Copper-catalyzed oxidative C[sbnd]H bond functionalization of N-allylbenzamide for C[sbnd]N and C[sbnd]C bond formation

Article abstract of DOI:10.1016/j.tetlet.2019.04.041

C[sbnd]H bond functionalization for C[sbnd]N and C[sbnd]C bond formations via cross-dehydrogenative coupling (CDC)of N-allylbenzamides with indole as amine source has been developed under a copper-catalyzed condition. To the best of our knowledge, these are the first examples in which different classes of N-containing compounds were directly prepared from the readily available N-allylbenzamides using an inexpensive catalyst-oxidant (CuSO₄/TBHP)system. Further, it was applied for the synthesis of α-substituted N-allylbenzamides by using Grignard reagent as nucleophiles.

Full text of DOI:10.1016/j.tetlet.2019.04.041

Accepted Manuscript
Copper-Catalyzed Oxidative C-H Bond Functionalization of N-Allylbenzamide
for C-N and C-C Bond Formation
Jala Ranjith, Palakodety Radha Krishna
PII:
S0040-4039(19)30390-9
https://doi.org/10.1016/j.tetlet.2019.04.041
TETL 50756
DOI:
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
12 March 2019
22 April 2019
25 April 2019
Please cite this article as: Ranjith, J., Krishna, P.R., Copper-Catalyzed Oxidative C-H Bond Functionalization of
N-Allylbenzamide for C-N and C-C Bond Formation, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/
j.tetlet.2019.04.041
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Graphical Abstract
Copper-Catalyzed Oxidative C-H Bond
Functionalization of N-Allylbenzamide for
C-N and C-C Bond Formation
Leave this area blank for abstract info.
Jala Ranjith and Palakodety Radha Krishna *

1
Tetrahedron Letters
Copper-Catalyzed Oxidative C-H Bond Functionalization of N-Allylbenzamide
for C-N and C-C Bond Formation
Jala Ranjith a and Palakodety Radha Krishna a*
aOrganic Synthesis and Process Chemistry Division, CSIR-Indian Institute of Chemical Technology, Hyderabad-500007, India.
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
C-H Bond functionalization for C-N and C-C bond formations via cross-dehydrogenative
coupling (CDC) of N-allylbenzamides with indole as amine source has been developed under a
copper-catalyzed condition. To the best of our knowledge, these are the first examples in which
different classes of N-containing compounds were directly prepared from the readily available
N-allylbenzamides using an inexpensive catalyst-oxidant (CuSO4/TBHP) system. Further, it was
applied for the synthesis of α-substituted N-allylbenzamides by using Grignard reagent as
nucleophiles
Available online
Keywords:
Copper-catalyzed
Oxidative coupling
CDC coupling
Grignard reaction
1. Introduction
The activation of C-H bonds for coupling reactions is a great
importance in organic synthesis since nitrogen-containing
compounds such as amide1 and indole aminal2 moieties are
present in a variety of biologically and medicinally active
compounds, and their synthesis and functionalization have
received great attention. However, transition-metal-catalyzed
C(sp2)-N bond formation has been intensively studied,3 C(sp3)-H
bonds which are naturally more abundant, still face great
challenges in C-N bond formation.4 Methodologies for direct α-
C-H oxidation when the carbon adjacent to the nitrogen and
oxygen atoms were developed under transition metals such as
iron, copper and metal-free conditions.5 Transition-metal-
catalyzed cross-dehydrogenative coupling (CDC) reactions have
emerged as powerful tools for organic synthesis. Besides being
highly atom- and step-economic way of constructing C-C,6 C-O7
and C-N8 bonds, such methods allow introduction of other
functional groups directly through oxidative sp3 C-H bond
activation, in particular for amines or amides when the carbon
adjacent to the nitrogen atom is the point of activation.
Scheme 1. C-H bond functionalization of allylbenzamides
The required substrates N-allylbenzamides were readily
prepared from the corresponding benzoyl chloride and allylamine
as per our earlier method.10 At the outset, N-allylbenzamide 1a
was chosen as the model substrate to optimize reaction
conditions including the oxidant equivalents, catalyst type and
solvent as disclosed in Table 1. Accordingly, a preformed
solution of N-allylbenzamide 1a (1.0 equiv), TBHP (70%
solution in water, 2.0 equiv) and TBAI (10 mol %) was dissolved
in CH3CN (2 mL) at room temperature. Then indole (1.0 equiv)
as a nucleophilic amine source was added and the resultant
solution was stirred for 10 h at same temperature, the reaction
proceeded to afford the desired product indole aminal (2a) in low
yield (Table 1, entry 1). Next, the replacement of TBAI with
other catalysts, including I2, NIS and CuBr resulted in no
improvement (Table 1, entries 2, 3 and 4). Then, the replacement
of catalyst with CuSO4 (2.5 mol %), the reaction proceeded to
Further, copper catalyst in combination with TBHP oxidant is
now emerging as a more powerful tool to functionalize C(sp3)-H
bonds followed by cross-coupling (CDC).9 Herein we disclose an
efficient and practical approach for the oxidative coupling of N-
allylbenzamides with indoles and Grignard reagent as an
nucleophile source into the α-substituted N-allylbenzamides
using CuSO4-TBHP as the system. To the best of our knowledge,
no report exists in the literature on these oxidative
transformations (Scheme 1).

