Expedient access to unsymmetrical triarylmethanes through N-heterocyclic carbene catalysed 1,6-conjugate addition of 2-naphthols to para-quinone methides

Abstract

The utility of N-heterocyclic carbene as a Brønsted base catalyst for the synthesis of functionalised unsymmetrical triarylmethanes from 2-naphthol and para-quinone methides is described. This protocol allows the installation of naphthyl substituents on p-quinone methides through 1,6-conjugate addition to deliver the unsymmetrical triarylmethanes in good to excellent yields. Mild reaction conditions and 100% atom economy make this method synthetically advantageous over the other hitherto known methods.

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The remarkable contribution of triarylmethanes has been comprehended not only in the dye industry but also in the development of organic functional materials.¹ In recent years, another dominant application of triarylmethanes has been reconnoitred in the area of drug discovery as many of the symmetrical as well as unsymmetrical triarylmethanes possess interesting medicinal properties (Fig. 1).² In addition, the triarylmethane core has been found as an integral part of some naturally occurring molecules.³ Moreover, some specially designed triarylmethane derivatives could be utilised as sensors for detecting metal as well as cyanide ions.⁴

Fig. 1 Some biologically important triarylmethanes.

Although, both symmetrical and unsymmetrical triarylmethanes could be accessed through traditional Friedel–Crafts arylation of arenes with diarylmethanol or its derivatives under Lewis⁵ or Brønsted acid⁶ catalysed/mediated conditions, the requirement of electron rich arenes and harsh reaction conditions restrict this method from the synthetic point of view. To address these issues, a few traditional metal catalysed methods have been developed.⁷ Out of these protocols, palladium⁸ or nickel⁹ or other metal¹⁰ catalysed coupling of diarylmethane derivatives with suitable aryl coupling partners have become the most popular method to access achiral and/or enantiometrically enriched unsymmetrical triarylmethanes. Very recently, another elegant approach has been disclosed based on rhodium catalysed 1,4-addition of arylboronic acids to o-quinone methides.¹¹ A metal free and base mediated direct coupling between diarylmethanes and aryl fluorides to access triarylmethanes has also been reported very recently.¹² Although all the above mentioned strategies show a wide substrate scope and excellent functional group tolerance, none of these methods meet 100% atom economy. Therefore, developing a simple and atom economical approach for the synthesis of triarylmethanes, especially under organocatalytic conditions, would be more striking and highly desirable.

While working in the areas of N-heterocyclic carbene (NHC) catalysis¹³ and the synthesis of triarylmethanes,¹⁴ we anticipated that NHC could act as a Brønsted base to activate 2-naphthols to react with para-quinone methides (p-QMs)¹⁵ through 1,6-conjugate addition, which would lead to unsymmetrical triarylmethanes. To our surprise, so far, only a limited number of literature precedents are available, where NHC was employed as a Brønsted base,¹⁶ although the nucleophilic nature of NHCs has been explored in many organocatalytic transformations.¹⁷ The Brønsted base behavior of NHC has been first uncovered in transesterification reactions.¹⁸ Following these seminal reports, 1,4-conjugate addition reactions such as intramolecular¹⁹ and intermolecular Michael,²⁰ oxa-Michael,²¹ aza-Michael²² and phospha-Michael reactions²³ have been disclosed based on the utility of NHC as a Brønsted base. NHC has also been used as a base in other transformation such as silyl enol ether formation²⁴ and ring opening of isochromene derivatives.²⁵ Very recently, our group reported 1,6-hydrophosphonylation of p-quinone methides and fuchsones to access diaryl- and triarylmethyl phosphonates, respectively, using NHC as a Brønsted base.²⁶ Herein, we disclose the synthesis of highly functionalised triarylmethane derivatives through 1,6-conjugate addition of 2-naphthols to p-QMs using NHC as a Brønsted base catalyst.

