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. Author manuscript; available in PMC: 2016 May 15.
Published in final edited form as: Org Lett. 2015 May 6;17(10):2400–2403. doi: 10.1021/acs.orglett.5b00910

Cobalt(III)-Catalyzed C–H Bond Amidation with Isocyanates

Joshua R Hummel 1, Jonathan A Ellman 1,*
PMCID: PMC4460580  NIHMSID: NIHMS691663  PMID: 25945401

Abstract

The first examples of cobalt(III)-catalyzed C–H bond addition to isocyanates are described, providing a convergent strategy for arene and heteroarene amidation. Using a robust air- and moisture-stable catalyst, this transformation demonstrates broad isocyanate scope, good functional-group compatibility and has been performed on gram scale.

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In recent years, many elegant strategies employing transition-metal-catalyzed C–H bond functionalization have emerged for the synthesis of amines and nitrogen heterocycles.1 Among the rich array of metal complexes that mediate C–H functionalization, Rh(III)-catalysts have proven to be exceptionally versatile due to their unique reactivity and high functional-group compatibility,2 with additions of C(sp2)–H bonds to polarized π-bonds providing for convergent introduction of heteroatom functionality.3–9 In this regard, we reported direct C(sp2)–H bond addition to isocyanates as a particularly step- and atom-economic strategy for the preparation of aromatic, heterocyclic and alkenyl amides.6f Direct C(sp2)–H bond additions to isocyanates have also been accomplished with Re10 and Ru11 catalysts.12 In contrast, catalytic C–H bond functionalization with earth-abundant first-row transition-metals has emerged only recently,13 and to our knowledge, additions to isocyanates have not been described. Herein we report the first examples of cobalt-catalyzed C–H bond amidation with isocyanates.14–15 This convenient benchtop procedure is effective for multiple heterocycle directing groups, shows good functional group compatibility, broad scope for aromatic and alkyl isocyanates, and is readily scalable.

For initial evaluation of Co(III)-catalyzed C–H bond additions to isocyanates, we chose 1-phenyl-1H-pyrazole (1a) and phenyl isocyanate (2a) as the coupling partners. First developed by Kanai, Matsunaga, and co-workers for additions to sulfonyl imines14p we anticipated that the cationic preformed catalyst [Cp*Co(C6H6)][PF6]2 (4a) might also facilitate C–H bond amidation with isocyanates. Indeed, the desired reactivity was achieved when catalyst 4a was utilized in the presence of catalytic potassium acetate at 80 °C, providing product 3a in 74% yield (Table 1, entry 1). Given that solvent effects have been observed to play a key role in obtaining optimal yield in Ru(II)-11 and Rh(III)-catalyzed C–H amidations,6 different solvents were evaluated. While the use of the ethereal solvents 1,4-dioxane and tetrahydrofuran (entries 1 and 2, respectively) as well as 1,2-dichloroethane (entry 3) provided comparable yields, the non-polar and non-coordinating solvent toluene resulted in a low yield (entry 4). Ultimately, the higher boiling solvent 1,4-dioxane was selected for further reaction optimization because it allowed reactions to be conducted at higher temperatures.

Table 1.

Optimization of Reaction Conditions for Co(III)-Catalyzed Amidation with Phenyl Isocyanatea

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entry Co(III)-catalyst (mol %) KOAc (mol %) temp (°C) solvent yield (%)b
1 4a (10) 20 80 1,4-dioxane 74
2 4a (10) 20 80 THF 62
3 4a (10) 20 80 DCE 66
4 4a (10) 20 80 toluene 8
5 4a (10) 20 120 1,4-dioxane 84 (84)c,d
6c 4a (2.5) 5 120 1,4-dioxane 80 (79)d
7 4a (1) 2 120 1,4-dioxane 66
8e 4a (10) 20 120 1,4-dioxane 84
9f 4a (10) 20 120 1,4-dioxane 84
10 4a (2.5) 5 100 1,4-dioxane 60
11 4b (5) 20 120 1,4-dioxane 5
12 4c (2.5) 5 100 1,4-dioxane 57
13 4a (10) -- 120 1,4-dioxane 7
14 -- 20 120 1,4-dioxane --
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a

Conditions: 2a (1.0 equiv), 1a (2.0 equiv) in 1,4-dioxane (2.0 M) for 20 h.

b

Determined by GC analysis relative to tetradecane as an external standard.

c

Reaction run on the benchtop under nitrogen.

d

Isolated yield at 0.20 mmol scale.

e

Reverse stoichiometry: 2a (2.0 equiv), 1a (1.0 equiv).

f

Reaction conducted in 1,4-dioxane (0.5 M).

