A scalable and regioselective synthesis of 2-difluoromethyl pyridines from commodity chemicals

Article abstract of DOI:10.1021/ol500402e

A scalable de novo synthesis of difluoromethyl pyridines from inexpensive materials is reported. The pyridyl subunit is built around the difluoromethyl group rather than a late stage introduction of this moiety. This user-friendly approach allows access to a diverse range of substitution patterns on all positions on the ring system and on the difluoromethyl group.

Full text of DOI:10.1021/ol500402e

Letter
pubs.acs.org/OrgLett
A Scalable and Regioselective Synthesis of 2‑Difluoromethyl
Pyridines from Commodity Chemicals
Jean-Nicolas Desrosiers,* Christopher B. Kelly,† Daniel R. Fandrick, Larry Nummy, Scot J. Campbell,
Xudong Wei, Max Sarvestani, Heewon Lee, Alexander Sienkiewicz, Sanjit Sanyal, Xingzhong Zeng,
Nelu Grinberg, Shengli Ma, Jinhua J. Song, and Chris H. Senanayake
Department of Chemical Development US, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Old Ridgebury Road, P.O. Box 368,
Ridgefield, Connecticut 06877, United States
S
* Supporting Information
ABSTRACT: A scalable de novo synthesis of difluoromethyl pyridines from
inexpensive materials is reported. The pyridyl subunit is built around the
difluoromethyl group rather than a late stage introduction of this moiety. This user-
friendly approach allows access to a diverse range of substitution patterns on all
positions on the ring system and on the difluoromethyl group.
approach are known including: deoxofluorination of pyridyl
aldehydes with dialkylaminosulfur trifluorides (DAST, Deoxo-
fluor)9 or SF4,10 Cu-mediated difluoromethylation of pyridyl
iodides using Bu3SnCF2H,11 direct radical difluoromethylation
utilizing Zn(SO2CF2H)2,12 and Cu-mediated coupling of
activated difluoroacetate derivatives followed by a hydrolysis/
decarboxylation sequence.13 Methods to introduce higher order
difluoroalkyl groups (−CF2R) are far sparser. This trans-
formation can be accomplished by treatment of a pyridyl
ncorporation of the difluoromethyl group (−CF2H) into
Iorganic molecules is highly attractive because of its unique
chemical and physical properties. The CF2H motif acts as a
hydrogen bond donor with enhanced lipophilicity and can also
serve as a bioisostere for thiol or hydroxyl groups while
possessing improved metabolic stability.1,2 Similarly, the
difluoroalkyl (−CF2R) subunit can be employed as a surrogate
for ether linkages.1 Insertion of the difluoromethyl moiety into
pyridines is of particular interest to both agroscience and
medicinal chemistry.3 By modulating pyridines with this
functionality at the 2-position, optimal herbicidal activity was
obtained leading to the discovery of the widely commercialized
Thiazopyr4 (Visor) and Dithiopyr5 (Dimension) agricultural
products. By capitalizing on their attributes, 2-difluoromethyl
pyridines (2-DFMPs) were also found to be potential inhibitors
of prostaglandin synthases6 and thrombin.7
10
ketone with DAST14/SF4 or using difluoroalkylsulfinate salts
and unactivated pyridines.15
Of the known approaches for 2-DFMP preparation,
deoxofluorination via the use of dialkylaminosulfur trifluorides
is most commonly utilized. However, these trifluorides can be
thermally unstable and generate corrosive HF when in contact
with moisture, and extensive purification is required to separate
the byproduct from the desired pyridine.16 Seeking an
alternative approach to difluoromethyl and other difluoroalkyl
pyridine preparation, we envisioned that construction of the
pyridyl scaffold around the difluoromethyl group might offer us
a selective, scalable, and cost-effective methodology (Figure 1).
Moreover, it might enable us to start from one of the least
expensive difluoromethyl building blocks, difluoroacetic acid
(DFA). The latter is synthesized from either tetrafluoro- or
tetrachloro-ethylene, which are both produced on a millions of
metric ton scale per year.17
The current routes for 2-DFMP synthesis rely on the
difluoromethylation8 of an existing functionalized pyridyl
system (Figure 1). Several innovative strategies utilizing this
Received: February 7, 2014
Published: March 6, 2014
Figure 1. Comparison of strategies to access CF2H pyridines.
