A palladium-catalyzed expeditious synthesis of dibenzofused carbazoles from readily available 2-arylindoles and diaryliodonium salts is reported. Interestingly, after the electrophilic C3 palladation of indole, an unexpected "through-space" 1,4-palladium migration to the 2-aryl moiety, by remote C-H bond activation followed by C-H arylation with diaryliodonium salt, and an unprecedented 1,2-aryl shift take place. Finally, an intramolecular cross-dehydrogenative coupling (CDC) at the C2 position affords dibenzo[a,c]carbazoles in high yields. Remarkably, the present migratory annulation occurs through three C-H bond activation one C-C bond cleavage, and the simultaneous construction of three new C-C bonds in a single operation.
Despite significant progress, copper-catalyzed/mediated C-H amination reactions with electron-rich anilines remain an unsolved problem due to catalyst deactivation and deleterious side reactions. Herein, we report a copper(II)-mediated C(sp(2))-H amination of benzamides with electronically neutral or electron-rich anilines. A dramatic influence of silver(I) and tetrabutylammonium bromide was observed on the reaction outcome. The present protocol also demonstrates the synthesis of a number of nonsteroidal anti-inflammatory drugs.
In this report, we have explored a triple mode of chemical reactivity of ethyl bromodifluoroacetate. Typically, bromodifluoroacetic acid has been used as a difluorocarbene precursor for difluoromethylation of soft nucleophiles. Here we have disclosed nucleophilicity and base dependent divergent chemical reactivity of ethyl bromodifluoroacetate. It furnishes lithium hydroxide and cesium carbonate promoted difluoromethylation of tosyl-protected aniline and electron-deficient phenols respectively. Interestingly, switching the base from lithium hydroxide to 4-N,N-dimethylamino pyridine (DMAP) tosyl-protected anilines afforded the corresponding N-ethylation product. Whereas, highly nucleophilic thiophenols furnished the corresponding Scarboethoxydifluoromethylation product via a rapid S N 2 attack to the bromine atom prior to the ester hydrolysis. This mechanistic divergence was established through several control experiments. It was revealed that difluoromethylation reaction proceeds through a tandem in situ ester hydrolysis/decarboxylativedebrominative difluorocarbene formation and subsequent trapping by the soft nucleophile-NHTs or electrondeficient phenolic ÀOH groups. In the presence of DMAP the hydrolysis of the ester is perturbed instead a nucleophilic attack at the ethyl moiety provides the N-ethylation product. Hence, besides the development of a practical base-promoted N-difluoromethylation of amines and electron-deficient phenols, divergent reactivity pattern of inexpensive and user-friendly ethyl bromodifluoroacetate has been explored.
Despite
the significant progress, C–H arylation with aryldiazonium
salts is a major challenge because of the faster rate of oxidative
addition compared to the C–H insertion, leading to a deleterious
homocoupling product. Recently, this limitation has been overcome
by merging a photoredox catalyst with transition-metal catalysts which
proceeds through a distinct single electron-transfer mechanism. However,
we have observed that the photoredox catalyst is not necessary for
the C–H arylation of aniline rather chemical reactivity can
be controlled by tuning the electronic nature of the substrate. We
report, herein, a palladium-catalyzed C–H arylation of aniline
carbamates with aryldiazonium salts under external oxidant, acid,
base free conditions at room temperature. Mechanistic studies suggest
that the present reaction proceeds through a directed electrophilic
metalation pathway which is the slowest step. However, the oxidative
addition may take place through either ionic (2e
–
) or radical (1e
–
) pathway to generate hypervalent
Pd(IV) or Pd(III) intermediate, respectively. A facile reductive elimination
from the hypervalent palladium complex furnishes the C–H arylation
product under mild conditions. The carbamate directing group is easily
removed from the product to obtain the corresponding ortho-arylated
aniline, which is a precursor for plethora of carbazole alkaloids
and other biologically active molecules. The reaction is scaled-up
to gram scale to furnish the desired product in comparable yields.
Finally, we have applied this C–H arylation methodology for
the synthesis of series of carbazole alkaloids such as clausine V,
clauszoline K,
O
-methoxymahanine, and
O
-methylmurrayamine-D.
We represent here, a divergent approach for the total synthesis of (�)-Mahanine and twelve other naturally occurring carbazole alkaloids. Remarkably, we have utilized a simplified scalable Suzuki coupling for CÀ C bond formation and a metal-free CÀ N coupling sequence to synthesize the functionalized carbazole scaffold from a single intermediate. Subsequently, either functional group manipulations or late-stage pyran ring annulation furnished a library of 13 carbazole alkaloids mostly isolated from a traditional medicinal plant Murraya koenigii. The construction of carbazole moiety at the initial-stage followed by late-stage pyran annulation under mild condition overcomes the decomposition problem of pyran-ring under acidic or other harsh reaction conditions.
The title carbazoles are obtained from readily available arylindoles and diaryliodonium salts via an unexpected “through‐space” 1,4‐palladium migration through remote C—H activation and 1,2‐aryl shift by a triple C—H activation cascade.
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