Performing the reaction at 120 °C rather than 80 °C moderately increased the yield (entries 1 vs 5). This reaction is amenable to benchtop set up, providing an isolated yield of 84%, identical to that achieved with glovebox setup (entry 5). Reducing the catalyst loading from 10 to 2.5 mol % did not significantly influence the reaction outcome for this substrate combination (entries 5 vs 6), although at 1 mol % of catalyst loading the yield dropped to 66% (entry 7). Using the reverse stoichiometry with 1a as the limiting reagent provided an identical yield to that achieved under standard conditions (en- tries 5 vs 8), although isolation of pure product was more challenging due to byproduct formation. Conducting the reaction at a concentration of 0.5 M did not affect the reaction yield (entries 5 vs 9); however, the higher concentration of 2.0 M was selected to provide conditions that minimize solvent waste. Lowering the reaction temperature to 100 °C to operate below the boiling point of 1,4-dioxane resulted in a moderate drop in yield to 60% when 2.5 mol % of 4a was employed (entries 6 vs 10). The non-cationic dimeric complex [Cp*CoCl2]2 (4b) provided only 5% yield even at higher catalyst loading and an elevated temperature (entry 11). Operating below the solvent boiling point, a comparable yield was observed with preformed cationic catalyst 4c relative to 4a (entries 10 vs 12). This result indicates that for Co(III)-catalyzed C–H bond additions to isocyanates, a completely non-coordinating counterion provides no rate enhancement relative to PF6.16 Removal of potassium acetate dramatically reduced the yield of desired product (entry 13). Moreover, no product was observed when catalyst 4a was excluded (entry 14), demonstrating that a Co(III)-catalyst is required for this C–H functionalization. Due to the lower cost of the PF6 counterion, cobalt catalyst 4a was selected for evaluating substrate scope. A catalyst loading of 10 mol % was used to achieve higher conversion for less reactive substrates (see Scheme 1). Finally, given that C–H bond amidation with isocyanates has been reported for Re, Ru, and Rh, ICP-MS analysis of Co(III)-catalyst 4a was performed to detect the levels of several 2nd and 3rd row metals known to mediate C–H functionalization. Complex 4a showed less than 1 ppm of Re, Ru, Rh, Ir, and Pt, and Pd at 1 ppm (see Supporting Information for details).

Scheme 1.

Scheme 1

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Substrate Scope for Amidation of N-Aryl-1H-Pyrazoles with Isocyanatesa,b

Substrate scope was first evaluated with a series of func tionalized isocyanates 2 and N-aryl-1H-pyrazoles 1 (Scheme 1). For aromatic isocyanates, electron-rich (3b), electron-neutral (3c, 3e), and electron-deficient (3d, 3f–h) derivatives all coupled in high yield. Additionally, high yields were maintained when substituents were placed at the para (3b–d), meta (3e–g), and ortho (3h) positions. Linear alkyl isocyanates coupled to provide the N-benzyl amide 3i and N-hexyl amide 3j in good yields, while a branched alkyl isocyanate gave the N-cyclohexyl amide 3k in moderate yield. A higher 10 mol % catalyst loading was necessary for some of the isocyanates. For example, while a good yield was obtained when employing 2.5 mol % of catalyst 4a in the synthesis of 3a, a dramatically lower 19% yield of 3j was observed at this lower loading for hexyl isocyanate.

A series of substituted N-aryl-1H-pyrazoles 1 were then evaluated and provided amide products 3 in good yields for electron-rich (3l, 3p), electron-neutral (3m–n, 3q), and electron-deficient (3o) substituents. For meta-substituted derivatives, C–H functionalization occurred exclusively at the less hindered position to give amides 3p and 3q, thereby demonstrating that regioselectivity can be controlled by steric effects.17 Notably, incorporation of both bromo (3n) and methyl ketone (3o) groups proceeded in good yield, highlighting the functional-group compatibility of Cp*Co(III) catalysis, which consequently enables subsequent transformations for late stage introduction of molecular complexity.

The directing group scope of this reaction was also investigated (Scheme 2). In addition to the amidation of N-aryl-1H-pyrazoles, the 2-pyridyl (3r) and 2-pyrimidinyl (3s) directing groups also provided amide products albeit in modestly diminished yields. The 2-pyrimidyl directing group was also further successfully applied to indole functionalization (3t).18 Given that both 2-phenylpyrimidine and 1-(pyrimidin-2-yl)-1H-indole contain two potential nitrogen directing groups, we were pleased to find that only mono-amidation products 3s and 3t were obtained without any double addition products. We also evaluated acetanilide, which we had previously determined to be an effective substrate for Rh(III)-catalyzed isocyanate additions.6f However, this substrate was not effective for Co(III)-catalyzed isocyanate addition because the KOAc additive resulted in competitive N-acylation rather than providing the desired C–H bond addition product 3u.

Scheme 2.

Scheme 2

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Directing Group Scope for C–H Bond Amidationa,b

A gram scale reaction was conducted to assess the scalability of this Co(III)-catalyzed C–H bond amidation with isocyanates (Scheme 3). Employing only 2.5 mol % of preformed catalyst 4a and 5 mol % of KOAc under the optimized reaction conditions, pyrazole 3a was furnished in 75% yield (1.18 g), which was a similar yield to that obtained on smaller scale.

Scheme 3.

Scheme 3

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Gram Scale Synthesis of Pyrazole 3a

In summary, the cationic preformed cobalt complex [Cp*Co(C6H6)][PF6]2 (4a) efficiently catalyzes C–H bond additions to isocyanates and represents the first example of earth-abundant metal catalysis of this type of transformation. In addition to the N-aryl-1H-pyrazole directing group, this process has been achieved with other nitrogen heterocycle directing groups. Using an air- and moisture-stable catalyst, this transformation is amenable to benchtop set up and has been performed on gram scale with low catalyst loading. The broad scope and high functional-group compatibility of this method showcases the ability of earth-abundant Cp*Co(III) catalysis to mediate practical synthetic transformations.

Supplementary Material

Supporting Information

Figure 1.

Figure 1

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Cobalt(III)-catalysts used for C–H functionalization.

ACKNOWLEDGMENT

This work was supported by the National Institutes of Health (R01-GM069559). We thank the reviewer who suggested that we perform ICP-MS analysis of Co(III)-catalyst 4a..

Footnotes

The authors declare no competing financial interests.

ASSOCIATED CONTENT

Supporting Information

Experimental details, gram scale synthesis, and characterization data. This material is available free of charge via the Internet at http://pubs.acs.org.

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Associated Data

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Supplementary Materials

Supporting Information
NIHMS691663-supplement-Supporting_Information.pdf (5.7MB, pdf)

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