Palladium-Catalyzed 2,2,2-Trifluoroethoxylation of Aromatic and Heteroaromatic Chlorides Utilizing Borate Salt and the Synthesis of a Trifluoro Analogue of Sildenafil

Article abstract of DOI:10.1002/chem.201704205

A simple and convenient method was developed for the introduction of a 2,2,2-trifluoroethoxy group to various aromatic and heteroaromatic systems. The novel process utilizes aromatic chlorides as substrates, and tetrakis(2,2,2-trifluoroethoxy) borate salt as an inexpensive and readily available fluoroalkoxy source in a palladium-catalyzed cross-coupling reaction. The power of the developed methodology was demonstrated in the synthesis of a fluorous derivative of Sildenafil.

Full text of DOI:10.1002/chem.201704205

A Journal of
Accepted Article
Title: Palladium Catalyzed 2,2,2-Trifluoroethoxylation of Aromatic and
Heteroaromatic Chlorides Utilizing Borate Salt and the Synthesis
of Trifluoro Analog of Sildenafil
Authors: Bálint Pethő, Márton Zwillinger, János Csenki, Anna Káncz,
Balázs Krámos, Judit Müller, György Tibor Balogh, and Zoltán
Novák
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Palladium Catalyzed 2,2,2-Trifluoroethoxylation of Aromatic and
Heteroaromatic Chlorides Utilizing Borate Salt and the Synthesis
of Trifluoro Analog of Sildenafil
Bálint Pethőa, Márton Zwillingera, János T. Csenkia, Anna E. Kánczb, Balázs Krámosc, Judit Müllerb
György T. Baloghb and Zoltán Nováka*
Abstract: A simple and convenient method was developed for the
introduction of 2,2,2-trifluoroethoxy group to various aromatic and
heteroaromatic systems. The novel process utilizes aromatic
chlorides as substrates, and tetrakis(2,2,2-trifluoroethoxy) borate salt
as an inexpensive and readily available fluoroalkoxy source in a
palladium-catalyzed cross coupling reaction. The power of the
developed methodology was demonstrated in the synthesis of a
fluorous derivative of Sildenafil.
strategy explains the increasing interest for direct C-, O- and N-
fluoroalkylation, and fluoroalkoxylation reactions.[7]
To overcome the difficulties of classical ether syntheses,[8]
many efforts have been made recently towards the 2,2,2-
trifluoroethoxylation of aryl-halides by copper-catalyzed
reactions,[9] granting a new approach to trifluoroethyl-aryl ethers.
10
]
Weng and co-workers[
developed a copper-mediated
procedure for the transformation of various (hetero)aryl
bromides to the corresponding trifluoroethyl ether, with good
function group tolerance. However the reaction requires
stoichiometric amounts of a copper-organic reagent and the
addition of strong base. The palladium-catalyzed cross-coupling
reaction between aryl halides and 2,2,2-trifluoroethanol (TFE) in
the presence of Cs2CO3 base were also developed, but in
general electron-deficient, highly activated aryl-halides (mostly
bromides) are the applicable substrates for the coupling.[11]
Nevertheless, the facile trifluoroethoxylation of versatile
(hetero)aryl-chlorides, the most economic, and easily available
group of haloarenes, remains challenging. Therefore, our
objective was to develop an operationally simple, reliable and
scalable catalytic method for the 2,2,2-trifluoroethoxylation of
chloroarenes, without external base, and thus eliminating the
necessity of genotoxic Cs2CO3. The applicability of tetravalent
fluoroalkoxy-borate salts[ 12 ] could offer a solution for this
approach, considering that the palladium catalyzed C-O bond
forming reactions of aryl chlorides is possible with borate
salts.[13]
In the last few decades, the synthesis of organic molecules
having fluoroalkyl groups becomes one of the most intensively
developed fields of the organic chemistry,[1 ] due to the high
interest of chemical industry.[2] Besides the wide application of
trifluoromethylated organic compounds,[3] other small fluoroalkyl
groups such as the 2,2,2-trifluoroethyl, can be found in
numerous drug molecules, and agrochemicals [Scheme 1].
Trifluoroethyl group attached to oxygen atom can have
beneficial effect on the metabolic stability and lipophilicity of
biologically active aryl-alkyl ethers. Furthermore, trifluoroethyl
group can also be considered as a relatively stable protecting
group for alcohols[4].
