Ligand-free suzuki cross-coupling reactions: Application to β-Halo-α,β-unsaturated aldehydes

Article abstract of DOI:10.1002/ejoc.201300491

A facile, efficient, ligand-free Suzuki-Miyaura reaction of β-halo α,β-unsaturated aldehydes with boronic acids in aqueous media at room temperature is described. Under the optimized conditions, both steroidal and nonsteroidal β-halo α,β-unsaturated aldehydes reacted rapidly with the boronic acids to provide a series of aryl-substituted derivatives in excellent yields. Moreover, the protocol was extended to the direct one-pot synthesis of polycyclic aromatic hydrocarbons through a Suzuki-Miyaura cross-coupling/aldol condensation cascade reaction under microwave irradiation. An efficient ligand-free Suzuki-Miyaura reaction is reported. A range of boronic acids varying in their electronic character were efficiently coupled to β-halo α,β-unsaturated aldehydes. This protocol was extended to the direct one-pot synthesis of polycyclic aromatic hydrocarbons through a Suzuki-Miyaura cross-coupling/aldol condensation cascade reaction under microwave irradiation. Copyright

Full text of DOI:10.1002/ejoc.201300491

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201300491
Ligand-Free Suzuki Cross-Coupling Reactions: Application to β-Halo-α,β-
Unsaturated Aldehydes
Pranjal Gogoi,*[a] Pranjal Bezboruah,[a] and Romesh C. Boruah*[a]
Keywords: Cross-coupling / Domino reactions / Aldehydes / Steroids / Polycycles
A facile, efficient, ligand-free Suzuki–Miyaura reaction of β-
halo α,β-unsaturated aldehydes with boronic acids in
aqueous media at room temperature is described. Under the
optimized conditions, both steroidal and nonsteroidal β-halo
α,β-unsaturated aldehydes reacted rapidly with the boronic
acids to provide a series of aryl-substituted derivatives in ex-
cellent yields. Moreover, the protocol was extended to the
direct one-pot synthesis of polycyclic aromatic hydrocarbons
through a Suzuki–Miyaura cross-coupling/aldol condensa-
tion cascade reaction under microwave irradiation.
gands, dihydronaphthalenes, phenanthrenes, and phen-
anthropyrans and their 9,10-dihydro derivatives (e.g., gym-
nopusin, erianthridin, and coeloginin).[7]
Introduction
The Suzuki–Miyaura cross-coupling reaction is one of
the most powerful and environmentally friendly methods
for the selective construction of carbon–carbon bonds,[1]
and it has found extensive use in the synthesis of significant
products such as drugs, fine chemicals, and optical de-
vices.[2] Enormous effort has been devoted to this reaction
as a result of the remarkably wide range of substrates that
are tolerated and the stability of organoboron compounds
to air and water and their low toxicity.[1,2] This reaction
has developed and reached a level of sophistication, and
admirable results can be obtained with Pd0 or with a PdII
precatalyst in the presence of ligands or additives.[3] How-
ever, the most commonly used phosphane ligands are sensi-
tive to air and moisture, which required an inert atmosphere
as prerequisite during handling, and even a trace amount of
such phosphane ligand may act as inhibitor in some metal-
catalyzed asymmetric reaction.[4] Therefore, the develop-
ment of ligand-free conditions by using a homogeneous pal-
ladium catalyst is of immense interest. There have been a
number of reports on ligand-free Suzuki–Miyaura cross-
coupling reactions.[5] However, most of the reported pro-
cedures are for the synthesis of biaryl compounds.
A few Suzuki cross-coupling reactions of β-halo α,β-un-
saturated aldehydes have been developed; however, the re-
ported methods require phosphane ligands and high reac-
tion temperatures.[7a,7c,8] Hesse et al. reported a ligand-free
system in which Pd(OAc)2 with a stoichiometric amount
of Bu4NBr as an additive was used.[9] To the best of our
knowledge, there is only one phosphane-free palladium-cat-
alyzed cross-coupling reaction of β-bromo α,β-unsaturated
aldehydes with organoboron compounds by using Pd2-
(dba)3 (dba = dibenzylideneacetone).[4] However, this
method requires a high reaction temperature and electron-
withdrawing groups on the boronic acid diminished the re-
activity of this coupling reaction; as a result, only low yields
were obtained (40%).
Results and Discussion
In the context of our ongoing interest in the chemistry
of β-halo α,β-unsaturated aldehydes,[10] we report herein a
ligand-free Suzuki cross-coupling reaction of easily access-
ible steroidal and nonsteroidal annulated β-halo α,β-unsat-
urated aldehydes with organoboron compounds at room
temperature to provide the products in excellent yields
(Scheme 1).
