Insertion of (E)-(1,2-dihalovinyl)lithium and (2-haloethynyl)lithium into zirconacycles

Article abstract of DOI:10.1039/b403337j

Insertion of (E)-(1,2-dihalovinyl)lithium into zirconacyclopentenes was followed by elimination of halide to afford an alkyne which inserts intramolecularly into the resulting carbonzirconocenium bond to give a methylenecyclopentene, whereas insertion of (2-haloethynyl)lithium gives the same product via a zirconocene alkenylidene.

Full text of DOI:10.1039/b403337j

Insertion of (E)-(1,2-dihalovinyl)lithium and (2-haloethynyl)lithium into
zirconacycles
David Norton,a Richard J. Whitby*a and Ed Griffenb
a School of Chemistry, University of Southampton, Southampton, UK SO17 1BJ. E-mail: rjw1@soton.ac
b AstraZeneca Pharmaceuticals, Alderley Park, Macclesfield, UK SK10 4TG
Received (in Cambridge, UK) 4th March 2004, Accepted 31st March 2004
First published as an Advance Article on the web 23rd April 2004
Insertion of (E)-(1,2-dihalovinyl)lithium into zirconacyclo-
pentenes was followed by elimination of halide to afford an
alkyne which inserts intramolecularly into the resulting carbon–
zirconocenium bond to give a methylenecyclopentene, whereas
insertion of (2-haloethynyl)lithium gives the same product via a
zirconocene alkenylidene.
species 8 (Scheme 3). There is now competition between trapping
of the zirconocenium species with an anion to give a stable species
which affords 3 on work up, and intramolecular insertion of the
initially formed alkyne into the carbon–zirconocenium bond to
afford 9 and hence methylidenecyclopentene 4 on work-up. Both
the presence and stereochemistry of the carbon-zirconium bond in
9e were confirmed by deuteration (MeOD–D2O) to afford 14e. We
have observed a similar intramolecular insertion of an alkyne into
We have shown that insertion of a range of carbenoids (1-lithio-
1-halo species) provides a useful method for further elaboration of
5-membered zirconacycles.1 We have also described the insertion
of (E)-(1,2-dichlorovinyl)lithium (1) into acyclic organozircono-
cene chlorides to afford terminal alkynes via elimination of the
initially formed b-chloroalkenylzirconium species (Scheme 1).2
We now report unexpected products when the equivalent insertion
was applied to the elaboration of zirconacycles.
3
a carbon–zirconocenium bond during elaboration of cyclic h -
propargyl zirconacycles with aldehydes/BF3·Et2O5 and related
intermolecular additions are known.6
Ring strain in bicyclo[3.3.0]octenes inhibits formation of the
cyclisation products 4a and c compared with the unstrained
bicyclo[4.3.0]nonene (4b) and monocycles 4d and 4e (Table 1,
entries 1 and 4, cf. 3, 8 and 11).
Zirconacyclopentenes 2 were formed by intramolecular co-
cyclisation of 1,6- or 1,7-enynes using zirconocene(but-1-ene)3a
(2a–d) or by addition of alkynes to in situ generated zirconocene-
(ethylene) (2e,f).3b The zirconacycles were cooled to 278 °C
before addition of (E)-1,2-dichloroethene followed by dropwise
addition of lithium diisopropylamide (LDA) to generate the
carbenoid 14 in situ. Aqueous work-up gave a mixture of the
expected alkynes 3 and the unexpected methylidenecyclopentenes
4 (Scheme 2; Table 1, entries 1, 3–5, 8, 11). The ratios of 3:4 were
estimated by GC† of crude reaction products since compounds 4
partially decomposed on chromatography. In cases where the
methylidenecyclopentenes 4 could not be obtained analytically
pure, the stable derivatives 5 were formed by in situ hydroboration/
oxidation.
We then examined the use of 1,2-dibromoethene, commercially
available as a 2:1 mixture of (Z):(E) stereoisomers, as a carbenoid
precursor, and found that it substantially increased the ratio of 4:3
(Table 1, entries 2, 6, 7, 9, 10). The result was synthetically useful,
but rather surprising as we would expect (Z)-(1,2-dibromovinyl)li-
thium to eliminate LiBr very rapidly to afford bromoethyne.
Furthermore working up the reaction from 2e with MeOD–D2O
afforded 4e with complete deuterium incorporation at one of the
methylene positions, and remarkably around 85% incorporation at
the other i.e. approximately a 15:85 mixture of 14e and 15e
(Scheme 3) was formed. To clarify matters we treated (Z)-
1,2-dichloroethene with 2 equiv. LDA at 278 °C for 10 min to
afford (2-chloroethynyl)lithium, as confirmed by trapping an
aliquot with PhMe2SiCl. Subsequent addition of a pre-cooled
solution of the zirconacycle 2e and stirring at 278 °C gave good
conversion into the methylenecyclopentene 4e after quenching.
Work-up with MeOD–D2O gave > 95% deuterium incorporation at
both methylene protons (i.e. 15e).
A reasonable mechanism for the formation of 4 is insertion of
carbenoid 1 into 2 to afford six-membered zirconacycle 7, which
eliminates the anti-periplanar chloride to give the zirconocenium
A mechanism which explains the formation of cyclised products
4 by insertion of 1-lithio-2-haloethyne, and in particular the
formation of bis-deuterated compound 15 on work-up with D2O is
given in Scheme 3. The rearrangement of 10 to 11 has precedent
Table 1 Insertions into zirconacyclopentenes
Ratio of Yield 3c Yield 4c Yield
Scheme 1 Insertion of (E)-(1,2-dichlorovinyl)lithium into acyclic organo-
zirconocenes.
Entry
SubstrateReagenta
3:4b
(%)
(%)
5c (%)
1
2
3
4
5
6
7
8
9
2a
2a
2b
2c
2c
2c
2c
2d
2d
2d
2e
2e
Cl (2 equiv.)
3:5
0:1
0:1
2:3
2:7
1:22
1:22
1:3
1:7
1:7
0:1
26
—
—
27
33
—
—
33
15
—
—
—
—
17
32
66
—
38
24
—
74d
56d
—
36
41
—
—
—
36
—
—
40
38
Br (2 equiv.)
Cl (2 equiv.)
Cl (2 equiv.)
Cl (4 equiv.)
Br (2 equiv.)
Br (2 equiv.)
Cl (2 equiv.)
Br (2 equiv.)
Br (2 equiv.)
Cl (1 equiv.)
10
11
12
Cl* (1 equiv.) 0:1
a LDA (1 equiv.) added to: Cl = (E)-HClCNCHCl, Br = 1:2 (E)-:(Z)-
HBrCNCHBr, Cl* = ClC·CH. b Determined by GC of the crude reaction
mixture. c Isolated yields from the enyne or alkyne precursors of
zirconacycles 2. d NMR yield.
Scheme 2 Reagents and conditions: (i) XCHNCHX, LDA, 278 °C, THF;
(ii) MeOH/NaHCO3 (aq.); (iii) 9-BBN (1 equiv.) or BH3·SMe2 (0.33
equiv.), THF; (iv) NaOH, H2O2.
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C h e m . C o m m u n . , 2 0 0 4 , 1 2 1 4 – 1 2 1 5
T h i s j o u r n a l i s © T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 4

