Microwave-assisted, tetrabutylammonium hydroxide catalysed 1,4-addition of water to α,β-unsaturated ketones and α,β-ynones in aqueous solution

Abstract

Microwave-assisted, tetrabutylammonium hydroxide catalysed 1,4-addition reactions of water to α,β-unsaturated ketones and α,β-ynones take place efficiently in water. Reactions of the resulting β-hydroxy ketones lead to the formation of either C–C bond cleavage or annulation products.

---

Recently, green chemistry has become an interesting topic in organic synthesis because reactions which adhere to green principles have many benefits, such as reduced chemical waste, use of benign solvents, and enhanced efficiencies and atom economy.¹ Especially important is that the use of green solvents leads to minimization or elimination of environmental pollutants. As a result, many attempts have been made to develop solvent free processes² or to use non-traditional solvents like ionic liquids³ and supercritical fluids.⁴ Among them, the most eco-friendly solvent is water because it is inexpensive, non-toxic, non-corrosive, and non-flammable.⁵ To carry out efficient organic reactions in water, a solvent with a high dielectric constant, microwave irradiation is often employed as the heating source.⁶ Microwave-assisted processes typically have reduced reaction times and higher efficiencies owing to the fact that heat is delivered directly at the molecular level.

With green chemistry principles in mind, we have devised a new method for carrying out 1,4-addition reactions of water to α,β-unsaturated ketones and α,β-ynones. The processes utilize H₂O as the solvent and MW irradiation as the heat source. Moreover, retro-aldol reactions of the resulting β-hydroxy ketone occur to generate C–C bond cleavage or annulation products.⁷ Specifically, secondary C–C double bond cleavage reactions of adducts derived from α,β-enones and α,β-enals⁸ occur through base catalysed retro-aldol fragmentation (Scheme 1). In addition, multi-substituted phenols⁹ are generated through reactions of α,β-ynones in the presence of β-diketones via a base-triggered cascade involving Robinson annulation.

Scheme 1 The reactions of α,β-unsaturated compounds via β-hydroxy ketone by base or acid catalyst under microwave irradiation.

3-(Anthracen-9-yl)acrylaldehyde (1a) was selected as the model substrate to explore features of the MW-assisted reactions of α,β-enals (Table 1). Reaction of 1a (0.4 mmol) in water under the various acid and base catalysts (20 mol%) were carried out for 10 min. Although acetaldehyde (2a) and anthracene-9-carbaldehyde (3a) are both formed in these reactions, the yield of only 3a could be determined because of the volatility of 2a. Reaction of 1a at 130 °C in aqueous solution containing NaOH gives 3a in a 9% yield (GC analysis, Table 1, entry 1). With addition of NaOH with TBA-Cl (tetrabutylammonium chloride, 20 mol%) as phase transfer catalyst, yield of 3a increased dramatically to 73% (entry 2). On the basis of this result, when tetrabutylammonium hydroxide (TBA-OH) is used to promote this process at 130 °C, the yield of 3a is 76% (entry 3). TBA-OH (tetrabutylammonium hydroxide) acts as dual-role of base catalyst for H₂O nucleophile and phase transfer catalyst. Other acid and base catalysts, such as K₂CO₃, amberlyst, phosphotungstic acid, and molecular sieves, are not affective in promoting the addition reaction (entries 4–9). In contrast, when the temperature is 150 °C and 20 mol% of TBA-OH is present, 3a is formed in a >99% GC yield (entry 10). The results demonstrate that the C–C double bond cleavage reaction of 1a is highly efficient when TBA-OH is employed as the catalyst and microwave irradiation is employed as the heat source.

Table 1 Microwave-assisted C–C double bond cleavage by various base or acid in aqueous conditions^a

Entry	Acid/base	Temp.(°C)	GC yield of 3a (%)
a Reaction conditions: 3-(anthracen-9-yl)acrylaldehyde (0.2 mmol), NaOH, TBA-OH, K2CO3 and HCl (20 mol%), amberlyst A26, molecular sieve, phosphotungstic acid and amberlyst 16 (100 mg), H2O (400 mg), reaction time (10 min).b Using TBA-Cl (tetrabutylammonium chloride) as PTC (phase transfer catalyst).
1	NaOH	130	9
2	NaOH^b	130	73
3	TBA-OH	130	76
4	K2CO3	130	Trace (<5)
5	Amberlyst A26 (base)	130	Trace (<5)
6	HCl	130	No reaction
7	Molecular sieve	130	No reaction
8	Phosphotungstic acid	130	No reaction
9	Amberlyst 16 (acid)	130	No reaction
10	TBA-OH	150	>99