© 2014 American Chemical Society
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Letter
We therefore attempted a de novo 2-DFMP synthesis using a
Bohlmann−Rahtz-like approach.18 From a bond disconnection
standpoint, the desired pyridine can be built by a dehydro-
annulation of intermediate 3 with an ammonia equivalent
(Figure 2). Retrosynthetically, this intermediate can be broken
Table 1. Synthesis of Sodium Enolates via α-Carbonylation
Figure 2. Attempts to exploit established routes to construct 2-DFMPs
and novel enolate-based approach.
a
down into the butenone 1 and nucleophile 2. Finally, to access
very practical and inexpensive starting materials, the butenone 1
is prepared from DFA derivatives and vinyl ethers.
Yield determined by NMR weight percent analysis using triethanol-
amine as a standard.
The synthesis of CF3 pyridines through a condensation of
aminocrotonates/aminoacrylonitriles and trifluorobutenones
has been reported.19 Inspired by this strategy, the synthesis
of 2-DFMPs was attempted by condensing dimethylamino
acrylates onto ethoxy-difluorobutenone (Figure 2, X = NMe2).
It was soon realized that the established methodologies are not
applicable to the synthesis of 2-DFMPs. Competitive formation
of 5 lead to an unacceptably low yield of 2-DFMPs.20 To avoid
concomitant amine transfer and gain better control over the
regiochemical outcome of the cyclization, construction of the
pyridine using the more nucleophilic sodium enolate (Figure 2,
X = ONa) was explored. Such sodium formyl enolates have
been used for more than 30 years21 for the synthesis of
heterocycles such as pyrimidines, but analogous pyridine
syntheses have not been reported.22
storage with 1 wt % BHT at 0 °C greatly improved shelf life
(see Supporting Information for stability studies).
With the requisite materials in hand, a brief solubility screen
of our sodium enolates revealed DMSO to have the best
solubilizing power for these species. Using DMSO as a reaction
medium, treatment of 1a with 2a gave complete conversion to
the desired intermediate enolate 3a after 1 h at rt. When the
same reaction was conducted in MeCN, precipitation and
isolation of 3a were possible, permitting us to characterize it.
To complete the pyridine synthesis, addition of an appropriate
ammonium salt was required. A range of salts were screened
(see Supporting Information for details), and ultimately
HCO2NH4 was selected as the optimal ammonium species.
Using this nitrogen source, 4a was prepared in 91% yield in a
two-step one-pot method (Table 2, entry 1). The reaction
could be scaled up significantly to a 3.31 mol scale to give 0.6
kg of 4a while still maintaining the high yield and purity
observed on smaller scales.
With the optimal conditions established, the remaining
enolates were screened under similar conditions to probe the
scope of the new protocol. It was found that a range of 2-
DFMPs could be constructed via this route (Table 2). Enolates
derived from esters (entries 1,2), sulfones (entries 3,4), amides
(entries 4,5), and ketones (entries 7−9) fare equally well, giving
good yields of their corresponding pyridines. The amide 4f
(entry 6) is of particular interest as morpholine-based amides
can be used as Weinreb amide surrogates with enhanced
thermal stability.26
We next explored whether difluoroalkyl pyridines could be
obtained by using commercially available difluoroalkyl acids
(Table 3). For this series, 2a was used as the enolate coupling
partner. Because of the inherent instability and in some cases
volatility of requisite butenones required, the decision was
made to use a crude solution, rather than trying to isolate these
materials. A range of difluoroalkyl pyridines were successfully
prepared using this strategy (Table 3). Alkyl groups (entries 1−
3) were well-tolerated under the reaction conditions as was a
representative olefinic moiety (entry 4). Both an aryl group
(entry 5) and a perfluoropropyl group (entry 6) were equally
successful for the alkyl systems. Substitution with additional
halogens (F, Cl) enabled us to prepare −CF3 and −CF2Cl
Despite the encouraging promise of a scalable and
economical route, several challenges remained: (1) preparation
of the sodium enolates; (2) establishing optimal conditions for
the initial condensation reaction; (3) determining the optimal
ammonium source for the final pyridine formation.
To address the first challenge, we initially attempted to
prepare model enolate 2a by treatment of EtOAc with ethyl
formate.23 In our hands, this route gave inconsistent results, low
yields, and significant CO evolution throughout the reaction.