After the synthesis of Na[B(OCH2CF3)4], its reactivity was
studied using 4’-chloroacetophenone as a substrate. To our
disappointment, the reaction gave only 10 % conversion after 1h
in DMF, dioxane and acetonitrile (Table 1, entries 1-3)
supposedly due to the higher stability of the trifluoroethoxy
borate salts compared to the methoxy analog. We observed that
tetraalkoxy-borates readily undergo ligand exchange reactions in
various alcohols, and the formed mixed borate salts proved to
be more reactive.[14] Taken advantage on the ligand exchange
around the boron center, we supplemented the solvent
optimization study with polar, protic solvents. Although
trifluoroethanol as solvent did not enhance the reaction, to our
great delight, applying water or other alcohols (entries 5-9) led to
full conversion of the aryl chloride. However in case of H2O,
MeOH and IPA, besides the desired product [3a] hydroxyl-,
methoxy and iso-propoxy-acetophenone [5] was also formed in
significant amounts (entries 5-7). We thought that steric effects
might play an important role in the transmetallation step,
therefore we intended to use bulky alcohols such as tert-butanol
(tBuOH) and tert-amylalcohol (tAmOH) to facilitate the coupling
reaction and keep the reaction performing with high selectivity.
As it was expected, in case of sterically congested tertiary
alcohol solvents, the formation of unwanted alkyl-aryl ether was
completely suppressed, and the trifluoroethoxylation occurred
Scheme 1. Examples for bioactive aryl trifluoroethyl ethers
Modification of current pharmaceuticals[ 5 ] with fluorous
functional groups can develop better ADME (Absorption,
Distribution, Metabolism and Excretion) properties,[6] thus this
strategy is frequently used in medicinal chemistry. This applied
a
B. Pethő, M. Zwillinger, J. T. Csenki, Dr. Z. Novák
MTA-ELTE “Lendület” Catalysis and Organic Synthesis Research
Group, Institute of Chemistry, Eötvös University, Faculty of Science,
Pázmány Péter stny. 1/A, H-1117 Budapest (Hungary)
E-mail: novakz@elte.hu
web: http://zng.elte.hu/
A. E. Káncz, J. Müller, Dr. Gy. T. Balogh
b
Compound Profiling Laboratory, and
Dr. B. Krámos, Spectroscopic Research Division
c
Gedeon Richter Plc.,
Gyömrői út 19-21, H-1103 Budapest (Hungary)
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Table 1. Solvent optimization study[a]
Entry
Solvent
Conv.
[%][b]
Yield[%][b]
(3a)
Yield[%][b]
Yield[%][b]
(4)
(5)
1
2
3
4
5
6
7
8
9
DMF
10
11
10
11
10
1>
32
1
-
-
-
dioxane
acetonitrile
CF3CH2OH
H2O
-
10
-
-
1>
-
-
100
100
100
100
100
-
68 [c]
99 [d]
41 [e]
-
MeOH
-
iPrOH
55
100
100
4
-
tBuOH
tAmylOH
-
-
[a] Reaction conditions: 4’-chloroacetophenone (0.1 mmol), Na[B(OCH2CF3)4]
(0.15 mmol; 1.5 eq.), Pd2dba3 (1 mol%), tBuXPhos (2 mol%), Solvent (0.1 ml),
100 °C, 1 h. [b] Determined by GC analysis [c] R = OH [d] R = OMe [e] R =
OiPr
Scheme 2. Preparation of carboaromatic trifluoroethyl-aryl ethers. [a] 1h. [b]
4h. [c] 24h. [d] Pd2dba3 (2 mol%), tBuXPhos (4 mol%) at 120 °C, 4h.
with 100% conversion in 1 hour under the developed
reaction conditions (entries 8 and 9).
the corresponding products [4m] and [4n] were isolated in 26%
and 62% respectively.
With an optimized[15], reliable and reproducible method in
hand, we turned our attention to the substrate scope of the
reaction, first examining various substituted aromatic chlorides
under the optimized reaction conditions [Scheme 2]. The
functional group tolerance, due to the slightly basic and relatively
mild conditions, was found to be excellent, as ketone- [3a],
aldehyde- [3b, 3i], benzyl chloride moiety [3c], ester- [3d, 3f],
cyano- [3e], nitro- [3g], amide- [3k] , alkyne [3l] and protected
alcohol- [3m] remained intact, showing a broad spectrum of
applicability and high efficiency (62-95% yield). Only the very
electron rich N,N-dimethylamino derivative 3j was obtained in
lower, 23% yield even after 24 hours. We also examined the
scalability of the reaction, with the lowest possible catalyst
loading. In case of 4’-chloroacetophenone the reaction was
carried out on 10 mmol (2 g) scale without loss of efficiency, in
the presence of 0.2 mol% Pd2dba3 catalyst and 0.4 mol%
tBuXPhos ligand the product 3a was obtained in 96% yield.