The optimisation studies were carried out with p-QM 1 and 2-naphthol under various reaction conditions using different NHC precursors (4–9), and the results are shown in Table 1. When the reaction was performed using 4 as a NHC precursor and NaH as a base in THF, the expected product 3 was obtained in 60% yield in 24 h (entry 1). The structure of 3 was indisputably confirmed by spectroscopic methods as well as X-ray analysis (Table 1). Prompted by this result, we elaborated the optimisation studies in different solvents (entries 2–7). Out of several solvents screened, dichloromethane was found to be the most suitable solvent for this methodology, as 3 was obtained almost in quantitative yield in 18 h under this condition (entry 3). Further experiments were carried out using other NHC precursors (5–9) in CH₂Cl₂. However, in all those cases (entries 8–12), the product 3 was obtained in relatively less yield when compared to entry 3. The effectiveness of other bases such as K₃PO₄ and Cs₂CO₃ for this transformation were found to be inferior when compared to NaH (entries 13 & 14). To confirm the role of NHC in this transformation, a couple of experiments were performed only in the presence of base without NHC precursors (entries 15 & 16), but in both the cases, the product was obtained in <10% yield. Surprisingly, when the reaction was carried out with DBU as a base without NHC precursor, 3 was isolated in 67% yield though the reaction was not completed even after 48 h (entry 17). In another experiment, the reaction between 1 and 2 was carried out with IPr (free NHC) in the absence of base and, in this case, 3 was obtained in 87% yield after 24 h. This observation clearly indicates that the NHC is actually acting as a catalyst.

Table 1 Optimisation of reaction condition^a

Entry	Catalyst	Base	Solvent	Time (h)	Yield (%)
a Reaction conditions: all reactions were carried out with 0.062 mmol of 1 in 0.3 mL of solvent at room temperature.b The reaction was carried out with free IPr NHC.
1	4	NaH	THF	24	60
2	4	NaH	Et2O	24	80
3	4	NaH	CH2Cl2	18	99
4	4	NaH	DCE	24	91
5	4	NaH	PhMe	21	93
6	4	NaH	DMSO	24	90
7	4	NaH	MeCN	24	20
8	5	NaH	DCE	22	93
9	6	NaH	DCE	24	78
10	7	NaH	CH2Cl2	24	80
11	8	NaH	CH2Cl2	24	60
12	9	NaH	CH2Cl2	24	84
13	4	K3PO4	CH2Cl2	24	90
14	4	Cs2CO3	CH2Cl2	24	94
15	—	NaH	CH2Cl2	24	7
16	—	Cs2CO3	CH2Cl2	24	5
17	—	DBU	CH2Cl2	48	67
18^b	IPr	—	CH2Cl2	24	87

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Having found the optimal reaction conditions (entry 3, Table 1), we went on to study the scope and limitations of this transformation using 2-naphthol and a diverse set of p-quinone methides, and the results are shown in Table 2. Electronic effects of the aryl substituents in p-QMs were found to have minimal influence in the reaction as the p-QMs derived from both electron-poor and electron-rich aromatic aldehydes underwent smooth conversion to their corresponding triarylmethanes in very high yields. In general, this methodology worked extremely well in the cases of p-QMs (1a–h) derived from electron-rich aromatic aldehydes as the expected triarylmethanes (3a–h) were obtained in excellent isolated yields (89–99%). Other p-QMs (1i–m) derived from benzaldehyde or arylated benzaldehydes also underwent 1,6-conjugate addition and provided the respective triarylmethanes (3i–m) in good to excellent yields (75–92%). This method was found to be robust for the p-QMs derived from halogen substituted aromatic aldehydes. For example, p-QMs 1n and 1o reacted with 2-naphthol under the optimal conditions and gave the corresponding products 3n and 3o respectively in very high yields. In the cases of electron-poor aryl substituted p-QMs (1p–q), the products 3p and 3q were isolated in 86 and 92% yields correspondingly. The heteroaryl-containing triarylmethanes 3r and 3s were obtained in moderate yields from the p-QMs (1r and 1s), prepared from furan-2-carboxaldehyde and thiophene-2-carboxaldehyde respectively. The ferrocene containing triarylmethane 3t was obtained from 1t in 74% yield under the standard conditions. The efficacy of this protocol was also examined with p-QM 1u, derived from 2,6-diisopropyl phenol, and in this case, the product 3u was obtained in 75% isolated yield.

