Palladium catalyzed hydrodefluorination of fluoro-(hetero)arenes

Article abstract of DOI:10.1021/acs.orglett.9b00889

Palladium catalyzed hydrodefluorination was developed for fine-tuning the properties of fluoro-(hetero)aromatic compounds. The robust reaction can be set up in air, requires only commercially available components, and tolerates a variety of heterocycles and functionalities relevant to drug discovery. Given the prevalence of fluorine incorporation around metabolic hotspots, the corresponding deuterodefluorination reaction may prove useful for converting fluorinated libraries to deuterated analogues to suppress the oxidative metabolism by kinetic isotope effects.

Full text of DOI:10.1021/acs.orglett.9b00889

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Palladium Catalyzed Hydrodefluorination of Fluoro-(hetero)arenes
Joseph J. Gair, Ronald L. Grey,* Simon Giroux, and Michael A. Brodney
Vertex Pharmaceuticals Inc, 50 Northern Avenue, Boston, Massachusetts 02210, United States
S
* Supporting Information
ABSTRACT: Palladium catalyzed hydrodefluorination was developed for
fine-tuning the properties of fluoro-(hetero)aromatic compounds. The
robust reaction can be set up in air, requires only commercially available
components, and tolerates a variety of heterocycles and functionalities
relevant to drug discovery. Given the prevalence of fluorine incorporation
around metabolic hotspots, the corresponding deuterodefluorination
reaction may prove useful for converting fluorinated libraries to deuterated
analogues to suppress the oxidative metabolism by kinetic isotope effects.
ine tuning the physiochemical and metabolic properties of
drug candidates by exchange of a hydrogen for a fluorine
chemists. Consider, for example, the hypothetical lead
optimization campaign in Figure 1B; wherein, a fluorine
atom was incorporated early in the campaign to improve
metabolic stability at the expense of target binding affinity. On
a more advanced scaffold (2), however, the vestigial fluorine
may provide marginal metabolic benefit at the expense of
affinity or solubility. To assess how fluorine impacts key
metabolic and physiochemical properties, medicinal chemists
typically prepare des-fluoro analogues (e.g., 3) via lengthy
resynthesis. A direct method for late stage hydrodefluorination
(HDF) of lead compounds would significantly accelerate this
process. Additionally, given the complementary relationship
between fluorination and deuteration as strategies for
stabilizing metabolic soft spots (inductive/blocking effects vs
kinetic isotope effects),11,15−20 a method for converting
fluorine to deuterium would enable medicinal chemists to
leverage routine fluorine scanning6,21−23 libraries to prepare
deuterated analogs (Figure 1B, 3).
F
substituent is an indispensable strategy in drug discovery.1−10
Owing to its small size and high electronegativity, fluorine
incorporation is a routine solution for improving the metabolic
stability of lead compounds while introducing minimal steric
perturbation.11−13 Beyond metabolic considerations, however,
the effect of fluorine substitution on key physiochemical
properties is often difficult to predict.1 In the development of
dipeptidyl peptidase-4 inhibitors, for example, incorporation of
fluorine at the 4 position of 1b (1b → 1c) gave a 1.5-fold
boost in potency and the optimal fluorination pattern in the
diabetes drug Sitagliptin (Figure 1A).5,14 In contrast,
The field of HDF reaction development has experienced
rapid growth.24−27 Despite these advances, HDF methodology
is not currently a routine tool in medicinal chemistry. Much of
the ground-breaking work in HDF methodology was
established with activated poly/per-fluorinated28−48 substrates
or by gas chromatographic analysis49−63 of reactions with
volatile substrates not conducive to product isolation. In cases
where isolated yields have been provided for HDF of
monofluoro-(hetero)arenes, the reported methods possess
features that might hinder their uptake in medicinal chemistry,
for example, use of custom synthesized catalysts,59 custom
electrochemical setup,60 harsh/sensitive reductants,56 or
stoichiometric transition metals.64 This work aims to harness
the known reactivity of transition metal catalysts toward HDF
to develop practical conditions for achieving high yielding
defluorination of (hetero)aromatic compounds encountered in
drug discovery.
Figure 1. (A) Importance of fluorine substitution in the discovery of
Sitagliptin. (B) Hydrodefluorination as a tool for streamlining
synthesis of desfluoro analogues.
fluorination at the 3 position (1b → 1a) resulted in a 30-
fold drop in potency and illustrates the potential for
superfluous fluorine substituents to undermine physiochemical
properties.
Given the significant impact of H/F substitution in drug
discovery, a method for removing fluorine substituents in
advanced compounds would be a valuable tool for medicinal
Received: March 12, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00889
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Alkaline solutions of isopropanol have been a mainstay in
HDF methodology for systems employing both heteroge-
neous49,51,57 and homogeneous59 palladium sources. From the
outset, we sought to develop a method that did not require
solvent quantities of alcohol because such conditions would
likely lead to nucleophilic aromatic substitution with electron-
deficient substrates and preclude selective deuterium labeling
because of competing H/D exchange under similar con-
ditions.57 Reaction development was therefore initiated using
20 volume percent alcohol solutions in toluene (Table 1).