Scheme 3 Two mechanisms for formation of methylenecyclopentenes.
from the work of Negishi on insertion of lithiated aryl alkynes into
oethynyl)lithium also gave 18 (41% isolated yield), but un-
expectedly also cyclohexene 21 (16% yield).§ Work-up of the
reaction mixture with MeOD–D2O gave the bis-deuterated product
22 ( > 95% D). The most likely mechanism is insertion of ClC·CLi
into 16 to give zirconacycloheptyne 20 which unlike the analogous
zirconacycle 12 does not rearrange to the alkenylidene 25.‡
Protonation of the alkyne moiety of 20 could induce cyclisation to
afford 23 and hence 21/22. The ratio of 18 to 21 formed does not
change significantly when the reaction mixture is kept at room
temperature for 2 h before quenching implying that cyclisation only
occurs on work-up. Bis-alkyne 19 is not formed even when a large
excess of ClC·CLi is used.
In conclusion we have discovered several novel transformations
of zirconacycles which imply the formation of unprecedented
zirconocene alkenylidene and 1-zircona-2-cycloheptyne inter-
mediates, as well as useful multi-component coupling reactions, in
the insertion of (E)-(1,2-dihalovinyl)lithium and (2-haloethynyl)li-
thium into zirconacycles.
zirconacycles, although the latter requires hours at room tem-
perature.7 Elimination of chloride from 11 is analogous to the
known rearrangement of 2-chlorozirconacyclopropanes.8 The re-
arrangement of 12 to the zirconocene alkenylidene 13 is unprece-
dented but, calculations indicate, thermodynamically favourable.‡
Zirconium alkenylidene complexes have not previously been
reported even as intermediates, although zirconium alkylidenes are
known.9 It is likely that 13 will dimerise to form a 1,3-bis(zircona-
)cyclobutane, though we could not observe it by NMR spectros-
copy.
Insertion of carbenoid 1 into zirconacyclopentane 16, derived by
co-cyclisation of 4,4-bis(methoxymethyl)-1,6-heptadiene with zir-
conocene(1-butene), followed by protic quench at 270 °C yielded
alkyne 18 (43%) together with the bis-alkyne 19 (7%) (Scheme 4).
Two equivalents of the carbenoid were required for optimum
yields. Warming the reaction mixture to room temperature for 16 h
before quenching gave predominantly 19 (49%, cf. 11% 18) which
suggests the complex 17 incorporating a second molecule of
carbenoid as the major neutral intermediate formed, and that room
temperature was required for its rearrangement/elimination.10
Isolated yields of 18 and 19 were 45 and 37% under the respective
conditions. No cyclisation to form the methylidenecyclopentane 24
analogous to the formation of 4 occurred.‡ Insertion of (2-chlor-
We thank AstraZeneca and the EPSRC for a CASE studentship
to D. N.
Notes and references
† GC carried out on Hewlett Packard 6890 with 30 m HP5 column, He as
carrier gas, 80–250 °C at 25 °C min21, FID detection.
‡ DFT calculations carried out with B3LYP/6-31G* method using Spar-
tan04 for Windows (Wavefuntion Inc.) indicate that 20 is 26 kJ mol21 more
stable than 25 whereas 12 (R1 = R2 = Me, R3 = R4 = H) is 62 kJ mol21
less stable than 13.
§ Identity of 21, and absence of 24 were confirmed by their independent
synthesis.
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Scheme 4 R = CH2OMe. Reagents and conditions: (i) (E)-HClCNCHCl;
(ii) LDA, 278 °C; (iii) MeOA, A2O (A = H, D); (iv) 25 °C, 2 h; (v)
ClC·CLi.
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10 K. Kasai, Y. Liu, R. Hara and T. Takahashi, Chem. Commun., 1998,
1989.
C h e m . C o m m u n . , 2 0 0 4 , 1 2 1 4 – 1 2 1 5
1215