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Synlett 2021; 32(19): 1957-1962
DOI: 10.1055/a-1623-1490
letter

A Rh(II)- or Ag(I)-Catalyzed Formal C–O Bond Insertion of Cyclic Hemiaminal with Aryl Diazoacetate

Cong Xu
,
Xiangrong Liu 
,
Xiongda Xie
,
Lin Deng
,
Xinfang Xu
,
Albert S. C. Chan
,
Wenhao Hu∗

Support for this research from the National Natural Science Foundation of China (21971262, 92056201), Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery (2019B030301005), and The Program for Guangdong Introducing Innovative and Entrepreneurial Teams (No. 2016ZT06Y337) is greatly acknowledged.
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Abstract

A mild and facile synthetic method via convergent assembly of two reactive intermediates generated in situ has been developed. This method provides an efficient way to construct six- and seven-membered N-heterocycles containing a biaryl linkage. This reaction features a gem-difunctionalization process of diazo compounds with cyclic hemiaminals, delivering α-hydroxyl-β-amino ester derivatives with a tertiary carbon center through a formal C–O bond-insertion transformation.


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Key words

metal carbene - cyclic hemiaminals - α-hydroxyl-β-amino esters - N-heterocycles - atom economy

α-Hydroxyl-β-amino acid derivatives are ubiquitous structural units that are widely present in natural products and bioactive compounds (Figure [1]),[1] such as Paclitaxel,[2] Mitosis inhibitor,[3] Leukotriene antagonists,[4] and sGC activators.[5] The importance of α-hydroxyl-β-amino acids in medicine chemistry has stimulated tremendous efforts to develop a variety of catalytic methods for their synthesis, especially for those containing a tertiary/quaternary carbon center at the α-position due to their unique structure and diverse biologic properties.[6] General synthetic methodology included but was not limited to nucleophilic addition to imines or ketones,[7] ring-opening reaction of epoxide or aziridine,[8] aminohydroxylation reaction,[9] reductive coupling reaction,[10] and so on. Despite these advances, general and atom-economic synthetic methods to access these molecules with structural diversity are still highly demanded.

In last two decades, the transition-metal-catalyzed multicomponent reaction via electrophilic trapping of reactive intermediates generated in situ, including onium ylides and zwitterionic intermediates that are derived from metal carbene species with corresponding nucleophiles, has provided a powerful tool for the expeditious synthesis of α,β-polyfunctionalized molecules with structural complexity.[11] [12] [13] In this context, our group has developed many Mannich-type interception processes of oxonium ylides for the efficient construction of α-hydroxyl-β-amino ester derivatives.[11,12] In these cases, diphenyl imines,[14] N-Boc[15] and N sulfinyl[16] imines were generally used in these transformations as the electrophiles (Scheme [1a], Path A).

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Figure 1 Examples of bioactive molecules containing an α-hydroxy-β-amino ester unit
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Scheme 1 Mannich-type interception of oxonium ylide with imine and formal C–O bond insertion

Recently, N,O-acetals have been used as nitrogen sources for the synthesis of α/β-amino acids in different catalytic transformations that involve a common intermediate, electrophilic iminium species, which are generated in situ through C–O bond cleavage in the presence of Brønsted acid or under metal catalysis.[17] [18] Inspired by these advances, we have developed a catalytic asymmetric aminomethylation reaction for the preparation of chiral β-amino esters through a Mannich-type interception of enol intermediate with iminium ion that is generated in situ from N,O-acetals (Scheme [1a], Path B).[18a] Shortly after this work, Sun[18b] and Shao[18c] independently employed N,O-acetal as a practical reagent for metal carbene gem-difunctionalization, providing α-hydroxy-β-amino acid derivatives in moderate to excellent yields. In these works, the alkoxy and iminium species generated in situ have been introduced to the final products, which features a high atom-economy process. It should be noted that a water-involved analogous three-component reaction could occur to deliver the free-hydroxy amino acid derivatives. In this case, the alkoxy group in N,O-acetals act as a leaving species (Scheme [1b]).[18b] [19] Inspired by these reports, we herein introduced cyclic hemiaminals to react with diazoesters, which features a metal carbene formal C–O bond-insertion process, providing biaryl-bridged N-heterocycles embodied with an α-hydroxyl-β-amino unit (Scheme [1c]).

