Triple Mode of Alkylation with Ethyl Bromodifluoroacetate: N, or O-Difluoromethylation, N-Ethylation and S-(ethoxycarbonyl)difluoromethylation

Article abstract of DOI:10.1002/adsc.201800824

In this report, we have explored a triple mode of chemical reactivity of ethyl bromodifluoroacetate. Typically, bromodifluoroacetic acid has been used as a difluorocarbene precursor for difluoromethylation of soft nucleophiles. Here we have disclosed nucleophilicity and base dependent divergent chemical reactivity of ethyl bromodifluoroacetate. It furnishes lithium hydroxide and cesium carbonate promoted difluoromethylation of tosyl-protected aniline and electron-deficient phenols respectively. Interestingly, switching the base from lithium hydroxide to 4-N,N-dimethylamino pyridine (DMAP) tosyl-protected anilines afforded the corresponding N-ethylation product. Whereas, highly nucleophilic thiophenols furnished the corresponding S-carboethoxydifluoromethylation product via a rapid S_N2 attack to the bromine atom prior to the ester hydrolysis. This mechanistic divergence was established through several control experiments. It was revealed that difluoromethylation reaction proceeds through a tandem in situ ester hydrolysis/decarboxylative-debrominative difluorocarbene formation and subsequent trapping by the soft nucleophile-NHTs or electron-deficient phenolic ?OH groups. In the presence of DMAP the hydrolysis of the ester is perturbed instead a nucleophilic attack at the ethyl moiety provides the N-ethylation product. Hence, besides the development of a practical base-promoted N-difluoromethylation of amines and electron-deficient phenols, divergent reactivity pattern of inexpensive and user-friendly ethyl bromodifluoroacetate has been explored. (Figure presented.).

Full text of DOI:10.1002/adsc.201800824

Title: Triple Mode of Alkylation with Ethyl Bromodifluoroacetate:
N, or O-Difluoromethylation, N-Ethylation and S-
(ethoxycarbonyl)difluoromethylation
Authors: Ranjan Jana, Arghya Polley, Gurupada Bairy, and Pritha Das
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800824
Link to VoR: http://dx.doi.org/10.1002/adsc.201800824

10.1002/adsc.201800824
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Triple Mode of Alkylation with Ethyl Bromodifluoroacetate: N,
or O-Difluoromethylation, N-Ethylation and S-
(ethoxycarbonyl)difluoromethylation
Arghya Polley,a,b Gurupada Bairy,a,b Pritha Das,a and Ranjan Janaa,b,*
a
Organic and Medicinal Chemistry Division, CSIR-Indian Institute of Chemical Biology, 4 Raja S. C. Mullick Road,
Jadavpur, Kolkata-700032, West Bengal, India
Phone: (+91) 33 2499 5819; fax: (+91) 33 2473 5197; e-mail: rjana@iicb.res.in
Academy of Scientific and Innovative Research (AcSIR), Kolkata-700032, India
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract: In this report, we have explored a triple mode of chemical reactivity of ethyl bromodifluoroacetate.
Typically, bromodifluoroacetic acid has been used as a difluorocarbene precursor for difluoromethylation of
soft nucleophiles. Here we have disclosed nucleophilicity and base dependent divergent chemical reactivity
of ethyl bromodifluoroacetate. It furnishes lithium hydroxide and cesium carbonate promoted
difluoromethylation of tosyl-protected aniline and electron-deficient phenols respectively. Interestingly,
switching the base from lithium hydroxide to 4-N,N-dimethylamino pyridine (DMAP) tosyl-protected
anilines afforded the corresponding N-ethylation product. Whereas, highly nucleophilic thiophenols furnished
the corresponding S-carboethoxydifluoromethylation product via a rapid SN2 attack to the bromine atom prior
to the ester hydrolysis. This mechanistic divergence was established through several control experiments. It
was revealed that difluoromethylation reaction proceeds through
a
tandem in situ ester
hydrolysis/decarboxylative-debrominative difluorocarbene formation and subsequent trapping by the soft
nucleophile-NHTs or electron-deficient phenolic -OH groups. In the presence of DMAP the hydrolysis of the
ester is perturbed instead a nucleophilic attack at the ethyl moiety provides the N-ethylation product. Hence,
besides the development of a practical base-promoted N-difluoromethylation of amines and electron-deficient
phenols, divergent reactivity pattern of inexpensive and user-friendly ethyl bromodifluoroacetate has been
explored.
