Intermolecular Acetoxyaminoalkylation of α-Diazo Amides with

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

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Intermolecular Acetoxyaminoalkylation of α‑Diazo Amides with (Diacetoxyiodo)benzene and Amines Nadine Döben,† Hong Yan,†,‡ Marvin Kischkewitz,† Jincheng Mao,‡ and Armido Studer*,† †

Institute of Organic Chemistry, University of Münster, Corrensstrasse 40, 48149 Münster, Germany State Key Laboratory of Oil and Gas Reservoir Geology and Exploitation, Southwest Petroleum University, Chengdu 610500, P. R. China

‡

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S Supporting Information *

ABSTRACT: Multicomponent reactions of diazo compounds have attracted much attention in recent years. Such transformations are generally conducted by applying transition metal catalysis and involve the corresponding metal carbenes as key intermediates. In this letter, a metal-free threecomponent intermolecular acetoxyaminoalkylation of αdiazo amides with tertiary aryl amines and (diacetoxyiodo)benzene is presented.

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Hypervalent iodine compounds are highly useful reagents for introducing various functional groups (such as OAc, CF3, OTf, alkynyl, CN, Ar, N3, ...) into a target molecule.13 Functional groups are transferred either in an ionic mode or via radical intermediates. It is well-known that hypervalent iodine reagents are easily reduced by low-valent metal ions, iodide, amines, and a TEMPO anion as well as some other organic reductants via single-electron transfer (SET) processes.13,14 Based on literature precedence13b that tertiary amines react with (diacetoxyiodo)benzene (PIDA) to the corresponding iminium ions, we speculated that tertiary amines can be directly transformed with α-diazo compounds in the presence of PIDA to the corresponding α-acetoxy-α-aminoalkylated compounds (Scheme 1, eq 2). The three-component sequence comprises C(sp3)−H activation via amine SET oxidation, subsequent deprotonation, and renewed SET oxidation to form the corresponding iminium ion, which in turn reacts with the α-diazo compound and undergoes subsequent nucleophilic attack by the acetate anion15 with concomitant loss of molecular dinitrogen to the acetoxyaminoalkylated product. First results along these lines are reported herein. For reaction optimization, α-diazo amide 1a (1 equiv), N,Ndimethylaniline (2a, 3 equiv), and (diacetoxyiodo)benzene (3, PIDA, 2 equiv) were chosen as reactants. Pleasingly, in dichloromethane (DCM) at room temperature for 4 h, product 4aa was obtained in 51% yield (Table 1, entry 1). An intensive solvent screening revealed that the threecomponent coupling is best conducted in methanol (Table 1, entries 2−15). Surprisingly, reaction in EtOH and in the more acidic trifluoroethanol was significantly lower yielding (Table 1, entries 14, 15). In MeOH, the yield was further improved upon extending the reaction time to 18 h (61%

iazo compounds are highly valuable building blocks in organic synthesis since they are easily accessed and readily converted to free carbenes or metal carbene species upon release of dinitrogen.1 These reactive intermediates undergo a plethora of useful organic reactions, such as cyclopropanation of alkenes2 and alkynes, 3 the Wolff rearrangement,4 X−H (X = carbon or heteroatom) insertions,5 cycloadditions,6 substitution reactions,7 generation of ylides,8 migratory insertions,9 and homologation reactions.10 Moreover, as amphiphilic reagents, diazo compounds can react with both nucleophiles and electrophiles and have therefore gained much attention as reaction partners in multicomponent processes, in particular for transformations proceeding via their corresponding metal carbene intermediates (Scheme 1, eq 1).11 However, metal-free α-difunctionalizations of diazo compounds with a nucleophile/electrophile pair are not well studied.12 Scheme 1. Multicomponent Reactions of Diazo Compounds

Received: November 2, 2018

© XXXX American Chemical Society

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DOI: 10.1021/acs.orglett.8b03504 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Table 1. Reaction Optimizationa

Scheme 2. Variation of the α-Diazo Amide Componenta

entry

solvent

time

yield (%)b

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17d

DCM CH3CN toluene THF DCE benzene 1,1,1-trifluorotoluene 1,4-dioxan EtOAc acetone methanol DMF DMSO ethanol HFIP methanol methanol

4 4 4 4 4 4 4 4 4 4 4 4 4 4 4 18 18

51 43 34 39 34 37 32 36 29 14 56 4 4 4 8 61c 39c

Conditions: α-diazo amide (0.1 mmol), N,N-dimethylaniline (0.3 mmol), PIDA (0.2 mmol), solvent (0.5 mL), air, rt. bYields were determined by 1H NMR spectroscopy using CH2Br2 as an internal standard. cIsolated yield. d0.2 mmol of N,N-dimethylaniline used. a

a Conditions: α-diazo amide (0.1 mmol), N,N-dimethylaniline (0.3 mmol), PIDA (0.2 mmol) in methanol (0.5 mL). bConducted at 60 °C. cConducted on a 1.0 mmol scale.

