Silver-Promoted Fluorination Reactions of α-Bromoamides

Article abstract of DOI:10.1002/chem.202004769

Silver-promoted C?F bond formation in α-bromoamides by using AgF under mild conditions is reported. This simple method enables access to tertiary, secondary, and primary alkyl fluorides involving biomolecular scaffolds. This transformation is applicable to primary and secondary amides and shows broad functional-group tolerance. Kinetics experiments revealed that the reaction rate increased in the order of 3°>2°>1° α-carbon atom. In addition, it was found that the acidic amide proton plays an important role in accelerating the reaction. Mechanistic studies suggested generation of an aziridinone intermediate that undergoes subsequent nucleophilic addition to form the C?F bond with stereospecificity (i.e., retention of configuration). The synthesis of sterically hindered alcohols and ethers by using Ag^I is also demonstrated. Examples of reactions of α-bromoamides with O nucleophiles are presented.

Full text of DOI:10.1002/chem.202004769

Accepted Article
Accepted Article
Title: Silver-Promoted Fluorination Reactions of α-Bromoamides
Authors: Satoshi Mizuta, Kanami Kitamura, Ayako Kitagawa, Tomoko
Yamaguchi, and Takeshi Ishikawa
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10.1002/chem.202004769
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Silver-Promoted Fluorination Reactions of α-Bromoamides
Satoshi Mizuta,*[a] Kanami Kitamura,[a] Ayako Kitagawa,[a] Tomoko Yamaguchi,[a] and Takeshi
Ishikawa[b]
Dedication ((optional))
[a]
[b]
Dr, S. Mizuta, K. Kitamura, A. Kitagawa, T. Yamaguchi
Gaduate School of Biomedical Sciences, Nagasaki University 1-14 Bunkyo, Nagasaki, 852-8521, Japan
E-mail: s-mizuta@nagasaki-u.ac.jp
Prof. Dr. T. Ishikawa
Department of Chemistry, Biotechnology, and Chemical Engineering, Graduate School of Science and Engineering, Kagoshima University
1-21-40 Korimoto, Kagoshima 890-0065, Japan
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: We report silver-promoted C–F bond formation in α-
bromoamides by using Ag–F under mild conditions. This simple
method enables access to tertiary, secondary, and primary alkyl
fluorides involving biomolecular scaffolds. This transformation is
available to primary and secondary amides and revealed a broad
functional group tolerance. Kinetic experiments exhibited that the
reaction rate increased in the order of 3°>2°>1°α-carbon. In addition,
we found that the acidic amide proton has an important role to
accelerate the reaction. Mechanistic studies suggested that the
generation of an aziridinone intermediate that undergoes
subsequent nucleophilic addition to form the C–F bond with the
stereospecificity
(i.e. retention of configuration). We also
demonstrated the synthesis of sterically hindered alcohols and
ethers by using Ag(I). Examples of reacting of α-bromoamides with
O-nucleophiles were presented.
Introduction
The development of mild methods for late-stage fluorination
access to complex molecules has been in great demand in
medicinal and biological chemistry.1 In particular, sterically
hindered organofluorine compounds are attractive structural
motifs as agrochemicals, pharmaceuticals, and 18F-labeled radio
tracers for positron emission tomography imaging.2, 3 For tertiary
alkyl C(sp3)−F bond formation, strategies involving a radical
process using electrophilic fluorine sources were developed in
the early stages.4 For example, Boger and Hiroya accomplished
the radical hydrofluorination of alkenes by using electrophilic
fluorinating reagents.5 Li and co-workers developed silver-
catalyzed radical fluorination of aklylboronates by using 1-
chl or omet hyl - 4-fl uor o- 1, 4- di azoni abicycl ooct ane
bis(tetrafluoroborate) (Selectfluor).6 Additionally, approaches for
the deoxyfluorination of alcohols have been explored extensively
using reagents, such as DAST, Deoxo-Fluor, PhenoFluor,
PyFluor and those related to sulfonyl fluorides.7 Recently,
Watson et al. reported N,N’-diisopropylcarbodiimide-derived
deoxfluorination using CuF2 as the fluorine source.8 Meanwhile,
C−H fluorination, hydrofluorination, and decarboxylative
fluorination using nucleophilic fluorine sources have been
achieved by chemical, photochemical, and electrochemical
approaches.9 Some examples of nucleophilic fluorination to
carbocation intermediates generated by electrochemical
oxidation from carboxylic acids have been reported by Baran.10
Figure 1. Nucleophilic substitution reactions with fluoride.
