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Chemical Science
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Table 2 Conjugate addition of phenylzinc halides to chalconea
chalcone under mild reaction conditions. This kind of reactivity
for these organozinc halides, to the best of our knowledge, has
never been reported. Only some isolated examples of conjugate
addition to electrophilic alkenes of “in situ” obtained organo-
zinc species from halides can be found in the literature.19–22
Furthermore, the remarkable difference in reactivity obtained
by going from THF to DME, two apparently very similar
solvents, struck us as completely unexpected. For these reasons,
we were prompted to gain some insight into the reaction
applicability, the role of the solvent and also the reaction
mechanism. These challenging problems were faced by
a combined experimental-computational approach. We report
herein the results of the conjugate addition of organozinc
halides, having different structures, to non-enolizable enones,
the diffusional analysis of the organometallic reagents in the
different solvents and a computational study of the reaction in
the two solvents, aimed at elucidating the reaction mechanism
and the role of the solvent in determining the reactivity.
Entry
“PhZnX”
Solvent
% convc
Time
1
2
3
4
5
6
7
PhZnI + LiCl
PhZnI + LiCl
PhZnI + LiCl
PhMgBr + ZnBr2
PhMgBr + ZnBr2
TMEDA + Zn(Ag)
PhZnI + LiCl
DMEb
DME
THF
DME
THF
97
98
23
30
11
0
24 h
24 h
24 h
24 h
24 h
24 h
2 h
DME
DMEd
99
a
b
Chalcone (1 mmol), “PhZnX” (1.5 mmol), solvent (2 mL). Toluene
c
was used as a cosolvent in the conjugate addition step. Apparent
conversion determined by GC analysis. d Reaction performed at 50 ꢀC.
prepared according to our protocol afforded almost quantitative
conversion of chalcone in the corresponding addition product
in 24 h at r.t., both in DME/toluene mixture and in DME only
(entries 1 and 2).
By contrast, the use of THF as a solvent gave a scarcely
reactive organometallic species, which afforded, under the
same conditions, a low conversion of the substrate (entry 3): this
huge difference in reactivity points out the unexpected impor-
tance of DME for the success of the reaction. Even organozinc
halides obtained by transmetallation from Grignard reagents,
used both in DME and THF (entries 4 and 5), poorly reacted
with chalcone, whereas the organometallic reagent obtained by
direct metallation using a different procedure13 (entry 6) was
completely unreactive. In order to minimize the risk of cross
contamination, in particular with other transition metals, the
glassware and stirring bars used for the reactions were carefully
washed with hot aqua regia. To further reduce the risk of
contamination, several trials have also been conducted using
new glassware and a new stirring bar.23 Furthermore, the zinc
powder used has a negligible content of transition metals, as
certied by the producer.
Results and discussion
Preparation of organozinc halides and conjugate addition to
enones
Aryl and alkylzinc compounds were prepared by direct insertion
of commercially available Zn powder in the presence of LiCl into
DME. Thus, the halide was treated with commercial zinc
powder (1.5 equiv., <46 mm, activated by the addition of
1,2-dibromoethane (3 mol%) and TMSCl (1 mol%)) and LiCl
(1.5 equiv.) at the reux of DME until complete conversion of
the substrate (GC analysis). Under these conditions, aryl iodides
were converted into the corresponding organometallic reagents
in two hours, whereas alkyl bromides required longer reaction
times (from 3 to 22 hours) to be completely reacted (Table 1).
The titer of the organozinc compounds was determined by GC
analysis aer iodolysis of the reaction products.17 To obtain
some insight into the reactivity of organozinc compounds
towards conjugate addition to unsaturated enones devoid of
enolizable positions, differently prepared phenylzinc reagents
were assayed in the conjugate addition to chalcone and the
results are provided in Table 2. The reaction of the phenylzinc
These results suggest the fundamental role of LiCl in the
formulation, which probably leads to the formation of a zincate
anion24 rather than an organozinc halide. Furthermore, it
highlights the importance of using DME as a solvent for the
preparation of the organozinc species. Finally, the reaction
temperature had a strong effect on the reaction rate: almost
complete conversion of the substrate into the product was
ꢀ
Table 1 Preparation of the organozinc halides
achieved in only two hours at 50 C (entry 7).
The optimized reaction conditions were used to react other
enone substrates with different organozinc halides and the
results are shown in Scheme 1. The reaction proceeded
smoothly for the conjugate addition of phenylzinc iodide to
differently substituted 1,3-diphenylprop-2-enones, affording
high yields of the isolated products 3a–g in short reaction times
(from 2 to 6 hours). It is worth noting that the pure products
were obtained just aer work-up of the reaction mixtures,
without any further purication. The steric hindrance on the
enone substrates affects the reaction rate: as a matter of fact, the
conjugate addition of phenylzinc iodide to enones bearing
bulky groups, such as 9-anthryl, tert-butyl or even 2-naphthyl,
afforded high yields of pure products 3h–j in 24–30 h at the
Entry
RX
1
Time
% conva
Titerb
1
2
3
4
5
PhI
1a
1b
1c
1d
1e
2 h
2 h
22 h
4 h
2 h
99
99
97
98
99
0.89 M
0.90 M
0.86 M
0.87 M
0.95 M
4-MeO2CC6H4I
c-HexBr
n-C8H17Br
4-CF3C6H4I
a
Apparent conversion determined by GC analysis aer hydrolysis of the
b
reaction mixture. Determined by GC analysis aer iodolysis of the
reaction mixture.17
258 | Chem. Sci., 2020, 11, 257–263
This journal is © The Royal Society of Chemistry 2020
Casotti, Gianluca
