Prolinate Salts as Catalysts for α-Aminoxylation of Aldehyde and

Letter pubs.acs.org/OrgLett

Prolinate Salts as Catalysts for α‑Aminoxylation of Aldehyde and Associated Mechanistic Insights Yujiro Hayashi,* Nariyoshi Umekubo, and Taku Hirama Department of Chemistry, Graduate School of Science, Tohoku University, 6-3 Aramaki-Aza, Aoba, Aoba-ku, Sendai, Miyagi 980-8578, Japan S Supporting Information *

ABSTRACT: Potassium and tetrabutylammonium prolinate salts are efficient catalysts in the α-aminoxylation reaction of aldehydes and nitrosobenzene, to afford synthetically useful chiral α-aminoxylated aldehydes in nearly enantiomerically pure form. This is the first reaction in which prolinate is more reactive and enantioselective than proline. Because of its higher reactivity, the catalyst loading can be reduced. A reaction mechanism involving the activation of nitrosobenzene through Nprotonation of a hydrogen-bonded water molecule is proposed.

P

roline has been one of the central organocatalysts in asymmetric reactions since List, Lerner, and Barbas’ seminal publication of the proline-mediated intermolecular aldol reaction in 2000.1 The molecule can promote several synthetically useful asymmetric reactions such as aldol,1,2 Mannich,3 α-amination,4 and α-aminoxylation5 reactions, in which chiral enaminocarboxylic acid is a reactive intermediate.6 However, there remains some controversy around prolinemediated reactions. Two major reaction models have been proposed: Houk and List proposed that the reaction proceeds from the anti-enamine through activation of an electrophile by protonation with a carboxylic acid (Figure 1A),7 whereas Seebach and Eschenmoser proposed two reaction modes: one involving the addition of syn-enamine toward an electrophile from the opposite side of the carboxylic acid of proline, which is the sterically favorable approach and which matches the observed configuration (Figure 1B). The second is an addition

of anti-enamine toward an electrophile from the opposite side of carboxylic acid of proline, which is the stereoelectronically favorable trajectory, but which does not afford the observed configuration (Figure 1C).8 One of the challenges in current organic chemistry is to develop reactive catalysts that can reduce reaction time (time economy)9 and catalyst loading. In particular, one challenge in organocatalysis is to develop a catalyst that is superior to proline; thus, many proline derivatives have been developed. In contrast to the intense investigation of proline as an asymmetric catalyst, the utility of prolinate salts is rather limited and its catalytic potential has not been fully explored. The 4siloxyproline tetrabutylammonium salt is effective for the intramolecular aldol reaction leading to the formation of bicyclo[3.n.1]alkanones,10 whereas the proline rubidium salt11and a combination of proline and amine12 promote the Michael reaction.13 In the α-amination of aldehydes with diethyl azodicarboxylate (DEAD), Blackmond observed a reversal of the enantioselectivity when the reaction was catalyzed by a tetrabutylammonium proline salt or a combination of proline and DBU;14 the enantioselectivity was moderate, and the reaction was explained according to the Seebach and Eschenmoser model involving the stereoelectronically more favorable pathway (Figure 1C). Enantiopure α-hydroxyaldehydes are synthetically important chiral building blocks, and α-aminoxylation of aldehydes is a

Figure 1. Reaction model of proline and prolinate salt.

Received: May 11, 2017

© XXXX American Chemical Society

A

DOI: 10.1021/acs.orglett.7b01433 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 2. Effect of Counterion of Prolinate Salt in αAminoxylation of 3-Phenylpropanala

powerful method for the synthesis of these compounds.15 MacMillan,5a Zhong,5b and our group5c,e independently reported the proline-mediated α-aminoxylation of aldehydes with nitrosobenzene at the same time. During the search for an effective catalyst in α-aminoxylation, we found that the inexpensive and easily obtainable prolinate salt is a reactive and enantioselective catalyst. In this letter, we will describe details of this catalysis and propose a reaction mechanism. We chose the reaction of 3-phenylpropanal and nitrosobenzene as a model and investigated the reaction using potassium L-prolinate salt as catalyst (Table 1). It was found Table 1. Effect of Solvent in α-Aminoxylation of 3Phenylpropanal Catalyzed by Potassium L-Prolinatea

