Silver-Catalyzed Radical Transformation of Aliphatic Carboxylic Acids to Oxime Ethers

Article abstract of DOI:10.1021/acscatal.6b02074

Oximes and oxime ethers are privileged building blocks and can be conveniently converted to ketones, amines, hydroxylamines, and nitriles. We describe the catalytic decarboxylation of aliphatic carboxylic acids to oxime ethers. With AgNO₃ as the catalyst, valuable oxime ethers bearing various substituents could be easily obtained. The broad substrate scope, easy accessibility of aliphatic carboxylic acids, and mild reaction conditions make this strategy immediately applicable to the synthesis, late-stage functionalization, and modification of biologically active compounds. Experimental studies show the reaction undergoes a radical process.

Full text of DOI:10.1021/acscatal.6b02074

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Article
Silver-catalyzed Radical Transformation of
Aliphatic Carboxylic Acids to Oxime Ethers
Yuchao Zhu, Xiaojin Wen, Song Song, and Ning Jiao
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02074 • Publication Date (Web): 22 Aug 2016
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SilverꢀCatalyzed Radical Transformation of
Aliphatic Carboxylic Acids to Oxime Ethers
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Yuchao Zhu, † Xiaojin Wen, † Song Song,*,† and Ning Jiao*,†,‡
†State Key Laboratory of Natural and Biomimetic Drugs, Peking University, School of
Pharmaceutical Sciences, Peking University, Xue Yuan Rd. 38, Beijing 100191, China
‡ State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
ABSTRACT. Oximes and oxime ethers are privileged building blocks, and could be
conveniently converted to ketones, amines, hydroxylamines, and nitriles. We describe the
catalytic decarboxylation of aliphatic carboxylic acids to oxime ethers. With AgNO3 as the
catalyst, the valuable oxime ethers bearing various substituents could be easily obtained. The
broad substrate scope, easy accessibility of aliphatic carboxylic acids, mild reaction
conditions make this strategy immediately applicable to the synthesis, lateꢀstage
functionalization and modification of biologically active compounds. Experimental studies
show the reaction undergoes a radical process.
KEYWORDS. Radical, Decarboxylation, Aliphatic Carboxylic Acids, Oxime Ether, Lateꢀ
Stage Functionalization.
INTRODUCTION:
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Carboxylic acids are basic synthetic materials because they are stable, inexpensive and easily
available.1 Among the abundant transformations of carboxylic acids, the decarboxylative
functionalization has been widely applied for the construction of new chemical bond.
Traditional named reactions such as Hunsdiecker reaction,2 CristolꢀFirth reaction,3 and Kochi
reaction4 reported decarboxylative halogenation of aliphatic carboxylic acids with
stoichiometric metal (Ag, Hg, Pb) reagents. As a milestone, Goossen and coworkers
disclosed the Pd/Cu coꢀcatalyzed decarboxylative cross coupling reaction of aromatic
carboxylic acids.5 Based on this tremendous work, various decarboxylative functionalization
reactions of aromatic,6 alkenyl,7 αꢀketone,8 and alkynyl9 carboxylic acids were developed.
Compared to the above success, the catalytic decarboxylative functionalization of aliphatic
carboxylic acids remains a challenging subject except for the special αꢀamino acids or
carboxylates as the substrates.10 In 2012, Li and coworkers innovatively disclosed Agꢀ
catalyzed decarboxylative chlorination11a of aliphatic carboxylic acids which opened up the
window of catalytic decarboxylations of aliphatic carboxylic acids (Scheme 1a). Up to now,
the fluorination,11b alkynylation,11c trifluoromethylthiolation,11d allylation,11e and azidation11fꢀ
g of aliphatic carboxylic acids were successfully achieved using the decarboxylative strategy.
With efficient photoꢀcatalysts, the groups of Macmillan,12a Glorious,12b Waser,12c Xiao,12d and
Chen12e developed the decarboxylative functionalization of aliphatic carboxylic acids. Groves
and coworkers successfully realized decarboxylative fluorination of aliphatic carboxylic acids
catalyzed by the wellꢀdesigned Mnꢀcatalyst.13
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a) Catalytic decarboxylation of alphatic carboxylic acids
[M]-cat.
