Tert-Butyl Nitrite Mediated Synthesis of Fluorinated O-Alkyloxime Ether Derivatives

Article abstract of DOI:10.1021/acs.orglett.9b02689

A tert-butyl nitrite (TBN)-mediated synthesis of fluorinated O-alkyloxime ether derivatives with bromodifluoroalkyl reagents as the fluorine sources has been developed. A variety of halodifluorinated compounds were found compatible, delivering the desired

Full text of DOI:10.1021/acs.orglett.9b02689

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
tert-Butyl Nitrite Mediated Synthesis of Fluorinated O‑Alkyloxime
Ether Derivatives
Xingxing Ma† and Qiuling Song*,†,‡,§
†Institute of Next Generation Matter Transformation, College of Materials Science & Engineering, Huaqiao University, 668 Jimei
Blvd, Xiamen, Fujian 361021, China
‡Key Laboratory of Molecule Synthesis and Function Discovery, Fujian Province University, College of Chemistry at Fuzhou
University, Fuzhou, Fujian 350108, China
§State Key Laboratroy of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, CAS, Shanghai, 200032, China
S
* Supporting Information
ABSTRACT: A tert-butyl nitrite (TBN)-mediated synthesis
of fluorinated O-alkyloxime ether derivatives with bromodi-
fluoroalkyl reagents as the fluorine sources has been
developed. A variety of halodifluorinated compounds were
found compatible, delivering the desired products in moderate
to excellent yields. This transformation features a simple
operation, can be done in air, and found to involve radicals.
This protocol represents a straightforward approach to access
various fluorinated O-alkyloxime ether derivatives.
luorinated compounds have found widespread applica-
It is well-known that indole and its derivatives are vital
Ftions in organic synthesis, pharmaceuticals, agrochemicals, building blocks due to their wide occurrence in natural
products and pharmaceutical molecules.8 Moreover, indoles
and materials science, due to their unique and intriguing
properties.1 And there are great variations regarding their
are π electron excessive aromatic heterocyclic compounds in
which there are multiple reaction sites including N-1, C-2, and
C-3; among them, C-3 is nucleophilic and is the most reactive
position.8d,e In addition, our group has reported myriad
protocols for halodifluoroalkyl compounds (BrCF2COOEt,
BrCF2CONRR′, ClCF2COONa, and ClCF2H) in multiple
roles,4 such as difluoroalkylating reagents,4a−e difluorocarbene
precursors,4f and the C1 synthon via quadruple cleavage4g−j
and C2 source in triple cleavage transformation very recently.4k
Herein, we disclosed an efficient and practical approach to
access the fluorinated O-alkyloxime ethers at the C-3 position
of indoles with TBN and difluoroalkyl reagents under mild
reaction conditions. Of note, the products have the potential to
provide the −OCF2− scaffold attributing to N−O bond
cleavage in the presence of Lewis acid or oxidant (Scheme 1).
Moreover, it is a challenge to obtain target products in high
yields under competition of two electrophiles in the same
system.