In 2020, Doyle and co-workers developed a method for
nucleophilic (radio) fluorination of N-hydroxyphthalmide esters
via the carbocation generation using a photoredox system.11
Nishikata et al. disclosed tertiary alkyl–fluorine bond formation of
α-bromoamides using CsF via a radical mechanism under
copper catalysis.12 Despite these advances, a synthetically
simple method for the nucleophilic substitution reactions of the
sterically hindered alkyl halide or tosylate using fluorides is
rare.13 The classical methods are not generally amenable to
tertiary alkyl–F bond formation, which still remains challenging
(Figure 1A). This is because the approach suffers from several
drawbacks: (1) the poor nucleophilicity of the fluoride ion, (2)
competition between substitution and elimination pathways
when using a Brønsted base, and (3) limited scope of substrates
due to the SN2 pathway.14 To overcome these intrinsic
drawbacks, we focused on generation of electrophilic o-
azaxylylene intermediates derived from 3-bromo-oxindoles with
nucleophilic fluoride transfer to form sp3 C–F bonds (Figure
1B).13h However, this method did not apply to linear α-
bromoamides. In this paper, we disclose silver-promoted
nucleophilic fluorination reactions of α-bromoamides under mild
conditions, providing access to primary, secondary and tertiary
1
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fluorides in high yields (Figure 1C). This approach revealed a
broad functional group tolelance, chemoselectivity and
stereospecificity. We also examined the C–F and C–O bond
formation by using AgOTf with nucleophiles.
evaluate the carbonyl group compatibility, we investigated the
initial scope of the reaction with α-bromobutyryl-carbonyl ester
and tertiary amides. The desired fluorinated products (4−6) were
not obtained.These results revealed that the NH group of the
primary and secondary amide plays an important role in the
transformation using AgF. Thus, we then focused on the
Results and Discussion
Table 2. Scope of Substrates [a]
α-Bromoisobutyrylamide have been used as a substrate for the
α-functionalization to lead sterically hindered compounds via
copper catalysis.16 We began by studying the fluorination
reaction of α-bromoisobutyrylamide 1 as a model substrate by
using a variety of fluorine sources (Table 1). The fluorination of
substrate 1 did not proceed when using 2.0 equivalent of KF,
CsF, tetrabutylammonium fluoride (TBAF), or CuF2 in MeCN at
room temperature for 12 h (Table 1, entries 1−4). In contrast,
AgF as a fluorine source successfully promoted the nucleophilic
fluorination of 1 without a base, providing the desired fluorinated
product 2a in quantitative yield within 2 h, regardless of the
heterogeneous reaction (Table 1, entry 5). This transformation
did not require air or moisture exclusion. Next, we examined the
solvent effect for the fluorination reactions with AgF. Extensive
experiments in solvents, such as DMSO, THF, dichloromethane,
MeOH, and toluene, gave low to moderate yields of 2a (Table 1,
entries 6–10). Interestingly, MeOH was allowed to be employed
as an O-nucleophile to give the corresponding ether 2b in a 48%
isolated yield with 38% of the fluorinated product, 2a (Table 1,
entry 9). This solvolytic reaction in MeOH proceeded by
generation of
a silver-promoted carbocation intermediate,
followed by the subsequent α-methoxy substitution.
Table 1. Optimization of Nucleophilic Fluorination of 1
Entry
Fluorine Source
Solvent
19F NMR yield (%)[a]
1
KF
CsF
TBAF
CuF2
AgF
AgF
AgF
AgF
AgF
AgF
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
THF
0
2
4
3
3
0
4
5[b]
6
99 (97)[c]
22
7
13
8
CH2Cl2
MeOH
toluene
32
9
38
10
49
[a] Fluorobenzene was used as an internal standard to determine the yield . [b]
The reaction was completed within 2h. [c] Isolated yield. [d] The side-product
2b was isolated in a 48% yield.
[a] Reactions run on a 0.1−0.2-mmol scale. For each compound, the isolated
yield is given. [b] One-pot process: the fluorination reaction with AgF and the
subsequent desilylation with the TBAF run.
Using standard conditions, we then studied the scope of the
substrates, as illustrated in Table 2. The reaction of primary
amide substrate, 2-bromo-2-methylpropanamide, with AgF in
MeCN produced the corresponding product 3 in 64% yield. To
2
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methodology is more accessible to secondary and tertiary alkyl
fluorides because the reaction rate increased in the order of
3°>2°>1°α-carbon (2a>12a>7, 18>14>11 See, supporting
information Figure S3). Among them, a significant difference in
the reaction rate was observed between 2-bromo-N-
phenylamide and N-benzyl-2-bromoamide (2a vs 18, 12a vs 14,
7 vs 11). The reaction of substrate 39 bearing both 2-
bromopropaneamide and 2-bromopropaneester with three
equivalents of AgF underwent mono-fluorination at the α-carbon
of amide with good yield of product 40 and with chemoselectivity
(Scheme 1). In order to study the susceptibility of the acidic
amide proton to this fluorination reaction, the reaction rate
constants for conversion of 2-bromo-N-(para-substituted
phenyl)propanamides and N-benzyl-2-bromopropanamide were
determined by 1H NMR analysis (See, supporting information
Figure S4). As shown in Figure 3, a linear of Hammett plot with a
positive slope (ρ = +0.28) was obtained, which suggests that the
acidity of amide proton facilitates the fluorine substitution of α-
bromoamides.