Table 2 Substrate scope^a

a Reaction conditions: all reactions were carried out with 20 mg scale of 1 in 0.3 mL of solvent at room temperature.b Reactions were carried out with 100 mg scale of 1 in 1.5 mL of solvent at room temperature.

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To elaborate the substrate scope further, 1 was subjected to 1,6-conjugate addition reaction with various 2-naphthol derivatives under optimised reaction conditions and the results are summarised in Table 3. It is evident from Table 3 that this protocol worked efficiently for all the 2-naphthol derivatives tried. For instance, the reaction of 1 with 6-methoxy-2-naphthol provided the desired triarylmethane 10a in 92% yield in 12 h. Other naphthol derivatives such as 6-bromo-2-naphthol and 6-phenyl-2-naphthol reacted smoothly with 1 to give the products 10b and 10c respectively in 95% yield. Under the reaction conditions, 6-hydroxyquinoline gave the corresponding product 10d in 86% isolated yield. However, in the case of relatively electron-poor 2-naphthol derivative 2e, the triarylmethane 10e was obtained only in 64% yield. Unfortunately, simple phenol failed to react with 1 under the optimal reaction conditions.

Table 3 Substrate scope^a

a Reaction conditions: all reactions were carried out with 0.062 mmol of 1 in 0.3 mL of solvent at room temperature.

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An enantioselective version of this reaction was also attempted. It is known in the literature that the enantioselective version of similar type of reactions is very challenging due to the potential reversibility of the reaction.²¹ Many different reaction conditions were employed for this transformation using a variety of chiral NHC pre-catalysts (11–13). When 11 and 12 were used as a catalyst for the reaction between 1 and 2, the product 3 was isolated in 70% and 95% yields respectively (Scheme 1). However, in both the cases, the product 3 was obtained as a racemic mixture at room temperature. Lowering the reaction temperature to sub-zero resulted in substantial lowering of the yield of 3 without any improvement in the enantioselectivity. When the reaction was carried out using 13 as a precatalyst in hexafluoroisopropanol (HFIP) as a solvent,²⁷ 3 was obtained in 30% yield with a marginal improvement in the enantioselectivity (8% ee).

Scheme 1 Enantioselective addition of 2-naphthol to p-QM 1.

A plausible mechanism for this reaction has been proposed based on the outcome of the reaction as well as the literature reports for similar kind of transformations (Scheme 2). In the initial step, NHC (I) abstracts the phenolic proton of 2-naphthol to generate the 2-naphthoxide anion, which immediately adds to the p-QM II in an 1,6-fasion to generate the intermediate III. Aromatization of the intermediate III followed by proton abstraction from IV leads to the formation of the product with the release of NHC I.

Scheme 2 Plausible mechanism.

Conclusions

In conclusion, we have disclosed here an atom-economical method for the synthesis of highly functionalised unsymmetrical triarylmethane derivatives through 1,6-conjugate addition of 2-naphthols to p-QMs using NHC as a Brønsted base catalyst. Further studies toward enhancing the asymmetric induction in this transformation are currently ongoing.

Acknowledgements

We are grateful to the Department of Science and Technology (EMR/2015/001759), New Delhi for financial support and IISER Mohali for providing infrastructure. PA thanks the CSIR New Delhi for a research fellowship. We also thank Mr Siddheshwar K. Bankar (IISER Mohali) for his help in solving the crystal structure. The NMR and HRMS facilities at IISER Mohali are gratefully acknowledged. XtaLabmini single crystal X-ray facility of the Department of Chemical Sciences at IISER Mohali is acknowledged for the data collections.