isolated yield, Table 1, entry 16) and decreasing the amount of N,N-dimethylaniline provided a worse result (Table 1, entry 16). With optimal reaction conditions in hand (see Table 1, entry 16), we next explored the substrate scope of the acetoxyaminoalkylation with respect to the α-diazo amide component keeping 2a as the amine reaction partner. Preparation of the starting diazo compounds is described in the Supporting Information, and results are summarized in Scheme 2. Open chain and cyclic symmetric N,N-dialkyl αdiazo amides 1a−1g gave the corresponding α-acetoxylated amides 4aa−4ga in moderate to good yields (38−61%). NAlkyl-N-aryl α-diazo amides 1h and 1i were compatible with the reaction conditions and provided the acetoxyaminoalkylated amides 4ha and 4ia in 57% and 52% isolated yield, respectively. α-Diazo-N,N-diphenylacetamide (1j) was far less reactive, and only a small amount of product was formed under the optimized reaction conditions, likely for steric reasons. However, upon increasing the reaction temperature to 60 °C, the three-component coupling proceeded smoothly and the corresponding product 4ja was obtained in 55% yield. Importantly, the Weinreb-type α-diazo-amide 1k could also be converted to the targeted acetoxyaminoalkylated amide 4ka (41%). We then explored the reaction scope by varying the amine component using α-diazoamide 1a under the standard conditions (Scheme 3). Para-methyl- and para-phenyl-N,Ndimethylaniline worked well, and the corresponding products 4ab and 4ac were both isolated in 50% yield, respectively. With para-fluoro-N,N-dimethylaniline, side reactions were noted. To some extent, formation of the unwanted side products could be suppressed upon addition of TEMPO and the targeted product 4ad was isolated in 34% yield. N,N-Dimethylaniline bearing a methyl group at the meta-position of the phenyl ring reacted

Scheme 3. Acetoxyaminoalkylation of 1a with Various N,NDimethylanilines and N-Aryl-tetra-hydroisoquinolinesa

Conditions: α-diazo amide (0.1 mmol), amine component (0.3 mmol), PIDA (0.2 mmol) in methanol (0.5 mL). bTEMPO (1 equiv) used as an additive. cReaction conducted for 4 h. a

with 1a under optimized conditions to the acetoxyaminoalkylated amide 4ae (48%). A significantly lower yield was achieved with N,N-dimethylnaphthalen-2-amine (4af: 21%). B

DOI: 10.1021/acs.orglett.8b03504 Org. Lett. XXXX, XXX, XXX−XXX

Letter

Organic Letters Pleasingly, we found that the metal-free acetoxyaminoalkylation is not limited to N,N-dimethylaniline derivatives. N-Aryltetrahydroisoquinolines were found to be excellent substrates for this three-component reaction providing the corresponding valuable α-functionalized isoquinolines in very good yields. Hence, reaction of N-phenyl-tetrahydroisoquinoline (2g) with 1a and PIDA provided product 4ag in excellent 93% isolated yield as a 3:1 diastereoisomeric mixture. As expected, C−H functionalization of the N-phenyl tetrahydroisoquinoline occurred with complete regioselectivity at the activated methylene group next to the arene ring. Unfortunately, the relative configuration of the major isomer could not be unambiguously assigned. Similar results were achieved with tetrahydroisoquinolines 2h−j to afford the corresponding products 4ah−aj in 86−95% yields but low diastereoselectivities. With unactivated amines such as triethyl amine, the cascade did not proceed and transformations with 1-phenylpyrrolidine and 1-phenylpiperidine were also not successful. Surprisingly, N,N-dibenzylaniline also did not engage in this reaction. Finally, the acetoxyaminoalkylation of α-diazoester 5 and αdiazoketone 7 was investigated. While ethyl diazoacetate (5) showed no reaction with N,N-dimethyl aniline (2a), its reaction with N-phenyl-tetrahydroisoquinoline (2j) delivered the targeted product 6 in 40% yield with a 6:1 diastereoselectivity (Scheme 4). Interestingly, a different

Scheme 5. Aminoalkylation Reaction of 2-Diazo-1phenylethan-1-one (7) with N-Aryltetrahydroisoquinolinesa

Conditions: α-diazo ketone (0.1 mmol), amine component (0.3 mmol), PIDA (0.2 mmol) in methanol (0.5 mL).

a

electrophile with the α-diazo amide to the isolated α-acetoxyα-aminoalkylated amide. In contrast, the reaction of more acidic α-diazoketones with N-aryl-tetrahydroisoquinolines provides in a cross-dehydrogenative coupling the corresponding α-diazo compounds.

Scheme 4. Acetoxyaminoalkylation of Ethyl Diazoacetate (5) with N-Phenyl-tetrahydroisoquinoline 2ja

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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.8b03504. Detailed experimental procedures, characterization data for all new compounds (PDF)

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Conditions: α-diazo ester (0.1 mmol), amine component (0.3 mmol), PIDA (0.2 mmol) in methanol (0.5 mL).

a

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected].

reaction outcome was noted for diazo ketone 7. Due to the higher α-acidity of the iminium ion adduct of 7, the intermediate diazonium salt undergoes deprotonation by the acetate anion rather than nucleophilic attack16 leading to valuable diazo products 8g−i in the reaction with N-aryltetrahydroisoquinolines 2g−i in 53−85% yield (Scheme 5). In summary, we disclosed a simple method for αdifunctionalization of α-diazoamides with N-alkyl-N-aryl amines using PIDA as an oxidant and reagent to provide αacetoxy-α-aminoalkylated amides in moderate to excellent yields. The three-component coupling proceeds under mild conditions at room temperature, and a transition metal catalyst is not required to run this cascade. Notably, α,α-difunctionalization of α-diazoamides is generally achieved using transition metal catalysis via the corresponding metallo carbenes as intermediates. The herein presented sequence works particularly well with N-arylated tertrahydroisoquinolines as substrates to deliver biologically interesting α-functionalized tetrahydroisoquinolines. Reactions are supposed to occur via initial PIDA-mediated oxidation of the amine component to the corresponding iminium ion with the acetate anion as counterion. This salt in turn reacts as an

ORCID

Jincheng Mao: 0000-0003-0301-1322 Armido Studer: 0000-0002-1706-513X Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was financially supported by the China Scholarship Council (stipend to H.Y.). REFERENCES

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Organic Letters

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DOI: 10.1021/acs.orglett.8b03504 Org. Lett. XXXX, XXX, XXX−XXX