---

To explore the substrate scope of this process, reactions of other α,β-enals and α,β-enones 1 were carried out (Table 2). In each case, the corresponding carbonyl product 3 is generated in moderate to high isolated yields (51–93%) with the volatile products 2 produced in each process not being analyzed. Even the β-alkyl substituted α,β-enal 1b participates in this C–C double bond cleavage reaction to give 3b in a 91% isolated yield (entry 2). However, α-methyl substituted α,β-enal 1d undergoes the cleavage reaction only inefficiently 51% (entry 4).

Table 2 Microwave-assisted C–C double bond cleavage of various α,β-unsaturated carbonyl compounds by TBA-OH catalyst in water^a

Entry	1	3	Isolated yield of 3(GC%)
a Reaction condition: α,β-unsaturated carbonyl compounds (0.2 mmol), TBA-OH (20 mol%), H2O (400 mg), microwave (M.W.) 150 °C, 10 min.
1			93 (>99)
2			91 (96)
3			60 (69)
4		(3c)	51 (55)
5		(3c)	91 (97)

---

Aldehydes generated from cleavage reactions of α,β-enals 1 are readily trapped by using benzene-1,2-diamine (5) to produce the corresponding benzimidazoles, 6 and 7 (Table 3). In these cases, even the volatile aldehyde products of the cleavage reaction, such as acetaldehyde, are trapped to give readily isolated imidazoles 6a (entries 1 and 2). For example, microwave irradiation of an aqueous solution of 3-(anthracen-9-yl)acrylaldehyde (1a) in the presence of TBA-OH and 5 at 150 °C for 10 min leads to formation of benzimidazole 6a and 7a in respective 62% and 58% isolated yields (Table 3, entry 1).

Table 3 The formation of benzimidazole derivatives via trapping of aldehyde by benzene-1,2-diamine^a

		α,β-Unsaturated compounds		Conversion (C–C double bond cleavage)	Isolated yield (%)
Entry	1	R^2	R^3		6	7
a Reaction condition: α,β-unsaturated carbonyl compounds (0.2 mmol), benzene-1,2-diamine (2.2 eq.), TBA-OH (20 mol%), H2O (400 mg), microwave (M.W.) 150 °C, 10 min.b Using 4 equiv. of bezene-1,2-diamine.
1	1a	H		>99	62 (6a)	58 (7a)
2	1c	H	Ph	>99	63 (6a)	48 (7b)
3	1d	CH3	Ph	>99	70 (6b)	60 (7b)
4^b	1f	n-C5H11	Ph	94	61 (6c)	50 (7b)

---

Especially interesting is the reaction of citral 1b under these conditions in that it produces 2-methylimidazole 6a (61%) and ketone 3b (89%) (eqn (1)). Thus, because ketones in the presence of 5 are not readily converted to imidazoles, the secondary derivatization technique serves as a convenient method to separate ketones and aldehydes formed in these reactions.

The reaction of chalcone (1g) in an aqueous solution containing TBA-OH is intriguing in that it produces the secondary conjugate addition product 4a (15%) along with the expected C–C bond cleavage products, acetophenone (2b, 30%) and benzaldehyde (3c, 40%) (Scheme 2). 1,5-Diketone 4a is likely formed in this reaction by 1,4-addition reaction of 1g with the enolate anion derived by TBA-OH deprotonation of the initially generated methyl ketone 2b. Other chalcone derivatives, 1h and 1i, display similar reactivity profiles.

Scheme 2 Base catalysed reaction of chalcone derivatives.

