Enantioselective Conjugate Addition of Stabilized Arylzinc Iodide to Enones: an Improved Protocol of the Hayashi Reaction

Article abstract of DOI:10.1002/adsc.202001141

Stabilised arylzinc iodide, prepared by direct insertion of zinc into aryl iodides, were used as nucleophiles in the Hayashi Rh-catalysed enantioselective conjugate addition to enones. The reaction conditions were optimized in the addition of phenylzinc i

Full text of DOI:10.1002/adsc.202001141

Title: Enantioselective conjugate addition of stabilized arylzinc iodide to
enones: an improved protocol of the Hayashi reaction
Authors: Gianluca Casotti, Vincenzo Rositano, and Anna Iuliano
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10.1002/adsc.202001141
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.202((will be filled in by the editorial staff))
Enantioselective conjugate addition of stabilized arylzinc iodide
to enones: an improved protocol of the Hayashi reaction
Gianluca Casotti,a Vincenzo Rositano,a and Anna Iulianoa*
a
Dipartimento di Chimica e Chimica Industriale, Università di Pisa, Via Giuseppe Moruzzi, 13, 56124, Pisa, Italy
Phone : +39 050 2219231 ; Fax: +39 050 2219260
E-Mail : anna.iuliano@ unipi.it
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.
organozinc halides, which tolerate the presence of
insertion of zinc into aryl iodides, were used as several electrophilic functional groups,[12] should
Abstract. Stabilised arylzinc iodide, prepared by direct
nucleophiles in the Hayashi Rh-catalysed enantioselective
conjugate addition to enones. The reaction conditions were
optimized in the addition of phenylzinc iodide to 2-
cyclohexen-1-one, obtaining good yields and 99% ee of the
addition product. The general applicability of the protocol
was checked using different arylzinc iodides and enones.
Organometallic reagents endowed with both halogen and
electrophilic groups were also successfully used.
allow the preparation of organometallic nucleophiles
endowed with electrophilic groups and hence the
access to a wider choice of conjugate addition
products. In addition, the search for more efficient
and greener protocols of transition metal catalysed
enantioselective conjugate additions prompts
scientists to develop straightforward methods for the
synthesis of the organometallic reagents.[13] To reach
these goals the direct insertion of zinc metal to
organic halides appears an appealing procedure,
provided it can be performed under mild conditions.
Keywords: Asymmetric catalysis; Conjugate addition;
Michael addition; Rhodium; Zinc
Introduction
The transition metal catalysed asymmetric
conjugate addition of organometallic reagents to
electron-poor alkenes represents one of the most
straightforward methods for the C-C bond formation
in an enantioselective way. The most used
organometallic reagents to perform the reaction are
arylboronic acids, in the presence of chiral Rh-
catalysts,[1–3] and dialkylzinc reagents combined with
chiral copper catalysts.[4,5] In this scenario less
attention has been paid to the use of organozinc
halides, although they are unreactive towards
carbonyl groups and can transmetalate both with Rh
and Cu, giving species able to perform conjugate
additions.[6–10] So far only Hayashi and co-workers
have used these organometallic reagents in
combination with chiral rhodium catalysts to achieve
successfully enantioselective conjugate addition to 2-
aryl-4-pyperidones,[8]
unsaturated
ketones,[11]
The
Scheme 1. Comparison with literature.
lactones and aldehydes (Scheme 1).[9]
organozinc halides were obtained by transmetalation
of the corresponding organolithium reagents, a
procedure entailing not only the need for cryogenic
temperatures, pyrophoric substances and the use of
two different organometallic reagents but also the
preparation of a highly reactive organolithium species,
which does not tolerate the presence of electrophilic
groups. It is a pity, given that the mild character of
To this purpose, we have recently developed a mild
and efficient protocol for the preparation of
organozinc iodide by silver catalysed zinc insertion
into aryl iodide in the presence of TMEDA, which
allowed to obtain in short times arylzinc iodides, also
endowed with electron-rich substituent groups.[14] In
1
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10.1002/adsc.202001141
Advanced Synthesis & Catalysis
addition, arylzinc iodides bearing electrophilic groups
were obtained. These organometallic reagents were
successfully used in Negishi cross-coupling
reactions.[14] Encouraged by these results and given
the great practical advantage of this strategy, we
became interested in performing the Hayashi Rh-
catalysed enantioselective conjugate additions to
electron poor alkenes with organozinc halides made
by direct insertion of zinc metal (Scheme 1). By
avoiding the use of highly reactive organometallic
reagents, these organozinc halides, obtained under
mild reaction conditions, might result even more
practical and convenient than the most commonly
used arylboronic acids, which require extra effort for
their preparation and purification. Herein a highly
effective and step-economic protocol for the
enantioselective Rh-catalysed conjugate addition of
arylzinc iodides to enones is presented, which
allowed to react organozinc species having different
structures, also those endowed with electrophilic
functional groups.
