Oxidative Asymmetric [2 + 3] Annulation of Aldehydes with Azomethine

Letter Cite This: Org. Lett. XXXX, XXX, XXX-XXX

pubs.acs.org/OrgLett

Oxidative Asymmetric [2 + 3] Annulation of Aldehydes with Azomethine Imines Enabled by N‑Heterocyclic Carbene Catalysis Shiru Yuan, Yuchen Luo, Jingyi Peng, Maozhong Miao, Jianfeng Xu,* and Hongjun Ren* Department of Chemistry, Zhejiang Sci-Tech University, Hangzhou 310018, People’s Republic of China S Supporting Information *

ABSTRACT: An efficient asymmetric [2 + 3] annulation of simple aldehydes with N,N′-cyclic azomethine imines via oxidative N-heterocyclic carbene (NHC) catalysis is disclosed, affording bicyclic pyrazolidinones bearing two vicinal tertiary stereogenic centers with moderate to good yields (56−84% for 19 examples), good to excellent diastereoselectivities (>20:1 for 17 examples), and good to excellent enantioselectivities (66− 98% for 19 examples). This direct α-carbon functionalization reaction of aldehyde can be readily performed on gram scale under mild conditions, and a five-membered transition state is proposed to rationalize the stereochemical outcome. Scheme 1. NHC-Catalyzed Oxidative [2 + x] Annulation of Simple Aldehydes and Our Current Work

he direct activation of α-carbons of simple aliphatic aldehydes to generate enolate equivalents as nucleophiles is a fundamental transformation in organic synthesis (e.g., aldol condensation and Mannich reaction). In the past decade, the development of catalytic asymmetric variants of such reactions has been realized by using chiral secondary amines as promising catalysts through enamine catalysis,1 SOMO catalysis,2 and visible-light photoredox catalysis.3 However, in another important arena of organocatalysis, owing to the distinctive umpolung reactivity of N-heterocyclic carbene (NHC),4 the carbonyl carbon of simple aldehydes is preferably activated as a nucleophilic carbon to undergo further transformations. Consequently, to achieve the functionalization of the α-carbon (through NHC-bonded enolate intermediate), indirect strategies by employing alternatives such as prefunctionalized aldehydes,5a−f α,β-unsaturated aldehydes,5g−i ketenes,5j,k esters,5l and acids5m,n have to be adopted, although some of those substrates are unstable and/or require a multistep synthesis. In 2012, Rovis and co-workers pioneered the direct NHCcatalyzed α-carbon functionalization of simple aldehydes by developing the first asymmetric [2 + 4] annulation of aldehydes with chalcones under oxidative reaction conditions (Scheme 1a).6a Later, Chi’s group6b and Wang’s group6c independently reported two enantioselective [2 + 4] annulation reactions to form six-membered heterocycles by exploiting different annulation partners. Recently, our group disclosed an NHCcatalyzed asymmetric oxidative [2 + 2] annulation of simple aliphatic aldehydes with isatin-derived ketimines to afford enantioenriched spirooxindole β-lactams (Scheme 1b).6d Nevertheless, to the best of our knowledge, the development of equally important and useful [2 + 3] annulation reactions to construct biologically valuable five-membered heterocyclic compounds via oxidative NHC catalysis has not been accomplished yet. N,N′-Cyclic azomethine imines are a class of inexpensive, bench-stable, and readily available building blocks that have

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© XXXX American Chemical Society

been widely used in catalytic asymmetric 1,3-dipolar cycloaddition reactions to synthesize dinitrogen-fused heterocycles.7 In the realm of NHC catalysis, Scheidt,7c Chi,7i and Glorius7k have done some elegant work using N,N′-cyclic azomethine imines as suitable reaction partners. As part of our ongoing efforts in establishing novel synthetic methodologies for the construction of biologically important heterocyclic compounds via NHC catalysis,6d,8 we envisaged that under oxidative reaction conditions the in situ generated NHC-bonded enolate intermediates from simple aldehydes would undergo a formal Received: September 20, 2017

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DOI: 10.1021/acs.orglett.7b02948 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Optimization of Reaction Conditionsa

[2 + 3] annulation reaction with N,N′-cyclic azomethine imines to afford enantioenriched bicyclic pyrazolidinones (Scheme 1c). Notably, the bicyclic pyrazolidinone motifs and their derivatives are privileged skeletons in many pharmaceuticals and drug candidates that exhibit diverse biological and medicinal activities (Figure 1),9 for example, as anti-Alzheimer agents, pesticides, herbicides, and antibiotics.

