Ring expansion of 5- to 6-member zirconacycles by carbenoid insertion

Article abstract of DOI:10.1016/j.tet.2003.09.056

A wide range of carbenoids (1-lithio-1-halo species), including those with α-SiR₃, OEt, SPh, SO₂Ph, P(O)(OEt)₂, and CN substituents, insert into 5-member zirconacycles (saturated and unsaturated, mono- and bi-cyclic) to afford functionalized 6-member zirconacycles. 1-Lithio-1-haloalkenes insert to afford 6-member zirconacycles with an alkylidene substituent next to the metal. Unexpected double insertion of some carbenoids, and evidence for endocylic β-hydride transfer processes provide additional mechanistic interest.

Full text of DOI:10.1016/j.tet.2003.09.056

Tetrahedron 60 (2004) 1401–1416
Ring expansion of 5- to 6-member zirconacycles
by carbenoid insertion
Sally Dixon, Shaun M. Fillery, Aleksandra Kasatkin, David Norton, Emma Thomas
*
and Richard J. Whitby
Department of Chemistry, Southampton University, Southampton, Hants SO17 1BJ, UK
Received 7 July 2003; revised 24 September 2003; accepted 24 September 2003
3 2 2
Abstract—A wide range of carbenoids (1-lithio-1-halo species), including those with a-SiR , OEt, SPh, SO Ph, P(O)(OEt) , and CN
substituents, insert into 5-member zirconacycles (saturated and unsaturated, mono- and bi-cyclic) to afford functionalized 6-member
zirconacycles. 1-Lithio-1-haloalkenes insert to afford 6-member zirconacycles with an alkylidene substituent next to the metal. Unexpected
double insertion of some carbenoids, and evidence for endocylic b-hydride transfer processes provide additional mechanistic interest.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Over that past 20 years efficient syntheses of a wide variety
of 5-member zirconacycles have been developed. The main
routes are by co-cyclisation of 1,n-dienes, -diynes and
1
-
enynes on a zirconocene (‘Cp Zr’) equivalent, or by
2
2
trapping zirconocene h 2alkene, -alkyne, and -benzyne
complexes, generated by complexation or by a b-C–H
activation process, with alkenes or alkynes (Eq. (1)). The
2
Scheme 1. Elaboration of 5-member zirconacycles.
use of unactivated alkenes and alkynes as substrates
together with the good diastereocontrol imposed by the
metal make these processes particularly attractive for
organic synthesis. The ready formation of nitrogen hetero-
A valuable method for the elaboration of carbon-metal
1
1
bonds is via insertion of ‘carbenoids’ (1-halo-1-metallo
species) since, as the products retain the carbon–metal bond
of the starting material, the process is inherently iterative. In
3
4
cycles, and the use of cleavable silicon tethers are
illustrations of the variety of organic structures which may
be formed. Many productive means for elaboration of the
carbon–zirconium bonds in the 5-member zirconacycles
have been developed. Examples include metathesis reac-
1
2
1
989 Negishi reported the first insertions of a-halo-
organolithium reagents into acyclic zirconocene chlorides.
The process is particularly facile as most organozirconocene
complexes are electronically unsaturated (16 electron) so
the reaction may occur by formation and 1,2-rearrangement
of an 18 electron ‘ate complex’ as shown in Eq. (2). We
have developed the insertion of a wide range of carbenoids
into organozirconocene chlorides derived by hydrozircona-
tion to provide useful multi-component coupling
5
6
tions to form heterocycles; halogenolysis; carbonylation
to yield ketones or alcohols depending on conditions and
(
work-up); tandem insertion of isonitriles and additional
7
8
9
p-components; addition to aldehydes; and various copper
or nickel induced or catalysed elaborations such as addition
of enones, aryl-, allyl-, and alkynyl-halides, and 1,n-di-
halides; 1,1-addition to acid chlorides, b-haloenones, or
1
3–15
methods.
1
0
propynoates; and 1,2-addition to alkynes (Scheme 1).
ð2Þ
ð1Þ
Keywords: Zirconium; Carbenoid; Ring expansion; Multi-component;
Zirconacycle; Insertion.
Homologation of 5- to 6-member zirconacycles through
carbenoid insertion potentially provides a rich new class of
substrates for the numerous zirconacycle elaborations
*
Corresponding author. Tel.: þ44-23-80592777; fax: þ44-23-80593781;
e-mail address: rjw1@soton.ac.uk
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.09.056

1402
S. Dixon et al. / Tetrahedron 60 (2004) 1401–1416
dibutylzirconocene, gave the zirconacyclopentane 2a.
Insertion of a methylene carbenoid (LiCH X) into 2a
2
should give the zirconacyclohexane 7 (Scheme 3). The
2
3
carbenoid LiCH Cl is known, but very unstable, so we
2
first tried to generate it in situ by halogen/lithium exchange.
However, addition of n-BuLi to a mixture of zirconacycle
2a and ICH Cl followed by aqueous work-up gave only the
2
iodide 3. Presumably n-BuLi attacks the zirconium centre
to form the zirconate complex 4 which undergoes iodine–
metal exchange with ICH Cl, either directly, or via the
2
lithium species 5. Negishi has previously reported a similar
ring opening of zirconacyclopentanes with alkyllithium
Scheme 2. Insertion of allyl-, allenyl- and propargyl- carbenoids into
zirconacycles.
24
reagents. The fate of the LiCH Cl (or [RZr(Bu)(CH Cl)
2
2
2
þ
Zr–Bu bond is likely. Although there are a few exceptions
Cp2] Li ) so formed is not clear, but insertion into the
2
5
described above, and hence valuable multi-component
coupling methods. Our initial reports concerned the
insertion of allyl-, allenyl- or propargyl-carbenoids into
we have found that in situ halogen/lithium exchange in the
presence of the zirconacycle is not a useful method for
generation/insertion of carbenoids. Reaction of ICH Cl with
1
6–18
1
3
zirconacycles (Scheme 2).
Although the h 2,h 2
2
zirconacycles so formed reacted with powerful electrophiles
such as aldehyde/BF ·Et O, they were poor substrates for
many of the elaboration methods described above, probably
because the metal is electronically saturated (18 electron
configuration).
n-BuLi at 2100 8C in a 4:1:1 mixture of THF, diethyl ether
1
1b
3
2
and pentane (Trapp solvent)
3
formed the desired carbe-
noid LiCH Cl. Addition of a 278 8C solution of the
2
2
zirconacycle 2a in THF via cannula partially formed the
desired zirconacyclohexane 7, and aqueous work-up gave a
2.5:1 mixture of the homologated methylethylcyclopentane
We now report the ring expansion of zirconacyclo-pentanes
and -pentenes to afford 6-member zirconacycles by inser-
8, and the dimethylcyclopentane 9 derived from starting
zirconacycle 2a (87% combined yield) (Scheme 3). Com-
plete conversion of 2a could be achieved by increasing the
19
tion of a wide range of carbenoids (Eq. (3)). Such
carbenoid insertions have also been reported for the ring
amount of LiCH Cl, but this also gave products of further
2
2
0,21
expansion of boracycles and silacycles.
insertion into 7 which were not separable from 8. Insertion
2
6
of LiCH Br generated from CH Br and n-BuLi gave very
2
2
2
similar results to the above.
ð3Þ
2.1.2. Carbamate-derived carbenoids. The failure of in
situ generation of LiCH X by halogen/lithium exchange and
2
the inconveniently low temperatures needed to generate it
separately from the zirconacycle prompted us to examine
1
2
2
. Results and discusion
the more stable a-lithiated carbamates R NCOOCHLiR as
2
2
7
carbenoids. We have previously shown that for the
insertion of allyl carbenoid into zirconacycles, carbamate
2.1. Insertion of H-, alkyl-, silyl-, phenylthio-, and ethoxy-
substituted carbenoids into zirconacycles
1
6a
was a suitable leaving group. Unfortunately, insertion of
the ‘methylene carbenoid’ derived by lithiation of 10 with
s-BuLi/tetramethylethylenediamine (TMEDA) was unsuc-
cessful, a problem traced to preferential bis-lithiation of 10.
Lithiation of the ethyl carbamate 11 (1.1 equiv.) using a
2.1.1. Insertion of methylene carbenoid. Intramolecular
co-cyclisation of the 1,6-heptadiene 1a using zirconocene-
1-butene) (the Negishi reagent), generated in situ from
2
2
(
Scheme 3. Reaction of zirconacyclopentane 2a (R¼CH
2
OMe) with ICH
2
Clþn-BuLi.

S. Dixon et al. / Tetrahedron 60 (2004) 1401–1416
1403
preformed mixture of s-BuLi and TMEDA in ether at
78 8C followed by addition, via cannula, of a solution of
2
zirconacycle 2a in THF at 278 8C gave, on aqueous quench
and chromatography, the product 12 (65%) of insertion as
well as 9 (32%) from hydrolysis of the starting zirconacycle
Figure 1. Electron donation to zirconium centre.
(
Eq. (4)). Increasing the amount of lithiated carbamate to
5 equiv. surprisingly only increased the ratio of 12 to 9 to
2.7:1 and the yield was lower.
the carbenoid centre. No change in diastereoisomer ratio
was observed after heating the mixture of zirconacycles
1
3b for 2 days at 80 8C. Protonation of 13b afforded the
trimethylsilyl compound 18b in good yield (Table 1, entry
). Zirconacycle 13b also showed no inclination to insert
1
ð4Þ
further carbenoids. For example reaction with 10 equiv. of
LiCH(SiMe )Cl gave only the monoinsertion product 18b
3
on work-up. One explanation for the resistance of 13b to
further carbenoid insertion is that the C–Si bond donates
electron density into the empty orbital on the metal (Fig. 1),
which is also required for carbenoid insertion (c.f.
Attempts to lithiate carbamate 11 in the presence of the
zirconacycle failed, so we next examined carbenoids which
could be generated in situ by deprotonation with amide
bases.
3
1
stabilisation of b-carbenium ions by silicon ). We have
observed other examples where the presence of electron
donation into the empty orbital on the zirconium prevents
3
2
carbenoid insertion.
2
a-Silyl carbenoids (LiCH(SiR )Cl) are remarkably stable,
.1.3. Insertion of a-silyl- and a-stannyl-carbenoids.
2
8
In the same way, insertion of the carbenoid derived from in
situ lithiation of 1.1 equiv. of (chloromethyl)phenyldi-
methylsilane into zirconacyclopentanes 2a,b and c gave
the zirconacyclohexanes 14a,b and c and homologated
products 19a,b and c in good yield (Table 1, entries 2, 3,
and 4). For zirconacyclohexane 14b we confirmed that it
was formed as a 1:1 mixture of diastereoisomers, and would
not insert further carbenoid. Insertion of the a-tributyl-
3
1
2
14a
and Negishi, and we have reported their insertion into
acyclic organozirconocenes. Takahashi recently reported
2
9
their insertion into zirconacyclopentadienes. Although
2
usually generated by deprotonation using an alkyllithium,
8
3
0
elimination to form a carbene using LiTMP is known. We
were delighted to find that reaction between 1.1 equiv. of
chloromethyltrimethylsilane and LDA at 278 8C in the
presence of zirconacyclopentane 2b afforded cleanly a new
zirconacyclohexane 13b upon warming to room tempera-
3
0
stannyl carbenoid LiCH(SnBu )Cl into 2a occurred in low
3
yield, possibly because of the much faster rate of tin/lithium
exchange c.f. silyl/lithium (Table 1, entry 5).
2
8b
ture (Table 1). It is interesting that Magnus noted
LDA is not a useful base for deprotonation of Me SiCH Cl
that
3
2
which may indicate the effectiveness of trapping by the
1
2.1.4. Insertion of S- and O-substituted carbenoids. We
next examined insertion of the S- and O-substituted
carbenoids PhSCHLiCl and EtOCHLiCl. Before our
zirconacycle in displacing an equilibrium. The H NMR of
1
3b showed four equal cyclopentadienyl signals (C D , d
6 6 H
1
4b
5
.71, 5.63, 5.57 and 5.50 ppm) implying that it was a 1:1
work
implied intermediates in the formation, and trapping by
these types of carbenoid were only known as
mixture of diastereoisomers. The lack of diastereoselec-
tivity in the carbenoid insertion is consistent with the chiral
but racemic zirconacycle reacting with the chiral but
racemic carbenoid with clean inversion of configuration at
3
3
cyclopropanation, of carbenes which is an indication of
how quickly zirconium may trap these exceptionally
unstable intermediates. Thus addition of LDA (1.2 equiv.)
Table 1. Insertion of electron rich alkylcarbenoids into zirconacyclopentanes
a
b
Entry
Zirconacyclopentane 2
Carbenoid
Zirconacyclohexane
Product
Yield (%)
1
R , R
1
2
1/2
R
Equiv.
1
2
3
4
5
6
7
–CH
–CH OMe, –CH
–CH OCMe OCH
H, H
OMe, –CH
2
OCMe
2
OCH
2
–
b
a
b
c
a
b
b
SiMe
SiMe
SiMe
SiMe
SnBu
SPh
3
2
2
2
1.1
1.1
1.1
1.1
1.0
1.2
1.1
13b
14a
14b
14c
15a
16b
17b
18b
19a
19b
19c
20a
21b
22b
78
70
77
64
11
77
45
2
2
OMe
Ph
Ph
Ph
2
2
2
–
c
–CH
2
2
OMe
3
–CH
–CH
2
OCMe
OCMe
2
OCH
OCH
2
–
–
2
2
2
OEt
a
Generated using LDA except.
Isolated yield based on diene 1.
Used LiTMP.
b
c