An alternative Claisen condensation was then attempted,
drawing on work done by American Cyanamid in 1946.24
Treatment of EtOAc in the presence of NaOEt under 20 atm of
CO in MTBE afforded, after simple filtration, highly pure 2a as
a solid. Using this modified protocol, a range of sodium formyl
enolates were prepared in high purity and in modest to
excellent yield (Table 1). This not only provided a repertoire of
solid reagents on hand for pyridine construction but also
greatly improved the scope of the reported methodologies.
While these enolates are stable to both oxygen and moisture,
they are somewhat deliquescent and are recommended to be
stored in a sealed container to minimize water absorption.
The other component to our putative cyclization reaction is
the butenone 1. The model butenone, 1a, can easily be
prepared from difluoroacetic anhydride or difluoroacetyl
chloride and ethyl vinyl ether in excellent yield and purity.25
1a is not stable for extended periods of time if stored neat, but
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Letter
a
Table 2. Scope of 2-DFMP Synthesis from 1a and Enolates
Table 4. Scope of 2-DFMP Synthesis from Enolates and
a
Substituted 4-Ethoxy-1,1-difluorobut-3-en-2-ones
a
Reaction conditions unless otherwise noted: (i) Enolate (1.2 equiv),
butenone (1 equiv), DMSO, 1 h at rt. (ii) HCO2NH4 (2 equiv), 80
a
Intermediate formation: Enolate (1.2 equiv), butenone (1 equiv),
DMSO, 1 h, rt. Pyridine formation: HCO2NH4 (2 equiv), 80 °C, 16 h.
b
c
°C, 16 h. Isolated yields. Intermediate formation required heating to
b
c
Isolated yields. Parentheses indicate yield on 3.31 mol scale.
50 °C for 16 h.
Table 3. Scope of CF2R Pyridines Synthesis from 2a and
a b
,
Various 4-Ethoxy-1,1-difluoroalkylbut-3-en-2-ones
a phenyl group was installed on the butenone (entry 2, 1k)
which led to the corresponding pyridine 4s in good yield (entry
2). Enolates 2j and 2k could be used successfully to synthesize
pyridines functionalized at position 6 (entries 3, 4). Next, a
displaceable β-alkoxy substituent was tethered to butenone 1l
which furnished pyridine 4v in 48% yield (entry 5).
In summary, we have disclosed a general, scalable method-
ology for the de novo construction of 2-DFMPs in good to
excellent yields starting from commodity chemicals. Using this
approach, modifications can be made to the pyridine ring or to
the difluoromethyl group itself by selection of the appropriate
enolate or butenone precursor. This method was extended to
the synthesis of difluoroalkyl pyridines, a target whose
preparation is nontrivial. Finally, the robustness of this new
protocol was established on the multimole scale.
a
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures, characterization data, and spectra of
the compounds. This material is available free of charge via the
Internet at http://pubs.acs.org
Butenone 1 formation: (i) Carboxylic acid (1 equiv), SOCl2 (1 equiv),
CH2Cl2, 0 °C to rt, 1.5 h. (ii) Pyridine (2.1 equiv), ethyl vinyl ether
■
S
b
(1.25 equiv), CH2Cl2, 0 °C to rt, 12 h. Pyridine formation: (i) Enolate
(1.2 equiv), butenone (1 equiv), DMSO, 1 h at rt. (ii) HCO2NH4 (2
equiv), 80 °C, 16 h. Isolated yields.
c
pyridines, respectably, in excellent yield (entries 7−8). 4p could
be further functionalized using known radical methods, to
access higher order difluoroalkyl pyridines.27
Looking to further diversify the methodology, an approach
was sought to access different substitution patterns on the
pyridine ring (Table 4). To accomplish this, the structure of
our butenone 1 was first varied. Initially the reactivity of
commercially available butenone 1j was explored. Using 1j, a
3,5-diester pyridine was successfully prepared in 53% yield
(Table 4, entry 1). To introduce a substituent at the 4-position,
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: nick.desrosiers@boehringer-ingelheim.com.
Present Address
†Department of Chemistry, University of Connecticut, 55
North Eagleville Road, Storrs, Connecticut, 06269-3060, USA.
Notes
The authors declare no competing financial interest.
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Letter
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