Letter Cite This: Org. Lett. 2018, 20, 5569−5572
pubs.acs.org/OrgLett
Cinchona−Diaminomethylenemalononitrile Organocatalyst for the Highly Enantioselective Hydrophosphonylation of Ketones and Enones Ryoga Arai, Shin-ichi Hirashima, Junko Kondo, Kosuke Nakashima, Yuji Koseki, and Tsuyoshi Miura* Tokyo University of Pharmacy and Life Sciences, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan
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S Supporting Information *
ABSTRACT: The use of diaminomethylenemalononitrile (DMM) organocatalyst to promote the challenging 1,2hydrophosphonylation of simple ketones and enones, which are also called α,β-unsaturated ketones, is proposed and validated. This reaction provided the corresponding chiral αhydroxy phosphonates in high to excellent yields and with enantioselectivity up to 96% ee.
O
Scheme 1. Overview of 1,2-Hydrophosphonylation of Simple Ketones
ptically active organophosphorus compounds are attractive target molecules because they exhibit remarkable biological activities1 and can be used as chiral ligands for asymmetric organometallic synthesis.2 In particular, chiral αhydroxy phosphonates and their derivatives are known as antivirus agents, anticancer agents, and HIV protease and renin inhibitors.3 The addition of dialkyl phosphonates to carbonyl compounds (Pudovik reaction) is one of the most convenient methodologies to easily obtain α-hydroxy phosphonates;4 several research groups have reported asymmetric Pudovik reactions involving aldehydes as reactive carbonyl compounds using metal catalysts5 and organocatalysts.6,7 However, simple ketones such as acetophenone derivatives act as inert substrates in such reactions owing to the electronic and steric constraints; therefore, catalytic enantioselective hydrophosphonylations are usually performed using reactive ketones such as ynones,8 isatins,9 ketoesters,10 trifluoromethyl ketones,11 and α-chloroketones.12 Feng et al. observed a moderate stereoselectivity in the asymmetric hydrophosphonylation of acetophenone when using chiral metal catalysts (Scheme 1, eq 1),13 and Ooi et al. also reported a low enantioselectivity for this reaction when using chiral triaminoiminophosphorane organocatalysts (eq 2).8b To the best of our knowledge, the sole successful example for such asymmetric hydrophosphonylation using chiral metal catalysts is the work published by He et al., which reported an excellent enantioselectivity (eq 3).14 However, unfortunately, their methodology provided only moderate yields (up to 71%) for acetopheone derivatives. Therefore, developing efficient hydrophosphonylation processes of simple ketones under metal-free conditions is highly desirable. Asymmetric reactions using organocatalysts bearing thiourea15 and squaramide16 motifs as double hydrogen bond donors © 2018 American Chemical Society
have attracted considerable attention over the past decade because of their excellent stereoselectivity and environmentally benign properties. Recently, we have demonstrated that the diaminomethylenemalononitrile (DMM) motif also acts as a double hydrogen-bond donor and that the organocatalysts Received: July 18, 2018 Published: September 10, 2018 5569
DOI: 10.1021/acs.orglett.8b02241 Org. Lett. 2018, 20, 5569−5572
Letter
Organic Letters
were slightly improved by doubling the amount of 1 (20 mol %). When the reactions were conducted at −60 °C, both yield and enantioselectivity considerably increased. To further improve the enantioselectivity, the other organocatalysts (Figure 1) were tested (Table 2). In the reactions using the
bearing it efficiently promote many valuable asymmetric reactions.17 In particular, DMM organocatalysts efficiently catalyze the hydrophosphonylation of aldehydes using diaryl phosphonate, achieving high stereoselectivity compared with thiourea and squaramide organocatalysts.17f Here, we describe the highly efficient Pudovik reaction between diaryl phosphonates and simple ketones using DMM organocatalysts. First, the optimization of the reaction conditions for 4′nitroacetophenone 7a, with diphenyl phosphonate 8 as model reactant using the DMM organocatalyst 1 (Figure 1), was
Table 2. Catalyst Screening
a
investigated (Table 1). Among all the representative reaction solvents used, toluene resulted in the most suitable one considering both yield and stereoselectivity that, in addition, Table 1. Study of Reaction Conditions
solvent (M)
1 2 3 4
EtOH (0.67) MeCN (0.67) THF (0.67) acetone (0.67) EtOAc (0.67) CH2Cl2 (0.67) toluene (0.67) toluene (1.0) toluene (1.0) toluene (1.0) toluene (1.0) toluene (1.0)
5 6 7 8 9 10 11 12
cat. (mol %)
temp (°C)
time (h)
yield (%)a
ee (%)b
10 10 10 10
rt rt rt rt
72 65 71 72
N.R. 20 20 37
--57 53 55
10 10
rt rt
71 92
19 62
64 21
10
rt
69
73
53
20 20 20 20 20
rt −20 −40 −60 −80
24 24 46 75 72
84 99 92 99 63
59 73 83 89 93
catalyst
time (h)
yield (%)a
ee (%)b
1 2 3 4 5 6
1 2 3 4 5 6
75 47 48 76 22 48
99 78 99 99 23 99
89 38 4 25 24 92
Isolated yield. bDetermined by chiral HPLC analysis.