Next, we demonstrated the synthetic applicability of the
transformation with the functionalization of versatile biologically
relevant, heteroaromatic scaffolds [Scheme 3]. Unsubstituted 4-
chloroquinoline [4a] was converted with excellent efficiency
(84%), likewise other substituted quinolines [4b-g] also provided
good yields (69-82% yields), while the relatively moderate result
(50%) of [4e] can be explained partly by steric hindrance.
Quinazoline [4h, 4i] and quinoxaline [4j] derivatives, as well as
substituted pyrazine [4k] were also transformed effectively. Bis-
trifluoroethoxylation of the dichloropyrazine [4l] was also
performed with excellent yield (85%). In addition to the studied
N-heterocycles, the functionalization of other heterocyclic
systems containing nitrogen and sulfur heteroatoms such as
thienopyridine and thienopyrimidine were also carried out, and
Providing a further evidence of the method’s utility, we
elaborated the synthesis of the trifluoroethoxy-analogue of the
blockbuster drug, Sildenafil (Viagra). Our aim was to replace the
ethoxy group of the original compound with the trifluoroethoxy
moiety [Scheme 4].
Scheme 3. 2,2,2-Trifluoroethoxylation of heteroaromatic chlorides. [a] 1h. [b]
4h. [c] 24h. [d] Pd2dba3 (2.7 mol%), tBuXPhos (5.4 mol%), 24h. [e]
Na[B(OCH2CF3)4] (1.5 mmol; 3.0 equiv.), Pd2dba3 (2 mol%), tBuXPhos
(4 mol%), 1h.
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To reach our goal, first, the sulfonation of 2-
chlorobenzaldehyde was carried out, leading to sulfonic acid 5 in
66% yield. This product was transformed to the corresponding
sulfonyl chloride with SOCl2, then the latter was amidated with
the methylpiperazine, to give 2-chloro-5-((4-methylpiperazin-1-
yl)sulfonyl)benzaldehyde 6 in 46% yield. On this aromatic
chloride the developed palladium-catalyzed methodology was
applied using the borate salt to obtain the desired aryl-
trifluoroethyl ether 7 in 73% yield. Following the key coupling,
the aldehyde was transformed by a Pinnick-oxidation to a
carboxylic acid intermediate 8. This compound underwent a
CDI-mediated amidation[ 16 ] to give 9, and a base-catalyzed
cyclization step to give the desired Sildenafil-analog, 10.
Similar to Sildenafil microsomal metabolism, N-demethylated
(piperazine,
M10),
N,N-deethylated
(piperazine,
M9),
hydroxylated (aliphatic, M6) and M9-demethylated derivatives
(piperazine, M8A) of 10 were indentificated as major metabolites
[20]
by similarity to MS-derived m/z and elution time of Sildenafil
.
The results justify the differences between HLM- and RLM-
related intrinsic clearance values of the two related compounds.
Table 2. Physico-chemical and in vitro ADME properties of Sildenafil and 10
Entry
Physico-chemical and in
vitro ADME parameters [a]
Sildenafil-citrate
Sildenafil-CF3 (10)
(in citrate form)
6.65 (6.78)[17]
9.15 (9.12)[17]
3.07 (3.18)[17]
2.99 / 2.69
1
2
3
4
5
6
7
pKa,(piperazine-N)
pKa,(pyrazolo-pyrimidin-NH)
logPOCT/w
logD7.4/6.5
logPDCE/w
ΔlogPOCT-DCE
Pe(cm/s)(PAMPA-GIpH6.5) /
HIAclass
6.43
8.58
3.40
3.34 / 3.13
3.76
-0.36
4.01 (3.75)[17]
-0.94 (-0.57)[17]
9.2*10-6 / high
5.5*10-6 / high
8
logPe (PAMPA-BBB) /
est.logBB
-4.77 / 0.29
7.7 / low
-4.74 / 0.34
14.6 / moderate
9
HLM Clint (mL/min/kg)
in vivo human Clplasma
RLM Clint (mL/min/kg)
in vivo male rat Clplasma
10
11
12
6 (ml/min/kg)[19]
172.9 / high
-
125.6 / high
-
48 (ml/min/kg)[19]
[a] logPOCT/w and logPDCE/w are partition coefficient in octanol-water and
dichloroethane-water systems, respectively. logPOCT-DCE is a difference
between logPOCT/w and logPDCE/w. PAMPA-GIpH6.5 and PAMPA-BBB are
in vitro non-cell permeability study for gastrointestinal (GI)- and blood-brain
barrier (BBB)-specific permeation, respectively. HLM and RLM Clint are
human and rat microsome-derived intrinsic clearances (see in SI)
Scheme 4. Synthesis of a Sildenafil analogue.
