Synthesis of Fluorinated Amide Derivatives via a Radical N-Perfluoroalkylation-Defluorination Pathway

Article abstract of DOI:10.1021/acs.orglett.0c00768

A one-pot approach to fluorinated hydroxamic acid, amide, and thioamide derivatives is reported. The reaction proceeds via an N-perfluoroalkylation of nitrosoarenes with perfluoroalkanesulfinates, resulting in labile N-perfluoroalkylated hydroxylamines. By the addition of suitable additives, a controllable oxy/thiodefluorination of the fluorinated hydroxylamine intermediates was achieved. The method highlights N-perfluoroalkylated amines as versatile intermediates for further synthesis.

Full text of DOI:10.1021/acs.orglett.0c00768

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Letter
Synthesis of Fluorinated Amide Derivatives via a Radical
N‑Perfluoroalkylation−Defluorination Pathway
Zhiyao Zheng,† Angela van der Werf,† Marie Deliaval, and Nicklas Selander*
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ABSTRACT: A one-pot approach to fluorinated hydroxamic acid,
amide, and thioamide derivatives is reported. The reaction
proceeds via an N-perfluoroalkylation of nitrosoarenes with
perfluoroalkanesulfinates, resulting in labile N-perfluoroalkylated
hydroxylamines. By the addition of suitable additives, a controllable
oxy/thiodefluorination of the fluorinated hydroxylamine inter-
mediates was achieved. The method highlights N-perfluoroalky-
lated amines as versatile intermediates for further synthesis.
Scheme 1. Defluorination of Fluorinated Amines
he incorporation of fluorine into organic compounds has
become increasingly important for pharmaceutical and
T
agrochemical sciences as the presence of a fluorinated moiety
can drastically change physical, chemical, and biological
properties.1 Thus, a large number of methods for the direct
introduction of perfluoroalkyl groups (most commonly CF3
groups), onto C-, O-, and S-atoms2 via electrophilic,3
nucleophilic,4 and radical5 pathways have been reported. The
corresponding N-perfluoroalkylation is, however, less inves-
tigated.6 One reason is the poor stability of perfluoroalkylated
amines, as they are prone to fluoride elimination, assisted by
the nitrogen lone pair,7 resulting in highly electrophilic
fluoroiminium species. Although the high reactivity of these
intermediates is challenging to control, the synthesis and direct
utilization of perfluoroalkyl amino compounds is an attractive
method for the diversification of fluorinated compounds.
Since the seminal work of Yarovenko,8 Ishikawa,9 and
Petrov10 on the in situ preparation of fluorinated ethylamine
and its use as a fluorination agent for the conversion of
alcohols into alkyl fluorides, the direct functionalization of
perfluoroalkyl amines has received limited attention. Recently,
Leroux reported an elegant method for the activation of
fluorinated ethylamines via fluoride abstraction by a Lewis acid
(e.g., BF3·OEt2) to afford relatively stable iminium salts.7c The
nucleophilic addition of electron-rich arenes or heteroarenes
enabled the synthesis of various aryl or heteroaryl fluoromethyl
ketones (Scheme 1a).11 Furthermore, trapping with electron-
rich olefins or C−H acidic compounds, followed by cyclization
with hydrazine or hydroxylamine, provided access to a wide
range of fluorinated pyrazoles and isoxazoles.11,12
Despite the above-mentioned progress, novel reactivity
discoveries of perfluoroalkyl amines are still rare, and the
direct transformation of these intermediates incorporating a
Received: February 28, 2020
A recent report by Baidya and co-workers disclosed an N-
selective nitroso aldol reaction between gem-difluoroenolates
and nitrosoarenes. The difluoroalkyl intermediate underwent
an intramolecular nucleophilic substitution, followed by a
rearrangement via C−F and N−O bond cleavage to furnish α-
ketoamides (Scheme 1b).13
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© XXXX American Chemical Society
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controllable defluorination process is desirable. Recently, we
developed a radical N-trifluoromethylation of nitrosoarenes6b
with sodium triflinate to obtain a range of isolable N-
trifluoromethylated hydroxylamines. However, when longer-
chain perfluoroalkanesulfinates5a,14 were used, we observed a
decomposition of the perfluorinated hydroxylamine upon
attempted isolation. As one of the decomposition products
was identified as a hydroxamic acid derivative (formal
oxydefluorination at the α-position), we set out to investigate
a controllable defluorination. Notably, fluorinated amides are
important motifs in biologically active molecules15 and
valuable building blocks for pharmaceuticals,16 dyes,17 and
functional materials.18 Only a few synthesis methods for
perfluorinated amides are reported;15b,17,19 most of them have
a limited substrate scope and rely on sensitive acid derivatives
or coupling reagents.
