Skip to main content
NCBI home page
ACS Omega logoLink to ACS Omega
. 2022 Nov 30;7(49):45341–45346. doi: 10.1021/acsomega.2c05909

Three Component Cascade Reaction of Cyclohexanones, Aryl Amines, and Benzoylmethylene Malonates: Cooperative Enamine-Brønsted Acid Approach to Tetrahydroindoles

Jose Cortes Vazquez †, Waad S Alharbi †, Jacqkis Davis †, Alexia Moore †, Vladimir N Nesterov †, Thomas R Cundari †, Hong Wang †,*, Weiwei Luo ‡,*
PMCID: PMC9753174  PMID: 36530259

Abstract

graphic file with name ao2c05909_0008.jpg

A three-component cascade reaction comprising cyclic ketones, arylamines, and benzoylmethylene malonates has been developed to access 4,5,6,7-tetrahydro-1H-indoles. The reaction was achieved through cooperative enamine-Brønsted catalysis in high yields with wide substrate scopes. Mechanistic studies identified the role of the Brønsted acid catalyst and revealed the formation of an imine intermediate, which was confirmed by X-ray crystallography.

1. Introduction

Nitrogen-containing heterocycles are essential components of a wide range of bioactive natural products.1 Nitrogen-based heterocycles have exhibited a wide range of biological activities including cancer, HIV, diabetes, tuberculosis, and Alzheimer’s disease.2 4,5,6,7-Tetrahydro-1H-indoles represent an important class of structural scaffolds in the design and derivation of new pharmacophores, which can act as inhibitors for tyrosine kinase,3 anti-hepatitis C virus,4 anti-cancer and anti-oxidant agents,5 and natural products.6 4,5,6,7-Tetrahydro-1H-indoles also serve as synthetic intermediates for natural products such as goniomitine7 and chuangxinmycin.8 Recently, 4,5,6,7-tetrahydro-1H-indoles have also been found to be present in sponge Scalarispongia species.9

Considerable efforts have been devoted to developing synthetic methods to construct 4,5,6,7-tetrahydro-1H-indoles due to their diverse biological activity. Syntheses of N-substituted 4,5,6,7-tetrahydro-1H-indoles have been achieved through metal Lewis acid catalysis,10 Brønsted acid catalysis,11 and microwave synthesis.12 Catalyst-free conditions have also been reported.13 Benzoylmethylene malonates are effective Michael acceptors14 and have been utilized for the synthesis of heterocycles including furans, quinoxalines, imidazoles, benzo[1,4]-thiazines, 2,4,5-trisubstituted oxazole, and pyrrolobenzoxazines.15 In 2016, Jia and coworkers reported Friedel–Crafts reactions with benzoylmethylene malonates to afford enantioselective Michael products using Cu(OTf)2 and (S)-iPr-bisoxazoline as the catalyst (Figure 1a).16 Kakiuchi et al. developed an efficient cyclization reaction with benzoylmethylene malonates and propargyl alcohols for the synthesis of hydrofurans (Figure 1b).17 Bisht and Peddinti reported a FeCl3 mediated reaction of preformed β-enamino ester and benzoylmethylene malonates affording pyrrolobenzoxazines (Figure 1c).18

Figure 1.

Figure 1

Open in a new tab

Reactions developed with benzoylmethylene malonates for heterocyclic compounds. (a) Jia et al., 2016.16 (b) Kakiuchi et al., 2007.17 (c) Bisht and Peddinti, 2017.18 (d) This work.

It has been reported that the reaction of activated alkenes18,19 or 2,3-diketoesters20 with aldehydes/ketones and amines can afford pyrroles or hydroxyindoles. Most of these reactions are through the β-enaminone intermediate, which is derived from a 1,3-diketone and an amine. β-Enaminone is a common synthetic intermediate/substrate for the synthesis of pyrrole.21 In contrast, there are only three reports in the literature likely going through enamine intermediate to construct pyrroles, two of which utilized nitroalkene as the enamine acceptor12, 19d and the other one utilized 3-nitrobenzo[b]thiophene as the enamine acceptor.19e We became interested in utilizing benzoylmethylene malonates to develop a new synthetic method for tetrahydroindoles/pyrroles through cooperative enamine-metal Lewis acid/Brønsted acid catalysis (Figure 1d). Very recently, our group has demonstrated the feasibility of arylamines serving as effective catalysts in enamine synthesis leveraging a reversed soft–hard strategy.22 The development of a new method to access tetrahydroindoles/pyrroles through enamine and benzoylmethylene malonates will extend the utility of enamine, providing a convenient approach to this important class of compounds not available with existing methods.