Li, Shen, Jiao, Groves
Alkyl
FG
Alkyl COOH
FG = F, Cl, SCF3, N3,
Alkynyl, Allyl
photoredox catalyst
Macmillan, Waser,
Xiao, Glorious, Chen
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b) The potential transformation oxime ethers
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ketones
amines
hydroxylamines
nitriles
NOBn
unknown
Alkyl COOH
Alkyl
R
c) The synthesis of oximes and oxime ethers
NOBn
NOBn
organotin or 120 oC
>
+
X
Alkyl
Alkyl
R
R'O2S
R
Kim's work
R = H, Me, CF3, CO2R'
R3
R1
NOBn
PhSiH3, or CatBH
hydrometalation
NOBn
+
R2
R'O2S
R
Alkyl
R
R = H, CN
Renaud's ,Carreira's work
d) This work
NOBn
NOBn
R
[Ag] cat.
Alkyl COOH
+
PhO2S
R
Alkyl
R
CF C F , C F , CN CO Et, H, Alkyl
, ,
3 2 5 4 9 2
=
Mild reaction conditions
Broad substrate scopes
Late-stage modification of drugs
Concise synthesis of bioactive compounds
Scheme 1. The Decarboxylative Functionalization of Carboxylic Acids.
Oximes and oxime ethers are privileged building blocks and are present in many
biologically active compounds.14 They could be easily converted to carbonyl and nitro
compounds, amines, hydroxylamines, or nitriles (Scheme 1b).15 Thus, the development of
efficient approaches to oximes and oxime ethers has drawn many chemists' attention.
Recently, Kim and coworkers innovatively reported the radical coupling of alkyl halide with
oxime ether reagent bearing a sulfonyl group to build oxime ethers (Scheme 1c). However,
stoichiometric organotin reagents are required during the radical initiation process, or
employed AIBN instead of organotin at high temperature (>120 oC), which limited their wide
application.16 The synthesis of aldoxime ethers from olefins with sulfonyl oximes was
reported by Renaud et al. which avoided the use of organotin reagents but suffered from a
twoꢀstep workup (Scheme 1c).17 Recently, Carreira and coworkers successfully realized the
reductive coupling reaction of olefins and sulfonyl oximes (R = H, CN) catalyzed by wellꢀ
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designed Coꢀcatalyst (Scheme 1c).18 Despite the significance of these methods, the direct
synthesis of oximes and oxime ethers from easily available aliphatic carboxylic acids is not
realized yet (Scheme 1b).
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As our continuous interest in developing radical reactions19 and decarboxylations,9d, 11g
herein, we report the Agꢀcatalyzed decarboxylative cross coupling of aliphatic carboxylic
acid with sulfonyl oximes 1 to synthesize oxime ethers which features the following
advantages compared to the previous reports (Scheme 1d): 1) the aliphatic carboxylic acids
are easily available and widespread in drugs and natural products; 2) the oxime ethers bearing
many functional groups especially CnF2n+1, which shows privileged roles in drug candidates,
were prepared; 3) the mild reaction conditions make this novel transformation immediately
applicable to the synthesis and lateꢀstage functionalization of bioactive molecules.
Furthermore, this reaction enriched the decarboxylative cross coupling of aliphatic carboxylic
acids with sulfonyl radical reagents.
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RESULTS AND DISCUSSION:
The electron withdrawing property of trifluoromethyl group (CF3) could protect drugs from
in vivo metabolism by cytochrome P450 oxidases. Thus, the introduce of CF3 group into drug
candidates plays a privileged role in drug discovery.20 In the last few years, the radical
trifluoromethylation21 reactions have gain remarkable progress. The CF3ꢀsubstituted oxime
ethers, the equivalents of CF3ꢀsubstituted ketones or amines, could be easily prepared from
CF3ꢀsubstituted reagent 1a with alkyl radicals. With this purpose, we chose
cyclohexanecarboxylic acid 2a as the model substrate and 1a as the reagent to explore the
reaction conditions (Table 1). With AgNO3 (20 mol%) in CH3CN/H2O (1:1) under argon
o
atmosphere at 50 C, several oxidants were tested (entries 1ꢀ4). No oxime ether product was
detected with PIDA or TBHP as the oxidant (entries 1ꢀ2). To our delight, the oxime ether 3a
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was obtained in good yield when Na2S2O8 (64%, entry 3) or K2S2O8 (71%, entry 4) was used.