The reaction gave comparable conversions when sodium tert-
pentoxide, sodium tert-butoxide, and sodium hydride were
employed as the base, but lithium and potassium salts gave
reduced reactivity (SI Table 4). Sodium tert-pentoxide
(NaOtAmyl) was used in the general reaction conditions
rather than sodium tert-butoxide because of its higher solubility
and commercial availability as a toluene stock solution.
Given our reservations about possible complications from
large excesses of alcohol, we were gratified to observe that
excellent isolated yields could be obtained using as little as 3
equiv of either isobutanol or isopropanol (Table 1, entries 14
and 15). Although substrate 4a was conveniently defluorinated
with either primary or secondary alcohols, it should be noted
that optimal alcohol identity and alcohol loading is substrate
dependent. Indazole 5, for example, was defluorinated much
more efficiently with isobutanol than with isopropanol and
suffered severe rate suppression in the presence of increasing
alcohol concentration (Figure 2B and C).
Table 1. Influence of Precatalyst and Alcohol on HDF
entry
Pd loading/source
alcohol
conversion
a
b
1
2% Pd black
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
nPrOH
nBuOH
iBuOH
iPrOH
BnOH
tBuOH
tAmylOH
49%
46%
56%
59%
80%
97%
96%
a
b
2
2% XPhosPdG1
2% BrettPhosPdG1
2% BrettPhosPdG3
2% RuPhosPdG4
4% RuPhosPdG4
4% RuPhosPdG4
4% RuPhosPdG4
4% RuPhosPdG4
4% RuPhosPdG4
4% RuPhosPdG4
4% RuPhosPdG4
4% RuPhosPdG4
3% RuPhosPdG4
3% RuPhosPdG4
a
b
3
a
b
4
a
b
5
c
b
6
c
b
7
c
b
8
96%
c
b
9
98%
c
b
10
97%
c
b
11
12
46%
0%
c
b
c
b
13
0%
a
d
e
14
iBuOH
iPrOH
93%
a
d
e
15
91%
Figure 2. (A) Reaction conditions for evaluating influence of alcohol
identity on efficiency of HDF with indazole 5. Reaction progress
versus time profiles for reactions conducted with varying loadings of
(B) isobutanol and (C) isopropanol.
a
b
24 h. Conversion determined by peak areas of starting material and
c
d
product separated by UHPLC (280 nm). 18 h. 3 equiv of alcohol.
e
Isolated yield.
Both homogeneous and heterogeneous palladium sources
were competent for HDF of substrate 4a (Table 1). It is
plausible that homogeneous precatalysts decompose to
heterogeneous active catalysts under the reaction conditions.
The reaction mixture starts as a pale-yellow solution and
gradually darkens (∼8 h) until the reaction is no longer visibly
transparent, consistent with formation of palladium particles.
RuPhos palladacycle generation 4 (RuPhosPdG4) was
employed in the general reaction conditions because it
afforded higher overall conversion (relative to both palladium
black and other homogeneous precatalysts) and could be
conveniently dispensed as a stock solution for rapid small scale
reaction optimization (Table 1, entries 1−5 and SI Table 1).
After establishing the utility of RuPhosPdG4 as an improved
precatalyst for HDF, the reaction was evaluated for
compatibility with various reductants, solvents, and bases.
Excellent conversions were observed with several primary and
secondary alcohols as terminal reductants (Table 1, entries 6−
11). Tertiary alcohols, on the other hand, gave no conversion
to defluorinated products (Table 1, entries 12−13). Excellent
conversions were observed for reactions conducted in toluene,
cyclopentylmethyl ether, 2-methyltetrahydrofuran, isopropa-
nol, and tert-pentanol (SI Table 3). No conversion was
observed for reactions conducted in hexafluoro-isopropanol.
In contrast to 5, benzoic acid 6 showed minimal dependence
on isobutanol loading, but achieved significant rate enhance-
ments with increasing concentrations of isopropanol (SI Figure
11). While the mechanistic underpinnings of these differences
are beyond the scope of this work, the practical conclusion for
application of this methodology is that 3 equiv of isobutanol
are a suitable (if not always optimal) starting point for a variety
of substrates. Reaction efficiency can then be enhanced by
optimizing alcohol identity and loading for individual fluoro-
(hetero)arenes. We thus set out to evaluate the scope of HDF
using these general conditions with the expectation that the
improved precatalyst and reduced alcohol loading would
enable useful reactivity with an unprecedented range of fluoro-
(hetero)arenes.
The general reaction conditions afforded useful to excellent
yields of HDF on a diverse panel of fluoro-(hetero)aromatic
scaffolds encountered in drug discovery (Figure 3). Hydro-
defluorination was compatible with ortho, meta, and para
fluoro-arenes (4, 7, and 8) as well as with crowded substrates
bearing substituents at both carbons proximal to fluorine (5).
