Palladium catalyzed chloroethoxylation of aromatic and heteroaromatic chlorides: An orthogonal functionalization of a chloroethoxy linker

Article abstract of DOI:10.1039/c8ob01146j

A novel disconnection based on cross-coupling chemistry was designed to access pharmaceutically relevant aryl-aminoethyl ethers. The developed palladium-catalyzed functionalization of aryl- and heteroaryl chlorides with a sodium tetrakis-(2-chloroethoxy) borate salt is orthogonal to the simple nucleophilic replacement of the chloro function of the ethylene linker. The transformation enables efficient 2-chloroethoxylation in the absence of an additional external base. Subsequent amine substitution of the alkyl halide affords 2-aminoethoxy arenes. The applicability of this method was demonstrated through the synthesis of various aryl- and heteroaryl-alkyl ethers, including the intermediates of marketed drug molecules.

Full text of DOI:10.1039/c8ob01146j

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Palladium Catalyzed Chloroethoxylation of Aromatic and
Heteroaromatic Chlorides: an Orthogonal Functionalization of
Chloroethoxy Linker†
Received 00th January 20xx,
Accepted 00th January 20xx
Bálint Pethő,a Dóra Vangel,a János T. Csenki,a Márton Zwillinger,a and Zoltán Novák*a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A novel disconnection based on cross-coupling chemistry was designed to access pharmaceutically relevant aryl-
aminoethyl ethers. The developed palladium-catalyzed functionalization of aryl- and heteroaryl chlorides with sodium
tetrakis-(2-chloroethoxy)-borate salt is orthogonal to the simple nucleophilic replacement of the chloro function of the
ethylene linker. The transformation enables efficient 2-chloroethoxylation in the absence of additional external base.
Subsequent amine substitution of the alkyl halide affords 2-aminoethoxy arenes. The applicability of this method was
demonstrated through the synthesis of various aryl- and heteroaryl-alkyl ethers, including intermediates of marketed drug
molecules.
between 2-haloalcohols and aryl chloride coupling partners is
not feasible.
Introduction
OH
R2
R3
+
HN
R1
+
X
Orthogonality is a key aspect of molecular constructions in
X
Standard Route
every
branch
of
synthetic
chemistry.1
Selective
functionalization of linkers2 for the access of crosslinked
functional groups is strategically important, but its efficient
execution encounters difficulties when reaction centers of the
linker have similar properties or could interact under the
reactions conditions. To circumvent these synthetic problems,
novel orthogonal methods should be developed. Transition
metal catalyzed cross-coupling reactions are one of the most
powerful tools for the selective functionalization of various
molecular scaffolds through the formation of new carbon-
carbon and carbon-heteroatom bonds.3 With the aid of this
methodology, a large pool of functional groups can be
introduced into aromatic, heteroaromatic and even to acyclic
systems with high efficiency. Thus, in pharmaceutical research
the transition metal-catalyzed cross-coupling technology has
widespread application.4 However, the functionalization of
cheaper and more versatile aromatic chlorides with cross-
coupling chemistry5 often encounters difficulties, and requires
special catalyst systems and reaction conditions. On the other
hand, introduction of some molecular motifs can also be
challenging with the aid of transition metal-catalyzed
reactions. One example of this is the 2-haloethoxy group,
because the transition metal catalyzed C-O bond formation
HO
S
O
OH
O
HO
O
O
N
N
O
H
N
N
O
S
O
HN
N
Rosiglitazone
Carvedilol
H
Raloxifene
O
O
S
N
N
N
O
N
O
O
O
O
O
S
NH
N
Cl
Quizartinib
NH2
O
HN
H
O
Tamsulosin
N
CF3
Toremifene
O
O
N
N
N
O
N
O
N
N
OH
Cl
HO
HO
O
N
S63845
O
N
Bazedoxifene
S
O
F
Novel Disconnection Approach
New Cross-coupling Method
R2
X
O
R2
N
FGO
HN
+
R3
R3
+
X
R1
R1
Scheme 1. Examples of drug molecules having aminoalkoxy function
In spite of the significant developments in the field of C-O
bond forming cross-coupling reactions for the synthesis of aryl-
alkyl ethers,6 this approach remained an elusive
transformation due to the presence of a nucleophilic oxygen
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atom and a sensitive alkyl halide moiety in the same coupling alcohol at 100°C in the presence of Pd2dba3 catalyst with
partner. Thus, the necessity of rather strong external bases in different phosphine ligands (Table 1). The study of the ligand
the aforementioned C-O bond forming coupling reactions lead effect revealed that bulky, dialkyl-biphenyl phosphines were
to the formation of different side products. Successful generally appropriate ligands for the efficient coupling.
