2 H, CH2), 1.62 (m, 6 H, 3 ϫ CH2), 2.10
(sept, J ϭ 7.6 Hz, 1 H, CHCH2), 2.62 (d, J ϭ 7.4 Hz, 2 H,
CHCH2), 6.92 (m, 2 H, SCHϭCCH), 7.21 (dd, J ϭ 3.0, 4.8 Hz, 1
H, SCHϭCH). 13C NMR (75 MHz, CDCl3): δ ϭ 25.0, 32.6, 36.4
(5 ϫ CH2), 41.1 (CH2CH), 120.2, 124.8, 128.6, 142.7 (ArC). GC-
LRMS: m/z (%) ϭ 167 (1.3) [Mϩ ϩ1], 166 (11.7) [Mϩ], 98 (100),
97 (66). HRMS for C10H14S: calcd. 166.0816; found 166.0823 [Mϩ].
2-(Cyclopentylmethyl)pyridine (10g):[32] Rf ϭ 0.16 (hexane/ethyl
acetate, 9:1). IR (film): ν˜ ϭ 3065, 3007 (ArCϪH), 1591, 1473 cmϪ1
1
(ArCϪC and CϭN). H NMR (300 MHz, CDCl3): δ ϭ 1.22 (m,
2 H, CH2), 1.63 (m, 6 H, 3 ϫ CH2), 2.27 (sept, J ϭ 7.7 Hz, 1 H,
CH), 2.79 (d, J ϭ 7.5 Hz, 2 H, ArCH2), 7.10 (m, 2 H, 2 ϫ ArH),
7.57 (def. t, J ϭ 7.6 Hz, 1 H, ArH), 8.52 (d, J ϭ 4.2 Hz, 1 H, ArH)
ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 24.8, 32.3 (4 ϫ CH2), 40.5
(CH), 44.2 (CH2Ar), 120.7, 122.9, 136.0, 149.0, 161.9 (5 ϫ ArC)
ppm. GC-LRMS: m/z (%) ϭ 161 (2.1) [Mϩ], 160 (6), 132 (9), 118
(7), 94 (9), 93 (100).
1-(2-Cyclopentylethyl)-4-fluorobenzene (13c): Rf ϭ 0.72 (hexane).
IR (film): ν˜ ϭ 3069, 3039 (ArCϪH), 1600, 1509 (ArCϪC), 1222
1
cmϪ1 (ArCϪF). H NMR (300 MHz, CDCl3): δ ϭ 1.10 (m, 2 H,
CH2), 1.55 (m, 6 H, 3 ϫ CH2), 1.75 (m, 3 H, CH, CH2), 2.58 (t,
J ϭ 8.0 Hz, 2 H, ArCH2), 6.94 (tt, J ϭ 2.1, 8.7 Hz, 2 H, 2 ϫ ArH),
7.12 (m, 2 H, 2 ϫ ArH) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ
25.2, 32.6, 34.3, 38.2 (6 ϫ CH2), 39.5 (CH), 114.7, 115.0, 129.5,
129.6, 138.55, 138.60, 159.5, 162.7 (6 ϫ ArC) ppm. GC-LRMS: m/
z (%) ϭ 193 (3.3) [Mϩ ϩ 1], 192 (22.8) [Mϩ], 110 (97), 109 (100),
83 (47), 55 (37). HRMS for C13H17F: calcd. 192.1314; found
192.1325 [Mϩ].
3-(Cyclopentylmethyl)pyridine (10h):[33] Rf ϭ 0.10 (hexane/ethyl
acetate, 9:1). IR (film): ν˜ ϭ 3081, 3050, 3027 (ArCϪH), 1574, 1477
1
cmϪ1 (ArCϪC and CϭN). H NMR (300 MHz, CDCl3): δ ϭ 1.19
(m, 2 H, CH2), 1.62 (m, 6 H, 3 ϫ CH2), 2.07 (sept, J ϭ 7.7 Hz, 1
H, CH), 2.60 (d, J ϭ 7.5 Hz, 2 H, ArCH2), 7.19 (dd, J ϭ 4.8,
7.7 Hz, 1 H, ArH), 7.48 (def. d, J ϭ 7.7 Hz, 1 H, ArH), 8.44 (m,
2 H, 2 ϫ ArH) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 24.8, 32.2
(4 ϫ CH2), 39.0 (CH2Ar), 41.6 (CH), 123.1, 136.1, 137.4, 147.0,
150.0 (5 ϫ ArC) ppm. GC-LRMS: m/z (%) ϭ 161 (24.9) [Mϩ], 94
(14), 93 (100), 92 (12), 69 (14).