Our initial efforts toward the formation of C−N and C−O
bonds to generate ethyl (E)-2,2-difluoro-2-(((2-phenyl-3H-
indol-3-ylidene)amino)oxy)acetate (3a) commenced with the
treatment of 2-phenyl-1H-indole (1a), ethyl bromodifluoro-
acetate (BrCF2COOEt), TBN as mediator, and K2CO3 as base
in MeCN at 80 °C, a 73% yield of the desired product 3a was
obtained. Whereafter we examined several bases including
Na2CO3, NaHCO3, Cs2CO3, and NaOH for improving the
physicochemical properties and bioactivities when a fluorine
atom or fluorine-containing groups are incorporated into the
parent molecules.2 It is therefore very significant for
researchers to pursue facile and efficient tactics for the
synthesis of fluorine-containing compounds. Among all of
the organofluorine molecules, the fluorinated O-alkyloxime
ethers are attractive synthetic targets because of their
significant application potential in medicinal and bioorganic
chemistry, such as monoamine oxidase, benzisoxazole deriva-
tives, which exhibit preferable cytokinin-like and neuroleptic
activities.3 Although abundant reliable processes have been
developed to construct the C−C(F) bond with halodifluor-
oalkyl reagents as a fluorine source,4−6 direct construction of
OCF2R along with C−N bond formation has not been
reported yet. To our knowledge, t-BuONO (tert-butyl nitrite,
TBN) has been deemed a good nitrating agent and a radical
precursor in recent decades, in which elegant work utilizing
TBN as a nitrogen source to assemble nitrogen-containing
molecules has been reported.7 Among them, TBN could
readily generate a NO radical to form a C−NO bond which
will be further tautomerized into ketoximes. Inspired by this
transformation, we envision that the newly formed OH might
have an opportunity to be captured by in situ generated CF2R
species from BrCF2COR (R = OR1 and NR2R3); thus,
fluorinated oxime derivatives could be afforded. In order to
validate our hypothesis, a suitable parent molecule should be
selected. In this context, indole and its derivatives arouse our
interest.
Received: July 31, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b02689
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Organic Letters
Letter
a
Scheme 1. Synthesis of Fluorinated Products via TBN-
Mediation
Scheme 2. Scope of 2-Phenyl Indole Derivatives
yield of this reaction (entries 2−5), among them, Na2CO3
demonstrated to be the optimal one under the above
conditions (Table 1, entry 2). The yields of desired product
Table 1. Identification of Reaction Conditions for the
Product 3a
a
entry
base
time (h)
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
K2CO3
12
12
12
12
12
8
3
3
3
3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
dioxane
CH3CN
CH3CN
CH3CN
80
80
80
80
80
80
80
80
80
100
60
40
73
81
68
66
53
83
88(82)
79
69
71
Na2CO3
NaHCO3
Cs2CO3
NaOH
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
a
Reaction condition:Indole (1) (0.2 mmol), ethyl bromodifluoro-
acetate (BrCF2COOEt) (1.5 equiv), TBN (1.2 equiv), Na2CO3 (1.8
equiv) in MeCN at 80 °C for 3 h, isolated yield, TBN = tert-Butyl
nitrite.
b
product 3a′ was obtained when unsubstituted indole was
employed as a substrate. Halo-substituted 2-(4-bromophenyl)-
1H-indole (1g) and trifluoromethyl (−CF3, 1h) were well
compatible, rendering the anticipated product (3g and 3h) in
80% and 72% yield accordingly. When the meta-bromo-
containing substrate 1i was employed, the target product 3i
was isolated in 77% yield. Subsequently, the substituents on
Ar1 rings were investigated under optimized reaction
conditions as well. Thereby 5-methyl-2-phenyl-1H-indole
(1j), 5-fluoro-2-phenyl-1H-indole (1k), and 2-phenyl-5-(tri-
fluoromethyl)-1H-indole (1l) proceeded under the viable
reaction conditions to afford the desired corresponding
products 3j, 3k, and 3l in 86%, 74%, and 62% yield,
respectively. It was noteworthy that the fused ring compound
1H-benzo[f ]indole 1m was tested under optimum reaction
conditions as well, leading to the desired product 3m in
excellent yield (92%).