α,β-Unsaturated ynones are another family of interesting substrates for the 1,4-addition reaction (eqn (2)). This is exemplified by MW-assisted reaction of 4-phenylbut-3-yn-2-one (8a). Specifically, treatment of 8a in an aqueous solution containing 20 mol% TBA-OH results in the formation of a mixture of 1,3-diketone 9a (30%), acetophenone (2b, 11%), and substituted phenol 10a (10%). The structure of 10a was determined by using COSY, HMBC, HSQC 2D NMR spectroscopy (See the ESI†). In addition to this result, the microwave-assisted reaction of 8a with 9a by TBA-OH catalyst in aqueous condition produced a mixture of substituted phenol 10a (93%) and o-alkylated phenol 11a (5%), generated by butylation of 10a with TBA-OH. The o-alkylated phenol 11a was converted into substituted phenol 10a by 10 mol% of AlCl₃ in MeOH for 2 h (eqn (3)).¹⁰ It is reasonable to speculate that the 1,3-diketone 9a is generated by 1,4-addition of water followed by tautomerization (Scheme 3). And 2b comes from 9a by retro-Claisen cleavage.¹¹ In addition, phenol derivative 10a is likely formed by Robinson annulation between 1,3-diketone 9a with ynone 8a occurring via intermediates 12a and 13a. To confirm this proposal, a mixture of 8a and 9a in H₂O was MW-heated at 100 °C for 10 min in the presence of TBA-OH followed by treatment with AlCl₃ in MeOH. This process led to formation of 10a in a 90% (Table 4, entry 1). The generality of the MW-assisted reactions of α,β-unsaturated ynones, which take place much more efficiently than those induced by using conventional heating,¹² was demonstrated by the examples displayed in Table 4 (entries 2–7). And they produced 2,3,5-trisubstituted phenols in good to moderate yields.

Scheme 3 Plausible mechanism of multi-substituted phenol by Michael addition reactions of diketone toward α,β-unsaturated ketone.

Table 4 The synthesis of multi-substituted phenol from alkyne and 1,3-diketone with base catalyst^a

Entry	α,β-Unsaturated ynone		Isolated yield (%)
			10
a Reaction condition: (1) α,β-unsaturated carbonyl compounds (0.2 mmol), 1,3-diketone compounds (1.1 eq.), TBA-OH (20 mol%), H2O (400 mg), microwave (M.W.) 100 °C, 10 min, (2) AlCl3 (10 mol%), MeOH (400 mg), room temperature, 2 h.b Microwave (M.W.) 100 °C, 30 min.
1	R^1 = Me	R^3 = COMe
	R^2 = Ph (8a)	R^4 = COPh (9a)
2	(8a)	R^3 = COMe
		R^4 = COMe (9b)
3	(8a)	R^3 = COPh
		R^4 = COPh (9c)
4^b	R^1 = Ph	(9a)
	R^2 = Ph (8b)
5	(8b)	(9b)
6	R^1 = Ph	(9a)
	R^2 = n-C4H9 (8c)
7	(8c)	(9b)

---

Conclusions

In the effort described above, we developed an eco-friendly, TBA-OH catalysed, microwave-assisted method for efficient 1,4-addition of water to α,β-unsaturated ketones and α,β-ynones. The observed C–C double bond cleavage reactions of α,β-enones and annulation reactions of α,β-ynones take place with high efficiencies in pure aqueous solutions. Efforts directed at developing applications of this ‘Green Chemistry’ method to the synthesis of important targets are progressing.

Acknowledgements

This work was supported by a grant from the National Research Foundation of Korea (NRF) (2011-0016830).