2
Tetrahedron
a Reaction conditions: N-allylbenzamide (0.62 mmol), CuSO4 (10
mol%), aq. TBHP (1.24 mmol), indole (0.6 mmol, 1.0 equiv.),
solvent (2 mL), temperature (rt) under nitrogen atmosphere.
afford the desired product indole aminal (2a) in 36% (Table 1,
entry 5). In order to improve the efficiency, we studied the
amount of CuSO4, to our delight, 10 mol% of catalyst provided
an 84% yield of the desired product 2a for 4 h at same
temperature (Table 1, entries 6, 7 and 8). Moreover, during the
optimization study, the required TBHP was reduced to 1.0 equiv
and 1.5 equiv and the yield of 2a correspondingly decreased to
50% and 67% respectively (Table 1, entries 9 and 10). In the
absence of the catalyst no product was formed (Table 1, entry
11). The replacement of TBHP with m-CPBA and oxone, the
product was undetected (Table 1, entries 12 and 13). Further
optimization using other solvents such as CH2Cl2, 1, 2-
dichloroethane (DCE), and THF resulted in the formation of 2a
in lower yields (Table 1, entries 14, 15 and 16). Through, these
results we concluded that CuSO4 (10 mol %) and TBHP (70%
solution in water, 2.0 equiv) in CH3CN (2 mL) at room
temperature are the optimal conditions for the synthesis of indole
aminal 2a (Table 1, entry 8).
b
The yields refer to isolated products purified by column
chromatography.
Having optimized reaction conditions in hand, we investigated
the scope and generality of the oxidative C-H/N-H cross-
coupling adjacent to an amide nitrogen atom, affording the cross
dehydrogenative coupling (CDC) product 2. As illustrated
(Scheme 2), all the substrates 1a-g well tolerated the optimized
conditions to furnish the corresponding indole aminal derivatives
2 in good to excellent yields. Alerted, we quickly sought to
broaden the scope of the N-allylbenzamide derivatives with
electron-donating, electron-withdrawing groups on phenyl ring
was investigated. The reaction with electron-donating derivatives
showed higher yields than electron-withdrawing derivatives (2b-
2e). Pleasingly, a heterocyclic bearing allylamide such as N-
allylisonicotinamide (1f) also underwent smooth reaction to
furnish the product 2f in 76% yield. Notably, the oxidative CDC
reaction was applicable to a bromoindole with N-allylbenzamide
(1a), N-allyl-4-fluorobenzamide (1c), when evaluated under the
established conditions to obtain the anticipated cross-coupling
products 2ab and 2cb in 81% and 83% yields respectively. Also,
the N-benzylbenzamide 1g could be employed in the reaction to
give the desired product 2g in 77% yield. Further, structural
confirmation of 2ab was ascertained by X-ray studies (see SI).
Table 1. Optimization of reaction conditionsa
Entry Catalyst
(mol%)
oxidant
(equiv.)
Solvent
Yield
(%)b
Scheme 2. Synthesis of Indol Aminalsa,b
1
TBAI (10)
TBHP (2)
TBHP (2)
TBHP (2)
TBHP (2)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
15
Trace
10
32
36
52
76
84
50
67
0
2
I2 (10)
3
NIS (10)
4
CuBr (10)
5
CuSO4(2.5) TBHP (2)
CuSO4 (5) TBHP (2)
6
7
CuSO4(7.5) TBHP (2)
CuSO4(10) TBHP (2)
CuSO4 (10) TBHP (1)
CuSO4 (10) TBHP(1.5)
8
9
10
11
12
13
14
15
16
-
TBHP (2)
aReaction conditions: 1a (1.0 equiv), CuSO4 (10 mol%), aq.
TBHP (2.0 equiv), indole (1.0 equiv.), solvent (2 mL),
temperature (rt) under nitrogen atmosphere. bIsolated yields.
CuSO4 (10) m-CPBA (2) CH3CN
0
CuSO4 (10) Oxone (2)
CuSO4 (10) TBHP (2)
CuSO4 (10) TBHP (2)
CuSO4 (10) TBHP (2)
CH3CN
CH2Cl2
DCE
0
Figure 1. ORTEP representation of Compound 2ab (CCDC
1837200)
56
20
0
THF