2. Results and Discussion

We started our investigation with cyclohexanone (1a), 4-methoxyaniline (2a) and dimethyl 2-(2-oxo-2-phenylethylidene) malonate (3a) (Table 1). Metal Lewis acids including Sc(OTf)3, Cu(OTf)2, and Y(OTf)3 were first assessed to catalyze this reaction in toluene at 50 °C. We were delighted to find out that the desired product (4a) was formed in all these reactions. However, the yields were low (18–45%, entries 1–3). The starting materials were mainly recovered after the reactions were worked up. We then tested different solvents using Y(OTf)3 as the catalyst (entries 4–9), which gave the highest yield in toluene (entry 2). Dichloromethane (DCM) turned out to be the best solvent offering 4a in 61% yield (entry 4). Interestingly, increasing the load of the catalyst by twofold did not increase the yield (entry 9). Addition of 4 Å MS enhanced the yield to 70% (entry 10). Raising the temperature to 60 °C significantly improved the efficiency of the reaction (88%, entry 11). The addition of more 4 Å MS or longer reaction time did not affect the reaction significantly (entries 12 & 13). Addition of a slight excess of 4-methoxyaniline improved the yield to 91% (entry 14). Yb(OTf)3 (entry 15) showed similar activity with Y(OTf)3. A Brønsted acid, i.e., diphenyl phosphate, was also attempted and turned out to be slightly better than metal Lewis acids (entries 16 & 17). Finally, when the temperature was raised to 65 °C, an excellent yield of 96% yield was achieved (entry 18).

Table 1. Optimization of Conditionsa.

2.

entry solvent catalyst T (°C) additive(4 Å MS) yield (%)b
1c toluene Sc(OTf)3 50   18
2c toluene Y(OTf)3 50   45
3c toluene Cu(OTf)2 50   10
4c DCM Y(OTf)3 50   61
5c THF Y(OTf)3 50   6
6c EtOAc Y(OTf)3 50   8
7c CH3CN Y(OTf)3 50   33
8c CHCl3 Y(OTf)3 50   46
9d DCM Y(OTf)3 50   50
10 DCM Y(OTf)3 50 10 mg 70
11 DCM Y(OTf)3 60 10 mg 88
12 DCM Y(OTf)3 60 20 mg 85
13e DCM Y(OTf)3 60 10 mg 87
14f DCM Y(OTf)3 60 10 mg 91
15f DCM Yb(OTf)3 60 10 mg 90
16f DCM (PhO)2PO2H 60 10 mg 93
17f CCl4 (PhO)2PO2H 60 10 mg 87
18f DCM (PhO)2PO2H 65 10 mg 96
Open in a new tab
a

The reactions were conducted with 1.0 mmol of 1a, 0.1 mmol of 2a, and 0.1 mmol of 3a for 24 h in 1 mL of solvent.

b

Isolated yield.

c

NMR yield.

d

20% of Y(OTf)3 was used.

e

Stirred for 48 h.

f

1.1 eq of 4-methoxyaniline was used.

We then investigated the substrate scope of this reaction with different benzoylmethylene malonates (Table 2). Benzoylmethylene malonates with different substituents on the phenyl rings were reacted with cyclohexanone and 4-methoxyaniline under optimal conditions. Both electron-donating and electron-withdrawing groups at meta, ortho, and para positions afforded the desired 4,5,6,7-tetrahydro-1H-indoles in high yields (4b-4i, 89–99%). Disubstituted aryl groups at the meta-positions including the bulky CF3 also gave good yields (4j and 4k). However, trisubstituted aryl groups at both para and ortho positions did not give any product, indicating that steric hindrance is at play in this case (4o, 0%). We also tried different ester groups of the benzoylmethylene malonates (4l–4n, 83–96%). Larger esters such as isopropoxy esters (4m and 4n) also worked well for this reaction.

Table 2. Substrate Scope of Benzoylmethylene malonatesa,b.

2.

Open in a new tab
a

Reaction conditions: 1a (1.0 mmol), 2a (0.11 mmol), 3 (0.1 mmol), 4 Å MS (10 mg), DCM (1 mL) at 65 οC for 24 h.

b

Isolated yields.