formation of aryl-alkyl ethers bearing halide leaving groups
Table 1. Study of ligand effect on the coupling reaction[a]
attached to the alkyl chain offers versatile transformation
possibilities. The halogen can be readily replaced with
heteroatom nucleophiles, such as amines to provide the 2-
aminoethoxy group, which can be found in many drug
molecules and other bioactive compounds (Scheme 1).7
The construction of 2-aminoethoxy arenes is mostly based on
the O-alkylation of phenol derivatives with the utilization of
Entry
Reagent
Ligand
3H (%) [b]
3a, (%)[b]
alkylene synthons with appropriate leaving groups.8 In case of
sensitive and complex substrates, the Mitsunobu reaction of 2-
aminoalcohols and phenols is a viable option,9 and in special
cases, addition reactions,10 or nucleophilic aromatic
substitutions could also be applied.11 A successful example of
the synthesis of aryl-aminoalkyl ethers through cross-coupling
reactions was described by Buchwald and co-workers (Scheme
2).6g Although there are numerous remarkable aspects of this
transformation, two important features remained unsolved.
First, aryl-iodides were used as substrates, while the
corresponding bromides or chlorides were inactive, and
selective C-O bond forming reaction could only be achieved by
longer alkyl linkers.
1
2
3
4
5
6
7
2a
2a
2a
2a
2a
2a
2a
CyJohnPhos
JohnPhos
BrettPhos
XPhos
1
24
1
1
63
92
13
0
54
t
Me4 BuXPhos
86
RockPhos
0
99
0
100(95)[c]
tBuXPhos
tBuXPhos
8
2b
45[c, d]
complex mixture
[a] 0.1 mmol aryl chloride 1a, 0.15 mmol Na[B(OCH2CH2Cl)4] 2a or 2-chloroethanol
2b, 200 µL tAmyl-alcohol. [b] Determined by GC analysis after 1 h; numbers in
parenthesis indicate conversions after 24 h. [c] Isolated yield. [d] 1.5 equiv of
Cs2CO3 was used as base.
Comparing the alkyl-substituents, ligands bearing tert-butyl
groups were more active, than their cyclohexyl-substituted
derivatives (entries 1 vs 2 and 4 vs. 7). Among the tested
Scheme 2. Cu-catalyzed aminoalkoxylation of aryl-iodides
t
ligands BuXPhos proved to be the best choice with respect to
Thus, the objective of our research was the development of an
efficient and selective catalytic method for the 2-
both activity and economy. With its application, 100%
conversion was reached in 1h, and after the workup the
chloroethoxylated product 3a was isolated in 95% yield. To
demonstrate the beneficial effect of borate coupling partners
over simple alcohols, the preparation of the same product was
attempted using the well-established reaction of
chloroacetophenone and 2-chloroethanol in the presence of
Cs2CO3. 13 This reaction gave a complex product mixture after
complete consumption of the substrate, and the desired
coupled product 3a was isolated only in 45% yield (entry 8).
With the optimized reaction conditions in hand, we turned our
attention to the applicability of the method in the synthesis of
various aromatic and heteroaromatic 2-chloroethoxy
derivatives (Scheme 3). The formyl group was tolerated well
and coupling reaction through the chloro function in ortho-,
meta-, and para-position to the aldehyde group was successful
under the optimized reaction conditions, affording products
3b-d in 79, 58 and 99% yield respectively. The coupling
reaction took place smoothly in the presence of electron
withdrawing groups such as nitro, cyano and trifluoromethyl,
providing products 3e-g in 80-91% yield. 4-Chloro-
vinylbenzene was also chloroethoxylated, providing 3h in 77%
yield. Electron donating groups such as methoxy- or MOM-
protected phenolic OH also enabled the cross-coupling on the
chloride, however, the electron rich nature of the substrates
resulted in lower reactivity. Products 3i and 3j were isolated in
chloroethoxylation of aryl chlorides. With
a subsequent
substitution reaction, a wide variety of nucleophiles can be
introduced to the aryl-chloroethyl ethers, granting a modular
synthetic route to 2-aminoethoxy-arenes, which are precious
targets of pharmaceutical research. With respect to this goal,
the application of borate salt-based catalytic methods for the
synthesis of aryl-alkyl ethers developed in our laboratory could
provide solution to the difficulties of the desired cross-
coupling.12
The development of a new cross-coupling approach to 2-
chloroethoxylation offers an alternative disconnection and
provides a new synthetic tool beyond the existing phenol-
based transformations to construct C-O bonds. This can be
useful, when instability issues, tautomerism or economic
reasons make the phenol-type starting material unavailable.