DMM organocatalysts 2 and 3, which have chiral primary and secondary amine units, the stereoselectivity decreased. The organocatalysts 4 and 5, which have thiourea and squaramide motifs instead of DMM, also acted as poor catalysts exhibiting low enantioselectivity. In contrast, the cinchona−DMM organocatalyst 6, which has two tert-butyl groups instead of the trifluoromethyl groups of 1, proved to be a good catalyst by achieving the highest enantioselectivity (up to 92% ee). Therefore, the DMM skeleton is a more suitable motif than thiourea and squaramide for the reaction of simple ketones with phosphonates. Under the optimal reaction conditions, we examined the scope and limitations of the addition of phosphonate 8 to various ketones 7 (Scheme 2). The acetophenone derivatives (7b−d) bearing cyano, bromo, and chloro substituents as electron-withdrawing groups on the benzene ring smoothly reacted with 8 in the presence of 6, providing the corresponding products 9b−d with high to excellent enantioselectivity. It was worth noting that reproducibility of the reactions has been ensured by addition of MS 4A. The reaction of 7e, having a methyl group as an electron-donating group, in the presence of 30 mol % of catalyst 6 produced 9e in high yield and with high stereoselectivity. The acetophenone derivative 7f, which has a methoxy group, exhibited low yield; however, high enantioselectivity was observed. Acetophenone 7g acted as a good substrate, producing 9g in high yield and with excellent enantioselectivity. Propiophenone 7h and butyrophenone 7i slowly reacted with 8 to give 9h and 9i, respectively, in good to high yields and with excellent enantioselectivity. The reaction of the propiophenone derivative 7j, which has a nitro group, was accelerated, giving 9j in high yield and with excellent enantioselectivity. Heteroaryl methyl ketone 7k was also tested, and it gave 9k with good enantioselectivity. Enantioselectivity of 9k was improved by the reaction at −65 °C. 3-Methylbutan-2-one 7l, an aliphatic ketone, exhibited moderate yield and stereoselectivity. Next, we investigated the applicability of our DMM catalyst 6 for the hydrophosphonylation of simple α,β-unsaturated ketones (enones) because the 1,2-addition of phosphonates to enones using chiral metal catalysts with high enantioselectivity
Figure 1. Structure of organocatalysts.
entry
entry
a
Isolated yield. bDetermined by chiral HPLC analysis. 5570
DOI: 10.1021/acs.orglett.8b02241 Org. Lett. 2018, 20, 5569−5572
Letter
Organic Letters
The yields when using 7s−t as a less reactive substrate were improved by addition of 30 mol % of 6 and/or reactions at −50 °C. The X-ray crystallographic analysis of 9g and 9o unambiguously showed their absolute configuration as S, and other products were tentatively assigned by a comparison with them (Figure 2).
Scheme 2. Asymmetric Hydrophosphonylation of Ketones Using Organocatalyst 6a,b
Figure 2. X-ray crystallographic analysis of products 9g and 9o. a
b
c
Isolated yield. Determined by chiral HPLC analysis. Added MS 4 A. dCatalyst 6 (30 mol %) was used. eAt −65 °C.
Although no experimental data enlightening the reaction mechanism were obtained, we inferred that the tertiary amine group of 6 traps a proton from the hydroxyl group of the phosphite form, which is generated by equilibrium with the phosphonate form.8 Then, two weak acid protons of the DMM motif interact with the oxygen atoms of the ketones to direct the approach of the phosphite (attack on the Si face of ketones). Ultimately, excellent enantioselectivity is obtained. In conclusion, the cinchona−DMM organocatalyst 6 efficiently catalyzes the hydrophosphonylation of simple ketones with diaryl phosphonate in toluene, giving the corresponding α-hydroxy phosphonates 9 in high yield and with excellent enantioselectivity. In addition, excellent enantioselective 1,2-addition of diarylphosphonate to enones can also be achieved using 6. This report is the first example of successful asymmetric Pudovik reactions for simple ketones and α,β-unsaturated ketones using organocatalysts under metal-free conditions. Further applications of DMM organocatalysts in other asymmetric reactions and the development of additional novel DMM organocatalysts are currently being investigated in our laboratory.
(up to 86% ee) has been reported only by Ishihara et al.18 The reactivity of α,β-unsaturated ketones such as benzylidene acetone derivatives with phosphonates in the presence of 6 was investigated (Scheme 3). The addition of 8 to (E)-4Scheme 3. Asymmetric Hydrophosphonylation of α,βUnsaturated Ketones Using Organocatalyst 6a,b
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b02241. Experimental procedures, analytical data, and NMR (PDF)
a
Isolated yield. bDetermined by chiral HPLC analysis. cCatalyst 6 (30 mol %) was used. dAt −50 °C.
phenylbut-3-en-2-one 7m selectively provided 9m in high yield and with excellent enantioselectivity. It is noteworthy that no 1,4-adduct was obtained. High yields and excellent stereoselectivities were observed in the reactions of benzylidene acetone derivatives 7n−t, regardless of the existence of electron-withdrawing and electron-donating groups on the benzene ring. Interestingly, (E)-hept-3-en-2-one 7u, an aliphatic α,β-unsaturated ketone, proved to be a good substrate by providing 9u in high yield and with high enantioselectivity.
Accession Codes
CCDC 1856528−1856529 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
[email protected], or by contacting The Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44 1223 336033. 5571
DOI: 10.1021/acs.orglett.8b02241 Org. Lett. 2018, 20, 5569−5572
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Organic Letters
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Tsuyoshi Miura: 0000-0003-1216-4507 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was supported by JSPS KAKENHI Grant Number 16K08178. The authors would like to thank Enago (www. enago.jp) for the English language review.
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DOI: 10.1021/acs.orglett.8b02241 Org. Lett. 2018, 20, 5569−5572