The substrate scope of arylamine and cyclic ketone were also explored (Table 3). The reaction of p-methoxyaniline and 3a worked smoothly with a 7-membered cyclic ketone, affording the desired 4,5,6,7-tetrahydro-1H-indole in 89% yield (5a). Five-membered cyclic ketone also reacted with p-methoxyaniline and 3a, albeit giving the product in lower yield (5b, 75%), likely due to the higher ring strain upon fusion with the 5-membered pyrrole ring. Six-membered heterocyclic ketones generated the desired products in good yields (5c & 5d, 87 and 83% yield, respectively). Substituted cyclohexanone also produced the product in excellent yield (5e, 99% yield). For the scope of arylamine, electron-donating groups including methyl and methoxy groups at ortho, meta, and para positions reacted efficiently with cyclohexanone and 3a, leading to the formation of the products in good yield in 24 h (6a–6d, 93–99% yield). When electron-withdrawing bromo was present at the ortho, para, and meta positions of the arylamines, longer reaction times (48 h) were needed and the yields decreased (6e–6h, 41–67% yield). It is notable that the o-bromoaniline gave the lowest yield (41%), possibly due to the proximity of the large substituent and the NH2 slowing down the formation of enamine with the cyclohexanone. This effect was also observed with 6i (64% yield), where a bulky t-butyl group is placed at the ortho position of the arylamine. In the case of fluoroaniline, it is interesting that the p-fluoroaniline was able to generate the product in 94% yield in 72 h. In contrast, m-fluoroaniline resulted in the product in only 59% yield in 72 h (6k). Strongly electron-withdrawing nitro group at the ortho and para position of the arylamines were also attempted but did not produce the desired product owning to their low nucleophilicity. Aliphatic amines were attempted under the optimized conditions to demonstrate the functionality of this method. The desired 4,5,6,7-tetrahydro-1H-indoles were obtained in good yield for 6l (68%) and high yields for 6m and 6n (88 and 94%). The structure of 4,5,6,7-tetrahydro-1H-indoles were confirmed with 1H and 13C NMR spectroscopy, mass spectrometry, and X-ray crystallography (6i, CCDC 2164186). Gram scale reaction of 1a, 2a, and 3a was also conducted (see SI), affording the product in 86% yield.

Table 3. Substrate Scope of Ketone and Arylaminea,b.

2.

Open in a new tab
a

Reaction conditions: 1 (1.0 mmol), 2 (0.11 mmol), 3a (0.1 mmol), 4 Å MS (10 mg), DCM (1 mL) at 65 °C for 24–72 h.

b

Isolated yields.

As noted above, when a bulkier group was present at the ortho position of arylamine (6f and 6i, Table 3), the reaction slowed down and the yields decreased. A similar steric effect was also observed for benzoylmethylene malonates when the ortho positions on the phenyl ring were occupied (4o, Table 1). To investigate the mechanism of this reaction,20,23 we decided to explore how steric effect affected the process of the reaction (Scheme 1). We selected 3i where a moderately bulky iodo group is present at the ortho position of the phenyl ring to react with o-t-butylaniline (2i) and cyclohexanone under optimized conditions (65 °C). As it turned out, no formation of 4,5,6,7-tetrahydro-1H-indole (9a) was detected (Scheme 1, a). Instead, another product was isolated as the major product (8a), which was identified as an imine intermediate confirmed via NMR spectroscopy, mass spectrometry, and X-ray crystallography (8a, CCDC: 2164187). Reaction of another benzoylmethylene malonate with a methyl group at the ortho position of the phenyl ring was also attempted, leading to similar results (8b). In sharp contrast, when the iodo group was placed at the meta position of the phenyl ring, the imine intermediate was not observed and 4,5,6,7-tetrahydro-1H-indole was isolated (9b). These data indicate that steric effects play an important role in this reaction. To prove that the imine is a synthetic intermediate in this reaction, 8a in DCM was heated to 100 °C in the presence of (PhO)2PO2H, and 4,5,6,7-tetrahydro-1H-indole (9a) was obtained with 60% yield with unreacted 8a still present in the reaction mixture, confirming that imine 8a can be converted to 9a (Scheme 1c).

Scheme 1. Mechanism Investigation: (a) Steric Effect; (b, c) Catalyst Investigation.

