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Mar 19, 2018 - R. N. Prasad Tulichala, Mallepalli Shankar, and K. C. Kumara Swamy*. School of Chemistry, University of Hyderabad, Hyderabad, Telangana...
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Article Cite This: J. Org. Chem. 2018, 83, 4375−4383

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Palladium-Catalyzed Decarboxylative ortho-Amidation of Indole-3carboxylic Acids with Isothiocyanates Using Carboxyl as a Deciduous Directing Group R. N. Prasad Tulichala, Mallepalli Shankar, and K. C. Kumara Swamy* School of Chemistry, University of Hyderabad, Hyderabad, Telangana 500 046, India S Supporting Information *

ABSTRACT: Palladium-catalyzed ortho-amidation of indole-3-carboxylic acids with isothiocyanates by using the deciduous directing group nature of carboxyl functionality to afford indole-2-amides is demonstrated. Both C−H functionalization and decarboxylation took place in one pot, and hence, this carboxyl group served as a unique, deciduous (or traceless) directing group. This reaction offers a broad substrate scope as demonstrated for several other heterocyclic carboxylic acids like chromene-3-carboxylic acid, imidazo[1,2-a]pyridine-2-carboxylic acid, benzofuran-2-carboxylic acid, pyrrole-2carboxylic acid, and thiophene-2-carboxylic acid. In the reaction using 2-naphthoic acid, of the two possible isomers, only one isomer of the amide was exclusively formed. The indole-2-amide product underwent palladium-catalyzed C−H functionalization to afford the diindole-fused 2-pyridones by combining two molecules of the indole moiety, with the elimination of an amide group from one of them, attached at the C3-position for the C−C/C−N bond formation. The structures of key products are confirmed by X-ray crystallography.

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recent reports from the groups of Zhao,10c Ackermann,10d Gooßen,10e,f and Baidya10g have described decarboxylative hydroarylation of alkynes using carboxylic acid as a deciduous directing group by Ru catalysis. These reports have clearly demonstrated that carboxyl moiety as traceless directing group offers to streamline the synthesis of diversely substituted arenes. However, examples of the use of carboxyl as traceless directing group involved the insertion of the C−H bond to nonpolar unsaturated alkene and alkynes,6 whereas that to the polarized C−N multiple bonds are considerably scarce. To our knowledge, only a few reports from the groups of Shi, Li, and co-workers disclosed catalytic systems (Rh and Ru) for the ortho-amidation of benzoic acids with concomitant protodecarboxylation utilizing the carboxyl group as a deciduous directing group (Scheme 1, eq ii).8c,e,10a Considerable progress has been made in the transition-metal-catalyzed addition of C− H bonds to polar C−N multiple bonds in recent years.11 In particular, strategies toward the direct insertion of C−H bonds into iso(thio)cyanates are highly demanding since they can provide synthetically valuable amides (Scheme 1, eq iii).8c,e,12,13 However, to the best of our knowledge, isothiocyanates have not been applied to the C−H functionalization reactions by using the traceless directing group strategy. These isothiocyanates react with nucleophiles in a fashion similar to isocyanates, although reaction rates are usually significantly lower. More importantly, isothiocyanates tend to be less sensitive to

INTRODUCTION Transition-metal-catalyzed C−H bond activation and functionalization has emerged as an efficient and versatile strategy in organic synthesis.1,2 The efficacy of these reactions could be intensely improved by transforming such catalytic reactions into atom- and step-economy processes, and this can be achieved by chelation-assisted (directing group) C−H bond activation and functionalization. The use of the directing group strategy enables a good regioselectivity, wide substrate scope, and application to total synthesis.2a,b,3 Functional groups that include imine, anilide, amide, ester, heterocyclic, amine, carboxylic acid, ketone, and hydroxyl have been employed as directing groups for transition-metal-catalyzed direct C−H bond functionalization.4 The strategy to exploit the traceless directing group strategy for C−H functionalization as well as removal of the directing group in a one-pot fashion not only avoids additional steps to remove the undesired directing group from products but also provides a high regioselectivity.5 Among the myriad directing groups evaluated so far, the carboxyl group can act as a deciduous or traceless directing group for the C−H functionalization due to the easy removal of carboxylic functionality by extrusion of CO2 under transitionmetal-mediated conditions allowing a traceless operation of the directing group.5a,b,6 By using Pd,7 Rh,8 Ir,9 and Ru10 catalysts, the traceless directing group strategy has been implemented for the C−H arylation, acyloxylation, borylation, silylation, amidation, and halogenation of arenes. Such reactions were pioneered by the groups of Satoh and Miura, 7a,8a,b Larrosa,7c,e,f,10a Gooßen,6a,b,7h,10d−f and others. Moreover, very © 2018 American Chemical Society

Received: January 6, 2018 Published: March 19, 2018 4375

DOI: 10.1021/acs.joc.8b00042 J. Org. Chem. 2018, 83, 4375−4383

Article

The Journal of Organic Chemistry Scheme 1. Deciduous Directing Group-Assisted Transition-Metal-Catalyzed C−H Functionalization

