Oxidative Cleavage of Indoles Mediated by Urea HydrogenPeroxide or H2O2 in Polar Solvents

Natalia Llopis,a Patricia Gisbert,a and Alejandro Baezaa,*a Departamento de Química Orgánica and Instituto de Síntesis Orgánica (ISO), Facultad de Ciencias, Universidad de Alicante.

Apdo. 99, E-03690 Alicante, SpainE-mail: alex.baeza@ua.es

Manuscript received: February 16, 2021; Revised manuscript received: May 24, 2021;Version of record online: June 4, 2021

Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100214

© 2021 The Authors. Advanced Synthesis & Catalysis published by Wiley-VCH GmbH. This is an open access article under theterms of the Creative Commons Attribution Non-Commercial NoDerivs License, which permits use and distribution in anymedium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Abstract: The oxidative cleavage of indoles (Wit-kop oxidation) involving the use of H2O2 or ureahydrogen peroxide in combination with a polarsolvent has been described. Among these solvents,1,1,1,3,3,3-hexafluoroisopropanol (HFIP) stands outas the one affording the corresponding 2-ketoaceta-nilides generally in higher yields The protocoldescribed has also enabled the oxidation of differentpyrroles and furans derivatives. Furthermore, theprocedure was implemented in a larger-scale andHFIP was distilled from the reaction mixture andreused (up to 4 cycles) without a significant detri-ment in the reaction outcome, which remarks itssustainability and applicability.

Keywords: Oxidation; Indoles; HFIP; HydrogenPeroxide; Witkop oxidation

Compounds bearing indole moieties are widely presentin many naturally occurring compounds, mainly alka-loids, with most of them possessing biologicalactivity.[1] Therefore, it is not surprising that severaldifferent strategies have been developed for theirfurther elaboration and transformation.[2] Among them,the oxidative cleavage of C2� C3 double bond ofindoles, known as Witkop oxidation,[3,4] gives access toa variety of 2-ketoacetanilide derivatives, which arekey intermediates in the synthesis of quinolones andrelated bioactive compounds. Traditionally the mainstrategies for this reaction involve using transition-metal based oxidants, hypervalent iodine compounds,singlet oxygen or ozone and organic peroxides

(Scheme 1).[4] In the last decades, concerns about thesafety, sustainability and environment impact of chem-ical protocols have prompted the development ofoperationally simple, atom-economy and greener oxi-dation methodologies.[5] In this sense, the use ofbiocatalysts together with H2O2 as oxidant[6] or therecent findings about the use of photocatalysts[7] orKCl (cat.)/Oxone system[8,9] (Scheme 1) for the oxida-tive cleavage of indoles represent a great achievementin this direction.

On the other hand, our research group has beenworking for some years on the use of fluorinatedalcohols as solvents and promoters in different organictransformations.[10,11] More concretely, in the last years,we became interested in the use of the combination of1,1,1,3,3,3-hexafluoroisopropanol (HFIP) and H2O2, orits most stable form UHP (urea-hydrogen peroxideadduct), as a green alternative for the oxidation oforganic compounds.[12,13] In this regard, we envisionedthe possibility of testing this system to carry out thissynthetic transformation in a catalyst-free reaction. Theresults of this study are herein disclosed.

Initially, the search for the optimal reaction con-ditions was conducted using 2-methylindole (1a) asmodel substrate and H2O2 or UHP indistinctly asoxidants in different solvents (Table 1). As can beobserved, regardless of the oxidant, the employment of

Scheme 1.Witkop oxidation.