Results and discussion
For the examination of the applicability of the palladium-
catalyzed C-O bond forming reaction between aryl chlorides
and borate reagents, first we prepared a novel tetrakis(2-
chloroethoxy) borate salt from inexpensive starting materials:
2-chloroethanol and NaBH4. The coupling of the borate salt
with p-chloroacetophenone was then examined in tert-amyl
2 | J. Name., 2012, 00, 1-3
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68% and 67% yield after the workup of the reaction mixture. A para-position were straightforwardly chloroethoxylated in the
notable limitation of the transformation occurred when the palladium-catalyzed transformation and then substituted with
methoxy group was para to the chloro function; the piperidine, diethylamine and N-methylmorpholine, affording
conversion of the reaction reached only 10% (not shown), products 4d-g in 71-88% yield. Compound 4h was obtained in
indicating that the electronic factors play a key role in the 73% yield in the two step procedure starting from 4-chloro-8-
transformation.
trifluoromethyl-quinoline, with pyrrolidine being used as the
Scheme 3. Chloroethoxylation of aromatic chlorides
To expand further the substrate scope of the coupling reaction
we examined 2-chloro- and 5-chloroquinolines. These
experiments showed that both the heterocyclic and the
carbocyclic part of the ring could be functionalized in the
palladium catalyzed reaction, and product 3k and 3l were
isolated in 88% and 66% yields. Thienopyridines are important
heterocyclic scaffolds in medicinal chemistry, therefore we
examined the chloroethoxylation of the chloro derivative of
this heterocycle. To our delight this special heterocyclic
building block underwent smooth transformation and the
target product 3m was isolated in 64% yield.
[a]
Scheme 4. One-pot aminoethoxylation of chloroarenes.
recovered starting material
yield is based on
amine
nucleophile
after
the
palladium-catalyzed
chloroethoxylation step. The same strategy was used to
prepare a highly electron-rich benzothiophene substrate,
though a large amount of unreacted starting material was
recovered beside the isolation of compound 4i as the desired
aminoethoxylated product.
After demonstrating of the applicability of the developed
coupling for the synthesis of 2-chloroethoxylated building
To illustrate the applicability of this method, we carried out
the synthesis of an analog and an intermediate of active
pharmaceutical ingredients (Scheme 5) containing condensed
heterocyclic cores such as indoles and benzothiophenes. First,
we prepared the aryl-chloride substrate 5a through the N-
benzylation of indole with 4-chlorobenzyl-bromide,14 for the
key aminoalkoxylation step. Then the palladium-catalyzed
coupling reaction with Na[B(OCH2CH2Cl)4] and subsequent
amination under the developed reaction conditions led to a
70% yield of the desired product 5b, which contains the core
of the selective estrogen receptor modulator (SERM) drug,
blocks, we extended the coupling with
a subsequent
substitution step to prepare aminoethoxy derivatives in a one-
pot manner (Scheme 4). Among the several well-known
methods for this purpose, our choice was to keep it simple,
utilizing the Finkelstein halogen exchange reaction followed by
nucleophilic substitution with secondary amines in the
presence of potassium iodide and potassium carbonate base.
For the examination of the two step one-pot functionalization
method we performed the palladium-catalyzed step on three
different aryl chlorides previously chloroethoxylated. Then
intermediates 3a, 3e and 3g were subjected to nucleophilic
replacement of the chloro group with N-methylpiperazine and
morpholine affording the aminoethoxylated products 4a-c in
44-72% yield. For the further studies we used different aryl
chlorides to expand the substrate scope of both the cross-
coupling step and the one-pot aminoalkoxylation strategy.