Acylation of Intermediate 5. Isolation of Ketones 14. General Pro-
cedure: 6-Chlorohex-1-ene (0.138 mL, 1.0 mmol) was added at Ϫ30
°C under an argon atmosphere to a stirred green suspension of
lithium powder (40 mg, 5.8 mmol) and DTBB (13.3 mg,
0.05 mmol) in THF (4 mL). The color disappeared after the sub-
strate addition, the reaction mixture was stirred until the green
color was regenerated (40 min), and the excess lithium was then
filtered off under inert conditions. The resulting solution was added
at 0 °C to a solution of zinc bromide (300 mg, 1.3 mmol) in THF
(5 mL), the color of the mixture changing to brown. A solution of
PdCl2(PPh3)2 (35 mg, 0.05 mmol) in THF (7 mL) was added to the
resulting mixture, which was stirred for 10 min at 0 °C. The corre-
sponding acid chloride (1.1 mmol) was then added. After 2 h stir-
ring, the reaction mixture was hydrolyzed with water (10 mL),
acidified (2  HCl, 10 mL), and extracted with ethyl acetate (3 ϫ
20 mL). The organic layer was washed with saturated NH4Cl solu-
tion (2 ϫ 15 mL) and dried over MgSO4, and the solvents were
evaporated (15 Torr) to yield a residue, which was purified by col-
umn chromatography (silica gel, hexane/ethyl acetate) to give com-
pounds 14. Structures and yields are given in Scheme 3 and Table 1;
physical, spectroscopic and analytical data follow.
3-Cyclopentyl-1-phenyl-1-propene (11a):[34] Rf ϭ 0.59 (hexane). IR
(film): ν˜ ϭ 3081, 3059, 3024 (CϭCH), 1598, 1496 cmϪ1 (CϭC). 1H
NMR (300 MHz, CDCl3): δ ϭ 1.19 (m, 2 H, CH2), 1.57 (m, 4 H,
2 ϫ CH2), 1.77 (m, 2 H, CH2), 1.93 (sept, J ϭ 7.5 Hz, 1 H, CH),
2.20 (t, J ϭ 6.9 Hz, 2 H, CHCH2), 6.22 (dt, J ϭ 7.0, 15.8 Hz, 1 H,
ArCHϭCH), 6.36 (d, J ϭ 15.8 Hz, 1 H, ArCHϭCH), 7.17 (def. t,
J ϭ 7.0 Hz, 1 H, ArH), 7.30 (m, 4 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 25.1, 32.3, 39.4 (5 ϫ CH2), 40.0 (CHCH2),
125.9, 126.7, 128.4, 130.1, 130.5, 137.9 (8C, ArCHϭCH) ppm. GC-
LRMS: m/z (%) ϭ 186 (16.5) [Mϩ], 118 (32), 117 (100), 115 (35),
104 (85), 91 (19).
1-Cyclopentyl-2-phenyl-1-propene (12): Rf ϭ 0.61 (hexane). IR
(film): ν˜ ϭ 3080, 3056, 3023 (CϭCH), 1599, 1493 cmϪ1 (CϭC). 1H
NMR (300 MHz, CDCl3): δ ϭ 1.30 (m, 2 H, CH2), 1.65 (m, 4 H,
2 ϫ CH2), 1.87 (m, 2 H, CH2), 2.05 (s, 3 H, CH3), 2.79 (sext, J ϭ
8.3 Hz, 1 H, CH), 5.72 (d, J ϭ 8.9 Hz, 1 H, CHϭ), 7.19, 7.32, 7.39 1-Cyclopentyl-2-pentanone (14a): Rf ϭ 0.55 (hexane/ethyl acetate,
(3m, 2 H, 2H and 1H respectively, ArH) ppm. 13C NMR (75 MHz, 9:1). IR (film): ν˜ ϭ 1713 cmϪ1 (CϭO). 1H NMR (300 MHz,
3838
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Eur. J. Org. Chem. 2004, 3833Ϫ3841

Tandem Intramolecular Carbolithiation-Lithium/Zinc Transmetallation
FULL PAPER
CDCl3): δ ϭ 0.90 (t, J ϭ 7.3 Hz, 3 H, CH3), 1.07 (m, 2 H, CH2),
(100), 92 (14), 77 (18). HRMS for C14H18O2: calcd. 218.1307; found
1.30 (sext, J ϭ 7.4 Hz, 2 H, CH3CH2), 1.57 (m, 6 H, 3 ϫ CH2), 218.1325 [Mϩ].
