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Access to N-unprotected 2-amide-substituted indoles from Ugi adducts via palladium-catalyzed intramolecular cyclization of o-iodoanilines bearing furan rings

Hui Peng, Kai Jiang, Guangjin Zhen, Furong Wang* and Biaolin Yin*
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou, 510640, P. R. China. E-mail: blyin@scut.edu.cn

Received 17th January 2020 , Accepted 28th February 2020

First published on 23rd March 2020


Abstract

A variety of N-unprotected 2-amide-substituted indoles were synthesized from readily available furfural-based Ugi adducts in moderate to good yields via palladium-catalyzed intramolecular cyclization of o-iodoanilines bearing furan rings. These reactions involved a cascade sequence consisting of dearomatizing arylation, opening of the furan ring, and deprotection of the N atom.


Polyfunctionalized indoles, including 2-amide-substituted indoles, are privileged motifs in medicinal chemistry and synthetic organic chemistry.1 The indole ring is probably the most common heterocycle found in natural products and pharmaceuticals,2 and functionalized indoles are versatile building blocks for the preparation of structurally complex and novel indolines, many of which show potent bioactivities (Fig. 1).3 Thus, much effort has been devoted to the development of strategies for the synthesis and functionalization of indoles and their derivatives.4 Among them, the most attractive routes are those involving transition-metal-catalyzed intermolecular or intramolecular cyclization of o-haloanilines with alkenes,5 alkynes,6 or allenes.7 Despite the attractiveness of these routes, it would be desirable to develop efficient catalytic methods for the preparation of functionalized indoles from o-haloanilines and furans, which are readily available, alternatives to alkenes for diversity-oriented synthesis strategies.8,9
image file: d0ra01830a-f1.tif
Fig. 1 Bioactive 2-amide-substituted indoles.

We speculated that Ugi adducts might be useful for this purpose. Ugi reactions involve four components—an aldehyde or ketone, an isocyanide, an amine, and a carboxylic acid—and afford a diverse array of functionalized α-acylamino amides,10 which can be subjected to a wide variety of postcondensation transformations to achieve further structural diversity.11 Recently, we and other groups developed a route to functionalized indoles via palladium-catalyzed intramolecular arylative dearomatization of 2-bromo-N-(furan-2-ylmethyl)anilines.5f,12 In this paper, we report a convenient protocol for the synthesis of α-amide-substituted indoles via palladium-catalyzed intramolecular arylative cyclization of furans that were generated by Ugi reactions of furfurals and o-haloanilines (Scheme 1).


image file: d0ra01830a-s1.tif
Scheme 1 Pd-catalyzed approaches to polyfunctionalized indoles from o-haloanilines.

The success of this protocol relies on suppression of the following side reactions: β-arylation of the furan ring, protonation of the ArI, and intramolecular C–N coupling. With this in mind, we chose N-(tert-butyl)-2-(furan-2-yl)-2-(N-(2-iodophenyl)acetamido)acetamide (1a)—which was prepared by means of a Ugi reaction of furfural, 2-iodoaniline, acetic acid, and tert-butyl isocyanide—as the substrate for optimization of the reaction conditions. We were pleased to find that upon treatment of 1a with Pd(PPh3)4 (0.05 equiv.), PPh3 (0.1 equiv.), and K2CO3 (2 equiv.) in 1,4-dioxane at 70 °C for 12 h, polysubstituted N-unprotected indole 2a was obtained in 30% yield along with unidentified by-products (Table 1, entry 1). This transformation clearly involved a cascade sequence consisting of arylation, ring-opening, and N-deacetylation. The in situ N-deacetylation is particularly interesting and useful and may have resulted from the weaker nucleophilicity of the N atom of the indole ring relative to that of the amide N of 1a. Other bases (Cs2CO3, NaHCO3, Na2CO3, and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)) were also tested, but 2a was not detected in any of these reactions (entries 2–5). Stronger base of Cs2CO3 resulted in side-reaction of C–N coupling. NaHCO3 and Na2CO3 as the base mostly led to the protonated product. DBU led to no reaction. Next, we attempted to improve the yield of 2a by increasing the reaction temperature (entries 6–9), and an 89% yield was obtained at 110 °C. Screening of various ligands other than PPh3 failed to produce better results (entries 10–13), and Pd(PPh3)4 was the optimal catalyst (compare entry 2 with entries 14–17). Evaluation of other solvents (THF, toluene, and DMSO) did not improve the yield (entries 18–20). Therefore, we concluded that the optimal conditions involved the use of Pd(PPh3)4 (0.05 equiv.) as the catalyst, K2CO3 (2.0 equiv.) as the base, 1,4-dioxane as the solvent, and 110 °C as the reaction temperature.

