Iron-catalyzed stereospecific arylation of enol tosylates using Grignard reagents

Article abstract of DOI:10.1039/c9cc09522e

The stereospecific Fe-catalyzed arylation of enol tosylates was reported. Various tri- or tetrasubstituted Z or E-enol tosylates of β-keto esters were arylated using common and Knochel-type Grignard reagents with complete stereofidelity. The precursors fo

Full text of DOI:10.1039/c9cc09522e

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Iron-catalyzed stereospecific arylation of enol
tosylates using Grignard reagents†
Cite this:DOI: 10.1039/c9cc09522e
Yi-Ming Wei,‡ Xiao-Di Ma,‡ Lei Wang and Xin-Fang Duan
*
Received 9th December 2019,
Accepted 16th December 2019
DOI: 10.1039/c9cc09522e
rsc.li/chemcomm
The stereospecific Fe-catalyzed arylation of enol tosylates was
reported. Various tri- or tetrasubstituted Z or E-enol tosylates of
b-keto esters were arylated using common and Knochel-type
Grignard reagents with complete stereofidelity. The precursors for
Z/E-zimelidine, tamoxifen and other bioactive compounds were
facilely prepared without precious and toxic transition metals.
The stereocontrolled synthesis of various substituted olefins is
an ongoing and important task in organic synthesis because
these structural motifs are ubiquitous in natural products,
biologically active compounds, molecular devices and liquid
crystals.1 Transition-metal catalyzed cross couplings of alkenyl
halides, tosylates (other esters) and ethers with various metal
reagents (or vice versa, alkenyl metal reagents with alkyl or aryl
(pseudo)halides) have become a very useful tool in this field.2,3
For example, Pd-catalyzed Suzuki or Negishi couplings of
configuration-defined alkenyl (pseudo)halides enabled the
stereocontrolled preparations of tri- or tetrasubstituted alkenes
(Scheme 1A).1d,4 Characterized by low prices and low toxicity,
Fe-catalyzed stereoselective synthesis of alkenes has attracted
Scheme 1 Stereoselective alkylation or arylation of alkenyl (pseudo)halides.
widespread attention. Although various Fe-catalyzed stereo- retention of the configuration until now.8 In this context,
selective alkylations of enol triflates, phosphates, tosylates, Fe-catalyzed stereocontrolled arylation of Z- or E-alkenyl (pseudo)-
carbamates and alkenyl iodides with alkyl magnesium or halides, especially those that generate thermodynamically less
lithium reagents have been well achieved (Scheme 1B),5 the stable Z-alkenes, is highly desired as an ecofriendly and sustainable
corresponding Fe-catalyzed arylation is very rare.6 One impor- alternative to reactions requiring noble or toxic metals.
tant reason for this is that the iron-catalyzed C(sp2)–C(sp2)
Recently we have developed efficient protocols for Fe-catalyzed
couplings remain challenging and are more limited than those biaryl cross couplings between aryl (pseudo)halides and aryl
catalyzed by palladium.7 Besides, the arylations that generate Grignard reagents,10 which prompted us to discover a stereo-
thermodynamically less stable alkenes (e.g. Z-trisubstituted selective arylation of alkenyl (pseudo)halides. Herein, we reported
acyclic alkenes) usually require challenging reaction conditions two protocols for Fe-catalyzed stereospecific arylation of Z or
to avoid isomerization.8,9 To the best of our knowledge, no reports E-enol tosylates (Scheme 1C), by which a variety of Z- and
have been documented on the Fe-catalyzed stereocontrolled aryla- E-tri- and tetrasubstituted acrylates were facilely prepared with
tion of Z-substituted acyclic alkenyl (pseudo)halides with complete complete stereocontrol. Since the stereoselective preparations
of various Z/E-enol tosylates have been well established by
Tanabe et al.,4b,c,11 and Grignard reagents are readily available,
we expect this mild and general method to be a valuable
College of Chemistry, Beijing Normal University, 100875, China.
E-mail: xinfangduan@vip.163.com
alternative for the stereospecific construction of olefins without
the need of precious and toxic transition metals.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c9cc09522e
‡ These authors contributed equally.
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Scheme 2 Optimized conditions for stereospecific arylation.