entry

solvent

time (h)

yield (%)b

er (%)c

1 2 3 4 5

CH2Cl2 CH3CN NMP DMF THF

0.6 4 8 14 18

61 99 15 37 20

99.5:0.5 99.5:0.5 99.0:1.0 99.0:1.0 99.5:0.5

entry

M

time (h)

yield (%)b

er (%)c

1 2 3 4 5 6 7 8 9 10d

H Li Na K Rb Cs Mg Ca Bu4N K + 18-crown-6

23 27 12 4 9 9 37 33 4 4

90 90 95 99 70 71 52 70 83 93

99.0:1.0 99.0:1.0 99.5:0.5 99.5:0.5 99.0:1.0 99.5:0.5 98.5:1.5 99.0:1.0 99.5:0.5 99.0:1.0

a

Unless otherwise shown, the reaction was performed by employing 3phenylpropanal (1.5 mmol), nitrosobenzene (0.5 mmol), and catalyst (0.01 mmol, 2 mol %) in CH3CN (0.5 mL). See Supporting Information for details. bYield of purified product. cDetermined by HPLC analysis on a chiral column material. d18-crown-6 (2 mol %) was employed.

Table 3. Generality of Asymmetric α-Aminoxylation of Aldehyde Catalyzed by Potassium L-Prolinatea

a

Unless otherwise shown, the reaction was performed by employing 3phenylpropanal (1.5 mmol), nitrosobenzene (0.5 mmol), and potassium L-prolinate (0.01 mmol, 2 mol %) in solvent (0.5 mL). See Supporting Information for details. bYield of purified product. c Determined by HPLC analysis on a chiral column material.

that the reaction proceeds in the presence of 2 mol % potassium L-prolinate in CH2Cl2 to afford the product with excellent enantioselectivity (99.5:0.5 er, entry 1). The absolute configuration was R, which is the same as that obtained in the reaction catalyzed by L-proline.5 The effect of solvent was also investigated. Excellent enantioselectivity was observed in all solvents examined, but the reactivity differed according to the solvent. The reaction was fast in halogenated solvents such as CH2Cl2 (entry 1). In polar solvent, the yield was low because of the generation of substantial amounts of side products such as trans-azoxybenzene.16 Good yield and nearly perfect enantioselectivity were obtained in CH3CN, which was selected as a suitable solvent (entry 2). The effect of metal in the prolinate salt was then investigated (Table 2). All the alkali metals such as Li, Na, K, Rb, and Cs promoted the reaction, and the product was obtained with nearly perfect enantiocontrol, although the reactivity of the prolinate salt differed according to the metals. The reaction was slow in the presence of alkaline earth metals such as Mg and Ca, taking over 30 h to reach completion. Proline also promoted the reaction in a highly enantioselective manner,5 but the reaction required 23 h. A combination of potassium salt and 18-crown-6 was effective, indicating that separated ion is a key species. The tetrabutylammonium salt and potassium salt were very reactive, with the reaction reaching completion within 4 h with 99% ee. Given that excellent results were obtained by using potassium and ammonium prolinates, the generality of the reaction was then investigated by using potassium L-prolinate as catalyst (Table 3). In addition to 3-phenylpropanal, propanal, octanal, isovaleraldehyde, and phenylacetaldehyde could also be

a

Unless otherwise shown, the reaction was performed by employing aldehyde (1.5 mmol), nitrosobenzene (0.5 mmol), and potassium Lprolinate (0.01 mmol, 2 mol %) in CH3CN (0.5 mL). See Supporting Information for details. bYield of purified product. cDetermined by HPLC analysis on a chiral column material. dThe catalyst loading is 1 mol %.