Figure 1. Representative examples of biologically active compounds containing the bicyclic pyrazolidinone motif.

Experimentally, we started our investigation by using hydrocinnamaldehyde 1a and 2-benzylidene-5-oxopyrazolidin2-ium-1-ide 2a as the model substrates, 1,8-diazabicycloundec7-ene (DBU) as the base, 3,3′,5,5′-(tBu)4-diphenoquinone 4a as the oxidant, and 4 Å molecular sieves as the additive, and the key results are summarized in Table 1. To our delight, when aminoindanol-derived NHC precatalyst A10 was used as the catalyst in 1,2-dichloroethane (DCE) at 25 °C for 48 h, the desired [2 + 3] annulation product 3a was successfully isolated in 52% yield, >20:1 dr, and 62% ee (Table 1, entry 1). Gratifyingly, replacing the mesityl substituent on the NHC precatalyst A with a 2,4,6-trichlorophenyl group (NHC precatalyst B11) dramatically enhanced the ee value from 62% to 91% (entry 2). Other NHC precatalysts derived from Lphenylalanine (C) and L-neopentylglycine (D) were proven to be less effective (entries 3 and 4). With NHC B as the optimal catalyst, we next set out to explore the solvent effect. A variety of nonpolar and polar solvents were examined, and CHCl3 furnished 3a with the highest 95% ee (entries 5−9). Further studies on reaction temperature revealed that 40 °C was the proper temperature as too high temperatures may cause side reactions (entries 10 and 11). Finally, prolonging the reaction time to 72 h afforded 3a in 78% yield, >20:1 dr, and 94% ee (entry 12). Phenazine 4b was not an efficient oxidant for this reaction as only a trace amount of 3a was formed (entry 13), and in the absence of 4 Å molecular sieves a drop in yield was observed (entry 14). Having established the optimized reaction conditions (Table 1, entry 12), we then evaluated the generality of this formal [2 + 3] annulation reaction. As illustrated in Scheme 2, a series of simple aliphatic aldehydes were first investigated. Hydrocinnamaldehydes with 4-OMe and 4-Br substituents on the β-phenyl ring reacted with 2a smoothly, affording bicyclic pyrazolidinones 3b and 3c with moderate yields, excellent diastereoselectivities, and enantioselectivities. Aldehydes with long chains such as hexanal and decanal were proven to be suitable substrates by providing the corresponding products 3d and 3e in 81% yield, >20:1 dr, 92% ee and 70% yield, >20:1 dr, 94% ee, respectively. It is worth noting that functional groups such as the C−C double bond on the aldehyde are compatible in this reaction as 3f was successfully formed in 65% yield, >20:1 dr, and 90% ee. Unfortunately, branched aldehydes such as α- or β-substituted aldehydes were not proper substrates for this reaction. A broad range of N,N′-cyclic azomethine imines with diverse electronic and steric properties on the phenyl ring

entry

cat.

solvent

yieldb (%)

drc

eed (%)

1 2 3 4 5 6 7 8 9 10e 11f 12e,g 13e,g,h 14e,g,i

A B C D B B B B B B B B B B

DCE DCE DCE DCE toluene CHCl3 THF CH3CN EtOAc CHCl3 CHCl3 CHCl3 CHCl3 CHCl3

52 59 52 20 39 52 33 33 39 65 56 78 trace 61

>20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1 >20:1

62 91 59 56 92 95 90 82 91 95 94 94

>20:1

94

a

Reaction conditions unless otherwise specified: 1a (0.2 mmol), 2a (0.1 mmol), NHC (20 mol %), DBU (0.12 mmol), oxidant 4 (0.12 mmol), solvent (1 mL), 4 Å MS (100 mg, powder) at 25 °C for 48 h. b Isolated yield based on 2a. cDiastereomeric ratio of 3a, determined via 1H NMR analysis of crude reaction mixtures. dEnantiomeric excess of 3a, determined via chiral phase HPLC analysis; absolute configuration of the major enantiomer was assigned based on X-ray structure of 3c (see Figure 2 and the Supporting Information). e40 °C. f 60 °C. g72 h. hPhenazine 4b was used as the oxidant. iNo 4 Å MS was used. Mes = 2,4,6-trimethylphenyl, DBU = 1,8-diazabicycloundec-7ene, DCE = 1,2-dichloroethane, THF = tetrahydrofuran.