(tetrabutyl ammonium bromide). Thus, the yield of 3aa was increased to 83% (entry 10). A slight decrease in the yield was observed when we used O2 (balloon) instead of the open air condition (entry 11). Under a N2 atmosphere, in a closed condition, the desired product was not observed (entry 12). The yield was lowered when the reaction was performed at room temperature (25 °C; entry 13). The screening of additives KOAc, AcOH, and AgSbF6 revealed that they were not very effective compared to TBAB (entries 14−16). Changing the solvent to DMF decreased the yield of 3aa to 77% (entry 17). Other solvents like DCE and DMA did not improve the yield (entries 18 and 19). The [Pd] catalysts like PdCl2 and Pd(OTf)2 were less effective than Pd(OAc)2 (entries 20 and 21). The desired product was obtained in 40% yield when we used Pd2(dba)3 in the presence of Ag2CO3 (entry 22). We also carried out the reaction in the presence of [{Cp*RhCl2]2] instead of Pd(OAc)2. Only a trace amount of the desired product was observed (entry 23). The reaction using phenyl isocyanate as the other substrate also led only to traces of amide (entry 24). The reaction of indole-3-carboxylic acid with phenyl isocyanate gave a complex mixture, and only a trace of the product could be isolated. This may be due to the moisture sensitivity of phenyl isocyanate relative to isothiocyanates. In our hands, the use of a lower stoichiometry (1−2 equiv) of 2a reduced the yield by ca. 10%. We have also studied the effect of other phase transfer catalysts: TBAC (tetrabutylammonium chloride) gave 35% yield of the product (entry 25), whereas TBAC·xH2O (tetrabutylammonium chloride hydrate), and TBAI (tetrabutyl ammonium iodide) gave only traces of the product (entries 26 and 27). The conclusion was that the combination of Pd(OAc)2, Cs2CO3, and TBAB in CH3CN solvent at 80 °C for 6 h in open air (83% yield; Table 1, entry 10) was the optimum conditions. As shown by the examples in Table 2, the above protocol was applicable to the C2-amidation of a broad array of indole-3carboxylic acids with isothiocyanates affording good to excellent yields of indole-2-carboxamides. The scope of isothiocyanates was investigated first by using 1-methyl-indole-3-carboxylic acid

moisture and less unpleasant to handle, but they still possess a sufficient degree of reactivity to be very useful reactants.14,15 As a part of our continuing studies on transition-metalcatalyzed C−H activation/functionalization,16 we report herein [Pd]-catalyzed C−H functionalization (ortho-amidation) of indole-3-carboxylic acids with isothiocyanates as electrophiles that results in expedient access to indole-2-carboxamides (Scheme 1, eq iv). Prominent features of our strategy include: (a) amidation at the indole C2-position, (b) high regioselectivity and good substrate scope, and (c) synthesis of useful indole-2-amides by using isothiocyanates under mild conditions.

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RESULTS AND DISCUSSION Palladium-Catalyzed Synthesis of Indole-2-carboxamides by Decarboxylative ortho-Amidation of Indole-3Carboxylic Acids with Isothiocyanates. We commenced our studies by employing 1-methyl-1H-indole-3-carboxylic acid 1a and phenyl isothiocyanate 2a as model substrates for optimization studies of the palladium-catalyzed decarboxylative amidation reaction. Thus, the reaction of 1a with 3 equiv of 2a was performed in the presence of Pd(OAc)2 and Ag2CO3 in CH3CN solvent at 80 °C in open air. In this reaction, we expected the formation of C2-thioamide, but surprisingly, we observed the C2-amidation product 3aa in 45% yield (Table 1, entry 1). The addition of a base like K2CO3 (2.0 equiv) led to further improvement of the yield (entry 2). A sequence of control experiments were performed to check the role of both [Pd] catalyst and Ag2CO3. In the absence of Pd(OAc)2, the desired product 3aa (entry 3) was not formed. Next, the reaction was conducted in the presence of Pd(OAc)2 catalyst but without Ag2CO3. In this case, we observed 61% of the desired product (entry 4). From this experiment, we concluded that there was no role of Ag2CO3 in the reaction. Further investigation on the effect of bases on the reaction outcome showed that Cs2CO3 as a base provided the best result (Table 1, entries 5−9). Gratifyingly, a drastic improvement in the yield was observed when we added the additive like TBAB 4376

DOI: 10.1021/acs.joc.8b00042 J. Org. Chem. 2018, 83, 4375−4383

Article

The Journal of Organic Chemistry Table 1. Optimization Study for Palladium-Catalyzed Decarboxylative Amidationa

entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27

catalyst

oxidant

Pd(OAc)2 Pd(OAc)2

Ag2CO3 Ag2CO3 Ag2CO3

Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 PdCl2 Pd(OTf)2 Pd2(dba)3 [{Cp*RhCl2]2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2 Pd(OAc)2

Ag2CO3

base K2CO3 K2CO3 K2CO3 Cs2CO3 K3PO4 KOtBu NEt3 LiOtBu Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3 Cs2CO3

additive

solvent

yield of 3aa (%)b

TBAB TBAB TBAB TBAB KOAc AcOH AgSbF6 TBAB TBAB TBAB TBAB TBAB TBAB TBAB TBAB TBAC TBAC·xH2O TBAI

CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN DMF DCE DMA CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN CH3CN

45 63 nd 61 70 58 53 trace 55 83c 80d 10e,f 32f,g 65 78 70 77 trace 70 67 78 40f trace traceh 35 trace trace

a

Reaction conditions: indole-3-carboxylic acid 1a (0.5 mmol), isothiocyanate 2a (1.5 mmol), [Pd] catalyst (10 mol %), oxidant (1.0 mmol), base (0.5 mmol), additive (0.25 mmol), solvent (2 mL), 80 °C (oil bath temperature) for 6 h in open air. bIsolated yields. cYield was lower by ca. 15% when 5 mol % of Pd catalyst or by 5−8% when 20−30 mol % of TBAB was used. dO2 (balloon) was used. eUnder a N2 atmosphere. fStarting material remained. gReaction was performed at rt (28 °C). h1.5 mmol of isocyanate was used.