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H2O or i-PrOH as solvents did not produce anyreaction (entries 1, 2, 10 and 11). However, theformation of some desired product was detected whenMeOH was used instead (entries 3 and 12). Asignificant change was observed when fluorinatedalcohols, 2,2,2-trifluoroethanol (TFE) and 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) were used as solvents.The oxidation reaction took place obtaining highconversion towards the formation of compound 2awith both oxidants (entries 4, 5, 13 and 14). SinceHFIP produced better conversions, a further refinementof the reaction conditions was conducted with thissolvent. Thus, increasing both oxidant equivalents(from 2.5 up to 5 equiv.) resulted in an amelioration ofthe conversion (Table 1, entries 9 and 17). However, afurther increase in the oxidant turned out to be negativefor the formation of the desired product. For the sakeof comparison, other polar solvents were also studiedsuch as MeCN and DMSO. To our surprise, thereaction worked with both oxidants, being especiallysuccessful using H2O2 (Table 1, entries 6, 7, 15 and16). Due to its ease of work-up, purification andcleaner reaction crude, we selected the reactionperformed with MeCN and H2O2 for a further refine-ment. Thus, as in the previous case, increasing theamount of oxidant produced a better yield for 2a

(Table 1, entry 8). It is worth mentioning that loweringthe temperature produced a substantial decrease in theconversion of 2a in all the cases.

As depicted in Table 1, the optimization studyrevealed that there was not a significant difference inthe results achieved when using H2O2 or UHP(5 equiv.) as oxidants and HFIP as solvent in the modelreaction (Table 1, entries 9 and 17). This situation ledus to evaluate the reaction scope under both conditions.Additionally, the good results achieved when MeCN incombination with H2O2 (Table 1, entry 8) prompted usto explore the reaction under these conditions too. Thebest results obtained for each substrate with thedifferent conditions essayed are shown in Scheme 2.As already mentioned, good yield was observed for N-acetylanthranilic acid (2a). The yield was even betterfor the N-methylated analogue 2b, with UHP being theoxidant that provided the best results in HFIP. Assomewhat expected, 5-methoxy-2-methylindole (1c)produced acid 2c in excellent yield. Similar or slightlysuperior results for these substrates were obtainedwhen the reaction was performed in MeCN. Next, freeN� H indoles (indole, 5-methoxyindole, 5-fluoroindoleand 8-ethylindole) lacking a substituent in position 2or 3 were tested without success. The reaction did notwork or if so, led to the formation of a complexmixture of oxidation products (isatins among them).Meanwhile, the N-alkylated analogues, such as N-methylindole (1d) and N-benzylindole (1e) clearlyreacted toward the formation of the correspondingisatins (2d and 2e). These were obtained in goodyields, being H2O2 in HFIP the conditions of choice.Next, skatole (1f) was essayed providing the corre-sponding formamide derivative 2f in good yield whenH2O2 and HFIP were employed. Contrariwise, thereaction with 1,3-dimethyl-1H-indole (1g) sluggishlyproduced, at best, the corresponding oxindole 2g in apoor 32% yield. This was the major isolated productamongst other oxidation products (Witkop oxidationamong them) regardless of the reaction conditionemployed. 2-Benzoylacetanilide (2h) was isolated in75% yield, starting from 3-phenyl-1H-indole (1h) andusing H2O2 in HFIP. To our delight, the use of 2-phenyl-1H-indole (1 i) gave the pesticide DianthalexinB (2 i)14 in high yield in a one-step operation procedurewhen UHP in HFIP was employed. Under the sameconditions, to our surprise, ester 2j was obtained ingood yield when the corresponding N-methyl-2-phenyl-1H-indole (1j) was used. Next, 2,3-dimethyl-1H-indole (1k) and the N-methylated analogue (1 l)were reacted obtaining high yields for acetamides 2kand 2 l in both solvents, being UHP the oxidant ofchoice for HFIP. However, lower yields were achievedwhen 2,3-diphenyl-1H-indole (1m) was tested underthe same conditions with the better of results beingreached with HFIP as solvent. Disubstituted 3-methyl-2-phenyl-1H-indoles (1n–1q) bearing different sub-

Table 1. Reaction conditions optimization.[a]

Entry Oxidant (equiv.) Solvent Conv (%)[b]

1 H2O2 (2.5) H2O <52 H2O2 (2.5) i-PrOH <53 H2O2 (2.5) MeOH 354 H2O2 (2.5) TFE 725 H2O2 (2.5) HFIP 846 H2O2 (2.5) MeCN 857 H2O2 (2.5) DMSO 818 H2O2 (5) MeCN 91 (81)[c]9 H2O2 (5) HFIP 89 (77)[c]10 UHP (2.5) H2O <511 UHP (2.5) i-PrOH <512 UHP (2.5) MeOH 3013 UHP (2.5) TFE 8014 UHP (2.5) HFIP 8515 UHP (2.5) MeCN 7016 UHP (2.5) DMSO 7717 UHP (5) HFIP 92 (79)[c]

[a] Reaction conditions: indole (0.15 mmol), oxidant and solvent(150 μL), 45 °C, 24 h. [b] Conversion toward the formation of2a determined by GC-MS. [c] Yield of the isolated productafter preparative TLC.

