Tert-Butyl Nitrite-Mediated Synthesis of N-Nitrosoamides, Carboxylic Acids, Benzocoumarins, and Isocoumarins from Amides

Article abstract of DOI:10.1021/acs.joc.7b00570

This work reports tert-butyl nitrite (TBN) as a multitask reagent for (1) the controlled synthesis of N-nitrosoamide from N-alkyl amides, (2) hydrolysis of N-methoxyamides to carboxylic acids, (3) metal- and oxidant-free benzocoumarin synthesis from ortho-aryl-N-methoxyamides via N-H, C-N, and C-H bond activation, and (4) isocoumarin synthesis using Ru(II)/PEG as a recyclable catalytic system via ortho-C-H activation and TBN as an oxygen source. The sequential functional group interconversion of amide to acid has also been examined using IR spectroscopic analysis. Additionally, this methodology is highly advantageous due to short reaction time, gram scale synthesis, and broad substrate scope.

Full text of DOI:10.1021/acs.joc.7b00570

Subscriber access provided by TRENT UNIV
Article
tert-Butyl Nitrite Mediated Synthesis of N-nitrosoamides,
Carboxylic Acids, Benzocoumarins and Isocoumarins from Amides
Subhash Laxman Yedage, and Bhalchandra M. Bhanage
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 05 May 2017
Downloaded from http://pubs.acs.org on May 5, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society.
1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 47
The Journal of Organic Chemistry
1
2
3
4
tert-Butyl Nitrite Mediated Synthesis of N-nitrosoamides, Carboxylic Acids,
5
6
Benzocoumarins and Isocoumarins from Amides
7
8
9
Subhash L. Yedage and Bhalchandra M. Bhanage*
Department of Chemistry, Institute of Chemical Technology, Mumbai-400019, India
E-mail: bm.bhanage@ictmumbai.edu.in,bm.bhanage@gmail.com
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ABSTRACT: This work reports tert-Butyl Nitrite (TBN) as a multitask reagent for 1) the
controlled synthesis of N-nitrosoamide from N-alkyl amides, 2) hydrolysis of N-methoxyamides
to carboxylic acids, 3) metal and oxidant free benzocoumarin synthesis from ortho-aryl-N-
methoxyamides via N-H, C-N and C-H Bond activation and 4) isocoumarin synthesis using
Ru(II)/PEG as a recyclable catalytic system via ortho C-H activation and TBN as an oxygen
source. The sequential functional group interconversion of amide to acid has also been examined
using IR spectroscopic analysis. Additionally, this methodology is highly advantageous due to
short reaction time, gram scale synthesis and broad substrate scope.
TOC Graphic
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 47
1
2
3
4
INTRODUCTION
5
6
7
8
9
Amide is an ubiquitous and key backbone in natural peptides and biologically active molecules.1
Its prevalence in nature is due to its stability which in turn is due to the presence of the stable C-
N bond.2 This is attributed to the fact that, there is an overlap between the lone pair of electrons
on nitrogen with the carbonyl π orbital (barrier to N-C resonance of 15–20 kcal/mol).3 As a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
+
result, the partial double bond character N=C-O− arises in the amide bond due to resonance,
which decreases the electrophilicity of the amide carbonyl group.4 Classically, in acidic medium,
the protonation of carbonyl amide is followed by nucleophilic addition to the carbonyl carbon
thus resulting in its hydrolysis.5 Similars equence of events take place in transamidation6 and
Friedel-Crafts acylation reaction.7 While in basic medium or in the presence of organometallic
reagents, the direct nucleophilic addition to carbonyl amide results in the synthesis of
acid/ketone.8 Moreover, enzyme/DNA catalytic system is also useful for hydrolysis of amide but
requires longer reaction time.9 To explore the chemistry of amides, contemporary research
involves metal catalyzed functionalization of amide C-N bond.10 Independently, Garg,11 Zou,12
Szostak,13 and Zeng14 have contributed in metal catalyzed cleavage of sterically hindered tertiary
amide C-N bonds for various organic transformations [Scheme 1, A(a)]. However, a few reports
are available on metal-catalyzed cleavage of secondary amides (transamidation)15 due to the
formation of thermodynamically stable metallacycle which makes the cleavage of C-N bond
difficult [Scheme 1, A(b)].16 Importantly, in the absence of metal catalyst, secondary amides
undergo N-nitrosylation followed by rearrangement via cleavage of C-N bond.17 The
nitrosylation of secondary amides using different nitrosyl sources such as sodium or potassium
nitrite in acid,18 silver nitrate,19 nitrosyl chloride17 and nitrogen oxides (e.g. N2O3, N2O4, etc.)20
have been well documented. However, difficulties in handling, the presence of acidic medium,
ACS Paragon Plus Environment