1a as the partner. Phenyl isothiocyanates bearing electron-rich, electron-neutral, or electron-deficient groups reacted well with 1a and afforded the corresponding indole-2-carboxamides 3aa− af in excellent yields (71−90%). The structure of the compound 3ae was confirmed by single crystal X-ray analysis (Figure S1, Supporting Information). We then examined the scope of the reaction with respect to the indole partner. NProtected indole-3-carboxylic acids were thus evaluated, and the substrates with protecting groups such as n-Bu, benzyl (Bn), MOM, and propargyl provided the indole-2-carboxamides 3bb, 3cg, 3da, and 3ea, respectively, in good yields. Interestingly, the tolerance of the terminal triple bond in the product (3ea) enhances the utility of this protocol. Indole-3-carboxylic acids with substituents at 5- and 6-positions on the phenyl ring of indole moiety also reacted smoothly with phenyl isothiocyanate 2a. Thus, 5,6-dimethoxy-1-methyl-indole-3-carboxylic acid (1f), 5-benzoxy-1-methyl-indole-3-carboxylic acid (1g), and 5methoxy-1-benzyl-indole-3-carboxylic acid (1h) reacted well with 2a affording the corresponding 2-amides 3fa, 3ga, and 3ha in excellent yields. 5-Methoxy-1-benzyl-indole-3-carboxylic acid (1h) reacted well with m-chloro phenyl isothiocyanate (2i) and afforded the corresponding amide 3hi in good yields. orthoSubstituted phenyl isothiocyanate did not react with the indole-

3-carboxylic acid perhaps due to steric effect. The reaction of 5fluoro-1-methoxymethyl-indole-3-carboxylic acid with 2c also gave the corresponding amide 3ic in good yields. We were pleased to find that the amidation reaction of indole-3carboxylic acids with alkyl isothiocyanates (2g−h) afforded the indole-2-carboxamide (3ag, 3cg, and 3ah) in excellent yields (83−90%). Indole or N-methylindole did not react under these conditions. Application of Decarboxylative Amidation to Other Carboxylic Acids. To extend the reaction scope of the above amidation reaction, we proceeded to study the decarboxylative amidation of heteroaromatic carboxylic acids with phenyl isothiocyanate under the optimized reaction conditions. The results are summarized in Table 3. As shown in the Table 3, 2H-chromene-3-carboxylic acid 4a reacted with 2a via C3amidation and decarboxylation to afford compound 5aa (Nphenyl-2H-chromene-4-carboxamide) in 85% yield (entry 1). This is an interesting example of amidation as this chromene-4carboxamide product is not known in the literature. Imidazo[1,2-a]pyridine-2-carboxylic acid 4b also reacted well with 2a to give the N-phenylimidazo[1,2-a]pyridine-3-carboxamide 5ba in 84% yield. As expected, 1-methyl-indole-2-carboxylic acid 4c underwent decarboxylative amidation with phenyl isothiocya4377

DOI: 10.1021/acs.joc.8b00042 J. Org. Chem. 2018, 83, 4375−4383

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The Journal of Organic Chemistry

Table 2. Substrate Scope for the Palladium-Catalyzed Decarboxylative Amidation by C−H Activation of Indole-3-carboxylic Acids (1) with Isothiocyanates (2)a

a

Reaction conditions: 1 (0.5 mmol), isothiocyanate 2 (1.5 mmol), Pd(OAc)2 (10 mol %), Cs2CO3 (0.5 mmol), TBAB (0.25 mmol), CH3CN (2 mL), 80 °C (oil bath temperature) for 6 h in open air.

Possible Pathway for Decarboxylative Amidation. To the best of our knowledge, there are no previous reports on the palladium-catalyzed decarboxylative ortho-amidation of indole3-carboxylic acids using isothiocyanates. It is important to note that in these reactions, decarboxylation takes place at C3, but amidation takes place at C2 carbon of the indole-3-carboxylic acid. Based on the literature reports on amidation,12,13 a few palladium-catalyzed decarboxylative reactions,7a,b,g,18,19 and on metal-catalyzed decarboxylation through carboxyl group as a traceless directing group,5−10 a tentative mechanism to rationalize the decarboxylative amidation reaction is depicted in Scheme 3. Initially, carboxylic acid 1a reacts with Cs2CO3 to afford cesium carboxylate I, which is converted to a fivemembered palladacycle intermediate II. It is likely that TBAB as a phase transfer catalyst facilitates this process of formation/ transfer of I, although we have not investigated this aspect

nate and resulted in the C3-amidation product 5ca in excellent yield (88%, entry 3). Benzofuran-2-carboxylic acid 4d and thiophene-2-carboxylic acid 4e also reacted smoothly under the optimized conditions to afford the corresponding 3-substituted amides (5da and 5ea) in good yields (entries 4 and 5). Pyrrole2-carboxylic acid 4f also produced the amidation product 5fa in a moderate yield (entry 6). What is perhaps more interesting is the reaction using 2-naphthoic acid, wherein two orthopositions are available for amidation. We observed the formation of only the 1-substituted isomer 6a as the sole product (Scheme 2).This is perhaps on the expected lines since the α-CH is connected to the other phenyl ring. The yield was moderate (ca. 62%) when we used 5 mol % of the palladium catalyst. We could also accomplish amidation using benzoic acid, wherein compound 6b (cf. Scheme 2) was isolated in decent yields.17 4378

