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Enantioselective Cyclopropenation of Alkynes with Acceptor/Acceptor-Substituted Diazo Reagents via Co(II)-Based Metalloradical Catalysis
Xin Cui, Xue Xu, Hongjian Lu, Shifa Zhu, Lukasz Wojtas, and X. Peter Zhang*
Department of Chemistry, University of South Florida, Tampa, Florida 33620-5250, United States
S b Supporting Information

ABSTRACT: The cobalt(II) complex of a new D2-symmetric chiral porphyrin 3,5-diMes-ChenPhyrin, [Co(P2)], has been shown to be a highly eective chiral metalloradical catalyst for enantioselective cyclopropenation of alkynes with acceptor/ acceptor-substituted diazo reagents, such as R-cyanodiazoacetamides and R-cyanodiazoacetates. The [Co(P2)]-mediated metalloradical cyclopropenation is suitable to a wide range of terminal aromatic and related conjugated alkynes with varied steric and electronic properties, providing the corresponding trisubstituted cyclopropenes in high yields with excellent enantiocontrol of the all-carbon quaternary stereogenic centers. In addition to mild reaction conditions, the Co(II)-based metalloradical catalysis for cyclopropenation features a high degree of functional group tolerance.

Scheme 1. Synthesis of Cyclopropenes Bearing Geminal Nitrile and Carbonyl Functionalities and Their Further Potential Transformations

yclopropenes are a unique class of carbocyclic compounds with unsaturated, highly strained three-membered ring structures. The combination of high strain and unsaturation renders cyclopropenes as versatile synthons for a wide variety of synthetic organic transformations.1 Consequently, signicant eorts have been devoted toward the synthesis of this class of molecules, especially optically active chiral cyclopropenes.1,2 Of dierent methods, catalytic asymmetric cyclopropenation of alkynes with diazo reagents constitutes one of the most direct and general methods for stereoselective construction of this type of strained ring structure.1,2 A number of catalytic systems based on dirhodium(II) complexes of chiral carboxamidate and carboxylate ligands have been successfully developed to catalyze enantioselective cyclopropenation using several dierent types of diazo reagents as carbene sources, including diazoacetates,3,4 diazosulfones,5 aryldiazoacetates,6 and styryldiazoacetates.7-9 While the existing chiral Rh2 catalysts were shown to be highly eective with both acceptor- and donor/acceptor-substituted diazo regents, asymmetric cyclopropenation with acceptor/acceptor-substituted diazo reagents remains to be developed.10 Owing to the presence of two electron-withdrawing groups at the R-carbon, this class of diazo reagents has inherent low reactivity with Lewis acidic metal catalysts toward formation of the corresponding metallocarbene intermediates. Even when they can be formed under forcing conditions, their subsequent reactions with substrates are often dicult in terms of controlling enantioselectivity due to the high electrophilicity of the acceptor/acceptor-substituted metallocarbenes.
r XXXX American Chemical Society

As stable metalloradicals with well-dened open-shell doublet d7 electronic structure, cobalt(II) complexes of porphyrins, [Co(Por)], have emerged as a new class of carbene transfer catalysts for olen cyclopropanation.11 With the introduction of D2-symmetric chiral porphyrins as supporting ligands,11a,12 the Co(II)-based metalloradical catalysts [Co(D2-Por*)] have been demonstrated to be highly eective for asymmetric cyclopropanation of a broad combination of olen substrates and diazo reagents with excellent diastereo- and enantioselectivity,13 including electron-decient olens13b and acceptor/acceptor-substituted diazo reagent.13d,13g It is evident that Co(II)-based metalloradical cyclopropanation possesses a distinct reactivity prole from the widely studied Rh2- and Cu-based closed-shell systems. Recent detailed mechanistic study conrmed the involvement of an unusual Co(III)-carbene radical as the key intermediate and elucidated an unprecedented stepwise radical addition-substitution pathway for the Co(II)-catalyzed olen cyclopropanation.14 To further validate the concept of metalloradical catalysis (MRC), we envisioned the possibility of Co(II)based catalytic process for alkyne cyclopropenation if the radical addition-substitution pathway of the Co(III)-carbene radical intermediate could be also operative for alkynes in a similar way to alkenes. To address the aforesaid challenges in the area, we decided to target R-cyanodiazoacetates and R-cyanodiazoacetamides, two types of common acceptor/acceptor-substituted diazo reagents that have not been previously applied for asymmetric cyclopropenation (Scheme 1).10 These catalytic processes would be synthetically attractive as the resultant multifunctionalized cyclopropenes bearing an all-carbon quaternary
Received: December 16, 2010