Keywords: base-promoted; ethyl bromodifluoroacetate; difluoromethylation; N-ethylation; S-
(ethoxycarbonyl)difluoromethylation.
trifluoromethylation,
the
indroduction
of
Introduction
difluoromethyl group into the organic moiety has
been less attended. Whereas, the difluoromethyl
group is isosteric and isopolar to the hydroxy (OH)
and thiol (SH) groups that acts as more lipophilic
hydrogen donor than -OH and -SH groups improving
membrane-permeability.[8] Hence, difluoromethyl
moiety is ubiquitously found in numerous
biologically active compounds (Figure 1).
Owing to their improved pharmacokinetic profiles
such as absorption, distribution, metabolism, and
excretion (ADME), fluorinated scaffolds are
ubiquitously found in pharmaceuticals, agrochemicals,
advanced biomaterials etc.[1] In clinics, radioactive
(18F) and non-radioactive (19F) fluorinated motifs are
used for positron emission tomography (PET) and
magnetic resonance imaging (MRI) respectively as
non-invasive
diagnostic
tools.[2-6]
Therefore,
development of efficient and practical methods for
fluorination and fluoroalkylation are a sustained
exertion in synthetic synthesis.[7] Compared to
1
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10.1002/adsc.201800824
Advanced Synthesis & Catalysis
Scheme 1. Divergent chemical reactivity of ethyl
bromodifluoroacetate.
Figure 1. Difluoromethyl moiety in medicinal scaffolds.
Results and Discussion
For N-difluoromethylation, simple aniline,
acetanilide, N-Boc, N-Piv-, N-pym, N-methyl
protected anilines were proved to be unsuccessful
substrates. Since difluoromethylation of phenol is
reported,[10,12,21] we hypothesized that the pKa of N-
tosyl anilines (TsNH) will be similar to phenolic-OH
(~16 Bordwell pKa table). Thus we chose N-
tosylaniline as a model substrate for optimization
studies. Gratifyingly, KOH in combination with 18-
Typically, difluoromethylation of nucleophilic
substrate is accomplished with highly reactive
difluorocarbene which is generated from HCF2Cl,[9]
HCF3,[10] CHF2I,[11] PhSO2CF2X,[12] ArCOCF2Cl,[13]
ClCF2CO2Na,[14]
FSO2CF2CO2H,[15]
BrCF2P(O)(OEt)2,[16] TMSCF2Br,[17] HCF2OTf,[18]
PhS(O)(NTs)CF2H,[19] FSO2CF2CO2TMS[20] etc.
However, use of ozone-depleting gaseous reagents,
hygroscopic acid salts, expensive and commercially
unavailable reagents and harsh reaction conditions
crown-6
in
DMF
afforded
product
the
desired
ethyl
difluoromethylation
with
constrain
their
application.
Therefore,
an
difluorobromoacetate in 40% yield (Table 1, entry 1).
No improvement was observed at elevated reaction
temperature upto 80 oC. Next, we attempted
difluromethylation merging photoredox catalysts
such as Rose bengal in combination with bases such
as K2CO3 and tBuOLi (Table 1, entries 2-3). However,
no noticeable effect of photoredox catalyst was
observed under the irradiation with 23 W white CFL
lamp (Table 1, entries 3-4). Subsequently, we decided
to screen bases and solvents to improve the yield.
Gratifyingly, the yield of the desired product was
increased to 75% with 2.0 equiv of Cs2CO3 in DMF
(Table 1, entry 6). Among several solvents tested
polar, aprotic, Lewis basic solvents such as N,N-
dimethylformamide (DMF), N,N-dimethylacetamide
(DMA) were found to be superior than
dimethylsulfoxide (DMSO) and acetonitrile for this
transformation (Table 1, entries 7-9). Finally, we
were able to replace expensive and moisture sensitive
Cs2CO3 for this tandem reaction by inexpensive
LiOH to afford N-difluoromethylation product in
82% yield (Table 1, entry 11). Other
difluoromethylating reagents such as ClCF2CO2Et,
ClCF2CO2Na, ClCF2P(O)(OEt)2, FSO2CF2CO2TMS
and ClCF2CO2H. (Table 1, entries 12-16) were
proved to be inferior under this reaction conditions.
operationally simple difluoromethylation with
environmentally benign reagent is highly desirable.