DOI: 10.1021/acs.joc.8b00042 J. Org. Chem. 2018, 83, 4375−4383

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The Journal of Organic Chemistry

followed by subsequent ortho-C−H bond activation with the elimination of AcOH. Now, phenyl isothiocyanate will enter into the catalytic cycle and coordinates to the palladium, resulting in intermediate III.12,13 Subsequently, the sevenmembered palladacycle complex IV is generated by insertion of the CN double bond into the Pd−C bond of intermediate III. A new C−C bond is formed in this step. Next, in the presence of AcOH, the cesium carboxylate species V8e is generated with protonation at the amidic nitrogen, thus regenerating the Pd(OAc)2 for the next catalytic cycle. Finally, decarboxylation of V followed by protonation provides the indole-2-thioamide VI and Cs2CO3. Thioamide VI may further be transformed to indole-2-carboxamide 3aa by aerobic (O2) oxidation.20 Under the nitrogen atmosphere, though, we could not isolate VI and this part would require further investigation. It is true that indole-2-carboxamides may be accessible by the corresponding acid chlorides, but from the chemistry point of view, the route described here is interesting in its own right. Utility of Indole-2-carboxamides: Synthesis of Diindole-Fused Pyridones via Palladium-Catalyzed C−H Bond Activation. We aimed for the [Pd]-catalyzed nitrile insertion reaction banking on our previous result using indole2-carboxamides by C−H and N−H bond cleavage.16d However, in the reaction by using 3ac in the presence of the Pd(OAc)2/ Ag2CO3/Cs2CO3 system in benzonitrile at 90 °C/14 h, rather surprisingly, we obtained the diindole-fused 2-pyridone 7 (cf. Scheme 4, 58% yield; X-ray) by C−C and C−N bond formation. The yield was better using MeCN (66%) or DMF (78%). [See Table S1 in the Supporting Information for more details.] This unusual formation of diindole-fused 2-pyridone product formation may be feasible by combining two molecules of the indole moiety attached at C3-position for the C−C and C−N bond formation with the elimination of one of the amide group (elimination via amine and CO2). The structure of this diindole-fused 2-pyridone 7 was confirmed by X-ray crystallography (Figure S2, Supporting Information). Although we could synthesize one more product 8, generalization to other systems was unsuccessful under the conditions employed. This part needs further investigation.

Table 3. Decarboxylative Amidation of Other Heteroaromatic Carboxylic Acidsa

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a

Reaction conditions: 4 (0.5 mmol), phenyl isothiocyanate 2a (1.5 mmol), Pd(OAc)2 (10 mol %), Cs2CO3 (0.5 mmol), TBAB (0.25 mmol), CH3CN (2 mL), 80 °C (oil bath temperature) for 6 h in open air. bIsolated yields.

CONCLUSIONS We have developed a new protocol of a palladium-catalyzed ortho-amidation of indole-3-carboxylic acids with isothiocyanates for the synthesis of indole-2-carboxamides via C−H bond activation/functionalization using the carboxylic group as a traceless directing group. This procedure features a high

thoroughly. The palladacycle II is expected to be derived from the coordination of Pd(OAc)2 to the carboxylic oxygen

Scheme 2. Formation of Substituted Amides 6a−b Using 2-Naphthoic and Benzoic Acids

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DOI: 10.1021/acs.joc.8b00042 J. Org. Chem. 2018, 83, 4375−4383

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The Journal of Organic Chemistry Scheme 3. Plausible Pathway for the Formation C2 Amidation Product 3aa

Cs2CO3 (0.5 mmol), and TBAB (0.25 mmol) was taken in a 10 mL round-bottom flask. To this, CH3CN (2 mL) was added, and the contents were heated at 80 °C for 6 h in open air. The progress of the reaction was monitored by TLC. After the mixture cooled to rt, the solvent was removed under a vacuum, and the crude product was purified by column chromatography by using silica gel with a hexane/ ethyl acetate (9:1) mixture as the eluent to afford the corresponding indole-2-carboxamides 3aa−ah. Compounds 3aa, 3ac, 3ag, and 3cg are known.23 1-Methyl-N-(p-tolyl)-1H-indole-2-carboxamide (3ab). This compound was prepared by using precursors 1a and 2b: yield 0.112 g (85%) as a white solid; mp 154−156 °C; Rf = 0.52 (9:1 hexane/ethyl acetate); IR (KBr) 3251, 1639, 1541, 1458 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.00 (s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 8.4 Hz, 2H), 7.43−7.36 (m, 2H), 7.22−7.18 (m, 3H), 6.18 (s, 1H), 4.07 (s, 3H), 2.37 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.6, 139.3, 135.2, 134.2, 132.2, 129.7, 126.0, 124.4, 122.0, 120.7, 120.2, 110.3, 104.3, 31.6, 21.0; HRMS (ESI) m/z [M + Na]+ calcd for C17H16N2ONa 287.1161, found 287.1160. N-(4-Chlorophenyl)-1-methyl-1H-indole-2-carboxamide (3ad). This compound was prepared by using precursors 1a and 2d: yield 0.111 g (78%) as a white solid; mp 216−218 °C; Rf = 0.48 (9:1 hexane/ethyl acetate); IR (KBr) 3292, 1645, 1516, 1464, 824, 746 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.93 (s, 1H, NH), 7.69 (dd, J = 8.0 and 0.8 Hz, 1H), 7.61 (d, J = 8.8 Hz, 2H), 7.46−7.36 (m, 4H), 7.23−7.19 (m, 1H), 7.03 (s, 1H), 4.11 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.5, 139.4, 136.3, 131.6, 129.5, 129.2, 125.9, 124.7, 122.0, 121.3, 120.9, 110.3, 104.5, 31.7; HRMS (ESI) m/z [M + H]+ calcd for C16H14ClN2O 285.0794, found 285.0791. N-(4-Cyanophenyl)-1-methyl-1H-indole-2-carboxamide (3ae). This compound was prepared by using precursors 1a and 2e: yield 0.103 g (75%) as a white solid; mp 218−220 °C; Rf = 0.50 (9:1 hexane/ethyl acetate); IR (KBr) 3313, 2228, 1645, 1583, 1459 cm−1; 1 H NMR (500 MHz, CDCl3) δ 8.13 (s, 1H), 7.79 (d, J = 8.5 Hz, 2H), 7.70−7.67 (m, 3H), 7.46−7.39 (m, 2H), 7.24−7.21 (m, 1H), 7.08 (s, 1H), 4.11 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.6, 142.0, 139.8, 133.5, 131.1, 125.9, 125.2, 122.3, 121.2, 119.8, 118.9, 110.5, 107.4, 105.3, 31.8; HRMS (ESI) m/z [M + H]+ calcd for C17H14N3O 276.1137, found 276.1138. 1-Methyl-N-(4-nitrophenyl)-1H-indole-2-carboxamide (3af). This compound was prepared by using precursors 1a and 2f: yield 0.105 g (71%) as a white solid; mp 232−234 °C; Rf = 0.69 (9:1 hexane/ethyl acetate); IR (KBr) 3313, 1650, 1609, 1542, 1505, 1340 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.30 (d, J = 7.2 Hz, 2H), 8.18 (s, 1H), 7.85 (d, J = 7.2 Hz, 2H), 7.72 (d, J = 6.4 Hz, 1H), 7.47−7.41 (m, 1H), 7.25−7.21 (m, 1H), 7.11 (s, 1H), 4.13 (s, 3H); 13C NMR (100 MHz,