1404
S. Dixon et al. / Tetrahedron 60 (2004) 1401–1416
to a mixture of zirconacycle 2b and chloromethylphenyl-
sulphide (1.5 equiv.) in THF at 278 8C gave the zircona-
cycle 16b. Aqueous work-up gave the phenyl sulphide 21b
in 77% yield (Table 1, entry 6). Attempts to analyse the
intermediate zirconacyclohexane 16b by NMR were
thwarted by its low thermal stability. As with the silicon
substituted carbenoids, only mono insertion was observed,
even with 10 equiv. of PhSCHLiCl, an observation which
may be explained by co-ordination of the sulphur lone pair
to saturate the zirconium centre (Fig. 1). In a similar way
metallation of chloromethylethyl ether (1.1 equiv.) by LDA
(
1.1 equiv.) in the presence of zirconacycle 2b at 278 8C
afforded the alkyl ethyl ether 22b in a modest 45% yield
after protic quench at 220 8C. (Table 1, entry 7) The
intermediate zirconacycle 17b decomposed above 220 8C.
3
Scheme 4. Insertion of Me SiCHLiCl into a zirconacyclopentene.
temperature for at least 16 h. In contrast the zirconacyclo-
hexene 44 derived from 36 was thermally unstable, and the
reaction needed to be quenched below 240 8C to get a good
yield of the expected product 38 (Table 2, entry 9). If
zirconacycle 44 was allowed to warm to room temperature
before quenching the diene 48 was the major product
(Scheme 5). A reasonable explanation for the formation of
48 from 44, and the markedly contrasting stability of 42 and
43, is by a b-hydride elimination/re-addition process
(Scheme 5). Thus transfer of a b-hydride in 44 to the
2.1.5. Insertion of electron rich carbenoids into unsatu-
rated zirconacycles. Zirconacyclopentenes are readily
formed by the zirconocene mediated intramolecular
co-cyclisation of 1,n-enynes, for example the formation of
1
2
3. Insertion of electron rich alkyl carbenoids into
zirconacyclopentene 23 has so far proved disappointing.
Although alkyl-, PhS-, and EtO-substituted carbenoids do
insert, the yields are low and the products too messy to
properly characterise. The silicon substituted carbenoid
3
8
zirconium gives the zirconium hydride 45, which can
re-add to the alkene to afford the zirconacyclopentene 46.
Irreversible elimination of phenylsulphinate to afford 47
followed by protonolysis gives the diene 48. The additional
conformational constraints provided by the fused 5-member
rings in 42 and 43 presumably prevent the orbital alignment
needed for the b-hydride transfer. Even though it appears
unfavourable the fused 6-member ring in 44 must allow
sufficient flexibility for hydride transfer. We have observed
similar b-hydride transfers, and dependence on the size (and
presence) of a ring fused to the 6-member zirconacycle, in
Me SiCHLiCl inserts efficiently into 23 to give, on aqueous
3
work-up, mostly the expected product 24, but also a
significant amount of the regioisomer 25 derived from
insertion into the zirconium–alkenyl bond (Scheme 4).
Insertion of many other carbenoids into 23 and related
zirconacyclopentenes is exclusively into the zirconium-
1
5,16d,e,17,18
alkyl bond.
2
.2. Insertion of electron poor –PO(OEt) , –SO Ph, and
2
2
–
CN substituted carbenoids into zirconacycles
1
9
several other systems.
We have previously reported insertion of the readily formed
electron poor –PO(OEt) , –SO Ph, and –CN substituted
2
2
2.2.3. LiClCHCN. Reaction of zirconacyclopentane 2a
36
with LiClCHCN 49 (1.3 equiv.), generated in situ from
3
4–36
14b
carbenoids
into acyclic organozirconocene chlorides,
and were delighted to find that they inserted with equal
facility into zirconacycles.
chloroacetonitrile and LDA at 278 8C, followed by aqueous
work-up gave only a low yield (24%) of the expected
insertion product 28 (Table 2, entry 3). The major
compound isolated was 50 (45%), the result of bis-insertion
of LiClCHCN (Scheme 6). Reducing the amount of
carbenoid to 1 equiv. improved the ratio of 28/50 to 2:1,
but did not improve the yield of 28. Increasing to 2 equiv. of
35
2
.2.1. (EtO) (O)PCHLiCl. Insertion of (EtO) (O)PCHLiCl,
2 2
generated in situ from diethyl chloromethylphosphonate
and LDA, into a variety of mono- and bicyclic-zircona-
cyclopentanes and -zirconacyclopentenes was fast and clean
(
Table 2, entries 1, 4, 5, 8, and 10). Even using a large
excess of the phosphonate substituted carbenoid gave no
double insertion. Starting zirconacycles 2a, 29, 36, and 39
were formed by co-cyclisation of the appropriate 1,7-dienes
1
or -enynes using dibutylzirconocene. Zirconacycle 31 was
formed by warming dibutylzirconocene in the presence of
7
a,37
excess ethylene.
the same as that in the starting zirconacycle.
The diastereoisomeric mix of 30 was
3
4
2
.2.2. PhSO CHLiCl. Insertion of PhSO CHLiCl, gen-
2 2
erated in situ from chloromethylphenylsulphone and LDA,
into saturated zirconacycle 2a required 4 equiv. of the
carbenoid for complete conversion, but was clean (Table 2,
entry 2). No double insertion was observed. Insertion into
the zirconacyclopentene 33 was also efficient (entry 6). The
phenylsulphonyl-substituted zirconacycles 42 and 43
(
Scheme 5) derived from 2a and 33 were stable at room
Scheme 5. b-Hydride transfer mechanism for elimination.

S. Dixon et al. / Tetrahedron 60 (2004) 1401–1416
Table 2. Insertion of electron poor carbenoids into zirconacycles
1405
a
b
Yield /%
Entry
Zirconacycle
A
Equiv. ACH Cl
2
Product
1
2
3
P(O)(OEt)
SO Ph
2
2
2
1.3
4.0
1.3
26
27
28
74
67
24
CN
4
P(O)(OEt)
1.3
30
63
c
56 (76 )
5
P(O)(OEt)
2
1.3
32
6
7
SO Ph
2
CN
2.0
1.3
34
35
84
58
8
9
P(O)(OEt)
SO Ph
2
2
1.3
1.3
37
38
81
d
60
1
1
0
1
P(O)(OEt)
CN
2
1.3
1.3
40
41
71
73
a
b
c
d
Formed by co-cyclisation of appropriate enyne or diene using Cp
2
ZrBu
2
except 31 (from Cp
ZrCl
2
ZrBu
2
þexcess ethene).
Isolated yield based on diene or enyne except 32 which was based on Cp
NMR yield.
Quenched at 278 8C.
2
2
.
carbenoid gave 57% isolated yield of the bis-insertion
product 50. In a similar way reaction of 2 equiv. of
LiClCHCN with zirconacyclopentane 51 gave the bis-
inserted product 52 in good isolated yield (Scheme 6).
Insertion of 1.3 equiv. of LiClCHCN into the zirconacyclo-
pentenes 33 and 39 gave clean conversion to the mono-
inserted products 35 and 41 (Table 2, entries 7 and 11). In an
attempt to force double insertion 33 was treated with
5
equiv. of LiClCHCN and gave a low yield of the bis-
inserted product 53 as a separable 1:1 mixture of
diastereoisomers (Scheme 6). In the formation of 50 and
5
2 the insertions of LiClCHCN occur on opposite sides of
the zirconium to afford the 7-member zirconacycle 54. In the
formation of 53 the second insertion occurs on the same side
as the first to afford zirconacycle 55, presumably because
insertion into the alkenyl–metal bond is so unfavourable.
2
.2.4. Comparison of –PO(OEt) , –SO Ph, and –CN
2 2
substituted carbenoids. The remarkably different beha-
viours towards the insertion of a second carbenoid of the
phosphonate, sulphone, and nitrile substituted zircona-
cyclohexanes may be accounted for by donation of electrons
from the lone pairs on the sulphone or phosphonate oxygens
to the empty orbital on the zirconium (56, Fig. 2) which is
not possible for the nitrile substituent. It is possible that
Scheme 6. Double insertion of lithiated chloroacetonitrile.

1406
S. Dixon et al. / Tetrahedron 60 (2004) 1401–1416
(Z)-1,4-dichloro-2-butene formed the carbenoid 59c (.95%
E) which inserted into 2a to give the diene 61c with .95:5 Z
selectivity, on aqueous work-up. Insertion of the alkynyl-
4
0
substituted carbenoid 59d occurred in modest yield (Table
, entry 4), and there was indication by gas chromatography
3
of double insertion being a problem. The insertion of
lithiated b-bromostyrene 59e into zirconacycle 2a (Table 3,
entry 5) gave the most surprising result in that the expected
insertion product 61e was accompanied by substantial
amounts of the bis-insertion product 62, where the second
insertion has taken place into the more hindered side of
the zirconacyclohexane (Eq. (5)). Increasing the amount of
carbenoid to 2 equiv. gave a good yield of 62. In the
intermediate zirconacyclohexene 63 (Scheme 7) the empty
orbital on the metal lies in the plane of the 6-member ring
Figure 2. Electron donation to zirconium in sulphone, phosphonate, and
nitrile substituted zirconacylohexanes.
3
the nitrile adopts the 18 electron h 2co-ordinated structure
58 (Fig. 2) analogous to that displayed by ‘propargyl
carbenoid’ inserted zirconacycles (Scheme 2). However,
calculations indicate that the structure 57 is significantly
3
9
more stable than 58, and 58 would be expected to be inert
to carbenoid attack as the metal has an 18 electron
configuration.
and only attack on the ‘CH ’ side seems reasonable to afford
2
2
.3. Insertion of 1-lithio-1-haloalkenes
the ‘ate’ complex 64. We suppose that 1,2-metallate
rearrangement of 64 is slower than its isomerisation to a
structure such as 65 in which insertion of the carbenoid into
the alkenyl–zirconium bond may occur. The isomerisation
of 64 into 65 could be via loss/re-addition of cyclopenta-
1
2
13
Negishi, and we, have shown that 1-lithio-1-haloalkenes
9 insert readily into acyclic organozirconium species, so
5
we investigated their insertion into zirconacycles (Tables 3
and 4).
2
4
dienide, or directly via pseudorotation. Modelling of
possible ate complex intermediates (64, 65, and others)
indicates (if we consider Cp to occupy a single co-ordi-
nation site) low energy forms which approximate to both
square-pyramidal and trigonal-bipyramidal forms. Since the
former is the intermediate in the Berry psuedorotation
2
.3.1. Insertion of 1-lithio-1-haloalkenes into saturated
zirconacycles. Addition of lithium tetramethylpiperidide
1.1 equiv.) to a mixture of zirconacyclopentane 2b and
-chloro-2-methylprop-1-ene (1.1 equiv.) gave 30% con-
version to the zirconacyclohexane 60a. Increasing to 3 and
equiv. of the carbenoid gave 2:1 and 20:1 ratios of the
(
1
4
1
mechanism for ligand interchange in the latter, it is
reasonable that isomerisation of 64 to 65 could be fast.
5
homologated zirconacycle 60a to starting material 2a.
However, increasing the amount of carbenoid also lead to
numerous unidentified side products and the hydrolysed
product 61a was isolated in only 33% yield (Table 3, entry
ð5Þ
1
5
2
). Insertion of the sterically less hindered dienyl-carbenoid
9b, generated in situ from (E)-1,4-dichloro-2-butene and
equiv. of LDA, into zirconacyclopentane 2a gave the
1
3
diene 61b in 68% yield as an 87:13 E/Z mixture after
hydrolysis. It was important to use only 1.1 equiv. of the
carbenoid as larger amounts gave messy reactions and poor
yield. Subsequent results (see below) suggest that multiple
insertions of the carbenoid occur to give unstable products.
The loss of stereospecificity occurs in the initial elimination
of (E)-1,4-dichloro-2-butene to give (Z)- and (E)-1-chloro-
2.3.2. Insertion of 1-lithio-1-haloalkenes into zircona-
cyclopentenes. A variety of 1-lithio-1-haloalkenes inserted
cleanly into unsaturated zirconacyclopentenes (Table 4),
including into the monocycle 68. Worthy of comment is
that the carbenoid 59e derived from b-bromostyrene
inserted just once into 67, even when a large excess
4
2
1
3
1
,3-butadiene as an 87:13 mixture. In a similar way
Table 3. Insertion of 1-halo-1-lithioalkenes into saturated zirconacycles
a
b
Entry
Zirconacycle
R, R
1-Halo-1-lithioalkene
Equiv. of 59
Product
1
R
2
c
Yield 61 (%)
2
R
X
59
61
1
2
3
4
5
–CH
–CH
–CH
–CH
–CH
2
2
2
2
2
OCMe
2
OCH
2
–
b
a
a
a
a
Me
H
CHvCH
CuCBu
Ph
Me
CHvCH
H
H
H
Cl
Cl
Cl
Cl
Br
a
b
c
d
e
5
1.1
3
1.2
1.2
a
b
c
d
e
33
68
87
54
OMe, –CH
OMe, –CH
OMe, –CH
OMe, –CH
2
2
2
2
OMe
OMe
OMe
OMe
2
2
48 (þ11% 62)
a
2 2
Formed by co-cyclisation of 1a or 1b using Cp ZrBu .
Formed by deprotonation of alkenyl halide using LiTMP (59a) or LDA (59b-e).
Isolated yield based on diene precursor of 2.
b
c