In conclusion, we developed an operationally simple
palladium-catalyzed transformation for the trifluoroethoxylation
of aryl- and heteroaryl utilizing novel, bench stable, tetravalent
alkoxy borate salt without the use of external base. The
applicability of the developed procedure was demonstrated with
the synthesis of variously substituted aryl- and heteroaryl-2,2,2-
trifluoroethyl ethers, as well as the total synthesis of a fluorinated
analog of Sildenafil. The physico-chemical properties of 10
showed slight differences with Sildenafil, including a weaker
affinity towards intramolecular H-bond formation. The fluorinated
analog showed enhanced metabolism too, which might not be
disadvantageous, considering the therapeutic field of Sildenafil.
Physicochemical and in vitro ADME characterization of
Sildenafil and 10 were also investigated [Table 2]. In case of
Sildenafil pKa, logP/D values (entries 1-5) were in strong
correlation with previously determined parameters[ 17 ]. In the
comparison study, physicochemical properties showed
significant differences in pKa values of acidic pyrazolo-
pyrimidine-NH function (entry 2) and in logPOCT-DCE values
(entry 6). The lower pKa,pyrazolo-pyrimidine-NH and logPOCT-DCE values
of 10 suggest weaker intramolecular H-bond between the H-
atom of the acidic NH at pyrazolo-pyrimidine and the O-atom of
the –OCH2CF3 group. QM and MM calculations indicate that the
formation of intramolecular NH…OCH2CF3 H-bond is preferred
both in Sildenafil and in 10 analogue. However, in accordance
with the reported experimental physicochemical parameters, this
interaction is slightly weaker in the 10 compound. Proton affinity
calculations also support the increased acidic character of
Acknowledgements
The support of the Hungarian Academy of Sciences (Lendület
LP2012-48/2012) is acknowledged. The research is the part of
NKFIH project No. KH125230. The authors thank Miklós Dékány
at Gedeon Richter Plc. and Ágnes Gömöry at the Hungarian
Academy of Sciences for the HRMS measurements, and Zoltán
Béni at Gedeon Richter Plc. for helpful discussions concerning
the calculations. Generous donation of some heteroaryl
chlorides is also acknowledged to Servier Research Institute for
Medicinal Chemistry.
pyrazolo-pyrimidine-NH moiety in 10 [18]
.
Although, 10 is slightly more lipophilic than Sildenafil, in
the in vitro gastrointestinal- and blood-brain barrier-specific
permeability studies, (entries 7 and 8) the two compounds
showed the same behaviour. Regarding microsome-derived
intrinsic clearance values, 10 showed greater metabolic rate in
human species (entry 9), while there were no significant
difference in the metabolic clearance, in rat species (entry 11).
Based on earlier study[19] for metabolic pathway indentification of
[20]
Sildenafil,
major microsomal dependent metabolic routes of
Keywords: Cross-Coupling • Borates • Heterocycles • Palladium •
Homogeneous Catalysis • Trifluoroethoxylation
10 was also investigated by LC-MS/MS analytical method.
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COMMUNICATION
Bálint Pethő, Márton Zwillinger, János T.
Csenki, Anna E. Káncz, Balázs Krámos,
Judit Müller, György T. Balogh and
Zoltán Novák*
Page No. – Page No.
Palladium Catalyzed 2,2,2-
Trifluoroethoxylation of Aromatic and
Heteroaromatic Chlorides Utilizing
Borate Salt and the Synthesis of
Trifluoro Analog of Sildenafil
A novel palladium catalyzed trifluorethyoxylation of aryl chlorides was developed with the aid of new type of borate based
trifluoroethoxylating reagent. Beyond the functionalization of various aromatic and heteroaromatic systems, the synthesis of the
trifluoro analog of Sidenafil (Viagra) was achieved together with the determination of its physicochemical properties.
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