Scheme 4. Palladium-Catalyzed Synthesis of Diindole-Fused 2-Pyridones

regioselectivity, good substrate scope, and functional group tolerance in terms of isothiocyanate substrates. It is important to note that in these reactions, decarboxylation takes place at C3, but amidation takes place at the C2 carbon. Other heteroaromatic carboxylic acids are also successfully converted to amidation products under this protocol. In the case of 2naphthoic acid, only one of the two possible isomers of the amide was exclusively formed. We have also utilized indole-2carboxamides for the synthesis of diindole-fused 2-pyridones by palladium-catalyzed C−H activation. Further work in this area would include lowering the catalyst load and application in targeted amides.

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EXPERIMENTAL SECTION

General Comments. 1H (400 or 500 MHz) and 13C (100 or 125 MHz) were recorded in CDCl3 or C6D6 with shifts referenced to SiMe4 (1H, 13C: δ = 0). IR spectra were recorded on an FTIR spectrophotometer. Melting points were determined by using a local hot-stage melting point apparatus and are uncorrected. Elemental analyses were carried out on a CHN analyzer. Mass spectra were recorded using LC−MS and HRMS (ESI-TOF analyzer) equipment. For column chromatography, silica gel of 100−200 mesh size was used. Indole-3-carboxylic acids 1a−i were prepared by following literature procedures.21 Isothiocyanates 2a−i and heteroaromatic carboxylic acids 4d−g are commercially available and are used as such. 2H-Chromene-3-carboxylic acid 4a, imidazo[1,2-a]pyridine-2carboxylic acid 4b, and indole-2-carboxylic acid 4c were prepared by following literature procedures.22 Analytical grade (AR grade) solvents were bought from chemical vendors. Synthesis of Indole-2-carboxamides 3: General Procedure. A mixture of indole-3-carboxylic acid (one of 1a−i, 0.5 mmol), isothiocyanate (one of 2a−i, 1.5 mmol), Pd(OAc)2 (10 mol %), 4380

