Coupling of chiral 1-bromo-1,2-dienes with zinc-based cuprates: A new procedure for the regio and stereoselective synthesis of functionalized acetylenic compounds

Article abstract of DOI:10.1016/S0040-4039(99)02249-2

Zinc alkylcyanocuprates (Knochel reagents) are found to be active in the cross-coupling reaction with allenic bromides affording acetylenic products with a high regio and stereoselective 1,3-anti substitution. The coupling process, which has been successf

Full text of DOI:10.1016/S0040-4039(99)02249-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 1227–1230
Coupling of chiral 1-bromo-1,2-dienes with zinc-based cuprates:
a new procedure for the regio and stereoselective synthesis of
functionalized acetylenic compounds
Anna Maria Caporusso,∗ Sara Filippi, Federica Barontini and Piero Salvadori
Centro di Studio del CNR per le Macromolecole Stereordinate ed Otticamente Attive, Dipartimento di Chimica e Chimica,
Industriale dell’Università di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
Received 12 October 1999; accepted 3 December 1999
Abstract
Zinc alkylcyanocuprates (Knochel reagents) are found to be active in the cross-coupling reaction with allenic
bromides affording acetylenic products with a high regio and stereoselective 1,3-anti substitution. The coupling
process, which has been successfully extended to functionalized cuprates, can also be performed with alkylzinc
chlorides in the presence of catalytic amounts of cuprous salts. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: coupling reactions; copper; copper compounds; allenes; alkynes.
Few simple organic molecules are the object of more interest than acetylenes for molecular engineering
work in organic and organometallic chemistry.1 In particular, optically active 1-alkynes are often essential
as versatile building blocks for the construction of more complex chiral molecules.2
In previous papers3–6 we discussed utilization of enantioenriched 3-substituted and 3,3-disubstituted
1-bromo-1,2-dienes 1 as precursors of chiral 1-alkynes 2, characterized by a tertiary or a quaternary
stereogenic center in the α-position to the triple bond, via a cross-coupling reaction with bromocuprates
(RCuBr)MgBr.LiBr, obtained in THF from equimolar amounts of Grignard reagents and LiCuBr2. The
reaction proceeds in a highly 1,3-anti stereoselective fashion, but the regioselectivity appears to be
sensitive to steric interactions at the reaction sites, the bulk of the R substituents in the copper species
being the dominant factor. The acetylenic compounds 2 can be obtained in good yields (70–98%)
independent of the structure of the allenic bromide only employing phenyl3 or n-alkyl bromocuprates;6
when tertiary, secondary or α-branched primary copper reagents are used, the competitive formation of
allenic derivatives 3 can be favoured (Table 1).6
We report here new results that emphasize the dramatic improvement of our coupling methodology
when cuprates based on organozinc derivatives are used.
∗
Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(99)02249-2
tetl 16177

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Table 1
Reaction of 1-bromo-1,2-dienes with organocupratesa