B

DOI: 10.1021/acs.orglett.7b01433 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

result indicates that water molecules are located around the Ha proton of enamine, and the slow diffusion coefficients suggest the rather tight hydrogen bond with water. Based on these results, we would like to propose the following mechanism. E-anti-Enamine would be generated from aldehyde and potassium prolinate.21 Water, generated in the enamine formation, would form a hydrogen bond with the carboxylate anion,22 and this proton would protonate the nitrogen of nitrosobenzene (Figure 3A), which is sufficiently

employed as a nucleophilic aldehyde. 4-Pentenal, as a functionalized aldehyde, was also a suitable aldehyde. Excellent enantioselectivity was obtained in all cases examined. In previous reports,5a 10 mol % proline was employed in the reactions of 4-pentenal and 3-phenylpropanal, whereas a 2 mol % catalyst loading was sufficient when potassium prolinate was used. In the case of propanal, the catalyst loading could be reduced to 1 mol % without affecting the enantioselectivity (entry 7). It is known that nitrosobenzene possesses two electrophilic sites such as nitrogen and oxygen: Yamamoto reported that enamine reacts on the nitrogen, but that it reacts on the oxygen in the presence of acid because of the protonation on the basic nitrogen.17 In fact, in the asymmetric organocatalytic reaction of nitrosobenzene with aldehyde via an enamine as an intermediate, two reaction paths, α-oxyamination and αaminoxylation, can be controlled through the use of a catalyst and an acid: the α-oxyamination adduct was obtained by the use of diphenylprolinol silyl ether18 as catalyst,19 whereas the αaminoxylation adduct was generated by using the same catalyst with a combination of acid.20 In the present reaction catalyzed by the prolinate salt, however, α-aminoxylation proceeds without additional acid. This result suggests that there might be some proton source that activates the nitrogen of nitrosobenzene for the formation of the α-aminoxylated adduct, but proline itself can not be generated under the present basic reaction conditions. To confirm this, equimolar reaction of enamine and nitrosobenzene was conducted without water: we prepared enaminocarboxylate from isovaleraldehyde, potassium prolinate, and 18-crown-6, which was treated with nitrosobenzene in the presence of MS4A. α-Oxyaminated product was obtained in 51% yield with low enantioselectivity (11% ee) without generation of α-aminoxy product (eq 1). This result

Figure 3. Model of α-aminoxylation of prolinate salt and proline.

basic.23 The reaction would then proceed through a transition state model similar to that described by Houk and List, in which an electrophile approaches from the same side as the carboxylate, to afford the α-aminoxylated product (Figure 3A). This model explains why the nature of the countercation does not affect the enantioselectivity and why the absolute configurations arising from the reactions of the prolinate salt and proline are the same. The solubility of proline and potassium prolinate in MeCN are 0.24 and 0.11 mg/mL,24 respectively. Thus, the higher reactivity of the prolinate salt cannot be explained based on the solubility. It may be explained as follows. In the prolinemediated reaction of nitrosobenzene,5 an acid protonates the basic nitrogen of nitrosobenzene to activate the electrophile; on the other hand, the nucleophilic enamine moiety attacks the oxygen of nitrosobenzene in a concerted manner (Figure 3B). In the reaction catalyzed by the prolinate salt, nucleophiles such as the enaminocarboxylate are more reactive than enaminocarboxylic acid because of the anchimeric assistance of the carboxylate group reported by Mayr.25 Thus, although acid activation would be weak, the reaction with the prolinate salt is fast because of the higher nucleophilicity of the enaminocarboxylate compared with the enaminocarboxylic acid. Moreover, in the case of proline, the concentration of enamine is low because of the formation of stable oxazolidinone 1 (Figure 2C).8,21 In contrast, the oxazolidinone would not be generated in the case of the prolinate salt, leading to a higher concentration of enaminocarboxylate. α-Aminoxylation of nitrosobenzene and α-amination of DEAD are similar reactions catalyzed by proline, but these reactions possess very different profiles when catalyzed by a prolinate salt and an ammonium ion. That is, in the αaminoxylation of nitrosobenzene, both alkalimetal and ammonium salts of proline are more reactive and excellent enantioselectivity are observed with the same absolute configuration as that obtained in the reaction catalyzed by proline. In the α-amination of DEAD, prolinate was not reactive, and use of the proline alkalimetal salt afforded the racemic product; moderate enantioselectivity of the opposite

indicates that water is essential in the α-aminoxylation catalyzed by prolinate salt. The low enantioselectivity would be attributed to the formation of an enamine intermediate before the hydrolysis as shown in eq 1. Gschwind observed the E-anti-enamine from aldehyde, proline, and DBU (Figure 2A),21 and ion-pair formation of enaminocarboxylate and a protonated amine base.21 We prepared E-anti-enamine from isovaleraldehyde, potassium prolinate, and 18-crown-6 and observed a negative NOE between water and Ha of the pyrrolidine ring (Figure 2B). This