fluorination of α-bromo carbonyl compounds based on
secondary amides. The α-bromoacetamides provided the α-
fluorinated amides in moderate to good yields (Table 2, 7−10). A
variety of functional groups, such as nitro, ketone, and silyl ether,
were well tolerated. The N-benzyl amide substrate was less
reactive compared with the N-aniline derivatives such as 2-
bromo-N-phenylacetamide; the reaction time required was 60 h
to give 11 in a 42% yield. A broad variety of sterically hindered
fluorinated products were obtained in high to excellent yields
(Table 2, 12a−32). These conditions showed abundant
functional group tolerance to yield the α-fluorinated primary and
secondary amides with electron-donating or electron-
withdrawing group(s) substituted at the phenyl ring and benzyl,
furfuryl, phenethyl, and tert-butoxycarbonyl(Boc) groups
(12a−24). The α-bromoisobutyryl amide bearing a quinoline ring
could also be fluorinated to give 25 in a 86% yield. α-
Dialkylbromides displayed good reactivity to deliver the sterically
hindered fluorides, 26−32, in high yields. We previously reported
ionic liquid-mediated hydrofluorination of o-azaxylylenes derived
from 3-bromo-oxindoles.13h In this study, the 3-bromo oxindole
derivative was treated with AgF; then, the corresponding product
(33) was isolated in a 28% yield.
Figure 3. Hammett plot for fluorine substitution reactions of para-substituted
aniline derived α-bromoamide.
Figure 2. Synthesis of fluorine-containing compounds (34—38)
To expand the reaction scope, we focused on enabling access
to fluorinated biomolecules: amino acid derivatives (34, 35),
peptides (36), and glycosides (37). Additionally, we achieved the
synthesis of α-fluorinated flutamide (38) according to our
procedure (Fig. 2).17
Scheme 1. Chemoselective reaction of 39 using AgF.
We hypothesized that the acidic amide proton accelerates the
Ag-promoted fluorination of α-bromoamides. For instance, the
fluorination reaction of α-bromobutyryl-carbonyl ester and
tertiary amides without an acidic proton did not proceed at all.
According to the kinetic experiments, we found that the
Scheme 2. Control Experiments
3
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We further investigated the control experiments. In the fluorine
substitution reactions, possible mechanistic pathways, a radical,
a SN1 and SN2-like pathway, were envisioned. To verify the
reaction process, α-bromoamide 1 was subjected to fluorination
standard conditions in the presence of TEMPO (2,2,6,6-
tetramethyl-1-piperidinyloxy) as a radical capture. The reaction
did not result in the TEMO adduct but resulted in the fluorinated
product in quantitative yield (Scheme 2A). Next, the silver-
mediated fluorination conditions using the AgOTf/alkalifluoride
combination were performed instead of using AgF.18 When using
CsF as a fluorine source, product 2a was obtained in a 98%
yield, and a 38% yield of 2a was obtained by using KF (Scheme
1B). A reaction of dehalogenation of 1a using AgOTf was
conducted as shown in Scheme 1C. The silver salt promoted the
dehalogenation reaction of α-bromoamide 1a, producing the
eliminated product. These results supported the presence of
cationic intermediates. Taken together, the nucleophilic
fluorination reaction of α-bromoamide with AgF or Ag(I) and
fluorides can proceed by generation of a cationic intermediate,
which is more favorable than the radical pathway.
Scheme 4. Proposed mechanism of silver-promoted fluorination with in situ-
generated aziridinone and keteniminium oxide intermediates
Houk et al. reported the detailed computational results that
support a preferential nucleophile attack on the O-protonated
aziridinone intermediate compared to on the N-protonated
intermediate.21 Thus, there may be an equilibrium between the
N-protonated intermediate A and an O-protonated intermediate
B through a proton transfer. Although it is not clear which N- or
O-protonated aziridinone intermediate causes the fluorination
event with the second inversion of configuration, the
stereospecificity in this transformation suggests the attribute of
being the double inversion process through the aziridinone
intermediates. Alternatively, a keteniminium oxide intermediate
C is also predicted because it could occur that a tautamerized
ketoxime is conjugated to C-3 when activating C−Br bond by
silver. To elucidate the mechanism, the detailed mechanistic
studies are underway.
