Initial Studies and Optimization

Initial studies into the gem-dichlorination of diazo compounds were performed by adding solid PhICl2, in one portion, to a solution of methyl phenyldiazoacetate (2.15a) and 2,6-lutidine dissolved in DCM at room temperature (eq 2.5). 2,6-Lutidine was originally added as a preventive measure to sequester trace HCl lingering on the PhICl2 from its synthesis. Mixture of the three reagents yielded a rapid reaction in which rapid gas evolution was observed while the colour of the solution changed from orange to faintly yellow. Products of dichlorination (2.16a),⁹⁷

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monochlorination (2.17a),⁹⁸ and oxygenation (2.18a)⁹⁹ were observed and confirmed via comparisons of their NMR spectra to the ones reported in the literature.

(2.5)

Using the conditions shown in eq 2.5, the dichlorinated product 2.16a was obtained in 82%

yield relative to 2.15a and 72% yield relative to PhICl2, indicating that double ligand transfer was occurring. Upon purification of the crude reaction mixture by FCC, chlorinated products 2.16a and 2.17a were recovered as a partially separable mixture. Subsequent reactions were performed to optimize for the yield of 2.16a and for its selective formation over monochloride 2.17a. The ratio of the two products were determined by analyzing the mixture of the two compounds, recovered after FCC, via ¹H NMR spectroscopy. Screening various reaction solvents (Table 2-1) found halogenated solvents such as dichloromethane and 1,2-dichloroethane provided the highest yields of 2.16a in the shortest reaction times (79–82% yield, entries 1–3). Ethereal solvents (i.e., DME and THF) were found to be inefficient reaction solvents, providing lower yields of 2.16a (51% and 23%, Table 2-1, entries 4–5). The dichlorination of 2.15a occurred very slowly in non-polar solvents such as toluene and hexanes (48 and 16 h, respectively) and, interestingly, gave high yields of 2.16a, (81% and 77%, entries 6–7). A rapid reaction was observed when acetonitrile was used as the reaction solvent, albeit providing lower amounts of 2.16a (65% yield, entry 8). When DMSO was used as the reaction solvent, rapid decomposition of PhICl2 was observed upon its addition accompanied by the observation of grey vapours above the surface of the reaction

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Table 2-1. Solvent Effects Upon the Reaction Between Methyl Phenyldiazoacetate and PhICl2a

aGeneral conditions: 2.15a (50 mg), PhICl2 (1.1 equiv), 2,6-lutidine (2.5 equiv) in solvent (0.1 or 0.2 M) at rt.^b Isolated yield after column chromatography, recovered as a mixture of the two chlorinated products.^cReaction contained no 2,6-lutidine.^dNot determined, reaction was incomplete.

mixture. Unsurprisingly, dichlorination did not occur in this case and the diazo compound appeared to remain unreacted (entry 9). 2,6-Lutidine was soon found to play an important role in the dichlorination of aryldiazoesters. For example, when performing the reaction in DCM in the absence of 2,6-lutidine, there was very little colour change and no gas evolution was observed.

Even after allowing the mixture to stir for 16 hours at room temperature, analysis of the reaction mixture, using TLC, suggested significant amounts of 2.15a remained in solution (entry 10) the formation of only small amounts of 2.16a. In contrast, the addition of excess 2,6-lutidine into a pre-mixed suspension of PhICl2 and 2.15a in DCM resulted in rapid gas evolution and product formation. These reactions typically completed within a few minutes. This rate enhancement was rationalized by hypothesizing that 2,6-lutidine activates PhICl2 in a similar manner to that observed for the pyridine-accelerated chlorination of alkenes and oxidation of alcohols using PhICl2.¹⁰⁰ It

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has been proposed that pyridine can activate PhICl2, via ligand exchange, generating the more electrophilic iodane 2.19 (eq 2.6).²⁵

(2.6)

We postulated that 2,6-lutidine, despite the steric hindrance about the Lewis basic nitrogen, was still able to perform a nucleophilic attack onto the iodine of PhICl2, generating a more reactive iodane analgous to 2.19. Activation of PhICl2 would allow its facile reaction with the diazo compound and thereby promote the dichlorination reaction. This prompted a reaction optimization study to determine the effects of using various pyridine analogs as Lewis basic additives (Table 2-2). Lowering the loading of 2,6-lutidine from 2.5 equiv to 0.05 equiv was found to increase selectivity of dichlorination versus monochlorination from 88:12 to 98:2 (entries 1–4). Pyridine and 4-(dimethylamino)pyridine (DMAP) were also capable of promoting the reaction as well.

When these pyridines were used, a marked increase in reaction rate —which positively correlated to the nucleophilicity of the pyridine— was observed. Under the same catalytic loading, an approximate 4-fold increase in reaction rate was observed when 2,6-lutidine was replaced with pyridine (Table 2-2, entries 4 vs 5). Another 4-fold increase was observed when changing from pyridine to DMAP (entries 6 vs 7). Conversely, using the extremely sterically-hindered 2,4,6-tri-tert-butylpyrimidine (TTBP, developed by Crich et al. as a cost-effective alternative to

2,6-di-tert-butylpyridine)^101,102 showed incomplete reaction (Table 2-2, entry 8), similar to that observed when the Lewis base was absent (Table 2-1, entry 10), indicating that it may be possible to prevent interaction of the nitrogens of the pyrimidine and the iodane via steric bulk. From this study, we determined that 5 mol% pyridine gave the best yields of 2.16a and lowered formation of 2.17a to amounts nearly undetectable by ¹H NMR spectroscopy. Using catalytic amounts of pyridine-type

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bases provided 2.16a in ≥79% yield. When acetonitrile was used as the reaction solvent, inclusion of 5 mol% of 2,6-lutidine or pyridine was found to produce rapid (within 10 minutes) formation of 2.16a in good yields as well (Table 2-2, entries 9–10). Based on the yield of 2.16a, the conditions shown in Table 2-2, entry 5, were considered to be the “standard conditions” for the dichlorination of diazo compounds and were used in a subsequent study scope of diazo compounds that this reaction was applicable to.

aGeneral conditions: 2.15a (50 mg), solvent (1.4 mL), and additive (1–250 mol%), and PhICl2 (1.1 equiv).^bThese conditions are considered the “standard conditions”.^cNot determined, reaction was incomplete.