transmetalation, clearly shows that the effectiveness
of the organozinc depended strongly on the
organometallic precursor: using the phenylzinc halide
obtained from the corresponding Grignard reagent
only traces of the conjugated addition product were
obtained after long reaction time (entry 1), whereas
the organometallic reagent used by Hayashi[8] had
given an almost quantitative yield of a nearly
enantiomerically pure product after one hour (entry 2).
The direct insertion of zinc into iodobenzene
promoted by LiCl, according to the Knochel’s
protocol,[15] gave an organozinc halide that produced
undesired reactions on the enone substrates,[16]
resulting in the achievement of a negligible amount
of addition product (entry 3). By contrast, using the
phenylzinc iodide prepared through direct insertion,
promoted by silver acetate in the presence of
TMEDA,[14] the addition product was obtained with
99% ee, albeit in low yield (entry 4). Even in this
case, the reason for the low yield was the formation
of large amounts of by-products, likely due to
undesired condensation and/or Michael reactions of
the in situ formed zinc enolate. To improve the yield,
trapping
the
enolate
by
addition
of
trimethylchlorosilane was attempted, but a worse
result was obtained (entry 5). By contrast, the use of
further TMEDA as additive was successful: a good
Results and Discussion
The conjugate addition of phenylzinc halide to 2-
cyclohexen-1-one was chosen as a benchmark
reaction to compare the effectiveness of
organometallic reagents obtained according to
different procedures: the results are collected in Table
1. The organometallic species were prepared,
according to established protocols, in the same
solvent used for the conjugate addition. All the
enantioselective reactions were carried out at rT and
stopped at complete substrate conversion or when it
did not proceed further. The comparison of the results
obtained with phenylzinc halides prepared via
yield of nearly enantiomerically pure
addition
product was obtained, even if a long reaction time
was required to react the substrate (entry 6). Probably,
TMEDA produced an extra-stabilisation of the
organozinc, which resulted less reactive, and a
stabilisation of the in situ formed enolate, so that side
reactions were removed, but, at the same time, the
addition slowed down. By contrast, the use of
TMEDA with organozinc prepared according to the
Knochel’s method was unsuccessful (entry 7).
Table 1. Enantioselective conjugate addition of phenylzinc halide to 2-cyclohexen-1-one.
Source of the PhZnX Additive Solvent
Time Yielda) Eeb)
THF
Entry
1
2c)
PhMgCl
-
72 h
1 h
traces
98 %
traces
24 %
traces
67%
n.d.
PhLi
-
THF
THF
THF
THF
THF
THF
THF
DME
DME
99%
n.d.
3
Insertion of Zn on PhI promoted by LiCld)
Insertion of Zn on PhI promoted by AgOAce)
Insertion of Zn on PhI promoted by AgOAce)
Insertion of Zn on PhI promoted by AgOAce)
Insertion of Zn on PhI promoted by LiCld)
Insertion of Zn on PhI promoted by AgOAce)
Insertion of Zn on PhI promoted by AgOAce)
Insertion of Zn on PhI promoted by AgOAce)
-
24 h
6 h
4
-
99%
n.d.
5
TMSCl (1.6 eq.)
TMEDA (1.5 eq.)
TMEDA (1.5 eq.)
TMEDA (1.5 eq.)
TMEDA (1.5 eq.)
TMEDA (0.75 eq.)
7 h
6
70 h
70 h
70 h
99%
n.d.