Although difluoromethylation of oxygen and sulfur
nucleophiles
are
well-studied[21]
but
difluoromethylation of nitrogen nucleophiles are less
explored.[22] Hence, we report, a tandem lithium
hydroxide-promoted difluoromethylation of tosyl-
protected anilines and electron-deficient phenols
using
inexpensive
and
user-friendly
ethyl
bromodifluoroacetate. Interestingly, we have
explored a hitherto unknown 4-N,N-dimethylamino
pyridine (DMAP) promoted N-ethylation of the same
substrate
using
ethyl
bromodifluoroacetate.
Furthermore, S- (ethoxycarbonyl)difluoromethylation
product via SN2 attack to the bromine atom was also
observed from the corresponding thiophenols which
provides
a
useful
intermediate
for
S-
trifluoromethylation and others by manipulating the
ester functionality. Thus, three different alkylation
products have been achieved from a single reagent
through three distinct mechanistic pathways.
2
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10.1002/adsc.201800824
Advanced Synthesis & Catalysis
Table 1. Optimization of the reaction condition for
difluoromethylation.[a,b]
Entry Difluoro
methylating
Base
Solvent Yield
(X equiv)
(%)b
reagents (2)
BrCF2CO2Et
BrCF2CO2Et
BrCF2CO2Et
BrCF2CO2Et
BrCF2CO2Et
BrCF2CO2Et
BrCF2CO2Et
BrCF2CO2Et
BrCF2CO2Et
BrCF2CO2Et
BrCF2CO2Et
ClCF2CO2Et
ClCF2CO2Na
3
1c
2d
3d
4
KOH (2)
DMF
40
55
60
57
40
75
K2CO3 (2) DMF
tBuOLi(2) DMF
tBuOLi(2) DMF
Cs2CO3(1) DMF
Cs2CO3(2) DMF
5
6
7
Cs2CO3(2) DMSO trace
Cs2CO3(2) DMA 67
Cs2CO3(2) MeCN 30
8
9
10
11
12
13
14
15
16
LiOH (2) DMF
LiOH (4) DMF
LiOH (4) DMF
43
82
28
26
32
ND
19
LiOH(4)
DMF
ClCF2P(O)(OEt)2 LiOH (4) DMF
FSO2CF2CO2TMS LiOH (4) DMF
ClCF2CO2H
LiOH (4) DMF
[a]All reactions were carried out in 0.1 mmol scale, 1a (1.0
equiv) and difluoromethylating reagents (2.0 equiv).
[b]Yields refer to here are overall isolated yields.
[c]18-crown-6 used 2.0 equiv.
[d]Rose Bengal (5 mol %) and white 23 W CFL lamp was
used.
A wide variety of N-tosyl-protected aniline
derivatives underwent difluoromethylation smoothly
under this mild reaction conditions furnishing high to
excellent yields. Several electron-withdrawing groups
such as NO2, CN, CF3, CHO, COMe, CO2Et (3b, 3h,
3f, 3l, 3q, 3n) as well as electron-donating groups
such as OMe, dioxymethylene and OTs (3c, 3x, 3m)
were compatible under the reaction conditions.
Halogens such as fluoro (3d), bromo (3j), iodo (3e,
3p) at the para or ortho positions remain intact for
further manipulations through cross-coupling.
However, ortho substituted anilines (3o, 3p, 3q)
provided good to moderate yields presumably due to
steric reason. To our delight, benzyl amines (3u, 3v,
Scheme 2), 2-amino pyridine (3y), 4-amino
morpholine (3z) also provided moderate yields of the
[a]8 equiv of base used.
[b]2 equiv Cs2CO3 used as base.
Scheme 2. Substrate scope for difluoromethylation.
promoted isomerization of the double bond to the
thermodynamically stable trans product (3ab)
through an ortho aza-quinone methide intermediate
(for crystallographic data, CCDC 1831075; see the
SI).[23] Besides para toluenesulphonamide, other
sulphonamide derivatives also provided the
corresponding difluoromethylation products in high
yields (3ae, 3af). However, ortho or para nosyl did
not afford any desired difluoromethylation product.
