Catalytic Asymmetric Construction of β-Azido Amides and Esters via

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

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Catalytic Asymmetric Construction of β‑Azido Amides and Esters via Haloazidation Pengfei Zhou, Xiaohua Liu,* Wangbin Wu, Chaoran Xu, and Xiaoming Feng* Key Laboratory of Green Chemistry & Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, China

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S Supporting Information *

ABSTRACT: A catalytic regio- and enantioselective haloazidation reaction with a chiral iron(II) complex catalyst under mild reaction conditions was reported. By this approach, the stereoselective α-halo-β-azido difunctionalization of both α,β-unsaturated amides and α,β-unsaturated esters was achieved. This method enabled the construction of a broad spectrum of valuable functionalized amides and esters, including enantiomerically enriched β-azido amides, aziridine amides, α-amino amide derivatives, β-triazole amides, functionalized peptide derivatives, and α-halo-β-azido-substituted esters.

Scheme 1. Catalytic Asymmetric Synthesis of β-Azido Carbonyl Compounds

A

zido-containing acids and other derivatives play important roles in organic chemistry, chemical biology, and medicinal chemistry, which constitute a family of synthetically valuable synthons.1 For instance, the azido-masked amino acid derivatives are widely used in the solid-phase peptide synthesis.2 CuAAC (copper-catalyzed azide−alkyne cycloaddition)3 and Staudinger ligation based on azides4 are the most successful tools in bioorthogonal reactions. In medicinal chemistry, the azido-modified amides are subjected to the modular assembly click reaction, not just greatly accelerating the drug discovery process but also generating the potential triazole pharmacophore.5 In view of the unique utility of this class of chiral organic azide compound, significant advances have been made in their synthesis. One successful attempt is based on diazo transfer reaction6 for the synthesis of chiral α-azido acid derivatives directly from natural or manmade α-amino acid derivatives. The catalytic enantioselective aldol or Mannich reactions of α-azido amide also enriched the ways to chiral α-azido acid derivatives.7 In comparison, a direct catalytic asymmetric approach that enables access to chiral β-azido acid derivatives is less studied.8−10 Catalytic asymmetric conjugate addition of azide to α,β-unsaturated carbonyl compounds provides a facial pathway for this purpose. In this regard, Jacobsen9 and Miller10 did seminal work independently (Scheme 1a). They used α,βunsaturated imides with an additional electron-withdrawing Nacyl group to enhance the electrophilicity of the β-position and realized the highly enantioselective azide conjugate addition reaction. However, the use of simple α,β-unsaturated amides or esters in the asymmetric azide conjugate addition has more advantages, in terms of substrate natural abundance, easy preparation, and one step to the target chiral β-azido acid derivatives. These substrates are less involved,11 and the related conjugate addition process remains challenging, due largely to their low electrophilicity and weak interaction with chiral catalysts.12 © XXXX American Chemical Society

In continuation of our research on the halofunctionalization of α,β-unsaturated carbonyl compounds13 via chiral N,N′dioxide−Lewis acid complex catalysis,14 we recently realized the first catalytic asymmetric haloazidation15 reaction of enones to get β-azido ketones (Scheme 1b).16 During this research, we observed an interesting phenomenon in the reaction process (Figrue 1). A mixture of N,N′-dixoide LRaPr2 and Fe(OTf)2 in CH2Cl2 is a red suspension which turns to dark red immediately upon the addition of TMSN3. It Received: January 9, 2019

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DOI: 10.1021/acs.orglett.9b00110 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters

coordination sites are occupied by THF and H2O. When α,βunsaturated carbonyl compound and TMSN3 are subjected into the catalyst system, they might take the place of THF and H2O, respectively. Thus, this intermediate enables the bonded azide species to easily deliver18 to activated α,β-unsaturated carbonyl compounds in an enantioselective manner. The generated enolate intermediate then underwent a fast electrophilic bromination to yield α-bromo-β-azido product. Due to the high efficiency of this process, we are intrigued to use an easily available and cheap chiral iron(II) catalyst19 for asymmetric haloazidation of less reactive α,β-unsaturated amides and esters. It represents a kind of useful but challenging substrate in our long-term project about chiral N,N′-dioxidebased asymmetric synthesis. Herein, we reported the results of diastereo- and enantioselective haloazidation reaction of α,βunsaturated amides and methyl esters (Scheme 1c). Wide substrate scope, mild reaction condition, readily available catalyst, and valuable haloazide motif transformations render this methodology useful for the synthesis of a number of optically active azido-containing acid derivatives. The initial attempt began with the bromoazidation of 1a and 1b (see Table S1 in SI). Screening of suitable reaction conditions led to an optimal reaction condition: treatment 1b with 1.2 equiv of BsNMeBr and 2.0 equiv of TMSN3 in the

Figure 1. Catalyst information in asymmetric haloazidation reaction.

indicates ready formation of new azido species with the catalyst. We conducted some experiments to identify this process. ESI-MS analysis of the dark red mixture containing Fe(OTf)2/L-RaPr2/TMSN3 in CH2Cl2 dispalyed clear peaks at m/z 948.3968 and 798.4344, which correspond to [Fe2+ + L-RaPr2 + OTf− + N3− + H+]+ and [Fe2+ + L-RaPr2 + N3−]+ species, respectively. IR analysis of this mixture showed a red shift (2069 and 2047 cm−1)17 of the azido group absorption compared to TMSN3 (2139 cm−1). These two experimental results strongly supported the formation of the iron−azide complex. Additionally, the X-ray crystal structure of the LRaPr2−Fe(OTf)2 complex implied the formation of a distorted octahedron geometry. The ligand coordinated with iron(II) via tetra-oxygen bonding fashion and the other two cis-position

Scheme 2. Substrate Scope with Respect to α,β-Unsaturated Amidesa

a Reactions were performed with Fe(OTf)2/L-PiPr2 (0.3 mol %, 1:1), 1 or 3 (0.2 mmol), TMSN3 (2.0 equiv), and BsNMeBr (1.2 equiv) in CH2Cl2 (0.2 M) at 0 °C. Yields of the isolated products are reported. dr was determined by 1H NMR of the crude product. The ee values were determined by HPLC. b2.4 equiv of BsNMeBr. cRun on a 3 mmol scale. d5 mol % of catalyst. e2.5 mol % of catalyst. fFe(OTf)2/ligand (1.2/1, 5 mol %).

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DOI: 10.1021/acs.orglett.9b00110 Org. Lett. XXXX, XXX, XXX−XXX