1.81 (m, 2 H, CH2), 2.22 (sept, J ϭ 7.7 Hz, 1 H, CH), 2.40 (m, 4
α-Cyclopentyl-4-nitroacetophenone (14g): Rf ϭ 0.40 (hexane/ethyl
H, CH2COCH2) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 13.8
(CH3), 22.3, 24.9, 25.9, 25.8, 32.6 (6 ϫ CH2), 35.6 (CH), 42.7, 49.1
(CH2COCH2), 211.5 (CϭO) ppm. GC-LRMS: m/z (%) ϭ 169 (2.3)
[Mϩ ϩ 1], 168 (17.4) [Mϩ], 111 (45), 101 (47), 100 (11), 85 (51), 83
(100), 67 (11), 59 (39), 58 (86), 57 (63), 55 (70). HRMS for
C11H20O: calcd. 168.1514; found 168.1499 [Mϩ].
acetate, 9:1). IR (film): ν˜ ϭ 3108, 3077, 3049 (CϭCH), 1736, 1693
(CϭO), 1602 (CϭC), 1526, 1346, 1318 cmϪ1 (NO2). 1H NMR
(300 MHz, CDCl3): δ ϭ 1.20 (m, 2 H, CH2), 1.62 (m, 4 H, 2 ϫ
CH2), 1.89 (m, 2 H, CH2), 2.39 (def. sept, J ϭ 7.7 Hz, 1 H, CH),
3.05 (d, J ϭ 7.0 Hz, 2 H, CH2CO), 8.11 (d, J ϭ 8.9 Hz, 2 H, 2 ϫ
ArH), 8.31 (d, J ϭ 8.6 Hz, 2 H, 2 ϫ ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 24.9, 32.6 (4 ϫ CH2), 35.7 (CH), 45.3
1-Cyclopentyl-3,3-dimethyl-2-butanone (14b):[36] Rf ϭ 0.70 (hexane/
ethyl acetate, 9:1). IR (film): ν˜ ϭ 1076 cmϪ1 (CϭO). 1H NMR (CH2), 55.3 (OCH3), 123.8, 129.0, 141.5, 150.1 (ArC), 198.6 (1CϭO)
(300 MHz, CDCl3): δ ϭ 1.03 (m, 2 H, CH2), 1.12 (s, 9 H, 3 ϫ ppm. GC-LRMS: m/z (%) ϭ 233 (0.9) [Mϩ], 216 (13), 167 (24),
CH3), 1.58 (m, 4 H, 2 ϫ CH2), 1.82 (m, 2 H, CH2), 2.26 (def. sept,
J ϭ 7.7 Hz, 1 H, CH), 2.51 (d, J ϭ 6.9 Hz, 2 H, CH2CO) ppm.
166 (32), 165 (100), 150 (71), 120 (10), 104 (43), 92 (17), 76 (25),
67 (16), 55 (19). HRMS for C13H15NO3: calcd. 233.1052; found
13C NMR (75 MHz, CDCl3): δ ϭ 25.0 (2 ϫ CH2), 26.3 (3 ϫ CH3), 233.1030 [Mϩ].
32.6 (2 ϫ CH2), 35.2 (CH), 42.7 (CH2CϭO), 43.9 [C(CH3)3], 215.9
Conjugate Addition of Intermediate 5 to α,β-Unsaturated Ketones.
(CϭO) ppm. GC-LRMS: m/z (%) ϭ 168 (6.6) [Mϩ], 111 (59), 83
(100), 57 (57), 55 (39). HRMS for C11H20O: calcd. 168.1514; found
168.1507 [Mϩ].
