Göran
Schulz
and
Andreas
Kirschning
*
Institute of Organic Chemistry and Center of Biomolecular Drug Research (BMWZ), Leibniz Universität Hannover, Schneiderberg 1B, 30167 Hannover, Germany. E-mail: andreas.kirschning@oci.uni-hannover.de
First published on 13th October 2020
The smooth oxidative radical decarboxylation of carboxylic acids with TEMPO and other derivatives as radical scavengers is reported. The key to success was the use of a two-phase solvent system to avoid otherwise predominant side reactions such as the oxidation of TEMPO by persulfate and enabled the selective formation of synthetically useful alkoxyamines. The method does not require transition metals and was successfully used in a new synthetic approach for the antidepressant indatraline.
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Scheme 1 Proposed mechanism of the classical Minisci protocol for generation of alkyl radicals from alkyl carboxylic acids using silver(II).2 |
The resulting carboxyl radical 2 releases CO2 to yield alkyl radical 3, which adds to pyridinium cation 4. The resulting radical cation 5 then rearomatises via radical 6 after deprotonation and oxidation to form the alkylated pyridine 7 (Scheme 1). Thereby, silver(II) acts as oxidant being reduced to silver(I). Alternatively, it was reported that the oxidation of radical 6 can also be promoted by the sulfate radical 9 to furnish sulfate 10.2
Over the past decade, this decarboxylative alkyl radical forming process has been utilised in numerous C–C3 and C–S4 coupling reactions, ring closing cascades,5 radical substitutions6 and azidations.7
Despite extensive research in this field, controlled and selective decarboxylations of this type still have some disadvantages. Often up to stoichiometric amounts of the expensive silver(I) salts are required.3,4,5a In selected rare cases it has been shown that the addition of a base can eliminate the need for transition metal catalysts.8,9 In fact, the sulfate radical 9 with a redox potential of 2.5–3.1 V is a strong single electron oxidant and can therefore form carboxyl radicals 2 from the carboxylates generated in situ.10 Particularly with the metal-free variants, but also with the silver-catalysed methods, the low selectivity is revealed by the fact that carboxylic acid 1 must be used in excess.8,9,11 In addition, the strongly oxidising conditions significantly limit the substrate and reagent range. This obstacle becomes clear, for example, when using a very common method for investigating radical mechanisms. By adding aminoxyl radicals such as 2,2,6,6-tetramethylpiperidin-1-yloxyl (TEMPO, 11) to the reaction mixture, highly reactive radical intermediates can be captured and identified as alkoxyamines.12,13 In the Minisci reaction, this method was used to determine mechanistic details and the resulting alkoxyamines were usually confirmed by mass spectrometry.8,14 One reason why this reaction has not been used preparatively so far is probably that TEMPO can be oxidised by peroxodisulfate salts.15
But alkoxyamines are an important group of reagents and functional groups widely used in organic chemistry (Scheme 2). They serve as initiators for the nitroxide-mediated polymerisation (NMP), a radical polymerisation induced by homolytic cleavage of the C–ON bond, in most cases under thermolytic conditions. The highly reactive alkyl radical and the persistent aminoxyl radical react with alkenes by a migratory insertion into the double bond.16 This reaction type has also been successfully employed in synthetic organic chemistry for ring-closing reactions.17 In 2016, Knowles et al. reported on the mesolytic cleavage of alkoxyamines by photoredox catalysis. The cross-coupling of the resulting carbocations with various nucleophiles led to the formation of new C–C, C–N or C–O bonds.18 Beyond these applications, alkoxyamines can easily be converted into alcohols19 or carbonyl compounds.20 Existing methods to form alkoxyamines start from haloalkanes,21 boronates,22 boranes,23 aldehydes12,13,24 or redox active esters.25
In view of these diverse considerations, we initiated a program to develop a method for the formation of alkoxyamines from carboxylic acids by metal-free radical decarboxylation.
Following this hypothesis, we optimised the conditions of decarboxylative aminoxylation using biphenylacetic acid (1a) as model acid. A mixture of 1a, TEMPO 11 (2.0 eq.), potassium persulfate (3.0 eq.) and K2CO3 (1.5 eq.) was stirred for 20 h at rt in 1,2-dichloroethane and water (1:
1). We started with an excess of TEMPO 11 because in single-phase solvent systems the yields were greatly reduced due to the oxidation of TEMPO by persulfate. After extraction of the reaction mixture with EtOAc, alkoxyamine 12a was collected in 11% yield. However, we also observed the formation of benzophenone (13) (Table 1, entry 1). This oxidative transformation upon treatment of phenylacetic acid derivatives with K2S2O8 in water has already been reported in 2017 by Bhat et al. They proposed that the benzyl radical could be oxidised to a cation by the sulfate radical. After the nucleophilic addition of water, a second oxidation takes place, which leads to the observed carbonyl product.26
Entry | K2S2O8 [eq.] | Solvent mix. (v![]() ![]() |
T [°C] |
12a![]() |
13![]() |
---|---|---|---|---|---|
a ![]() |
|||||
1 | 3.0 | DCE/H2O (1![]() ![]() |
25 | 11 | 39 |
2 | 3.0 | DCE/H2O (2![]() ![]() |
80 | 28 | 30 |
3 | 1.0 | DCE/H2O (2![]() ![]() |
80 | 49 | 13 |
4 | 1.0 |
DCE/H
2
O (3![]() ![]() |
80 | 60 (59) | 11 |
5b | 1.0 | DCE/H2O (3![]() ![]() |
80 | (56) | n.d. |
6c | 1.0 | DCE/H2O (3![]() ![]() |
80 | 46 | 22 |
7d | 1.0 | DCE/H2O (3![]() ![]() |
80 | 27 | 28 |
8 | 1.0 | MeCN/H2O (3![]() ![]() |
80 | 2 | 36 |
9 | 1.0 | DMF/H2O (3![]() ![]() |
80 | 3 | 2 |
10 | (NH4)2S2O8 (1.0 eq.), AgNO3 (2.5 mol%), CH2Cl2/H2O (1![]() ![]() |
<1 | 18 |
Following this proposal, we assumed that changing the ratio of 1,2-dichloroethane and water in favour to the former should reduce by-product formation. Additionally, we raised the reaction temperature to 80 °C to accelerate the decarboxylation step. With these changes of conditions the yield for alkoxyamine 12a could be raised to 28% (entry 2) with benzophenone (13) still being formed as the main product. As a result, the amount of oxidising agent was reduced to one equivalent. The yield for 12a was now at 49% (entry 3). In contrast, both a higher amount of base and its absence led to a decrease in yield.