Scheme 1

Open in a new tab

To gain further insight into the mechanism, we investigated the role of the acid catalyst ((PhO)2PO2H). The reaction of 3i, 1a, and 2i in the absence of an acid catalyst at 65 °C resulted in 55% yield of imine 8a without observation of 9a, similar to the result with the catalyst (8a, 56% yield) (Scheme 1b). When 8a in DCM was heated to 100 °C without a catalyst, no product was observed, which is in sharp contrast with a similar reaction conducted in the presence of the acid catalyst (Scheme 1c). These data suggest that the acid catalyst, i.e., (PhO)2PO2H, plays a crucial role in the transformation of 8a to 9a. A mechanism of the reaction was proposed based on these experimental data (Scheme 2). Enamine A is formed in situ from cyclic ketone and arylamine, which then reacts with benzoylmethylene malonate (3) through a Michael-type addition to give 8. An equilibrium between imine 8 and enamine B can be established. The carbonyl group is then activated by (PhO)2PO2H to initiate an intramolecular cyclization reaction (C) to afford D, after which the loss of water provides the final 4,5,6,7-tetrahydro-1H-indole.

Scheme 2. Proposed Mechanism.

Scheme 2

Open in a new tab

3. Conclusions

In summary, we have developed a novel synthetic method to access 4,5,6,7-tetrahydro-1H-indoles/pentasubstituted pyrroles, which is of high biological and pharmaceutical importance. This three-component cascade reaction involving cyclic ketones, arylamines, and benzoylmethylene malonates is concise, versatile, and efficient, affording 4,5,6,7-tetrahydro-1H-indoles in high yields with wide substrate scopes. The three-component reaction is achieved through cooperative enamine-acid (Brønsted and metal Lewis acid) catalysis. Mechanistic studies indicate that the steric effect plays a crucial role in determining the output of the reaction. The formation of an imine intermediate was revealed and confirmed with X-ray crystallography. The Brønsted acid catalyst was proved to be the key to prompt the intramolecular cyclization reaction of the imine intermediate, leading to the form 4,5,6,7-tetrahydro-1H-indoles. Our DFT calculations suggest that 4,5,6,7-tetrahydro-1H-indoles with bulky groups could possess axial chirality (see SI). New reactions based on cooperative enamine-metal Lewis acid catalysis as well as the development of asymmetric catalytic methods to access 4,5,6,7-tetrahydro-1H-indoles with axial chirality are underway in our laboratory.

Acknowledgments

We acknowledge the National Science Foundation MRI Program (CHE-1726652) and the University of North Texas for supporting the acquisition of the Rigaku XtaLAB Synergy-S X-ray diffractometer. This material is based on work supported by the National Science Foundation under grant no. [1954422]. We thank Dr. Guido Verbeck and the Laboratory for Imaging Mass Spectrometry at the University of North Texas for Mass Spectrometry data. The authors thank the Saudi Arabian Cultural Mission in the USA for their support of W.S.A. W.L. is grateful for the financial support from the National Natural Science Foundation of China (22201022) and Natural Science Foundation of Hunan Province (2021JJ40563).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.2c05909.

  • Experimental procedures, 1H and 13C NMR and other characterization data, single crystal X-ray analysis, and computational methods (PDF)

  • Crystallographic data for the 6i complex (CIF)

  • Crystallographic data for 8a (CIF)

Author Contributions

The manuscript was written through contributions of all authors.

The authors declare no competing financial interest.

Supplementary Material

ao2c05909_si_001.pdf (5.9MB, pdf)
ao2c05909_si_002.cif (913.7KB, cif)
ao2c05909_si_003.cif (1.6MB, cif)