Isolation of Compounds 15. General Procedure: 6-Chlorohex-1-ene
(0.138 mL, 1.0 mmol) was added at Ϫ30 °C under an argon atmos-
phere to a stirred green suspension of lithium powder (40 mg,
5.8 mmol) and DTBB (13.3 mg, 0.05 mmol) in THF (4 mL). The
Cyclohexyl Cyclopentylmethyl Ketone (14c): Rf ϭ 0.57 (hexane/ethyl
acetate, 9:1). IR (film): ν˜ ϭ 1708 cmϪ1 (CϭO). 1H NMR color disappeared after the substrate addition, the reaction mixture
(300 MHz, CDCl3): δ ϭ 1.06 (m, 2 H, CH2), 1.30 (m, 6 H, 3 ϫ was stirred until the green color was regenerated (40 min), and the
CH2), 1.58 (m, 4 H, 2 ϫ CH2), 1.80 (m, 6 H, 3 ϫ CH2), 2.25 (m, excess lithium was then filtered off under inert conditions. The re-
2 H, 2 ϫ CH), 2.45 (d, J ϭ 7.2 Hz, 2 H, CH2CO) ppm. 13C NMR sulting solution was added at 0 °C to a solution of zinc bromide
(75 MHz, CDCl3): δ ϭ 24.9, 25.6, 25.8, 28.4, 32.6 (9 ϫ CH2), 35.3
(260 mg, 1.1 mmol) in THF (5 mL), the color of the mixture chang-
(CHCH2CϭO), 46.9 (CH2CϭO), 50.8 (CHCϭO), 214.2 (CϭO) ing to brown. A solution of CuCN·2LiCl [prepared by dissolving
ppm. GC-LRMS: m/z (%) ϭ 195 (1.4) [Mϩ ϩ 1], 194 (9.5) [Mϩ], copper() cyanide (100 mg, 1.1 mmol) and lithium chloride (93 mg,
127 (14), 126 (15), 111 (48), 83 (100), 55 (50). HRMS for C13H22O: 2.2 mmol) in THF (5 mL)] was added to the resulting mixture,
calcd. 194.1671; found 194.1671 [Mϩ].
which then changed to a black color. The solution was stirred at 0
°C for 10 min, and a mixture of the electrophile (1.1 mmol) and
BF3·Et2O (2.2 mmol) was added. After 2 h stirring the reaction
mixture was hydrolyzed with water (10 mL), acidified (2  HCl,
10 mL), and extracted with ethyl acetate (3 ϫ 20 mL). The organic
layer was washed with saturated NH4Cl solution (2 ϫ 15 mL) and
dried over MgSO4. The solvents were evaporated (15 Torr) to yield
a residue, which was purified by column chromatography (silica gel,
hexane) to give compounds 15. Structures and yields are given in
Scheme 3 and Table 1; physical, spectroscopic and analytical data
follow.
α-Cyclopentylacetophenone (14d):[37] Rf ϭ 0.69 (hexane/ethyl acet-
ate, 9:1). IR (film): ν˜ ϭ 3063, 3027 (CϭCH), 1599, (CϭC), 1688
cmϪ1 (CϭO). 1H NMR (300 MHz, CDCl3): δ ϭ 1.18 (m, 2 H,
CH2), 1.60 (m, 4 H, 2 ϫ CH2), 1.88 (m, 2 H, CH2), 2.39 (def. sept,
J ϭ 7.6 Hz, 1 H, CH), 2.99 (d, J ϭ 7.0 Hz, 2 H, CH2CO), 7.45,
7.55, 7.96 (3m, 2 H, 1 H and 2 H respectively, 5 ϫ ArH) ppm. 13C
NMR (75 MHz, CDCl3): δ ϭ 24.9, 32.7 (4 ϫ CH2), 36.0 (CH),
44.8 (CH2CϭO), 128.1, 128.5, 132.8, 137.2 (ArC), 200.4 (CϭO)
ppm. GC-LRMS: m/z (%) ϭ 189 (1.0) [Mϩ ϩ1], 188 (6.2) [Mϩ],
121 (17), 120 (87), 105 (100), 77 (45), 51 (11).
