Visible light-promoted self-coupling of N-chloramines at room temperature: A metal-free access to substituted amides

Article abstract of DOI:10.1080/00397911.2019.1678172

An efficient protocol to synthesize substituted amides via self-coupling of N-chlorobenzylamines has been developed under visible light-promoted mild condition. Both the electron-deficient and electron-rich benzylamines undergo self-coupling very readily to produce the amide linkage under given reaction conditions.

Full text of DOI:10.1080/00397911.2019.1678172

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
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Visible light-promoted self-coupling of N-
chloramines at room temperature: A metal-free
access to substituted amides
Narendra R. Chaubey
To cite this article: Narendra R. Chaubey (2019): Visible light-promoted self-coupling of
N-chloramines at room temperature: A metal-free access to substituted amides, Synthetic
Communications, DOI: 10.1080/00397911.2019.1678172
To link to this article: https://doi.org/10.1080/00397911.2019.1678172
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https://doi.org/10.1080/00397911.2019.1678172
Visible light-promoted self-coupling of N-chloramines at
room temperature: A metal-free access to
substituted amides
Narendra R. Chaubey
Department of Chemistry, Institute of Science, Banaras Hindu University, Varanasi, India
ABSTRACT
ARTICLE HISTORY
Received 2 April 2019
An efficient protocol to synthesize substituted amides via self-cou-
pling of N-chlorobenzylamines has been developed under visible
light-promoted mild condition. Both the electron-deficient and elec-
tron-rich benzylamines undergo self-coupling very readily to produce
the amide linkage under given reaction conditions.
KEYWORDS
Amides; metal-free; N-
chlorobenzylamines; visible
light; self-coupling
GRAPHICAL ABSTRACT
Introduction
The amide linkage is an important and well-recognized functional group.[1]
Constructing the amide linkage is especially important for the assembly of complex
homogeneous glycoproteins. Very fundamental building blocks of our body are made
up of these proteins, which are known as the “first substance of life.” In addition,
amides constitute the key moiety of many useful organic molecules including pharma-
ceuticals, agrochemicals, organic materials, and polymers (Fig. 1). Due to these reasons,
synthesis of amides is of immense importance. Traditional ways for the synthesis of
amide linkage involve the reaction of amines with carboxylic acids,[2] acid chlorides,[3]
aldehydes,[4] esters,[5] alcohols,[6] etc. In the past few years, several newer and greener
approaches have been developed for the synthesis of amides.[7–19]
Kumar et al. performed dehydrogenative coupling of amines with alcohols and esters,
using a manganese pincer complex as the catalyst at 110 ꢀC (Scheme 1a).[8] Reddy et al.
made use of phenacyl azides as the coupling partner with methanamines
(Scheme 1b).[9] Sayes et al. carried out coupling of carboxylic acids with primary and
CONTACT Dr. Narendra R. Chaubey
narendra581981@gmail.com
Department of Chemistry (Centre of Advanced
Studies), Institute of Science, Banaras Hindu University, Varanasi 221005, Uttar Pradesh, India.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2019 Taylor & Francis Group, LLC

2
N. R. CHAUBEY
Figure 1. Importance of amide linkage.
Scheme 1. Previous report.

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Table 1. Optimization of reaction conditions.
Entry
Catalyst (0.2 eq.)
Oxidant
Yield 2a (%)a
1
2
3
Cu(OAc)2
Cu(OAc)2
TBHP (4 eq.)
TBHP (4 eq.)
TBHP (4 eq.)
32b
50
38
–
4
5
6
7
Cu(OAc)2
CuBr
Trace
32
35
TBHP (4 eq.)
TBHP (4 eq.)
DTBP (4 eq.)
I2
Cu(OAc)2
23
8
9
10
11
12
13
Cu(OAc)2
Cu(OAc)2
K2S2O8 (3 eq.)
TBHP (4 eq.)
TBHP (4 eq.)
TBHP (4 eq.)
TBHP (4 eq.)
TBHP (3 eq.)
20
84
c
–
–
–
–
80c
traced
79c,e
56c
Reaction conditions: 1a (1 mmol), catalyst (0.2 eq.), oxidant (4 eq.), acetonitrile (4 mL), 60 ꢀC, 12 h in sealed tube.
aIsolated yield of 2a. bReaction was carried out with 4-methoxybenzylamine. cReaction carried out under 18 W white
LED at room temperature for 48 h. dReaction carried out without white LED at room temperature. eReaction was car-
ried out in DMSO as solvent.
secondary amines, using diphenylsilane as the coupling reagent (Scheme 1c).[10]
Recently, Banerjee et al. carried out a metal-free protocol for self-coupling of benzyl
amines in the presence of I2/TBHP system at 100 ꢀC (Scheme 1d).[15] Our group has
also accomplished the synthesis of amides using N-chloramines as one of the coupling
partners with toluene derivatives[11] and aldehydes.[12] In view of the above and as a
part of our interest in developing useful synthetic protocols for the synthesis of amides
and developing a greener and milder way to synthesize amide linkage, we report herein
a newer and easier protocol for the synthesis of substituted amides via visible light-
promoted self-oxidative coupling of N-chlorobenzylamines (Scheme 1e) at room
temperature.
Results and discussion
With an intent to achieve direct self-coupling at room temperature, the reaction was
initially carried out using 4-methoxybenzylamine in the presence of 20 mol% of anhyd-
rous copper (II) acetate and 4 eq. of aq. TBHP in acetonitrile at 60 ꢀC, which gave rise
to the product 4-methoxy-N-(4-methoxybenzyl)benzamide 2a in 32% yield (Table 1,
entry 1). Considering the high reactivity of N-chloramines, it was envisioned to employ
rather N-chloro-4-methoxybenzylamine 1a, which afforded an improved yield of the
product 2a under the same conditions (50%, Table 1, entry 2). When the reaction was
carried out without using copper acetate, it reduced the yield of the reaction (38%, entry
3). Carrying out the reaction in absence of aq. TBHP diminished the product formation
(entry 4). Similar lower yields were obtained when copper acetate was replaced by CuBr