References

  1. a Kerru N.; Gummidi L.; Maddila S.; Gangu K. K.; Jonnalagadda S. B. A Review on Recent Advances in Nitrogen-Containing Molecules and Their Biological Applications. Molecules 2020, 25, 1909. 10.3390/molecules25081909. [DOI] [PMC free article] [PubMed] [Google Scholar]; b Gordon E. M.; Barrett R. W.; Dower W. J.; Fodor S. P. A.; Gallop M. A. Applications of combinatorial technologies to drug discovery. 2. Combinatorial organic synthesis, library screening strategies, and future directions. J. Med. Chem. 1994, 37, 1385–1401. 10.1021/jm00036a001. [DOI] [PubMed] [Google Scholar]; c Zhang B.; Studer A. Recent advances in the synthesis of nitrogen heterocycles via radical cascade reactions using isonitriles as radical acceptors. Chem. Soc. Rev. 2015, 44, 3505–3521. 10.1039/C5CS00083A. [DOI] [PubMed] [Google Scholar]; d Kaur R.; Chaudhary S.; Kumar K.; Gupta M. K.; Rawal R. K. Recent synthetic and medicinal perspectives of dihydropyrimidinones: A review. Eur. J. Med. Chem. 2017, 132, 108–134. 10.1016/j.ejmech.2017.03.025. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. a Chaudhari K.; Surana S.; Jain P.; Patel H. M. Mycobacterium Tuberculosis (MTB) GyrB inhibitors: An attractive approach for developing novel drugs against TB. Eur. J. Med. Chem. 2016, 124, 160–185. 10.1016/j.ejmech.2016.08.034. [DOI] [PubMed] [Google Scholar]; b Sameem B.; Saeedi M.; Mahdavi M.; Shafiee A. A review on tacrine-based scaffolds as multi-target drugs (MTDLs) for Alzheimer’s disease. Eur. J. Med. Chem. 2017, 128, 332–345. 10.1016/j.ejmech.2016.10.060. [DOI] [PubMed] [Google Scholar]; c Akhtar J.; Khan A. A.; Ali Z.; Haider R.; Yar M. S. Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. Eur. J. Med. Chem. 2017, 125, 143–189. 10.1016/j.ejmech.2016.09.023. [DOI] [PubMed] [Google Scholar]; d Kaur R.; Dahiya L.; Kumar M. Fructose-1,6-bisphosphatase inhibitors: A new valid approach for management of type 2 diabetes mellitus. Eur. J. Med. Chem. 2017, 141, 473–505. 10.1016/j.ejmech.2017.09.029. [DOI] [PubMed] [Google Scholar]; e Patel R. V.; Keum Y.-S.; Park S. W. Sketching the historical development of pyrimidones as the inhibitors of the HIV integrase. Eur. J. Med. Chem. 2015, 97, 649–663. 10.1016/j.ejmech.2014.07.005. [DOI] [PubMed] [Google Scholar]
  3. Guan H.; Laird A. D.; Blake R. A.; Tang C.; Liang C. Design and synthesis of aminopropyl tetrahydroindole-based indolin-2-ones as selective and potent inhibitors of Src and Yes tyrosine kinase. Bioorg. Med. Chem. Lett. 2004, 14, 187–190. 10.1016/j.bmcl.2003.09.069. [DOI] [PubMed] [Google Scholar]
  4. Andreev I. A.; Manvar D.; Barreca M. L.; Belov D. S.; Basu A.; Sweeney N. L.; Ratmanova N. K.; Lukyanenko E. R.; Manfroni G.; Cecchetti V.; et al. Discovery of the 2-phenyl-4,5,6,7-Tetrahydro-1H-indole as a novel anti-hepatitis C virus targeting scaffold. Eur. J. Med. Chem. 2015, 96, 250–258. 10.1016/j.ejmech.2015.04.022. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Fatahala S.; Shalaby E.; Kassab S.; Mohamed M. A Promising Anti-Cancer and Anti-Oxidant Agents Based on the Pyrrole and Fused Pyrrole: Synthesis, Docking Studies and Biological Evaluation. Anti-Cancer Agents Med. Chem. 2015, 15, 517–526. 10.2174/1871520615666150105113946. [DOI] [PubMed] [Google Scholar]
  6. Niu S.; Zhou T.-T.; Xie C.-L.; Zhang G.-Y.; Yang X.-W. Microindolinone A, a Novel 4,5,6,7-Tetrahydroindole, from the Deep-Sea-Derived Actinomycete Microbacterium sp. MCCC 1A11207. Mar. Drugs 2017, 15, 230. 10.3390/md15070230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Morales C. L.; Pagenkopf B. L. Total Synthesis of (±)-Goniomitine via a Formal Nitrile/Donor–Acceptor Cyclopropane [3 + 2] Cyclization. Org. Lett. 2008, 10, 157–159. 10.1021/ol702376j. [DOI] [PubMed] [Google Scholar]