Figure 2. Enaminocarboxylate and enaminocarboxylic acid. C

DOI: 10.1021/acs.orglett.7b01433 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters

(3) (a) List, B. J. Am. Chem. Soc. 2000, 122, 9336. (b) Hayashi, Y.; Tsuboi, W.; Ashimine, I.; Urushima, T.; Shoji, M.; Sakai, K. Angew. Chem., Int. Ed. 2003, 42, 3677. (c) Notz, W.; Tanaka, F.; Watanabe, S.; Chowdari, N. S.; Turner, J. M.; Thayumanavan, R.; Barbas, C. F., III J. Org. Chem. 2003, 68, 9624. (d) Córdova, A. Chem. - Eur. J. 2004, 10, 1987. (4) (a) Bogevig, A.; Juhl, K.; Kumaragurubaran, N.; Zhuang, W.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2002, 41, 1790. (b) List, B. J. Am. Chem. Soc. 2002, 124, 5656. (5) (a) Brown, S. P.; Brochu, M. P.; Sinz, C. J.; MacMillan, D. W. C. J. Am. Chem. Soc. 2003, 125, 10808. (b) Zhong, G. Angew. Chem., Int. Ed. 2003, 42, 4247. (c) Hayashi, Y.; Yamaguchi, J.; Hibino, K.; Shoji, M. Tetrahedron Lett. 2003, 44, 8293. (d) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Shoji, M. Angew. Chem., Int. Ed. 2004, 43, 1112. (e) Hayashi, Y.; Yamaguchi, J.; Sumiya, T.; Hibino, K.; Shoji, M. J. Org. Chem. 2004, 69, 5966. (f) Bogevig, A.; Sunden, H.; Córdova, A. Angew. Chem., Int. Ed. 2004, 43, 1109. (6) Selected reviews on organocatalysis: (a) Enantioselective Organocatalysis; Dalko, P. I., Ed.; Wiley-VCH: Weinheim, 2007. (b) Asymmetric Organocatalysis 1; Lewis Base and Acid Catalysts; List, B., Ed.; Thieme: Stuttgart, 2012. (7) (a) Bahmanyar, S.; Houk, K. N.; Martin, H. J.; List, B. J. Am. Chem. Soc. 2003, 125, 2475. (b) Hoang, L.; Bahmanyar, S.; Houk, K. N.; List, B. J. Am. Chem. Soc. 2003, 125, 16. (8) Seebach, D.; Beck, A. K.; Badine, D. M.; Limbach, M.; Eschenmoser, A.; Treasurywala, A. M.; Hobi, R.; Prikoszovich, W.; Linder, B. Helv. Chim. Acta 2007, 90, 425. (9) Hayashi, Y.; Ogasawara, S. Org. Lett. 2016, 18, 3426. (10) Itagaki, N.; Kimura, M.; Sugahara, T.; Iwabuchi, Y. Org. Lett. 2005, 7, 4185. (11) Yamaguchi, M.; Shiraishi, T.; Hirama, M. J. Org. Chem. 1996, 61, 3520. (12) Xu, K.; Zhang, S.; Hu, Y.; Zha, Z.; Wang, Z. Chem. - Eur. J. 2013, 19, 3573. (13) Yoshida reported that a primary amino acid lithium salt is an effective catalyst for the Michael reaction, but lithium prolinate is not: Sato, A.; Yoshida, M.; Hara, S. Chem. Commun. 2008, 6242. (14) (a) Blackmond, D. G.; Moran, A.; Hughes, M.; Armstrong, A. J. Am. Chem. Soc. 2010, 132, 7598. (b) Hein, J. E.; Bures, J.; Lam, Y.; Hughes, M.; Houk, K. N.; Armstrong, A.; Blackmond, D. G. Org. Lett. 2011, 13, 5644. (15) Marques-Lopez, E.; Herrera, R. P.; Christmann, M. Nat. Prod. Rep. 2010, 27, 1138. (16) Ramachary, D. B.; Barbas, C. F., III Org. Lett. 2005, 7, 1577. (17) (a) Yamamoto, H.; Momiyama, N. Chem. Commun. 2005, 3514. (b) Yamamoto, H.; Kawasaki, M. Bull. Chem. Soc. Jpn. 2007, 80, 595. (c) Merino, P.; Tejero, T.; Delso, I.; Matute, R. Synthesis 2016, 48, 653. (18) (a) Hayashi, Y.; Gotoh, H.; Hayashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (b) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A. Angew. Chem., Int. Ed. 2005, 44, 794. (19) Palomo, C.; Vera, S.; Velilla, I.; Mielgo, A.; Gomez-Bengoa, E. Angew. Chem., Int. Ed. 2007, 46, 8054. (20) Mielgo, A.; Velilla, I.; Gomez-Bengoa, E.; Palomo, C. Chem. Eur. J. 2010, 16, 7496. (21) Schmid, M. B.; Zeitler, K.; Gschwind, R. M. Chem. - Eur. J. 2012, 18, 3362. (22) More than two molecules of water may participate in the reaction. See: Moteki, S. A.; Maruyama, H.; Nakayama, K.; Li, H.-B.; Petrova, G.; Maeda, S.; Morokuma, K.; Maruoka, K. Chem. - Asian J. 2015, 10, 2112. (23) Cheong, P. H.; Houk, K. N. J. Am. Chem. Soc. 2004, 126, 13912. (24) See Supporting Information for details. (25) Kanzian, T.; Lakhdar, S.; Mayr, H. Angew. Chem., Int. Ed. 2010, 49, 9526. (26) Breslow reported the low ee in the aldol reaction of glyceraldehyde synthesis catalyzed by L-proline under pH 8.7−9.8. Breslow, R.; Ramalingam, V.; Appayee, C. Origins Life Evol. Biospheres 2013, 43, 323.