7
traces
68 %
8 f)
9f)
10f)
99%
99%
99%
48 hg) 65 %
40 h 90 %
a) Isolated yield. b) Determined by HPLC analysis on chiral stationary phase (see Supporting Information). c)
Literature data.[8] d) Prepared according to Knochel’s protocol.[15] e) Prepared according to our protocol.[14] f) The
chiral catalytic complex was prepared in situ.[17] g) Incomplete conversion.
2
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10.1002/adsc.202001141
Advanced Synthesis & Catalysis
To further simplify the procedure, the chiral catalytic
complex was prepared in situ, by stirring for 30 min a
solution of [Rh(C2H4)2Cl]2 and (R)-BINAP (1: 2
ratio) in the reaction solvent,[17] then adding the enone
and the solution of the organometallic reagent: the
same results, both in terms of yield and ee, were
obtained (entry 8). The use of DME as reaction
solvent resulted in a slower reaction, giving
incomplete conversion after 48h, which did not
improve further: however, the isolated yield was
similar to that obtained using THF (entry 9). This
result suggested that also DME contribute to the
stabilisation of both organozinc and enolate so that
the substrate was cleanly converted to the addition
product, but its conversion was incomplete.The best
result was obtained by lowering the amount of
TMEDA and using DME as the reaction solvent:
complete conversion of the enone in 40h was
observed and the addition product was obtained in
90% isolated yield (entry 10). It is to note that an
(R)-configurated addition product in 99% ee was
always obtained, suggesting that the different source
of the phenylzinc halide, as well as the different
preparation of the catalytic complex, did not alter the
asymmetric induction mechanism.
With the optimized conditions in hand, we checked
the effect of the structure of the stabilized arylzinc
iodides on the outcome of the reaction. To this
purpose, the enantioselective conjugate addition of
different arylzinc iodides on 2-cyclohexen-1-one was
performed (Scheme 2). The obtained results suggest
that there is small or no effect of the presence of a
substituent on the phenyl ring of the organozinc
reagent on the stereochemical outcome of the reaction.
An (R)-configurated product was always obtained in
99% ee. By contrast, the reaction rate was in general
positively affected by the presence of the substituent:
slightly higher isolated yields of products 3b, 3e and
3f were obtained in shorter reaction times. The
reaction was faster when
a
strong electron-
withdrawing group was present on the phenyl ring
(3d), whereas a strong electron-donating group
slowed down the reaction (3c and 3g). It is worthy of
note to have obtained products 3e and 3f, which
could not be prepared starting from the organozinc
halide obtained by transmetalation, because of the
presence of groups undergoing nucleophilic attack or
metal-halogen exchange with organolithium reagents.
It is particularly interesting to note the possibility of
further functionalization of products like 3f, for
example, with well-established palladium-catalyzed
cross-coupling reactions.[18] This can be achieved
thanks to both the high selectivities of the zinc-
insertion protocol and the conjugate addition reaction.
The generality of this protocol was checked by
reacting acyclic enones, both benzalacetone and
substituted chalcones, with different stabilized
arylzinc iodides: the results are shown in Scheme 3.
These substrates were less reactive than 2-
cycloehexen-1-one towards stabilised arylzinc halides
to the point that the reaction conducted in DME
without any additive did not give a decent conversion,
even after prolonged reaction time. Therefore THF
was used as the reaction solvent and no TMEDA was
added: under these conditions the reactions proceeded
smoothly, affording good yields of isolated addition
products. The reaction rate depended both on the
substrate and the arylzinc structure. As far as the
structure of the substrate is concerned, chalcones
were less reactive than benzalacetone, so that longer
reaction times were needed to obtain good yields of
products 5g-i. The most reactive arylzinc halides
were again those bearing electron-withdrawing
groups: 5c and 5d were obtained in less time with
respect to the other products. The presence of an
ortho substituent on the arylzinc iodide was
detrimental for the reaction: only poor yield of 5e was
obtained after long reaction time. The conjugate
addition was less enantioselective with these acyclic
enones, the ees ranging from 80 to 91% for the
majority of the products. A lower ee was obtained in
the case of 5d, whereas 5e was obtained in very high
ee, suggesting that although the steric hindrance on
the arylzinc iodide slows down the reaction, however,
it makes highly enantioselective the conjugate
addition.
Scheme 2. Enantioselective conjugate addition of arylzinc
iodides to 2-cyclohexen-1-one.