Screening of silver salts showed their solubility has great influence in this reaction. Similar
yield was obtained when changing AgNO3 to the soluble AgOTf (69%, entry 5). On the
contrary, the insolvable AgI afforded only trace product (entry 6). Other metal catalysts such
as CuCl2, FeCl2 and MnBr2 are less active (entries 7ꢀ9). Lower yields were obtained when the
reaction carried out in other solvents such as THF/H2O or DMSO/H2O (entries 10ꢀ11).
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Table 1. Examination of Reaction Conditions.a
BnON
CF3
COOH
cat. (20 mol%)
oxidant (1.5 equiv)
NOBn
CF3
+
PhO2S
Solvent, 50 oC, 12 h
2a
1a
3a
yields (%)b
entry
Oxidant
cat. (20 mol%)
Solvent
1
2
3
PIDA
TBHP
AgNO3
AgNO3
AgNO3
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
n.d.
n.d.
64
Na2S2O8
71 (70)c
69
4
5
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
AgNO3
AgOTf
AgI
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
CH3CN/H2O
THF/H2O
6
trace
trace
trace
trace
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7
CuCl2
FeCl2
MnBr2
AgNO3
8
9
10
11
K2S2O8
AgNO3
DMSO/H2O
64
a
Reaction conditions: 2a (0.2 mmol), 1a (0.3 mmol), catalyst (0.04 mmol), oxidant (0.3
o
b
mmol), solvent (2 mL), stirred at 50 C under argon atmosphere for 12 h. Yield was
1
determined by H NMR analysis of the crude reaction mixture using Cl2CHCHCl2 as an
internal standard. c Isolated yield.
With the optimum conditions in hand, we next explored the scope of carboxylic acid 2 with
reagent 1a (Scheme 2). A series of CF3ꢀsubstituted oxime ethers 3 were synthesized by the
present decarboxylation strategy. The secondary (3aꢀe), primary (3fꢀk), or tertiary (3l)
aliphatic carboxylic acids are reactive in this transformation. Cyclic and branched carboxylic
acid were tolerated to afford 3aꢀc in moderate to good yields (52ꢀ70%). Besides, the reaction
of heterocyclic carboxylic acids proceed smoothly to afford the corresponding oxime ether 3d
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and 3e in 65% and 48% yields, respectively. In addition, the primary carboxylic acids, which
showed lower reactivity in previous radical decarboxylative reactions,11 performed well to
give aim products in moderate to good yields (3f-k, 52ꢀ85%) with the tolerance of halo,
amide, or ester groups. Similar phenomenons were reported in MacMillan’s work.12a Among
them, 3j was isolated in 84% yield, showing the carbon radical next to the oxygen atom is
stable.
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Scheme 2. Transformation of Aliphatic Carboxylic Acids to CF3-substituted Oxime
Ethersa
a Reaction conditions: see entry 4 in Table 1. Isolated yields.
The aldoximes could be easily synthesized from the decarboxylative cross coupling of
aliphatic carboxylic acid 2 with reagent 1b (Scheme 3). The adamantaneꢀ1ꢀcarboxylic acid
and 4ꢀoxoadamantaneꢀ1ꢀcarboxylic acid reacted well to give 4a and 4b in 91% and 82%
yields, respectively. Surprisingly, the sterically hindered carboxylic acids reacted smoothly to
give oxime ether 4c (80%) and 4d (60%). The 2ꢀ(4ꢀchlorophenoxy)ꢀ2ꢀmethylpropanoic acid,
which contains a halogen group and an ether group, reacted efficiently to provide 4e in
synthetic useful yield (40%). Oxime ether 4f bearing ester group was obtained in 70% yield.
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Furthermore, the decarboxylative cross coupling of secondary alkyl carboxylic acids with 1b
proceeded to deliver the cyclic (4gꢀh) and branched product (4i-k) in high yields (78ꢀ93%).
Moreover, the oxime ether products (4kꢀp) were isolated in good yields (40ꢀ84%), showing
the reaction is tolerable to various functional groups. It is worthy to mention that several
primary carboxylic acids were conveniently converted to the corresponding oxime ether
products (4nꢀp) which could not be prepared from reagent 1b with olefins reported by
Renaud17 and Carreira.18
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Scheme 3. Transformation of Aliphatic Carboxylic Acids to Aldoxime Ethers.a
a
Reaction conditions: Reaction conditions: 2 (0.2 mmol), 1b (0.4 mmol), AgNO3 (0.04
o
mmol), K2S2O8 (0.3 mmol), CH3CN/H2O (1 mL/1 mL), stirred at 50 C under argon
atmosphere for 12 h. Isolated yields.