were next explored. The use of 4-Me- and 4-OMe-substituted azomethine imines furnished the desired products 3g and 3h in 81% yield, >20:1 dr, 93% ee and 74% yield, >20:1 dr, 94% ee, respectively. However, when electron-withdrawing groups (4CF3, 4-F, and 4-Cl) were installed on the phenyl ring, a slight drop in enantioselectivity was observed (3i−k). The substitution position on the phenyl ring had a significant impact on the stereochemical outcome as compared with 4-Br (product 3l) and 3-Br (product 3m), and 2-Br-substituted azomethine imine led to the corresponding product 3n with lower dr (5:1 dr) and higher ee (95% ee). The same influence was also noted when 1-naphthyl- and 2-naphthyl-substituted azomethine imines were utilized as the substrates (products 3o and 3p). We reasoned this decrease in diastereoselectivity and increase in enantioselectivity may be attributed to the steric hindrance between the bulky ortho-substituent from azomethine imine and the benzyl group from aldehyde. Heteroaryl-substituted azomethine imines were also found to be well tolerated under the optimal conditions, forming the desired products 3q−s in good yields, excellent diastereoselectivities, and moderate to good enantioselectivities. B

DOI: 10.1021/acs.orglett.7b02948 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters Scheme 2. Scope of Reactionsa

Figure 2. ORTEP diagram of 3c.

desired bicyclic pyrazolidinone product 3a was straightforwardly synthesized in 73% yield, >20:1 dr, and 94% ee (Scheme 3). Scheme 3. Practical Synthesis of 3a

On the basis of the experimental observations, a plausible five-membered transition state is proposed to rationalize the stereochemical outcome (Scheme 4). The addition of NHC Scheme 4. Proposed Transition States

a

Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), NHC B (20 mol %), DBU (0.12 mmol), oxidant 4a (0.12 mmol), CHCl3 (1 mL), 4 Å MS (100 mg, powder) at 40 °C for 72 h. Isolated yields based on 2. The dr’s were determined via 1H NMR analysis of crude reaction mixtures. The ee’s were determined via chiral phase HPLC analysis.

catalyst B to aldehyde 1a followed by oxidation and deprotonation generates the geometrically preferred (Z)enolate intermediate. The (Z)-enolate intermediate then reacts with azomethine imine 2a through the favored transition state (TS-I) to furnish the major product trans-3a, whereas in the disfavored transition state (TS-II), because of the steric repulsion between the benzyl group and the phenyl ring, cis3a would form as the minor product. In both cases, the azomethine imine 2a approaches the (Z)-enolate intermediate from the face opposite the bulky indanyl group of NHC B. However, a stepwise reaction mechanism which may also explain the observed trans selectivity can not be completely ruled out (see the SI for details). In summary, we have developed the first asymmetric [2 + 3] annulation reaction of simple aldehydes through direct α-

The absolute configuration of the chiral bicyclic pyrazolidinone products was determined via X-ray crystallographic analysis of compound 3c, which was isolated as a single crystal. As shown in Figure 2, the two newly formed tertiary stereogenic centers of 3c were unambiguously confirmed to be (2S,3R). The configurations of other chiral products were assigned on the assumption of a uniform mechanistic pathway. To further demonstrate the potential utility of this formal [2 + 3] annulation reaction, an additional gram-scale experiment was performed. Under the optimal reaction conditions, the C

DOI: 10.1021/acs.orglett.7b02948 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

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carbon functionalization via oxidative NHC catalysis. This efficient strategy affords biologically valuable bicyclic pyrazolidinones bearing two vicinal tertiary stereogenic centers with moderate to good yields, good to excellent diastereoselectivities, and enantioselectivities. A practical example is presented to demonstrate the utility of this protocol, and a rationale is postulated to explain the stereochemical outcome.

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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.7b02948. X-ray crystallographic data for 3c (CIF) Experimental procedures, full spectroscopic data for all new compounds, and 1H, 13C NMR, and HPLC spectra (PDF)

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AUTHOR INFORMATION

Corresponding Authors

*E-mail: [email protected]. *E-mail: [email protected]. ORCID

Maozhong Miao: 0000-0001-6777-7189 Jianfeng Xu: 0000-0003-2111-2944 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We gratefully acknowledge the National Natural Science Foundation of China (Grant No. 21602203), the Natural Science Foundation of Zhejiang Province (Grant No. LQ16B020001), the Natural Science Foundation of Zhejiang Sci-Tech University (Grant No. 15062018-Y), as well as the Zhejiang Provincial Top Key Academic Discipline of Chemical Engineering and Technology of Zhejiang Sci-Tech University for financial support.

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REFERENCES

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DOI: 10.1021/acs.orglett.7b02948 Org. Lett. XXXX, XXX, XXX−XXX