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Published in final edited form as: Org Lett. 2023 Aug 1;25(31):5907–5910. doi: 10.1021/acs.orglett.3c02213

Oxetane-, Azetidine- and Bicyclopentane-Bearing N-Heterocycles from Ynones: Scaffold Diversification via Ruthenium-Catalyzed Oxidative Alkynylation

Madeline M Evarts 1, Zachary H Strong 1, Michael J Krische 1
PMCID: PMC10445484  NIHMSID: NIHMS1925803  PMID: 37527501

Graphical Abstract

graphic file with name nihms-1925803-f0001.jpg

Three-fold scaffold diversification is achieved via ruthenium-catalyzed oxidative alkynylation of commercially available primary alcohols to form α,β-acetylenic ketones (ynones), which provide entry to oxetane-, azetidine- and bicyclopentane-bearing pyrazoles, isoxazoles and pyrimidines.

In connection with the development of ruthenium-catalyzed carbonyl additions via hydrogen transfer,1 our laboratory recently reported the first metal-catalyzed oxidative alkynylations of primary alcohols or aldehydes to form α,β-acetylenic ketones (ynones).2 These processes offer an alternative to multi-step ynone syntheses that rely upon acetylide-mediated aldehyde addition-oxidation or the conversion of carboxylic acids to Weinreb (or morpholine) amides followed by acetylide-mediated acyl substitution.3 To demonstrate how ruthenium-catalyzed oxidative alkynylation can streamline the synthesis of clinical candidates for small molecule drug discovery, this method was applied to the construction of N-heterocycles bearing oxetane,4 azetidine5 and bicyclopentane6 moieties. Such strained rings function as metabolically stable bioisosteres to diverse functional groups and have emerged as important substructures in pharmaceutical and agrochemical ingredients (Figure 1).7,8 Furthermore, as ynones are readily converted to pyrazoles, isoxazoles and pyrimidines via condensation with hydrazines,3,9 hydroxylamine3,10 and amidines,3,11 respectively, the aforementioned strained rings could potentially be appended to three distinct N-heterocycles. In this communication, we report that such three-fold scaffold diversification12 is indeed possible, as illustrated by the rapid assembly of oxetane-, azetidine- and bicyclopentane-bearing pyrazoles, isoxazoles and pyrimidines.

Figure 1.

Figure 1.

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Azetidine and bicyclopentane bioisosteres in drug discovery.

Optimal conditions identified for the ruthenium-catalyzed oxidative alkynylation, which utilize the catalyst assembled in situ from RuI(CO)3(η3-C3H5)13 and rac-BINAP, were applied to the coupling of triisopropylsilyl (TIPS) acetylene (500 mol%) with commercially available oxetane-, azetidine- and bicyclopentane-containing alcohols 2a-2e (100 mol%) (Scheme 1). Gratifyingly, good to excellent isolated yields of the corresponding ynones 3a-3e were formed. Remarkably, primary alcohols 2b, 2d and 2e each incorporate a quaternary carbon center adjacent to the site of C-C coupling, yet ynone formation remains efficient, although higher catalyst loadings are required. The direct formation of ynones 3a-3e from the corresponding alcohols 2a-2e in the absence of discrete redox reactions or premetalated acetylides is step-economic and minimizes waste generation.

Scheme 1. Ruthenium-catalyzed oxidative alkynylation to form oxetane-, azetidine- and bicyclopentane-bearing ynones 3a-3e.a.

Scheme 1.

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a Yields of material isolated by silica gel chromatography. bCatalyst (10 mol%). See Supporting Information for further details.