As mentioned in Scheme 1c, the cross coupling of sulfonyl oximes 1 with alkyl halides or
olefins afforded aldoxime ethers efficiently (R = H). The groups of Kim, Renaud, and
Carreira reported the synthesis of oxime ethers bearing CF3, Me, CO2R', and CN substituent,
respectively.16ꢀ18 However, to the best of our knowledge, there is no one system that can
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synthesize oxime ethers bearing diverse functional groups. Inspired by the above results, we
synthesized several sulfonyl oxime reagents bearing other substituent groups (1cꢀh).
Gratifyingly, the present transformation is applicable to all these sulfonyl oxime reagents
(Scheme 4). Alkyl substituted sulfonyl reagents 1cꢀd were compatible to give the
corresponding dialkyl oxime ether 5a-b in 40% and 28% yields, respectively. The CNꢀ
substituted sulfonyl oxime 1e showed high reactivity to give 5c in 79% yield. On the other
hand, the esterꢀsubstituted reagent 1f could react with acid to give modified αꢀamino acid
product 5dꢀe with moderate yields (66ꢀ69%). To be emphasized, the perfluoroalkyl
substituted oxime ether 5f-g were isolated when we used 1gꢀh as reagents, showing this
reaction could be used in the synthesis of multiple fluorineꢀcontaining compounds.
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Scheme 4. Transformation of Aliphatic Carboxylic Acids to Substituted Oximes Ethers.a
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a Reaction conditions: see entry 4 in Table 1. Isolated yields. b CH3CN/H2O (2 mL/2 mL) was
used for 16 h. c 30 mol% AgNO3 was used for 16 h.
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It’s worthwhile to mention that in several compounds such as 3fꢀg, 3i, 3k, 4aꢀf, there are
only one geometric isomer, while in others, both E and Z isomers around the C=N bond are
existed. Based on the experimental data, we speculate the steric hindrance of the substrates
influences the E and Z configuration of products. Moreover, the present decarboxylative
strategy showed excellent chemoꢀselectivity. For example, the reaction between reagent 1b
and diꢀacid 2u proceeded smoothly to afford monoꢀdecarboxylative product 4q in 78% yield
(Eq 1).
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The synthesis and late-stage modification of bioactive molecules. The properties of the
carboxylic acids make them widespread in drugs as well as some bioactive molecules. The
simple and mild reaction conditions make it possible to apply the present system in the lateꢀ
stage functionalization of bioactive molecules containing carboxylic acid group (Scheme 5).
Under the standard conditions, fenbufen, the nonsteroidal antiinflammatory drug,22 and
dehydrocholic acid, the choleretic drug23 could be modified to their oxime derivatives 3m-n
in 76% and 55% yields without the affecting of ketone group (Eq 2ꢀ3). Glycyrrhetinic acid, a
natural product containing hydroxyl, carbonyl, and alkenyl groups reacted with 1b to afford
4r in 42% yield (Eq 4).
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Scheme 5. The Late-stage Modification of Drugs and Natural Products.
Inspired by the above work, we further demonstrated the synthetic utility of our strategy by
preparation of two bioactive molecules (Scheme 6). The amide 8, which is a thyrotropinꢀ
releasing hormone receptor type 1 (TRHꢀR1) antagonist,24 is condensed from diphenyl acetic
acid and secondary amine 7. As alkyl substituted oxime ethers are the analogue of secondary
amine, we speculated that our strategy could be applied in the concise synthesis of 8. As our
expected, the decarboxylative cross coupling of acid 2d and 1c afforded the oxime ether 6 in
67% yield. The reduction of 6 with LiAlH4 delivered secondary amine which reacted with
diphenyl acetic acid in the presence of HATU to afford TRHꢀR1 antagonist 8. Compared to
the traditional approach (6 steps), our method is more concise (3 steps) with similar yield
(Scheme 6A). Furthermore, the amidoxime group is present in many biologically active
compounds such as fungicides25a or insecticides.25b The CNꢀsubstituted reagent 1e reacted
with aliphatic carboxylic acid 2y to afford CNꢀsubstituted oxime ether 9 which was easily
transformed to product 10 in 87% yield over two steps (Scheme 6B).
