Aerobic photooxidative direct asymmetric aldol reactions of benzyl alcohols using water as the solvent

Abstract

We report an aerobic photooxidative direct asymmetric aldol reaction using water as the solvent. In this reaction, primary benzyl alcohols are oxidized into benzaldehydes under an oxygen atmosphere using anthraquinone-2-sodium sulfonate monohydrate as an organophotocatalyst. Stereoselective aldol reactions then proceed using a proline-type organocatalyst.

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The aldol reaction is a fundamental and reliable method for forming carbon–carbon bonds. The products of this reaction, β-hydroxy carbonyl compounds, are contained in many natural products and are used in many medicines.¹ Direct asymmetric aldol (DAA) reactions catalyzed by organocatalysts have been actively developed in recent decades because such reactions offer advantages, such as stability in the presence of air and water and reactants with low toxicities, over alternative reactions.² A great deal of attention has been paid to the use of water as a solvent for these reactions because it is a safe, inexpensive, and environmentally benign solvent.³ Various organocatalytic DAA reactions using water as the solvent have been reported.⁴

Catalytic tandem reactions, in which a series of multistep reactions are performed in a single vessel, can be powerful tools from an environmental viewpoint because they save energy and waste.^5,6 Alcohols are readily accessible, low cost, and easy to handle, so some researchers have reported the reactions in which alcohols are used as starting materials to produce aldehydes in situ.^7,8 To the best of our knowledge, no oxidative DAA reactions using alcohol have yet been developed. There are some difficulties in performing such a reaction: (1) the alcohol has to be selectively oxidized to the aldehyde and (2) the aldehyde that is generated, the ketone reactant, the asymmetric organocatalyst (such as a proline derivative), and the final product have to be able to survive the oxidative reaction conditions. Recently, Kudo and coworkers described highly stereoselective sequential oxidation/asymmetric aldol reactions of several benzyl alcohols using resin-supported catalysts, but the sequential addition of the ketone of interest was required after the oxidation reaction had been performed because the ketones used could not tolerate the oxidative conditions.⁹

We have been investigating mild oxidation reactions using molecular oxygen and irradiation with fluorescent lamps.¹⁰ Recently, we reported oxidation reactions catalyzed by anthraquinones, which acted as organophotocatalysts.¹¹ Furthermore, we have also been studying organocatalyzed asymmetric aldol reactions using water or brine as the reaction solvent.¹² It occurred to us that using water as the solvent would allow the selective oxidation of a benzyl alcohols (which would be relatively soluble in water) to be achieved without the other compounds in the reaction mixture (such as aldehydes, ketones, organocatalysts, and products) being oxidized and react with enamine generated by ketone with organocatalyst to give oxidative DAA reactions (Scheme 1). Here, we describe a detailed study of an oxidative DAA reaction using water as the solvent.

Scheme 1 Oxidative direct asymmetric aldol reaction from benzyl alcohol.

First, we examined the asymmetric organocatalyzed reaction of 4-bromobenzyl alcohol (1a) and cyclohexanone (2a) in the presence of anthraquinone-2-sodium sulfonate monohydrate (AQN-2-SO₃Na·H₂O) using water under an air atmosphere (i.e., open) with irradiation from a fluorescent lamp for 12 h. Among the proline derivatives (4a–d) that were used as organocatalysts, only trans-4-tert-butyldiphenylsiloxy L-proline (4a) gave the β-hydroxy ketone 3a, and it gave a 28% yield with high stereoselectivity (Table 1).^4c

Table 1 Study of organocatalyst

Entry	Catalyst	Yield^a (%)	anti : syn^b	% ee^c
a Isolated yields.b Determined by ^1H NMR spectroscopic analysis.c Determined by HPLC.
1		28	17 : 1	>99
2		0	—	—
3		0	—	—
4		0	—	—
5		0	—	—

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The results of the tests using different solvents and organophotocatalysts are shown in Table 2. We found that a combination of H₂O and AQN-2-SO₃Na·H₂O that is soluble in water gave the photooxidative DAA reaction product 3a. General organic solvents gave none of the desired product 3a because AQN-2-SO₃Na·H₂O is insoluble in these solvents.

