I2/Aqueous TBHP-Catalyzed Coupling of Amides with Methylarenes/Aldehydes/Alcohols: Metal-Free Synthesis of Imides

Article abstract of DOI:10.1021/acs.orglett.6b01684

We present a metal-free method for the synthesis of imides by the direct coupling of NH-amides with methylarenes under iodine/aqueous TBHP conditions. The optimized conditions worked very well with benzaldehydes and benzyl alcohol and furnished the corresponding imides in good to excellent yields. A series of control and radical scavenger experiments were also performed, which suggested the involvement of radical pathways. The labeling experiment in the presence of ¹⁸O-labeled H₂O suggested water as a source of oxygen in the imides.

Full text of DOI:10.1021/acs.orglett.6b01684

Letter
pubs.acs.org/OrgLett
I2/Aqueous TBHP-Catalyzed Coupling of Amides with Methylarenes/
Aldehydes/Alcohols: Metal-Free Synthesis of Imides
Hariprasad Aruri,†,‡,∥ Umed Singh,†,‡,∥ Sanjay Kumar,†,‡ Manoj Kushwaha,§ Ajai Prakash Gupta,§
Ram A. Vishwakarma,†,‡ and Parvinder Pal Singh*,†,‡
§
†Medicinal Chemistry Division and Quality Control and Quality Assurance, CSIR-Indian Institute of Integrative Medicine, Canal
Road, Jammu 180001, India
‡Academy of Scientific and Innovative Research, Canal Road, Jammu 180001, India
S
* Supporting Information
ABSTRACT: We present a metal-free method for the synthesis of imides by the direct coupling of NH-amides with
methylarenes under iodine/aqueous TBHP conditions. The optimized conditions worked very well with benzaldehydes and
benzyl alcohol and furnished the corresponding imides in good to excellent yields. A series of control and radical scavenger
experiments were also performed, which suggested the involvement of radical pathways. The labeling experiment in the presence
of 18O-labeled H2O suggested water as a source of oxygen in the imides.
he wide occurrence of imides from nature to pharmaceut-
ical to material explains their importance in chemical space.
T
The natural products containing an imide moiety are
rebeccamycin,1a fumaramidmycin,1b palauimidine,1c berkeleya-
mide B and C,1d penimidine A,1e pestalamides A and B,1f
granulatimide,1g isogranulatimide,1h and brabantamides A−C.1i
The pharmaceutical products having an imide moiety are
thalidomide,1j anircetam,1k and ethosuximide.1l Similarly,
examples of fungicide and polymer are capton and Kapton,
respectively.2 Considering their wide occurrence and impor-
tance, the methods for their synthesis are of high interest.
Historically, these were synthesized either by acylation of amides,
by coupling of amines with dicarboxylic acids (or anhydride),3a
or by Mumm rearrangement of isoimides.3b Alternatively,
oxidation of N-alkylamides was also used for the synthesis of
imides, which was reviewed recently.4 By comparing all these
methods, acylation of amides is considered as one of the easy and
direct methods, but it has limited substrate scope due to the weak
nucleophilicity of amides and the requirement of activated acyl
partners. To counter these limitations, C−H activation methods
provide an attractive strategy, and recently, few attempts were
made where copper- and iron-based C−H activation methods
were employed for the acylation of amides using aldehyde as a
coupling partner (Figure 1).5,6 By employing aldehyde as an acyl
coupling partner, Hong et al. also reported a Ru-catalyzed
(Shivo’s catalyst) method for the synthesis of imides.7 In last two
decades, iodide/iodine in the presence of oxidant represents a
metal-free and effective alternative method for C−H activation to
construct C−C and C−heteroatom bonds.8 Moreover, iodide/
iodine along with TBHP has been successfully utilized for
Figure 1. Previous and present approaches.
activation of benzylic and aldehydic C−H to construct amides;9
however, to the best of our knowledge, no reports have been
demonstrated for the synthesis of imides. Here, we have
developed a metal-free method for the synthesis of imides
employing an iodine/TBHP catalytic system.