The modification of methyl group to CF3 group may change the bioactive molecules'
physicochemical properties such as dipole moments, metabolic rate, and pKa.26 The methyl
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substituted secondary amines show distinctive properties and are present in many bioactive
molecules.27 Our present chemistry may provide an efficient approach to corresponding CF3
substituted secondary amines (Scheme 6c). For example, bioactive compounds 8 and 12 both
contain the methyl substituted amine group. Employment of the present Agꢀcatalyzed
decarboxylation strategy (Scheme 2) as the key step, followed by the reduction, CF3
substituted product 11 and 13 were obtained in high yields. It is worthy to emphasize that the
CF3 substituted compound 13 may have potential bioactivity as it is an analogue of TRHꢀR1
antagonist 8. This kind of compounds containing a CF3 group has never been reported due to
the limitations of traditional synthetic methods.
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Scheme 6. Synthesis and CF3-Modification of Biologically Active Compounds.
Mechanistic studies. To gain the insight mechanism of this reaction, we did several
mechanistic experiments. When TEMPO (2 equiv) was added to the reaction of 2l and 1b
under standard conditions, no decarboxylative product 4a was detected and the substrate was
recovered (eq 5). Secondly, when we used 2z as the substrate, the cyclic byproduct 14 was
obtained in 14% yield (eq 6), indicating the generation of carbon radical in this reaction.
These results suggest the reaction undergoes a radical pathway.
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Furthermore, the competing experiment was conducted (Scheme 7). Using 2i as the
substrate, the reactivity of reagents 1a-c, 1e-f was compared. We found the CN substituted
reagent 1e is more reactive than reagent 1b, giving the corresponding product 15 and 40 with
an approximately 3:1 ratio (eq 7). The CF3 substituted reagent 1a is less reactive than reagent
1b but more reactive than reagent 1f (eq 8ꢀ9). Finally, the Me substituted reagent 1c is less
reactive. The yield of Me substituted product 17 was trace compared to the ester substituted
product 16 (34%). In general, the reactivity of these reagents are 1e > 1b > 1a > 1f >> 1c.
These results indicate that the electron deficient oxime reagents are more reactive. On the
other hand, the small steric hindrance may be the cause of the high reactivity of reagent 1b.
Scheme 7. The Competing Experiments.
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Based on the experiment results, we proposed a plausible mechanism involving the
catalytic generation of carbon radical. As Scheme 8 showed, firstly, AgI was oxidized into
AgII intermediate by K2S2O8,28 then the aliphatic carboxylic acids underwent an SET process
to generate corresponding carbon radical A and release CO2. The carbon radical then attacked
sulfonyl reagents to afford the radical B, from which the aim product and sulfonyl radical was
generated. The sulfonyl radical underwent a process of releasing SO2 and generating aryl
radical which was quenched by either Hꢀabstraction or reductionꢀprotonation sequence to
generate the corresponding aromatic compound.11g
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Scheme 8. Proposal Mechanism.
CONCLUSION :
In conclusion, we disclosed a novel and efficient Agꢀcatalyzed direct radical
transformation of aliphatic carboxylic acids to oxime ethers. The present strategy provides an
efficient and practical approach to oxime ethers with broad substrate scopes. The easy
accessibility of aliphatic carboxylic acids, mild reaction conditions, high chemoꢀselectivity
make this reaction very attractive, and successfully applied in the concise synthesis and lateꢀ
stage modification of bioactive molecules. Mechanism studies showed the reaction undergoes
a radical process. Further exploration of the synthetic utility of this transformation is ongoing
in our laboratory.
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ASSOCIATED CONTENT
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Supporting Information. Experimental procedures, analytical data for products, NMR
spectra of products. This material is available free of charge via the Internet at
http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
*Eꢀmail: jiaoning@pku.edu.cn; ssong@bjmu.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from National Basic Research Program of China (973 Program) (grant
No. 2015CB856600) and National Natural Science Foundation of China (No. 21325206,
21632001), and National Young Topꢀnotch Talent Support, and Peking University Health
Science Center (BMU20150505) Program are greatly appreciated. We thank Yiqun Zhang in
this group for reproducing the results of 4g and 5e.
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