  8. Ishibashi H.; Akamatsu S.; Iriyama H.; Hanaoka K.; Tabata T.; Ikeda M. New, Concise Route to Indoles Bearing Oxygen or Sulfur Substituent at the 4 Position. Synthesis of (±)- and (S)-(−)-Pindolol and (±)-Chuangxinmycin. Chem. Pharm. Bull. 1994, 42, 271–276. 10.1248/cpb.42.271. [DOI] [Google Scholar]
  9. Lee Y.-J.; Kim S. H.; Choi H.; Lee H.-S.; Lee J. S.; Shin H. J.; Lee J. Cytotoxic Furan- and Pyrrole-Containing Scalarane Sesterterpenoids Isolated from the Sponge Scalarispongia sp. Molecules 2019, 24, 840. 10.3390/molecules24050840. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. a Gorin D. J.; Davis N. R.; Toste F. D. Gold(I)-Catalyzed Intramolecular Acetylenic Schmidt Reaction. J. Am. Chem. Soc. 2005, 127, 11260–11261. 10.1021/ja053804t. [DOI] [PubMed] [Google Scholar]; b Andreev I. A.; Belov D. S.; Kurkin A. V.; Yurovskaya M. A. Synthesis of 4,5,6,7-Tetrahydro-1H-indole Derivatives Through Successive Sonogashira Coupling/Pd-Mediated 5-endo-dig Cyclization. Eur. J. Org. Chem. 2013, 2013, 649–652. 10.1002/ejoc.201201417. [DOI] [Google Scholar]; c Yao T.; Xia T.; Yan W.; Xu H.; Zhang F.; Xiao Y.; Zhang J.; Liu L. Copper-Catalyzed Chemodivergent Cyclization of N-(ortho-alkynyl)aryl-Pyrrole and Indoles. Org. Lett. 2020, 22, 4511–4516. 10.1021/acs.orglett.0c01519. [DOI] [PubMed] [Google Scholar]; d Yao T.; Zhang F.; Zhang J.; Liu L. Palladium-Catalyzed Intermolecular Heck-Type Dearomative [4 + 2] Annulation of 2H-Isoindole Derivatives with Internal Alkynes. Org. Lett. 2020, 22, 5063–5067. 10.1021/acs.orglett.0c01643. [DOI] [PubMed] [Google Scholar]; e Wang X. M.; Zhang P.; Xu Q.; Guo C. Q.; Zhang D. B.; Lu C. J.; Liu R. R. Enantioselective Synthesis of Nitrogen-Nitrogen Biaryl Atropisomers via Copper-Catalyzed Friedel-Crafts Alkylation Reaction. J. Am. Chem. Soc. 2021, 143, 15005–15010. 10.1021/jacs.1c07741. [DOI] [PubMed] [Google Scholar]
  11. a Noland W. E.; Lanzatella N. P.; Sizova E. P.; Venkatraman L.; Afanasyev O. V. In situ vinylpyrrole synthesis. Diels-Alder reactions with maleimides to give tetrahydroindoles. J. Heterocycl. Chem. 2009, 49, 503–534. 10.1002/jhet.95. [DOI] [Google Scholar]; b Shi Q.-Q.; Fu L.-P.; Shi Y.; Ding H.-Q.; Luo J.-H.; Jiang B.; Tu S.-J. Three-component synthesis of poly-substituted tetrahydroindoles through p-TsOH promoted alkoxylation. Tetrahedron Lett. 2013, 54, 3176–3179. 10.1016/j.tetlet.2013.04.029. [DOI] [Google Scholar]; c Lambat T. L.; Abdala A. A.; Mahmood S.; Ledade P. V.; Chaudhary R. G.; Banerjee S. Sulfamic acid promoted one-pot multicomponent reaction: a facile synthesis of 4-oxo-tetrahydroindoles under ball milling conditions. RSC Adv. 2019, 9, 39735–39742. 10.1039/C9RA08478A. [DOI] [PMC free article] [PubMed] [Google Scholar]; d Vojacek S.; Schulig L.; Wössner N.; Geist N.; Langel W.; Jung M.; Schade D.; Link A. Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors. ChemMedChem 2019, 14, 853–864. 10.1002/cmdc.201900054. [DOI] [PubMed] [Google Scholar]
  12. Chen J.; Chang D.; Xiao F.; Deng G.-J. Three-Component Ordered Annulation of Amines, Ketones, and Nitrovinylarenes: Access to Fused Pyrroles and Substituted Indoles under Metal-Free Conditions. J. Org. Chem. 2019, 84, 568–578. 10.1021/acs.joc.8b02410. [DOI] [PubMed] [Google Scholar]