Page 3 of 47
The Journal of Organic Chemistry
1
2
3
4
5
6
the formation of side products, utilization of multiple reagents and lack of step economy are
some of the limitations of the protocols making use of these existing nitrosyl sources.
7
8
9
Scheme 1. A) Comparison of A) previous approaches with B) Present work
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Recently, TBN has been used in nitrosylation of amines and urea,21 diazotization22 and C-
nitration reactions.23 Moreover, TBN is inexpensive and commercially available, possesses good
solvent solubility and is also easy to handle. Advantageously, when used in organic reactions it
provides only t-BuOH as the nontoxic side product.21-23
In this perspective, we herein report the first important application of TBN for the N-
nitrosylation of N-alkylamides, synthesis of carboxylic acids, benzocoumarins and isocoumarins
from N-alkoxyamides (Scheme 1B). These reactions proceed through one pot cleavage of N-H,
C-N and C-H bonds of amides.
RESULTS AND DISCUSSION
a) N-nitrosoamide synthesis from alkyl amides
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 47
1
2
3
4
5
6
7
8
9
N-nitrosoamide is an important intermediate useful in various organic transformations.24
Synthesis of N-nitrosoamides has been well established and requires tedious reaction processes
(Scheme 1, a).17-20 However, the transformation of this intermediate has limitations due to the use
of acidic medium and the generation of hazardous side products. Notably, use of organonitrites,
provide nitrosyl radical in neutral reaction conditions with only alcohol as the side product.21-23
In view of the characteristic feature of organonitrites, we have initiated the optimization of
reaction conditions for N-nitrosylation of N-methyl benzamide 1a, using n-butyl nitrite (I) as the
nitrosyl source at 60 oC for 3 h.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 1.Optimization of reaction conditionsa
Entry -NO reagent Solvent
(equiv.)
Time
(h)
3
3
3
1
0.5
1
1
1
temp. Yield (%)b
(oC)
2a
-
2a
96
51
´
1
2
I
I
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DMF
CH2Cl2
n-hexane
-
60
40
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
46
83
87
63
74
89
89
93
48
93
93
97
3
I
Trace
4
I
-
-
-
-
-
-
-
-
-
-
5
I
6
7
8
9
10
11
12
13
II
III
IV
V
V
V
V
V
1
1
1
1
1
aReaction conditions: N-methylbenzamide 1a (1 mmol), alkyl nitrite I-V (1.5 mmol), Solvent (3 mL).
bIsolated yield. rt= Room temperature (29 oC).
ACS Paragon Plus Environment

Page 5 of 47
The Journal of Organic Chemistry
1
2
3
4
A mixture of trace amount of N-nitrosoamide 2a and 96% methylbezoate 2a´ were observed
5
6
7
8
(Table 1, entry 1). On minimizing the temperature, the yield of product 2a increases while that of
2a decreases (Table 1, entries 2-3). Importantly, by decreasing the reaction time, the selectively
´
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
towards N-nitrosoamide 2a was increased and good yield of 2a was observed within 1 h (Table
1, entries 4-5). Moreover, the reactivity of other alkyl nitrite isomers was also checked. The yield
of 2a produced on using ethyl nitrite (II), isobutyl nitrite (III), isopentyl nitrite (IV) and t-butyl
nitrite (V) were 74%, 89%,89% and 93% respectively (Table 1, entries 6-9). From the above
observations, it was found that the reactivity of nitrites towards the N-nitrosylation of 1a follows
the order tert-butyl nitrite > isopentyl nitrite = isobutyl nitrite > n-butyl nitrite > ethyl nitrite.
Subsequently, solvent studies revealed that non-polar solvents were more effective than polar
solvents (Table 1, entries 10-12). Delightfully, the reaction resulted in 97% yield of 2a when
performed under neat condition (Table 1, entry 13). Notably, under neat conditions, the solid
amide converts into yellow colored liquid N-nitrosoamide which can be easily observed by
naked eyes. With the optimized parameters in hand, we focused our attention on substrate scope
for N-nitrosoamide synthesis (Table 2). N-methylamides containing electron donating groups at –
para and –meta positions provided the respective N-nitrosoamides (2b-2g) in 83% to 96% yields.
Ortho substituted amides regioselectively provided 2h and 2i in 84% and 82% yields after 1.25
h. Amides containing electron withdrawing groups such as –Cl and –Br at –meta and –para
position afforded 2j-2l in 85% to 89% yields. Significantly, strong electron withdrawing group
like 4-nitroamide also provided a good yield of 2m after 1.25 h. Next, N-benzylbenzamide
provided 62% of N-nirosoamide product 2n. However, aliphatic N-methylamide 1o, benzamide
1p, phenylbenzamide 1q and N-tert-butylbenzamide 1r were inactve for nitrosylation.
Interestingly, the external double bond containing N-methylcinnamamide 1s
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 47
1
2
3
4
Table 2 Substrate scope of N-nitrosoamide synthesisa
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReaction conditions: amide 1a-1u (1 mmol) and t-BuONO (1.5 mmol) were stirred at room
temperature. bIsolated yields. c1.25 h, d20 min.
ACS Paragon Plus Environment

