Insertion of metallated epoxynitriles into organozirconocene chlorides. A convergent synthesis of 2-cyano-1,3-dienes

Article abstract of DOI:10.1016/S0040-4039(00)01006-6

Lithiated epoxynitriles insert efficiently into alkenyizirconocene chlorides via a 1,2-metallate rearrangement to form intermediates which eliminate Cp₂Zr(Cl)O- to afford substituted 2-cyano-1,3-dienes. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01006-6

Tetrahedron Letters 41 (2000) 6201±6205
Insertion of metallated epoxynitriles into organozirconocene
chlorides. A convergent synthesis of 2-cyano-1,3-dienes
Alexander N. Kasatkin and Richard J. Whitby*
Department of Chemistry, Southampton University, Southampton, Hants SO17 1BJ, UK
Received 16 May 2000; accepted 14 June 2000
Abstract
Lithiated epoxynitriles insert eciently into alkenylzirconocene chlorides via a 1,2-metallate rearrange-
ment to form intermediates which eliminate Cp2Zr(Cl)O^ to a€ord substituted 2-cyano-1,3-dienes. # 2000
Elsevier Science Ltd. All rights reserved.
Keywords: zirconium; carbenoid; metallated epoxides; epoxynitrile; cyanodiene.
Recently, we have shown that insertion of a wide range of metal carbenoids (R1R2CLiX, 1)
into carbon±zirconium bonds is a fast and ecient process,1 possibly occurring via 1,2-
rearrangement of a `zirconate' intermediate 2 (Eq. (1)).2 Here we describe the use of a-lithiated
a,b-epoxynitriles as carbenoid components in the reaction with organozirconocene chlorides.
Metallated epoxides play an important role in organic synthesis either as nucleophiles or (more
usually) as implied intermediates in the formation of carbenes.3 Generally a stabilising group is
needed to allow formation by deprotonation,4 although unstabilised systems may be generated by
tin/lithium exchange.5 The reaction of lithiated a-silylepoxides with organoaluminiums via a
mechanism including intramolecular nucleophilic ring opening followed by b-elimination of
R2AlO^ to a€ord vinylsilanes has been reported (Eq. (2)).6,7 It is likely that other reactions of
oxiranyl carbanions with organometallics, which have been described as occurring via insertion of
carbenes into carbon±metal bonds, actually occur via such 1,2-metallate rearrangements.
ꢀ1†
*Corresponding author. E-mail: rjw1@soton.ac.uk
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01006-6

6202
ꢀ2†
a,b-Epoxynitriles8 are readily deprotonated with LDA4c but in the absence of an electrophile
they underwent extremely rapid self-condensation even at ^90ꢁC.9 Slow addition of LDA to a
mixture of (E)-1-octenylzirconocene chloride (3) (readily available by hydrozirconation of
1-octyne with the Schwartz reagent10) and 2,3-epoxy-3-methylbutyronitrile (4) in THF at ^90ꢁC
followed by warming to ^60ꢁC and acidic hydrolysis a€orded (E)-2-cyano-1,3-diene 5 in good
yield (Table 1, entry 1). A reasonable mechanism for the transformation includes epoxide opening
by 1,2-migration of the alkenyl fragment in the `ate'-complex 6 followed by syn-b-elimination of
the zirconium alkoxide (Scheme 1). In contrast to 3, octylzirconocene chloride reacted with the
epoxide 4 in the presence of LDA to give 3-cyano-2-methylundec-2-ene in low yield. The reaction
of 3 with the cyclic b,b-disubstituted epoxynitrile 8 led to the expected 1,3-diene 9 together with a
small amount of the 1,4-diene 10 (entry 2). The formation of 10 is presumably due to g-
deprotonation of the a,b-unsaturated nitrile 9 with LDA to give the pentadienyllithium species 11
Table 1
Insertion of lithiated epoxynitriles into (E)-1-octenylzirconocene chloride (3)a

6203
Scheme 1.
which underwent a-protonation on hydrolysis (Eq. (3)). Indeed, treatment of 9 with 1 equiv. of
LDA (THF, ^78ꢁC, 30 min) followed by quenching with 2 M HCl aq. a€orded the b,g-unsaturated
nitrile 10 in 78% yield (Eq. (3)). The (Z)- and (E)-b-monoalkylsubstituted epoxynitriles 12 reacted
with 3 giving the expected cyanodiene 1311 as 90:10 and 53:47 mixtures of (Z, E)- and (E, E)-
isomers, respectively (entries 3 and 4). The presence of a protected hydroxyl in the starting
material (the epoxides 14) did not signi®cantly a€ect either the yield or stereoselectivity (entries 5
and 6). In a similar way, the (Z)- and (E)-b-phenylsubstituted epoxides 16 furnished the cyano-
diene 1711 as mixtures of Á3-double-bond isomers with the (Z,E)-isomer predominating in both
cases (entries 7 and 8). However, the yields and stereoselectivities were considerably higher than
in the reactions of b-alkylsubstituted epoxides.
ꢀ3†
The lack of stereoselectivity in the reaction of (E)-1-octenylzirconocene chloride (3) with b-
monosubstituted epoxynitriles cannot be explained within the mechanism shown in Scheme 1
where both 1,2-migration and b-elimination stages are stereospeci®c. A plausible explanation is
that the initially formed a-lithiated epoxides 18 and 19 are not con®gurationally stable and
interconvert rapidly under the reaction conditions (Scheme 2).12 The reaction of 3 with the
Scheme 2.