Gratifyingly, electron-deficient phenols and enols
also underwent difluoromethylation efficiently using
cesium carbonate in place of lithium hydroxide (3ah-
3al) as lower yield was obtained with lithium
hydroxide. However, electron-rich phenols provided
corresponding
Benzimidazole
difluoromethylation
difluoromethylation
products.
(3aa)
also
underwent
smoothly.
this
As
reaction
hypothesized, the difluoromethylation takes place
chemoselectively at tosyl-protected N-center where
acetyl protected aniline moiety remain intact (3ac,
Scheme 2; for crystallographic data, CCDC 1831072;
see the Supporting Information). Interestingly, the
stereochemistry of an ortho cis-stilbenyl substrate
(3ad) remained intact which did not undergo base-
3
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10.1002/adsc.201800824
Advanced Synthesis & Catalysis
the corresponding formates (-OCHO) under this
condition, which was formed exclusively with lithium
hydroxide (for details; see the SI). Presumably, the
difluoromethylation product undergoes further basic
hydrolysis to provide the corresponding formate. A
control study without ethyl bromodifluoroacetate did
not furnish the corresponding formate product, which
obviates the possibility of formate formation from
N,N-dimethylformamide (DMF) solvent.[24]
To demonstrate the practical utility, we have
synthesized pantoprazole, a proton pump inhibitor
blockbuster drug using this protocol. The nitro groups
of difluoromethylated 3,4-dinitrophenol (3aj) were
reduced with Pd/C under hydrogen and taken forward
to the cyclisation step without purification. Thioether
formation followed by oxidation lead to the
pantoprazole (Scheme 3).
[a]4 equiv of base and reagent used.
[b]2 equiv dodecyl chlorodifluoroacetate used.
Scheme 4. Substrate scope of N-Ethylation.
Reaction conditions: a) 10 mol % Pd/C, H2 balloon, MeOH,
rt, 12 h; b) CS2, Na2CO3, H2O, 25-70 C, 12 h, 76%; c)
o
NaOH, H2O MeOH, rt,12 h, 94%; d) Na2WO4.2H2O,
NaOH, H2O2, rt, 0.5 h, 90%.
screening with bases, we observed that 2.0 equiv of
DMAP provided the corresponding N-ethylation
product in high yield. Next we explored the substrate
scope for N-ethylation and found that a series of
tosyl-protected aniline provided the desired product
in excellent yields. Several para- (4a-4d) and meta-
substituted (4e-4g) tosyl-protected anilines provided
the desired N-ethylation products in excellent yields.
Contrary to the difluoromethylation, ortho-substituted
substrates (4k, 4l) furnished the N-ethylation products
in almost quantitative yields. Gratifyingly,
heteroaromatic substrates (4i, 4j), benzylamine (4q)
also furnished the desired product albeit in moderate
yields. To examine the reactivity further, dodecyl
chlorodifluoroacetate was subjected to the reaction
conditions furnishing the corresponding N-dodecyl
product (4o) in high yields. However, sterically
hindered benzyl and secondary alkyl esters were
unsuccessful substrates to provide the desired
alkylation product.
Scheme 3. Synthesis of pantoprazole.
Interestingly, during optimization we observed a
mixture of N-difluoromethylation and N-ethylation
product was obtained with 2 equiv of 1,8-
diazabicyclo[5.4.0]undec-7-ene (BDU). From the
literature, the Nagashima group reported an inter and
intramolecular N-alkylation of tosylamides by ester
under ruthenium-catalysis.[25] Thus we were interested
to explore this unusual chemical reactivity of N-
ethylation under metal-free conditions. Further
Next, we were curious to explore the reactivity of
highly nucleophilic thiols towards this alkylation
reaction. In contrary to the previous reports for
difluoromethylation,
a
(ethoxycarbonyl)difluoromethylation of thiophenol
via a simple nucleophilic substitution (SN2) of the
bromine atom took place with 4.0 equiv of lithium
4
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10.1002/adsc.201800824
Advanced Synthesis & Catalysis
Scheme 6. Control experiments.
hydroxide. However, better yields were obtained
using 2.0 equiv of cesium carbonate. This result was
further extended to several aromatic, heteroaromatic
and benzylic thiols. This product could be further
diversified for S-trifluoromethylation[26] and other
synthetic manipulation of the ester group.
corresponding carboxylic acid was observed
indicating that ester hydrolysis and decarboxylation
steps occur prior to the amination reaction. When the
reaction was performed in the presence of 10 equiv of
D2O, 84% deuterium incorporation was observed.