Page 7 of 47
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
provided yellow colored crystalline N-methyl-N-nitrosocinnamamide 2s, which was
unambiguously confirmed by an X-ray crystallographic analysis (CCDC 1514778). Furthermore,
the alkynyl and heteroaromatic groups containing N-methylamides reacted smoothly with TBN
and provided 91% and 86% yield of N-nitrosoamides 2t and 2u. Additionally, the present
reaction was scaled up to gram-scale yielding 83% (1.36 g) of 2a and 89% (1.6 g) of 2s.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
b) Carboxylic acid synthesis from N-alkoxyamides
After the successful synthesis of N-nitrosoamide using organonitrite, this protocol was further
extended for the synthesis of carboxylic acids by the hydrolysis of N-alkoxyamides. Generally,
the classical hydrolysis of amides using stoichiometric amount of acid/base as well as catalytic
amount of enzyme/DNA has been documented (Scheme 1, b).5,8a-b,9 However, the
aforementioned protocols require harsh reaction conditions and long reaction time which
suggests the use of TBN for the reaction. To overcome this drawback and extend the scope of
TBN, we selected alkoxyamide as a model substrate and water as a solvent. Interestingly, 97%
yield of benzoic acid 4a was observed within 35 min. The acid formation from amide was easily
observed by the formation of a white colored solid on the surface of water with the simultaneous
liberation of nitrogen. With optimal reaction conditions in hand, we explored the substrate scope
for acid synthesis from respective N-alkoxyamides (Table 3). Various N-methoxyamides such as
aromatic, heteroaromatic as well as aliphatic amides were well tolerated and provided the
respective carboxylic acids in excellent yields. The N-benzyloxyamide reacted smoothly
affording 96% yield of 4a´. Notably, 3a could be transformed into 4a even at gram scale
resulting in 87% yield of the corresponding benzoic acid. The effect of electron donating and
withdrawing groups on aromatic ring was studied using N-methoxy aromatic amide. The amides
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 47
1
2
3
4
5
6
containing electron donating groups such as –Me, –OMe, tert-butyl and –Ph on phenyl ring also
provided the carboxylic acids 4b-4g in 89% to 98% yields.
7
8
9
Table 3. Substrate scope of carboxylic acid synthesis via cleavage of amide C-N bonda
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReaction conditions: amide 3a-3t (1 mmol), t-BuONO (1.5 mmol), H2O (3 mL), room
temperature (29 oC), 35 min. Isolated Yield.
Significantly, the present protocol is easily tolerated with electron withdrawing substituent like –
F –Cl, –I, –CN and –NO2 on N-methoxybenzamide and the carboxylic acids 4h-4l were obtained
ACS Paragon Plus Environment