extended time was beneficial for the oxydefluorination, yielding
hydroxamic acid 7b in 25% yield (entry 1).
a
Table 1. Condition Screening for Oxydefluorination
conditions for
yield 7b
yield 3b
yield 4b
b
b
b
entry
1
oxydefluorination
(%)
(%)
(%)
50 °C, 24 h
HCl (20 equiv), rt, 6 h
HCl (20 equiv), HOAc,
0 °C, 6 h
InCl3 (3 equiv), 50 °C, 6 h
BF3·OEt2 (10 equiv), rt, 6 h
Zn/HCl (40 equiv), HOAc,
65 °C, 6 h
25
36
41 (35)
-
-
-
-
-
-
c
2
3
cd
,
e
f
Herein, we report a one-pot N-perfluoroalkylation reaction
of nitrosoarenes for the synthesis of fluorinated hydroxamic
acids, amides, and thioamides via N-perfluorinated hydroxyl-
amine intermediate 2 (Scheme 1c).
4
5
6
26/24
24
-
-
-
-
-
f
cd
,
e
-
72 (70)
e
7
8
NaOAc (6 equiv), rt, 16 h
NaOAc (6 equiv), rt, 16 h
-
-
-
-
69 (64)
68 (64)
We first investigated the scope of the perfluoroalkylation
reaction with respect to various nitrosoarenes and sodium
perfluoroalkanesulfinates (for details, see the SI, Table S-1). As
f
e
a
Method A: 1b (0.10 mmol), NaSO2(CF2)3CF3 (0.3 mmol),
1
judged by H NMR, a variety of nitrosoarenes bearing either
hydroquinone (0.11 mmol), Cu(ClO4)2·6H2O (1 mol %), EtOAc
b
t
(0.8 mL), and BuOOH (70% aq., 0.3 mmol), rt, 1 h. 19F NMR
electron-withdrawing or electron-donating substituents at the
ortho-, meta-, or para- positions were transformed into the
corresponding hydroxylamines in moderate to high yields
(2a−2q, 56−88% by NMR). In addition, the sodium sulfinate
component could be varied to include both shorter
(perfluoropropyl) and longer (8H-perfluorooctyl) perfluor-
oalkyl chains (2s−2u, 68−80%, Scheme 2).
c
yields determined with HFIP as an internal standard. 37% HCl was
used. 1.0 mL of HOAc was used. Isolated yield (0.5 mmol).
Method B: CuCl2 (5 mol %) and BuOOH (55% in decane, 0.3
mmol) were used instead of Cu(ClO4)2·6H2O and aq. BuOOH.
d
e
f
t
t
We then screened a variety of Brønsted and Lewis acids for
their effects on the oxydefluorination (see also the Supporting
Information). Using HCl as a promoter led to an increased
yield of 7b (36%, entry 2), while AcOH as a cosolvent resulted
in a slight improvement: the reaction at 0 °C afforded
hydroxamic acid 7b in 41% yield (35% isolated, entry 3). Our
attempts to use InCl3 or BF3·OEt2 as promoters were
unsuccessful, both when the perfluoroalkylation was conducted
under nondry conditions (Method A) and when TBHP in
decane (Method B) was used (entries 4 and 5). Gratifyingly,
under acidic reductive conditions (Zn/HCl in AcOH), amide
3b was obtained in 72% yield after oxydefluorination and N−
O bond reduction (entry 6).
a
Scheme 2. N-Perfluoroalkylation of Nitroso Compounds
Furthermore, we examined the effect of bases on the
oxydefluorination. While K2CO3 and pyridine led to
decomposition, intermediate 2b was converted into the
corresponding O-acetylated hydroxamic acid using NaOAc.
The unexpected product 4b was isolated in 64% yield (entries
7 and 8).
a
General Conditions: 1 (0.50 mmol), NaSO2CF2RF (1.5 mmol),
hydroquinone (0.55 mmol), Cu(ClO4)2·6H2O (1 mol %), EtOAc
(4.0 mL), and BuOOH (70% aq, 1.5 mmol). After adding Ac2O
(1.0 mL) and NaHCO3 (3.0 mmol), stirring for 24 h, isol. yield.
b
t
It is worth to mention that when moderate yields were
obtained, no evident side products were identifiable in these
one-pot reactions. If the oxydefluorination was not efficient,
the hydroxylamine intermediates decomposed, and complex
mixtures were obtained.