However, when d-3h was subjected under the
reaction conditions with 20 equiv of water, no
deuterium exchange was observed indicating that a
concerted decarboxylative protonation may take
place. To investigate the origin of proton source,
deuterated d1-1h was prepared and subjected to the
reaction condition. However, no deuterium
incorporation into the product was observed.
For the N-alkylation, when an equimolar mixture
of DMAP and ethyl bromodifluoroacetate was heated
o
at 70 C in the absence of tosylamide, a quaternary
ammonium salt 10 was isolated exclusively. Electron
spray ionisation (ESI) mass analysis of a reaction
mixture, which was stirred at room temperature
indicates the formation quaternary ammonium salt of
non-hydrolized product, mono N-demethylation
followed by alkylation products etc. (for details, see
the SI). It suggests that DMAP may generate an
activated adduct by replacing bromide ion which
undergoes N-alkylation from the ethoxy carbon end.
Furthermore, although difluoromethylation of
electron-deficient phenol with Cs2CO3 was successful
but electron-rich phenol 8 furnished nucleophilic
substitution product at the bromine end Scheme 6f.
Which is further supported
Scheme 5. Substrate scope of SN2 substitution with
thiophenol.
To elucidate this divergent mechanism, we
performed several control experiments. When a
preformed nucleophilic substitution product 7 was
subjected
to
the
reaction
condition,
no
When
27]
decarboxylative protonation took place.[26a,
the reaction was arrested after two hours, a mixture of
starting material and product was obtained. However,
neither SN2 attack product nor
Scheme 7. Plausible mechanism.
by the fact that highly nucleophilic thiols provided
only SN2 addition product (Scheme 5) which did not
undergo ester hydrolysis or decarboxylation even
after prolonged stirring. From control experiments,
we speculate that the present N- or O-
difluoromethylation reaction proceeds through
tandem
base-promoted
ester
hydrolysis/decarboxylative difluorocarbene formation
and subsequent nucleophilic addition of the
5
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10.1002/adsc.201800824
Advanced Synthesis & Catalysis
room temperature for 16 h. After the reaction is completed
as indicated by TLC the reaction mixture was diluted with
EtOAc (15 mL) and washed with water (50 mL), followed
by brine (25 mL). The organic extract was dried over
MgSO4, filtered and evaporated under reduced pressure.
The crude mixture was purified by a silica gel column
chromatography using (pet ether/EtOAc) to furnish
corresponding diflurinated sulfonamide, 3a (49 mg, 82%
yield).
tosylamide as depicted in Scheme 7. However,
reaction with strong nucleophiles such as electron-
rich phenols and thiophenols promote nucleophilic
substitution of the bromine atom. Whereas, in case of
4-N,N-dimethylaminopyridine
(DMAP),
ester
hydrolysis and carbene formation is sluggish.
Alternatively, it may generate a better leaving
pyridinium bromide intermediate which undergo SN2
attack at the alkoxycarbon of the ethyl group.
Furthermore, highly nucleophilic thiols undergo a
rapid SN2 displacement of the bromine atom before
hydrolysis of the ester takes place.
General procedure for the N-ethylation of sulfonamide,
2a (Scheme 4):
In an oven dried 10 mL round bottom flask containing a
stir bar was added DMAP (49 mg, 2 equiv) and
sulfonamide (58 mg, 1 equiv). Dry DMF (0.1 M) was then
added followed by ethyl bromodifluoroacetate (52 µL, 2
equiv). then round bottom flask was closed and the mixture
was stirring at 70 oC for 12 h. After the reaction is
completed as indicated by TLC the reaction mixture was
diluted with EtOAc (15 mL) and washed with water (50
mL), followed by brine (25 mL). The organic extract was
dried over MgSO4, filtered and evaporated under reduced
pressure. The crude mixture was purified by a silica gel
column chromatography using (pet ether/EtOAc) to furnish
corresponding ethylated sulfonamide, 4a (51 mg, 80%
yield).