Page 9 of 47
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
in 72% to 92% yields respectively. This method is also useful for the conversion of
heteroaromatic N-methoxyamides to the respective acids 4m-4p. Moreover, hydrolysis of
aliphatic, alkenyl and alkynyl N-methoxyamides, 3q-3t, could also be satisfactorily carried out.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To investigate the chemoselectivity of amides with TBN, we employed the substrate 3u
containing a primary as well as N-methoxyamide and substrate 3v containing both, an internal
secondary amide and N-methoxyamide. In both the cases, the selective hydrolysis of N-
methoxyamide was observed, while the primary and internal secondary amides were stable
towards hydrolysis (Scheme 2).
Scheme 2. TBN for chemoselective hydrolysis of amides
For better understanding, the selective reactivity of amides with TBN at room temperature for
the synthesis of N-nitrosoamide/acid has been classified into three groups (Scheme 3). The
amides in Group 1 containing electron rich N-substituents show low reactivity. Group 2
contains moderately reactive amides in which N-methylamides exclusively undergo nitrosylation
and N-benzylamides undergo nitrosylation and were further transformed into carboxylic acids.
The amides present in Group 3 show high reactivity towards the hydrolysis reaction as
compared to other groups.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 47
1
2
3
4
Scheme 3. Classification of amides based on reactivity with t-BuONO for the nitrosylation
5
6
and hydrolysis reactions.
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
From these observations, we concluded that the TBN reactivity increases with decreasing
electron deficiency on the nitrogen of the amides.
C) Benzocoumarin synthesisfrom ortho-aryl-N-methoxybenzamide
Inspired by the results obtained with TBN in the case of nitrosylation and hydrolysis of amides,
we further extended this protocol for the synthesis of benzocoumarin. Benzocoumarin and their
derivatives are important scaffolds found in natural products and pharmaceuticals due to their
remarkable biological activity.25 Consequently, extensive efforts have been developed for their
synthesis. Benzocoumarin can be synthesized from ortho-aryl benzoic acid using metal catalyst26
or under metal-free conditions27 using a stoichiometric amount of oxidizing agents (Scheme 1, c).
Based on above one-pot conversion of N-methoxyamide to a carboxylic acid, we tested ortho-
aryl-N-methoxybenzamide 5a as a new substrate for the benzocoumarin synthesis. Guided by
prior reports,26-27 (NH4)2S2O8, Ag2O, Cu(OAc)2, benzo quinone and N-iodosuccinimide (NIS)
o
oxidants were screened in DCE at 60 C for 18 h. Remarkably, even in the absence of oxidant
and solvent, 76% yield of 6a was observed. Assuming the radical reaction pathway, on
ACS Paragon Plus Environment

Page 11 of 47
The Journal of Organic Chemistry
1
2
3
4
decreasing the reaction temperature, 81% (GC Yield) yield of product 6a was observed at 40 oC.
5
6
o
However, decreasing the reaction temperature below 40 C and time less than 18 h, the yield of
7
8
9
product decreased.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Table 4. Substrate scope of benzocoumarin synthesis.a
aReaction conditions: amide (5a-5f, 1 mmol), t-BuONO (1.5 mmol), 40 oC, 18 h. Isolated Yield.
Thus, the optimized reaction conditions for benzocoumarin synthesis was 5a (1 mmol), t-
BuONO (1.5 mmol), at 40 °C for 18 h. The optimized reaction conditions were subsequently
applied for the synthesis of a variety of benzocoumarin from 2-phenyl-N-methoxybenzamide
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 47
1
2
3
4
5
6
derivatives (Table 4). It was found that a variety of 2-phenyl-N-methoxybenzamides could be
converted to the desired product in good yields. The model reaction having N-methoxy, N-
7
8
9
benzyloxy and N-benzyl shows 81%, 78% and 63% isolated yield of product 6a, 6a´ and 6a´´,
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
respectively. The present reaction could also tolerate electron-donating groups. Para-CH3
containing amide 5b provided the 83% yield of 6b. However, the meta-substituted amides 5c and
5d gave a good yield with two regioisomers in ratios of 6c/6c´ 1.6:1 and 6d/6d´ 3.7:1
respectively. Furthermore, the reaction tolerates electron withdrawing groups like –Cl and –Br
resulting in the synthesis of 6e and 6f in 81% and 78% yield respectively. To check the reactivity
o
of amide 5b was stirred by the addition of 1 mmol of N-iodosuccinimide at 80 C for 24 h.
Surprisingly, 2-iodo-3-methyl benzocoumarin 6g was observed instead of 3-methyl
benzocoumarin 6b. Notably, 6g is an important iodo derivative useful for coupling reactions.
d) Isocoumarin synthesis from N-methoxybezoamide
Isocoumarin as a structural motif has attracted attention of synthetic and medicinal chemists due
to numerous biological activities.28 Traditionally, multistep synthesis of isocoumarin has been
well reported.29 Importantly, one pot synthesis of isocoumarin has been developed using
Rh(III)/Ru(II) catalytic system via ortho C-H activation of benzoic acid (Scheme 1, d).30 Of late,
PEG was used as a biodegradable solvent in organic transformations due to the recyclability of
homogeneous transition metal catalytic system.31 We have earlier reported the Ru(II)/PEG-400
catalytic system for isocoumarin synthesis from benzoic acid.32 Considering the importance of
isocoumarins, herein we report N-methoxyamide as a novel surrogate for isocoumarin synthesis
using TBN as oxygen source for the rapid cleavage of the amide C-N bond and the Ru(II)/PEG
catalytic system for ortho-C–H bond activation. The model reaction of N-methoxybenzamide 3a,
ACS Paragon Plus Environment