Having evaluated the oxydefluorination of hydroxylamine
intermediates 2, we examined the scope of this one-pot
protocol for the synthesis of amides 3 (Scheme 3).20
Nitrosobenzene was transformed into amide 3a in 55% yield
via the one-pot perfluoroalkylation/oxydefluorination under
reductive conditions. High yields were generally obtained for
ortho-substituted amides (3b, 3e, 3g, and 3h, 53−70%), with
the exception of 3c (42% yield). Halogen substituents were
also well tolerated (3g−j, 53−70%). The meta-CF3-substituted
Although the hydroxylamines 2 were not isolable, electron-
deficient hydroxylamine products were found to be more
stable; acetylated hydroxylamine 6q could be isolated in 61%
yield after the acetylation of 2q (Scheme 2). An aliphatic
nitroso compound was a suitable substrate as well. However,
the corresponding hydroxylamine was found to be the least
stable; oxydefluorinated product 7r was obtained in 54%
isolated yield, instead of the expected hydroxylamine.
Intrigued by the oxydefluorination reaction observed for
product 7r and the relative stability of hydroxylamines 2 in
solution, we set out to find general conditions facilitating the
oxydefluorination in a one-pot process. As shown in Table 1,
stirring the reaction mixture at a higher temperature for an
B
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a
a
Scheme 3. Synthesis of Amides 3 with Zn/HCl
Scheme 4. Oxydefluorination with NaOAc
a
Reaction conditions: Step (1) Method A, 0.50 mmol scale. Step (2)
NaOAc (3.0 mmol) was added to the reaction mixture, 16 h at rt.
b
Isolated yields over two steps. 19F NMR yields determined with
c
HFIP as an internal standard, using Method A. Isolated yields using
Method B for Step (1), 0.50 mmol scale. DCM (4.0 mL) was added
d
as a cosolvent in Step 2. TCE (4.0 mL) was added as a cosolvent in
Step 2.
only traces of 4k were observed using Method A, whereas 44%
yield was reached using Method B (Scheme 4).
In analogy with NaOAc, we next explored KSAc as an
additive for the defluorinative functionalization. We envisioned
that thioamide derivatives could be obtained under similar
conditions. Such a procedure could serve as an alternative
method for the synthesis of fluorinated thioamides.21 Unlike
the oxydefluorination with NaOAc, the thioacetate-promoted
reaction led to the formation of thioamides 5, involving a
concomitant cleavage of the N−O bond. Additionally, dry
conditions (Method B) had to be used in order to obtain the
thioamide products (Scheme 5).
a
Reaction conditions: Step (1) Method A (cf., Table 1), 0.50 mmol
scale. Step (2) HOAc (5 mL), Zn (powder, 20 mmol), and HCl (37%
aq, 20 mmol) were added to the reaction mixture, 2 h at 65 °C.
b
c
Isolated yields over two steps. 1.0 mmol scale. Method B (cf., Table
1) was used for Step (1), 0.50 mmol scale. 0.20 mmol scale.
d
Substrates bearing ortho-substituents reacted smoothly,
affording thioamides 5b and 5c in 68 and 63% yield,
respectively. For other substrates, a cosolvent was required
(5a, 5j, 5k, and 5o). Nitrosobenzene was transformed into
thioamide 5a in 57% yield, whereas the meta-substituted
thioamides 5j and 5k were obtained in slightly lower yields
(47−50%). Ester derivative 5o was isolated in 62% yield.
To demonstrate the applicability of our method, amide 3b
was reduced by LiAlH4 into amine 9 in 65% yield.
Furthermore, thioamide 5c was efficiently transformed into
benzothiazole 10 in 70% yield, via an oxidative cyclization
using CAN.22 The S-phenyl thioimidate 11 could be obtained
in 88% yield from 5c by reaction with a diaryliodonium salt
(Scheme 6).23
A proposed mechanism for the defluorinative functionaliza-
tion is presented in Scheme 7. The defluorination of
hydroxylamine intermediate 2 is likely facilitated by the
nitrogen lone pair7,13 and hyperconjugation from the
perfluoroalkyl group, yielding oxaziridine A.24 Our attempts
to detect intermediate A (by NMR and MS) were fruitless, as a
rapid conversion into the products was observed. In the
amide 3k was obtained in a low yield (31%, Method A),
whereas dry conditions (Method B) led to a slightly higher
yield (38%). A range of para-substituted amides were obtained
in good yields (3l−p, 49−63%), including electron-rich (3l
and 3m, 60 and 49%) and electron-poor (3n and 3o, 63 and
61%) arenes. Notably, aminoglutethimide derivative 3p was
obtained in 55% yield. Amides derived from other perfluor-
oalkanesulfinates were isolated in similar yields (3s−u, 58−
64%).