Table 2 Study of AQN derivatives and solvents

Entry	AQN derivative	Solvent	Yield^a (%)	anti : syn^b	% ee^c
a Isolated yields.b Determined by ^1H NMR spectroscopic analysis.c Determined by HPLC.
1	AQN-2-COOH	H2O	13	14 : 1	>99
2	AQN-2,7-di-SO3Na	H2O	24	14 : 1	>99
3	AQN-1,8-di-SO3K	H2O	6	18 : 1	>99
4	AQN-2-Cl	H2O	10	>20 : 1	>99
5	AQN-2-SO3Na·H2O	H2O	28	17 : 1	>99
6	AQN-2-SO3Na·H2O	Hexane	0	—	—
7	AQN-2-SO3Na·H2O	PhCl	0	—	—
8	AQN-2-SO3Na·H2O	EtOAc	0	—	—
9	AQN-2-SO3Na·H2O	MeOH	0	—	—
10	AQN-2-SO3Na·H2O	CHCl3	0	—	—

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We then conducted further experiments to optimize the reaction conditions (Table 3). After several investigations, a prolonged reaction time (48 h) and the addition of AcOH (entry 10) which may accelerate the formation of enamine as an active species derived from 2a and 4a gave the best result.

Table 3 Study of further experiments to optimize the reaction conditions

Entry	Cyclohexanone (equiv.)	Additive	Time (h)	Yield^a (%)	anti : syn^b	% ee^c
a Isolated yields.b Determined by ^1H NMR spectroscopic analysis.c Determined by HPLC.d 0.2 equiv. of AQN-2-SO3Na·H2O was used.
1	5	K2CO3	12	25	1.4 : 1	0
2	5	AcOH	12	27	>20 : 1	98
3	5	TFA	12	4	18 : 1	90
4	5	AgOTf	12	0	—	—
5	5	Yb(OTf)3	12	0	—	—
6	2	—	12	13	16 : 1	>99
7	10	—	12	26	>20 : 1	>99
8^d	5	—	12	32	>20 : 1	>99
9	5	—	48	62	16 : 1	94
10	5	AcOH	48	71	13 : 1	94
11	10	—	48	53	14 : 1	94
12^d	5	—	48	41	6.7 : 1	94

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We examined the scope and limitations of the reaction using the optimized conditions. As is shown in Table 4, the corresponding aldol adducts were obtained in moderate to good yields with strong enantioselectivities (entries 1–7). Reactions in which para- or meta-nitrobenzyl alcohols were used were conducted under an O₂ atmosphere to promote the oxidation of alcohols (entries 8 and 9). However, substrates with an ortho-substituted or without electron-withdrawing groups on the benzene rings or heterocyclic rings gave poor results (entries 10–15). It seems that electron-withdrawing group on the benzene ring promote the aldol reaction by making electron poor at the carbonyl carbon of the corresponding benzaldehyde. We changed the ring size of cycloalkanone and found that cycloheptanone is not applicable to the reaction, even though cyclopentanone is (entries 16–21). Unfortunately, though we investigated the reactions with acyclic ketones, we could just get corresponding aldol adduct in low yields (entries 22 and 23).