Table 1 Optimization of reaction conditionsa

image file: d0ra01830a-u1.tif

Entry [Pd] Ligand Base T (°C) Yieldb (%)
a Reaction conditions: 1a (0.2 mmol), catalyst (0.05 equiv.), ligand (0.1 equiv.), and base (2 equiv.) in 2.0 mL of 1,4-dioxane were allowed to react under nitrogen for 12 h. DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DPPP, 1,3-bis(diphenylphosphino)propane; DPPB, 1,4-bis(diphenylphosphino)butane; DPPF, 1,1′-bis(diphenylphosphino)ferrocene; xantphos, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene.b Yields were determined by 1H NMR spectroscopy. ND = not detected.c THF was the solvent.d Toluene was the solvent.e DMSO was the solvent.
1 Pd(PPh3)4 PPh3 K2CO3 70 30
2 Pd(PPh3)4 PPh3 Cs2CO3 70 ND
3 Pd(PPh3)4 PPh3 NaHCO3 70 ND
4 Pd(PPh3)4 PPh3 Na2CO3 70 ND
5 Pd(PPh3)4 PPh3 DBU 70 ND
6 Pd(PPh3)4 PPh3 K2CO3 80 31
7 Pd(PPh3)4 PPh3 K2CO3 100 44
8 Pd(PPh3)4 PPh3 K2CO3 110 89
9 Pd(PPh3)4 PPh3 K2CO3 120 25
10 Pd(PPh3)4 DPPP K2CO3 110 18
11 Pd(PPh3)4 DPPB K2CO3 110 19
12 Pd(PPh3)4 DPPF K2CO3 110 12
13 Pd(PPh3)4 Xantphos K2CO3 110 48
14 Pd2(dba)3 PPh3 K2CO3 110 50
15 Pd(OAc)2 PPh3 K2CO3 110 18
16 Pd(PPh3)2Cl2 PPh3 K2CO3 110 54
17 Pd(CH3CN)2Cl2 PPh3 K2CO3 110 31
18c Pd(PPh3)4 PPh3 K2CO3 110 45
19d Pd(PPh3)4 PPh3 K2CO3 110 21
20e Pd(PPh3)4 PPh3 K2CO3 110 66


With the optimized conditions in hand, we prepared a series of Ugi adducts 1 with various R1–R4 groups and a furan moiety in moderate yields, and we subjected the resulting compounds to the arylative cyclization conditions to investigate the substrate scope (Table 2). In all cases, the reaction proceeded smoothly to afford corresponding indoles 2 in moderate to good isolated yields (40–77%). Specifically, with R1 = H, R2 = Me, and R4 = t-Bu, several R3 groups (H, Me, F, and Cl) were screened and found to provide corresponding indolyl aldehydes 2a–2d in 45–66% yields (entries 1–4). Reaction of 1c, which bears an electron-withdrawing 4-F group, gave a substantial amount of a by-product generated by protonation without opening of the furan ring, which resulted in a relatively low yield of 2c (45%). Similarly, with R1 = Me, R2 = Me, and R4 = t-Bu, compounds with H, Me, MeO, and CF3 at R3 afforded 2e–2h in 60–77% yields (entries 5–8). Substrate 1h, which has an electron-withdrawing 4-CF3 at R3, gave a lower yield (60%) than the other three substrates. In addition to H or Me, R1 could be Ph or 4-Me-Ph: 2i and 2j were obtained in 67% and 72% yields, respectively (entries 9 and 10). Notably, when R2 was an aryl group (4-MeO-Ph), 2e was produced in 77% yield (entry 11). In contrast, when R3 was n-Pr, the yield of 2e was only 40% (entry 12). Finally, when R4 was cyclohexyl, 2m–2o were obtained in good yields (entries 13–15).