5-Cyclopentyl-2-pentanone (15a):[39] Rf ϭ 0.35 (hexane/ethyl acet-
4-tert-Butyl-α-cyclopentylacetophenone (14e): Rf ϭ 0.61 (hexane/
ethyl acetate, 9:1). IR (film): ν˜ ϭ 3088, 3056, 3034 (CϭCH), 1717,
1681 (CϭO), 1606 cmϪ1 (CϭC). 1H NMR (300 MHz, CDCl3): δ ϭ
1.19 (m, 2 H, CH2), 1.33 (s, 9 H, 3 ϫ CH3), 1.59 (m, 4 H, 2 ϫ
CH2), 1.85 (m, 2 H, CH2), 2.96 (d, J ϭ 7.0 Hz, 2 H, ArCOCH2),
7.46 (m, 2 H, 2 ϫ ArH), 7.90 (m, 2 H, 2 ϫ ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 24.9 (2 ϫ CH2), 31.0 (3 ϫ CH3), 32.6 (2 ϫ
CH2), 36.0 (CH2CH), 44.6 (ArCOCH2), 125.1, 128.0, 134.6, 166.6
(6 ϫ ArC), 199.8 (CϭO) ppm. GC-LRMS: m/z (%) ϭ 245 (0.2)
[Mϩ ϩ1], 244 (0.1) [Mϩ], 187 (18), 176 (44), 162 (12), 161 (100), 118
1
ate, 9:1). IR (film): ν˜ ϭ 1717 cmϪ1 (CϭO). H NMR (300 MHz,
CDCl3): δ ϭ 1.27 (m, 4 H, 2 ϫ CH2CH2CH), 1.54 (m, 5 H,
CHCH2CH2CH2CϭO), 1.73 (m, 4 H, 2 ϫ CH2CH2CH), 2.14 (s, 3
H, CH3), 2.42 (t, J ϭ 7.4 Hz, 2 H, CH2CϭO) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 23.1, 25.1 (3 ϫ CH2), 29.8 (CH3), 32.6, 35.6
(3 ϫ CH2), 39.9 (CH), 44.0 (CH2CϭO), 209.5 (CϭO). GC-LRMS:
m/z (%) ϭ 154 (1.8) [Mϩ], 121 (13), 97 (16), 96 (20), 94 (16), 71
(22), 69 (18), 67 (25), 59 (21), 58 (100), 55 (24).
3-(Cyclopentylmethyl)cyclopentan-1-one (15b):[40] Rf ϭ 0.34 (hex-
(11). HRMS for C16H21O: calcd. 229.1592; found 229.1558 [Mϩ Ϫ ane/ethyl acetate, 9:1). IR (film): ν˜ ϭ 1740 cmϪ1 (CϭO). 1H NMR
CH3].
(300 MHz, CDCl3): δ ϭ 1.09 (m, 2 H, CH2), 1.54 (m, 8 H, 4 ϫ
CH2), 1.80 (m, 4 H, 2 ϫ CH2), 2.20 (m, 4 H, 2 ϫ CH, CH2) ppm.
13C NMR (75 MHz, CDCl3): δ ϭ 25.01, 25.04 (2 ϫ CH2CH2CH),
29.8 (CH2), 32.8, 32.9 (2 ϫ CH2CH2CH), 36.4, 38.5 (2 ϫ CH),
38.6, 42.2, 45.6 (3 ϫ CH2), 220.1 (CϭO) ppm. GC-LRMS: m/z
(%) ϭ 167 (1.6) [Mϩ ϩ1], 166 (13.3) [Mϩ], 137 (11), 125 (30), 122
(11), 83 (100), 81 (15), 69 (27), 68 (16), 67 (33), 56 (13), 55 (44).
HRMS for C11H18O: calcd. 166.1358; found 166.1356 [Mϩ].
α-Cyclopentyl-4-methoxyacetophenone (14f):[38] Rf ϭ 0.33 (hexane/
ethyl acetate, 9:1). IR (film): ν˜ ϭ 3074, 3053 (CϭCH), 1711, 1676
(CϭO), 1258, 1031 cmϪ1 (ArCϪOϪC). 1H NMR (300 MHz,
CDCl3): δ ϭ 1.17 (m, 2 H, CH2), 1.58 (m, 4 H, 2 ϫ CH2), 1.86
(m, 2 H, CH2), 2.37 (def. sept, J ϭ 7.7 Hz, 1 H, CH), 2.93 (d, J ϭ
7.2 Hz, 2 H, CH2CO), 3.85 (s, 3 H, OCH3), 6.92 (d, J ϭ 8.9 Hz, 2
H, 2 ϫ ArH), 7.94 (d, J ϭ 8.9 Hz, 2 H, 2 ϫ ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ ϭ 24.8, 32.6 (4 ϫ CH2), 36.2 (CH), 44.3 3-(Cyclopentylmethyl)cyclohexan-1-one (15c): Rf ϭ 0.27 (hexane/
(CH2), 55.3 (OCH3), 113.5, 130.2, 131.4, 163.1 (6C, ArC), 198.9 ethyl acetate, 9:1). IR (film): ν˜ ϭ 1713 cmϪ1 (CϭO). 1H NMR
(CϭO) ppm. GC-LRMS: m/z (%) ϭ 218 (1.0) [Mϩ], 150 (78), 135 (300 MHz, CDCl3): δ ϭ 1.07 (m, 2 H, CH2), 1.22Ϫ2.09 (m, 16 H,
Eur. J. Org. Chem. 2004, 3833Ϫ3841
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3839