DOI: 10.1021/acs.joc.8b00042 J. Org. Chem. 2018, 83, 4375−4383

Article

The Journal of Organic Chemistry

1077, 1030 cm−1; 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.56 (d, J = 8.8 Hz, 2H), 7.52−7.49 (m, 1H), 7.32−7.30 (m, 1H), 7.16− 7.11 (m, 1H), 7.07 (s, 1H), 6.93 (d, J = 8.8 Hz, 2H), 5.88 (s, 2H), 3.84 (s, 3H), 3.39 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 158.7 (d, J = 240.0 Hz), 159.7, 156.9, 135.8, 134.4, 130.7, 126.8, 122.1, 114.4, 113.9 (d, J = 26.0 Hz), 112.0, 111.9, 107.0 (d, J = 5.0 Hz), 106.7, 106.5, 75.2, 56.2, 55.6; HRMS (ESI) m/z [M + H]+ calcd for C18H18FN2O3 329.1301, found 329.1303. N-Cyclohexyl-1-methyl-1H-indole-2-carboxamide (3ah). This compound was prepared by using precursors 1a and 2h: yield 0.106 g (83%) as a white solid; mp 175−177 °C; Rf = 0.36 (9:1 hexane/ethyl acetate); IR (KBr) 3282, 2931, 1629, 1536, 1464 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 1H), 7.39 (d, J = 8.4 Hz, 1H), 7.32 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 7.4 Hz, 1H), 6.81 (s, 1H), 6.08 (s, 1H), 4.06 (s, 3H), 4.00−3.93 (m, 1H), 2.07−2.04 (m, 2H), 1.80−1.76 (m, 2H), 1.49−1.40 (m, 2H), 1.31−1.22 (m, 4H); 13C NMR (125 MHz, CDCl3) δ 161.9, 139.0, 132.6, 126.4, 126.1, 124.0, 123.9, 121.7, 120.5, 110.2, 52.7, 48.5, 33.3, 32.5, 31.6, 25.6, 25.0; HRMS (ESI) m/z [M + H]+ calcd for C16H21N2O 257.1654, found 257.1652. 1-Benzyl-N-(3-chlorophenyl)-5-methoxy-1H-indole-2-carboxamide (3hi). This compound was prepared by using precursors 1h and 2i: yield 0.147 g (75%) as a white solid; mp 140−142 °C; Rf = 0.50 (9:1 hexane/ethyl acetate); IR (KBr) 3129, 1649, 1595, 1441, 1025, 824, 746 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.87 (brs, 1H, NH), 7.76−7.75 (m, 1H), 7.43−7.41 (m, 1H), 7.30−7.20 (m, 5H), 7.14− 7.10 (m, 4H), 7.00−6.98 (m, 2H), 5.83 (s, 2H), 3.88 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.2, 155.1, 138.9, 138.1, 134.8, 134.7, 131.6, 130.0, 128.6, 127.3, 126.5, 126.4, 124.5, 120.1, 117.9, 116.3, 111.9, 104.9, 102.5, 55.8, 48.1; LC−MS m/z 391 [M + 1]+. Anal. Calcd for C23H19ClN2O2: C, 70. 68; H, 4.90; N, 7.17. Found: C, 70.57; H, 4.86; N, 7.09. Synthesis of Heteroarene/Arene-2-carboxamides 5aa−fa and 6. The procedure was the same as that for 3 using 0.5 mmol of one of the acids 4a−g. Compounds 5ba−ea and 6 are reported in the literature,24 but 5aa and 5fa are new. N-Phenyl-2H-chromene-4-carboxamide (5aa). This compound was prepared by using precursors 4a and 2a: yield 0.107 g (85%) as a white solid; mp 136−138 °C; Rf = 0.28 (9:1 hexane/ethyl acetate); IR (KBr) 3255, 1649, 1595, 1447, 1041 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.69 (s, 1H), 7.60−7.58 (m, 2H), 7.38−7.35 (m, 2H), 7.27−7.24 (m, 1H), 7.18−7.15 (m, 1H), 7.13 (dd, J = 7.5 Hz and J = 1.5 Hz, 1H), 7.10 (s, 1H), 6.97−6.94 (m, 1H), 6.90 (d, J = 8.0 Hz, 1H), 5.09 (d, J = 1.0 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 163.5, 154.9, 137.5, 131.6, 129.1, 128.5, 127.7, 127.1, 124.7, 121.9, 120.8, 120.3, 116.2, 64.8; HRMS (ESI) m/z [M + H]+ calcd for C16H14NO2 252.1024, found 252.1027. 1-Methyl-N-phenyl-1H-pyrrole-3-carboxamide (5fa). This compound was prepared by using precursors 4f and 2a: yield 0.065 g (65%) as a white solid; mp 105−107 °C; Rf = 0.32 (9:1 hexane/ethyl acetate); IR (KBr) 3303, 1640, 1593, 1443, 1340 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.64 (s, 1H), 7.58 (d, J = 7.6 Hz, 2H), 7.37 (t, J = 8.0 Hz, 2H), 7.14 (t, J = 7.4 Hz, 1H), 6.81−6.72 (m, 2H), 6.18−6.16 (m, 1H), 4.00 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.0, 138.1, 129.1, 128.8, 125.8, 124.0, 120.1, 112.3, 107.5, 36.9; HRMS (ESI) m/z [M + H]+ calcd for C12H13N2O 201.1028, found 201.1029. N-(4-Methoxyphenyl)-1-naphthamide (6a). This compound was prepared by using precursors 4g and 2c: yield 0.111 g (80%) as a white solid; mp 175−177 °C; Rf = 0.36 (9:1 hexane/ethyl acetate); IR (KBr) 3227, 1647, 1603, 1469, 1030 cm−1; 1H NMR (500 MHz, CDCl3) δ 8.38−8.36 (m, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.92−7.90 (m, 1H), 7.73−7.71 (m, 2H), 7.61−7.54 (m, 4H), 7.49 (t, J = 7.8 Hz, 1H), 6.94 (d, J = 9.0 Hz, 2H), 3.85 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 167.4, 156.7, 134.6, 133.8, 131.2, 130.9, 130.1, 128.4, 127.3, 126.6, 125.3, 125.0, 124.7, 121.8, 114.3, 55.6; LC−MS m/z 278 [M + 1]+. Anal. Calcd for C18H15NO2: C, 77.96; H, 5.45; N, 5.05. Found: C, 77.85; H, 5.38; N, 5.12. N-(3-Methoxyphenyl)-1-benzamide (6b). Benzoic acid (0.820 mmol) and 3-methoxy-phenylisothiocyanate were used. Yield: 0.137 g (74%). This is a known compound (see Supporting Information for 1 H and 13C NMR).17

