Iron-catalyzed cross-coupling between 1-bromoalkynes and grignard-derived organocuprate reagents

Article abstract of DOI:10.1002/ejoc.201000393

An efficient iron-catalyzed cross-coupling reaction between alkynyl bromides and Grignard-derived organocuprates has been developed. A series of alkynylarenes were successfully synthesised by starting from different 1-bromoalkynes and Grignard reagents. The methodology was successfully used for the two-step stereoselective synthesis of combretastatins and represents a valid alternative to the classical syntheses of alkynylarenes.

Full text of DOI:10.1002/ejoc.201000393

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000393
Iron-Catalyzed Cross-Coupling between 1-Bromoalkynes and Grignard-Derived
Organocuprate Reagents
Daniele Castagnolo[a] and Maurizio Botta*[a,b]
Keywords: Alkynes / Cross-coupling / Iron / Grignard reagents / Homogeneous catalysis
An efficient iron-catalyzed cross-coupling reaction between
alkynyl bromides and Grignard-derived organocuprates has
been developed. A series of alkynylarenes were successfully
synthesised by starting from different 1-bromoalkynes and
Grignard reagents. The methodology was successfully used
for the two-step stereoselective synthesis of combretastatins
and represents a valid alternative to the classical syntheses
of alkynylarenes.
which C(aryl)–C(sp) bonds are constructed by the palla-
dium/copper-catalyzed cross-coupling of aryl halides and
terminal alkynes.[6] On the other hand, the Corey–Fuchs
approach together with its modification,[7] the Seyferth–Gil-
bert homologation,[8] represent an alternative method for
the synthesis of alkynylarenes. However, both of these syn-
thetic approaches present several limitations such as the
availability of substrates, namely aryl iodides and arene-
carbaldehydes, the need of strong reaction conditions and
in some cases poor yields. Hence, the synthesis of alkynyl-
arenes through cross-coupling reaction between 1-halo-
alkynes and Grignard-derived organocuprates could repre-
sent a valid and versatile alternative to the well-known
methodologies. Finally, the use of iron instead of palladium
catalysts provides obvious economical and environmental
merits.
Introduction
Transition-metal-catalyzed cross-coupling reactions are
very powerful in forming new C–C bonds, and constitute
the basis of many contemporary syntheses.[1] The search for
novel electrophiles and efficient catalysts continues to cap-
ture significant interest. Iron catalysts, first reported by Ko-
chi and co-workers,[2] have been very actively investigated in
the last decade for their performance in C–C bond-forming
cross-coupling reactions.[3] A variety of iron-catalyzed
cross-couplings between alkyl/alkenyl/aryl halides and
Grignard reagents have been reported.[4] However, although
iron-catalyzed cross-coupling at C(sp3) (alkyl halides) and
C(sp2) (alkenyl and aryl halides) centers have been widely
documented, to the best of our knowledge, successful appli-
cations of iron-catalyzed cross-couplings between Grignard
reagents and alkynyl halides [C(sp) center] as substrates
have not been yet reported. Due to our previous studies in
the field of acetylene chemistry,[5] we were tempted to ex-
plore the reactivity of haloalkynes in iron-catalyzed cross-
coupling reactions. Herein, we report the first example of
iron-catalyzed reactions between 1-haloalkynes and aryl
Grignard-derived organocuprates for the preparation of
alkynylarenes. The use of magnesium-derived organocup-
rates as nucleophilic species instead of simple Grignard rea-
gents represents the key factor that allows the cross-cou-
pling to occur.