S. Dixon et al. / Tetrahedron 60 (2004) 1401–1416
1407
Scheme 8. Attempted insertion of alkenyl fluorides. (a) Ar¼Ph, (b) Ar¼p-
PhC
Scheme 7. Possible mechanism for double insertion.
6 4
H .
(
5 equiv.) was used (c.f. Table 3, entry 5 and Eq. (4)). This
complete in less than 5 min at 278 8C indicating that in
these cases the reaction was occurring by direct insertion of
the 1-lithio-1-haloalkene.
observation lends support to the notion that the ‘double
insertion’ product 62 is indeed derived from initial attack on
the side of zirconium remote from where it finally inserts
(
Scheme 7). In the zirconacyclohexene 69b, from mono-
insertion of 59e into 67, attack of the carbenoid on the
empty orbital on zirconium is blocked from both sides so
double insertion does not occur.
3. Conclusions
We have demonstrated that a wide range of carbenoids
(electron poor and electron rich, alkyl and alkenyl) insert
into a range of 5-member zirconacycles (saturated and
unsaturated, mono- and bi-cyclic) to afford functionalised
6-member zirconacycles. There is great opportunity for
further elaboration of these novel structures to create multi-
component coupling reactions of use in organic synthesis.
Several mechanistically interesting observations also
require further work. The double insertion of lithiated
chloroacetonitrile and lithiated b-bromostyrene 59e, in
contrast to the inertness of other systems towards further
carbenoid insertion, is an indication of the electronic
requirements at the metal for carbenoid insertion to occur
which we only partially understand. The suggested facile
transfer of a b-hydride from within a zirconacycle ring to
the metal in formation of 48 appears unprecedented and
orbital alignment seems so bad that further experimental
and theoretical investigation is warranted. The remarkable
double insertion of lithiated b-bromostyrene into the same
side of zirconacycle 2a to afford 61 confirms earlier
2
.3.3. Insertions via alkynate complex rearrangement. In
an attempt to improve yields we examined insertion of the
carbenoids generated by in situ deprotonation of the
b-fluorostyrenes 71a and b into zirconacyclopentene 23.
Initial results were promising—reasonable yields of the
expected products 72a and 72b (Scheme 8). However,
further study showed that the products were only arising
after the reaction mixture was warmed to room temperature.
Quenching at 240 8C gave ,5% conversion. It became
clear that the mechanism involved very fast elimination of
fluoride from 71 to afford the arylalkynes, which lithiated
and added to the zirconacycle to afford the ate complex 74.
Slow rearrangement of 74 at room temperature, as has been
previously reported by Negishi in monocyclic systems,
affords 75 and hence the products 72 on aqueous work-up
4
3
4
4
(Scheme 8). Indeed substituting 1 equiv. of p-biphenyl-
acetylene for 71a in the reaction gave 85% conversion to
7
2
2b by gas chromatography, and 65% isolated yield. When
3 was treated with (E)-b-chlorostyrene or (E)-b-bromo-
1
6e,19b
styrene and LDA (1.5 equiv.) conversion to 72a was
results
that show that the regiochemistry of carbenoid
Table 4. Insertion of 1-halo-1-lithioalkenes into unsaturated zirconacycles
a
Yield of
70 (%)
Zirconacycle
Carbenoid
X
Equiv.
of 59
69/70
2
3
4
R
1
R
Entry
R
R
59
1
2
3
4
CH
CH
2
C(CH
C(CH
–(CH
2
OMe)
OMe)
2
CH
CH
2
Et
Et
Bu
Pr
67
67
23
68
CHvCH
Ph
CuCBu
CuCBu
2
Cl
Br
Cl
Cl
c
e
d
d
3
3
2
1.2
a
b
c
81
64
86
2
2
2
2
2
)
3
–
b
H
Pr
d
54
a
Isolated yield based on starting enyne except.
Yield based on 4-octyne.
b

1408
S. Dixon et al. / Tetrahedron 60 (2004) 1401–1416
insertion is not (always) dominated by the direction of initial
attack of the carbenoid on the metal. Several mechanisms
are possible, and again a combination of experimental and
theoretical studies will be needed for clarification.
and distilled before use. The following compounds were
prepared by literature methods, and had spectral properties
consistent with those published: 3,3-dimethyl-1-oxa-4-aza-
spiro[4.5]decane-4-carboxylic acid methyl (10) and ethyl
2
7
30
(11) esters;
(methoxymethyl)hepta-1,6-diene, 1a;
tributyl(chloromethyl)stannane;
4
4,4-bis-
5,5-diallyl-2,2-
5,46
Overall we believe that as well as providing useful new
synthetic methods for organic synthesis our work is
uncovering fascinating new aspects of the chemistry of
zirconium and provides an exciting field for further research.
4
7
48
dimethyl-1,3-dioxane, 1b; undec-1-en-6-yne; 1,2-diallyl-
4
9
50
benzene; dodec-1-en-7-yne; trimethyl(oct-7-en-1-ynyl)-
40
7
c
silane;
(E)-1-chlorooct-1-en-3-yne;
1-((E)-2-fluoro-
5
1
52
vinyl)benzene 71a; 4-(2-fluorovinyl)biphenyl 71b. The
following compounds were prepared by standard pro-
cedures, and had the spectral properties given: dec-1-en-6-
yne was prepared by alkylation of lithiated pentyne with
4. Experimental
1
4
4
.1. General
5-bromo-1-pentene and had spectral properties: H NMR: d
5
.80 (1H, ddt, J¼16.9, 10.2, 6.8 Hz), 5.03 (1H, ddt, J¼17.1,
3.5, 1.7 Hz), 4.99 (1H, ddt J¼10.2, 3.4, 1.1 Hz), 2.21–2.10
C
.1.1. Spectroscopy and analysis. NMR spectra were
1
3
recorded on Bruker AM300 or DPX400 spectrometers.
Unless otherwise stated all spectra were recorded in
deuterochloroform at 300 MHz (proton) or 75 MHz (car-
bon) and are referenced to the residual chloroform peak at
1
(6H, m), 1.63–1.43 (4H, m), 0.97 (3H, t, J¼7.4 Hz).
NMR: d 138.28 (CH), 115.07 (CH ), 80.54 (C), 80.05 (C),
32.97 (CH ), 28.47 (CH ), 22.66 (CH
(CH ), 13.63 (CH
(M 2CH
4,4-Bis(methoxymethyl)non-1-en-6-yne was prepared by
2
), 20.90 (CH
), 18.31
2
2
2
2
þ
). LRMS (EI): 136 (M , 4%), 121
2
þ
3
þ
þ
7
.27 ppm ( H NMR), and 77.20 ppm (centre peak of triplet,
C NMR). The NMR spectra of organozirconium com-
3
, 50), 107 (M 2C
2
H
5
, 80), 93 (M 2C
3
H
7
, 97).
1
3
5
3 1
˚
ethylation of 4,4-bis(methoxymethyl)hept-1-en-6-yne:
H
pounds were recorded in deuterobenzene (stored over 4 A
molecular sieves) and referenced to residual benzene peak
at 7.16 ppm ( H NMR) and 128.0 ppm (centre peak of
NMR: d 5.80 (1H, ddt, J¼16.8, 10.3, 7.7 Hz), 5.90–5.80
(2H, m), 3.32 (6H, s), 3.25 (2H, d, J¼9.2 Hz), 3.21 (2H, d,
J¼9.2 Hz), 2.22–2.10 (6H, m), 1.13 (3H, t, J¼7.4 Hz).
Petrol refers to the fraction of petroleum ether which boils
between 40 and 60 8C, and was distilled before use. THF
and ether used in reactions was freshly distilled from
1
1
3
triplet, C NMR). Chemical shifts are reported in parts per
million downfield of TMS and the following abbreviations
used to denote coupling patterns: s¼singlet; d¼doublet,
1
3
t¼triplet, q¼quartet, br¼broad, fs¼fine splitting). C NMR
spectra were proton decoupled and are reported as C, CH,
CH , CH , depending on the number of directly attached
sodium/ benzophenone. Pentane was dried over CaH and
2
degassed before use. n-Butyllithium (n-BuLi) was used as a
2.5 M solution in hexanes (Aldrich) and was stored at 4 8C.
Note that batches of n-BuLi which have aged at room
temperature may give poor results for zirconacycle
formation, even though titration for base shows no decline.
We suspect that some decomposition to LiH occurs, but as
this may be solubilised as part of n-BuLi clusters its acts as a
competent base. Lithium diisopropylamide (LDA) was
either used as purchased from Aldrich as a 2.0 M solution
in heptane/ THF/ethybenzene or made freshly from
diisopropylamine in THF and n-BuLi (2.5 M solution in
hexanes). Lithium 2,2,6,6-tetramethylpiperidide (LiTMP)
was prepared freshly from 2,2,6,6-tetramethylpiperidine in
THF and n-BuLi (in hexanes) at a concentration of <0.5 M
by stirring at 0 8C for 20 min.
2
3
protons, this being determined by DEPT experiments.
Infrared spectra were recorded for all compounds but are
not reported. Mass spectra including accurate mass were
recorded on a VG Analytical 70-250-SE double focusing
mass spectrometer using Chemical Ionisation (CI) (with
ammonia as the reagent gas) or Electron Impact Ionisation
(
EI) (at 70 eV). LRMS (EI and CI) were also recorded on a
ThermoQuest TraceMS GCMS. Atmospheric pressure
chemical ionisation (APCI) mass spectra were recorded on
a VG Platform spectrometer in acetonitrile. Values of m/z
are reported in atomic mass units (a.m.u.) followed in
parentheses by the peak intensity (relative to the base peak
of 100%). Elemental analyses were performed by the
University College London Microanalysis Service, or at
AstraZeneca, Alderley Park.
4.2. Formation of zirconacycles by intramolecular co-
cyclisation of 1,n-dienes or -enynes
4
.1.2. General procedures. All reactions were carried out
under an argon atmosphere using standard Schlenk and
syringe techniques. All apparatus was dried in a hot oven
To a solution of Cp ZrCl (0.292 g, 1.00 mmol) in THF
2 2
(
.140 8C, 12 h) before being cooled in a sealed dessicator
(7.0 mL) was added n-BuLi (2.00 mmol, 0.80 mL, 2.5 M
in hexanes) at 278 8C. The reaction mixture was stirred
at 278 8C for 1 h, then a diene or an enyne (1.00 mmol)
in THF (2.0 mL) added and the cooling bath was
removed. After stirring at 20 8C for 2 h the resulting
solution of the zirconacycle was used directly in the next
reaction. With the exception of zirconacycles 29 and 51
the solution could be kept at room temperature overnight
without harm. The above procedure is assumed to
produce 1.00 mmol of zirconacycle for the purposes of
the following experimental.
over silica gel, or assembled while hot and cooled under
vacuum (0.1 mm Hg). ‘Usual work-up’ refers to quenching
the reaction with methanol (5 mL) followed by saturated
NaHCO aq. (5 mL) and stirring at room temperature for
3
3
The ether solution is then washed with brine, (sometimes
preceded by water) dried over MgSO , the solvents removed
4
in vacuo and the crude product purified by chromatography
on silica.
–16 h before extracting the organic products into ether.
4.1.3. Materials. Unless given below all materials were
obtained from commercial sources and if necessary dried
By the above method the following zirconacycles were