A 1,2-dichloroethane–water ratio of 3:
1 further improved the yield in favour of 12a to 60% (59% isolated yield) (entry 4). The reduction of the TEMPO amount from two to one equivalent resulted in comparable yield (entry 5). This indicates that only a very small amount of TEMPO is oxidized under the reaction conditions. Principally, the use of one equiv. of TEMPO is also feasible. However, if more polar, water-soluble aminoxyl radicals are used, an excess of the radical would likely be beneficial. The counter ion of the oxidising agent exerts a non-negligible influence on the transformation, as shown by the lower yields when using sodium or ammonium persulfate (entries 6 and 7). Finally, the reaction was repeated using acetonitrile or DMF as co-solvents (entries 8 and 9), with a dramatic decrease in yield, confirming the need for a two-phase system for the reasons given above.
In 2014, Xia et al. reported on the alkylation of purine nucleosides, whereby silver catalysis was also used in a Minisci-type reaction.27 The authors investigated the mechanism of this transformation by adding TEMPO to the reaction mixture. According to their experimental data, the resulting alkoxyamine could be obtained in 87% yield from cyclohexanecarboxylic acid. We repeated the experiment under exactly the conditions described by Xia and colleagues. When cyclohexanecarboxylic acid was used, we observed a lower conversion rate, with only traces of the desired product being formed. For diphenylacetic acid (1a) the yield of 12a was less than 1%, while benzophenone (13) formed as the main product (entry 10).
This radical decarboxylation can be conducted with other TEMPO derivatives 14a–f using phenylacetic acid 1b as model substrate (Scheme 5). In applications of alkoxyamines in nitroxide-mediated polymerisations and also in the cyclisation reactions in organic synthesis, the structure of the aminoxyl radicals used plays an important role.16
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Scheme 5 Use of other aminoxyl radicals 14a–f in oxidative decarboxylations with phenylacetic acid (1b) (a![]() ![]() |
Both the dissociation and the recombination rate of the C–O bond, whose homolytic cleavage initiates the radical cross-coupling reaction cascade, depends strongly on the structure of the aminoxyl radical. This concerns the ring size, the steric size as well as the polarity of the persistent radical.30
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Scheme 6 Advanced intermediate 18 of the industrial sertraline (17) synthesis as a starting point for a new total synthesis of indatraline (16). |
Our synthesis started with a Favorskii-type ring contraction using a slightly modified two-step protocol originally reported by the Herzon group (Scheme 7).33 First, we treated tetralone 18 with trimethylsilyltrifluoromethanesulfonate and triethylamine to obtain TMS-enol ether 19 almost quantitatively. The subsequent click reaction with nonaflyl azide and the resulting nitrogen-releasing rearrangement led to amide 20 as anti-diastereomer dr (9:
1) in 71% yield.
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Scheme 7 A new total synthesis approach for (±)-indatraline (16) based on the decarboxylative aminoxylation of carboxylic acid 21. |
The saponification of amide 20 proved to be problematic, since methods for the hydrolysis of nonaflyl amides have not yet been reported. Alkaline conditions were unsuccessful, probably because of the strong electron-withdrawing effect of the nonaflyl group, which stabilises a negative charge on the nitrogen atom. However, under acidic conditions, using a mixture of aqueous sulfuric acid and 1,4-dioxane at 100 °C, carboxylic acid 21 was obtained in 87% yield. Next, the key step of the synthesis, the protocol of oxidative decarboxylation presented here, was investigated, and fortunately we collected alkoxyamine 22 in 51% yield. The oxidation of alkoxyamine by mCPBA resulted in indenone 23 in 92% yield. The synthesis was then completed according to the established protocols of Davies34 and Froimowitz.35 This included diastereoselective reduction with K-Selectride®. The resulting syn-indenol 24 was finally converted into (±) indatraline (16) by mesylation and subsequent nucleophilic substitution with methylamine.
Footnote |
† Electronic supplementary information (ESI) available. See DOI: 10.1039/d0ob01773f |
This journal is © The Royal Society of Chemistry 2021 |