β-Halo-α,β-unsaturated aldehydes are versatile organic
synthons for a variety of heterocyclic compounds and
macrocyclic ligands.[6] Suzuki–Miyaura cross-coupling reac-
tions of those halides with organoboron compounds pro-
vide useful intermediates for the synthesis of heterocycles,
polycyclic aromatic hydrocarbons (PAHs), polyaromatic li-
[a] Medicinal Chemistry Division, CSIR – North East Institute of
Science and Technology,
NH-37, Jorhat, Assam 785006, India
Scheme 1. Ligand-free Suzuki–Miyaura cross-coupling reactions of
β-halo α,β-unsaturated aldehydes with boronic acids.
E-mail: gogoipranj@yahoo.co.uk
rc_boruah@yahoo.co.in
Homepage: http://www.rrljorhat.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300491
Initially, we choose 1-bromo-3,4-dihydronaphthalene-2-
carbaldehyde (1c) as the starting material to perform the
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Ligand-Free Suzuki Cross-Coupling Reactions
optimization studies (Table 1). We examined the reaction Table 2. Ligand-free Suzuki–Miyaura reaction of β-halo α,β-unsat-
urated aldehydes with boronic acids.[a,b]
under various catalytic conditions. We initially studied the
effects of an organic cosolvent with an aqueous solution
of base (2 m). Different organic cosolvents including THF,
acetone, ethanol, DMF, and acetonitrile facilitated the cou-
pling reaction. Although the cross-coupling reaction was
faster in the presence of an organic cosolvent, the reaction
conducted in pure water also afforded good results. The use
of different bases including Na2CO3, K3PO4, K2CO3, and
Cs2CO3 gave almost identical results, whereas KOH de-
livered a low yield of the product. Quantitative yield of the
desired product was obtained in the presence of 0.5 mol-%
of Pd(OAc)2, and a decrease in the catalyst loading from
0.5 to 0.005 mol-% resulted in a sluggish coupling reaction
(Table 1, entries 12–14).
Table 1. Effect of solvent, base, and catalyst loading on the Suzuki
cross-coupling reaction.[a]
Entry Base
Solvent
Catalyst
[mol-%]
Time Yield[b]
[h]
[%]
1
2
3
4
5
6
7
8
–
THF
THF
–
THF
EtOH
–
–
0.5
0.5
0.5
1
1
n.d.
n.d.
71
99
95
97
97
92
96
97
30
66
72
61
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
K3PO4
Na2CO3
Cs2CO3
KOH
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
4
(CH3)2CO 0.5
CH3CN
DMF
THF
THF
THF
THF
THF
THF
0.5
0.5
0.5
0.5
9
10
11
12
13
14
0.5
K3PO4
K3PO4
K3PO4
0.25
0.01
0.005
10
[a] Reaction conditions: Aldehyde 1c (1 mmol), pMePhB(OH)2
(1.2 mmol), base (2 m in H2O, 2 mL), solvent (2 mL). [b] Yield is
given for the isolated product; n.d. = not determined.
We investigated the scope of the ligand-free Suzuki–
Miyaura cross-coupling reaction with respect to the boronic
acids. As shown in Table 2, the reaction took place under
very mild conditions at room temperature to afford excel-
lent yields of the expected products in spite of the nature
of the boronic acid. Substituted aromatic boronic acids
containing electron-deficient groups showed slightly lower
reactivity than those containing electron-rich or electron-
neutral groups. For example, 4-cyanophenylboronic acid,
with an electron-withdrawing group, provided a lower yield
of the product than arylboronic acids with electron-donat-
ing groups (Table 2, 3e and 3h). A higher reactivity was ob-
served for 4-methylbenzeneboronic acid and 4-methoxy-
benzeneboronic acid (Table 2; 3b, 3f, 3i).
[a] Reaction
conditions:
β-Halo-α,β-unsaturated
aldehyde
(1 mmol), boronic acid (1.2 mmol), K3PO4 (2 m in H2O, 2 mL),
THF (2 mL), r.t., vigorous stirring. [b] Yield is given for the iso-
lated product.
The reaction conditions are notably compatible with a
range of functional groups on the aryl ring. Remarkably,
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P. Gogoi, P. Bezboruah, R. C. Boruah
SHORT COMMUNICATION
an aldehyde group remained intact without forming the 1,2- catalyzed cross-coupling with bis(pinacolato)diboron devel-
adduct with the organoboron compounds.[11] We also exam- oped by Miyaura.[13]
ined the introduction of cyclopropyl and fluorinated aryl
groups, which are of great importance in pharmaceutical tion initially proceeds through the in situ generation of a
drug-discovery processes.[12] Pd0 species from Pd(OAc)2 in the presence of the boronic
Regarding the mechanism, it is presumed that the reac-
Having established a range of boronic acid partners, we acid and a base,[14] which catalyzes the coupling of the β-
next examined the scope of the cross-coupling reaction with halo α,β-unsaturated aldehyde with the organoboron com-
various steroidal and nonsteroidal β-halo α,β-unsaturated pound. This cross-coupling reaction is probably facilitated
aldehydes. This cross-coupling reaction showed excellent re- by intramolecular coordination of the neighboring carbonyl
sults with β-halo α,β-unsaturated aldehydes bearing five-, oxygen atom to the palladium to form intermediate [I][15]
six-, and seven-membered rings. Under the optimized reac- during the oxidative addition step (Figure 1). However, the
tion conditions, steroidal A-ring- and D-ring-annulated β- reactivity of the β-halo α,β-unsaturated aldehyde can be at-
halo α,β-unsaturated aldehydes coupled with electron-rich, tributed to the influence of the electron-withdrawing alde-
electron-neutral, and electron-deficient boronic acids. When hyde group, which activates the vinyl halide (even a chloride
this coupling reaction was carried out with chloroformyl moiety) and allows the C–C coupling reaction to take place
substrates, we obtained the desired products (3l 90%, 3r under mild conditions.