To elucidate the reaction pathway, a stereospecificity in the
transformation of optically active α-bromoamide (S)-12S into the
fluorinated product 12a was examined (Scheme 3). The
retention substituted fluorination proceeded in the presence of
AgF, providing the corresponding product (S)-12a. The
configuration was acertained by the specific optical rotation of
(S)-12a derived from (S)-alanine.19 When reaction systems of
AgOTf and CsF instead of AgF was used, the stereospecificity
(i.e. retention of configuration) was identically observed.
Whereas a chiral diastereomer (R,R)-41 reacted with the
stereospecificity according to the standard conditions, which
gave the optically active compound (R,R)-42. The configulation
was determined by 1H NMR analysis due to the difference of
chemical shift of the fluoride (R,S)-42 derived from (S)-alanine.
As a result, we found that the configuration of products remained
the same as that of starting materials throughout the fluorination
reactions.
Scheme 3. Studies of the stereochemistry using (S)-12S and (R,R)-41
The stereoselective behaviour is consistent with results
described previously by D'Angeli and Quast that implicate the
double inversion process through an aziridinone intermediate.20
Our experimental studies revealed a significant of the amide NH
of α-bromoamides because α-bromobutyryl-carbonyl ester and
tertiary amides were unsuccessful. These results also endorsed
that the mechanism of silver-promoted fluorination of α-
bromoamides proceeds through the aziridinone intermediate,
followed by the subsequent fluorine attack (Scheme 4). Silver
Scheme 5. Formation of hindered alcohols and ethers with O-nucleophiles
At last, methods for the synthesis of hindered alcohols and
ethers remain a big challenge.22 Having demonstrated the
reaction systems with Ag(I) and nucleophiles, we sought to
develop α-functionalization of a-bromoamide, which enabled us
to access sterically hindered compounds (Scheme 5). We
investigated the substitution reactions with polar nucleophiles,
salts initiate the C–Br cleavage to form
a N-protonated
aziridinone intermediate A with the first inversion of configuration.
4
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such as O-nucleophiles. The solvolysis of 1 with MeOH in the
presence of AgOTf occurred, producing the methyl ether product
2b in a 79% yield. Using KOAc as a nucleophile led to the
corresponding product 2c in a 72% yield. Some silver reagents,
such as AgCN, AgSCF3, and AgSCN, did not act as
nucleophiles under standard conditions, resulting in recovery of
the starting materials. When Ag2O was available, the alcohol
product 2d was obtained in a 61% yield. In addition, the
hydroxylation of optically active α-bromoamide (S)-12S with
Ag2O proceeded with the high stereoretention of alcohol product
(S)-12b. Finally, introduction of the trifluoromethoxy group
(OCF3) was conducted with trifluoromethyl arylsulfonate (TFMS)
as a useful trifluoromethoxylating reagent under slightly modified
conditions, thus providing the hindered OCF3 ether 43 in a 42%
yield.23 The robust and ease of this process was demonstrated
by the formation of hindered ethers and alcohols with O-
nucleophiles.
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Conclusion
In summary, we developed a novel and concise method for Ag-
promoted fluorine substitution of α-bromoamides using AgF
under mild conditions. This approach readily provided a variety
of fluorinated compounds with broad functional group tolerance,
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and
stereospecificity.
Stereochemical
experiments using the chiral α-bromoamides were proposed with
the in situ-generated aziridione intermediate and with the double
inversion processs. We also presented the synthesis of sterically
hindered alcohols and ethers involving the OCF3 group. We
anticipate that this methodology will provide useful fluorine-
containing building blocks for the benefit of medicine and
agricultural chemicals.
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A 15 mL test tube quipped with a magnetic stirring bar was
charged with α-bromoamide (0.1 mmol), AgF (2 equiv), and
MeCN (0.1 M). The resulting mixture was stirred at room
temperature for 12 h. For the precipitate removal, the mixture
was filtered through a Celite pad and washed with AcOEt. The
solvent was removed in vacuo, the crude was purified by column
chromatography on SiO2 gel to give the fluorinated products.
Acknowledgements ((optional))
This research was supported partially by the Platform Project for
Supporting Drug Discovery and Life Science Research (Basis
for Supporting Innovative Drug Discovery and Life Science
Research) from AMED under Grant Number JP19am0101088
(to S.M.). This study was supported financially by Grants-in-Aid
for Scientific Research (No. 20H04285 to S.M. and T. I.) from
Japan Society for Promotion of Science. The authors would like
to thank Enago (www.enago-jp) for the English language review.
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Keywords: fluorination • silver • α-bromoamide • aziridinone • α-
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