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Journal of the American Chemical Society Table 1. Reaction Conditions for Cyclopropenation of Phenylacetylene with r-Cyano(N,N-dimethyl)diazoacetamide by Cobalt(II) Porphyrinsa

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Table 2. [Co(P2)]-Catalyzed Enantioselective Cyclopropenation of Phenylacetylene with Acceptor/Acceptor-Substituted Diazo Reagentsa

entry 1 2 3 4 5 6 7 8 9
a

[Co(Por)]b [Co(TPP)] [Co(P1)] [Co(P2)] [Co(P2)] [Co(P2)] [Co(P2)] [Co(P2)] [Co(P2)] [Co(P2)]

solvent PhCF3 PhCF3 PhCF3 PhC1 PhF PhMe PhH CH2C12 CC14

yield (%)c <5 10 95 40 38 26 45 <5 70

ee (%)d 71 82 nde nde nde nde nde 77

Reactions were carried out at room temperature for 10 h in one-time fashion without slow addition of the diazo reagent using 1 mol % [Co(Por)] under N2 with 1.0 equiv of R-cyanodiazo(N,N-dimethyl) acetamide and 1.5 equiv of phenylacetylene. Concentration: 0.10 mmol diazo/mL. b See Figure 1 for structure. c Isolated yields. d Enantiomeric excess determined by chiral HPLC. e Not determined.

Figure 1. Structures of D2-symmetric chiral cobalt(II) porphyrins.

stereogenic center can serve as invaluable chiral synthons for a range of stereoselective synthetic applications (Scheme 1).1,2 As the outcome of the eort, we report herein a highly ecient catalytic system based on a new chiral Co(II) metalloradical catalyst for enantioselective cyclopropenation of alkynes with both R-cyanodiazoacetates and R-cyanodiazoacetamides. In addition to high enantioselectivity, the Co(II)-catalyzed cyclopropenation can operate at room temperature using a stoichiometric ratio of reactants without the need of slow addition of the diazo reagents. Furthermore, the metalloradical catalytic process features a remarkable degree of tolerance toward various functionalities, including CHO, OH, and NH2 groups. Initial experiments were focused on the evaluation of ligand and solvent eects on cyclopropenation of phenylacetylene (1a) with R-cyano(N,N-dimethyl)diazoacetamide (2a) by [Co(Por)] under conditions that were deemed most practical: 1 mol % catalyst loading; room temperature; stoichiometric ratio of reactants; and one-time protocol without slow addition (Table 1). While the ineectiveness of [Co(TPP)] for the reaction might be expected due to the absence of the H-bonding donor amide units (entry 1), we were somewhat surprised by the inferior performance of [Co(P1)] (Figure 1; entry 2), which has been previously shown to be highly eective for various cyclopropanation reactions.12,13 This result indicated dierent requirements of catalyst
B

Reactions were carried out in one-time fashion without slow addition of the diazo reagent using 1 mol % [Co(P2)] under N2 with 1.0 equiv of diazo reagent and 1.5 equiv of phenylacetylene. Concentration: 0.10 mmol diazo/mL PhCF3. b Isolated yields. c Enantiomeric excess determined by chiral HPLC. d At room temperature for 12 h. e At 40 C for 24 h. f [R] absolute conguration determined by anomalous-dispersion eects in X-ray diraction measurements on the crystal.