Encouraged by the above successful results, we wonder
whether this transformation could be employed into other
bromodifluoroalkyl compounds. But low yields of the
corresponding products were obtained with the above
optimized reaction conditions with a significant amount of
starting materials remaining. We then screened the reaction
conditions and found that prolonging the reaction time to 8 h
led to a better result (see Supporting Information (SI) for
details). With these optimal reaction conditions in hand,
various bromodifluoroalkyl reagents, such as 2-bromo-2,2-
difluoro-N-phenylacetamide and its derivatives, were subjected
to 2-phenyl indole (1a) (Scheme 3). Various 2-bromo-2,2-
difluoro-N-phenylacetamides (4a−4e) which bear electron-
donating and -withdrawing groups or disubstituted on an
aromatic ring and a heterocycle were well-tolerated, rendering
the corresponding products in moderate to good yields (5a−
5e). The crystal structures of 5b were determined by X-ray
crystallography (CCDC: 1935697) (Scheme 3; see SI for
9
10
11
12
3
3
53
trace
a
Reaction condition: 2-phenylindole (1a, 0.2 mmol), ethyl bromodi-
fluoroacetate (2a, 1.8 equiv), TBN = tert-Butyl nitrite (1.8 equiv),
base (1.8 equiv), solvent (2.0 mL) under air at 40−100 °C for 3−12
b
h, GC yields Isolatded yield.
were raised to 83% and 88% yields respectively when the
reaction time was shortened to 8 and 3 h (entries 6−7). It did
not significantly improve the efficiency of this transformation
while solvents tetrahydrofuran (THF) and 1,4-dioxane took
the place of acetonitrile (MeCN) (entries 8−9). Finally, the
temperature of this transformation was investigated (entries
10−12). To our surprise, the observed reaction efficacy was
poor at both 100 and 60 °C. When the temperature was
reduced to 40 °C, only a trace amount of fluorinated product
3a was detected (entry 12). Eventually, the optimized
conditions were obtained: 2-phenyl-1H-indole (1a, 1 equiv)
reacted with BrCF2COOEt (2, 1.5 equiv) with TBN (1.2
equiv) at 80 °C using Na2CO3 as base in MeCN for 3 h.
Having the optimized reaction conditions in hand, we next
explored the scope of the indole derivatives for investigating
the generality of this reaction, which are summarized in
Scheme 2. In general, this transformation revealed a high
reaction efficiency with diverse functional groups ranging from
electron-donating to electron-withdrawing ones, thus obtaining
the target fluorinated compounds in good to excellent yield.
Specifically, electron-releasing groups such as methoxy (1b)
and alkyl (1c−1f) on the Ar2 ring of 4-substituted were
performed under standard reaction conditions to afford the
expected products in 83%−95% yield. However, no desired
B
DOI: 10.1021/acs.orglett.9b02689
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Organic Letters
Letter
a
Scheme 3. Scope of Bromodifluoroalkyl Compounds
Scheme 4. Gram-Scale Reaction and Transformation of
Product 3a
Scheme 5. Direct Synthesis of Compound 8
Scheme 6. Control Experiments
a
Reaction conditions: Indole (1) (0.2 mmol), ethyl bromodifluoro-
amide (BrCF2COR) (1.5 equiv), TBN (1.2 equiv), Na2CO3 (1.8
equiv) in MeCN at 80 °C for 8 h, isolated yield, TBN = tert-Butyl
nitrite.
details). The substrates 4f and 4g were examined under the
same reaction conditions to afford the desired products (5f and
5g) in 74% and 78% yield, respectively. Finally, when reactant
2-bromo-2,2-difluoro-N-(3-methylbenzyl)acetamide (4h) was
subjected to the reaction conditions, the corresponding desired
(Z)-2,2-difluoro-N-(3-methylbenzyl)-2-(((2-phenyl-3H-indol-
3-ylidene)amino)oxy) acetamide (5h) was obtained in 82%
yield.