Table 4 Scope and limitation

Entry		Product		H2O (mL)	Time (h)	Yield^a (%)	anti : syn^b	% ee^c
a Isolated yields. Numbers in parentheses are yields determined by ^1H NMR spectroscopic analysis of crude.b Determined by ^1H NMR spectroscopic analysis.c Determined by HPLC.d Without AcOH.e 10 equiv. of ketone was used.f Reactions were carried out under oxygen atmosphere.g 27 equiv. of ketone was used.
1	Ar^1 =	4-BrC6H4 (3a)		3	48	71	13 : 1	94
2		3-BrC6H4 (3b)		3	48	60	16 : 1	>99
3^d		4-CIC6H4 (3c)		2	48	63	14 : 1	95
4		3-CIC6H4 (3d)		3	48	65	17 : 1	97
5		4-CF3C6H4 (3e)		3	60	62	12 : 1	98
6		4-CNC6H4 (3f)		3	60	58	7.4 : 1	>99
7^d^,^e		4-CO2Me6H4 (3g)		2	48	73	15 : 1	>99
8^d^,^f		4-NO2C6H4 (3h)		0.5	120	61	9.7 : 1	94
9^d^,^f		3-NO2C6H4 (3i)		0.5	120	54	8.5 : 1	>99
10^d^,^f		2-NO2C6H4 (3j)		1	120	(14)	—	—
11^d^,^f		C6F5 (3k)		0.5	120	(0)	—	—
12^f		4-OMeC6H4 (3l)		0.5	120	(7)	—	—
13		2-Naphthyl (3m)		0.5	48	(4)	—	—
14		4-Pyridyl (3n)		3	48	(7)	—	—
15		2-Furyl (3o)		3	48	(0)	—	—
16^d	Ar^2 =	4-CIC6H4 (3p)		2	48	50	2.4 : 1	>99
17		4-CNC6H4 (3q)		3	60	53	2.2 : 1	>99
18^e^,^f		4-NO2C6H4 (3q)		0.2	120	55	3.2 : 1	>99
19^d	Ar^3 =	4-CIC6H4 (3s)		2	48	(2)	—	—
20		4-CNC6H4 (3t)		3	60	(7)	—	—
21^e^,^f		4-NO2C6H4 (3u)		0.5	120	(8)	—	—
22^d^,^f^,^g				0.5	120	(5)	—	—
23^d^,^f^,^g				0.5	120	(Trace)	—	—

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Next, we performed some experiments to reveal the reaction mechanism (Scheme 2). When we conducted the reaction under Ar, the yield of the desired product is very low (eqn (1)). If there is no irradiation from fluorescent lamp, the reaction is suppressed perfectly (eqn (2)). In eqn (3), we added sodium L-ascorbate as a radical scavenger, the photooxidation of the alcohol is suppressed to a certain extent. Thus, we suppose that the oxidation step involves radical steps.

Scheme 2 Study of reaction mechanism: yields are determined by ¹H NMR spectroscopic analysis of the crude.

According to the results mentioned above, we depicted the plausible path of this reaction (Scheme 3). To begin with AQN-2-SO₃⁻ is excited by the irradiation of fluorescent lamp and H atom at the benzylic position of alcohol 1 is abstracted to produce benzyl radical. Then, this intermediate traps molecular oxygen to generate aldehyde via forming peroxy radical and hydroperoxide. Finally, the aldehyde react with ketone 2 assisted by proline-type catalyst and desired aldol adduct 3 is obtained.

Scheme 3 Plausible path.

Conclusions

In conclusion, we have described a photooxidative stereoselective aldol reaction starting from an alcohol substrate. This method uses molecular oxygen and visible light with AQN-2-SO₃Na·H₂O to oxidize the alcohol. We found that this photooxidation is not what interrupts the asymmetric aldol reaction because high enantioselectivity is preserved. The reaction can be performed using water as the solvent. We believe that this method should be applicable to other reactions starting from aldehydes. Further investigations into photooxidative reactions are now in progress in our laboratory.