The conditions are suitable for HDF of substrates bearing
acidic and phenolic OH groups (6, 18, 26, 28) as well as NH
moieties in amides (7 and 9), pyrazole (4), indazoles (5 and
12), imidazoles (15 and 16), azaindole (19), and secondary
B
DOI: 10.1021/acs.orglett.9b00889
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 3. (A) General reaction conditions for HDF. (B) Substrate scope and isolated yields of HDF reactions using the general conditions except
c
where noted otherwise (a 10 mol % Pd, b 3 mol % Pd, 60 °C).
amines (23 and 27). The reaction is compatible with a variety
of potentially coordinating heterocycles (in addition to those
listed above) including tertiary anilines (8), benzimidazoles
(10 and 11), benzotriazoles (17), (iso)quinolines (20, 21, 26),
and pyridines (23−25). Given the scarcity of published HDF
reactivity on heterocyclic scaffolds relevant to medicinal
chemistry,53,62 the reported procedure constitutes a significant
advance in HDF methodology as a tool for drug discovery.
A notable limitation of using primary alcohols as terminal
reductants is that aniline containing substrates (29 and 30)
undergo efficient defluorination and unintended N-alkylation,
likely via aldehyde byproducts from primary alcohol oxidation
(Figure 3B and SI Figure 51−52). Although alcohol β-hydride
elimination appears to serve as the terminal reductant for
catalyst turnover, deuterium labeling experiments demonstrate
that alcoholic β-hydrogens are not the primary direct source of
hydrogen incorporated into the defluorinated product. For
example, defluorination conducted in the absence of β-
deuterides (neat CH3CH2OD) gave 70% deuterodefluorina-
reaction was conducted in neat isopropanol (Figure 5 and SI
Figure 43). However, when defluorination of 22b was
conducted with 3 equiv of isobutanol, the desired HDF
product was obtained in 72% isolated yield.
Figure 5. Reduced alcohol loading expands scope to substrates
susceptible to nucleophilic aromatic substitution.
After demonstrating the improved scope of this method, we
sought to leverage low alcohol conditions toward site specific
deuterium labeling of metabolic hotspots while minimizing
background H/D exchange. Modest deuterium labeling (70%)
was achieved using only 3 equiv of isopropanol-d8 (Figure 6).
1
tion as determined by H NMR (Figure 4).
Importantly, this work provides an alternative to the widely
reported49,51,57,59 use of neat isopropanol in HDF method-
ology and thereby enables HDF of electron-deficient hetero-
cycles that are susceptible to nucleophilic aromatic sub-
stitution. Substrate 22b, for example, afforded the nucleophilic
aromatic substitution product in 86% isolated yield when the
Figure 6. Demonstration of deuterodefluorination.
While this level of isotopic enrichment is not sufficient for
large-scale production of deuterated therapeutics, it is relevant
to preparation of deuterated analogues for applications in drug
discovery including characterization of metabolite regiochem-
istry by HRMS65,66 and parsing metabolic mechanisms67 by
competitive kinetic isotope effects. The method gave 91%
Figure 4. Deuterium labeling experiments to identify sources of H/D
in HDF/DDF.
C
DOI: 10.1021/acs.orglett.9b00889
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00889.
(16) Russak, E. M.; Bednarczyk, E. M. Impact of Deuterium
Substitution on the Pharmacokinetics of Pharmaceuticals. Ann.
Pharmacother. 2019, 53, 211−6.
(17) DeWitt, S. H.; Maryanoff, B. E. Deuterated Drug Molecules:
Focus on FDA-Approved Deutetrabenazine. Biochemistry 2018, 57,
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Experimental details and NMR spectra (PDF)
AUTHOR INFORMATION
■
(18) Tung, R. D. Deuterium Medicinal Chemistry Comes of Age.
Future Med. Chem. 2016, 8, 491−494.
Corresponding Author
*E-mail: Ron_Grey@vrtx.com.
ORCID
(19) Timmins, G. S. Deuterated Drugs: Where Are We Now? Expert
Opin. Ther. Pat. 2014, 24, 1067−1075.
(20) Gant, T. G. Using Deuterium in Drug Discovery: Leaving the
Label in the Drug. J. Med. Chem. 2014, 57, 3595−3611.
(21) Olsen, J. A.; Banner, D. W.; Seiler, P.; Obst Sander, U.; D’Arcy,
Ronald L. Grey: 0000-0001-8948-5056
Simon Giroux: 0000-0003-1499-2576
Notes
A.; Stihle, M.; Muller, K.; Diederich, F. A Fluorine Scan of Thrombin
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Inhibitors to Map the Fluorophilicity/Fluorophobicity of an Enzyme
Active Site: Evidence for C−F···C−O Interactions. Angew. Chem., Int.
Ed. 2003, 42, 2507−2511.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
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We thank Barry Davis and Duncan Locke at Vertex
Pharmaceuticals for high resolution mass spectrometry
acquisition and analysis. We thank Frank Holland and Gregory
May at Vertex Pharmaceuticals for assistance with challenging
chromatographic separations.
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