  13. Yamazaki S.; Iwata Y. Catalytic Enantioselective Friedel-Crafts/Michael Addition Reactions of Indoles to Ethenetricarboxylates. J. Org. Chem. 2006, 71, 739–743. 10.1021/jo052041p. [DOI] [PubMed] [Google Scholar]
  14. a Horwitz M. A.; Fulton J. L.; Johnson J. S. Enantio- and Diastereoselective Organocatalytic Conjugate Additions of Nitroalkanes to Enone Diesters. Org. Lett. 2017, 19, 5783–5785. 10.1021/acs.orglett.7b02735. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. a Selvi T.; Srinivasan K. Synthesis of 2,4,5-trisubstituted oxazoles through tin(iv) chloride-mediated reaction of trans-2-aryl-3-nitro-cyclopropane-1,1-dicarboxylates with nitriles. Chem. Commun. 2014, 50, 10845–10848. 10.1039/C4CC04764H. [DOI] [PubMed] [Google Scholar]; b Morikawa S.; Yamazaki S.; Furusaki Y.; Amano N.; Zenke K.; Kakiuchi K. Zinc- and Indium-Promoted Conjugate Addition–Cyclization Reactions of Ethenetricarboxylates with Propargylamines and Alcohol: Novel Methylenepyrrolidine and Methylenetetrahydrofuran Syntheses. J. Org. Chem. 2006, 71, 3540–3544. 10.1021/jo0602118. [DOI] [PubMed] [Google Scholar]; c Selvi T.; Srinivasan K. Boron Trifluoride Mediated Ring-Opening Reactions of trans-2-Aryl-3-nitro cyclopropane-1,1-dicarboxylates. Synthesis of Aroylmethylidene Malonates as Potential Building Blocks for Heterocycles. J. Org. Chem. 2014, 79, 3653–3658. 10.1021/jo402848v. [DOI] [PubMed] [Google Scholar]
  16. Weng J.-Q.; Fan R.-J.; Deng Q.-M.; Liu R.-R.; Gao J.-R.; Jia Y.-X. Enantioselective Friedel–Crafts Alkylation Reactions of 3-Substituted Indoles with Electron-Deficient Alkenes. J. Org. Chem. 2016, 81, 3023–3030. 10.1021/acs.joc.6b00123. [DOI] [PubMed] [Google Scholar]
  17. Morikawa S.; Yamazaki S.; Tsukada M.; Izuhara S.; Morimoto T.; Kakiuchi K. Lewis Acid-Catalyzed Conjugate Addition–Cyclization Reactions of Ethenetricarboxylates with Substituted Propargyl Alcohols: Stereoselectivity in the Efficient One-Pot Synthesis of Methylenetetrahydrofurans. J. Org. Chem. 2007, 72, 6459–6463. 10.1021/jo070882l. [DOI] [PubMed] [Google Scholar]
  18. Bisht S.; Peddinti R. K. FeCl3-Mediated Domino Reaction of Benzoxazinones with Aroylmethylidene Malonates: Synthesis to Functionalized Pyrrolobenzoxazines. J. Org. Chem. 2017, 82, 13617–13625. 10.1021/acs.joc.7b02207. [DOI] [PubMed] [Google Scholar]
  19. a Trautwein A. W.; Jung G. Solid-phase synthesis of pyrroles from enaminones and nitroalkenes. Tetrahedron Lett. 1998, 39, 8263–8266. 10.1016/S0040-4039(98)01887-5. [DOI] [Google Scholar]; b Guan Z.-H.; Li L.; Ren Z.-H.; Li J.; Zhao M.-N. A facile and efficient synthesis of multisubstituted pyrroles from enaminoesters and nitroolefins. Green Chem. 2011, 13, 1664–1668. 10.1039/c1gc15278e. [DOI] [Google Scholar]; c Maiti S.; Biswas S.; Jana U. Iron(III)-catalyzed four-component coupling reaction of 1,3-dicarbonyl compounds, amines, aldehydes, and nitroalkanes: a simple and direct synthesis of functionalized pyrroles. J. Org. Chem. 2010, 75, 1674–1683. 10.1021/jo902661y. [DOI] [PubMed] [Google Scholar]; d Ranu B. C.; Dey S. S. An efficient synthesis of pyrroles by a one-pot, three-component condensation of a carbonyl compound, an amine and a nitroalkene in a molten ammonium salt. Tetrahedron Lett. 2003, 44, 2865–2868. 10.1016/S0040-4039(03)00439-8. [DOI] [Google Scholar]; e Santhini P. V.; Babu S. A.; Krishnan R A.; Suresh E.; John J. Heteroannulation of 3-Nitroindoles and 3-Nitrobenzo[b]thiophenes: A Multicomponent Approach toward Pyrrole-Fused Heterocycles. Org. Lett. 2017, 19, 2458–2461. 