Notes and references

1. (a) R. A. Sheldon, J. Mol. Catal. A: Chem., 1996, 107, 75; (b) P. T. Anastas and J. C. Warner, Green Chemistry: Theory and Practice, Oxford University Press, New York, 1998, p. 30; (c) M. poliakoff and P. Licence, Nature, 2007, 450, 810; (d) P. T. Anastas and I. T. Hovarsth, Chem. Rev., 2007, 107, 2169.
2. (a) K. Tanaka and F. Toda, Chem. Rev., 2000, 100, 1025; (b) G. Rothenberg, A. P. Downie, C. L. Raston and J. L. Scott, J. Am. Chem. Soc., 2001, 123, 8701.
3. (a) C. J. Adams, M. J. Earle, G. Robert and K. R. Seddon, Chem. Commun., 1998, 19, 2097; (b) J. Dupont, R. F. de Souza and P. A. Z. Suarez, Chem. Rev., 2002, 102, 3667.
4. (a) W. Leitner, Acc. Chem. Res., 2002, 35, 746; (b) E. J. Beckman, J. Supercrit. Fluids, 2004, 28, 121.
5. (a) U. M. Llindström, Chem. Rev., 2002, 102, 2751; (b) T. Okuhara, Chem. Rev., 2002, 102, 3641; (c) R. A. Sheldon, Green Chem., 2005, 7, 267; (d) C. Liu, Y. Zhang, N. Liu and J. Qiu, Green Chem., 2012, 14, 2999.
6. (a) C. O. Kappe, Angew. Chem., Int. Ed., 2004, 43, 6250; (b) D. Bogdal and A. Loupy, Org. Process Res. Dev., 2008, 12, 710; (c) B. Rissafi, A. E. Louzi, A. Loupy, A. Petit, M. Soufiaoui and S. F. Tétouani, Eur. J. Org. Chem., 2002, 15, 2518; (d) A. Loupy, M. Pellet, A. Petit and G. Vo-Thanh, Org. Biomol. Chem., 2005, 3, 1534; (e) H. Lee, Y.-K. Sim, J.-W. Park and C.-H. Jun, Chem.–Eur. J., 2014, 20, 323.
7. (a) J. Schmidt, C. Ehasz, M. Epperson, K. Klas, J. Wyatt, M. Hennig and M. Forconi, Org. Biomol. Chem., 2013, 11, 8419; (b) A. M. Frey, S. K. Karmee, K. P. de Jong, J. H. Bitter and U. Hanefeld, ChemCatChem, 2013, 5, 594; (c) Y. V. Pfeifer, P. T. Haase and L. W. Kroh, J. Agric. Food Chem., 2013, 61, 3090; (d) R. M. Archer, S. F. Royer, W. Mahy, C. L. Winn, M. J. Danson and S. D. Bull, Chem.–Eur. J., 2013, 19, 2895; (e) T. Honma and H. Inomata, J. Supercrit. Fluids, 2014, 90, 1.
8. (a) Y. Kondo, K. Kon-I, A. Iwasaki, T. Ooi and K. Maruoka, Angew. Chem., Int. Ed., 2000, 39(2), 414; (b) K. Kobiro, J. Fudan Univ., Nat. Sci., 2005, 44(5), 701; (c) H. Chen, H. Ji, X. Zhou and L. Wang, Tetrahedron, 2010, 66, 9888; (d) N. Anand, K. H. P. Reddy, K. S. R. Rao and D. R. Burri, Catal. Lett., 2011, 141, 1355; (e) X. Chen, K. Sumoto, S. Mitani, T. Yamagami, K. Yokoyama, P. Wang, S. Hirao, N. Nishiwaki and K. Kobiro, J. Supercrit. Fluids, 2012, 62, 178; (f) D. Enders and T. V. Nguyen, Tetrahedron Lett., 2012, 53, 2091; (g) D. Azarifar and Z. Najminejad, Synlett, 2013, 24(11), 1377.
9. (a) C. Ivanov and T. Tcholakova, Synthesis, 1981, 5, 392; (b) G. A. Kraus, H. Cho, S. Crowley, B. Roth, H. Sugimoto and S. Prugh, J. Org. Chem., 1983, 48, 3439; (c) É. T. Oganesyan, A. V. Pyshchev and L. I. Butenko, Pharm. Chem. J., 1999, 33(9), 480; (d) D. Tejedor, G. Méndez-Abt, L. Cotos, M. A. Ramirez and F. Ga1qrcía-Tellado, Chem.–Eur. J., 2011, 17, 3318.
10. The formed o-alkylated phenol is converted into dealkylated phenol under the AlCl₃ in MeOH conditions, according to the followed reference: V. V. Namboodiri and R. S. Varma, Tetrahedron Lett., 2002, 43, 1143
    .
11. (a) R. G. Pearson and E. A. Mayerle, J. Am. Chem. Soc., 1951, 73, 926; (b) Y. M. A. Yamada and Y. Uozumi, Tetrahedron, 2007, 63, 8492; (c) A. Kawata, K. Takata, Y. Kuninobu and K. Takai, Angew. Chem., Int. Ed., 2007, 46, 7793; (d) S. Biswas, S. Maiti and U. Jana, Eur. J. Org. Chem., 2010, 2861; (e) F. Xie, F. Yan, M. Chen and M. Zhang, RSC Adv., 2014, 4, 29502.
12. For the use of conventional thermal methods for the synthesis of polysubstituted phenols from alkynylketones and 1,3-dicarbonyl compounds, see: J. Li, R. Hua and T. Liu, Curr. Org. Synth., 2013, 10, 486.

---

Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c4ra09932j

---