INTRODUCTION: make synthetic schemes shorter and more efficient, highly

INTRODUCTION:

Carbon-carbon
bond formation plays a key role in designing chemical synthesis.1
The generation of carbon-carbon bonds directly from two different C-H bonds via formal removal of two hydrogen
atoms. The so-called “cross-dehydrogenative coupling” (CDC), represents a new
conceptual approach in planning synthesis. For synthesis,C-C bonds play an
important role. Previously we use the neucleophilic additions, substitutions
and Fridel craft reaction to from a C-C bonds in acyclic structures. Now with
the development of pericyclic reactions and transition metal catalysed
reactions increased the efficiency of C-C bond formations in modern days and
their scope has been increased. These reactions require a functionalized partner
to synthesized the desired C-C bond formation product.

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            In transition metal catalysis we use
copper catalyst as CuBr2, CuCl, CuCl2 etc as the
effective catalysts and tert-butylhydrogenperoxide(TBHP) as the typical oxidant
under oxidative conditions a method that termed cross-dehydrogenativecoupling
(CDC). The coupling would eliminate the preparation of functional groups and
make synthetic schemes shorter and more efficient, highly desirable features of
C-C bond formations. Notable progress has recently been made in arene-arene
coupling via the oxidative reaction
of sp2 C-H/sp2 C-H bonds. The present Account describes the development of CDC reaction
and attention on functionalization of sp3 C-H bonds with another C-H bonds.

SCHEME
1:

 

Alkynylation (sp3-sp
Coupling): The formation of C-C bonds of alkynyl sp C-H bonds and R-sp3 C-H
bonds of nitrogen in amines for generate propargylic amines.2 There
are three reasons (a) propargylic amines are of great pharmaceutical interest
and are synthetic intermediates for various nitrogen compounds; (b) the sp3 C-H
bond R to nitrogen in amines can be readily activated to generate iminium ions via single electron- transfer (SET)
processes or by transition metals as described by Leonard and Murahashi; and (c)
They have described the aldehyde-alkyne-amine coupling reactions to afford
propargyl amines catalyzed by various of 
transition metals through the formation of the same intermediate (Scheme
1) cause of the catalytic alkynylation of the sp3 C-H R to nitrogen with a
terminal alkyne it occur readily under oxidative conditions.

SCHEME  2: Alkynylation of ?-C-H bonds of nitrogen in
amines

SCHEME
3: Aldehyde-alkyne  amine coupling:

FeCl3-catalyzed cross-dehydrogenative coupling between
imidazohetrocycles and oxoaldehydes:

 An Fe+3-catalyzed
efficient dicarbonylation of imidazo hetrocycles has been developed through
cross-dedydrogenative coupling between imidazo hetrocycles and oxoaldehydes
under ambient air in high yields.3 The present protocol is also
applicable to indolizines. Imidazopyridine produced bis imidazopyridine with
arylaldehyde. Experimental result suggest that the reactions proceed through
the non-radical pathway.

 

 

 

 

SCHEME
4:

CuBr-catalyzed
direct indolation of terahydroisoquinolines via
CDC reaction between SP3 C-H and SP2 C-H bonds:

A
novel and efficient C-C bond formation method was developed via the CDC reaction of indoles and
tetrahydroisoquinolines, catalyzed by copper-bromide in the presence of an
oxidizing agent,tert-BuOOH.4 The CDC reaction provides a simple and efficient
catalytic method to construct indolyl tetrahydroisoquinolines via a combination of C-C bonds
formation.5

 

SCHEME
5:

SCHEME
6: Alkynylation of tetrahydroisoquinoline derivatives

DDQ-Mediated
direct CDC reaction between benzylethers and simple ketones:

A
direct CDC coupling between benzylethers and simple ketones was developed
without using any metal catalyst.5 By using DDQ various benzylethers
and simple ketones were couple together directly to form ?-alkoxyl ketones
efficiently.

A
mechanism in which the DDQ serves the double roles of an oxidizing agent an
organomediator was proposed.

SCHEME
7:

Cu+2-catalyzed
(CDC) of cyclic benzylic  ethers with
simple carbonyl compounds by Na2S2O8 :

Cu+2-catalyzed
CDC reaction of cyclic benzylic ethers with a variety of simple carbonyl
compounds mediated by Na2S2O8 is developed.6
The scope of carbonil components is broad, including simple aldehydes as well
as ketones. The use of Na2S2O8 as the oxidant
for the CDC reaction is attractive best on economical and environmental factors.

SCHEME
8:

Cobalt-catalyzed
CDC coupling reaction of (Benz)oxazoles with ethers:

The
cobalt-catalysed CDC of (Benz)oxazoles and ethers is described access to some
important bio-active heteroaryl ether derivatives was achieved using cobalt
carbonate(CoCO3) as an inexpensive catalyst at levels as low as 1.0
mol% ; investigation of the mechanism indicates a catalytic cycle involving a
radical process.7

SCHEME
9:

Cross-dehyrogenative
coupling (CDC) using copper and mixed catalysts:

Pd(OAc)2/Cu(OTf)2/tert-BuOOH
catalyst:

CDC
reaction of resorcinol derivatives have been assessed with initial evalutions
using 2,4-dihydroxyactophenone with this substrate and THF, the use of only
Pd(OAc)2/tert-BuOOH led to no product, there was a clear need for a
copper co-catalyst and among CuO, PPh3CuCl, Cu(acac)2, CuI,
CuCl2 and Cu(OTf)2. The first three were ineffective,
from the remaining, Cu(OTf)2 prove to be optimum, substitution of
tert-BuOOH with H2O2 gave no product where as (PhCOO)2
gave a lower yield.8 The reaction was then expanded to include other
keto groups and ethers at the R1 site. All ketones reacted
comparably but the aldehyde gave a lower yield. Ingeneral, yields from the
other ester derivative were comparable amongst themselves and to that from the
aldehyde, and the n-butyle ester gave the lowest yield.