3
After successful C-H/N-H oxidative coupling reaction, we
explored the protocol for C-C bond formation through oxidative
functionalization of C-H bond activation (Scheme 3). Since 3a or
3a' were the presumable intermediates, we isolated them
independently and conducted the next set of reactions. Thus, the
N-allylbenzamide 1a when treated with aq. TBHP and CuSO4 in
Then tert-butoxy radical can be hydrogen atom acceptor in
reaction with 1a, forming radical A. This reacts further to afford
peroxide 3a, which decomposes to the iminium intermediate B
by copper catalysis. Finally, CDC coupling of iminium
intermediate with indole nucleophile gave the desired product 2a.
Scheme 4. Control experiments
CH3CN,
gave
the
desired
product
N-(1-(tert-
butylperoxy)allyl)benzamide (3a) in good yield. Peroxide 3a
when exposed to 3.0 equiv of PhMgBr in dryTHF, N-(1-
phenylallyl) benzamide 4aa was obtained in 92% yield within 15
min at room temperature (Scheme 3). Encouraged by these
findings, we next examined the scope of aliphatic Grignard
reagents such as EtMgBr, vinylMgBr, allylMgBr, and (but-3-yn-
1-yloxy)(tert-butyl)dimethylsilaneMgBr which an oxidative
functionalization successfully on 3a furnished the corresponding
products (4ab-4ae) in good to excellent yields. Moreover, N-(1-
(tert-butylperoxy) prop-2-yn-1-yl) benzamide 3a' was prepared
the same way as compound 3a by using N-propargylbenzamide.
Similarly, peroxide 3a' on exposure to PhMgBr and EtMgBr
afforded the desired compounds 4a'a and 4a'b in good yields.
Scheme 3. Synthesis of α-substituted N-allylbenzamides with
Grignard Reagentsa,b
Scheme 5. Proposed Mechanism
aReaction conditions: 3a (1.0 equiv), R1MgBr (3.0 equiv), in dry
THF (2 mL) solvent, temperature (rt) under nitrogen atmosphere.
bIsolated yields.
To gain insight into the mechanism of these oxidative
coupling reactions some control experiments were carried out
(Scheme 4). First, 5 equiv of radical scavenger 2,2,6,6-
tetramethyl-1-piperidinyloxyl (TEMPO) was added into the 1a
under standard conditions, and it was found that the reaction was
completely inhibited. Thus, it indicates a radical nature of the
mechanism (Scheme 4a). Next, 1a was treated with aq.TBHP and
CuSO4, to afford the corresponding peroxide 3a (Scheme 4b).
In conclusion we have demonstrated C-H functionalization of
N-allylbenzamide derivatives by an efficient novel copper
catalyzed protocol in “one-pot” fashion. The direct oxidative
coupling of N-allylbenzamide with indoles furnished
dehydrogenative C (sp3)-N cross coupling products in mild
conditions using TBHP as the oxidant, CuSO4 as the catalyst.
Likewise, we have obtained α-substituted amides by treating tert-
butylperoxyallylbenzamide with Grignard reagents. Efforts to
find newer applications of this protocol are currently underway in
our laboratory.
Further,
to
learn
the
reaction
path,
N-(1-(tert-
butylperoxy)allyl)benzamide 3a was treated with indole under
the optimized conditions, the desired indole aminal 2a was
obtained (Scheme 4c). It gives clear idea that the reaction goes
through the tert-butylperoxy intermediate, indole would
participate via CDC coupling reaction.
On the basis of the control experiments and previous reports,
we propose a possible mechanism as shown in Scheme 5.
Initially, the role of copper (II) species is to catalyze the
decomposition of the oxidant tBuOOH into tBuO• and tBuOO•.11
Acknowledgments

4
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5
Highlights
1. C-H Bond functionalization
2. Cross-dehydrogenative coupling (CDC)
3. Grignard Reaction