S. Dixon et al. / Tetrahedron 60 (2004) 1401–1416
1409
1
made from the diene or enyne precursors indicated in
parenthesis: 2a (4,4-bis(methoxymethyl)hepta-1,6-diene,
(65 mg, 30%) and 9 (59 mg, 32%). H NMR: d 3.33 (6H, s),
3.20 (4H, m), 1.76 (1H, dd, J¼13.5, 7.5 Hz), 1.72 (1H, dd,
J¼13.5, 7.5 Hz), 1.60–1.10 (6H, m), 1.00 (2H, m), 0.94
1
(
a); 2b (5,5-diallyl-2,2-dimethyl-1,3-dioxane, 1b); 2c
1,6-heptadiene); 23 (undec-1-en-6-yne); 29 (1,2-diallyl-
1
3
(3H, d, J¼6.5 Hz), 0.88 (3H, t, J¼7.5 Hz) ppm. C NMR
benzene); 36 (dodec-1-en-7-yne); 39 (trimethyl(oct-7-en-1-
ynyl)silane); 33 (dec-1-en-6-yne); 51 (octa-1,7-diene); 67
(75 MHz, CDCl ): d 78.15 (CH ), 78.00 (CH ), 59.38
3
2
2
(2£CH ), 46.44 (CH), 45.28 (C), 41.88 (CH ), 39.85 (CH),
39.50 (CH ), 36.20 (CH ), 21.47 (CH ), 18.13 (CH ), 14.50
2 2 2 3
3
2
(
4,4-bis(methoxymethyl)non-1-en-6-yne).
þ
(
CH ) ppm. LRMS (CI, NH ): 215 (MþH , 100%), 182
þ þ
3 3
3
3
4.3. Insertion of electron rich alkyl-substituted
carbenoids into zirconacycles
(MþH 2OCH , 44%), 151 (MþH 22(OCH ), 97%).
þ
HRMS (EI): calcd for C H O (M ) 214.1933, found
13 26 2
214.1932.
4
.3.1. rac-(3R,4R)-3-(Iodomethyl)-1,1-bis(methoxy-
methyl)-4-methylcyclopentane 3. To a solution of zircona-
cycle 2a (1.00 mmol) at 278 8C was added iodochloro-
methane (1.1 mmol, 176 mg) followed by n-BuLi
4.3.4. rac-(2R,3S)-2,8,8-Trimethyl-3-(2-trimethylsilyl-
ethyl)-7,9-dioxaspiro[4.5]decane 18b. To a solution of
zirconacycle 2b (1.00 mmol) at 278 8C, was added
chloromethyltrimethylsilane (0.135 g, 1.1 mmol) in THF
(1 mL) followed by LDA (1.1 mmol) dropwise over 10 min.
After stirring for 30 min at 278 8C, the reaction was
allowed to warm to room temperature before usual work-up
and chromatography (eluent 10% ether in petrol) gave 18b
(
1.1 mmol) and the reaction was stirred for 30 min at this
temperature. The reaction was warmed to room temperature
before usual work-up and chromatography (eluent 10%
ether in petrol) gave the title compound as a colourless oil
1
(
3
(
(
(
215 mg, 77%). H NMR: d 3.40 (1H, dd, J¼3.0, 9.5 Hz),
1
.34 (6H, s), 3.20 (4H, s), 3.09 (1H, dd, J¼8.0, 9.5 Hz), 1.85
(223 mg, 78%) as a colourless oil. H NMR: d 3.56 (4H, m),
1H, dd, J¼13, 7.3 Hz), 1.84 (1H, dd, J¼13, 7.3 Hz), 1.52
1.93 (1H, dd, J¼13.0, 7.0 Hz), 1.85 (1H, dd, J¼13.0,
8.0 Hz), 1.60 (1H, m), 1.50, (1H, m), 1.41 (6H, s), 1.30 (2H,
m), 1.00 (2H, m), 0.94 (3H, d, J¼7.0 Hz), 0.54 (1H, ddd,
J¼14.0, 13.0, 5.0 Hz), 0.38 (1H, ddd, 14.0, 13.0, 5.0 Hz),
1H, m), 1.38 (1H, m), 1.20 (1H, dd, J¼13, 7.2 Hz), 1.17
1
3
1H, dd, J¼13, 7.3 Hz), 0.95 (3H, d, J¼6.5 Hz) ppm.
C
NMR: d 77.99 (CH ), 77.67 (CH ), 59.39 (2£CH ), 48.35
2
2
3
1
3
(
1
CH), 44.62 (C), 42.06 (CH ), 40.71 (CH ), 39.72 (CH),
2
0.00 (9H, s) ppm. C NMR: d 97.80 (C), 70.53 (CH ),
2
2
þ
97 (M 2CH ), 184 (M 2HI). HRMS (EI): calcd for
7.79 (CH ), 12.58 (CH ) ppm. LRMS (APCI): 312 (M ),
3
70.48 (CH ), 49.44 (CH), 42.94 (CH ), 40.21 (CH ), 39.50
2
2
2
2
þ
þ
2
C H IO (M ) 312.0586, found 312.0583.
(CH), 39.06 (C), 27.71 (CH ), 24.26 (CH ), 23.81 (CH ),
2 3 3
3
þ
18.54 (CH ), 14.91 (CH ), 21.57 (CH ) ppm. LRMS (CI):
3 2 3
1
1
21
2
þ
(10), 90 (55), 73 (13). HRMS (CI): calcd for C H O Si
þ
2
85 (MþH , 100%), 269 (M 2CH , 80), 211 (23), 137
3
4
.3.2. rac-(3R,4R)-3-Ethyl-1,1-bis(methoxymethyl)-4-
1
6 33 2
þ
methylcyclopentane 8. n-BuLi (2.1 mmol,) was added
dropwise to a 2100 8C solution of iodochloromethane
(MþH ) 285.2250, found 285.2221.
(
2.0 mmol, 351 mg) in Trapps solvent (4 mL THF, 1 mL
pentane, 1 mL ether). A solution of the zirconacycle 2a
1.00 mmol) was cooled to 278 8C and slowly added via
By the same method, using appropriate zirconacycle and
chloromethyldimethylphenylsilane, the following were
prepared.
(
cannula. The reaction was stirred for 1 h, upon which usual
work-up and chromatography (eluent 10% ether/petrol)
gave a 2.5:1 mixture of 8 and 9 (171 mg, 87%) from which
a pure sample of the title compound could be isolated
by careful chromatography (0–10% ether in petrol) and
Kugelrohr distillation (70 8C, 1 mm Hg) as a colourless oil.
4.3.5. rac-(1S,2R)-4,4-Dimethoxymethyl-2-methyl-1-(2-
phenyldimethylsilylethyl)cyclopentane 19a. Colourless
1
oil. H NMR: d 7.56 (2H, m), 7.41 (3H, m), 3.30 (6H, s),
3.19 (4H, m), 1.80–0.80 (11H, m), 0.72 (1H, ddd, J¼14.0,
1
3
13.5, 5.5 Hz), 0.27 (6H, s) ppm. C NMR: d 133.71 (CH),
128.90 (C), 128.00 (CH), 127.86 (CH), 78.11 (CH ), 77.99
1
H NMR: d 3.34 (6H, s), 3.19 (4H, m), 1.76 (1H, dd, J¼
2
1
3.0, 7.5 Hz), 1.72 (1H, dd, J¼13.0, 7.5 Hz), 1.60–1.30
(CH ), 59.39 (2£CH ), 49.62 (CH), 42.13 (C), 39.42 (CH ),
39.29 (CH), 27.54 (CH ), 18.31 (CH ), 13.98 (CH ), 22.91
2 2 2
2
3
2
(
(
2H, m), 1.10–0.95 (4H, m), 0.93 (3H, d, J¼6.5 Hz), 0.88
1
3
þ
3H, t, J¼7.5 Hz) ppm. C NMR: d 78.14 (CH ), 77.98
(2£CH ) ppm. LRMS (CI): 335 (MþH , 5%), 320
2
3
þ
(
4
CH ), 59.38 (2£CH ), 48.52 (CH), 45.37 (C), 42.09 (CH ),
þ
M 2CH , 100). Anal. calcd for C H O : C, 71.95; H,
(MþH 2CH , 100). HRMS (CI): calculated for
2
3
2
3
þ
1.50 (CH), 39.19 (CH ), 26.54 (CH ), 18.29 (CH ), 12.79
2
C H O Si (MþH ) 335.2406, found 335.2412.
20 35 2
2
3
(
CH ) ppm. LRMS (APCI): 200 (M , 30%), 185
3
þ
2.08. Found: C, 72.15; H, 12.04.
(
4.3.6. rac-(2R,3S)-2,8,8-Trimethyl-3-(2-phenyldimethyl-
silylethyl)-7,9-dioxaspiro[4.5]decane 19b. Colourless oil.
3
12 24 2
1
1
H NMR: d 7.40 (2H, m), 7.25 (3H, m), 3.5 (4H, m), 1.85
4
.3.3. rac-(3R,4R)-1,1-Bis(methoxymethyl)-3-methyl-4-
(1H, dd, J¼14.0, 8.0 Hz), 1.78 (1H, dd, J¼14.0, 8.0 Hz),
1.50 (1H, m), 1.35 (1H, m), 1.30 (6H, s), 1.20 (2H, m), 1.00
(2H, m), 0.90 (3H, d, J¼8.0 Hz), 0.75 (1H, m), 0.55 (1H,
propylcyclopentane 12. Ethyl carbamate 11 (1.1 mmol,
65 mg), in ether (3 mL) was cooled to 278 8C and a
2
1
3
mixture of TMEDA (1.2 mmol) and s-BuLi (1.2 mmol) in
ether (2 mL) added dropwise. After 30 min at 278 8C a
solution of zirconacycle 2a (1.00 mmol) at the same
temperature was added via cannula. After 30 min the
reaction was allowed to warm to room temperature before
usual work-up and chromatography (eluent 2–10% ether in
petrol) gave the title compound as a colourless oil (74 mg,
ddd, J¼15.0, 13.0, 4.0 Hz), 0.20 (6H, s) ppm. C NMR: d
139.61 (C), 133.70 (CH), 128.98 (CH), 127.92 (CH), 97.71
(C), 70.51 (CH ), 70.44 (CH ), 49.37 (CH), 42.93 (CH ),
2
2
2
40.19 (CH ), 39.57 (C), 39.04 (CH), 27.66 (CH ), 24.31
2
2
(CH ), 23.85 (CH ), 18.59 (CH ), 14.00 (CH ), 22.87
3
3
3
2
þ
(2£CH ) ppm. LRMS (CI): 347 (MþH , 5%), 332
3
þ
(MþH 2CH , 100). HRMS (CI): calcd for C H O Si
3
21 35 2
þ
3
5%) together with mixed fractions estimated to contain 12
(MþH ) 347.2406, found 347.2381.

1410
S. Dixon et al. / Tetrahedron 60 (2004) 1401–1416
þ
(M 23Bu, 6), 235 (Bu SnH, 50), 179 BuSnH (100).
NMR data for zirconium complex 14b as a 1:1 mixture of
1
7.42 (CH ) ppm. LRMS (EI): 433 (M 2Bu, 75%), 319
2
þ
HRMS (EI): calcd for C H O Sn (M 2Bu) 433.2129,
found 433.2127.
diastereoisomers, H NMR (C D ): d 7.4 (2H, m), 7.10 (3H,
6
6
2
2
1
0 41 2
20
þ
m), 5.70, 5.65, 5.53, 5.50 (10H, 4£s), 3.60 (4H, m), 3.40
2
(
6H, m), 2.27 (1H, m), 2.0–1.0 (10H, m), 0.3–0.1 (12H,
1
3
4
1
7
4
2
£s) ppm. C NMR (75 MHz, C D ): d 143.67, 143.58,
6
6
33.92, 133.87, 111.53, 110.72, 110.01, 109.97, 97.52,
0.91, 70.71, 59.25, 56.75, 56.31, 52.14, 50.52, 49.91,
8.76, 46.78, 41.34, 39.71, 38.93, 35.04, 34.14, 33.47,
7.22, 25.75, 24.72, 23.72, 1.39, 1.34, 20.47, 21.36 ppm.
4.3.10. rac-(2R,3S)-2,8,8-Trimethyl-3-(2-phenylsul-
phanylethyl)-7,9-dioxaspiro[4.5]decane 21b. To a solu-
tion of zirconacycle 2b (1.00 mmol) at 278 8C (chloro-
methyl)phenyl sulphide (1.5 mmol, 238 mg) in THF (1 mL)
was added followed by the dropwise addition of LDA
(1.2 mmol) over 5 min. After stirring at 278 8C for 1 h the
solution was warmed to 0 8C and usual work-up and
chromatography (eluent 25% ether in petrol) gave the title
4.3.7. rac-Dimethyl(2-((1S,2R)-2-methylcyclopentyl)-
1
ethyl)(phenyl)silane 19c. Colourless oil. H NMR: d 7.56
(
2H, m), 7.40 (3H, m), 1.90–1.75 (2H, m), 1.60–1.53 (3H,
m), 1.43 (1H, m), 1.30–1.10 (4H, m), 0.974 (3H, d, J¼
.6 Hz), 0.853 (1H, ddd, J¼14.7, 12.5, 4.4 Hz), 0.727 (1H,
1
compound (246 mg, 77%) as a colourless oil. H NMR: d
6
7.22 (4H, m), 7.10 (1H, m), 3.50 (4H, m), 2.90 (1H, ddd,
J¼14.0, 10.0, 7.0 Hz), 2.72 (1H, ddd, J¼14.0, 10.0, 7.0 Hz),
1.90 (1H, dd, J¼14.0, 7.0 Hz), 1.81 (1H, m), 1.75 (1H, dd,
J¼14.0, 7.0 Hz), 1.40–1.30 (2H, m), 1.32 (6H, s), 0.90–
1
3
ddd, J¼14.7, 12.5, 5.5 Hz), 0.12 (6H, s) ppm. C NMR: d
39.94 (C), 133.76 (CH), 128.91 (CH), 127.88 (CH), 50.81
CH), 40.27 (CH), 35.18 (CH ), 32.16 (CH), 28.65 (CH ),
1
(
2
2
1
3
2
2
(
3.66 (CH ), 19.85 (CH ), 14.28 (CH ), 22.78 (CH ),
2
0.80 (3H, m), 0.85 (3H, d, J¼6.5 Hz) ppm. C NMR: d
136.94 (C), 129.10 (CH), 129.01 (CH), 125.91 (CH), 97.80
(C), 70.42 (CH ), 70.23 (CH ), 45.77 (CH), 42.50 (CH ),
3
2
3
þ
M2C H , 27), 135 (SiMe Ph , 100), 121 (22). HRMS
2.91 (CH ) ppm. LRMS (EI): 231 (M 2CH , 4%), 168
3
3
þ
þ
6
6
2
2
2
2
(
EI): calcd for C H Si (M 2CH ) 231.1569, found
1
40.30 (CH ), 39.93 (C), 39.55 (CH), 33.58 (CH ), 32.57
2 2
5
23
3
2
31.1568.
(CH ), 24.56 (CH ), 23.49 (CH ) 18.42 (CH ) ppm. LRMS
2 3 3 3
þ
þ
for C H O S (M ) 320.1810, found 320.1807.
(APCI): 320 (M , 40%), 305 (M 2Me, 100). HRMS calcd
þ
4.3.8. Trimethyl(2-((E)-2-pentylidenecyclopentyl)ethyl)-
silane 24 and trimethyl((Z)-2-(2-methylcyclopentyli-
1
9 28 2
dene)hexyl)silane 25. Obtained as a colourless oil and an
1
4.3.11. rac-(2R,3S)-2-(2-Ethoxyethyl)-3,8,8-trimethyl-
7,9-dioxaspiro[4.5]decane 22b. To a solution of zircona-
cycle 2b (1.00 mmol) at 278 8C, chloromethyl ethyl ether
(1.1 mmol, 104 mg) in THF (2 mL) followed by LDA
(1.1 mmol) were added dropwise. After stirring for 30 min
at 278 8C, the reaction was allowed to warm to room
temperature over 2 h, then usual work-up and chroma-
tography (eluent 10% ether/petrol) gave title product as a
colourless oil (115 mg, 45%). A sample for analysis was
8
7:13 inseparable mixture. H NMR: d 5.15 (1H major,
tq, J¼7.0, 2.4 Hz), 2.59 (1H minor, pentet, J¼6.5 Hz),
.3–1.1 (15H majorþ17H minor, m), 0.92 (3H, t,
J¼7.2 Hz), 0.56 (1H major, ddd, J¼14.3, 12.1, 4.4 Hz),
.462 (1H major, ddd, J¼14.3, 12.1, 5.2 Hz), 0.02 (9H
2
0
1
3
minor, s), 20.002 (9H major, s) ppm. C NMR: 24: d
46.47 (C), 120.17 (CH), 47.22 (CH), 32.38 (CH ), 32.17
1
2
(
(
(
CH ), 29.53 (CH ), 29.31 (CH ), 28.61 (CH ), 24.21
2 2 2 2
1
CH ), 22.50 (CH ), 14.42 (CH ), 14.21 (CH ), 21.55
2
Kugelrohr distilled (80 8C at 1 mm Hg). H NMR: d 3.55
2
2
3
CH ) ppm. 25: d 138.51 (C), 127.44 (CH), 36.21 (CH),
3
(4H, m), 3.50–3.30 (4H, m), 1.91 (1H, dd, J¼13.5, 6.5 Hz),
1.84 (1H, dd, J¼14.0, 7.5 Hz), 1.90–1.80 (1H, m), 1.50–
1.20 (3H, m), 1.39 (6H, s), 1.18 (3H, t, J¼7.5 Hz), 1.00 (2H,
3
2
1
4.77 (CH ), 34.64 (CH ), 30.46 (CH ), 29.10 (CH ),
2 2 2 2
3.85 (CH ), 22.92 (CH ), 22.58 (CH ), 19.71 (CH ),
2
2
2
3
1
3
4.31 (CH ) 20.28 (CH ) ppm. GCMS (CI): 24, retention
3
m), 0.95 (3H, d, J¼6.0 Hz) ppm. C NMR: d 97.56 (C),
3
þ
time 9.16 min, 239 (MþH , 13%), 136 (12), 90 (100), 73
70.25 (CH ), 70.17 (CH ), 69.74 (CH ), 66.08 (CH ), 43.27
2
2
2
2
þ
þ
(
5
Me Si , 48). 25, retention time 8.66 min, 239 (MþH .
(CH), 42.38 (CH ), 40.37 (CH ), 39.80 (C), 39.65 (CH),
2 2
3
þ
1%), 122 (22), 90 (94), 73 (Me Si , 100).
3
33.90 (CH ), 24.08 (CH ), 23.59 (CH ), 18.18 (CH ), 15.20
2 3 3 3
þ þ
CH ) ppm. LRMS (APCI): 256 (M , 5%), 241 (M 2Me,
3
(
4
.3.9. rac-(2-((1S,2R)-4,4-Bis(methoxymethyl)-2-methyl-
100). Anal. calcd for C H O : C, 70.27; H, 11.01. Found:
15 28 3
cyclopentyl)ethyl)tributylstannane 20a. To a solution of
zirconacycle 2a (1.00 mmol) at 278 8C was added chloro-
methyltributylstannane (340 mg, 1.00 mmol), followed by
the dropwise addition of LiTMP (1.1 mmol) over 15 min.
After warming to room temperature usual work-up and
chromatography (eluent 3% ether in petrol) gave the title
product as a colourless oil (54 mg, 11%). Uninserted
C, 70.45; H, 11.05.
4.4. Insertion of lithiated diethyl chloromethyl-
phosphonate into zirconacycles
4.4.1. General procedure. To a solution of the zirconacycle
(1.00 mmol) in THF (10.0 mL) at 290 8C, diethyl chloro-
methylphosphonate (0.243 g, 1.30 mmol) was added
followed by LDA (1.30 mmol). The mixture was stirred at
290 to 240 8C for 2 h, then quenched with 2 M HCl aq.
(5.0 mL) and extracted with ether (3£5 mL). The organic
1
product 9 was also isolated (108 mg, 58%). H NMR
(
400 MHz): d 3.34 (6H, s), 3.22 (2H, d, J¼8.5 Hz), 3.18
(
2H, d, J¼8.5 Hz), 1.81 (1H, dd, J¼13.3, 6.8 Hz), 1.72 (1H,
dd, J¼13.3, 7.3 Hz), 1.70 (1H, m), 1.5–1.4 (7H, m), 1.29
(
6H, tq, J¼7.5, 7.5 Hz), 1.3–1.2 (2H, m), 1.00 (1H, dd,
layer was washed with brine (2£10 mL), dried over MgSO
4
J¼13.3, 5.3 Hz), 0.97 (1H, dd, J¼13.3, 5.3 Hz), 0.93 (3H, d,
J¼6.5 Hz), 0.89 (9H, t, J¼7.3 Hz), 0.80 (6H, m), 0.8–0.6
and concentrated under reduced pressure. The products
were isolated by column chromatography on silica gel
(petrol/EtOAc, 1:1) as colourless to pale yellow oils in the
yields given in Table 2. Diethyl pentylphosphonate 32 is a
known compound and had data consistent with that
1
3
(
2H, m) ppm. C NMR (100 MHz): d 78.20 (CH ), 78.04
2
(
CH ), 59.39 (CH ), 59.37 (CH ), 50.70 (CH), 45.19 (C),
3
2
3
4
2.15 (CH ), 39.47 (CH), 39.25 (CH ), 30.93 (CH ), 29.45
2 2 2
5
4
(
CH ), 27.57 (CH ), 18.39 (CH ), 13.87 (CH ), 8.89 (CH ),
3
previously reported.
2
2
3
2