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stituents at position 5 were also analyzed. As somehowexpected, better yields were obtained when electron-donating group were present. It is also remarkable thatthe higher performance of HFIP in comparison toMeCN, with the results of the latter being notablylower. 1,2,3,4-Tetrahydrocarbazole (1r) was next sub-mitted to the optimized conditions giving rise tobenzocondensed macrocyclic amide 2r in high yields,especially with the combination UHP/HFIP. Formylin-doles were also assayed and whereas indole-2-carbox-

aldehyde (1s) produced oxindole (2s) as sole productin high yields with both oxidants, the regioisomer 3-formylindole produced a complex mixture of unidenti-fied oxidation products. This was due to as aconsequential Dakin oxidation.[12b] Finally is worthmentioning that the reaction with indole-3-carboxylicacid and ethyl indole-2-carboxylate was also attemptedwithout success.

With the aim to expand the applicability of theprocedure described, the oxidation of pyrrole and furanderivatives was also taken into account (Scheme 3). Inthis regard, N-methyl and N-benzylpyrrole (3a and3b) were essayed under the optimized reactionconditions using HFIP as solvent. In both cases goodyields were obtained for a mixture of N-benzyl and N-methyl-1,5-dihydro-2H-pyrrol-2-one along with thecorresponding N-alkylmaleimide respectively (4a and4b), using UHP as oxidant. In contrast, 1H-pyrroleproduced a complex mixture of oxidation products.Next, 1H-pyrrole-2-carbaldehyde (3c) was also tested,affording, 3-pyrrolin-2-one (4c) as major oxidationproduct in good conversion as a consequence of aDakin oxidation and a double bond isomerization.[12b,15]Furans were eventually evaluated, in which furanproduced an unidentified complex mixture of oxidationproducts. 2-Methylfuran (3d) gave rise in moderateyield to the formation of lactone (4d), and finally, 2,3-dihydrofuran (3e) produced cyclic hemiacetal 4e ingood yield.

Additionally, it is important to mention thatbenzofurans were also considered as substrates for the

Scheme 2. Scope of the oxidative cleavage of indoles. a)

Reaction conditions: indole (0.15 mmol), oxidant (5 equiv.) andsolvent (150 μL), 45 °C, 24 h. Yield of the isolated product afterpreparative TLC.

Scheme 3. Evaluation of pyrroles and furan derivatives. a

Reaction conditions: substrate (0.15 mmol), oxidant (5 equiv.)and HFIP (150 μL), 45 °C, 24 h. Yield of the isolated productafter preparative TLC. b Products ratio determined by GC-MSand 1H NMR. c Not purely isolated, conversion determined byGC-MS. d Product decomposed during purification, estimatedyield by 1H NMR.

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oxidation protocol described. However, the reactionbarely worked even when more forcing conditions(higher temperatures and oxidant amount as well aslonger reaction time) were employed. On the contrary,1,3-diphenylisobenzofuran (5) smoothly reacted toafford o-dibenzoylbenzene (6) in excellent yieldsespecially when UHP was the oxidant of choice(Scheme 4).