enantiomer was obtained in the reaction catalyzed by the tetrabutylammonium salt of proline.14 We further investigated the aldol reaction using the prolinate salt, encouraged by the excellent intramolecular aldol reaction using siloxyproline tetrabutylammonium salt reported by Iwabuchi.10 However, although an intense investigation of the intermolecular aldol reaction of two different aldehydes catalyzed by prolinate salts was undertaken, we found that aldol addition followed by dehydration was the major reaction between two different aldehydes, such as p-nitrobenzaldehyde and propanal, and the minor amounts of aldol product that were observed were formed with low enantioselectivity.21,26 These results can be explained by the basicity of the electrophile: the nitrogen of DEAD and the oxygen of the aldehyde group are less basic than the nitrogen of nitrosobenzene, and these sites are not protonated by water. The amination and aldol reactions do not proceed via a rigid transition state as shown in Figure 3A because of the lack of assistance of acid activation; therefore, the products are afforded with low enantioselectivity. In summary, we found that both potassium and tetrabutylammonium prolinate are more reactive and more enantioselective catalysts than proline in the α-aminoxylation of aldehydes and nitrosobenzene, and the same enantiomer was generated as formed in the reaction catalyzed by proline. This is the first reported reaction in which prolinate is more reactive and selective than proline. Given that the catalyst is inexpensive, a small amount of the catalyst promotes the reaction, and the synthetically useful α-aminoxy aldehydes were obtained in nearly enantiomerically pure form, the present method can be considered synthetically important. A reaction mechanism involving the activation of nitrosobenzene through N-protonation of a hydrogen-bonded water molecule has also been proposed.

■

ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b01433. Experimental procedure, analytical data (1H and 13C NMR, IR, HRMS) (PDF)

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Yujiro Hayashi: 0000-0002-1838-5389 Notes

The authors declare no competing financial interest.

■ ■

ACKNOWLEDGMENTS We thank Professor Dieter Seebach at ETH for the valuable discussions. REFERENCES

(1) List, B.; Lerner, R. A.; Barbas, C. F., III J. Am. Chem. Soc. 2000, 122, 2395. (2) Recent review, see: Mase, N.; Hayashi, Y. In Comprehensive Organic Synthesis II; Mikami, K., Ed.; Elsevier: Amsterdam, 2014; Vol. 2, pp 273−339. D

DOI: 10.1021/acs.orglett.7b01433 Org. Lett. XXXX, XXX, XXX−XXX