3
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10.1002/adsc.202001141
Advanced Synthesis & Catalysis
Scheme 3. Enantioselective conjugate addition to acyclic enones
To check if the lower enantioselectivity could be
organometallic nucleophiles by direct insertion of
zinc into aryl iodides and the in situ preparation of
the chiral catalytic complex make straightforward this
protocol. The comparison of the results obtained in
the conjugate addition of phenylzinc iodide to 2-
cyclohexen-1-one with those obtained by Hayashi,
demonstrate that the enantioselectivity of the reaction
is not affected by the different source of the
organozinc. The protocol demonstrated its
effectiveness and versatility in particular in the
addition of arylzinc iodides endowed with reactive
groups under transmetalation conditions, allowing to
obtain the conjugate addition products 3e, 3f, 5c and
5f in good yields and high ees.
produced by a possible background reaction of the
organometallic reagent, as in other cases,[17] a blank
experiment was performed, by reacting chalcone with
phenylzinc iodide without Rh catalyst. No conversion
of the substrate was observed after 48h, suggesting
that the lower enantioselectivity is likely attributable
only to the structural features of the acyclic enones.
Conclusion
An efficient protocol for the enantioselective
Hayashi conjugate addition of arylzinc halides to
enones was realized, based on the use of stabilized
arylzinc iodide. The achievement of the
were performed in flame dried glassware under argon
atmosphere. Ethereal solvents were dried twice over
molecular sieves and distilled before the use. Zinc was
flame dried under high vacuum before the use. All other
solid reagents were dried under high vacuum before the
use.
Experimental Section
General information.
General procedure for the preparation of ArZnX[14]
Proton (1H NMR) and carbon (13C NMR) nuclear magnetic
resonance spectra were recorded at 400 MHz and 100 MHz,
respectively. The chemical shifts are given in parts per
million (ppm) on the delta (δ) scale. GC-FID analyses were
performed on GC instrument with a Split/Splitless injector
a FID detector. The melting points were measured using an
instrument Melting Point B-545. Analytical TLC was
performed on precoated silica gel ALUGRAM Xtra
G/UV254 plates. Purifications were performed by flash
chromatography on silica gel (40-63 µm). All reactions
In a typical procedure, zinc powder (490 mg, 7.5 mmol)
was flame dried under vacuum and cooled under argon
atmosphere in a round-bottomed flask equipped with a
reflux condenser and magnetic stirrer; silver acetate (8.4
mg, 0.05 mmol) was then added under argon and the
mixture dried again under vacuum; the flask was refilled
with argon and anhydrous THF (5 mL) or anhydrous DME
(5 mL) and chlorotrimethylsilane (15 µL, 0.075 mmol)
4
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10.1002/adsc.202001141
Advanced Synthesis & Catalysis
were added. The mixture was stirred and heated at the
reflux for 5 minutes. After cooling, anhydrous TMEDA
(750 µL, 5 mmol) and the aromatic iodide (5 mmol) were
added.
[2]
V. R. Jumde, A. Iuliano, Adv. Synth. Catal. 2013,
355, 3475–3483.
[3]
V. Zullo, A. Iuliano, Eur. J. Org. Chem. 2019,
2019, 1377–1384.
The mixture was heated at the reflux and stirred for the
time needed for each substrate,[14] then was cooled, settled
down and the supernatant was used in the following
addition reaction. To verify full conversion, an aliquot of
the supernatant solution was quenched with NH4Cl and
extracted with Et2O and another aliquot was iodolyzed and
extracted with Et2O, both the samples were analysed by
GLC.
[4]
T. Jerphagnon, M. G. Pizzuti, A. J. Minnaard, B. L.
Feringa, Chem. Soc. Rev. 2009, 38, 1039–1075.
[5]
A. Alexakis, J. E. Bꢀckvall, N. Krause, O. Pꢁmies,
M. Diꢂguez, Chem. Rev. 2008, 108, 2796–2823.
[6]
T. Klatt, J. T. Markiewicz, C. Sämann, P. Knochel,
J. Org. Chem. 2014, 79, 4253–4269.
General procedure for the conjugate addition of
arylzinc halides to acyclic enones (A)
[7]
R. Shintani, T. Yamagami, T. Kimura, T. Hayashi,
Org. Lett. 2005, 7, 5317–5319.