M. Yus, R. Ortiz
T. Arnauld, A. G.
FULL PAPER
[5d]
8 ϫ CH2), 2.34 (m, 2 H, 2 ϫ CH) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 25.0 (2 ϫ CH2), 25.3 (CH2), 31.5, 32.7, 32.8 (3 ϫ
CH2), 37.0 (CH), 38.2 (CHCH2CϭO), 41.5 (CHCH2CH), 43.2
(CH2CH2CϭO), 48.4 (CHCH2CϭO), 212.3 (CϭO) ppm. GC-
LRMS: m/z (%) ϭ 180 (2.6) [Mϩ], 98 (10), 97 (100), 69 (14), 67
(16), 55 (26). HRMS for C12H20O: calcd. 180.1514; found
180.1509 [Mϩ].
ela, Tetrahedron 2002, 58, 6207Ϫ6210.
M. Barrett, B. T. Hopkins, Tetrahedron Lett. 2002, 43,
1081Ϫ1083. For a polymer supported arene-catalyzed lithi-
[5e]
ation used in the activation of nickel, see:
F. Alonso, P.
´
Candela, C. Gomez, M. Yus, Adv. Synth. Catal. 2003, 345,
[5f]
´
P. Candela, C. Gomez, M. Yus, Russ. J. Org.
275Ϫ279.
Chem., in press.
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[7]
For a review, see: D. Guijarro, M. Yus, Recent Res. Dev. Org.
Chem. 1998, 2, 713Ϫ744.
5-Cyclopentyl-3,4-dimethylpentan-2-one (15d): (diastereomeric mix-
ture ca. 1:1) Rf ϭ 0.48 (hexane/ethyl acetate, 9:1). IR (film): ν˜ ϭ
[7a]
For reviews, see:
M. Yus, F. Foubelo, Rev. Heteroatom
[7b]
Chem. 1997, 17, 73Ϫ107.
M. Yus, F. Foubelo, Targets in
1
1711 cmϪ1 (CϭO). H NMR (300 MHz, CDCl3): δ ϭ 0.79 (d, J ϭ
Heterocyclic Systems 2002, 6, 136Ϫ171. [7c] M. Yus, Pure Appl.
6.7 Hz, 3 H, CHCH3), 0.92 (d, J ϭ 6.7 Hz, 3 H, CHCH3), 0.97 (d,
J ϭ 7.0 Hz, 3 H, CHCH3), 1.01 (d, J ϭ 6.9 Hz, 3 H, CHCH3),
1.08 (m, 4 H, 2 ϫ CH2), 1.56 (m, 10 H, 4 ϫ CH2, 2 ϫ CH), 1.81
(m, 10 H, 4 ϫ CH2, 2 ϫ CH), 2.13 (s, 6 H, 2 ϫ COCH3), 2.42 (m,
2 H, 2 ϫ CH cycle) ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 10.6,
12.1, 15.2, 17.9 (4 ϫ CH3), 25.0 (2 ϫ CH2), 28.4, 28.8 (2 ϫ
COCH3), 31.9, 32.3, 33.0, 33.7 (4 ϫ CH2), 33.2, 33.9, 37.4, 37.5 (4
ϫ CH), 38.9, 41.7 (4 ϫ CH2), 51.7, 53.1 (2 ϫ CHCO), 212.7, 212.8
(CϭO) ppm. GC-LRMS: m/z (%) ϭ 182 (0.2) [Mϩ], 99 (12), 83
(14), 72 (100), 69 (17), 57 (11), 55 (20). HRMS for C12H22O: calcd.
182.1671; found 182.1680 [Mϩ].
Chem. 2003, 75, 1453Ϫ1475.
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[8a]
For reviews, see:
F. Foubelo, M. Yus, Trends Org. Chem.
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For a review, see: A. Guijarro, C. Gomez, M. Yus, Trends Org.
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For reviews, see:
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F. Alonso, M. Yus,
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For reviews on carbolithiation reactions, see: [12a] Ref.[1d], chap-
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Acknowledgments
This work was generously supported by the Spanish Ministerio de
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Ciencia y Tecnologıa (grant no. BQU2001Ϫ0538) and the Gen-
2003, 59, 8525Ϫ8542.
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GRUPOS03/135). R. O. thanks the Spanish Ministerio de Educa-
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M. Yus, C. Gomez, P. Cand-
3840
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3833Ϫ3841

Tandem Intramolecular Carbolithiation-Lithium/Zinc Transmetallation
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Eur. J. Org. Chem. 2004, 3833Ϫ3841
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3841