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Organic Letters presence of 0.3 mol % of L-PiPr2-Fe(OTf)2 in CH2Cl2 at 0 °C. With the optimized conditions in hand, we investigated the substrate scope of the developed catalytic system. As summarized in Scheme 2, primary and secondary aminederived α,β-unsaturated amides well underwent the reaction. Amides bearing cyclic or acyclic secondary amine did not have an obvious impact on the yield and stereoselectivity (2b−2f, 91−99% yield, 97 → 99% ee, >19:1 dr). To prove the scalability of this reaction, the bromoazidation of 1d was conducted on a 3 mmol scale. Product 2d was obtained in a slightly lower yield with comparable enantioselectivity with prolonged reaction time. α,β-Unsaturated amide 1g containing Weinreb amide was also an excellent substrate, as the corresponding bromoazidation product 2g was obtained in 96% yield with 97% ee and >19:1 dr under 0.3 mol % of iron(II) catalyst. Additionally, amide 1h derived from Nmethylaniline was well tolerated to give 2h in a 94% yield and 96% ee with >19:1 dr. It is noteworthy that when 1-indolinyl (1i) or aniline (1j) substituted amides were used asymmetric bromoazidation reaction occurred, accompanied by direct bromination at the para-site of the aryl ring of the amine. Thus, an excessive amount of BsNMeBr (2.4 equiv) was used to promote 1i and 1j to transform into the exclusive bromoazidation/bromination products 2i and 2j, which could be isolated in excellent yields and enantiomeric excesses (98% yield with 99% ee and 95% yield with >99% ee, respectively). Although full conversion was observed with 1a in the presence of 2.4 equiv of BsNMeBr, the desired product 2a was obtained in only 69% isolated yield due to the undefined side product mixtures. Substrates (1k−1s) synthesized from diverse β-aryl- or alkyl-substituted cinnamic acids with dimethylamine were tested next. Efficient and highly stereoselective bromoazidation was realized utilizing para-electronwithdrawing groups substituted with N,N-dimethylcinnamamide derivatives (1m−1o) and N,N-dimethyl-3-(m-tolyl)acrylamide (1p) as well under the standard reaction conditions. Para-tolyl acrylamide (1l) underwent the difunctionalization smoothly when the catalyst loading increased to 2.5 mol % to yield the related product 2l in good yield with high enantioselectivity. However, electron-rich 4-methoxyphenyl-containing substrate 1k was proven unsuitable in this catalytic system with only moderate isolated yield and diastereo- and enantioselectivity for the product 2k. It might be caused by the competing background reaction without any of the catalyst species (see Scheme S1 in SI). The competing background reaction of electron-rich unsaturated amides might proceed via a bromonium ion intermediate. When β-alkylsubstituted acrylamides (1q−1s) were subjected to the reaction, they gave the α-bromo-β-azidation products 2q−2s in high enantioselectivity, although the diastereoselectivity decreased gradually with the growth of the alkyl chain length. It should be mentioned that 3-alkenyl oxindole (1t) could also undergo the reaction with high enantioselectivity under the optimal conditions, although accompanied with electrophilic bromination. The successful employment of chiral L-PiPr2−Fe(OTf)2 catalyst for bromoazidation of diverse α,β-unsaturated amides encouraged us to verify if the enantioselective bromoazidation process was tolerable to N-but-2-enoyl-substituted amino acid derivatives, which could feasibly lead to the azido-functionalized mimic of dipeptide. Gratifyingly, the reaction proceeded nicely with respect to substrates derived from N-Me-Gly (3a), affording the desired product 4a in 95% yield, >19:1 dr, and

95% ee. Moreover, the reactions of chiral substrates derived from N-Me-L-Ala (3b), L-Ala (3c), and L-Pro (3d) afforded the dipeptide precursors (4b−4d) featuring the anti-α-bromo-βazido group in high diastereoselectivity without erosion of the enantioselectivity. Notably, the ability to control the enantioselectivity regardless of the chirality center of the amide unit was proven by the use of L-PiPr2/Fe(II) and ent-LPiPr2/Fe(II) catalysts in diastereodivergent bromoazidation of N-but-2-enoyl-substituted amino acetates (such as L-Ala-OBzl, L-Phg, L-Phe, and L-Leu). Under the L-PiPr2/Fe(II) catalyst, synthetically useful levels of anti−anti-diastereoselection (4e− 4h; 4:epi-4 = 3:1 to >19:1) were observed. When enantiomer ligand ent-L-PiPr2 was used, the reaction afforded anti−syndiastereomers epi-4e−4h in higher diastereoselectivity (4:epi-4 = 1:12 to 99% ee and >19:1 dr (Scheme 3). Scheme 3. Iodoazidation of 1b and X-ray Crystal Structure of the Products

The absolute configuration was assigned to be (R,R) by X-ray crystallography analysis. Note that the fluoro- and chloroazidation of 1b were sluggish under the chiral iron complex. To illustrate the potential synthetic utility of chiral α-bromoβ-azido amides, we performed some transformations as collected in Scheme 4. Me3P/H2O was used to reduce azides to the corresponding amines, which spontaneously underwent substitution of bromine to furnish aziridine amide.20 Thus, NH aziridines 5 and 10 were afforded without any erosion of the stereoselectivity. Furthermore, ring opening of the N-H aziridine amide 10 with various nucleophiles, such as MeOH, azide, H2O, aniline, and N-methylindole, leads to chiral α-amino amide derivatives (11−15), bearing trans-βmethoxy, azido, hydroxy, phenylamino, and N-methyl-1Hindol-3-yl substituents, respectively. Next, CuAAC of 4c with glucose-containing terminal alkyne enabled the synthesis of carbohydrate conjugate 6 in good yield and excellent diastereoselectivity. In addition, the click reaction permitted the coupling of biotin-functionalized alkyne and dipeptide mimic 4c by a 1,4-triazole linker. All these transformations occurred smoothly with good yield and maintained diastereoand enantioselectivities. Lastly, the desired Staudinger ligation product 8 also can be obtained in 27% yield without reaction condition optimization. Encouraged by the results obtained in the bromoazidation of α,β-unsaturated amides, we subsequently turned to extend the substrate scope to either β-aryl- or β-alkyl-substituted methyl acrylates 16, which showed much lower reactivity than the amide analogues (Scheme 5). To our delight, the corresponding anti-α-bromo-β-azido esters 17 were afforded with good yields and high level of enantioselectivity in the presence of 10 mol % of L-PiPr2-Fe(OTf)2 catalyst after longer reaction time (72 h in most cases, see SI). Meanwhile, the reaction tolerated C

