Ruthenium(II)-catalyzed C−H functionalizations have recently emerged as a reliable tool for the efficient chemo- and site-selective construction of C−C and C−Het bonds. Within this thesis, efforts have been devoted to developing new synthetic methods employing versatile ruthenium(II) catalysts.
In the first project, a novel catalytic system consisting of [RuCl2(p-cymene)]2 and MPAAs as the ligands was elaborated and exhibited excellent activity and regioselectivity in unprecedented direct meta-alkylation with tertiary alkyl bromides 50. A broad substrate scope of 2-phenylpyridines 187 as well as tertiary alkyl halides 50 were found under the optimized reaction conditions. Various functional groups, including chloro, ether and ester were well tolerated (Scheme 6.1). Moreover, other N-containing heterocycles, such as pyrimidine and pyrazole, served as competent directing groups for promoting this transformation in arenes 197 and 131, respectively. Interestingly, heteroarenes such as thiophene 38t could successfully be alkylated in a site-selective fashion.
R2 N R1
+ R3
R4 R5
R6 Br
R2 N R1
R3 R5
R6 R4
107 50 187/198
[RuCl2(p-cymene)]2
(2.5−5.0 mol %) K2CO3, 1,4-dioxane
100 °C, 20 h Piv-Val-OH (30 mol %)
OMe Me
Me
Cl N
MeMe Me Ac
187da: 58%
N
MeMe MeO
Me
187ja: 72%
187bh: 59%
Me Me Me
N
S
187ta: 55%
F N N
Me MeMe
198ca: 52%
N
Scheme 6.1: Ruthenium(II)-catalyzed direct meta-alkylation with tertiary alkyl bromides 50
Importantly, ruthenium(II) catalysis also allowed for the facile direct meta-alkylation of ketimines 188.
Electron-deficient ketimines 188 were favorably converted comparing to their election-rich analogues.
Sterically hindered tertiary alkyl bromides 50 smoothly gave rise to the desired meta-alkylated products 189. The auxiliary from the alkylated products can easily be removed within a one-pot hydrolysis, thus yielding a wide range of meta-functionalized aryl ketones 189 (Scheme 6.2).
Futhermore, the imine double bond in the meta-alkylated ketimines underwent one-pot reduction, furnishing secondary amines 207 in good yields. Although the yields of these alkylations were moderate comparing to the case of heterocycle-directed reactions, compounds 189 and 207 are generally more useful building blocks in organic synthesis.
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Scheme 6.2: Ruthenium(II)-catalyzed direct meta-alkylation of ketimines 188
Not only tertiary alkyl bromides 50, but also secondary alkyl bromides 44, both cyclic and acyclic, were competent electrophiles for this novel transformation (scheme 6.3). Electron-rich as well electron-deficient ketimines 188 were smoothly converted. The intermolecular competition experiments revealed electron-deficient arenes to be preferentially alkylated.
+
206be: 58% 206ae: 60% 206ge: 60% 206je: 62% 206ih: 62%
Scheme 6.3: Ruthenium(II)-catalyzed direct meta-alkylation with secondary alkyl bromides 44 Further investigation of this approach realized the ruthenium(II)-catalyzed direct alkylation of N-(pyrimidyl-2-yl)anilines 161 (Scheme 6.4). Again, the ruthenium(II)-MPAA catalytic system proved to be the most efficient. The direct alkylation smoothly took place at the meta-position of an electron-donating directing group, which in not anticipated by classical electrophilic aromatic substation. Another important aspect of this reaction is the N-pyrimidyl could readily be cleaved, thus leading to meta-alkylated aniline 191. Moreover, excellent site-electivity was achieved when ortho- or even di-substituted anilines 161 were employed, furnishing selectively the meta-functionalized products in good yields.
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Piv-Val-OH (30 mol %) [RuCl2(p-cymene)]2
215
a Ad-Ile-OH as additive HCl (conc.)
mw, 150 °C, 1 h
Scheme 6.4: Ruthenium(II)-catalyzed direct meta-alkylation of aniline derivatives 161
Future investigations of the ruthenium(II)-catalyzed direct meta-alkylation should be performed addressing three major issues. First of all, meta-alkylations accomplished in this thesis were realized via cyclometalation assisted by N-containing directing group. Extending the substrate scope to readily available, weakly-coordinating directing groups including ketones or esters is of major interest.
Secondly, since research directed towards enantioselective cross-coupling of secondary alkyl halides is active nowadays, developing transition metal-catalyzed enatioselective direct alkylation reactions should be an important goal. At last, despite the preliminary understanding of the reaction mechanism, detailed explanation of how the elementary steps of activation of the tertiary halide and C−C bond formation take place remain unclear and need further elucidation. Better insight of the reaction mechanism is crucial for further development of ruthenium(II)-catalyzed meta-selective C−H functionalization.
Within the second project, a ruthenium(II)-catalyzed cross-dehydrogenative coupling of aryl carbamates 192 with acrylates 15a was achieved (Scheme 6.5). The cationic ruthenium(II) catalyst enabled the highly efficient olefination of electron-rich arenes 192 with high site-selectivity.
Carbamates bearing ortho-, meta-, or para-substitutions underwent facile alkenylation, delivering a broad range of protected phenols 193. Importantly, the weakly-coordinating cabarmate group could easily be removed, thus providing a practical method for the preparation of o-coumaric acids which are important intermediates in enzymology and useful building blocks in organic synthesis.
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DME, 110 °C, 24 h
Scheme 6.5: Ruthenium(II)-catalyzed oxidative alkenylation of carbamate 192
The third project focused on redox-neutral annulations of alkynes 155 via ruthenium(II)-catalyzed C−H/N−O bond functionalization of oximes 194. A well-defined cationic ruthenium(II)-catalyst allowed the synthesis of highly substituted isoquinolines 176 (Scheme 6.6). Electron-rich as well as electron-deficient oximes could be efficiently converted. Unsymmetrical aryl-alkyl-alkynes 155 bearing functional groups were regioselectively transformed to the corresponding isoquinolines.
R2
176da: 86% 176na: 86% 176oa: 77% 176af: 72% 176ae: 77%
Scheme 6.6: Well-defined ruthenium(II) complex-catalyzed alkyne annulation
However, only poor yields were obtained with terminal alkynes in most of the ruthenium(II)-catalyzed annulation reactions. Presumably this is the result of dimerization of the terminal alkyne. Interestingly, in a recent published work, this shortage was successfully overcome via ruthenium(II)-catalyzed C−H/N−N bond functionalization.230 This offered broad implications for future developments of ruthenium(II)-catalyzed alkyne annulations for more functionalized heterocycle synthesis.
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