In a first attempt, reaction between 1a and 2a in the presence
of a TBAI/TBHP catalytic system, a trace amount of required
product 3a was obtained (Table 1, entry 1) along with some
quantity of benzaldehyde. Upon replacement of TBAI with I2,
24% of product 3a was obtained (Table 1, entry 2) along with
some quantity of benzaldehyde. Next, the addition of additive
such as Na2CO3 gave the required product 3a in a yield of 72%
(Table 1, entry 3). After this, the reaction was again attempted
with TBAI along with TBHP and Na2CO3, but only a trace
amount of product 3a was observed (Table 1, entry 4). In a
Received: June 10, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01684
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
substituted toluenes gave coupled products 3d, 3e, and 3f in
yields of 72, 67, and 65% respectively. Ortho-substituted toluenes
such as o-bromotoluene also reacted with 1a and gave the
corresponding product 3g in a yield of 58%. A bicyclic system
such as 2-methylnapthalene also successfully underwent reaction
with 1a and furnished the corresponding product 3h with 64%
yield. Interestingly, a disubstituted methylarene such as
mesitylene also reacted smoothly with 1a and furnished
monosubstituted product 3i in a yield of 62%.
Table 1. Optimization Studies
b
entry
catalyst
solvent
additive
yield (%)
1
2
3
4
5
6
TBAI
I2
neat
neat
neat
neat
neat
neat
neat
neat
neat
DCE
ACN
trace
24
To further extend the generality of this method, different
substituted NH-amides were also explored (Scheme 2). o-
I2
Na2CO3 (0.5 equiv)
Na2CO3 (0.5 equiv)
Na2CO3 (0.5 equiv)
Na2CO3 (1 equiv)
ZnBr2
72
TBAI
KI
I2
trace
65
71
Scheme 2. Coupling of Various N-Methylbenzamide with
Methylarenes
c
7
I2
69
c
8
c
I2
FeCl3·6H2O
CuI
54
9
I2
trace
trace
trace
10
11
I2
Na2CO3
I2
Na2CO3
a
All of the reactions were performed with 1 mmol of amide 1a, 20
mmol of toluene 2a, 6 mmol of aq TBHP, 0.2 mmol of catalyst, 0.5
b
c
mmol of additive at 110 °C, 20 h. Isolated yields. 0.2 mmol of
additive was used.
further attempt, replacement of catalyst I2 with KI furnished 65%
of product 3a (Table 1, entry 5). An increase in the amount of
Na2CO3 from 0.5 equiv to 1 equiv did not affect the product
formation (Table 1, entry 6). Screening with other additives such
as ZnBr2, FeCl3·6H2O, and CuI as additives was also attempted,
but none gave any improvement (Table 1, entries 7−9). The
screening in different solvents such as DCE and ACN suppressed
the formation of coupled product (Table 1, entries 10 and 11). In
the optimization reactions, the benzaldehyde was observed as a
side product with varying quantities; however, the quantification
of benzaldehyde was not made, as the same was taken as 20-fold
excess. The reaction with 0.2 equiv of iodine, 6 equiv of TBHP,
and 0.5 equiv of Na2CO3 was considered as the best condition
(Table 1, entry 3).
After the optimization study, the generality of the optimized
conditions with different substituted methylarenes was inves-
tigated (Scheme 1). Substituted methylarenes on reaction with
N-methylbenzamide 1a gave moderate to good yields of coupled
products along with some quantity of the corresponding
aldehydes and alcohols. Reaction of N-methylbenzamide 1a
with p-methoxytoluene and p-tert-butyltoluene proceeded
smoothly and gave 3b and 3c in a yield of 69 and 71%,
respectively. Reaction of 1a with p-chloro-, bromo-, and iodo-
a
Reaction conditions: amide 1 (0.22 mmol), methylarene 2 (4.4
mmol), aq TBHP (1.32 mmol), I2 (20 mol %), Na2CO3 (50 mol %),
110 °C. Isolated yield.
b
Fluoro-N-methylbenzamide successfully benzoylated under the
optimized conditions with methylarene and gave corresponding
product 4a in a yield of 74%. Similarly, reaction of o-fluoro-N-
methylbenzamide with p-methoxy, p-tert-butyl, and p-chloroto-
luene furnished the corresponding products 4b, 4c, and 4d in
yields of 67, 72, and 71%, respectively. p-Tolyl-N-methylbenza-
mide also reacted with methylarene and 4-chlorotoluene and
produced 75 and 71% of the corresponding products 4e and 4f,
respectively. p-Tolyl-N-methylbenzamide smoothly reacted with
sterically hindered 1-methylnapthalene and 2-methylnapthalene
and furnished 48 and 57% of corresponding imides 4g and 4h,
respectively. m-Methoxy-N-methylbenzamide and o-methyl-N-
methylbenzanmide also reacted with toluene and gave 4i and 4j
in yields of 68% and 74%, respectively. Aliphatic amides such as
N-methylacetamide and caprolactam also underwent reaction
with toluene and produced the corresponding imides 4k and 4l in
yields of 65% and 62%, respectively. Under the optimized
conditions, primary amides such as benzamides did not give
acylated products.