Notes and references

1. (a) D. F. Duxbury, Chem. Rev., 1993, 93, 381; (b) V. Nair, S. Thomas, S. C. Mathew and K. G. Abhilash, Tetrahedron, 2006, 62, 6731; (c) M. Shiri, M. A. Zolfigol, H. G. Kruger and Z. Tanbakouchian, Chem. Rev., 2010, 110, 2250.
2. (a) S. D. Cho, K. Yoon, S. Chintharlapalli, M. Abdelrahim, P. Lei, S. Hamilton, S. Khan, S. K. Ramaiah and S. Safe, Cancer Res., 2007, 67, 674; (b) P. M. Wood, L. L. Woo, J. R. Labrosse, M. N. Trusselle, S. Abbate, G. Longhi, E. Castiglioni, F. Lebon, A. Purohit and M. J. Reed, J. Med. Chem., 2008, 51, 4226; (c) S. Mondal and G. Panda, RSC Adv., 2014, 4, 28317.
3. (a) S. Antus, E. Schindlbeck, S. Ahmad, O. Seligmann, V. M. Chari and H. Wagner, Tetrahedron, 1982, 38, 133; (b) K. Baba, K. Maeda, W. Tabata, M. Doi and M. Kozawa, Chem. Pharm. Bull., 1988, 36, 2977.
4. (a) L. Yu, D. Chen, J. Li and P. G. Wang, J. Org. Chem., 1997, 62, 3575; (b) E. M. Nolan and S. J. Lippard, Chem. Rev., 2008, 108, 3443; (c) X. Chen, T. Pradhan, F. Wang, J. S. Kim and J. Yoon, J. Chem. Rev., 2012, 112, 1910; (d) P. Kaur, D. Sareen, S. Kaur and K. Singh, Inorg. Chem. Commun., 2009, 12, 272.
5. For selected examples, see (a) S. J. Ji, M. F. Zhou, D. G. Gu, Z. Q. Jiang and T. P. Loh, Eur. J. Org. Chem., 2004, 1584; (b) V. Nair, K. G. Abhilash and N. Vidya, Org. Lett., 2005, 7, 5857; (c) C. R. Liu, M. B. Li, C. F. Yang and S. K. Tian, Chem. Commun., 2008, 1249; (d) G. K. S. Prakash, C. Panja, A. Shakhmin, E. Shah, T. Mathew and G. A. Olah, J. Org. Chem., 2009, 74, 8659; (e) R. F. A. Gomes, J. A. Coelho, R. F. M. Frade, A. F. Trindade and C. A. M. Afonso, J. Org. Chem., 2015, 80, 10404; (f) G. Pallikonda and M. Chakravarty, J. Org. Chem., 2016, 81, 2135.
6. (a) S. Shirakawa and S. Kobayashi, Org. Lett., 2006, 8, 4939; (b) M. Wilsdorf, D. Leichnitz and H. U. Reissig, Org. Lett., 2013, 15, 2494; (c) M. H. Zhou, Y. J. Jiang, Y. S. Fan, Y. Gao, S. Liu and S. Zhang, Org. Lett., 2014, 16, 1096; (d) W. Zhao, Z. Wang, B. Chu and J. Sun, Angew. Chem., Int. Ed., 2015, 54, 1461; (e) Z. Wang, Y. F. Wong and J. Sun, Angew. Chem., Int. Ed., 2015, 54, 13711; (f) S. Saha, S. K. Alamsetti and C. Schneider, Chem. Commun., 2015, 51, 1461; (g) M. L. Li, D. F. Chen, S. W. Luo and X. Wu, Tetrahedron: Asymmetry, 2015, 26, 219; (h) Y. F. Wong, Z. Wang and J. Sun, Org. Biomol. Chem., 2016, 14, 5751.
7. M. Nambo and C. M. Crudden, ACS Catal., 2015, 5, 4734.