SCHEME
10:

2.
Cu catalysis:

In
a follow up study, Cu(NO3)2 incombination with t-BuOOH was also investigated.
Here, yield improvements were observed in every case and the data are also
summarized for comparison with the results from the Fe-catalyzed reactions.9

 

SCHEME
11:

3.Cu
catalysis in the presence of DDQ:

CDC
reaction also happen when Cu-salt mixed with DDQ and InCl3. The role
of InCl3 is to activate DDQ to ferther incrised its oxidation
potertial. While the role of copper catalyst is to activate the malonates.10

SCHEME
12:

 

4.Cu
catalysis in the presence of DABCO:

The
CDC reaction between ?-SP3 C-H bonds of nitrogen in
tetrahydroisoquinolines and SP2 C-H bonds was also found with
electron deficient alkenes, generating the Morita-Baylis-Hillman(MBH) reaction
product.11 DABCO was found to be effective catalyst in this
reaction. Moderate yields were obtained with 5 mol% CuBr and 10 mol% DABCO at
the temperature 500c.

SCHEME
13: Aza-Baylis-Hillman type CDC reaction

5.CDC
reaction with Cu and Co mixed salts:

We
found, using the comination of CuBr (2.5 mol%) and CoCl2(10 mol%) as
a catalyst, various 1-3-dicarbonyl compounds reacts smoothly with cyclohexane
to give the desired product.12

SCHEME
14: Allylic Alkylation via CDC reaction

SCHEME
15: Benzylic Alkylation via CDC reaction

6. Reaction of 1-phenyl-pyrrolidine with nitromethane via CDC reaction:

Cyclic amines such as
1-phenyl-pyrrolidine also generated the desired product in good yield (SCHEME
16). In this case, bis-CDC-product is also formed in 4% isolated yield along
with the mono-CDC-product.13

SCHEME 16:

7. CDC reaction of tetrahydroisoquinoline with
malonates:

The ?-diesteramine
derivatives were obtained when stoichiometric tetrahyderoisoquinolines and
dialkyl malonates were used with 5 mol% CuBr together with 1 eqv TBHP under
room temperature(SCHEME  17). To further
improve the high efficiency of this new methodology, 1 mol scale of the
reaction was carried uot  with 0.5 mol%
CuBr as the catalyst. The desired product was obtained 72% isolated yield.14

SCHEME
17 

8.
Enantioselectivity of coupling of tetrahydroisoquinolines with terminal alkynes
via CDC reaction:

A varity of substrates
were examined by using the combination of Cu(1)OTf/1 as the chiral
catalyst(SCHEME 18). For aromatic substituted alkynes, reaction usually provided
both good yields, EFG or EDG group R2 on aryl ring did not
sutantially influence the isolated yields and eantioselectives of the desirable
products.15 The presents of an o-methoxy substitution group on aryl
ring(R1) did improved the enantiomeric excesses up to 74%. The
enhanced enantioselective is most likely due to the co-ordination of the oxygen
in the o-methoxy substituent to copper or staric effect of o-substituent on
aryl ring.

SCHEME 18:

 

 

CONCLUSION:

This
perspective is a comprehensive survey of CDC processes using both metal and
organic catalysts, and reactions without the involvement of metals. Two
complementary types of reactions are described: (a) C–C bond forming reactions
between aromatic and heteroaromatic compounds with ethers and (b) oxidative
amination reactions of heteroaryls containing NH groups with ethers leading to
C–N bond formation. Among these reactions, comparable chemistry involving
alcohols is also discussed. What we have found in the course of this survey is that
the reactivity of any ether is not assured and ethers do not all react in
comparable manners. For example, cyclic ethers are not all similar in their
reactivities. Part of the reason for this may be due to the bond dissociation
energies of the C–H bonds of ethers. Also, stereoelectronic effects have been
shown to influence hydrogen atom abstraction from ethers. There are examples
where the unreactivity of certain ethers is either noted by the reporting
authors. It is our view that there are a large number of heteroaryls whose reactivity
under CDC and oxidative-amination conditions are yet to be explored. These as
yet unstudied reactions will lead to a greater understanding and appreciation
of reactivity manifolds, and at the same time expand the palette of
functionalized heterocyclic systems.  There
is some unavoidable overlap between those reviews and this perspective, there
are substantial differences. Further, this perspective also covers up to the
most recently published data and we have attempted to make this a one-stop
reference for this chemistry. Looking ahead, the development of
enantioselective versions of the reactions described herein will substantially
advance the utility of this chemistry, in that enantioenriched molecules can be
accessed via relatively simple reactions. Whilst this is a challenging undertaking,
approaches to chiral CDC reactions are already being realized. Thus, it is
likely only a matter of time before enantioselective versions of many
transformations described herein become chemically feasible.