Page 13 of 47
The Journal of Organic Chemistry
1
2
3
4
TBN and diphenylacetylene 7a was chosen for lactonization in presence of [RuCl2(p-cymene)]2
5
6
(5 mol%), Cu(OAc)2 (0.25 mmol), and AgSbF6 (5 mol%).
7
8
9
Table 5. Substrate scope of the ruthenium-catalyzed isocoumarin synthesisa
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
aReaction conditions: N-methoxybenzamide 3a-3o (0.5 mmol), t-BuONO (0.75 mmol), alkyne
7a – 7d (1 mmol), [{RuCl2(p-cymene)}2] (3 mol%), Cu(OAc)2 (0.25 mmol), AgSbF6 (5 mol%),
PEG-400 (4 mL), Isolated yield.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 47
1
2
3
4
5
6
7
8
9
The reaction proceeded with 89% yield of 8aa in DCE as solvent. The catalyst loading plays a
crucial role, whereby, decreasing the catalyst amount to less than 3 mol% resulted in a lower
yield of 8aa. Next, PEG-400 as a recyclable and green solvent was tested and up to 81% yield of
8aa was observed. However, as compared to PEG-400, in the presence of PEG-600 yield of 8aa
decreases. This might be due to the low solubility of starting material in the latter. In temperature
study, it was observed that by increasing or decreasing the temperature above or below 60 oC, the
yield of 8aa also decreased. Whenever, the reaction time is less than 12 h, the yield of the
product decreases. Thus, the final optimized reaction conditions for isocoumarin synthesis are 3a
(0.5 mmol), diphenylacetylene 7a (1 mmol), t-BuONO (0.7 mmol) [{RuCl2(p-cymene)}2] (3
mol%), Cu(OAc)2 (0.25 mmol), AgSbF6 (10 mol%), PEG-400 (4 mL) at 60 °C for 12 h shown
the 92% (GC Yield) yield of 8aa. With the optimal reaction conditions in hand, we further
explored the detailed substrate scope for isocoumarin synthesis from N-methoxyaromatic amides
with alkyne (Table 5). The model reaction having N-methoxy and N-benzyloxy shows 89% and
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
83% isolated yield of product 8aa and 8a´a, respectively. However, N-benzyl containing amide
was inactive for isocoumarin synthesis. The reaction tolerates a broad range of N-
methoxybenzamide containing various electron donating and withdrawing groups. The electron
donating groups like –Me, –tert-butyl, –OMe and –Ph at para position of N-methoxybenzamide
afforded the corresponding products, 8ba-8ea, in 83% to 91% yields. The reaction proceeded
regioselectively resulting in products 8fa-8ga with exclusively coupling at the less hindered side.
In addition, ortho-substituted aromatic amides such as N-methoxy-2-naphthamide and 2-methyl-
N-methoxybenzamide were also tolerated and the corresponding isocoumarins 8ha and 8ia were
observed in 73% and 78% yield respectively. Next, the halide containing amides at the para
position also provided good yields of 8ja-8la. Notably, the strong electron withdrawing group
ACS Paragon Plus Environment

