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

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

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).

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 conditions^a

Entry	[Pd]	Ligand	Base	T (°C)	Yield^b (%)
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
18^c	Pd(PPh3)4	PPh3	K2CO3	110	45
19^d	Pd(PPh3)4	PPh3	K2CO3	110	21
20^e	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 scope^a

Entry	R^1	R^2	R^3	R^4	1 (% yield^b)	2 (% yield^b)
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).

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.

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

1. (a) A. R. Katritzky and A. F. Pozharskii, Handbook of Heterocyclic Chemistry, Pergamon, Oxford, 2000, ch. 4; (b) R. J. Sundberg, Indoles, Academic Press, San Diego, 1996.
2. For reviews on bioactive indoles: (a) T. Eicher, S. Hauptmann and P. A. Speicher, The Chemistry of Heterocycles: Structure, Reactions, Syntheses, and Applications, Wiley-VCH: Veriag GmbH, 2nd edn, 2003; (b) L. F. Fu, Advances in the Total Syntheses of Complex Indole Natural Products, Springer-Verlag, Berlin, Heidelberg, 2010.
3. For selected reviews on using indoles as building blocks in organic synthesis: (a) A. A. Festa, L. G. Voskressensky and E. V. Van der Eycken, Chem. Soc. Rev., 2019, 48, 4401–4423; (b) J. M. Saya, E. Ruijter and R. V. A. Orru, Chem.–Eur. J., 2019, 25, 8916–8935; (c) Y. S. Wang, F. K. Xie, B. Lin, M. S. Cheng and Y. X. Liu, Chem.–Eur. J., 2018, 24, 14302–14315; (d) J.-B. Chen and Y.-X. Jia, Org. Biomol. Chem., 2017, 15, 3550–3567; (e) W. W. Zi, Z. W. Zuo and D. W. Ma, Acc. Chem. Res., 2015, 48, 702–711; (f) S. P. Roche, J.-J. Y. Tendoung and B. Treguier, Tetrahedron, 2015, 71, 3549–3591; (g) L. M. Repka and S. E. Reisman, J. Org. Chem., 2013, 78, 12314–12320; (h) D. Zhang, H. Song and A. Y. Qin, Acc. Chem. Res., 2011, 44, 447–457.
4. For recent reviews on the synthesis of indoles: (a) X.-Y. Liu and Y. Qin, Acc. Chem. Res., 2019, 52, 1877–1891; (b) K. Nagaraju and D. W. Ma, Chem. Soc. Rev., 2018, 47, 8018–8029; (c) L. L. Anderson, M. A. Kroc, T. W. Reidl and J. Son, J. Org. Chem., 2016, 81, 9521–9529; (d) M. Platon, R. Amardeil, L. Djakovitchb and J.-C. Hierso, Chem. Soc. Rev., 2012, 41, 3929–3968; (e) M. Shiri, Chem. Rev., 2012, 112, 3508–3549.
5. For selected recent examples of condensation of o-haloanilines with alkenes to indoles: (a) D. S. Chen, Y. Y. Chen, Z. L. Ma, L. Zou, J. Q. Li and Y. Liu, J. Org. Chem., 2018, 83, 6805–6814; (b) S. J. Gharpure and D. Anuradha, Org. Lett., 2017, 19, 6136–6139; (c) M. Paraja and C. Valdés, Chem. Commun., 2016, 52, 6312–6315; (d) A. P. Kale, G. S. Kumar and M. Kapur, Org. Biomol. Chem., 2015, 13, 10995–11002; (e) A. P. Kale, G. S. Kumar, A. R. K. Mangadan and M. Kapur, Org. Lett., 2015, 17, 1324–1327; (f) B. L. Yin, C. B. Cai, G. H. Zeng, R. Q. Zhang, X. Li and H. F. Jiang, Org. Lett., 2012, 14, 1098–1101; (g) T. Jensen, H. Pedersen, B. Bang-Andersen, R. Madsen and M. Jørgensen, Angew. Chem., Int. Ed., 2008, 47, 888–890.