6204
(Z)-isomer 18 to a€ord (Z, E)-cyanodienes is faster than with the (E)-isomer 19 probably due to
the steric repulsion between a trans-b-substituent in 19 and the Cp-ligands. The fact that the (Z)-
epoxynitriles 12, 14, 16 which give the more reactive 18 as the initial lithiation product showed
higher stereoselectivity in the reaction with 3 than the corresponding (E)-epoxides (entries 3
versus 4, 5 versus 6, and 7 versus 8) is in good agreement with the explanation.
To con®rm the mechanism of loss of stereochemical integrity we examined generation/trapping
of the carbenoid formed from the epoxynitrile (E)-12 (Eq. (4)). Treatment of (E)-12 with LDA in
the presence of Me2(t-Bu)SiCl gave a signi®cant decrease in stereochemical purity of the silylation
product 20 compared with the starting epoxide. Addition of LDA to a 1:1:1 mixture of (E)-12, 3
and Me2(t-Bu)SiCl gave only 20 in more than 90% yield, suggesting that silylation of the
carbenoid is much faster than its trapping with the alkenylzirconocene compound.
ꢀ4†
Overall we have shown that the insertion of lithiated a,b-epoxynitriles into alkenylzirconocene
chlorides represents a convergent and ecient route to a range of 2-cyano-1,3-dienes.13,14
Acknowledgements
We thank the Engineering and Physical Sciences Research Council (EPSRC) for a postdoctoral
award (GR/N00647). R.J.W. thanks P®zer for generous uncommitted support.
References
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P.; Barber, C. Pure Appl. Chem. 1990, 62, 1933. But see Ref 1b for an alternative view.
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6. Taniguchi, M.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1991, 32, 2783.
7. Recently we have found that the reaction of lithiated a-silylepoxides with zirconacycles proceeds in a similar way,
see: Kasatkin, A. N.; Whitby, R. J. Tetrahedron Lett. 2000, 41, 5275.
8. The starting a,b-epoxynitriles were prepared by Darzan's reaction of ClCH2CN with the corresponding aldehydes
in MeCNÐ50% NaOH aq.Ðcetyltrimethylammonium chloride (cat.) system. The initially formed ꢂ1:1 mixtures
of (E)- and (Z)-epoxides proved to be easily separable by column chromatography.
9. Kasatkin, A. N.; Whitby, R. J. unpublished results.
10. Wipf, P.; Jahn, H. Tetrahedron 1996, 52, 12853.
11. The stereochemistry of the (Z, E)- and (E, E)-2-cyano-1,3-dienes 13, 15, 17 was determined by comparison of
chemical shifts of the CN- and ole®nic C-3-carbons in their 13C NMR spectra. For all the compounds ꢀCN was a

6205
2.2±3.1 ppm lower ®eld and ꢀC-3 was a 4.9±5.4 ppm higher ®eld for (Z,E)-isomers compared to (E,E)-isomers due
to the g-gauche e€ect.
12. For a similar isomerisation of lithiated benzothiazolyl-substituted epoxides, see Ref. 4e.
13. For other synthetic routes to 2-cyano-1,3-dienes, see: (a) Arthur Jr., P.; Miegel, J. K.; Mochel, W. E.; Pratt, B. C.;
Werntz, J. H. J. Org. Chem. 1958, 23, 803. (b) Nakano, M.; Okamoto, Y. Synthesis 1983, 917. (c) Masuyama, Y.;
Yamazaki, H.; Toyoda, Y.; Kurusu, Y. Synthesis 1985, 964. (d) Bestmann, H. J.; Schmidt, M. Angew. Chem. 1987,
99, 64; Angew. Chem., Int. Ed. Engl. 1987, 26, 79. (e) Janecki, T. Synthesis 1991, 167.
14. Typical experimental procedure: To a stirred suspension of Cp2Zr(H)Cl (0.284 g, 1.10 mmol) in THF (10 mL) was
added 1-octyne (0.110 g, 1.00 mmol). The mixture was stirred at 20ꢁC for 1 h to give a clear yellow solution of 3.
After cooling to ^90ꢁC 2,3-epoxy-3-methylbutyronitrile (4) (0.126 g, 1.30 mmol) was added followed by a solution
of LDA [1.30 mmol, freshly prepared from diisopropylamine (0.131 g, 1.30 mmol) and BuLi (1.30 mmol, 2.5 M in
hexanes) in 2 mL of THF]. The mixture was stirred at ^90 to ^60ꢁC over 1 h and quenched by addition of 2 M HCl
aq. After stirring at 20ꢁC for 30 min and extraction with ether the organic layer was washed with brine, dried over
MgSO4 and concentrated under reduced pressure. The crude product was puri®ed by column chromatography on
silica gel (40±60 petroleum ether:EtOAc, 8:1) to give (E)-2-methyl-3-cyano-2,4-undecadiene (5) (0.122 g, 64%
yield).