Notes and references

1. R. Mahrwald, in Modern Aldol Reactions, Wiley-VCH, Weinheim, Germany, 2004, vol. 1 and 2.
2. For selected reviews on organocatalysts, see: (a) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138; (b) H. Pellisier, Tetrahedron, 2007, 63, 9267; (c) S. Mukherjee, J. W. Yang, S. Hoffmann and B. List, Chem. Rev., 2007, 107, 5471; (d) A. Dondoni and A. Massi, Angew. Chem., Int. Ed., 2008, 47, 4638; (e) A. Lattanzi, Chem. Commun., 2009, 1452; (f) X. Liu, L. Lin and X. Feng, Chem. Commun., 2009, 6145; (g) X.-H. Chen, J. Yu and L.-Z. Gong, Chem. Commun., 2010, 46, 6437; (h) B. Bhanushali and C.-G. Zhao, Synthesis, 2011, 1815.
3. For reviews on organic synthesis in water, see: (a) P. A. Grieco, in Organic Synthesis in Water, Blackie A&P, London, 1998; (b) S. Kobayashi and K. Manabe, Acc. Chem. Res., 2002, 35, 209; (c) U. M. Lindstrom, Chem. Rev., 2002, 102, 2751; (d) C. J. Li, Chem. Rev., 2005, 105, 3095; (e) M. Raj and V. K. Singh, Chem. Commun., 2009, 6687; (f) J. Paradowska, M. Stodulski and J. Mlynarski, Angew. Chem., Int. Ed., 2009, 48, 4228; (g) M. Gruttadauria, F. Giacalone and R. Noto, Adv. Synth. Catal., 2009, 351, 33; (h) N. Mase and C. F. Barbas III, Org. Biomol. Chem., 2010, 8, 4043.
4. For examples of organocatalyzed aldol reactions in water without any organic solvent using pyrrolidine derivatives, see: (a) S. S. Chimni, D. Mahajan and V. V. S. Babu, Tetrahedron Lett., 2005, 46, 5617; (b) N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka and C. F. Barbas III, J. Am. Chem. Soc., 2006, 128, 734; (c) Y. Hayashi, T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima and M. Shoji, Angew. Chem., Int. Ed., 2006, 45, 958; (d) Y. Hayashi, S. Aratake, T. Okano, J. Takahashi, T. Sumiya and M. Shoji, Angew. Chem., Int. Ed., 2006, 45, 5527; (e) Y. Wu, Y. Zhang, M. Yu, G. Whao and S. Wang, Org. Lett., 2006, 8, 4417; (f) D. Font, C. Jimeno and M. A. Pericàs, Org. Lett., 2006, 8, 4653; (g) W.-P. Huang, J.-R. Chen, X.-Y. Li, Y.-J. Cao and W.-J. Xiao, Can. J. Chem., 2007, 85, 208; (h) F. Giacalone, M. Gruttadauria, A. M. Marculescu and R. Noto, Tetrahedron Lett., 2007, 48, 255; (i) S. Aratake, T. Itoh, T. Okano, T. Usui, M. Shoji and Y. Hayashi, Chem. Commun., 2007, 2524; (j) V. Maya, M. Raj and V. K. Singh, Org. Lett., 2007, 9, 2593; (k) M. Gruttadauria, F. Giacalone, A. M. Marculescu, P. L. Meo, S. Riela and R. Noto, Eur. J. Org. Chem., 2007, 4688; (l) D. Font, S. Sayalero, A. Bastero, C. Jimeno and M. A. Pericàs, Org. Lett., 2008, 10, 337; (m) L. Zu, H. Xie, H. Li, J. Wang and W. Wang, Org. Lett., 2008, 10, 1211; (n) M. Lombardo, F. Pasi, S. Easwar and C. Trombini, Synlett, 2008, 2471; (o) S. S. Chimni, S. Singh and D. Mahajan, Tetrahedron: Asymmetry, 2008, 19, 2276; (p) S. S. Chimni, S. Singh and A. Kumar, Tetrahedron: Asymmetry, 2009, 20, 1772; (q) S.