Results and Discussion
The reaction of TIPS-bromoacetylene (1) with PhMgBr
in the presence of catalytic amounts of Fe(acac)3, was first
explored (Scheme 1; Table 1, Entries 1–3). The reaction was
carried out at different temperatures and with different
amounts of PhMgBr. In all the cases phenylalkyne 2 was
not obtained, but biphenyl (3), due to the homocoupling
reaction of the Grignard reagent, and 1,3-diyne 4, due to
the homocoupling of the alkyne 1, were isolated from the
reaction mixtures. Alkyne 2 was obtained in small amounts
The most frequently utilized method for the preparation
of alkynylarenes is the Sonogashira–Hagihara reaction, in
[a] Dipartimento Farmaco Chimico Tecnologico, Università degli only when an excess of Grignard reagent was used. It has
Studi di Siena
been well documented that the extensive homo-couplings of
Via Alcide de Gasperi 2, 53100 Siena, Italy
the arylmagnesium species remain a big issue in iron-cata-
lyzed cross-coupling reactions.[4d,9] It has been assumed that
the homo-coupling side-reaction may arise from the forma-
tion of ferrate complexes with the highly reactive organom-
agnesium compounds.[10] Knochel et al. recently reported
a partial remedy to homocoupling side-reactions in iron-
catalyzed biaryl syntheses by the use of arylmagnesium cup-
Fax: +39-0577-234-333
E-mail: botta.maurizio@gmail.com
[b] Sbarro Institute for Cancer Research and Molecular Medicine,
Center for Biotechnology, College of Science and Technology,
Temple UniVersity, BioLife Science Building,
Suite 333, 1900 N 12th Street, Philadelphia, Pennsylvania
19122, USA
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000393.
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Eur. J. Org. Chem. 2010, 3224–3228

Iron-Catalyzed Cross-Coupling
rates, prepared from arylmagnesium halides and CuI 2 and 3 were obtained in almost the same ratio (Entry 6).
sources.[4f] Hence, we decided to investigate the reaction of Finally, the reaction of PhMgBr/CuCl with 1 in the absence
1-haloalkynes with phenylmagnesium cuprate reagents, pre- of Fe(acac)3 did not result in the formation of 2, whereas 3
pared in situ from PhMgBr and CuCl and in the presence and starting material 1 were recovered from the reaction
of Fe(acac)3. The reaction of stoichiometric amounts of mixture (Entry 8). It seems clear that the presence of Fe-
PhMgBr/CuCl complex and alkyne 1 at 25 °C led to the (acac)3 is fundamental to achieve the cross-coupling prod-
formation of the desired compound 2 and biphenyl (3) in uct 2. On the basis of this latter result, the plausible mecha-
an almost 1:1 ratio (Entry 5).
nisms, based on the mechanism generally accepted for the
cross-coupling reactions catalyzed by iron, is proposed in
Scheme 2. The oxidative addition of bromoalkyne 1 to the
low-valent iron intermediate FeI, which is generated by the
reaction of Fe(acac)3 with the Grignard reagent, gives alk-
ynyliron species A. At this stage two pathways would be
possible: (a) transmetallation of the phenyl group from
magnesium to iron followed by reductive elimination of
cross-coupling product 2; (b) disproportionation, leading to
the formation of intermediates B and C, which in turn give
homocouplig products 3 and 4 by reductive elimination re-
generating catalyst FeI. Experimental results suggest that
when aryl Grignard species are used, the intermediate A
follows pathway (b). On the other hand, when the reaction
was carried out between 1 and the PhMgBr/CuCl complex
(Entries 4–7), pathway (a) seems to be preferred. It might
be assumed that organocuprates interact with intermediate
A leading to transmetallation intermediate D faster than
Grignard reagents. This hypothesis might be confirmed by
the well-known affinity of CuI toward triple bonds;[11] in
this case, copper would accelerate the transmetallation step
reducing the tendency of A to give disproportionation side-
reactions. Finally, when the cross-coupling reactions are
carried out with 2.2 equiv. of the PhMgBr/CuCl reagent,
smaller amounts of homocoupling side products were ob-
tained. The excess of organocuprate reagent would interact
with A rapidly leading to the formation of D and reducing
the amount of homocoupling side products.
Scheme 1. Cross-coupling between 1 and PhMgBr/CuCl leading to
product 2 and side-products 3 and 4.
Table 1. Fe(acac)3-catalyzed cross-coupling between PhMgBr or
PhMgBr/CuCl and alkyne 1.[a]
Entry PhMgBr
[equiv.]
CuCl
[equiv.]