1229
We have found that zinc cyanocuprates RCu(CN)ZnCl·2LiCl (Knochel reagents),7 generated in THF
at −10°C from alkylzinc chlorides and the soluble copper salt CuCN.2LiCl, react with bromoallenes
1 more slowly than the corresponding magnesium bromocuprates but afford acetylenes 2 with higher
regioselectivity (Table 1). In this case, acetylenic products are obtained with a generally high yield
even starting from hindered 3,3-disubstituted allenic substrates and secondary or α-branched primary
copper compounds (entries 1–6); only when a tertiary group is bonded to the copper atom do the
steric requirements of the substrate determine the product distribution (entries 8, 9). Interestingly,
even with 3-phenyl-1-bromopropadiene, 1c, zinc alkylcyanocuprates selectively afford 1-alkynes, while
with bromocuprates substantial amounts of polymeric byproducts are obtained (entries 10, 11).3 As
an exception, it is noteworthy that the phenylbromocuprate (PhCuBr)MgBr.LiBr provides 3-phenyl-1-
alkynes with a higher regioselectivity than the corresponding zinc-based cuprate (entries 12, 13).3
The zinc–cuprate procedure can be greatly extended to the preparation of a large variety of func-
tionalized acetylenic systems. In fact, bromoallenes 1d and 1f, as hindered model substrates, have been
converted in a regiospecific way into pure 1-alkynes by treatment with copper derivatives characterized by
various functional groups (entries 14–21). In general, the necessary organozinc chlorides were prepared
from the corresponding Grignard reagents by transmetallation with ZnCl2 (entries 14–20). However,
functionalized zinc derivatives can be directly obtained from organic halides with several methods7
avoiding the use of protection–deprotection steps as well as functional group interconversions (entry
21).
Finally, the cross-coupling reaction can be done with zinc reagents using catalytic amounts of copper.
Bromoallenes 1 react with alkylzinc chlorides in the presence of 5–10 mol% (relative to RZnCl) of
CuCN·2LiCl, or some other cuprous salts, affording alkynes 2 with high chemo and regioselectivity
(Table 2). The reaction rate is generally slow, especially increasing the steric requirements of both
the reagent and the substrate, but increasing the reaction temperature can overcome this inconvenience
(entries 28, 29).8
In all cases, carrying out the coupling process either with stoichiometric or catalytic zinc cuprates, the
conversion of enantioenriched bromoallenes 1 into optically active acetylenic compounds 2 proceeds in a
highly anti stereoselective fashion. Eq. (1) presents the stereochemical data5 obtained in the preparation
of (S)-3-methyl-3-propyl-1-heptyne from (S)-1-bromo-3-methyl-1,2-hexadiene via the copper catalyzed
coupling.
(1)
In this context it is worthwhile noting that: (i) the reaction of bromoallenes with Grignard reagents in
the presence of cuprous salts gives quantitatively the allenic derivatives 3 with complete inversion of the
allenyl moiety;6,9 (ii) the coupling of the same chiral substrates with organozinc chlorides promoted by
nickel or palladium complexes also affords allenes but with almost complete loss of stereochemistry.10
Acknowledgements
We thank the Ministero dell’Università e della Ricerca Scientifica e Tecnologica-Progetto Naz, le
Stereoselezione in Sintesi Organica, Metodologie ed Applicazioni for financial support.

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Table 2
Reaction of 1-bromo-1,2-dienes with organozinc compounds in the presence of cuprous saltsa
References
1. For reviews, see: Modern Acetylene Chemistry; Stang, P. J.; Diederich, F., Eds.; VCH: Weinheim, 1995.
2. See, for example: Giacomelli, G.; Rosini, C.; Caporusso, A. M.; Palla, F. J. Org. Chem. 1983, 48, 4887–4891 and references
cited therein.
3. Caporusso, A. M.; Polizzi, C.; Lardicci, L. J. Org. Chem. 1987, 52, 3920–3923.
4. Caporusso, A. M.; Polizzi, C.; Lardicci, L. Tetrahedron Lett. 1987, 28, 6073–6076.
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7. Knochel, P.; Singer, R. D. Chem. Rev. 1993, 93, 2117–2188 and references cited therein.
8. The following procedure for the preparation of 3-phenyl-6-hepten-1-yne is representative (Table 2, entry 33): 3-butenyl
magnesium bromide 1.08N in THF (18 mmol) was added, at 0°C, to a stirred solution of ZnCl2 (18 mmol) in THF (5 ml).
The mixture was stirred for 30 min at room temperature, then treated, at −10°C, with a solution of 1.8 mmol of CuCN·2LiCl,
prepared in THF (5 ml). Stirring was continued at 0°C during 30 min, then the reaction mixture was cooled at −70°C and
1-bromo-3-phenylpropadiene 1c (1.80 g, 9 mmol) was added over a period of 5 min. The cooling bath was removed and
the mixture was allowed to warm to 20°C and monitored for completion by GLC. Upon completion (1 h), the reaction
was quenched with saturated ammonium chloride. Standard ethereal work-up and bulb-to-bulb distillation (10−2 mmHg)
provided the pure ene–yne (1.20 g, 82%) characterized by spectral and analytical data.
9. Uccello-Barretta, G.; Balzano, F.; Caporusso, A. M.; Iodice, A.; Salvadori, P. J. Org. Chem. 1995, 60, 2227–2231.
10. Caporusso, A. M.; Lardicci, L.; Da Settimo, F. Tetrahedron Lett. 1986, 27, 1067–1068.