-P. Zhang, X.-K. Fu and S.-D. Fu, Tetrahedron Lett., 2009, 50, 1173; (r) S.-D. Fu, X.-K. Fu, S.-P. Zhang, X.-C. Zou and X.-J. Wu, Tetrahedron: Asymmetry, 2009, 20, 2390; (s) M. R. Vishnumaya and V. K. Singh, J. Org. Chem., 2009, 74, 4289; (t) M. D. Nisco, S. Pedatella, H. Ullah, J. H. Zaidi, D. Naviglio, O. Ozdamar and R. Caputo, J. Org. Chem., 2009, 74, 9562; (u) N. Mase, N. Noshiro, A. Mokuya and K. Takabe, Adv. Synth. Catal., 2009, 351, 2791; (v) Y.-N. Jia, F.-C. Wu, X. Ma, G.-J. Zhu and C.-S. Da, Tetrahedron Lett., 2009, 50, 3059; (w) Y.-J. An, Y.-X. Zhang, Y. Wu, Z.-M. Liu, C. Pi and J.-C. Tao, Tetrahedron: Asymmetry, 2010, 21, 688; (x) R. Pedrosa, J.-M. Andrés, R. Manzano, D. Román and S. Téllez, Org. Biomol. Chem., 2011, 9, 935.
5. (a) G. H. Posner, Chem. Rev., 1986, 86, 831; (b) T. L. Ho, in Tandem Organic Reactions, Wiley-Interscience, New York, 1992; (c) N. Hall, Science, 1994, 266, 32; (d) J.-C. Wasilke, S. J. Obrey, T. Baker and G. C. Bazan, Chem. Rev., 2005, 105, 1001.
6. (a) M. J. Burk, J. R. Lee and J. P. Martinez, J. Am. Chem. Soc., 1994, 116, 10847; (b) V. P. Balema and E. Hey-Hawkins, Z. Anorg. Allg. Chem., 1986, 622, 2053; (c) D. E. Fogg and E. N. dos Santos, Coord. Chem. Rev., 2004, 248, 2365.
7. For reviews on the electrophilic reactions using alcohols as substrates, see: (a) R. J. K. Taylor, M. Reid, J. Foot and S. A. Raw, Acc. Chem. Res., 2005, 38, 851; (b) G. Guillena, D. J. Ramón and M. Yus, Angew. Chem., Int. Ed., 2007, 46, 2358; for recent examples of the sequential reactions including alcohols oxidations, see: (c) X.-Q. Li, W.-K. Wang and C. Zhang, Adv. Synth. Catal., 2009, 351, 2342; (d) H. Sun, F.-Z. Su, J. Ni, Y. Cao, H.-Y. He and K.-N. Fan, Angew. Chem., Int. Ed., 2009, 48, 4390; (e) M. Davi and H. Lebel, Org. Lett., 2009, 11, 41; (f) A. J. Blacker, M. M. Farah, M. I. Hall, S. P. Marsden, O. Saidi and J. M. J. Williams, Org. Lett., 2009, 11, 2039; (g) R. Grigg, S. Whitney, V. Sridharan, A. Keep and A. Derrick, Tetrahedron, 2009, 65, 4375; (h) J. Brioche, G. Masson and J. Zhu, Org. Lett., 2010, 12, 1432; for examples of direct amide synthesis form alcohols, see: (i) C. Gunanathan, Y. Ben-David and D. Milstein, Science, 2007, 317, 790; (j) K. R. Reddy, C. U. Maheswari, M. Venkateshwar and M. L. Kantam, Eur. J. Org. Chem., 2008, 3619; (k) L. U. Nordstrøm, H. Vogt and R. Madsen, J. Am. Chem. Soc., 2008, 130, 17672; (l) S. C. Ghosh, S. Muthaiah, Y. Zhang, X. Xu and S. H. Hong, Adv. Synth. Catal., 2009, 351, 2643; (m) T. Zweifel, J.-V. Naubron and H. Grützmacher, Angew. Chem., Int. Ed., 2009, 48, 559; (n) K. Shimizu, K. Oshima and A. Satsuma, Chem.–Eur. J., 2009, 15, 9977; (o) B. E. Maki and K. A. Scheidt, Org. Lett., 2009, 11, 1651; (p) A. J. A. Watson, A. C. Maxwell and J. M. J. Williams, Org. Lett., 2009, 11, 2667; (q) J. H. Dam, G. Osztrovszky, L. U. Nordstrøm and R. Madsen, Chem.–Eur. J., 2010, 16, 6820; (r) S. Muthaiah, S. C. Ghosh, J.-E. Jee, C. Chen, J. Zhang and S. H. Hong, J. Org. Chem., 2010, 75, 3002.