Chlorobenzenes bearing formyl, nitro or ester group in the
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General procedure for the 2-chloroethoxylation of
chloroarenes: A 4 ml screw cap vial was charged with Pd2dba3
(4.6 mg, 5,0 µmol, 1 mol%), 2-di-tert-butylphosphino-2′,4′,6′-
triisopropylbiphenyl (tBuXphos, 4.2 mg, 10.0 µmol, 2 mol%),
the aryl chloride substrate (0.5 mmol, 1 equiv) and 100 µl tert-
amyl alcohol. The atmosphere was changed to argon, then the
suspension of sodium tetrakis(2-chloroethoxy) borate in 900 µl
tert-amyl alcohol was added via syringe, and stirring started at
100 °C, usually for one hour. When the reaction was complete,
the mixture was diluted with brine (10 ml) and extracted with
EtOAc (3*15 ml). The combined organic layers were
evaporated and purified by column chromatography.
Scheme 5. Synthesis of Bazedoxifene-analogue and the intermediate of
Raloxifene
General procedure for the one-pot synthesis of 2-
aminoethoxy arenes: A 4 ml screw-cap vial equipped with a
stirring bar was charged with Pd2dba3 (4.6 mg, 5 µmol, 1.0
Bazedoxifene. Another example to illustrate the applicability of
our aminoalkoxylation method was the design of an
alternative synthetic route to Raloxifene intermediate 6c. First,
t
mol%), BuXPhos (4.2 mg, 10 µmol, 2.0 mol%) the substrate if
the Friedel-Crafts acylation of
a commercially available
benzothiophene-derivative (6a) was achieved,15 leading to the
starting material (6b) equipped with chloro function necessary
for the cross-coupling reaction. The 2-chloroethoxylation with
the borate salt under the catalytic conditions and subsequent
substitution step with piperidine afforded the desired
Raloxifene intermediate (6c) in almost quantitative yield.
solid (0.5 mmol, 1 equiv), and tert-amyl alcohol (100 µl). The
atmosphere was changed to argon, and the solution was
stirred at RT for
5
minutes. The suspension of
Na[B(OCH2CH2Cl)4] (263.9 mg, 0.75 mmol, 1.5 equiv) in tert-
amyl alcohol (900 µl), and the substrate (0.5 mmol) if liquid
was added and the mixture was stirred at 100 °C for 1-24
hours. The mixture was allowed to cool down to room
temperature, KI (166 mg, 1 mmol, 2 equiv), K2CO3 (138 mg, 1
mmol, 2 equiv) and secondary amine (eg.: piperidine, 2 ml)
was added to the solution, then stirred at 100 °C for further 4-
24 hours. The mixture was cooled down to room temperature,
diluted with water (10 ml), and extracted with EtOAc (3X15
ml). The combined organic layers were evaporated under
reduced pressure, and purified by column chromatography
(silica gel, DCM:MeOH eluent mixture).
Conclusions
In conclusion, we have developed an alternative, simple and
convenient synthetic route to the access of 2-chloroethoxy-
arenes using palladium-catalyzed cross-coupling reaction of
aryl chlorides and tetraethoxyborates. This methodology is
orthogonal to nucleophilic substitution and enables the
modular synthesis of various molecules containing ethoxy
linkers between nucleophilic centers (eg. amines) and aromatic
cores. The utilization of a novel borate salt ensures efficient
transformation with good functional group tolerance due to
the absence of external base, and eliminates synthetic
difficulties of the traditional alkoxylation with haloalcohols.
This special feature of the transformation provides a new
synthesis concept in the field of C-O bond forming reactions.
With a subsequent simple nucleophilic substitution reaction
step, wide variety of 2-aminoethoxy-arenes can be prepared in
a one-pot manner. Beyond several aminoalkoxylated model
compounds, the applicability of the two step one-pot reaction
was demonstrated with the synthesis of a Bazedoxifene-
analogue and the final intermediate of Raloxifene. Thus,
previously unavailable synthetic routes to bioactive molecules
Conflicts of interest
There are no conflicts to declare”
Acknowledgements
This work was supported by National Research, Development
and Innovation Office (Grant No. KH125230). This project was
also supported by the János Bolyai Research Scholarship of the
Hungarian Academy of Sciences. The authors thank to Prof.
Timothy J. Peelen for proofreading of this manuscript.
can be performed with the application of this method, which Notes and references
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