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Organic Letters Scheme 4. Transformations of the α-Bromo-β-azido Productsa

bromoazide products. What’s more, a scale-up version with 16j demonstrates the scalability of this reaction. Similarly, electronrich substrates, such as (E)-3-(4-acetoxyphenyl)acrylate, represent one limitation of this methodology that poor diastereo- and enantioselectivity were observed in this case. In summary, we have developed an iron(II)-catalyzed asymmetric bromoazidation of α,β-unsaturated amides and esters for the synthesis of valuable chiral β-azido carboxylic acid derivatives. The reactions proceed under mild conditions and showed wide substrate scope with various functional groups. Synthetic transformations indicate the promising utility of the azido products.

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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.9b00110. Experimental details and characterization data (PDF) Accession Codes

CCDC 1860960, 1860963, 1873574, 1873585, 1873588− 1873589, and 1882902 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.

a

Reaction conditions: (i) PMe3, THF, then aq HCl. (ii) Terminal alkyne, CuSO4, L-ascorbic acid sodium salt, tBuOH/H2O (1/1). (iii) 7, THF/H2O (9/1). (iv) BF3·Et2O, MeOH, then (Boc)2O, MeOH. (v) BF3·Et2O, NaN3, MeCN, then (Boc)2O, MeOH. (vi) TsOH·H2O, MeCN/H 2 O (9/1), then (Boc) 2O, MeOH. (vii) BF3 ·Et 2O, nucleophile, THF, then (Boc)2O, MeOH.

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Scheme 5. Substrate Scope with Respect to Methyl Acrylate Derivativesa

AUTHOR INFORMATION

Corresponding Authors

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

Pengfei Zhou: 0000-0003-0077-8739 Xiaohua Liu: 0000-0001-9555-0555 Xiaoming Feng: 0000-0003-4507-0478 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We appreciate the National Natural Science Foundation of China (21432006 and 21625205) and the Fundamental Research Funds for the Central Universities (2012017yjsy001) for the financial support.

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REFERENCES

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a

Reactions were carried out with Fe(OTf)2 (10 mol %), L-PiPr2 (10 mol %), 16 (1.0 equiv), TMSN3 (4.0 equiv for 16a−16i, 2.0 equiv for 16j−16t), and BsNMeBr (2.0 equiv for 16a−16i, 1.2 equiv for 16j− 16t) in CH2Cl2 or CHCl2CHCl2 (0.2 M) at 35 or 0 °C for 24−72 h. Yields of the isolated products are reported. Diastereomeric ratio (dr) was determined by 1H NMR of the crude product. Enantiomeric excess (ee) was determined by HPLC. bRun on a 1 mmol scale.

a variety of functional groups, such as silyl ethers (17c and 17e), esters (17f, 17g, and 17p), phthalimide (17h), tosyloxy group at aryl and alkyl substituents (17i and 17o), aryl halides (17l and 17m), aryl boronates (17n), and aryl aldehyde (17q), which leave a lot room for further manipulation of these D

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DOI: 10.1021/acs.orglett.9b00110 Org. Lett. XXXX, XXX, XXX−XXX

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DOI: 10.1021/acs.orglett.9b00110 Org. Lett. XXXX, XXX, XXX−XXX