T
[°C]
2
3
4
[%][b]
[%]
[%]
1
2
3
4
5
1.1
2.2
2.2
1.1
1.1
2.2
2.2
1.1
0/25
–20
0/25
–20
25
0
25
98
82
88
39
41
98
88
91
35
37
6
4
35
1.1
1.1
2.2
2.2
32
6
63[c]
65[c]
30[c,d]
28[c,d]
98[f]
7
8[e]
25
[a] All the reactions were carried out in the presence of Fe(acac)3
(10 mol-%). [b] Ratios were determined by GC–MS and H-NMR
analysis of the crude mixtures. [c] Isolated yields. [d] Based on
PhMgBr total amount. [e] The reaction was performed without
Fe(acac)3. [f] Bromoalkyne 1 was recovered.
1
A considerable amount of 4 was also obtained. The same
reaction was performed at –20 °C, but also in this case com-
pounds 2, 3 and 4 were obtained in a 1:1:1 ratio (Entry 4).
The use of an excess of PhMgBr/CuCl reagent (2.2 equiv.)
led the reaction to completion after 3 h, and 2 was obtained
in 65% yield, together with a smaller amount of 3 (28%
yield, based on PhMgBr total amount; Entry 7). When the
reaction was performed at lower temperature, compounds
A variety of haloalkynes 1a–d were then coupled with
different Grignard-derived organocuprates. Haloalkynes
1a–d were prepared from corresponding terminal alkynes
through NBS bromination[12] and treated with different
RMgBr/CuCl reagents under the same conditions set up
Scheme 2. Plausible catalytic cycle.
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D. Castagnolo, M. Botta
SHORT COMMUNICATION
Table 2. Cross-coupling between PhMgBr/CuCl and different alkynyl bromides 1a–d.
[a] Prepared in situ from RMgBr and CuCl, THF, 25 °C, 20 min. [b] Isolated yields. [c] Reaction was performed at –20 °C.
before (Table 2). The reaction of TIPS-bromoalkyne 1a
with arylMgBr/CuCl reagents led to the desired arylalkynes
2a–f in high yields after 3 h (Entries 1–6). High yields were
obtained with aryl compounds containing electron-donat-
ing groups (OMe, SMe) (Entries 2, 6), whereas the presence
of an electron-attracting moiety on the aromatic ring led to
the desired product in lower yield (Entry 3). The reaction
of thienylmagnesiumcuprate with 1a led to alkyne 2g in
lower yield (Entry 7). The reactivity of an aliphatic Grig-
Scheme 3. Michael addition of PhMgBr/CuCl to 2.
The same reaction was performed by using an equimolar
nard/Cu reagent was also tested. Phenethylmagnesium chlo- ratio of 1d and the PhMgBr/CuCl reagent, leading to the
ride was converted into its copper derivative and then cross- formation of 2o/5 in 1:5 ratio as revealed by 1H NMR
coupled with 1a to yield alkyne 2h in excellent yield (En- analysis. The formation of 5 as the main product was due
try 8). This latter result proved the versatility of the present to the Michael 1,4-addition of the organocuprate to 2o. Nu-
methodology and its utility also in the synthesis of alkylal- cleophilic organocuprate seems to prefer to react with the
kynes through the cross-coupling of C(sp3) and C(sp) elecrophilic 2o as it forms to give the 1,4-addition product
centres. Phenylbromoalkyne 1b was then treated with aryl- 5, rather than to react with bromoalkyne(iron) complex A
magnesiumcuprates leading to desired compounds 2i–j in in a cross-coupling. On the contrary, when 1d was treated
good yields (Entries 9–10). Also the reaction of thienyl and under standard conditions (25 °C) with thienylMgBr/CuCl,
phenethyl Grignard-derived cuprates led to the desired the desired compound 2p was obtained in good yield (En-
products 2k–l in high yield (Entries 11–12). Alkyne 1c was try 16), and no traces of the corresponding alkene were de-
then treated with arylmagnesiumcuprates leading to com- tected. Compound 2p, due to the presence of an electron-
pounds 2m–n in good yield (Entries 13–14).
rich thienyl ring, could be considered a poor Michael ac-
The presence of an MeO group on the aromatic ring of ceptor and poor electrophile in comparison with alkyne 2o.
