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Ruthenium-Catalyzed Direct Hydroxymethylation of Aryl C-H Bonds Yunxiang Wu, and Bing Zhou ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.7b00078 • Publication Date (Web): 15 Feb 2017 Downloaded from http://pubs.acs.org on February 15, 2017
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ACS Catalysis
Ruthenium-Catalyzed Direct Hydroxymethylation of Aryl C-H Bonds Yunxiang Wu,a, b Bing Zhou*, a, b a
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica (SIMM), Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, PR China
b
University of Chinese Academy of Sciences, Beijing 100049, China
KEYWORDS: C-H Activation; Ruthenium; Hydroxymethylation; hydroxymethylarene; Formaldehyde
ABSTRACT: An ideal addition of “inert” aryl C-H bonds to formaldehyde has been achieved to synthesize a variety of hydroxymethylarenes via a Ru(II)-catalyzed C-H activation. Many different directing groups (not limited to strongly heterocyclic directing groups) can be used and this challenging C-H hydroxymethylation proceeds in the presence of water and air, and without stoichiometric undesirable by-products, thus offering an environmentally benign method of hydroxymethylarene synthesis that can be readily scaled-up.
Hydroxymethylated arenes are ubiquitous in many natural products, pharmaceuticals, biologically active compounds, fragrances, and polymers, and they are also used as important intermediates in synthetic organic chemistry (Figure 1).[1] Traditionally, hydroxymethylarenes can be synthesized by reduction of either aryl aldehydes or esters. Alternatively, nucleophilic addition of highly reactive aryl Grignard reagents and other related organometallic reagents to formaldehyde is a fundamental and important reaction for the introduction of a hydroxymethyl group into an aromatic or a heteroaromatic ring (Scheme 1a).[2] However, this approach requires organohalides as the starting materials to produce the organometallic reagents, thus inevitably causing environmental problems owing to their tedious and sluggish preparation. Moreover, this method has some other limitations such as the need for manipulation of air- and moisture-sensitive reagents, poor tolerance of functional groups, and generation of stoichiometric unwanted salt wastes. In addition, hydroxymethylarene could also be synthesized by a direct electrophilic addition of arenes to formaldehyde in presence of acid.[3]
In this context, as a complementary method, a transition-metal-catalyzed direct nucleophilic C-H addition to formaldehyde has its own advantages for hydroxymethylarene synthesis from a synthetic and environmental point of view (Scheme 1b). Obviously, this process would be the most step-, atom-, and redoxeconomical in that substrate preactivation and manipulation of air- and moisture-sensitive organometallic reagents are avoided. However, to the best of our knowledge, there is no report on the transition-metal-catalyzed direct C-H hydroxymethylation with formaldehyde, presumably due to the following challenges: 1) the nucleophilicity of the C-Metal bond is low; 2) insertion of aldehyde into the C-Metal bond is reversible;[4] 3) the rate of protonation versus β-H-elimination of the resulting the transitionmetal alkoxide intermediates is competitive;[5] 4) formaldehyde is a gas so that a mild reaction condition is necessary.
Scheme 1. C-H Hydroxymethylation reaction. (a) Traditional way: halogenation, metalation, nucleophilic addition to formaldehyde, then hydration. (b) Catalytic direct C-H addition toward formaldehyde.
Figure 1. Representative natural products and biologically active compounds.
Recently, the groups of Miura, Takai, and Shi made significant contributions to carry out the addition of aryl CH bonds to aryl or alkyl aldehydes by addition of external silanes to trap the transition-metal alkoxide intermeidates, thus producing the corresponding silylethers.[6]
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Alternatively, the metal alkoxide intermediates could be trapped by directing groups to form stable cyclic products.[7] In stark contrast to these trapping strategies, only very few examples has been reported on the direct nucleophilic aryl C-H addition to aldehydes to produce desired alcohol. Recently, a significant breakthrough was made by Li and Shi, who independently reported the alcohol synthesis by rhodium(III)-catalyzed chelation-assisted C(sp2)-H addition to electron-withdrawing aldehydes (Scheme 2a).[8] Very recently, the group of Wang expanded the scope of aldehydes to electron-rich aldehydes by a manganese-catalyzed C-H activation, although stoichiometric ZnBr2 and Me2Zn are required as Lewis acid to activate the aldehydes, thus inevitably generating stoichiometric unwanted wastes (Scheme 2b).[9] Despite great advances, all reactions were limited to aryl or alkyl aldehydes and C-H addition to significantly more challenging formaldehyde have unfortunately proven elusive thus far. Furthermore, the scope with respect to the directing group was largely limited to strongly coordinating directing groups (eg. pyridine, pyrimidine and pyrazole) that are difficult to remove or modify. Therefore, it remains an unmet challenge to develop transition-metal-catalyzed environmentally benign C-H addition to challenging formaldehyde. Given the importance of hydroxymethylarenes in organic chemistry and pharmaceutical industries, and with our continuing interest in the sustainable organic synthesis,[10] we herein report the first catalytic addition of aryl C-H bonds to formaldehyde which proved viable with highly selective ruthenium(II) catalysts (Scheme 2c).[11] Notably, many different directing groups (not limited to strongly heterocyclic directing groups) can be used in the C-H hydroxymethylation reaction and this protocol was carried out in the presence of water and air, and without stoichiometric undesirable waste under mild reaction conditions.
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(entryies 3-5) and we were pleased to observe that the situation changed significantly when the Ru(II) complex was used as the catalyst, providing the desired product 3a in 47% yield (entry 5). Screening of the solvent proved DCE to be the optimal choice (entries 6-8). Next, some acid additives were screened (entries 9-11) and the addition of NaH2PO4 gave a dramatically improved yield (up to 87%) (entry 11). Reactions at higher temperatures resulted in decreased reactivity (entry 12). To our delight, replacement of polyformaldehyde with formalin (40% HCHO in H2O) gave the 3a in 92% yield (entry 13). Control reaction confirmed that the transformation did not occur in the absence of the ruthenium catalyst (entry 14) or AgSbF6 (entry 15). Table 1. Reaction optimization. [a]
entry
catalysts
additive
solvent
yield (%)[b]
1
[Cp*RhCl2]2/AgSbF6
-
THF
8
2
Cp*Rh(MeCN)3(SbF6)2
-
THF
6
3
[Cp*IrCl2]2/AgSbF6
-
THF