Our condition optimizations clearly showed that the isomer-
ization into the thermodynamically more stable E-3aa was liable
to occur as expected (Scheme 2). By taking advantage of this
isomerisation under heated conditions, a stereospecific arylation
leading to a single E-product was established (method B). Further
optimizations indicated that temperature, ligand, Ti(OEt)4 and
phenolate were crucial for the stereospecific formation of Z-3aa,
and meanwhile the reactions without either Ti(OEt)4 or PhOM
at 0 1C could hardly generate the arylated products, clearly
indicating that the phenolate-assisted Fe/Ti synergistic effect10a,b
was the key to the reaction (Scheme 2 and see the ESI†). Thus, the
combination of FeCl3/SIPr with Ti(OEt)4/PhOM as a cocatalyst
system enabled a facile stereospecific arylation under mild con-
ditions (method A, Scheme 2). Although this combination has
been used to promote biaryl couplings in our group,10a,b it
has never been applied to the stereoselective arylation of enol
tosylates. To our delight, it turns out to be a highly effective
Fe-based catalyst system that can achieve stereospecific arylation
of Z-enol tosylates with complete stereofidelity, leading to the
thermodynamically less stable Z-products as a single isomer.
With the optimized conditions in hand, we investigated the
scope of the Fe-catalyzed stereospecific arylation reaction. Initially,
the arylations of various trisubstituted tosyloxyacrylates with
different Grignard reagents was carried out, and the results are
outlined in Scheme 3. A wide variety of Z-trisubstituted acrylates
which are prone to isomerization into E-isomers were stereo-
specifically prepared using method A (Scheme 3a). In the pre-
Scheme 3 Z- and E-trisubstituted acrylates by stereospecific arylations.a,b
a The reaction was carried out on 5 mmol scale using method A unless indicated.
b Only a single isomer was observed and isolated unless indicated. c Grignard
reagent was prepared by ArI + i-PrMgClÁLiCl and used without removing i-PrI.
d Grignard reagent was prepared by ArI + i-PrMgClÁLiCl and used after removing
f
i-PrI. e Using Z-substrate. Using a mixture of Z- and E-substrates.
vious reports of Pd-catalyzed stereoselective arylations of enol tosyloxyacrylates could also be arylated stereospecifically
tosylates via Suzuki reaction, the reaction conditions required (Z-3bb–Z-3cj), where 2-substituted (Z-3ba), pyridyl (Z-3bh) and
judicious optimizations and were often conducted under heated functionalized (Z-3ci and Z-3cj) Grignard reagents performed
conditions.1d,4c,d By contrast, our present reactions proceeded equally well. The stereospecific arylation by method A also proved
smoothly at 0 1C, which fully showed the high activity of the facile for 3-aryl-3-(tosyloxy)acrylates (Z-3dk–Z-3ee). It should be
Fe/Ti cocatalyst, and meanwhile reduced the possibility of the mentioned that a selective arylation of OTs over Br could also be
isomerization into E-isomers. Notably, in addition to common achieved with stereospecificity (Z-3ee).
Grignard reagents (Z-3ab–Z-3ad), thiophene and hindered
As outlined in Scheme 3b, various E-trisubstituted acrylates were
2-functionalized Grignard reagents could arylate 1a smoothly also prepared stereospecifically using method A (E-3ab–E-3ee).
as well (Z-3ae–Z-3ag). We also found that in the arylations using Since these E-isomers are thermodynamically more stable, they
Knochel-type Grignard reagents, the removal of the concomitant could also be generated as a single isomer using method B in
i-PrI formed during the preparation of functionalized Grignard the absence of NHC ligand at heated conditions (E-3ab–E-3ee).
reagents hardly improved the yields (Z-3ag and Z-3cj).10c Thus, The tolerance to sensitive functional groups of two coupling
omitting the procedure of removing i-PrI not only made the substrates under heated conditions is obviously a prominent
reaction more convenient, but also could further expand the advantage of our present protocol. Besides, by taking full
applications of Knochel-type Grignard reagents in coupling advantage of isomerization, a single E-isomer could be also
reactions.10 Likewise, linear and branched chain substituted prepared facilely by using Z-tosyloxyacrylates and a mixture
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of Z and E-tosyloxyacrylates under the conditions of method B
(E-3ac–E-3af). The use of a mixture of Z and E-tosyloxyacrylates as
starting compounds also has obvious advantages because the
preparations of these starting materials need no stereocontrol.
This should be due to the inherent thermodynamic stability of
these E-trisubstituted acrylates. Our preliminary experiments also
indicated that Z-trisubstituted acrylates could be completely con-
verted into their E-isomers under the conditions of method B.12
Thus, it can be inferred that the reason for the high stereo-
selectivity and stereofidelity of method A lies in that the mild
conditions avoid the isomerization of Fe intermediates (formed by
oxidative addition in catalytic cycle) and the formed products.