6. For selected recent examples of condensation of o-haloanilines with alkynes to indoles: (a) D. P. Chen, J. Z. Yao, L. L. Chen, L. F. Hu, X. F. Li and H. W. Zhou, Org. Chem. Front., 2019, 6, 1403–1408; (b) P. K. R. Panyam, R. Sreedharan and T. Gandhi, Org. Biomol. Chem., 2018, 16, 4357–4364; (c) P. K. R. Panyama and T. Gandhi, Adv. Synth. Catal., 2017, 359, 1144–1151; (d) T. A. Moss, A. S. Lister and J. Wang, Tetrahedron Lett., 2017, 58, 3136–3138; (e) X. H. Pan, C. Y. Yang, J. L. Cleveland and T. D. Bannister, J. Org. Chem., 2016, 81, 2194–2200; (f) K. V. Chuang, M. E. Kieffer and S. E. Reisman, Org. Lett., 2016, 18, 4750–4753; (g) G. P. da Silva, A. Ali, R. C. da Silva, H. Jiang and M. W. Paixão, Chem. Commun., 2015, 51, 15110–15113; (h) H. C. Lin and U. Kazmaier, Eur. J. Org. Chem., 2009, 1221–1227.
7. For selected recent examples of condensation of o-haloanilines with allenes to indoles: (a) Y. Higuchi, T. Mita and Y. Sato, Org. Lett., 2017, 19, 2710–2713; (b) H. Iwasaki, K. Suzuki, M. Yamane, S. Yoshida, N. Kojima, M. Ozeki and M. Yamashita, Org. Biomol. Chem., 2014, 12, 6812–6815; (c) S. Z. He, R. P. Hsung, W. R. Presser, Z.-X. Ma and B. J. Haugen, Org. Lett., 2014, 16, 2180–2183; (d) M.-G. Braun, M. H. Katcher and A. G. Doyle, Chem. Sci., 2013, 4, 1216–1220.
8. For reviews on diversity-oriented synthesis: (a) E. Lenci, G. Menchi, F. I. Saldívar-Gonzalez, J. L. Medina-Franco and A. Trabocchi, Org. Biomol. Chem., 2019, 17, 1037–1052; (b) H. H. Kinfe, Org. Biomol. Chem., 2019, 17, 4153–4182; (c) T. J. Pawar, H. Jiang, M. A. Vázquez, C. V. Gómez and D. C. Cruz, Eur. J. Org. Chem., 2018, 1835–1851; (d) D. Tejedor, S. López-Tosco, G. Méndez-Abt, L. Cotos and F. García-Tellado, Acc. Chem. Res., 2016, 49, 703–713; (e) S. Kotha, D. Deodhar and P. Khedkar, Org. Biomol. Chem., 2014, 12, 9054–9091.
9. For reviews on the furans as building blocks in organic synthesis: (a) M. Decostanzi, R. Auvergne, B. Boutevin and S. Caillol, Green Chem., 2019, 21, 724–747; (b) X. Kong, Y. Y. Zhu, Z. Fang, J. A. Kozinski, I. S. Butler, L. Xu, H. Song and X. J. Wei, Green Chem., 2018, 20, 3657–3682; (c) S. Chen, R. Wojcieszak, F. Dumeignil, E. Marceau and S. Royer, Chem. Rev., 2018, 118, 11023–11117; (d) I. V. Trushkov, M. G. Uchuskin and A. V. Butin, Eur. J. Org. Chem., 2015, 2999–3016; (e) F. van der Pijl, F. L. van Delft and F. P. J. T. Rutjes, Eur. J. Org. Chem., 2015, 4811–4829.
10. For reviews on Ugi reaction: (a) Q. Wang, D.-X. Wang, M.-X. Wang and J. Zhu, Acc. Chem. Res., 2018, 51, 1290–1300; (b) S. Shaabani and A. Dçmling, Angew. Chem., Int. Ed., 2018, 57, 16266–16268; (c) B. H. Rotstein, S. Zaretsky, V. Rai and A. K. Yudin, Chem. Rev., 2014, 114, 8323–8359.
11. For selected recent examples of further transformation of Ugi-adducts: (a) H. J. Ghazvini, T. J. J. Müller, F. Rominger and S. Balalaie, J. Org. Chem., 2019, 84, 10740–10748; (b) Y. He, Z. Liu, D. J. Wu, Z. H. Li, K. Robeyns, L. V. Meervelt and E. V. Van der Eycken, Org. Lett., 2019, 21, 4469–4474; (c) A. Zidan, M. Cordier, A. M. El-Naggar, N. E. A. A. El-Sattar, M. A. Hassan, A. K. Ali and L. E. Kaïm, Org. Lett., 2018, 20, 2568–2571; (d) A. Zidan, J. Garrec, M. Cordier, A. M. El-Naggar, N. E. A. Abd El-Sattar, A. K. Ali, M. A. Hassan and L. E. Kaim, Angew. Chem., Int. Ed., 2017, 56, 12179–12183; (e) X. Du, J. Yu, J. Gong, M. Zaman, O. P. Pereshivko and V. A. Peshkov, Eur. J. Org. Chem., 2019, 2502–2507; (f) Y. He, Z. Li, K. Robeyns, L. V. Meervelt and E. V. V. Eycken, Angew. Chem., Int. Ed., 2018, 57, 272–276.
12. L. Kaim, L. Grimaud and S. Wagschal, Chem. Commun., 2011, 47, 1887–1889.
13. (a) J. Liu, X. Xu, J. Li, B. Liu, H. Jiang and B. Yin, Chem. Commun., 2016, 52, 9550–9553; (b) J. Liu, H. Peng, L. Lu, X. Xu, H. Jiang and B. Yin, Org. Lett., 2016, 18, 6440–6443.

---

Footnote

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

---