4
N. R. CHAUBEY
Scheme 2. Reaction scope. Reaction conditions: 1 (1 mmol), aq. TBHP (4 eq.) in 4 mL of acetonitrile
was stirred under 18 W white LED for 48 h in a sealed tube.
(entry 5, 32%) and iodine (entry 6, 35%). Use of other oxidants such as DTBP and
K2S2O8 also diminished the product yield (entries 7 and 8). In the quest to develop a
metal-free and sustainable way at room temperature, 1a was then subjected to reaction
under Cu(OAc)2/aq. TBHP under 18 W white LED system at room temperature, which
readily afforded the product 2a in excellent yield (84%, entry 9). To remove the metal
from the reaction protocol, a reaction was carried out in the absence of Cu(OAc)2.
Surprisingly, almost similar yield of the product was obtained (80%, entry 10). When
the same reaction was carried out without white LED, only a trace amount of the prod-
uct was observed (entry 11). In an effort to further improve in the yield, a reaction was
carried out in DMSO as the solvent but almost similar yield of the product was
observed (entry 12). Hence, we were successful in developing a metal-free protocol for
self-coupling of N-chlorobenzylamines at room temperature (Scheme 2).
Under the optimized set of reaction conditions, a number of substrates 1 were made
to react to explore the scope of the transformation. Both the electron-withdrawing and
donating substituent on para position of the aryl moiety performed well with excellent
product yields (2b: 80%, 2c: 78%, 2d: 75%, 2e: 76%, 2f: 74%, and 2g: 60%).
Chloramines of meta-substituted benzylamines 1i and 1j also underwent the reaction
with reasonably good product yields (2h: 73%, 2i: 67%). N-Chlorobenzylamine also

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Scheme 3. Control experiments.
Scheme 4. Plausible reaction mechanism.
afforded an excellent yield of the product (2j: 82%). Only failure was observed in the
case of chloramines of ortho-substituted benzylamine 1k and heterocyclic counterpart 1l
where only a trace amount of product formation was observed. We also checked the
scope of above self-coupling strategy for aliphatic amines (n-butylamine and n-hexyl-
amine) but above attempts ended without any self-coupled product.
Our next move was to study the mechanistic insights of the reaction with the help of
some control experiments (Scheme 3). N-Chlorobenzylamine, when subjected to the
optimized reaction conditions and reaction stopped after 4 h, disclosed the formation of
benzaldehyde along with a trace amount of amide product. When equimolar quantities
(0.5 mmol) of benzaldehyde and N-chlorobenzylamine 1j were made to react under the
same conditions for 48 h, it led to desirable amount of the corresponding amide. When
the substrate 1j was subjected to reaction in the presence of TEMPO (2 eq.), the prod-
uct formation was suppressed.
Based on the above experiments and existing literature,[11,12,20] a plausible mechanism
is outlined in Scheme 4. In the presence of TBHP and visible light, N-chloramine con-
verts into corresponding aldehyde. Another mole of N-chloramine or corresponding N-
centered radical on condensation with this aldehyde gives the amide.
In conclusions, an efficient and new protocol to synthesize substituted amides has
been developed using self-coupling strategy of N-chloro-derivatives of benzyl amines

6
N. R. CHAUBEY
under visible light-promoted mild conditions. Substrates having both the electron-defi-
cient and electron-rich substituent readily undergo self-coupling to afford the amide
product under the established conditions. To the best of our knowledge, this is the first
such protocol for such self-coupling of N-chlorobenzylamines at room temperature
without using any metal or other chemical catalyst.
Experimental section
Typical experimental procedure for self-coupling of N-chlorobenzylamines: To a solu-
tion of N-chloramine of 4-methoxybenzylamine 1a (1 mmol) in 4 mL of acetonitrile, 4
eq. of aq. TBHP was added. The resulting reaction mixture was stirred under 18 W
white LED for 48 h. The mixture was quenched with saturated NaHCO3 solution and
extracted with (15 ꢁ 3 mL) of ethyl acetate. The organic layer was dried over anhydrous
sodium sulfate and evaporated under reduced pressure to obtain the crude residue. The
crude was purified by column chromatography to obtain the pure amide 2a.
Physical and spectral data of 4-methoxy-N-(4-methoxybenzyl)benzamide (2a)
1
Yield 80%; H NMR (500 MHz, CDCl3) d 7.74 (d, J ¼ 8.0 Hz, 2 H), 7.27 (d, J ¼ 8.5 Hz,
2 H), 6.88 (m,4 H), 6.35 (bs, 1 H), 4.55 (d, J ¼ 5.5 Hz, 2 H),3.83 (s, 3 H),3.79 (s, 3 H).13C
NMR (125 MHz, CDCl3) d 166.8, 162.1, 159.0, 130.4, 129.2, 128.7, 126.7, 114.1, 113.7,
55.4, 55.3, 43.5.[15]
1
Full experimental details including all information, H and 13C NMR spectra, HRMS
data have been provided in supporting information as a separate file.
Acknowledgments
Dr. Narendra R. Chaubey is thankful towards Prof. K. N. Singh, Department of Chemistry,
BHU, India and UGC, New Delhi for D. S. Kothari Post-Doctoral Fellowship.
Disclosure statement
No potential conflict of interest was reported by the authors.
Funding
Dr Narendra R. Chaubey is thankful toward UGC, New Delhi, for D. S. Kothari Post-
Doctoral Fellowship.
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