In a typical procedure, [RhCl(C2H4)2]2 (11.4 mg, 3 mol%)
and (R)-BINAP (37.4 mg, 6 mol%) were placed under
inert and dry atmosphere and then 1 mL of THF was added.
The mixture was stirred for 45 minutes and then the enone
(1 mmol) and the arylzinc halide solution in THF (1.5
mmol) were added. The reaction mixture was stirred at
room temperature until the GC-FID analysis showed
complete conversion of the substrate or when it did not
proceed further. Water was added to the mixture and the
aqueous phase was extracted with ethyl acetate (3x10 mL).
The combined organic phases were dried over anhydrous
Na2SO4 and the solvent was removed under reduced
pressure. The crude product was purified by flash
chromatography and analysed by chiral HPLC.
[8]
R. Shintani, N. Tokunaga, H. Doi, T. Hayashi, J.
Am. Chem. Soc. 2004, 126, 6240–6241.
[9]
N. Tokunaga, T. Hayashi, Tetrahedron:
Asymmetry 2006, 17, 607–613.
[10]
[11]
[12]
R. Shintani, T. Hayashi, Nat. Protoc. 2007, 2,
2903–2909.
A. Kina, K. Ueyama, T. Hayashi, Org. Lett. 2005,
7, 5889–5892.
For the preparation of the racemic products, the same
procedure was followed using racemic BINAP instead of
(R)-BINAP.
P. Knochel, H. Leuser, L.-Z. Cong, S. Perrone, F.
F. Kneisel, in Handb. Funct. Organometallics,
Wiley-VCH Verlag GmbH, Weinheim, Germany,
2008, pp. 251–346.
General procedure for the conjugate addition of
arylzinc halides to 2-cyclohexen-1-one (B)
[13]
[14]
[15]
C. Fan, Q. Wu, C. Zhu, X. Wu, Y. Li, Y. Luo, J.-B.
He, Org. Lett. 2019, 21, 8888–8892.
In a typical procedure, [RhCl(C2H4)2]2 (11.4 mg, 3 mol%)
and (R)-BINAP (37.4 mg, 6 mol%) were placed under
inert and dry atmosphere and then 1 mL of DME was
added. The mixture was stirred for 45 minutes and then
TMEDA (113 µL, 0.75 mmol), the enone (1 mmol) and the
arylzinc halide solution in DME (1.5 mmol) were added.
The reaction mixture was stirred at room temperature until
the GC-FID analysis showed complete conversion of the
substrate or when it did not proceed further. Water was
added to the mixture and the aqueous phase was extracted
with ethyl acetate (3x10 mL). The combined organic
phases were dried over anhydrous Na2SO4 and the solvent
was removed under reduced pressure. The crude product
was purified by flash chromatography and analysed by
chiral HPLC.
G. Casotti, A. Iuliano, A. Carpita, Eur. J. Org.
Chem. 2019, 2019, 1021–1026.
A. Krasovskiy, V. Malakhov, A. Gavryushin, P.
Knochel, Angew. Chem. Int. Ed. 2006, 45, 6040–
6044.
[16]
[17]
[18]
G. Casotti, G. Ciancaleoni, F. Lipparini, C. Nieri,
A. Iuliano, Chem. Sci. 2020, 11, 257–263.
S. Facchetti, I. Cavallini, T. Funaioli, F. Marchetti,
A. Iuliano, Organometallics 2009, 28, 4150–4158.
For the preparation of the racemic products, the same
procedure was followed using racemic BINAP instead of
(R)-BINAP.
E. I. Negishi, Angew. Chem. - Int. Ed. 2011, 50,
6738–6764.
Acknowledgements
This work was supported by the University of Pisa through the
PRA_2018_36 grant
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T. Hayashi, K. Yamasaki, Chem. Rev. 2003, 103,
2829–2844.
5
This article is protected by copyright. All rights reserved.

10.1002/adsc.202001141
Advanced Synthesis & Catalysis
UPDATE
Enantioselective conjugate addition of stabilized
arylzinc iodide to enones: an improved protocol of
the Hayashi reaction
Adv. Synth. Catal. Year, Volume, Page – Page
Gianluca Casotti, Vincenzo Rositano, Anna
Iuliano*
6
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