8. For selected examples, see (a) G. A. Molander and M. D. Elia, J. Org. Chem., 2006, 71, 9198; (b) T. Niwa, H. Yorimitsu and K. Oshima, Org. Lett., 2007, 9, 2373; (c) J. Y. Yu and R. Kuwano, Org. Lett., 2008, 10, 973; (d) J. Zhang, A. Bellomo, A. D. Creamer, S. D. Dreher and P. J. Walsh, J. Am. Chem. Soc., 2012, 134, 13765; (e) A. Bellomo, J. Zhang, N. Trongsiriwat and P. J. Walsh, Chem. Sci., 2013, 4, 849; (f) S. C. Matthew, B. W. Glasspoole, P. Eisenberger and C. M. Crudden, J. Am. Chem. Soc., 2014, 136, 5828; (g) J. Zhang, A. Bellomo, N. Trongsiriwat, T. Jia, P. J. Carroll, S. D. Dreher, M. T. Tudge, H. Yin, J. R. Robinson, E. J. Schelter and P. J. Walsh, J. Am. Chem. Soc., 2014, 136, 6276; (h) M. Nambo and C. M. Crudden, Angew. Chem., Int. Ed., 2014, 53, 742; (i) M. Nambo, M. Yar, J. D. Smith and C. M. Crudden, Org. Lett., 2015, 17, 50.
9. (a) B. L. H. Taylor, M. R. Harris and E. R. Jarvo, Angew. Chem., Int. Ed., 2012, 51, 7790; (b) M. R. Harris, L. E. Hanna, M. A. Greene, C. E. Moore and E. R. Jarvo, J. Am. Chem. Soc., 2013, 135, 3303; (c) Q. Zhou, H. D. Srinivas, S. Dasgupta and M. P. Watson, J. Am. Chem. Soc., 2013, 135, 3307.
10. (a) X. Zhao, G. Wu, Y. Zhang and J. Wang, J. Am. Chem. Soc., 2011, 133, 3296; (b) Y. Y. Sun, J. Yi, X. Lu, Z. Q. Zhang, B. Xiao and Y. Fu, Chem. Commun., 2014, 50, 11060.
11. Y. Huang and T. Hayashi, J. Am. Chem. Soc., 2015, 137, 7556.
12. X. Ji, T. Huang, W. Wu, F. Liang and S. Cao, Org. Lett., 2015, 17, 5096.
13. (a) P. Arde, B. T. Ramanjaneyulu, V. Reddy, A. Saxena and R. V. Anand, Org. Biomol. Chem., 2012, 10, 848; (b) P. Arde, V. Reddy and R. V. Anand, RSC Adv., 2014, 4, 49775; (c) B. T. Ramanjaneyulu, S. Mahesh and R. V. Anand, Org. Lett., 2015, 17, 6; (d) B. T. Ramanjaneyulu, S. Mahesh and R. V. Anand, Org. Lett., 2015, 17, 3952.
14. V. Reddy and R. V. Anand, Org. Lett., 2015, 17, 3390.
15. For selected recent examples, where p-QMs has been utilised as an electrophile, see: (a) W. D. Chu, L. F. Zhang, X. Bao, X. H. Zhao, C. Zeng, J. Y. Du, G. B. Zhang, F. X. Wang, X. Y. Ma and C. A. Fan, Angew. Chem., Int. Ed., 2013, 52, 9229; (b) L. Caruana, F. Kniep, T. K. Johansen, P. H. Poulsen and K. A. Jørgensen, J. Am. Chem. Soc., 2014, 136, 15929; (c) K. Gai, X. Fang, X. Li, A. Lin and H. Yao, Chem. Commun., 2015, 51, 15831; (d) A. Lopez, A. Parra, C. Jarava-Barrera and M. Tortosa, Chem. Commun., 2015, 51, 17684; (e) Z. Yuan, X. Fang, X. Li, J. Wu, H. Yao and A. Lin, J. Org. Chem., 2015, 80, 11123; (f) A. Parra and M. Tortosa, ChemCatChem, 2015, 7, 1521; (g) Y. Lou, P. Cao, T. Jia, Y. Zhang, M. Wang and J. Liao, Angew. Chem., Int. Ed., 2015, 54, 12134; (h) L. Caruana, M. Fochi and L. Bernardi, Molecules, 2015, 20, 11733; (i) F. S. He, J. H. Jin, Z. T. Yang, X. Yu, J. S. Fossey and W. P. Deng, ACS Catal., 2016, 6, 652; (j) K. Zhao, Y. Zhi, A. Wang and D. Enders, ACS Catal., 2016, 6, 657.