substrate 1c did not seem to change its reactivity in cross- The organocuprate reacts with the (1d)iron complex faster
couplings compared to 1b. On the other hand, the electron- than with 2p, which consequently does not act as the sub-
rich alkyne 1a seemed to be the best substrate for cross- starte for the 1,4-addition side-reaction. The present meth-
coupling reactions with arylmagnesium cuprates. Finally, odology could represent a versatile and stereoselective ap-
the reactivity of electron-deficient bromoalkyne 1d was ex- proach to the synthesis of cytotoxic and antimitotic agents
plored. The reaction of 1d with the PhMgBr/CuCl complex related to Combretastatin A-4 (CA4), one of the most cyto-
at room temp. gave alkene 5 as the main product (78% toxic agents tested so far against several cancer cell lines.[14]
yield).[13] Only traces of the desired alkyne 2o were observed
Combretastatins are generally prepared by non-stereose-
by 1H NMR analysis. When the same reaction was per- lective Wittig reactions between arenecarbaldehydes and
formed at –20 °C, alkyne 2o was obtained in 18% yield to- phosphonium bromides, which leads to the formation of a
gether with 5 (56%) (Entry 15) (Scheme 3).
mixture of (Z)/(E)-alkene isomers.[15] Alkynes 2m–n could
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Iron-Catalyzed Cross-Coupling
solution was stirred for 1 h. The organic layer was separated; the
aqueous phase was extracted twice with Et2O. The organic layers
were then collected, washed with saturated sodium chloride solu-
tion, dried with magnesium sulfate, and concentrated in a rotary
evaporator. The crude product was purified by column chromatog-
raphy (Et2O/hexanes, 98:2).
be considered as the synthetic precursors of combretastatin
analogs. Partial hydrogenation of 2m–n with Lindlar’s cata-
lyst led selectively to (Z)-alkenes 6a–b in excellent yields
(78% and 82%) (Scheme 4).[16] Compound 6b is known to
be one of the most active CA4 analogs possessing anti-
mitotic activity with inhibition of tubuline polymerization
IC50 values similar to that of natural Combretastatin A-4
(2.5Ϯ0.1 of 6b vs. 2.0Ϯ0.3 of CA4).[17]
Supporting Information (see footnote on the first page of this arti-
cle): Full characterization of new compounds, NMR spectra.
Acknowledgments
This study was supported by grants from the FLUINHIBIT Con-
sortiums.
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Scheme 4. Synthesis of Combretastatin analogs.
Conclusions
We report the first example of iron-catalyzed cross-cou-
pling reaction between C(sp) and C(sp2/sp3) centres.
Haloalkynes were converted into aryl/alkyl-acetylenes
through coupling with magnesium-derived organocuprates
generated in situ from Grignard reagents and CuCl. The
use of organocopper instead of simple Grignard reagents
was the key factor to suppress the undesirable side homo-
coupling and to lead the reaction to completion. The pres-
ent methodology represents a valid and alternative way to
standard methodologies in the synthesis of substituted al-
kynes. Finally, it could represent a fast and versatile ap-
proach for the synthesis of natural and synthetic biolo-
gically active combretastatin and stilbenoid analogues that
can be obtained in only two steps with a high degree of
stereoselectivity.
Experimental Section
A dry 50 mL flask, equipped with a mechanical stirrer and a sep-
tum, was charged with THF (4 mL) and CuCl (2.2 mmol), and
cooled to 0 °C. Then the arylmagnesium bromide/chloride
(2.2 mmol), as a solution in THF, was added dropwise in 5 min.
After completion of the addition, the reaction mixture was stirred
at room temperature for an additional 20 min. In a separate 10 mL
flask, equipped with a mechanical stirrer and a septum, alkynyl
bromide (1 mmol) was dissolved in THF (2 mL). To the alkyne
solution was added Fe(acac)3 (35 mg, 0.1 mmol), and the resulting
solution was stirred at room temperature for 10 min. The alkyne
solution was then transferred dropwise into the first solution
through a cannula. The reaction mixture was stirred at room tem-
perature for an additional 3 h. An NH4Cl saturated solution
(10 mL) and NH4OH (2 drops) were then added, and the resulting
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Received: March 23, 2010
Published Online: May 5, 2010
After publication in Early View, new ref.[16] was added and
the former ref.[16] changed to ref.[17]
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