To start with, cyclic hemiaminal containing biphenyl scaffold 1a and diazo compound 2a were selected as model reactants to optimize the reaction conditions (Table [1]). The reaction was initially carried out in the presence of 2.0 mol% Rh2(OAc)4 in dichloromethane at room temperature, which led to the product 3a in low yield with moderatedr (17%; entry 1). Then, different metal complexes were explored (entries 2–6). No clear improvement was observed in terms of yields or diastereoselectivities when Pd(allyl)2Cl2 was employed as catalyst (entry 2). To our delight, copper salts, Cu(CH3CN)4PF6 and Cu(OTf)2, showed a fairly good catalytic performance, giving 3a in 60% and 91% yield, respectively (entries 3 and 4); whereas, no reaction occurred when CuI was used as catalyst (entry 5). The best results were obtained in terms of yield when AgOTf was employed, giving full conversion into target product 3a with 55:45 dr (in 92% isolated yield; entry 6). Further screening of the reaction solvents, including 1,2-dichloroethane and toluene, caused a clear decrease in yield with slight improvement in stereoselectivity (entries 7 and 8). The reaction did not occur when ethyl acetate or N,N-dimethylformamide was employed as solvent (entries 9 and 10). Furthermore, a clear decrease in yield was observed when 2 mol% AgOTf was used (49% yield; entry 11).

Table 1 Optimization of the Reaction Conditionsa

Entry

Catalyst

Solvent

Yield (%)b

Dr(3a-1/3a-2)b

 1

Rh2(OAc)4

DCM

 17

57:43

 2

Pd(allyl)2Cl2

DCM

 37

52:48

 3

Cu(CH3CN)4PF6

DCM

 60

57:43

 4

Cu(OTf)2

DCM

 91

57:43

 5

CuI

DCM

 <5

–

 6

AgOTf

DCM

>95 (92)c

55:45

 7

AgOTf

DCE

 71

63:37

 8

AgOTf

toluene

 77

63:37

 9

AgOTf

EtOAc

 <5

–

10

AgOTf

DMF

 <5

–

11d

AgOTf

DCM

 49

55:45

a Reaction conditions: To the mixture of1a (0.1 mmol) and metal catalyst (for AgOTf, 10 mol%; for all others, 2.0 mol%) in indicated solvent (1.0 mL), was added 2a (0.15 mmol) in the same solvent (1.0 mL) via syringe pump over 15 min at room temperature.

b Yield and dr were determined by 1H NMR spectroscopic analysis of the crude reaction mixture.

c Isolated yield.

d 2 mol% catalyst

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Scheme 2 Scope of the synthesis of seven-membered N-heterocycles 3. Reagents and conditions: 1 (1.0 mmol 1.0 equiv), 2 (1.5 mmol, 1.5 equiv), and AgOTf (10 mol%) in anhydrous DCM (5.0 mL) at room temperature for 2.0 h. The dr values were determined based on 1H NMR analysis of the crude reaction mixture; isolated yields are given.

With the established optimal conditions in hand, the scope of this formal C–O bond insertion reaction was investigated (Scheme [2]). Generally, hemiaminals with a range of substitutions on the biaryl moiety were well tolerated in this reaction. The electric properties and position of substituent groups on the phenyl ring of the hemiaminals had little influence on the reactivity, affording desired products 3a–g in 83–93% yield with moderate diastereoselectivities.

The scope of diazoacetates was then explored. The aryl group of diazoacetates bearing halogen or methyl substituents at para-, meta-, or ortho-positions proceeded in the reaction smoothly, furnishing the desired products 3h–l in 87–92% yield. The diazo compounds with substituents, CH3 or Br, on the ortho-position of aryl moiety delivered the corresponding products 3k and 3l in high yields with 81:19 and 82:18 dr, respectively. Moreover, the naphthyl substituted substrate gave the product 3m in 50% yield with 82:18 dr. Variation of the protecting group on the nitrogen of hemiaminals was also studied. The corresponding reactions with ortho-methyl phenyl diazoacetates generated the products 3n and 3o in good to high yields, both with up to 85:15dr. Both of the diastereoisomers of 3f were confirmed by X-ray diffraction analysis, and other products were assigned by analogy.[20]

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Scheme 3 Scope for the synthesis of six-membered N-heterocycles 5. Reagents and conditions: 4 (1.0 mmol, 1.0 equiv), 2 (1.5 mmol, 1.5 equiv), and Rh2(OAc)4 (2.0 mol%) in anhydrous DCE (5.0 mL) at room temperature for 2.0 h. Thedr values were determined based on 1H NMR analysis of the crude reaction mixture; isolated yields are given.