environment for the two carbene transfer processes and prompted us to develop new catalysts by taking advantage of the modular design and tunability of the D2-symmetric chiral porphyrin system.11a,12 To this end, replacement of the aliphatic t-butyl substituent in P1 with aromatic mesityl group led to the design and synthesis of new D2-symmetric chiral porphyrin 3,5-diMesChenPhyrin (P2; Figure 1). Gratifyingly, [Co(P2)] was found to be a highly eective catalyst for the reaction, leading to the formation of the desired 1,1-cyclopropeneamidonitrile 3aa in 95% yield and 82% ee (entry 3). During the process of optimizing the reaction conditions, triuorotoluene was shown to be the solvent of choice and performed signicantly better than other solvents screened (entries 4-9). The [Co(P2)]-based metalloradical cyclopropenation system was found to be applicable for dierent acceptor/acceptorsubstituted diazo reagents under the similar practical conditions (Table 2). Like the N,N-dimethyl diazo 2a (entry 1), N,N-diethyl analog 2b could also function as eective carbene source for Co(II)-catalyzed enantioselective cyclopropenation of 1a (entry 2). Notably, the catalytic system went equally well with N-methoxy-Nmethyl R-cyanodiazoacetamide 2c, providing the corresponding chiral cyclopropenyl Weinreb amide 3ac (entry 3), which can serve as a potential synthon for preparation of chiral cyclopropenyl
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Journal of the American Chemical Society Table 3. [Co(P2)]-Catalyzed Asymmetric Cyclopropenation of Dierent Combinations of Aryl/Vinyl Alkynes and A/AType Diazo Reagentsa

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Table 4. Diastereoselective Thiol Addition to Cyclopropenesa

Reactions were carried out overnight in toluene using 10 mol % DBU with 1.0 equiv of cyclopropene 3af (98% ee) and 1.5 equiv of thiol. The reaction temperature was initially at -30 C and gradually warmed to room temperature. b Isolated yields of single diastereomers. c Enantiomeric excess determined by chiral HPLC. d [1S,2R,3S] absolute conguration determined by anomalous-dispersion eects in X-ray diraction measurements on crystal. e 100 mol % DBU; room temperature; 48 h .

Reactions were carried out in one-time fashion without slow addition of the diazo reagent using 1 mol % [Co(P2)] under N2 with 1.0 equiv of diazo reagent and 1.5 equiv of phenylacetylene. Concentration: 0.10 mmol diazo/mL PhCF3; Isolated yields; Enantiomeric excess determined by chiral HPLC. b At room temperature for 12 h. c At 40 C for 24 h. d [R] absolute conguration; see footnote f of Table 2.

cyanoaldehyde and cyanoketone derivatives.15 In addition to the tertiary analogs, secondary R-cyanodiazoacetamides could also be productively used as exemplied with N-isopropyl R-cyanodiazoacetamide 2d, forming the desired cyclopropene 3ad in 96% yield and 96% ee (entry 4). Besides R-cyanodiazoacetamides, [Co(P2)] was shown to enable cyclopropenation with R-cyanodiazoacetates as well. For example, both ethyl and t-butyl R-cyanodiazoacetates (2e and 2f) could be eectively utilized to cylopropenate 1a to form 1,1-cyclopropeneesternitrile 3ae and 3af, respectively, in good yields and excellent enantioselectivities (entries 5 and 6). The absolute conguration of the all-carbon quaternary stereogenic center in 3af was established as [R] by X-ray crystal structural analysis (see Supporting Information). The [Co(P2)]-catalyzed asymmetric cyclopropenation could be successfully expanded for a wide range of terminal aromatic and related conjugated alkynes in combination with various acceptor/acceptor-substituted diazo reagents (Table 3). For example, using N-isopropyl diazo 2d as the carbene source, enantioselective cyclopropenation reactions
C