Scheme 1. Coupling of N-Methylbenzamide with Various
Methylarenes
Under the optimized conditions, the compatibility of bulky
groups bearing amides was also investigated (Scheme 3). N-
Propyl, N-cyclobutyl, N-(1-phenylethyl), and N-phenethylben-
zamide reacted with toluene and furnished the corresponding
products 5a−d with moderate to good yields.
During the optimization and generality study with methylar-
enes, most of the reactions also gave the corresponding
aldehydes and alcohols along with the required products,
indicating the same could be explored for the coupling. When
the reaction was performed between p-tolyl-N-methylbenzamide
and benzaldehyde under an optimized catalytic system, the
corresponding coupled product was obtained in trace quantities.
a
Reaction conditions: amide 1(0.22 mmol), methylarene 2 (4.4
mmol), aq TBHP (1.32 mmol), I2 (20 mol %), Na2CO3 (50 mol %),
110 °C. Isolated yield.
b
B
DOI: 10.1021/acs.orglett.6b01684
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Organic Letters
Letter
Scheme 3. Coupling of Various N-Alkylbenzamides with
Table 2. Radical Scavenger Experiments
Methylarenes
yield (3 or 4)
yield (8)
entry
1
R/R2/R3
conditions
(%)
(%)
p-tolyl/H/Me
p-tolyl/H/Me
Ph/H/CHO
a
a
b
b
b
nf
nf
30
nf
nf
no
no
no
no
71
c
2
a
3
Reaction conditions: amide 1 (0.22 mmol), methylarene 2 (4.4
d
4
Ph/H/CHO
mmol), aq TBHP (1.32 mmol), I2 (20 mol %), Na2CO3 (50 mol %),
b
5
Ph/3,4-di-OMe/CHO
110 °C. Isolated yield.
a
Reaction conditions: Amide 1 (0.22 mmol), methylarene 2 (4.4
mmol), aq TBHP (1.32 mmol), I2 (20 mol %), Na2CO3 (50 mol %),
Surprisingly, when the same reaction was performed in 1,2-
dichloroethane (DCE) as solvent, the corresponding product 4e
was obtained in a yield of 92% (Scheme 4). Other benzaldehydes
b
110 °C, 20 h: amide 1 (0.22 mmol), aldehyde 6 (0.22 mmol),
TEMPO (0.44 mmol), aq TBHP (0.44 mmol), I2 (10 mol %),
c
Na2CO3 (50 mol %), 80 °C, 12 h, DCE; 0.44 mmol of 1,1-
d
diphenylethylene was used instead of TEMPO; TEMPO (2.2 mmol);
Scheme 4. Coupling of Various N-Alkylbenzamides with
Aldehydes
nf: not formed; no: not observed
furnished the corresponding imides. The intermediacy of alcohol
and aldehyde was also confirmed by performing an independent
reaction with benzyl alcohol and benzaldehyde, where the
corresponding required product 4e was obtained in a yield of 92
and 85% (Scheme 4). These experiments confirmed the above
proposed path. Next, the intake of oxygen was also understood
by performing the reaction under dry conditions, where only a
trace amount of required product 4e was observed (Scheme 5, eq
Scheme 5. Control Experiments
a
Reaction conditions (unless otherwise noticed): amide 1 (0.22
mmol), aldehyde 6 (0.22 mmol), aq TBHP (0.44 mmol), I2 (10 mol
b
c
%), Na2CO3 (50 mol %), DCE, 80 °C, 12 h. Isolated yield. Reaction
d
with benzaldehyde. Reaction with benzyl alcohol, aq TBHP (0.66
mmol), I2 (10 mol %), Na2CO3 (50 mol %), DCE, 80 °C, 15 h.
such as p-methoxybenzaldehyde and 3,4-dimethoxybenzalde-
hyde on reaction with N-methylbenzamide gave the correspond-
ing imides 3b and 7a in yields of 82% and 75%, respectively.
Similarly, when reactions between N-methylbenzamide and
electron-withdrawing groups substituted benzaldehyde were
attempted, good to moderate yields of their corresponding
products were obtained (7b−d, 3d). On the other hand, benzyl
alcohols were used as acyl sources for coupling with HN-amides.