10.1021/acs.orglett.7b01147. [DOI] [PubMed] [Google Scholar]; f Vivekanand T.; Vinoth P.; Agieshkumar B.; Sampath N.; Sudalai A.; Menéndez J. C.; Sridharan V. Highly efficient regioselective synthesis of pyrroles via a tandem enamine formation–Michael addition–cyclization sequence under catalyst- and solvent-free conditions. Green Chem. 2015, 17, 3415–3423. 10.1039/C5GC00365B. [DOI] [Google Scholar]; g Wang X.; Xu X.-P.; Wang S.-Y.; Zhou W.; Ji S.-J. Highly Efficient Chemoselective Synthesis of Polysubstituted Pyrroles via Isocyanide-Based Multicomponent Domino Reaction. Org. Lett. 2013, 15, 4246–4249. 10.1021/ol401976w. [DOI] [PubMed] [Google Scholar]; h Bayat M.; Nasri S.; Notash B. Synthesis of new 3-cyanoacetamide pyrrole and 3-acetonitrile pyrrole derivatives. Tetrahedron 2017, 73, 1522–1527. 10.1016/j.tet.2017.02.005. [DOI] [Google Scholar]; i Dommaraju Y.; Borthakur S.; Rajesh N.; Prajapati D. An efficient catalyst-free chemoselective multicomponent reaction for the synthesis of pyrimidine functionalized pyrrolo-annelated derivatives. RSC Adv. 2015, 5, 24327–24335. 10.1039/C5RA00796H. [DOI] [Google Scholar]
  20. a Sha Q.; Arman H.; Doyle M. P. Three-Component Cascade Reactions with 2,3-Diketoesters: A Novel Metal-Free Synthesis of 5-Vinyl-pyrrole and 4-Hydroxy-indole Derivatives. Org. Lett. 2015, 17, 3876–3879. 10.1021/acs.orglett.5b01855. [DOI] [PubMed] [Google Scholar]; b Wang L.; Zhong J.; Lin X. Atroposelective Phosphoric Acid Catalyzed Three-Component Cascade Reaction: Enantioselective Synthesis of Axially Chiral N-Arylindoles. Angew. Chem., Int. Ed Engl. 2019, 58, 15824–15828. 10.1002/anie.201909855. [DOI] [PubMed] [Google Scholar]
  21. a Fang G.; Liu J.; Fu J.; Liu Q.; Bi X. Silver-Catalyzed Cascade Reaction of β-Enaminones and Isocyanoacetates To Construct Functionalized Pyrroles. Org. Lett. 2017, 19, 1346–1349. 10.1021/acs.orglett.7b00201. [DOI] [PubMed] [Google Scholar]; b Philkhana S. C.; Badmus F. O.; Dos Reis I. C.; Kartika R. Recent Advancements in Pyrrole Synthesis. Synthesis 2021, 53, 1531–1555. 10.1055/s-0040-1706713. [DOI] [PMC free article] [PubMed] [Google Scholar]; c Cacchi S.; Fabrizi G.; Filisti E. N-Propargylic β-Enaminones: Common Intermediates for the Synthesis of Polysubstituted Pyrroles and Pyridines. Org. Lett. 2008, 10, 2629–2632. 10.1021/ol800518j. [DOI] [PubMed] [Google Scholar]
  22. a Fernando E. H. N.; Vazquez J. C.; Davis J.; Luo W.; Nesterov V. N.; Wang H. Can Primary Arylamines Form Enamine? Evidence, α-Enaminone, and [3+3] Cycloaddition Reaction. J. Org. Chem. 2021, 86, 14617–14626. 10.1021/acs.joc.1c01462. [DOI] [PubMed] [Google Scholar]; b Karunaratne C. V.; Sarkisian R. G.; Reeves J.; Deng Y.; Wheeler K. A.; Wang H. Multicomponent reaction through cooperative trio catalysis incorporating enamine, Brønsted acid and metal Lewis acid catalysis: a concise route to access chromans. Org. Biomol. Chem. 2017, 15, 4933–4936. 10.1039/C7OB00753A. [DOI] [PubMed] [Google Scholar]; c Deng Y.; Liu L.; Sarkisian R. G.; Wheeler K.; Wang H.; Xu Z. Arylamine-Catalyzed Enamine Formation: Cooperative Catalysis with Arylamines and Acids. Angew. Chem., Int. Ed. 2013, 125, 3751–3755. 10.1002/ange.201209268. [DOI] [PubMed] [Google Scholar]
  23. Li C.; Liang X.; Zhang F.; Qi C. Synthesis of tetrahydro-4H-indol-4-one derivatives catalyzed by carbonaceous material. Catal. Commun. 2015, 62, 6–9. 10.1016/j.catcom.2014.12.026. [DOI] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

ao2c05909_si_001.pdf (5.9MB, pdf)
ao2c05909_si_002.cif (913.7KB, cif)
ao2c05909_si_003.cif (1.6MB, cif)

Articles from ACS Omega are provided here courtesy of American Chemical Society

RESOURCES