Conclusion
In conclusion, we have disclosed here, a base and
nucleophile dependent divergent chemoselectivity of
commercially available, inexpensive, air and moisture
stable ethyl bromodifluoroacetate. A single reagent
has been applied for the N-, O-difluoromethylation
via tandem ester hydrolysis/decarboxylative-
debrominative difluorocarbene formation followed by
trapping with NH, or OH moiety. In contrast, N-
ethylation is promoted by the N,N-dimethylamino-
pyridine which prefers SN2 attack to the bromine
atom to generate an activated adduct followed by a
nucleophilic addition to the ethyl carbon adjacent to
the carboxy group. In case of highly nucleophilic
thiols nucleophilic substitution of the bromide atom
takes place prior to the ester hydrolysis. Thus, ethyl
bromodifluoroacetate is used as a mechanistic switch
to incur divergent chemical synthesis.
General
procedure
for
the
(ethoxycarbonyl)difluoromethylation of thiol 5a
(Scheme 5): A mixture of thiol, 5a (31 mg, 1 equiv), ethyl
bromodifluoroacetate (52 µL, 2 equiv) was dissolved in
dry DMF (0.1 M) in an oven dried 10 mL round bottom
flask containing a stir bar. Cesium carbonate (130 mg, 2
equiv), was added to the reaction mixture and stirred at
room temperature for 16 h. After the reaction is completed
as indicated by TLC the reaction mixture was diluted with
EtOAc (15 mL) and washed with water (50 mL), followed
by brine (25 mL). The organic extract was dried over
MgSO4, filtered and evaporated under reduced pressure.
The crude mixture was purified by a silica gel column
chromatography using (pet ether/EtOAc) to furnish
corresponding ethoxycarbonyl)difluoromethylation thiol,
6a (50 mg, 90% yield).
Experimental Section
General Information
All commercial reagents were used without additional
purification. Solvents were dried using standard methods
and distilled before use. TLC was performed on silica gel
plates (silica gel 60, f254), and the spots were visualized
with UV light (254 and 365 nm) or by charring the plate
dipped in KMnO4 stain. 1H NMR was recorded at 300, 400
and 600 MHz frequency and 13C NMR spectra were
recorded at 75 MHz, 100 MHz and 150 MHz respectively
in CDCl3, or DMSO using tetramethylsilane (TMS) as the
internal standard. Chemical shifts were measured in parts
per million (ppm) referenced to 0.0 ppm for TMS. HRMS
(m/z) were measured using ESI techniques (Q-Tof positive
ion). Crystals were grown in chloroform and crystal data
was recorded in (Bruker Kappa Apex-2, CCD area
detector) instrument.[28]
Acknowledgements
This work was supported by DST, SERB, Govt. of India for the
Ramanujan fellowship; award no. SR/S2/RJN-97/2012 and extra
mural research grant no. EMR/2014/000469. AP, PD thanks
CSIR and GB thanks UGC for their fellowships.
References
[1] T. Hiyama, Organofluorine Compounds: Chemistry
and Applications; Springer: Berlin, 2000.
[2] I. Ojima, Fluorine in Medicinal Chemistry and
Chemical Biology; Wiley-Blackwell: Chichester, U.K.,
2009.
Representative
general
procedure
for
the
difluoromethylation of sulfonamide, 2a (Scheme 2): A
mixture of sulfonamide, 2a (50 mg, 1 equiv), ethyl
bromodifluoroacetate (52 µL, 2 equiv) was dissolved in
dry DMF (0.1 M) in an oven dried 10 mL round bottom
flask containing a stir bar. Lithium hydroxide (19 mg, 4
equiv), was added to the reaction mixture and stirred at
[3] P. Kirsch, Modern Fluoroorganic Chemistry; Wiley-
VCH: Weinheim, Germany, 2013.
6
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10.1002/adsc.201800824
Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
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8
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10.1002/adsc.201800824
Advanced Synthesis & Catalysis
FULL PAPER
Triple Mode of Alkylation with Ethyl
Bromodifluoroacetate: N, or O-
Difluoromethylation, N-Ethylation and S-
(ethoxycarbonyl)difluoromethylation
Adv. Synth. Catal. Year, Volume, Page – Page
Arghya Polley, Gurupada Bairy, Pritha Das, and
Ranjan Jana*
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