Next, we explored the stereospecific arylations of fully substi-
tuted tosyloxyacrylates whose stereoselective preparations were also
well reported by the Tanabe group.11c The results were outlined in
Scheme 4. The present Fe-catalyzed arylation still proved to be
facile for the tetrasubstituted substrates. Noteworthily, Fe-catalyzed
arylations are often sensitive to steric hindrance;13 and meanwhile
even in the Pd-catalyzed stereoselective arylations of enol tosylates,
the highly hindered aryl groups would prevent the reaction or lead
to isomerization.1d,14 Our experiments clearly showed that the
present arylation of tetrasubstituted substrates could still proceed
with stereospecificity only at 0 1C despite the high steric hindrance
Scheme 5 Stereospecific syntheses of precursors for pharmaceuticals
and bioactive compounds. See the ESI.†
(Z/E-4am and Z/E-4bn). Once again, heteroaryl and Knochel-type pharmaceutical precursors and bioactive compounds using
functionalized Grignard reagents were also well suited to this the aforementioned two methods (Scheme 5). Both Z- and
reaction (Z/E-4bo–Z/E-4cp). The relative stability between Z- and E-precursors to Z- and E-zimelidines (Z-6 and E-6) were prepared
E-tetrasubstituted acyclic olefins is not as easy to determine as that using 3-pyridyl Grignard reagent where the selectivity between
of trisubstituted olefins, and our preliminary experiments to con- OTs and Br was well achieved. These precursors could be further
vert Z-4bn into E-4bn under the heated conditions of method B transformed into zimelidines according to the reported
were unsuccessful.15 As a result, we did not use method B to procedures.4d,16 Meanwhile, Z- and E-tetrasubstituted precursors
implement the arylations of acyclic tetrasubstituted substrates.15 to Z- and E-tamoxifens (Z-7 and E-7)14a,17 were also synthesized
Instead, 2-(tosyloxy)cyclohex-1-enecarboxylate was arylated using stereospecifically using method A. Besides, an inhibitor of
both method A and B, affording the tetrasubstituted products monoamine transporters featuring a 2-naphthyl cyclohex-1-
(5a and 5b) in 66–79% yields.
enecarboxylate skeleton (8)18 and chromeno[3,4-c]pyridin-5-one (9),
To demonstrate the synthetic potential of this Fe-catalyzed a selective human dopamine D4 receptor antagonist19 were
stereospecific arylation reaction, we synthesized a range of facilely synthesized using method A and B. To the best of our
knowledge, although the stereospecific syntheses of all these
compounds have already been achieved by Pd-catalyzed aryla-
tions, their syntheses via Fe-catalyzed arylations have been
achieved for the first time. Obviously, these preparations
proved to be straightforward and convenient with readily avail-
able Grignard reagents and enol tosylates. Furthermore, the use
of two nontoxic metals (Fe and Ti) as catalysts is a distinct
advantage of our syntheses.
In conclusion, while achieving both chemo- and stereo-
selectivity simultaneously is a highly challenging task in
organic synthesis, our approaches presented here achieve this
goal well unprecedentedly using sustainable transition metal
catalysts (Fe/Ti) in constructing various Z/E tri- and tetra-
substituted acrylates.20 The general protocol (method A) can
implement stereospecific arylations under mild conditions to
generate various Z and E-alkenes, showing high tolerance to
sensitive functional groups and steric hindrance with complete
Scheme 4 Z- and E-tetrasubstituted acrylates by stereospecific arylations.a,b
stereofidelity. Meanwhile, method B could stereospecifically
synthesize various thermodynamically more stable acrylates
under heated conditions without NHC or phosphine ligands.
a The reaction was carried out on 5 mmol scale under the same conditions as
Scheme 3. b All reactions were conducted using method A unless indicated.
c The reaction was carried out using method B.
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Using only a catalytic amount of Ti(OEt)4, this mild Fe-catalyzed
arylation with Grignard reagents is comparable to the corres-
ponding Pd-catalyzed stereoslective Suzuki/Negishi arylations
in terms of functional group tolerance and stereoselectivity.
Thus, we expect that our Fe-catalyzed arylation combined with
the previously reported Fe-catalyzed stereoselective alkylation
will promote the replacement of noble and toxic transition
metals in accessing stereodefined olefins.
´
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8 Even in the Pd-catalyzed steroselective arylations of enol tosylates,
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conditions were required to prevent isomerization, see 1d. Besides,
the isomerization to thermostatically stable E-isomers was observed
in the Fe-catalyzed alkylation and arylation of enol phosphates and
tosylates, see 5f and 5g.
9 A recently reported Co-catalyzed arylation showed that the reactions
of acyclic Z-tosylates gave the E-configured products, see: J. Li and
P. Knochel, Angew. Chem., Int. Ed., 2018, 57, 11436.
We gratefully acknowledge the National Science Foundation
of China (21372031 and 21572022).
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Conflicts of interest
There are no conflicts to declare.
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´
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