88%). However, the chloroformyl substrate required a
longer reaction time relative to that of the bromoformyl
substrate (Table 2, 3l and 3r). All the products were charac-
terized by physical and high-resolution spectroscopic data.
The starting materials were conveniently prepared from
their corresponding ketones by using the Vilsmeier reac-
tion.[10]
To further extend the scope of the ligand-free protocol,
an efficient cascade reaction was investigated, that is, Su-
zuki–Miyaura coupling followed by aldol condensation for
the synthesis of substituted PAHs from β-bromo α,β-unsat-
urated aldehydes and 2-[2-(4,4,5,5-tetramethyl-1,3,2-diox-
aborolan-2-yl)phenyl]acetonitriles. Steroidal and nonsteroi-
Figure 1. Probable mechanism and intermediate [I].
dal polycyclic systems were obtained in the one-pot process
under microwave irradiation. The results are summarized in
Table 3. Requisite starting boronic ester 4 was easily pre-
pared from the corresponding bromide through palladium-
Conclusions
In conclusion, we have reported a simple, efficient, and
high-yielding ligand-free Suzuki cross-coupling reaction of
steroidal and nonsteroidal β-halo α,β-unsaturated alde-
hydes with boronic acids. A range of boronic acids varying
in their electronic character were efficiently coupled with
structurally different β-halo α,β-unsaturated aldehydes.
This protocol was extended to the direct one-pot synthesis
of polycyclic aromatic hydrocarbons through a Suzuki–Mi-
yaura cross-coupling/aldol condensation cascade reaction
under microwave irradiation. This phosphane-free catalytic
system might be very helpful for metal-catalyzed asymmet-
ric reactions. Further investigation into the scope of this
reaction is now being investigated in our laboratory.
Table 3. One-pot synthesis of steroidal and nonsteroidal PAHs.[a,b]
Experimental Section
General Procedure for the Ligand-Free Suzuki Cross-Coupling Reac-
tion: K3PO4 (2 m in H2O, 1 mL) and Pd(OAc)2 (1 mg, 0.5 mol-%)
were successively added to a solution of β-halo α,β-unsaturated
aldehyde 1 (1 mmol, 1 equiv.) and boronic acid 2 (1.2 mmol,
1.2 equiv.) in THF (2 mL). The reaction mixture was vigorously
stirred at room temperature for the time indicated in Table 2. The
reaction mixture was diluted with H2O (10 mL) and extracted with
Et2O (3ϫ 10 mL). The combined organic fraction was dried and
concentrated. The residue was purified by chromatography
(EtOAc/hexanes) to afford the corresponding coupled product 3.
[a] Reaction conditions: Aldehyde
K3PO4 (3 mmol), DMF (1 mL), microwave, 360 W, 20 min.
[b] Yield is given for the isolated product.
1 (1 mmol), 4 (1.2 mmol),
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Ligand-Free Suzuki Cross-Coupling Reactions
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General Procedure for the Ligand-Free Domino Suzuki–Aldol Reac-
tion: To a solution of aryl bromide 1 (1 mmol, 1 equiv.) in DMF
(1 mL) was added boronate 4 (1.2 mmol, 1.2 equiv.), Pd(OAc)2
(8 mg, 4 mol-%), and K3PO4 (3 mmol, 3 equiv.). The mixture was
irradiated in a closed vessel in a microwave reactor (Synthos 3000)
at 360 W and 140 °C for 20 min. The mixture was diluted with
EtOAc and filtered through a short pad of Celite. The solution was
concentrated and purified by column chromatography to provide
PAH 5.
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cle): Experimental details, spectroscopic data, and copies of the 1H
NMR and 13C NMR spectra of all final products
[8]
Acknowledgments
The authors acknowledge the Council of Scientific and Industrial
Research (CSIR), New Delhi for their financial support. P. B.
thanks the University Grant Commission (UGC), New Delhi for
the award of a Junior Research Fellowship. The authors are grate-
ful to the Director, CSIR-NEIST, Jorhat, for his keen interest.
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Received: April 5, 2013
Published Online: July 4, 2013
Eur. J. Org. Chem. 2013, 5032–5035
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