CDCl3) δ 160.5, 143.8, 139.8, 130.9, 125.9, 125.4, 124.2, 122.3, 121.2, 119.3, 110.5, 105.4, 31.9; HRMS (ESI) m/z [M + H]+ calcd for C16H14N3O3 296.1035, found 296.1031. 1-Butyl-N-(p-tolyl)-1H-indole-2-carboxamide (3bb). This compound was prepared by using precursors 1b and 2b: yield 0.122 g (80%) as a white solid; mp 138−140 °C; Rf = 0.67 (9:1 hexane/ethyl acetate); IR (KBr) 3298, 2957, 2921, 1645, 1593, 1454 cm−1; 1H NMR (400 MHz, CDCl3) δ 7.86 (s, 1H), 7.68 (d, J = 8.0 Hz, 1H), 7.51 (d, J = 7.6 Hz, 2H), 7.44 (d, J = 8.4 Hz, 1H), 7.34 (t, J = 7.6 Hz, 1H), 7.21−7.16 (m, 3H), 6.98 (s, 1H), 4.59 (t, J = 7.4 Hz, 2H), 2.36 (s, 3H), 1.87−1.80 (m, 2H), 1.43−1.33 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 160.6, 138.6, 135.2, 134.2, 131.8, 129.6, 126.1, 124.2, 122.0, 120.5, 120.3, 110.5, 104.5, 44.5, 32.8, 20.9, 20.2, 13.9; HRMS (ESI) m/z [M + H]+ calcd for C20H23N2O 307.1810, found 307.1806. 1-(Methoxymethyl)-N-phenyl-1H-indole-2-carboxamide (3da). This compound was prepared by using precursors 1d and 2a: yield 0.098 g (70%) as a white solid; mp 188−190 °C; Rf = 0.28 (9:1 hexane/ethyl acetate); IR (KBr) 3302, 1644, 1593, 1443, 1086 cm−1; 1 H NMR (400 MHz, CDCl3) δ 8.45 (s, 1H), 7.72−7.67 (m, 3H), 7.59 (d, J = 8.4 Hz), 7.41 (t, J = 7.6 Hz, 3H), 7.29−7.17 (m, 3H), 5.92 (s, 2H), 3.43 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 159.9, 139.3, 137.8, 132.9, 129.2, 126.4, 125.2, 124.6, 122.2, 121.6, 120.1, 110.8, 107.9, 74.9, 56.2; HRMS (ESI) m/z [M − H]− calcd for C17H17N2O2 281.1290, found 281.1293. N-Phenyl-1-(prop-2-yn-1-yl)-1H-indole-2-carboxamide (3ea). This compound was prepared by using precursors 1e and 2a: yield 0.104 g (76%) as a white solid; mp 151−153 °C; Rf = 0.20 (9:1 hexane/ethyl acetate); IR (KBr) 3365, 3267, 1640, 1526, 1433 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.97 (s, 1H), 7.72−7.67 (m, 3H), 7.57 (d, J = 8.0 Hz, 1H), 7.46−7.40 (m, 3H), 7.29−7.18 (m, 2H), 7.08 (s, 1H), 5.50 (s, 2H), 2.30 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 160.2, 138.6, 137.6, 130.9, 129.2, 126.3, 125.1, 124.7, 122.2, 121.4, 120.1, 110.6, 105.7, 78.8, 72.3, 33.9; HRMS (ESI) m/z [M + H]+ calcd for C18H15N2O 275.1184, found 275.1189. 5,6-Dimethoxy-1-methyl-N-phenyl-1H-indole-2-carboxamide (3fa). This compound was prepared by using precursors 1f and 2a: yield 0.135 g (87%) as a white solid; mp 198−200 °C; Rf = 0.36 (9:1 hexane/ethyl acetate); IR (KBr) 3308, 1650, 1593, 1464, 1097 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.87 (s, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.40 (t, J = 7.8 Hz, 2H), 7.17 (t, J = 7.4 Hz, 1H), 7.06 (s, 1H), 6.93 (s, 1H), 6.82 (s, 1H), 4.08 (s, 3H), 4.01 (s, 3H), 3.96 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.6, 149.6, 146.2, 138.0, 134.7, 130.3, 124.4, 120.1, 118.7, 104.4, 102.3, 92.5, 56.3, 56.2, 32.0; HRMS (ESI) m/z [M + Na]+ calcd for C18H18N2O3Na 333.1215, found 333.1212. 5-(Benzyloxy)-1-methyl-N-phenyl-1H-indole-2-carboxamide (3ga). This compound was prepared by using precursors 1g and 2a: yield 0.153g (86%) as a white solid; mp 194−196 °C; Rf = 0.31 (9:1 hexane/ethyl acetate); IR (KBr) 3267, 1640, 1593, 1464, 1009 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.64 (d, J = 7.6 Hz, 2H), 7.50 (d, J = 7.2 Hz, 2H), 7.44−7.33 (m, 6H), 7.20−7.12 (m, 3H), 6.92 (s, 1H), 5.14 (s, 2H), 4.08 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 160.6, 154.0, 137.8, 137.4, 135.1, 132.3, 129.3, 128.7, 128.0, 127.6, 126.2, 124.6, 120.1, 116.5, 111.3, 104.1, 103.8, 70.8, 31.8; HRMS (ESI) m/z [M + H]+ calcd for C23H21N2O2 357.1603, found 357.1601. 1-Benzyl-5-methoxy-N-phenyl-1H-indole-2-carboxamide (3ha). This compound was prepared by using precursors 1h and 2a: yield 0.155 g (87%) as a white solid; mp 168−170 °C; Rf = 0.27 (9:1 hexane/ethyl acetate); IR (KBr) 3129, 1649, 1595, 1441, 1025 cm−1; 1 H NMR (400 MHz, CDCl3) δ 7.88 (s, 1H), 7.62−7.59 (m, 2H), 7.40−7.31 (m, 3H), 7.28−7.21 (m, 3H), 7.18−7.11 (m, 4H), 7.01 (s, 1H), 6.98 (dd, J = 9.2 Hz and J = 2.4 Hz, 1H), 5.85 (s, 2H), 3.88 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 160.4, 155.0, 138.3, 137.8, 134.6, 132.2, 129.1, 128.7, 127.3, 126.6, 124.5, 120.7, 120.2, 116.0, 111.9, 104.8, 102.6, 55.8, 48.1; HRMS (ESI) m/z [M + Na]+ calcd for C23H20N2O2Na 379.1423, found 379.1422. 5-Fluoro-1-(methoxymethyl)-N-(4-methoxyphenyl)-1H-indole-2carboxamide (3ic). This compound was prepared by using precursors 1i and 2c: yield 0.112g (68%) as a white solid; mp 188−190 °C; Rf = 0.30 (9:1 hexane/ethyl acetate); IR (KBr) 3282, 1645, 1531, 1448, 4381