With ynones 3a-3e in hand, condensation to form the corresponding pyrazoles, isoxazoles and pyrimidines was explored (Scheme 2). Exposure of ynones 3a-3e to p-bromophenyl hydrazine in the presence of cuprous acetate (5 mol%) enabled efficient formation of the respective pyrazoles 4a-4e.9 The conversion of ynones 3a-3e to isoxazoles 5a-5e required a two-step protocol involving isolation of the (Z)-oximes followed by gold-catalyzed cycloisomerization.10,14,15 Finally, access to pyrimidines 6a-6e was achieved by condensation with p-bromophenyl amidine.11 The quaternary carbon center adjacent to the ketone functional group of ynones 3b, 3d and 3e did not impede condensation to form the pyrazoles (4b, 4d and 4e), isoxazoles (5b, 5d and 5e) or pyrimidines (6b, 6d and 6e), which is notable as α-quaternary heterobenzylic centers are challenging to prepare via metal-catalyzed cross-coupling. Whereas condensation to form pyrazoles 4a-4e and isoxazoles 5a-5e occurs with retention of the TIPS moiety, formation of pyrimidines 6a-6e is accompanied by desilylation. The carbon-silicon bond of pyrazoles (4b, 4d and 4e) and isoxazoles (5b, 5d and 5e) were resistant to functionalization under a variety of conditions; however, protodesilylation mediated by TBAF occurs efficiently, as illustrated by formation of the des-silyl compound 7 (eq. 1). Exposure of pyrazole 7 to N,N-dibromo-5,5-dimethylhydantoin delivered 4-bromopyrazole 8 in excellent yield as a single regioisomer (eq. 2).

Scheme 2. Conversion of ynones 3a-3e to oxetane-, azetidine- and bicyclopentane-bearing pyrazoles 4a-4e, isoxazoles 5a-5e and pyrimidines 6a-6e.a .

Scheme 2.

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aYields of material isolated by silica gel chromatography. Ar = p-bromophenyl. bYield of chromatographically purified (Z)-oxime. See Supporting Information for further details.

graphic file with name nihms-1925803-f0002.jpg (eq. 1)
graphic file with name nihms-1925803-f0003.jpg (eq. 2)

A one-pot oxidative alkynylation-condensation would enable direct access to pyrazoles and pyrimidines bearing oxetane, azetidine and bicyclopentane moieties from alcohols 2a-2e (Scheme 3). Toward this end, azetidinol 2c was exposed to conditions for ruthenium-catalyzed oxidative alkynylation and the crude reaction mixture was treated p-bromophenyl hydrazine in the presence of substoichiometric cuprous acetate. The azetidine-containing pyrazole 4c was isolated in 53% yield over the two-step one-pot operation. Similarly, addition of p-bromophenyl amidine to the crude reaction mixture from the ruthenium-catalyzed oxidative alkynylation of azetidinol 2c leads to direct formation of pyrimidine 6c in 45% yield.

Scheme 3. One-pot oxidative alkynylation-condensation to form pyrazole 4c and pyrimidine 6c.a.

Scheme 3.

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a Yields of material isolated by silica gel chromatography. Ar = p-bromophenyl. See Supporting Information for further details.

In summary, we report a concise routes to oxetane-, azetidine- and bicyclopentane-bearing pyrazoles, isoxazoles and pyrimidines via oxidative alkynylation of alcohols 2a-2e to form ynones 3a-3e. Whereas classical ynone formation typically requires multiple steps,3 oxidative alkynylation merges redox and C-C bond construction events, enabling ynone formation in a single manipulation. Furthermore, by telescoping oxidative alkynylation and condensation events, the targeted pyrazoles and pyrimidines are directly accessible from alcohols 2a-2e.

Supplementary Material

Supporting Info

Acknowledgments.

The Robert A. Welch Foundation (F-0038) and the NIH-NIGMS (RO1-GM069445) are acknowledged for partial support of this research.

Footnotes

Supporting Information Available.

Experimental procedures, spectroscopic and chromatographic data for all new compounds (1H NMR, 13C NMR, IR, HRMS). This material is available free of charge via the internet at http://pubs.acs.org.

Notes.

The authors declare no competing financial interest.

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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Associated Data

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Supplementary Materials

Supporting Info
NIHMS1925803-supplement-Supporting_Info.pdf (2.6MB, pdf)

Data Availability Statement

The data underlying this study are available in the published article and its Supporting Information.

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