S. Dixon et al. / Tetrahedron 60 (2004) 1401–1416
1411
4
.4.2. Diethyl rac-2-((1R,2S)-4,4-bis(methoxymethyl)-2-
1
chromatography (eluent 40–50% ether in petrol) gave the
1
title compound as a pale yellow oil (228 mg, 67%). H
methylcyclopentyl)ethylphosphonate 26. H NMR: d 4.12
4H, m), 3.33 (6H, s), 3.18 (4H, m), 1.95–1.70 (4H, m),
(
1
0
NMR: d 7.86 (2H, d, J¼7.0 Hz), 7.60 (1H, t, J¼7.0 Hz),
7.53 (2H, t, J¼7.0 Hz), 3.26 (6H, s), 3.1–2.9 (6H, m), 2.00
(1H, m), 1.68 (1H, dd, J¼12.5, 7.0 Hz), 1.63 (1H, dd, J¼
12.5, 6.6 Hz), 1.5–1.2 (3H, m), 0.99 (1H, dd, J¼12.5,
11.0 Hz), 0.91 (1H, dd, J¼12.5, 10.3 Hz), 0.87 (3H, d, J¼
.60–1.25 (4H, m), 1.35 (6H, t, J¼6.5 Hz), 1.02 (2H, m),
1
3
.97 (3H, d, J¼6.9 Hz) ppm. C NMR (100 MHz): 77.96
(
CH ), 77.52 (CH ), 61.55 (CH , J ¼6.5 Hz), 61.51 (CH ,
CP 3 CP
2
2
2
CP
2
J ¼6.5 Hz), 59.35 (2CH ), 47.37 (CH, J ¼17 Hz), 45.27
1
3
(
C), 41.95 (CH ), 39.73 (CH), 38.89 (CH ), 26.35 (CH ,
2
6.3 Hz) ppm. C NMR: d 139.22 (C), 133.71 (CH), 129.31
2
2
J ¼5 Hz), 24.60 (CH , J ¼140 Hz), 18.15 (CH ), 16.62
(CH), 128.04 (CH), 77.77 (CH ), 77.73 (CH ), 59.25 (CH ),
3
59.23 (CH ), 53.38 (CH ), 45.27 (CH), 45.18 (C), 41.57
3 2
CP
2
CP
3
2
2
(2CH , J ¼6 Hz) ppm (also run at 75 MHz to unambigu-
ously distinguish between couplings and chemical shift
3
CP
(CH ), 39.84 (CH), 38.81 (CH ), 26.21 (CH ), 17.89
2 2 2
þ
þ
(13), 166 (15), 134 (100). HRMS (EI): calcd for C H O S
differences). HRMS (EI): calcd for C H O P (M )
5
(CH ) ppm. LRMS (EI): 341 (MþH , 1%), 276 (6), 167
1
6
33
3
3
36.2066, found 336.2070.
1
8 28 4
þ
(
M ) 340.1708, found 340.1698.
4.4.3. Diethyl rac-2-((2S,3S)-1,2,3,4-tetrahydro-2-methyl-
naphthalen-3-yl)ethylphosphonate 30. (containing 6% of
trans-isomer). H NMR: d 7.1–7.0 (4H, m), 4.15–4.0 (4H,
4.5.2. 1-(2-((E)-2-butylidenecyclopentyl)ethylsulphonyl)-
benzene 34. To a solution of zirconacycle 33 (1.00 mmol) at
278 8C was added chloromethyl phenyl sulphone (0.381 g,
2 mmol) as a solution in THF (1.5 mL) followed by the
dropwise addition of LDA (2 mmol). The reaction mixture
was warmed to 220 8C over 1 h, kept at 220 8C for 4 h and
0 8C for 2 h before usual work-up and chromatography
(30% ether in petrol) gave the title compound as a clear oil
1
m), 2.92 (1H, dd, J¼16.6, 5.5 Hz), 2.79 (1H, dd, J¼16.9,
5
1
.1 Hz), 2.60–2.50 (2H, m), 2.10 (1H, m), 1.9–1.5 (5H, m),
.32 (6H, t, J¼7.0 Hz), 0.885 (3H, d, J¼6.2 Hz) ppm.
1
3
C
NMR: d 135.59 (C), 135.33 (C), 129.61 (CH), 129.16 (CH),
1
25.82 (CH), 125.63 (CH), 61.62 (CH , d, J ¼6 Hz), 38.37
2
CP
(
(
CH, d, J ¼16.7 Hz), 37.79 (CH), 31.79 (CH ), 30.39
2 2 CP 2 CP
CP 2
1
CH ), 24.47 (CH , d, J ¼4.6 Hz), 23.88 (CH , d, J ¼
(245 mg, 84%). H NMR (400 MHz): d 7.92 (2H, d, J¼
1
trans-Isomer ring Me group visible in H NMR: d 1.03
40.2 Hz), 16.63 (CH , d, J ¼6 Hz), 13.97 (CH ) ppm.
7 Hz), 7.66 (1H, t, J¼7.5 Hz), 7.57 (2H, t, J¼7.5 Hz), 5.06
(1H, tq, J¼7, 2.5 Hz), 3.17–3.06 (2H, m), 2.35 (1H, septet,
J¼7 Hz), 2.28–2.23 (1H, broad d, J¼16 Hz), 2.11 (1H, dt,
J¼16, 8 Hz), 2.00–1.89 (3H, m), 1.78 (1H, td, J¼12, 7 Hz),
1.72–1.63 (2H, m), 1.57–1.46 (1H, m), 1.33 (2H, pentet,
3
CP
3
1
1
3
(3H, d, J¼6.2 Hz), and in C NMR: d 19.74 ppm, both
confirming stereochemistry. HRMS (EI): calcd for
C H O P (M ) 310.1698, found 310.1688.
17 27 3
þ
1
3
J¼7 Hz), 1.22–1.13 (1H, m), 0.87 (3H, t, J¼7 Hz) ppm.
C
NMR (100 MHz): d 144.66 (C), 139.71 (C), 133.98 (CH),
4
.4.4. Diethyl 2-((E)-2-pentylidenecyclohexyl)ethylphos-
1
phonate 37. H NMR: d 5.00 (1H, t, J¼7.7 Hz), 4.06 (4H,
129.65 (CH), 128.45 (CH), 121.85 (CH), 54.93 (CH ), 43.03
2
m), 2.10–1.70 (5H, m), 1.65–1.20 (14H, m), 1.25 (6H, t,
J¼7.0 Hz), 0.83 (3H, t, J¼7 Hz) ppm. C NMR: d 140.25
(CH), 32.58 (CH ), 31.87 (CH ), 29.21 (CH ), 26.98 (CH ),
2
2
2
2
1
3
24.27 (CH ), 23.09 (CH ), 14.22 (CH ) ppm. LRMS
2 2 3
þ
þ
þ
(
C), 122.48 (CH), 61.49 (CH , d, J ¼6.3 Hz), 45.51 (CH,
(CI): 310 (MþNH , 20%), 293 (MþH , 15), 150 (M 2
2
CP
4
þ
d, J ¼17.4 Hz), 33.70 (CH ), 32.55 (CH ), 28.15 (CH ),
PhSO H, 100). HRMS (CI): calcd for C H O S (MþH )
CP
2
2
2
2
17 25 2
2
2
1
6.88 (CH ), 26.13 (CH ), 24.55 (CH , d, J ¼4.5 Hz),
293.1575, found 293.1584.
2
2
2
CP
4.11 (CH , d, J ¼140 Hz), 23.39 (CH ), 22.44 (CH ),
2
CP
2
2
6.62 (CH , d, J ¼5.7 Hz), 14.13 (CH ) ppm. HRMS (EI):
4.5.3. 1-(2-((E)-2-Pentylidenecyclohexyl)ethylsulpho-
nyl)benzene 38. To a solution of zirconacycle 36
3
CP
3
þ
calcd for C H O P (M ) 316.2167, found 316.2173.
17 33 3
(1.00 mmol) at 278 8C was added chloromethyl phenyl
4
hexyl)ethylphosphonate 40. H NMR: d 5.06 (1H, s), 4.08
.4.5. Diethyl 2-((E)-2-((trimethylsilyl)methylene)cyclo-
1
sulphone (0.248 g, 1.3 mmol) in THF (1.5 mL) followed by
the dropwise addition of LiTMP (1.3 mmol) over 10 min.
The reaction mixture was kept at 278 8C for 2 h before
usual work-up and chromatography (30% ether in petrol)
(
1
1
4H, br s), 2.23 (1H, dt, J¼13.2, 7.5 Hz), 2.07 (1H, dt, J¼
3.2, 6.6 Hz), 2.02 (1H, m), 1.78 (1H, m), 1.7–1.3 (9H, m),
.32 (6H, t, J¼7.0 Hz), 0.08 (9H, s) ppm. C NMR:
1
3
1
gave the title compound as a yellow oil (0.191 g, 60%). H
d 160.71 (C), 120.13 (CH), 61.40 (CH ), 47.84 (CH, d,
2
NMR: d 7.92 (2H, dt, J¼7, 2 Hz), 7.66 (1H, tt, J¼8, 2 Hz),
7.57 (2H, tt, J¼7, 1 Hz), 4.95 (1H, t, J¼7 Hz), 3.15–2.94
(2H, m), 2.13–1.84 (6H, m), 1.72–1.19 (11H, m), 0.87 (3H,
JCP¼ 16.5 Hz), 33.98 (CH ). 32.88 (CH ), 28.77 (CH ),
2
2
2
2
1
4.66 (CH ), 23.99 (CH , d, J ¼139.6 Hz), 23.54 (CH ),
6.17 (CH ), 0.33 (CH ) ppm (J ,6 Hz not resolved).
3 3 CP
2
2
CP
2
1
3
t, J¼ 7 Hz) ppm. C NMR: d 139.52 (C), 139.42 (C),
133.73 (CH), 129.40 (CH), 128.17 (CH), 123.10 (CH),
55.11 (CH ), 43.57 (CH), 33.83 (CH ), 32.44 (CH ), 27.96
þ
HRMS (EI): calcd for C H O PSi (M ) 332.1973, found
6 33 3
1
3
32.1979.
2
2
2
(CH ), 26.85 (CH ), 25.95 (CH ), 24.62 (CH ), 23.20
2 2 2 2
4.5. Insertion of lithiated chloromethylphenylsulphone
into zirconacycles
(CH ), 22.45 (CH ), 14.16 (CH ) ppm. LRMS (CI): 338
2 2 3
þ
C H SO (M ) 320.1810, found 320.1812.
þ
(MþNH , 100%), 321 (MþH , 30). HRMS (EI): calcd for
4
þ
1
9
28
2
4
.5.1. rac-1-(2-((1S,2R)-4,4-Bis(methoxymethyl)-2-
methylcyclopentyl)ethylsulphonyl)benzene 27. To zirco-
nacycle 2a (1.00 mmol) in THF (5 mL) at 278 8C was
added chloromethylphenylsulphone (763 mg, 4.0 mmol) in
THF (2 mL), followed by the dropwise addition of LDA
(4.0 mmol) over 10 min. The reaction was allowed to warm
to room temperature and stirred for 12 h. Usual work-up and
4.5.4. (E)-1-Pentylidene-2-vinylcyclohexane 48. Method
as for the preparation of 38 except that the reaction mixture
was stirred at room temperature for 8 h before quenching.
The crude product was purified by flash column chroma-
tography in petrol and was subsequently Kugelrohr distilled
to yield a clear oil (69 mg, 84% pure by NMR, 33%