It is very easy to convert products 3 into valuable
compounds due to the low bond energy of the N−O bond.9
To further indicate the synthetic potential of our strategy, we
undertook a gram-scale synthesis of ethyl (E)-2,2-difluoro-2-
(((2-phenyl-3H-indol-3-ylidene)amino)oxy)acetate (3a); to
our delight, the efficiency of this transformation was well
maintained (2.7 g, 78% yield) (Scheme 4, eq 1). Subsequently,
further transformations of 3a were carried out. First, the
compound N-(2-cyanophenyl)-N-pivaloylbenzamide (6) was
prepared using 1.2 equiv of pivalic acid under air at 80 °C for 1
h in MeCN (Scheme 4, eq 2). The 3a could undergo a ring-
opening reaction catalyzed by TsOH to lead to N-(2-
cyanophenyl)benzamide (7) in 90% yield (Scheme 4, eq 3),
which is one of the most important building blocks due to their
anti-inflammatory effects, such as DPP-IV inhibitors.10 The
ester group of 3a was hydrolyzed under basic conditions to
access (Z)-2-phenyl-3H-indol-3-one O-difluoromethyl oxime
(8), which has an intriguing potential to provide −OCF2H
construction that can serve as a bioisostere of hydroxyl and
thiol groups, in 83% yield (Scheme 4, eq 4). In addition, we
found that the use of excessive Na2CO3 in the model reaction
could furnish the compound 8 directly (Scheme 5).
efficiency of this transformation, resulting in the desired
product 3a in trace yields (Scheme 6, eq 5), which suggests
that a single electron transfer (SET) process may be involved
in this transformation. We then carried out a simple
experiment to capture possible radical species in the system
in the absence of 2-phenyl indole and BrCF2COOEt (Scheme
6, eq 6). The mass of the species NO radical was trapped by
TEMPO via GC-MS. Since this is a cascade reaction, we
decided to carry out the three-compoment reaction in a
stepwise manner: (1) only 2-phenyl-1H-indole 1a and TBN
were subjected to the standard reaction conditions for 1 h,
without further purification, rendering a reaction mixture N;
(2) by direct addition of Na2CO3 and BrCF2COOEt to the
above reaction mixture N, the target product 3a was obtained
in 73% yield (Scheme 6, eq 7).
Based on the above-mentioned experiment evidence and
previous work,4 a possible mechanism for this cascade reaction
is described in Scheme 7. The C-3 position of indole in the
presence of base attacks the NO radical generated in situ from
TBN, leading to an intermediate species M. Subsequently, M
goes through a 1,3-H shift to deliver the reaction intermediate
P. Finally, the desired products 3 and 5 are acquired when
exposed to base and bromodifluoroalkyl reagents.
To gain further insights into the reaction mechanism, several
control experiments were performed (Scheme 6). Addition of
radical scavengers TEMPO or BHT dramatically reduced the
C
DOI: 10.1021/acs.orglett.9b02689
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Organic Letters
Letter
Scheme 7. Mechanism Proposal
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In summary, we have developed an approach to access
various brand-new fluorinated O-alkyloxime ether derivatives
which might have significant potential due to the low bond
dessociation energy of the N−O band. This transformation
involved an SET and a 1,3-H shift under a transition-metal-free
protocol. This transformation features mild reaction con-
ditions, high efficiency, good functional group tolerance, and
compatibility. In addition, this process allows the efficient
construction of the C−N bond and C−O bond simulta-
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of fluorinated O-alkyloxime ether derivatives are currently
underway in our laboratory.
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.9b02689.
Experimental details, characterization data of com-
pounds, NMR, and X-ray crystallographic data (PDF)
Accession Codes
CCDC 1935697 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: qsong@hqu.edu.cn.
ORCID
Qiuling Song: 0000-0002-9836-8860
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
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Financial support from the National Natural Science
Foundation of China (21772046) and the Natural Science
Foundation of Fujian Province (2016J01064) is gratefully
acknowledged. We also thank the Instrumental Analysis Center
of Huaqiao University for analysis support. X.M. thanks the
Subsidized Project for Cultivating Postgraduates’ Innovative
Ability in Scientific Research of Huaqiao University. Finally,
we thank Jianke Su in this group (Institute of Next Generation
Matter Transformation, College of Materials Science &
Engineering Huaqiao University) for reproducing the prepara-
tion of compounds 3a, 3e, and 5f.
D
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