Table 2 Substrate scopea

image file: d0ra01830a-u2.tif

Entry R1 R2 R3 R4 1 (% yieldb) 2 (% yieldb)
a Reaction conditions: 1 (0.2 mmol), catalyst (0.05 equiv.), ligand (0.1 equiv.), and base in 2.0 mL solvent were allowed to react at 110 °C for 12 h. Cy, cyclohexyl.b Isolated yields are given.
1 H Me H t-Bu 1a (50) 2a (66)
2 H Me Me t-Bu 1b (45) 2b (63)
3 H Me F t-Bu 1c (52) 2c (45)
4 H Me Cl t-Bu 1d (41) 2d (64)
5 Me Me H t-Bu 1e (42) 2e (77)
6 Me Me Me t-Bu 1f (42) 2f (63)
7 Me Me MeO t-Bu 1g (40) 2g (70)
8 Me Me CF3 t-Bu 1h (40) 2h (60)
9 Ph Me H t-Bu 1i (46) 2i (67)
10 p-Tolyl Me H t-Bu 1j (33) 2j (72)
11 Me PMB H t-Bu 1k (55) 2e (77)
12 Me n-Pr H t-Bu 1l (32) 2e (40)
13 Me Me H Cy 1m (57) 2m (50)
14 Me Me MeO Cy 1n (53) 2n (61)
15 Me Me CF3 Cy 1o (42) 2o (66)


Products 2 bear amide, carbonyl and alkenyl functional groups, all of which are amenable to numerous further transformations that can be used to prepare structurally diverse indoles. For example, hydrogenation of the double bonds of 2e–2g and 2i afforded the corresponding products (3e–3g and 3i) in good yields (Scheme 2).


image file: d0ra01830a-s2.tif
Scheme 2 Hydrogenation of 2.

In Scheme 3, we depict two possible pathways for this transformation (electrophilic palladation and carbopalladation) on the basis of the above-described experimental results and previously reported results regarding arylation of furans.12,13 Specifically, an oxidative addition reaction between aryl iodide 1 and palladium(0) forms intermediate A. Intramolecular electrophilic palladation of the furan ring of A at the α-position results in the generation of intermediate B, which undergoes base-mediated furan ring-opening and β-elimination to afford intermediate C. A reductive elimination reaction of C provides F and palladium(0), completing the catalytic cycle. Deprotection of F yields 2. Alternatively, A undergoes carbopalladation to form intermediate D, which isomerizes to π-allylic palladium complex E. Ring-opening of E produces F.


image file: d0ra01830a-s3.tif
Scheme 3 Possible pathway for the formation of 2.

Conclusions

In summary, we have developed a protocol for the synthesis of N-unprotected 2-amide-substituted indoles by means of Pd-catalyzed dearomatizing intramolecular arylation reactions of readily available furfural-based Ugi adducts. This protocol involves an intramolecular condensation of an o-haloaniline bearing a furan ring and a subsequent cascade involving dearomatizing arylation, opening of the furan ring, and N-deprotection. The bioactivities of the obtained polysubstituted indoles are being explored in our laboratory, and the results will be reported in due course.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This work was supported by grants from the National Program on Key Research Project (no. 2016YFA0602900), the National Natural Science Foundation of China (no. 21871094), the Science and Technology Program of Guangzhou, China (no. 201707010057), Guangdong Natural Science Foundation (no. 2017A030312005), and the Science and Technology Planning Project of Guangdong Province, China (no. 2017A020216021).

Notes and references

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Footnote

Electronic supplementary information (ESI) available. See DOI: 10.1039/d0ra01830a

This journal is © The Royal Society of Chemistry 2020