1412
S. Dixon et al. / Tetrahedron 60 (2004) 1401–1416
estimated yield) the residue being (E)-1-methyl-2-pentyl-
5
(CH), 120.20 (C, CN), 46.15 (CH), 33.92 (CH ), 32.78
2
5
idenecyclohexane from quenching of the uninserted
1
(CH ), 28.77 (CH ), 27.82 (CH ), 23.51 (CH ), 15.47
2
2
2
2
zirconacycle. H NMR (400 MHz): d 5.91 (1H, ddd, J¼
(CH2), 0.45 (3£CH ) ppm. HRMS (CI): calcd for
3
þ
1
7, 10, 7 Hz), 5.09 (1H, t, J¼7 Hz), 5.04–4.98 (2H, m), 2.71
C H NSi (MþH ) 222.1678, found 222.1672.
1
3 24
(
(
1H, broad s), 2.39 (1H, m), 2.07–1.91 (3H, m), 1.75–1.70
2H, m), 1.58 (1H, broad s), 1.5–1.2 (7H, m), 0.91 (3H, t,
4.6.6. 3-((E)-2-Butylidenecyclopentyl)propanenitrile 35.
1
1
3
J¼6 Hz). C NMR (100 MHz, CDCl ): d 142.16 (CH),
H NMR: d 5.17 (1H, tq, J¼7, 2.5 Hz), 2.43 (1H, dd, J¼8,
3
1
40.89 (C), 122.31 (CH), 114.43 (CH ), 48.85 (CH), 34.62
2
7 Hz), 2.40–2.27 (3H, m,), 2.20 (1H, broad pentet, J¼
8 Hz), 1.99–1.84 (4H, m), 1.86–1.80 (1H, m), 1.65–1.50
(2H, m), 1.37 (2H, sextet, J¼7 Hz), 1.28–1.19 (1H, m), 0.89
(
CH ), 32.70 (CH ), 28.42 (CH ), 28.16 (CH ), 27.25
2 2 2 2
(
1
(
CH ), 25.24 (CH ), 22.74 (CH ), 14.44 (CH ). GCMS (EI):
2 2 2 3
þ
M 2C H , 72), 121 (100).
þ
þ
13
78 (M , 49%), 163 (M 2CH , 10), 149 (M 2C H ), 136
3
(3H, t, J¼7 Hz) ppm. C NMR: d 144.58 (C), 121.62 (CH),
2 5
þ
120.29 (C), 43.28 (CH), 32.25 (CH ), 31.65 (CH ), 30.01
2
3
7
2
(
CH ), 28.93 (CH ), 24.05 (CH ), 22.89 (CH ), 15.48 (CH ),
2 2 2 2 2
þ
4
4.6. Insertion of lithiated 2-chloroacetonitrile into
zirconacycles
14.02 (CH ) ppm. LRMS(CI): 195 (MþNH , 20%), 178
þ þ
2 5
3
(MþH , 75), 148 (M 2C H , 80). HRMS (EI): calcd for
þ
12 19
C H N (M ) 177.1518, found 177.1518.
4
.6.1. General procedure. To a solution of the zirconacycle
(
(
(
1.00 mmol) in THF (5 mL) at 290 8C, 2-chloroacetonitrile
0.098 g, 1.30 mmol) was added followed by LDA
1.30 mmol). The mixture was stirred at 290 to 260 8C
4.6.7. 2-(((E)-2-Butylidenecyclopentyl)methyl)succino-
1
nitrile 53. Isomer1. H NMR (400 MHz): d 5.27 (1H, tq,
J¼7, 2.5 Hz), 3.00 (1H, dq, J¼9.5, 6.5 Hz), 2.73 (2H, d, J¼
6.5 Hz), 2.56 (1H, pentet, J¼7 Hz), 2.34–2.17 (2H, m),
2.02–1.90 (3H, m), 1.85–1.59 (4H, m), 1.46–1.35 (3H, m),
for 1 h, then quenched with 2 M HCl aq. (5.0 mL) and
extracted with ether (3£5 mL). The organic layer was
1
3
washed with brine (2£10 mL), dried over MgSO and
0.91 (3H, t, J¼7 Hz) ppm. C NMR (100 MHz): d 143.94
(C), 122.77 (CH), 119.27 (C), 115.54 (C), 42.15 (CH), 36.44
(CH ), 32.63 (CH ), 31.52 (CH ), 27.93 (CH ), 27.06 (CH),
4
concentrated under reduced pressure. The products were
isolated by column chromatography on silica gel (petrol/
EtOAc, 3:1 to 6:1). Products were isolated as colourless
to pale yellow oils in the yields given in Table 4. For
compounds 50 and 52, 2 equiv. of the carbenoid were used,
and for 53, 5 equiv.
2
2
2
2
24.00 (CH ), 23.59 (CH ), 22.65 (CH ), 13.83 (CH ) ppm.
2
2
2
3
þ
(M 2CH , 8), 187 (M 2C H , 45). Isomer 2. H NMR
þ
LRMS (CI): 234 (MþNH , 16%), 217 (MþH , 32), 201
4
þ
þ
1
3
2 5
(400 MHz): d 5.19 (1H, tq, J¼7, 2.5 Hz), 2.99–2.92 (1H,
m), 2.75 (2H, t, J¼6 Hz), 2.61 (1H, broad s), 2.38–2.32
(1H, m), 2.21 (1H, dt, J¼17, 8.5 Hz), 2.07 (1H, ddd, J¼14,
11, 4.5 Hz), 2.01–1.94 (3H, m), 1.83–1.76 (1H, m), 1.65–
1.57 (2H, m), 1.38 (2H, pentet, J¼7 Hz), 1.28–1.19 (1H,
4
.6.2. rac-3-((1R, 2R)-4,4-Bis(methoxymethyl)-2-methyl-
1
cyclopentyl)propanenitrile 28. H NMR: d 3.27 (6H, s),
.15 (2H, d, J¼8.6 Hz), 3.10 (2H, d, J¼8.6 Hz), 2.33 (1H,
3
1
3
ddd, J¼16.9, 7.7, 5.5 Hz), 2.23 (1H, ddd, J¼16.9, 8.5,
m), 0.91 (3H, t, J¼7 Hz) ppm. C NMR (100 MHz): d
144.53 (C), 122.06 (CH), 119.27 (C), 115.97 (C), 41.84
(CH), 37.07 (CH ), 32.65 (CH ), 31.91 (CH ), 29.31 (CH ),
7
6
.4 Hz), 1.95–1.10 (8H, m), 0.99 (2H, m), 0.90 (3H, d, J¼
.3 Hz) ppm. C NMR: d 120.06 (C), 77.95 (CH ), 77.89
2
1
3
2
2
2
2
(
3
(
2
CH ), 59.39 (CH ), 45.77 (CH), 45.41 (C), 41.83 (CH ),
2
27.59 (CH), 24.42 (CH ), 23.06 (CH ), 22.01 (CH ), 14.24
2 2 2
3
2
þ
9.85 (CH), 38.70 (CH ), 29.68 (CH ), 18.03 (CH ), 16.26
2
(CH ) ppm. LRMS (CI): 234 (MþNH , 100%), 217
þ þ
2 5
2
3
3
4
þ
CH ) ppm. HRMS (CI): calcd for C H O N (MþH )
(MþH , 35), 187 (M 2C H , 30).
2
13 24
2
26.1807, found 226.1796.
4.7. Insertion of 1-lithio-1-haloalkenes into saturated
zirconacycles
4.6.3. rac-3-((1R,2R)-2-(2-Cyanoethyl)-4,4-bis(methoxy-
1
methyl)cyclopentyl)propanenitrile 50. H NMR: d 3.26
(
6H, s), 3.13 (2H, d, J¼8.6 Hz), 3.10 (2H, d, J¼8.6 Hz),
4.7.1. rac-(2R,3S)-2,8,8-Trimethyl-3-(3-methylbut-2-
enyl)-7,9-dioxaspiro[4.5]decane 61a. To a solution of
zirconacycle 2b (1.00 mmol) at 278 8C was added 1-chloro-
2-methyl-1-propene (452 mg, 5 mmol) in THF (2 mL). The
solution was then cooled to 290 8C, and LiTMP (5 mmol)
was added dropwise over 10 min. After stirring for 30 min
at 290 8C usual work-up and chromatography (eluent 25%
ether in petrol) gave the title product (83 mg, 33%) as a
2
8
1
5
.37 (2H, ddd, J¼16.9, 7.7, 5.5 Hz), 2.24 (2H, ddd, J¼16.9,
.5, 7.4 Hz), 1.95–1.73 (4H, m), 1.58 (2H, m), 1.37 (2H, m),
.02 (2H, m) ppm. C NMR: d 119.68 (C), 77.76 (CH2),
9.40 (CH ), 45.68 (C), 44.05 (CH), 38.43 (CH ), 29.16
1
3
3
2
(
CH2), 16.18 (CH ) ppm. HRMS (CI): calcd for
2
þ
C H N O (MþH ) 265.1916, found 265.1916.
1
5 25 2 2
1
4
.6.4. 3-(2-(2-Cyanoethyl)cyclohexyl)propanenitrile 52.
1
colourless oil. H NMR: d 5.05 (1H, t septet, J¼8.0, 1.5 Hz),
(
(
88:12 mixture of cis- and trans-isomers). H NMR: d 2.29
1
3.56 (4H, m), 2.15 (1H, m), 1.80 (1H, ddd, J¼13.2, 7.4,
2.9 Hz), 1.75–1.65 (2H, m), 1.60 (3H, d, J¼1.5 Hz), 1.52
(3H, s), 1.45 (1H, m), 1.35 (6H, s), 1.30 (1H, m), 0.97 (2H,
3
4H, m), 1.95–1.10 (14H, m) ppm. C NMR: d 119.91 (C),
7.80 (CH), 27.4 (CH ), 25.20 (CH ), 23.11 (CH ), 15.37
3
2
2
2
1
3
(
(
CH ) ppm (cis-isomer). d 119.92 (C), 40.02 (CH), 30.57
2
m), 0.95 (3H, d, J¼7.0 Hz) ppm. C NMR: d 131.77 (C),
CH ), 28.88 (CH ), 25.50 (CH ), 14.57 (CH ) ppm (trans-
2
123.26 (CH), 97.67 (C), 70.46 (CH ), 70.39 (CH ), 46.91
2
2
2
2
2
isomer). HRMS (CI): calcd for C H N (MþHþ)
(CH), 42.78 (CH ), 40.63 (CH ), 39.67 (C), 39.05 (CH),
2 2
1
2
19
2
1
91.1548, found 191.1555.
31.84 (CH ), 25.97 CH ), 24.47 (CH ), 24.02 (CH ), 23.95
2 3 3 3
þ
237 (12), 195 (99), 177 (56). HRMS (CI) calcd for
(
CH ), 18.50 (CH ) ppm. LRMS (CI): 253 (MþH , 100%),
3
3
4
propanenitrile 41. H NMR: d 5.11 (1H, s), 2.4–1.3
(
.6.5. 3-((E)-2-((Trimethylsilyl)methylene)cyclohexyl)-
1
þ
consistent with that previously reported.
C H O (MþH ) 253.2168, found 253.2160. Data
1
6 29 2
1
3
46
13H, m), 0.10 (9H, s) ppm. C NMR: d 159.59 (C), 121.20

