Label-assisted mass spectrometry for the acceleration of reaction discovery and optimization

Abstract

The identification of new reactions expands our knowledge of chemical reactivity and enables new synthetic applications. Accelerating the pace of this discovery process remains challenging. We describe a highly effective and simple platform for screening a large number of potential chemical reactions in order to discover and optimize previously unknown catalytic transformations, thereby revealing new chemical reactivity. Our strategy is based on labelling one of the reactants with a polyaromatic chemical tag, which selectively undergoes a photoionization/desorption process upon laser irradiation, without the assistance of an external matrix, and enables rapid mass spectrometric detection of any products originating from such labelled reactants in complex reaction mixtures without any chromatographic separation. This method was successfully used for high-throughput discovery and subsequent optimization of two previously unknown benzannulation reactions.

Figure 1. Use of LA-LDI-TOF-MS to monitor progress of a representative known reaction

a, General strategy for monitoring the progress of chemical reactions using LA-LDI-TOF-MS, which entails labeling one of the reactants with a tag that permits matrix-free laser-induced desorption/ionization and rapid detection of any products originating from such labeled analyte. b, Reaction scheme of a representative chemical transformation of 1 to 2, which was studied using LA-LDI-TOF-MS. c, MS spectra for conversion of alcohol 1 to ester 2. d, Plot of relative ion intensity ratio (I₂/I₁) vs mole ratio (M₂/M₁) (y = 0.1324x + 0.0216, R² = 0.99365). Error bars represent standard deviations.

Figure 2. Reaction screen using LA-LDI-TOF-MS and identification of two catalytic benzannulations

a, High-throughput screening of 696 potential reactions. Siloxy alkyne 3 contains a pyrene tag, which enables matrix-free detection of any products originating from this compound using LA-LDI-TOF-MS platform. TADDOL: (α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanol); DMAP: 4-Dimethylaminopyridine; DABCO: 1,4-diazabicyclo[2.2.2]octane; TASF: tris(dimethylamino)sulfonium difluorotrimethylsilicate. b, Initial identification of the benzannulation of siloxy alkyne 3 with 2-pyrone in the presence of AuCl₃ to give carboxylic acid 4. c, Initial identification of the benzannulation of siloxy alkyne 3 with N-isoquinoline oxide in the presence of AgNTf₂ to give oxime 5.

Figure 2. Reaction screen using LA-LDI-TOF-MS and identification of two catalytic benzannulations

a, High-throughput screening of 696 potential reactions. Siloxy alkyne 3 contains a pyrene tag, which enables matrix-free detection of any products originating from this compound using LA-LDI-TOF-MS platform. TADDOL: (α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanol); DMAP: 4-Dimethylaminopyridine; DABCO: 1,4-diazabicyclo[2.2.2]octane; TASF: tris(dimethylamino)sulfonium difluorotrimethylsilicate. b, Initial identification of the benzannulation of siloxy alkyne 3 with 2-pyrone in the presence of AuCl₃ to give carboxylic acid 4. c, Initial identification of the benzannulation of siloxy alkyne 3 with N-isoquinoline oxide in the presence of AgNTf₂ to give oxime 5.

Figure 2. Reaction screen using LA-LDI-TOF-MS and identification of two catalytic benzannulations

a, High-throughput screening of 696 potential reactions. Siloxy alkyne 3 contains a pyrene tag, which enables matrix-free detection of any products originating from this compound using LA-LDI-TOF-MS platform. TADDOL: (α,α,α,α-tetraaryl-1,3-dioxolane-4,5-dimethanol); DMAP: 4-Dimethylaminopyridine; DABCO: 1,4-diazabicyclo[2.2.2]octane; TASF: tris(dimethylamino)sulfonium difluorotrimethylsilicate. b, Initial identification of the benzannulation of siloxy alkyne 3 with 2-pyrone in the presence of AuCl₃ to give carboxylic acid 4. c, Initial identification of the benzannulation of siloxy alkyne 3 with N-isoquinoline oxide in the presence of AgNTf₂ to give oxime 5.

Figure 3. Mechanism and scope of Au-catalyzed benzannulation of siloxy alkyne with 2-pyrones

Siloxy alkyne 6 undergoes a [4+2] cycloaddition with 2-pyrone 7 to give a putative intermediate A, which undergoes subsequent fragmentation to deliver carboxylic acid 9. Compound numbers are shown in bold. Isolated yields are shown below each compound number. R is a generic alkyl or aryl substituent.

Figure 4. Mechanism and scope of Au-catalyzed benzannulation siloxy alkynes with isoquinoline N-oxides

Siloxy alkyne 6 undergoes a [4+2] cycloaddition with isoquinoline N-oxide 11 to give a putative intermediate B, which undergoes subsequent fragmentation to deliver oxime 12. Compound numbers are shown in bold. Isolated yields are shown below each compound number. R is a generic alkyl or aryl substituent. Due to instability, the yield of compound 13h was determined by NMR using an internal standard. The product of this reaction was subsequently isolated as the corresponding imine in 82% yield following treatment of 13h with MoCl₅ and Zn in acetonitrile as described in Supplementary Information.