of phenylacetylenes substituted with alkyl groups at dierent positions proceeded equally well as phenylacetylene (entries 1 and 2). In addition, various halogenated phenylacetylenes could be enantioselectively cyclopropenated with both R-cyanodiazoacetamides and -acetates (entries 3-8). Among the chiral cyclopropene products, the absolute conguration of the all-carbon quaternary stereogenic center in 3df (entry 5) was established to be [R] by X-ray crystal structural analysis (see Supporting Information). Chiral cyclopropene derivatives from reactions of aromatic alkynes containing both electron-withdrawing and -donating groups could also be obtained in good yields and high enantioselectivities (entries 9 and 10). The Co(II)-catalyzed reaction could be extended for nonaromatic conjugated alkynes as demonstrated with cyclopropenation reaction of cyclohexenylethyne with diazo 2d for the high-yielding formation of enantioenriched 1,1-cyclopropeneamidonitrile 3jd (entry 11). Consistent with the proposed radical mechanism of nonelectrophilic carbene radical intermediate,14 the Co(II)-catalyzed carbene transfer process was found to tolerate functional groups that would otherwise undergo ylide-type chemistry associated with electrophilic metallocarbenes. For example, the aldehyde functionality could be tolerated without complication from potential ylidemediated epoxidation (entry 12). The functional group tolerability of [Co(P2)]-catalyzed asymmetric cyclopropenation was further highlighted by the reactions of phenylacetylene derivatives containing hydroxyl and amino substituents (entries 13-15). In all the cases, no O-H or N-H insertion products were observed. The above demonstrated cyclopropenation process via [Co(P2)]based metalloradical catalysis presents a viable route to access densely functionalized cyclopropenes containing enantioenriched all-carbon quaternary stereogenic centers, which should nd a range of applications as chiral building blocks for stereoselective organic syntheses through further functional group transformations. For instance, they can be transformed to highly functionalized
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Journal of the American Chemical Society cyclopropane derivatives by nucleophilic or electrophilic addition to the activated -bonds as a result of the high ring strain.1,2 In particular, nucleophilic addition with soft nucleophiles would provide an entry to chiral heterosubstituted cyclopropanes, which would be dicult or impossible to access via direct asymmetric cyclopropanation of alkenes. As an initial eort toward this type of applications, we demonstrated that cyclopropene 3af could undergo highly diastereoselective addition reactions with thiol nucleophiles to furnish heterosubstituted cyclopropane derivatives (Table 4).16 For example, when 3af in 98% ee was treated with 1.5 equiv of n-propanethiol, the corresponding 1,1,2,3-tetra-substituted cyclopropane 4a could be isolated in 98% yield as a sole diastereomer in the same high optical purity (entry 1). The absolute conguration of the three continuous stereogenic centers in 4a was established to be [1S,2R,3S] by X-ray crystal structural analysis (see Supporting Information). Highly diastereoselective addition reactions of 3af could be similarly accomplished with isopropanethiol and tert-butylthiol, aording enantiopure thiolated cyclopropanes 4b and 4c, respectively, albeit in relatively lower yields due to the higher steric hindrance (entries 2 and 3). Furthermore, we showed that the thiolated cyclopropane 4a could be oxidatively converted to cyclopropyl sulfone 5a in a high yield without loss of its optical purity upon simple treatment with m-chloroperbenzoic acid (CPBA) at room temperature (eq 1).

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In summary, we have developed a highly enantioselective process based on the new metalloradical catalyst [Co(P2)] for cyclopropenation of aryl/vinyl alkynes with both R-cyanodiazoacetamides and R-cyanodiazoacetates. It represents the rst successful applications of these two types of acceptor/acceptor-substituted diazo reagents for asymmetric cyclopropenation,10 providing a practical method for the preparation of multifunctionalized cyclopropenes bearing enantioenriched all-carbon quaternary stereogenic centers that may serve as useful chiral synthons for stereoselective synthesis (Scheme 1). Among several salient features, the Co(II)-based system enjoys an unusual degree of functional group tolerance, which is believed to have close relevance to the radical pathway of Co(II)-based metalloradical catalysis.14

ASSOCIATED CONTENT
S b

Supporting Information. Experimental details and analytical data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

AUTHOR INFORMATION
Corresponding Author

[email protected]

ACKNOWLEDGMENT We are grateful for nancial support by the National Science Foundation (CAREER award: CHE-0711024). REFERENCES
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