Various un/substituted benzyl alcohols on coupling with N-
methylbenzamide furnished corresponding products (4e, 3b,d,
7e,f) in good to excellent yields (Scheme 4).
To gain insight into the mechanism, a series of control
experiments were performed. When the reactions were
performed in the presence of free-radical scavengers such as
TEMPO and 1,1-diphenylethylene (DPE), product formation
was significantly suppressed (Table 2, entries 1−5), indicating
the involvement of radical pathway. Interestingly, the reaction
with 3,4-dimethoxybenzaldehyde in the presence of TEMPO
gave TEMPO-aldehyde adduct 8, further confirming the radical
pathway (Table 2, entry 5). During optimization and diversity
generation studies with methylarenes, the existence of benzyl
alcohol and benzaldehyde was always noticed on TLC (by
comparing with commercial standards), suggesting the possi-
bility of conversion of methylarenes to alcohols and then to
benzaldehyde, which ultimately reacted with amides and
a
Conditions: amide 1 (0.22 mmol), dry toluene 2a (4.4 mmol), TBHP
in decane 5−5.5 M (1.32 mmol), I2 (20 mol %), Na2CO3 (50 mol %),
N2 atmosphere, 110 °C, 20 h. Conditions: amide 1 (0.22 mmol),
b
methylarene 2a (4.4 mmol), aq TBHP (1.32 mmol); 110 °C, 20 h.
c
Conditions: amide 1 (0.22 mmol), methylarene 2a (4.4 mmol), I2 (20
mol %), 110 °C, 20 h.
1), suggestimg the water might be the source for oxygen. In
another reaction, when p-tolyl-N-methylbenzamide reacted with
toluene in the presence of only TBHP, no required product
formation was observed, but instead benzaldehyde formation was
noticed (Scheme 5, eq 2). On the other hand, when the reaction
was performed between p-tolyl-N-methylbenzamide and toluene
in the presence of I2, no product formation was observed
(Scheme 5, eq 3). These experiments suggested that activation of
methylarenes was initiated by TBHP. The incorporation of
oxygen was further confirmed through labeling experiments by
performing the reaction with 18O-labeled H2O, where LC−MS
analysis showed the presence of 18O in the product (Figure 2).
On the basis of the above experiment and previous literature
reports,9,10 a plausible pathway is proposed as shown in Figure 3.
On the basis of the intermediate capturing and labeling
experiments, the present reaction undergoes the following
C
DOI: 10.1021/acs.orglett.6b01684
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01684.
Detailed experimental procedures and characterization
data for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: ppsingh@iiim.ac.in.
Author Contributions
∥H.A. and U.S. contributed equally.
Notes
The authors declare no competing financial interest.
Figure 2. Labeling experiments.
ACKNOWLEDGMENTS
■
We acknowledge the financial support of CSIR through Research
Grant No. BSC 0108. H.A., U.S., and S.K. thank CSIR and UGC
for their fellowships. IIIM communication number: IIIM/1935/
2016.
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Figure 3. Plausible mechanism.
sequence, wherein methylarene is first converted into benzyl
alcohol and then to benzaldehyde, which ultimately reacts with
amide and finally furnishes the required imide. The reaction is
initiated by redox reaction between iodine and TBHP, which
generates tert-butoxy and tert-butylhydroperoxide radicals. The
generated tert-butoxy and tert-butylhydroperoxide radicals
abstract hydrogen atom from methylarene and give benzyl
radical I, which further undergoes a single-electron reaction and
furnishes benzyl carbocation II. The benzyl cation reacts with
water to generate benzyl alcohol. The generated benzyl alcohol
again gets oxidized by tert-butoxy and tert-butyl hydroperoxide
radicals and iodine to form the key intermediate benzaldehyde.
On the basis of the literature reports, two pathways (path a and
b) are proposed for the coupling of benzaldehyde with amide.9a,c
In our radical scavenger experiments (Table 2, entries 3−5),
formation of TEMPO−aldehyde adduct 8 was observed,
suggesting the intermediacy of benzoyl radical III and
involvement of path b (as also reported previously for amide
synthesis),9b,10 wherein benzoyl radical undergoes nucleophilic
reaction with amide, followed by single electron release and de-
protonation to generate final product 3.
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In summary, a metal-free method for the N-acylation of NH-
amides with methylarenes, benzaldehydes, and benzyl alcohol
was developed involving a I2/TBHP catalytic system.
D
DOI: 10.1021/acs.orglett.6b01684
Org. Lett. XXXX, XXX, XXX−XXX