16. (a) Y. J. Kim and A. Streitwieser, J. Am. Chem. Soc., 2002, 124, 5757; (b) T. L. Amyes, S. T. Diver, J. P. Richard, F. M. Rivas and K. Toth, J. Am. Chem. Soc., 2004, 126, 4366; (c) R. S. Massey, C. J. Collett, A. G. Lindsay, A. D. Smith and A. C. O'Donoghue, J. Am. Chem. Soc., 2012, 134, 20421.
17. For selected reviews, see: (a) D. Enders, O. Niemeier and A. Hanseler, Chem. Rev., 2007, 107, 5606; (b) E. M. Phillips, A. Chan and K. A. Scheidt, Aldrichimica Acta, 2009, 42, 55; (c) P. C. Chiang and J. W. Bode, TCI MAIL, 2011, 149, 2; (d) A. T. Biju, N. Kuhl and F. Glorius, Acc. Chem. Res., 2011, 44, 1182; (e) V. Nair, R. S. Menon, A. T. Biju, C. R. Sinu, R. R. Paul, A. Jose and V. Sreekumar, Chem. Soc. Rev., 2011, 40, 5336; (f) C. D. Campbell, K. B. Ling and A. D. Smith, in N-Heterocyclic Carbenes in Transition Metal Catalysis and Organocatalysis, ed. C. S. J. Cazin, Springer, Dortrecht, 2011, vol. 32, p. 262; (g) S. J. Ryan, L. Candish and D. W. Lupton, Chem. Soc. Rev., 2013, 42, 4906; (h) M. N. Hopkinson, C. Richter, M. Schedler and F. Glorius, Nature, 2014, 510, 485; (i) D. M. Flanigan, R. Michailidis, N. A. White and T. Rovis, Chem. Rev., 2015, 115, 9307.
18. (a) G. A. Grasa, R. M. Kissling and S. P. Nolan, Org. Lett., 2002, 4, 3583; (b) T. Kano, K. Sasaki and K. Maruoka, Org. Lett., 2005, 7, 1347; (c) M. Movassaghi and K. A. Schmidt, Org. Lett., 2005, 7, 2453.
19. T. Boddaert, Y. Coquerel and J. Rodriquez, Adv. Synth. Catal., 2009, 351, 1744.
20. J. Chen and Y. Huang, Nat. Commun., 2014, 5, 4437.
21. E. M. Phillips, M. Reidrich and K. Scheidt, J. Am. Chem. Soc., 2010, 132, 13179.
22. Q. Kang and Y. Zhang, Org. Biomol. Chem., 2011, 9, 6715.
23. M. Hans, L. Delaude, J. Rodriquez and Y. Coquerel, J. Org. Chem., 2014, 79, 2758.
24. J. J. Song, Z. Tan, J. T. Reeves, D. R. Fandrick, N. K. Yee and C. H. Senanayake, Org. Lett., 2008, 10, 877.
25. X. W. Fan and Y. Cheng, Org. Biomol. Chem., 2012, 10, 9079.
26. P. Arde and R. V. Anand, Org. Biomol. Chem., 2016, 14, 5550.
27. It has been reported in the literature that HFIP helps in improving the enantioselectivity in some specific cases. Although the exact function of HFIP is not well understood, it is believed that HFIP stabilises the transition state through a strong hydrogen bond. For examples, see: (a) A. Berkessel, J. A. Adrio, D. Hüttenhain and J. M. Neudörfl, J. Am. Chem. Soc., 2006, 128, 8421; (b) I. A. Shuklov, N. V. Dubrovina and A. Börner, Synthesis, 2007, 2925; (c) B. Satpathi and S. S. V. Ramasastry, Angew. Chem., Int. Ed., 2016, 55, 1777.

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Footnote

† Electronic supplementary information (ESI) available: Experimental procedure, spectra. CCDC 1452070. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c6ra11116e

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