Finally, the methodology herein described wasimplemented in a larger scale experiment (Figure 1). 2-methylindole (1a) (5.0 mmol) was submitted to theoptimal reaction conditions using H2O2, with UHPbeing implemented as the selected oxidant because itallows an easier purification by recrystallization. As aresult, the corresponding N-acetylanthranilic acid (2a)was obtained in 67% yield after recrystallization (n-pentane/CH2Cl2 3/1). The high efficiency and lowenvironmental impact of the whole process was clearlydemonstrated by the fact that the E-factor calculatedturned out to be 22.4 which is within the rank for finechemical industry and below the lowest limit for thepharmaceutical industry.[16]

In addition, to further demonstrate the sustainabilityof the methodology, the recycling of the solvent wasconsidered in this larger scale reaction. Thus, asdepicted in Figure 1, HFIP could be recovered and

reused up to four times observing only a slight erosionon the conversion after each cycle.

In order to gain some insight into the possiblereaction mechanism, a couple of control experimentswere carried out. Accordingly, oxindoles 2o and 7were submitted to the optimized reaction conditionswith both oxidants and after 24 hours no reaction wasobserved (Scheme 5). This result suggest that theoxidative cleavage does not proceed via the formationof the corresponding oxindole and that once suchcompound is formed the reaction does not evolvefurther. Additionally, a radical-based mechanism wasrelinquished since the reaction carried out usingTEMPO as radical scavenger worked practically thesame in both solvents (HFIP and MeCN). Based on theresults, previous experience and the literatureprecedents[6,17] a possible reaction mechanism has beenproposed (Scheme 5). As depicted, indole would attackH2O2 which can act as electrophile thanks to theactivation carried out by HFIP,[18] rendering the hydro-peroxide A as an intermediate. This can evolve towardthe formation of dioxetane B after an intramolecularcyclization reaction. This unstable compound wouldrearrange to afford the desired product. Other mecha-nisms proposals leading to the formation of otherproducts described in the article can be found in thesupporting information file.

In summary, we have disclosed herein the develop-ment of an alternative strategy for the oxidativecleavage of indoles (Witkop oxidation) using UHP orH2O2 as oxidants. From the results obtained, thereaction seems to work well in the presence of highlypolar solvents when indoles bearing a substituent onposition 2 and/or 3 were employed. However, amongall of solvent tested, HFIP usually showed a higherperformance and wider substrate scope, acting assolvent and reaction promoter. The products wereobtained generally in good yields under smoothreaction conditions. Additionally, other heteroaromaticcompounds were also conveniently oxidized. Thesuccess of this protocol relies on the electrophilic

Scheme 4. Oxidative cleavage of isobenzofuran (5).

Figure 1. Large-scale reaction, E-factor and recycling ofsolvent.

Scheme 5. Control experiments and proposed reaction mecha-nism.

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activation of H2O2 by the fluorinated alcohol. Finally,the applicability of the procedure was clearly accom-plished by the implementation of a large-scale experi-ment and recycling of the HFIP.

Experimental SectionGeneral Procedure for the Oxidative Cleavage ofIndolesIn a capped tube, the corresponding indole derivative(0.15 mmol), HFIP (150 μL) and oxidant (5 equiv.) were addedsequentially in one portion and the mixture was subjected toconventional heating (sand bath) for 24 hours at 45 °C. Aftercooling down the reaction mixture, it was filtered throughCelite® plug using ethyl acetate as eluent. Then, the solvent wasevaporated under reduced pressure. The corresponding pureproducts were obtained after purification by preparative TLC,using mixtures of hexane and ethyl acetate as eluent.

Following the general procedure described, the reaction wascarried out at large scale employing 2-methylindole (5.0 mmol,0.65 g), HFIP (3 mL) and H2O2 (5 equiv., 1 mL), which wereadded sequentially in a round-bottom flask. The reaction wasstirred at 45 °C (sand bath) for 24 hours. After this time, thereaction mixture was evaporated under reduced pressure. Thecorresponding product was purified by recrystallization inCH2Cl2/n-pentane (1/3) and filtered, yielding the N-acetylan-thranilic acid (2a) in 67% (0.58 g).

AcknowledgementsWe would like to thank the Spanish Ministerio de Economía,Industria y Competitividad (CTQ2017-88171-P) and SpanishMinisterio de Ciencia, Innovación y Universidades (PGC2018-096616-B-I00) and the University of Alicante (VIGROB-316/19,UADIF19-106) for the financial support. S.-J. Burlingham isacknowledged for the English correction of the manuscript.

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