Encouraged by the above results, we then expanded this protocol to the six-membered hemiaminals 4 for the synthesis of the corresponding N-heterocycles 5, 5,6-dihydrophenanthridines bearing an α-hydroxy-β-amino ester motif (Scheme [3]). However, previous conditions with AgOTf in dichloromethane did not give any desired products (see Table S1, entry 1, in the Supporting Information for details). A brief optimization revealed that 5,6-dihydrophenanthridine 5a could be obtained in 89% isolated yield when the reaction was conducted in 1,2-dichloroethane in the presence of Rh2(OAc)4 (>95% conversion, see Table S1 in the Supporting Information for details). With the optimal reaction conditions identified, cyclic hemiaminals 4a–d with a range of substituents on the aromatic ring, Ar1 or Ar2, were investigated. All the reactions proceeded smoothly to give the products 5a–d in good to high yields. Various aryl diazoacetates bearing halogen (Cl, Br) or methoxy substituents gave the corresponding products in 60–85% yield.

The gram-scale reaction and synthetic transformations for the generated products were performed under the optimal conditions to demonstrate the practical application of this method (Scheme [4]). A gram-scale reaction of cyclic hemiaminal 1a with diazo compound 2a provided 1.24 g 3a in 90% yield with 55:45dr (Scheme [4a]). The Boc group could be removed smoothly in the presence of trifluoroacetic acid, followed by N-methylation or acylation, furnishing products 6 and 7 in 90 and 75% yield, respectively (Scheme [4b] and c).

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Scheme 4 Gram-scale reaction and derivatizations

Moreover, the effect of representative products 3 and 5 on cell viability was evaluated via CCK8 assay in HCT116 (colon cancer), MCF-7 (breast cancer), and A549 (lung adenocarcinoma) human cancer cell lines (see Table S2 in the Supporting Information for details). According to these results, compound 5c-2 exhibits significant anticancer potency with more than 80% inhibition (HCT116 cells, IC50 = 21.76 μM). Compound 5f-1 exhibits higher activity than the other tested compounds towards two kind of cancer cells (HCT116 cells, IC50 = 15.05 μM; A549 cells, IC50 = 24.67 μM, see Table S2 for details).

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Scheme 5 Proposed mechanism

According to the previous studies,[17] [18] a plausible mechanism is proposed in Scheme [5]. Initially, the cyclic hemiaminal 1a splits into the hydroxyl anion and the iminium ion I via a reversible process under catalysis of Ag or Rh as Lewis acids. Meanwhile, metal catalyst converts the diazo compound 2a into carbene intermediate II. Then, nucleophilic addition of hydroxyl anion to carbene II affords the corresponding metal intermediate III, which would be trapped by the strong electrophilic iminium ion I immediately to deliver the final product 3a and regenerate the metal catalyst. As a result, the incorporation of hemiaminal 1a into one molecule has been completed via a formal C–O bond-insertion process.

In conclusion, we have developed a facile synthetic method for the expeditious construction of biaryl-bridged six- and seven-membered N-heterocycles bearing an α-hydroxyl-β-amino ester motif with a quaternary carbon center at the α-position in good to excellent yields and moderate diastereoselectivities.[21] This reaction features high atom-economy that involves convergent assembly of two active intermediates generated in situ. Further study focused on the asymmetric catalysis and synthetic application of this method is continuing in our laboratory.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-1623-1490.
  • Supporting Information
  • CIF File

Corresponding Author

Wenhao Hu
Guangdong Key Laboratory of Chiral Molecule and Drug Discovery, School of Pharmaceutical Sciences, Sun Yat-Sen University
Guangzhou 510006
China   

Publication History

Received: 10 August 2021

Accepted after revision: 30 August 2021

Accepted Manuscript online:
30 August 2021

Article published online:
14 September 2021

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   Permissions and Reprints All articles of this category
Zoom Image
Figure 1 Examples of bioactive molecules containing an α-hydroxy-β-amino ester unit
Zoom Image
Scheme 1 Mannich-type interception of oxonium ylide with imine and formal C–O bond insertion
Zoom Image
Scheme 2 Scope of the synthesis of seven-membered N-heterocycles 3. Reagents and conditions: 1 (1.0 mmol 1.0 equiv), 2 (1.5 mmol, 1.5 equiv), and AgOTf (10 mol%) in anhydrous DCM (5.0 mL) at room temperature for 2.0 h. The dr values were determined based on 1H NMR analysis of the crude reaction mixture; isolated yields are given.
Zoom Image
Scheme 3 Scope for the synthesis of six-membered N-heterocycles 5. Reagents and conditions: 4 (1.0 mmol, 1.0 equiv), 2 (1.5 mmol, 1.5 equiv), and Rh2(OAc)4 (2.0 mol%) in anhydrous DCE (5.0 mL) at room temperature for 2.0 h. Thedr values were determined based on 1H NMR analysis of the crude reaction mixture; isolated yields are given.
Zoom Image
Scheme 4 Gram-scale reaction and derivatizations
Zoom Image
Scheme 5 Proposed mechanism