DOI: 10.1021/acs.joc.8b00042 J. Org. Chem. 2018, 83, 4375−4383

Article

The Journal of Organic Chemistry Synthesis of Diindole-Fused Pyridones (7−8) via PalladiumCatalyzed C−H Bond Functionalization: General Procedure. In an oven-dried round-bottom flask (10 mL), silver carbonate (1.0 mmol) was dried in vacuo (ca. 0.2 mmHg) while heating (ca. 100 °C) using a hot air gun for 0.5 h. To this, Pd(OAc)2 (10 mol %), indole-2carboxamide (3ac or 3bb, 1.0 mmol), Cs2CO3 (0.5 mmol), and DMF (3.0 mL) were added. The RBF was sealed with a stopper, and the contents were stirred at 110 °C (oil bath temperature) for 14 h. After the completion of the reaction as monitored by TLC, the mixture was cooled to rt, filtered, and extracted with diethyl ether (3 × 25 mL). The combined organic extract was washed with brine solution (4 × 10 mL). The organic part was dried over anhydrous Na2SO4, and the solvent was removed using a rotary evaporator. The crude products were purified by column chromatography (100−200 mesh silica) using hexane/EtOAc (9:1) as an eluent to afford the final products 7−8. 6-(4-Methoxyphenyl)-5,8-dimethyl-6,8-dihydropyrido[2,3-b:5,4b′]diindol-7(5H)-one (7). This compound was prepared by using precursor 3aa: yield: 0.079 g (78%) as a yellow solid; mp 245−247 °C; Rf = 0.35 (9:1 hexane/ethyl acetate); IR (KBr) 3055, 2931, 1640, 1469 cm−1; 1H NMR (400 MHz, C6D6) δ 9.06 (d, 1H, J = 8.0 Hz), 8.88 (d, 1H, J = 7.6 Hz), 7.51 (qrt, 2H, J = 7.2 Hz), 7.40 (d, 2H, J = 7.6 Hz), 7.10−7.06 (m, 4H), 6.83−6.79 (m, 2H), 4.23 (s, 3H), 3.35 (s, 3H), 2.64 (s, 3H); 13C NMR (100 MHz, C6D6) δ 160.0, 155.6, 137.6, 136.9, 135.6, 135.2, 132.01, 131.95, 131.9, 130.6, 128.6, 128.0, 127.2, 126.4, 125.3, 120.1, 118.5, 114.2, 113.4, 112.7, 96.4, 54.5, 32.6, 30.5; HRMS (ESI) m/z [M + H]+ calcd for C26H22N3O2 408.1712, found 408.1714. 5,8-Dibutyl-6-(p-tolyl)-6,8-dihydropyrido[2,3-b:5,4-b′]diindol7(5H)-one (8). This compound was prepared by using precursor 3bb: yield 0.083 g (70%) as a yellow solid; mp 110−112 °C; Rf = 0.24 (9:1 hexane/ethyl acetate); IR (KBr) 3050, 2962, 1650, 1464 cm−1; 1H NMR (400 MHz, C6D6) δ 9.11 (d, 1H, J = 8.0 Hz), 8.93 (d, 1H, J = 7.6 Hz), 7.55−7.50 (m, 2H), 7.43−7.41 (m, 3H), 7.25 (s, 1H), 7.18 (d, 2H, J = 8.0 Hz), 7.01 (d, 2H, J = 8.0 Hz), 3.27 (t, 2H, J = 8.0 Hz), 2.15 (s, 3H), 1.99−1.93 (m, 2H), 1.47−1.38 (m, 2H), 1.22−1.18 (m, 2H), 0.90 (t, 3H, J = 7.4 Hz), 0.79−0.72 (m, 2H), 0.62 (t, 3H, J = 7.2 Hz); 13C NMR (100 MHz, C6D6) δ 156.7, 141.6, 139.0, 137.64, 137.62, 136.1, 130.3, 130.0, 128.1, 126.8, 125.3, 123.9, 123.0, 122.6, 122.24, 122.16, 121.5, 120.2, 111.2, 110.5, 98.5, 44.9, 44.7, 33.7, 31.4, 21.3, 20.8, 20.3, 14.4, 13.9; HRMS (ESI) m/z [M + H]+ calcd for C32H34N3O 476.2702, found 476.2706. X-ray Data. X-ray data for compounds 3ae and 7 were collected using Mo Kα (λ = 0.71073 Å) radiation. The structures were solved and refined by standard methods.25 Compound 3ae: C17H13N3O, M = 275.30, monoclinic, space group P21/n, a = 16.2541(13), b = 5.0990(3), c = 16.9467(11) Å, α = 90, β = 96.534(3), γ = 90, V = 1395.41(17) Å3, Z = 4, μ = 0.129 mm−1, data/ restraints/parameters 3047/0/195, R indices (I > 2σ(I)) R1 = 0.0521, wR2 (all data) = 0.1242, CCDC no. 1814184. Compound 7: C26H21N3O2, M = 407.1634, monoclinic, space group C2/c, a = 17.005(3), b = 15.917(2), c = 30.298(5) Å, α = 90, β = 99.023(3), γ = 90, V = 8099(2) Å3, Z = 4, μ = 0.128 mm−1, data/ restraints/parameters 9774/0/565, R indices (I > 2σ(I)) R1 = 0.1278, wR2 (all data) = 0.2763, CCDC no. 1814185.

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ORCID

R. N. Prasad Tulichala: 0000-0002-4148-8642 K. C. Kumara Swamy: 0000-0002-7617-706X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the Department of Science & Technology (DST, New Delhi) for the single crystal X-ray diffractometer and HRMS facility (PURSE, IRHPA and FIST grants). We also thank UGC for the UPE-II and NRC programs. K.C.K. thanks DST for a J. C. Bose fellowship (SR/S2/JCB-53/2010) and CSIR (02(0240)/15/EMR-II) for funding. R.N.P.T. and M.S. thank UGC (New Delhi) for fellowships.

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S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.8b00042.

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ORTEP drawings as shown by X-ray crystallography and copies of 1H/13C NMR spectra of all new products (PDF) Crystal data for 3ae and 7 (CIF)

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DOI: 10.1021/acs.joc.8b00042 J. Org. Chem. 2018, 83, 4375−4383

Article

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DOI: 10.1021/acs.joc.8b00042 J. Org. Chem. 2018, 83, 4375−4383