S. Dixon et al. / Tetrahedron 60 (2004) 1401–1416
1413
4
[
.7.2. rac-(3R,4R)-1,1-Bis(methoxymethyl)-3-methyl-4-
(2E)-2,4-pentadienyl]cyclopentane 61b. To a solution of
(CH), 77.45 (C), 59.18 (CH ), 46.38 (CH), 45.16 (C), 41.62
3
(CH ), 39.44 (CH), 39.06 (CH ), 33.69 (CH ), 30.93 (CH ),
2
2
2
2
zirconacycle 2a (1.00 mmol) in THF (5 mL) at 290 8C
was added (E)-1,4-dichloro-2-butene (138 mg, 1.1 mmol)
followed by the dropwise addition of LDA (2.2 mmol) over
21.92 (CH ), 19.18 (CH ), 18.08 (CH ), 13.56 (CH ) ppm.
2 2 3 3
þ
þ
LRMS (EI): 292 (M , 1%), 260 (M 2MeOH, 12), 247 (8),
215 (35), 107 (65), 91 (72). HRMS (EI): calcd for C H O
9 32 2
1
þ
(M ) 292.2402, found 292.2403.
1
0 min. After stirring at 290 8C for 1 h usual work-up and
chromatography (eluent 10% ether/petrol) gave the title
compound as a colourless oil (161 mg, 68%). A sample for
4.7.5. rac-1-((Z)-3-((1R,2R)-4,4-Bis(methoxymethyl)-2-
methylcyclopentyl)prop-1-enyl)benzene 61e. To zircona-
cycle 2a (1.00 mmol) at 278 8C was added (E)-b-bromo-
styrene (183 mg, 1.00 mmol) followed by LDA (1.0 mmol)
dropwise over 20 min. The reaction was stirred at 278 8C
for 5 min before usual work-up and chromatography (eluent
4% ether in petrol) gave the title compound as a colourless
oil (138 mg, 48%) together with bis-inserted product
1
analysis was Kugelrohr distilled (80 8C at 1 mm Hg). H
NMR: d 6.28 (1H, dt, J¼17.0, 10.5 Hz), 6.04 (1H, dd, J¼
1
7.0, 10.5 Hz), 5.69 (1H, ddd, J¼17.0, 10.5, 9.5 Hz), 5.07
(
(
1H, dd, J¼17.0, 2.0 Hz), 4.93 (1H, dd, J¼9.5, 2.0 Hz), 3.32
6H, s), 3.20 (4H, m), 2.34 (1H, ddd, J¼10.5, 6.5, 2.9 Hz),
1
3
2
.0–0.9 (10H, m) ppm. C NMR: d 137.29 (CH), 134.21
(
CH), 131.58 (CH), 114.69 (CH ), 77.90 (CH ), 77.78
2 2
1
(
CH ), 59.22 (CH ), 59.00 (CH ), 46.57 (CH), 45.06 (C),
2
62 (43 mg, 11%). H NMR (400 MHz): d 7.32 (2H, t,
3
3
4
1.94 (CH), 41.34 (CH ), 39.23 (CH ), 36.57 (CH ), 17.77
2
J¼7.5 Hz), 7.27 (2H, d, J¼7.5 Hz), 7.21 (1H, t, J¼7.5 Hz),
6.41 (1H, d, J¼11.5 Hz), 5.68 (1H, dt, J¼11.5 7.3 Hz), 3.34
(3H, s), 3.31 (3H, s), 3.21 (1H, d, J¼9.0 Hz), 3.19 (1H, d,
J¼9.0 Hz), 3.18 (1H, d, J¼9.0 Hz), 3.16 (1H, d, J¼9.0 Hz),
2
2
þ
for C H O : C, 75.58; H, 10.99. Found: C, 75.48; H,
(
CH ) ppm. LRMS (APCI): 238 (M , 100%). Anal. calcd
3
1
5 26 2
1
0.85.
2
.61 (1H, m), 2.08 (1H, ddd, J¼15.0, 7.5, 7.5 Hz), 1.82 (1H,
4
[
.7.3. rac-(3R,4R)-1,1-Bis(methoxymethyl)-3-methyl-4-
(2Z)-2,4-pentadienyl]cyclopentane 61c. To a solution of
dd, J¼13.0, 7.0 Hz), 1.74 (1H, dd, J¼13.0, 7.0 Hz), 1.6–1.5
(1H, m), 1.5–1.4 (1H, m), 1.05 (1H, dd, J¼10.1, 7.0 Hz),
1.02 (1H, dd, J¼10.1, 7.0 Hz), 0.95 (3H, d, J¼6.0 Hz) ppm.
zirconacycle 2a (1.00 mmol) in THF (5 mL) at 290 8C was
added (Z)-1,4-dichlorobut-2-ene (125 mg, 1.00 mmol),
followed by LDA (1.0 mmol) dropwise over 15 min. The
reaction was stirred at 290 8C for 35 min before usual
1
3
C NMR (100 MHz): d 137.97 (C), 132.05 (CH), 129.18
(CH), 128.97 (CH), 128.21 (CH), 126.53 (CH), 78.10 (CH2)
77.98 (CH ), 59.39 (CH ), 59.37 (CH ), 47.27 (CH), 45.33
2
3
3
work-up and chromatography (AgNO doped silica, eluent
3
(C), 41.87 (CH ), 39.78 (CH), 39.47 (CH ), 32.55 (CH ),
2 2 2
þ
18.52 (CH ) ppm. LRMS (EI): 288 (M , 12%), 256
3
4
–50% ether in petrol) gave the title compound as a
colourless oil (143 mg, 60%) and non-inserted product 9
43 mg, 23%). A sample of 61c for analysis was Kugelrohr
þ
þ
þ
(M 2MeOH, 30), 211 (M 2Ph, 38), 137 (70). HRMS
(EI): calcd for C H O (M ) 288.2089, found 288.2092.
19 28 2
(
1
distilled (80 8C at 1 mm Hg). H NMR (400 MHz): d 6.64
(
(
(
(
(
(
0
1
7
1H, dt, J¼16.6, 10.5 Hz), 6.00 (1H, t, J¼10.5 Hz), 5.46
1H, dt, J¼10.5, 7.5 Hz), 5.17 (1H, d, J¼16.6 Hz), 5.07
1H, d, J¼10.5 Hz), 3.33 (3H, s), 3.32 (3H, s), 3.20–3.15
4H, m), 2.42 (1H, m), 1.98 (1H, dt, J¼14.1, 7.5 Hz), 1.74
2H, dd, J¼13.1, 7.0 Hz), 1.54 (1H, m), 1.41 (1H, m), 1.04
1H, dd, J¼13.1, 11.0 Hz), 1.02 (1H, dd, J¼13.1, 2.0 Hz),
4.7.6. rac-(1E,3Z)-2-(((1R,2R)-4,4-Bis(methoxymethyl)-
2-methylcyclopentyl)methyl)-1,4-diphenylbuta-1,3-
diene 62. Method as for 61 except that 2 equiv. of (E)-b-
bromostyrene and LDA were used to afford 62 as a
1
colourless oil (250 mg, 64%). H NMR (400 MHz): d 7.56
(2H, d, J¼7.5 Hz), 7.45–7.35 (4H, m,), 7.35–7.25 (4H, m),
6.67 (1H, s), 6.56 (1H, d, J¼12.2 Hz), 6.35 (1H, d, J¼
12.2 Hz), 3.42 (3H, s), 3.39 (3H, s), 3.27 (1H, d, J¼8.5 Hz),
3.23 (1H, d, J¼8.5 Hz), 3.23 (1H, d, J¼9.0 Hz), 3.20 (1H, d,
J¼9.0 Hz), 2.79 (1H, dd, J¼13.6, 3.5 Hz), 2.23 (1H, dd, J¼
13.6, 10.0 Hz), 1.86 (1H, dd, J¼13.1, 7.0 Hz), 1.78 (1H, dd,
J¼13.1, 7.3 Hz), 1.68 (1H, m), 1.50 (1H, m, 1.08 (1H, dd,
J¼13.1, 10.5 Hz), 1.05 (1H, dd, J¼13.1, 10.5 Hz), 0.91 (3H,
1
3
.96 (3H, d, J¼6.5 Hz) ppm. C NMR (100 MHz): d
31.46 (CH), 130.68 (CH), 128.67 (CH), 115.91 (CH ),
2
7.07 (CH ), 76.97 (CH ), 58.36 (CH ), 45.94 (CH), 44.24
2
2
3
(
1
C), 40.83 (CH ), 38.55 (CH), 38.31 (CH ), 30.48 (CH ),
2
2
2
þ
calcd for C H O : C, 75.58; H, 10.99. Found: C, 75.68; H,
7.25 (CH ) ppm. LRMS (APCI): 238 (M , 100%). Anal.
3
1
5 26 2
1
1.05.
1
3
d, J¼6.0 Hz) ppm. C NMR (100 MHz): d 139.27 (C),
4
.7.4. rac-(3R,4R)-1,1-Bis(Methoxymethyl)-3-methyl-4-
138.00 (C), 137.92 (C), 134.03 (CH), 130.38 (CH), 129.43
(CH), 129.04 (CH), 129.01 (CH), 128.20 (CH), 78.03
(CH ), 77.90 (CH ), 59.36 (CH ), 59.32 (CH ), 45.80 (CH),
p
p
p
(
2
(Z)-non-2-en-4-ynyl)cyclopentane 61d. To zirconacycle
a (1.00 mmol) in THF (5 mL) at 278 8C was added (E)-1-
2
2
3
3
chloro-oct-1-en-3-yne (171 mg, 1.00 mmol), followed by
LDA (1.0 mmol) dropwise over 15 min. The reaction was
stirred at 278 8C for 40 min before usual work-up and
chromatography (eluent 3% ether in petrol) gave the title
45.30 (C), 41.69 (CH ), 40.23 (CH), 39.77 (CH ), 34.90
2 2
p
(CH ), 18.01 (CH ) ppm ( —contain overlapping peaks).
2
3
þ
þ
(M 22MeOH, 5), 218 (55), 129 (100). HRMS (EI): calcd
LRMS (EI): 390 (M , 8%), 358 (M 2MeOH, 6), 326
þ
for C H O (M ) 390.2559, found 390.2553.
1
þ
compound as a colourless oil (158 mg, 54%). H NMR
(
2
7 34 2
400 MHz): d 5.824 (1H, dt, J¼10.7, 7.5 Hz), 5.434 (1H,
dtt, J¼10.7, 2.1, 1.4 Hz), 3.329 (3H, s), 3.324 (3H, s), 3.2
4.8. Insertion of 1-halo-1-lithioalkenes into unsaturated
zirconacycles
(
(
1
7
1
4H, m), 2.524 (1H, dddd, J¼14.1, 7.5, 4.3, 1.5 Hz), 2.337
2H, dt, J¼2.3, 6.9 Hz), 2.087 (1H, dddd, J¼14.1, 8.8, 7.5,
.3 Hz), 1.756 (1H, dd, J¼7.0, 3.5 Hz), 1.731 (1H, dd, J¼
.0, 3.8 Hz), 1.6–1.4 (6H, m), 1.097 (1H, dd, J¼13.3,
0.8 Hz), 1.001 (1H, dd, J¼13.0, 11.0 Hz), 0.975 (3H, d,
4.8.1. (4E)-1,1-Bis(methoxymethyl)-3-((Z)-penta-2,4-di-
enyl)-4-propylidenecyclopentane 70a. To zirconacycle
67 (1.00 mmol) in THF (5 mL) at 290 8C was added
(Z)-1,4-dichloro-2-butene (375 mg, 3.0 mmol), followed by
LDA (6.0 mmol) dropwise over 25 min. The reaction was
1
3
J¼6.3 Hz), 0.923 (3H, t, J¼7.3 Hz). C NMR (100 MHz):
d 141.02 (CH), 109.79 (CH), 94.46 (C), 77.88 (CH ), 77.77
2