The oxydefluorination reaction of ortho-substituted sub-
strates, with sodium acetate as a promoter, delivered O-acyl
hydroxamic acids 4b−f in high yields (59−78%, Scheme 4).
Electron-rich and electron-poor arenes as well as ortho-
disubstituted substrates worked well using nondry reaction
conditions (Method A). For product 4f, the yield was
improved from 44 to 62% by the addition of 1,1,2,2-
tetrachloroethane (TCE) as a cosolvent.
However, for substrates lacking an ortho-substituent (4a, 4j,
4k, and 4n), dry reaction conditions (Method B) and a
cosolvent were necessary to obtain high yields. For example,
C
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a
An analogous rearrangement to E, followed by a cleavage of
the N−O and C−S bonds,25 affords iminoyl fluoride B,
acetate, and sulfur. The subsequent nucleophilic addition of
thioacetate gives intermediate F, which then is hydrolyzed to
form thioamide product 5. Upon GCMS analysis of the crude
reaction mixtures for thioamides 5a and 5b, we detected the
corresponding intermediates F, in support of our mechanistic
hypothesis.
Scheme 5. Synthesis of Thioamides 5
In summary, an efficient one-pot N-perfluoroalkylation−
defluorination functionalization was developed. After perfluor-
oalkylation of the nitrosoarene starting materials, labile
perfluoroalkyl hydroxylamines were obtained. Although not
isolable, the hydroxylamine intermediates were readily
converted into a variety of perfluoroalkylated amides,
hydroxamic acids, and thioamides, through a controllable
defluorination pathway. This work demonstrates the versatility
of fluorinated hydroxylamines as intermediates for the
synthesis of novel fluorine-containing targets.
a
Reaction conditions: Step (1) Method B, 0.50 mmol scale. Step (2)
KSAc (3.0 mmol) was added to the reaction mixture 16 h, rt. Isolated
b
yields over two steps. DCM (4.0 mL) was added as a cosolvent in
Step (2).
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00768.
Scheme 6. Synthesis Applications
Detailed experimental data and characterization data
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
Nicklas Selander − Department of Organic Chemistry,
Arrhenius Laboratory, Stockholm University SE-106 91
Stockholm, Sweden; orcid.org/0000-0002-9085-0476;
Email: nicklas.selander@su.se
Authors
Zhiyao Zheng − Department of Organic Chemistry, Arrhenius
Laboratory, Stockholm University SE-106 91 Stockholm,
Sweden; orcid.org/0000-0003-2187-675X
Scheme 7. Mechanistic Proposal
Angela van der Werf − Department of Organic Chemistry,
Arrhenius Laboratory, Stockholm University SE-106 91
Stockholm, Sweden; orcid.org/0000-0001-6517-8879
Marie Deliaval − Department of Organic Chemistry, Arrhenius
Laboratory, Stockholm University SE-106 91 Stockholm,
Sweden; orcid.org/0000-0003-1396-2818
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00768
Author Contributions
†Z.Z. and A.v.d.W. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
presence of Zn/HCl, A is reduced to iminoyl fluoride B, which
after hydrolysis affords amide 3 (Scheme 7).
■
We thank the Knut och Alice Wallenbergs Foundation (Dnr:
2018.0066) for the financial support, the Carl Trygger
Foundation for a postdoc scholarship (Z.Z.), and Erika
Linde for initial studies.
In the presence of sodium acetate, O-acyl hydroxamic acid 4
can be obtained via a nucleophilic attack by acetate, followed
by a rearrangement of intermediate C. To confirm that the
acetyl group originates from sodium acetate (and not EtOAc),
the reaction was performed with sodium propionate, yielding
O-propionyl hydroxamic acid 8b in 44% yield (see the SI).
When potassium thioacetate is used as a nucleophile, the
opening of oxaziridine A by thioacetate gives intermediate D.
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