8. The aldol-type reactions using alcohols as starting materials have been achieved, though the products resulted in achiral or racemic: (a) H. Shabany, E. Abel, J. P. Evans, I. M. McRobbie and G. W. Gokel, Tetrahedron Lett., 2000, 41, 6705; (b) K. Tanaka, S. Motomatsu, K. Koyama and K. Fukase, Tetrahedron Lett., 2008, 49, 2010; (c) K. Shimizu, R. Sato and A. Satsuma, Angew. Chem., Int. Ed., 2009, 48, 3982; (d) S. Kim, S. W. Bae, J. S. Lee and J. Park, Tetrahedron, 2009, 65, 1461; (e) A. Denichoux, T. Fukuyama, T. Doi, J. Horiguchi and I. Ryu, Org. Lett., 2010, 12, 1; (f) O. Kose and S. Saito, Org. Biomol. Chem., 2010, 8, 896; (g) H. Fan, Y. Yang, J. Song, G. Ding, C. Wu, G. Yang and B. Han, Green Chem., 2014, 16, 600.
9. K. Akagawa, S. Takigawa, E. Mano and K. Kudo, Tetrahedron Lett., 2011, 52, 770.
10. (a) A. Itoh, S. Hashimoto, T. Kodama and Y. Masaki, Synlett, 2005, 2107; (b) A. Itoh, S. Hashimoto and Y. Masaki, Synlett, 2005, 2639; (c) S. Hirashima and A. Itoh, Synthesis, 2006, 1757; (d) K. Kuwabara and A. Itoh, Synthesis, 2006, 1949; (e) S. Hirashima, S. Hashimoto, Y. Masaki and A. Itoh, Tetrahedron, 2006, 62, 7887; (f) T. Sugai and A. Itoh, Tetrahedron Lett., 2007, 48, 2931; (g) T. Sugai and A. Itoh, Tetrahedron Lett., 2007, 48, 9096; (h) S. Hirashima and A. Itoh, Photochem. Photobiol. Sci., 2007, 6, 521; (i) S. Hirashima and A. Itoh, Green Chem., 2007, 9, 318.
11. (a) L. Cui, N. Tada, H. Okubo, T. Miura and A. Itoh, Green Chem., 2011, 13, 2347; (b) L. Cui, S. Furuhashi, Y. Tachikawa, N. Tada, T. Miura and A. Itoh, Tetrahedron Lett., 2013, 54, 162; (c) L. Cui, Y. Matsusaki, N. Tada, T. Miura, B. Uno and A. Itoh, Adv. Synth. Catal., 2013, 355, 2203; (d) Y. Shimada, K. Hattori, N. Tada, T. Miura and A. Itoh, Synthesis, 2013, 2684.
12. (a) T. Miura, Y. Yasaku, N. Koyata, Y. Murakami and N. Imai, Tetrahedron Lett., 2009, 50, 2632; (b) T. Miura, M. Ina, K. Imai, K. Nakashima, Y. Yasaku, N. Koyata, Y. Murakami, N. Imai, N. Tada and A. Itoh, Tetrahedron: Asymmetry, 2011, 22, 1028; (c) T. Miura, H. Kasuga, K. Imai, M. Ina, N. Tada, N. Imai and A. Itoh, Org. Biomol. Chem., 2012, 10, 2209.

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Footnote

† Electronic supplementary information (ESI) available: See DOI: 10.1039/c5ra05155j

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