1414
S. Dixon et al. / Tetrahedron 60 (2004) 1401–1416
stirred at 290 8C for 30 min before usual work-up and
chromatography (AgNO doped silica, eluent 3–50% ether
in petrol) gave the title compound as a pale yellow oil
1
29.33 (CH ), 29.27 (CH ), 24.19 (CH ), 22.54 (CH ), 22.09
2 2 2 2
(CH ), 19.37 (CH ), 14.21 (CH ), 13.75 (CH ) ppm. LRMS
2 2 3 3
3
þ
C H (M ) 258.2348, found 258.2338.
(CI): 259 (MþH , 90%), 137 (100). HRMS (EI): calcd for
þ
(
1
1
(
213 mg, 81%). H NMR (400 MHz): d 6.61 (1H, dt, J¼
1
9 30
7.1, 10.5 Hz), 6.03 (1H, t, J¼10.5 Hz), 5.47 (1H, dt, J¼
0.5, 7.5 Hz), 5.19 (1H, m), 5.17 (1H, d, J¼17.1 Hz), 5.08
4.8.4. (4E,8Z)-5-Propylpentadeca-4,8-dien-10-yne 70d.
To zirconocene dichloride (292 mg, 1.00 mmol) in THF
(5 mL) at 278 8C under argon was added n-BuLi (2.0 mmol)
and stirred for 20 min before the reaction was placed under an
ethene atmosphere. The reaction was warmed to room
temperature and 4-octyne (110 mg, 1.00 mmol) was added
and the reaction stirred for 3 h to form zirconacycle 68.
The solution was then cooled to 278 8C and 1-chloro-oct-1-
en-3-yne (157 mg, 1.1 mmol) added, followed by LDA
(1.1 mmol) dropwise over 15 min. The reaction was stirred
at 278 8C for 45 min before usual work-up and chroma-
tography (eluent petrol) gave the title compound as a
1H, d, J¼10.5 Hz), 3.34 (3H, s), 3.32 (3H, s), 3.28 (1H, d,
J¼8.7 Hz), 3.24 (1H, d, J¼8.7 Hz), 3.19 (2H, s), 2.58–2.47
2H, m), 2.20 (1H, d, J¼16.6 Hz), 2.12 (1H, d, J¼16.6 Hz),
.12 (1H, m), 1.98 (2H, dq, J¼7.5, 7.5 Hz), 1.83 (1H, dd,
J¼13.1, 7.5 Hz), 1.11 (1H, dd, J¼13.1, 10.5 Hz), 0.94 (3H,
(
2
1
3
t, J¼7.5 Hz) ppm. C NMR: d 143.52 (C), 132.58 (CH),
1
31.35 (CH), 129.95 (CH), 123.14 (CH), 117.00 (CH ),
2
7
7.70 (CH ), 75.35 (CH ), 59.43 (CH ), 59.42 (CH ), 45.81
2
2
3
3
(
2
2
C), 41.81 (CH), 37.75 (CH ), 35.86 (CH ), 32.64 (CH ),
2 2 2
þ
2.67 (CH ), 14.44 (CH ) ppm. LRMS (EI): 264 (M , 2%),
2 3
þ
32 (M 2MeOH, 23), 187 (26), 165 (40), 133 (44), 105
1
(
(
45), 91 (100). HRMS (EI): calcd for C H O
1
M 2MeOH) 232.1827, found 232.1830
colourless oil (134 mg, 54%). H NMR (400 MHz): d 5.81
(1H, dt, J¼10.5, 7.5 Hz), 5.42 (1H, dt, J¼10.5, 2.0 Hz), 5.16
6 24
þ
(
1H, t, J¼7.0 Hz), 2.39 (2H, dt, J¼7.5 Hz), 2.34 (2H, td,
4
.8.2. 1-((1Z)-3-((E)-4,4-Bis(methoxymethyl)-2-propyl-
J¼7.0, 2.0 Hz), 2.07 (2H, t, J¼7.5 Hz), 2.04–1.94 (4H, m),
idenecyclopentyl)prop-1-enyl)benzene 70b. To zircona-
cycle 67 (1.00 mmol) in THF (5 mL) at 278 8C was added
1.53 (2H, m), 1.45–1.30 (6H, m), 0.92 (3H, t, J¼7.5 Hz),
1
3
0.90 (6H, t, J¼7.5 Hz) ppm. C NMR: d 142.48 (CH),
138.59 (C), 125.56 (CH), 109.44 (CH), 94.70 (C), 77.47 (C),
36.08 (CH ), 32.18 (CH ), 31.11 (CH ), 29.96 (CH ), 29.02
(
(
E)-b-bromostyrene (200 mg, 1.1 mmol) followed by LDA
1.1 mmol) dropwise over 15 min. The reaction was stirred
2
2
2
2
at 278 8C for 30 min before usual work-up and chroma-
tography (eluent 4% ether in petrol) gave the title compound
as a colourless oil (200 mg, 64%). H NMR (400 MHz): d
(CH ), 23.38 (CH ), 22.11 (CH ), 21.71 (CH ), 19.37
2 2 2 2
(CH ), 14.35 (CH ), 14.02 (CH ), 13.78 (CH ) ppm.
2 3 3 3
1
þ þ
LRMS (EI): 246 (M , 15%), 217 (M 2C H , 18), 203
2 5
þ þ
(M 2C H , 95), 189 (M 2C H , 25), 161 (50), 147 (53).
3 7 4 9
7
(
.29 (2H, dd, J¼7.5, 7.5 Hz), 7.24 (2H, d, J¼7.5 Hz), 7.18
1H, t, J¼7.5 Hz), 6.41 (1H, d, J¼11.6 Hz), 5.66 (1H, dt,
J¼11.6, 7.0 Hz), 5.19 (1H, t, J¼7.0 Hz), 3.30 (3H, s), 3.28
3H, s), 3.23 (1H, d, J¼9.0 Hz), 3.19 (1H, d, J¼9.0 Hz),
þ
HRMS (EI): calcd for C H (M ) 246.2348, found
18 30
246.2346.
(
3
.18 (2H, s), 2.66 (1H,ddd, J¼14.0, 7.0, 7.0 Hz), 2.57 (1H,
4.9. Insertions via rearrangement of alkynate complexes
m), 2.24 (1H, ddd, J¼14.0, 7.0, 7.0 Hz), 2.18 (1H, d,
J¼16.8 Hz), 2.06 (1H, d, J¼16.8 Hz), 1.94 (2H, dq, J¼7.5,
4.9.1. 1-((1Z)-3-((E)-2-Pentylidenecyclopentyl)-1-pro-
penyl)benzene 72a. To a stirred solution of zirconacycle
23 (0.5 mmol) in THF (5 mL) at 278 8C was added 1-[(E)-
2-fluoro-1-ethenyl]benzene (0.06 mL, 0.5 mmol) followed
by LiTMP (0.5 mmol). The mixture was warmed slowly to
room temperature then stirred for 12 h before usual work-up
and chromatography (eluted with petrol) yielded the title
7
.5 Hz), 1.86 (1H, dd, J¼12.8, 8.0 Hz), 1.10 (1H, dd,
1
3
J¼12.8, 10.5 Hz), 0.90 (3H, t, J¼7.5 Hz) ppm. C NMR
(
(
(
100 MHz): d 143.58 (C), 137.96 (C), 131.57 (CH), 129.57
CH), 128.94 (CH), 128.23 (CH), 126.55 (CH), 123.21
CH), 77.71 (CH ), 75.46 (CH ), 59.42 (CH ), 59.39 (CH ),
2
2
3
3
4
5.90 (C), 42.22 (CH), 37.85 (CH ), 35.88 (CH ), 33.50
2 2
1
(
(
CH ), 22.67 (CH ), 14.33 (CH ) ppm. LRMS (EI): 282
2
M 2MeOH, 10%), 237 (M 2Ph, 5), 197 (M 2
compound as a colourless oil (63 mg, 49.5%). H NMR
2
3
þ
þ
þ
(400 MHz): d 7.30 (5H, m), 6.46 (1H, br d, J¼11.8 Hz),
5.73 (1H, dt, J¼11.8, 7.0 Hz), 5.21 (1H, tq, J¼7.0, 2.0 Hz),
2.60 (1H, dddd, J¼14.7, 10.3, 4.5, 1.5 Hz), 2.45 (1H, m),
2.35–2.15 (3H, m), 1.98 (2H, apparent q, J¼5.9 Hz), 1.86
PhCHCHCH , 10), 165 (32), 133 (31), 117 (35), 91 (100).
2
þ
HRMS (EI): calcd for C H O (M ) 314.2246, found
2
1 30 2
3
14.2245.
(
1H, m), 1.70 (1H, m), 1.50–1.40 (2H, m), 1.35–1.21 (4H,
1
3
4
.8.3. (2E)-1-((2Z)-2-Nonen-4-ynyl)-2-pentylidenecyclo-
m), 0.90 (3H, t, J¼6.8 Hz) ppm. C NMR (100 MHz): d
145.65 (C), 138.03 (C), 132.07 (CH), 129.36 (CH), 128.93
(CH), 128.25 (CH), 126.53 (CH), 120.76 (CH), 44.60 (CH),
33.33 (CH ), 32.75 (CH ), 32.05 (CH ), 29.34 (CH ), 29.32
pentane 70c. To a stirred solution zirconacycle 23
1.00 mmol) in THF (5.0 mL) at 278 8C was added (E)-1-
(
chloro-1-octen-3-yne (0.2 mL, 2.0 mmol) followed by
LiTMP (2.0 mmol). The mixture continued to stir at
2
2
2
2
(CH ), 24.17 (CH ), 22.57 (CH ), 14.23 (CH ) ppm. LRMS
2
2
2
3
þ þ
(EI): 254 (M , 42%), 197 (M 2C H , 11), 137 (100), 117
4 9
2
78 8C for 20 min then at room temperature overnight
before usual work-up and Kugelrohr distillation (110 8C,
5 mm Hg) gave the title compound as a pale yellow oil
z
2
(PhCHvCHCH , 91), 115 (100). HRMS (EI): calcd for
þ
1
C H (M ) 254.2035, found 254.2047. By the same
1
9 26
1
(
223 mg, 86%). H NMR (400 MHz): d 5.77 (1H, dt, J¼
method 4-[3-(2-butylidene-cyclopentyl)-propenyl]-biphenyl
72b was formed from 4-(2-fluorovinyl)biphenyl in 52%
yield.
1
6
2
0.6, 7.4 Hz), 5.40 (1H br d, J¼10.6 Hz), 5.13 (1H t, J¼
.8 Hz), 2.44 (1H, dt, J¼13.3, 6.8 Hz), 2.33 (1H, m), 2.30–
.15 (4H, m), 1.91 (2H, m), 1.75–1.60 (2H, m), 1.44 (2H,
sextet, J¼6.8 Hz), 1.36 (3H, m), 1.25 (5H, m), 0.85 (6H,
4.9.2. 4-[3-(2-Butylidene-cyclopentyl)-propenyl]-biphe-
nyl 72b. To a stirred solution of zirconacycle 23
(1.00 mmol) at 278 8C was added 4-ethynyl-biphenyl
(178 mg, 1.00 mmol) followed by LiTMP (1.0 mmol). The
1
3
m) ppm. C NMR (100 MHz): d 145.66 (C), 141.38 (CH),
20.65 (CH), 110.09 (CH), 94.49 (C), 77.72 (C), 43.90
CH), 34.95 (CH ), 32.47 (CH ), 32.07 (CH ), 31.11 (CH ),
1
(
2
2
2
2

S. Dixon et al. / Tetrahedron 60 (2004) 1401–1416
1415
solution was then warmed to room temperature and stirred
for 12 h before usual work-up and chromatography (petrol)
gave the title compound as a colourless oil (210 mg, 64%).
Chem., Int. Ed. Engl. 1990, 29, 771–772. (d) Ura, Y.; Li, Y. Z.;
Xi, Z. F.; Takahashi, T. Tetrahedron Lett. 1998, 39,
2787–2790. (e) Buchwald, S. L.; Qun, F. J. Org. Chem.
1989, 54, 2793–2797.
1
H NMR: d 7.65–7.57 (4H, m), 7.50–7.31 (5H, m), 6.50
(
1H, d, J¼11.8 Hz), 5.77 (1H, dt, J¼11.8, 7.0 Hz), 5.25 (1H,
tq, J¼7.4, 2.0 Hz), 2.68 (1H, dddd, J¼14.3, 7.0, 4.8,
.8 Hz), 2.49 (1H, m), 2.42–2.20 (3H, m), 2.00 (2H, br d,
6. (a) Nugent, W. A.; Taber, D. F. J. Am. Chem. Soc. 1989, 111,
6435–6437. (b) Xi, C. J.; Huo, S. Q.; Afifi, T. H.; Hara, R.;
Takahashi, T. Tetrahedron Lett. 1997, 38, 4099–4102.
(c) Buchwald, S. L.; Nielsen, R. B. J. Am. Chem. Soc. 1989,
111, 2870–2874. (d) Tidwell, J. H.; Buchwald, S. L. J. Am.
Chem. Soc. 1994, 116, 11797–11810. (e) Nishihara, Y.;
Aoyagi, K.; Hara, R.; Suzuki, N.; Takahashi, T. Inorg. Chim.
Acta 1996, 252, 91–99. (f) Aoyagi, K.; Kasai, K.; Kondakov,
D. Y.; Hara, R.; Suzuki, N.; Takahashi, T. Inorg. Chim. Acta
1994, 220, 319–326. (g) Ubayama, H.; Xi, Z. F.; Takahashi, T.
Chem. Lett. 1998, 517–518.
1
J¼7.0 Hz), 1.90 (1H, ddt, J¼11.8, 4.8, 6.6 Hz), 1.74 (1H,
m), 1.56 (1H, m), 1.40–1.26 (5H, m), 0.91 (3H, t, J¼
1
3
7
(
1
1
(
(
(
1
.0 Hz) ppm. C NMR: d 145.66 (C), 141.03 (C), 139.27
C), 137.10 (C), 132.72 (CH), 132.37 (CH), 129.39 (CH),
29.04 (CH), 127.90 (CH), 127.35 (CH), 127.14 (CH),
26.97 (CH), 120.82 (CH), 44.63 (CH), 33.52 (CH ), 32.80
2
CH ), 32.07 (CH ), 30.18 (CH ), 29.38 (CH ), 24.22
2 2 2 2
CH ), 22.60 (CH ), 14.26 (CH ) ppm. LRMS (EI): 330
2 2 3
þ
zþ
M , 32%), 249 (9), 193 (p-PhC H CHvCHCH , 100),
7. (a) Swanson, D. R.; Rousset, C. J.; Negishi, E.; Takahashi, T.;
Seki, T.; Saburi, M.; Uchida, Y. J. Org. Chem. 1989, 54,
3521–3523. (b) Rousset, C. J.; Swanson, D. R.; Lamaty, F.;
Negishi, E. Tetrahedron Lett. 1989, 30, 5105–5108.
6
4
2
þ
78 (88). HRMS (EI): calcd for C H (M ) 330.2348,
25 30
found 330.2352.
(
c) Negishi, E.; Holmes, S. J.; Tour, J. M.; Miller, J. A.;
Cederbaum, F. E.; Swanson, D. R.; Takahashi, T. J. Am.
Chem. Soc. 1989, 111, 3336–3346. (d) Takahashi, T.; Kotora,
M.; Kasai, K.; Suzuki, N.; Nakajima, K. Organometallics
Acknowledgements
We thank the Engineering and Physical Sciences Research
Council (EPSRC) for a postdoctoral award (GR/N00647) to
A. K. and studentships to S. D., S. M. F., D. N. and E. T. We
thank our industrial partners for collaborating on this work
through the CASE scheme: Julian Blagg (Pfizer, Sandwich)
and Ed Griffen (AstraZeneca, Alderley Park). R. J. W.
thanks Pfizer for generous uncommitted support during the
course of this work.
1
994, 13, 4183–4185. (e) Takahashi, T.; Huo, S. Q.; Hara, R.;
Noguchi, Y.; Nakajima, K.; Sun, W. H. J. Am. Chem. Soc.
999, 121, 1094–1095. (f) Barluenga, J.; Sanz, R.; Fananas,
1
F. J. Chemistry 1997, 3, 1324–1336. (g) Takahashi, T.; Xi,
Z. F.; Nishihara, Y.; Huo, S. Q.; Kasai, K.; Aoyagi, K.;
Denisov, V.; Negishi, E. Tetrahedron 1997, 53, 9123–9134.
. (a) Davis, J. M.; Whitby, R. J.; Jaxa-Chamiec, A. Tetrahedron
Lett. 1992, 33, 5655–5658. (b) Davis, J. M.; Whitby, R. J.;
Jaxa-Chamiec, A. Tetrahedron Lett. 1994, 35, 1445–1448.
8
(
c) Davis, J. M.; Whitby, R. J.; Jaxa-Chamiec, A. Synlett 1994,
110–112. (d) Probert, G. D.; Whitby, R. J.; Coote, S. J.
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1
1
1
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3
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5
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2
0. Matsumoto, K.; Aoki, Y.; Oshima, K.; Utimoto, K.; Rahman,
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2
1
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4
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3
1. Colvin, E. Silicon in Organic Synthesis; Butterworths:
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5
2. For example we have found that Cp Zr(OMe)R and 1-aza-2-
2
zirconacyclopentanes are inert towards carbenoid insertion
5
6. Kong, J.; White, C. A.; Krylov, A. I.; Sherrill, D.; Adamson,
R. D.; Furlani, T. R.; Lee, M. S.; Lee, A. M.; Gwaltney, S. R.;
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whereas Cp Zr(Cl)R and zirconacyclopentanes react well, the
2
difference in behavior being postulated to be due to donation
of the O or N lone pair into the available orbital on the
formally 16 electron metal centres.
3
3. (a) Olofson, R. A.; Lotts, K. D.; Barber, G. N. Tetrahedron
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3
4. (a) Durst, T.; Tin, K.-C.; de Reinach-Hirtzbach, F.; Decesare,