Page 15 of 47
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
like -NO2 could be tolerated and 8ma was obtained in 57% yield. Moreover, the reactivity study
of heteroarene was carried out and N-methoxyfuran-2-carboxamide led to product 8na in 82%
yield. Next, the substrate containing external double bond (methoxycinnamamide) was studied
and 8oa was obtained in 88% yield. Unfortunately, terminal alkyne (phenylacetylene) was not
effective for the present reaction and 8ab was not observed. After the substrate scope of N-
methoxybenzamides, the comparative reactivity of benzoic acid and N-methoxybenzamide was
checked. The aliphatic internal alkynes, 3-hexyne and 2-butyne, reacted effectively in the case of
N-methoxybenzamide and provided 8ac and 8ad in 78% and 73% yield respectively. However,
they reacted ineffectively when benzoic acid was used as the substrate. After the successful
substrate study for isocoumarin synthesis, the recyclability study of Ru(II) homogeneous catalyst
was carried out. It was observed that the catalytic system was effective up to the 4th recycle [92,
90, 89 and 89% (GC Yield)].
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
To gain insight into the reaction mechanism, we analyzed the TBN mediated functional group
interconversion of amide to acid, using IR spectroscopy (Figure 1). The spectrum (a) and (b)
denotes only TBN and N-methoxybenzamide respectively. The spectrum (c) is the reaction
mixture after 5 min and shows the disappearance of 3216 cm-1 (amide N-H) and 1646 cm-1
(amide C=O) of the amide. At the same time, a new band at 1726 cm-1was observed which
represents the formation of N-nitrosoamideintermediate. After 15 min., the band at 1726 cm-1
disappears and a new band at 1761 cm-1 was observed which represents the formation of 1-
(benzoyloxy)-2-methoxydiazene intermediate (spectrum d). After 25 min., the band 1761 cm-1
disappears with the liberation of N2 and a new band at 1702 cm-1 was observed which
corresponds to C=O of benzoic acid (spectrum e). Finally, after 35 min, the band at 1761 cm-1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 47
1
2
3
4
5
completely disappears and we observed an intense band at 1702 cm-1 that confirmed the
complete conversion into benzoic acid (spectrum f).
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Figure 1. IR spectroscopic observations of TBN for sequential interconversions of amide to acid
via N-nitrosoamide intermediate
A tentative reaction mechanism based on existing literature23c and control experiments has been
proposed (Scheme 4). Initially, the nucleophilic addition of the amide N-H to electron deficient
nitrogen of TBN takes place to generate intermediate A. From the intermediate A, release of the
tBuO- ion results in the formation of intermediate B, which absorbs the proton form intermediate
C and undergoes rearrangement to D.17 D is highly air and moisture sensitive and undergoes
rapid hydrolysis to furnish carboxylic acid 4a. In the case of presence of ortho-aryl functionality
in D, it subsequently forms intermediate E through the expulsion of N2 and OMe radical.26a The
generated OMe radical thus abstracts H radical from intermediate E to affords 6a.
ACS Paragon Plus Environment

Page 17 of 47
The Journal of Organic Chemistry
1
2
3
4
Scheme 4. Plausible Reaction Mechanism
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
In isocoumarin synthesis, the removal of chloride ligand from [RuCl2(p-cymene)]2 complex by
AgSbF6 salt gives active ruthenium species F.32 Then Ru(II) forms a complex with
hexafluoroantimonate which transforms into the five-membered ruthenacycle G by ortho-C-H
bond activation of D with the release of MeOH and N2 (oxidative addition). This is followed by
co-ordination of the ruthenium with diphenylacetylene 7a to form H and subsequent alkyne
insertion which generates the seven-membered intermediate I. The reductive elimination of I
gives the annulated product 8aa. The Ru0 species at the final step is oxidized by Cu(II) to
regenerate the active Ru(II) species for the next catalytic cycle.32
In conclusion, we have applied TBN as a multitask reagent for sequential nitrosylation reactions
for i) the synthesis of N-nitrosoamide from N-alkyl amide under solvent free condition at room
temperature, ii) the synthesis of carboxylic acids from amides under acid/base/metal/oxidant free
condition with short reaction time and water as a green solvent, iii) the synthesis of
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 47
1
2
3
4
5
6
7
8
9
benzocoumarin from ortho-aryl-N-methoxybenzamide under metal/oxidant/solvent free
conditions and iv) one pot synthesis of isocoumarin from N-methoxyaromatic amide using
Ru(II)/PEG-400 as a recyclable catalytic system. Significantly, the protocols described herein
could tolerate a wide substrate scope and could be carried out at gram scale. Importantly, the
developed protocol is environmentally benign due to the formation of t-BuOH, MeOH, and N2 as
non hazardous side products.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
EXPERIMENTAL SECTION
All the nitrite sources, solvents, oxidants, [RuCl2(p-cymene)]2, Cu(OAc)2 and AgSbF6 were
purchased from commercial sources. All reactions were carried out in oven-dried glassware. All
amide derivatives were prepared by literature procedures.1 Analytical TLC was performed with
silica gel plates (0.25 mm thickness). Column chromatography was performed with silica gel
1
(40−200 mesh). NMR spectra were recorded with 400 MHz or 300 MHz H NMR and 126 or
101 MHz or 76 MHz 13C NMR spectrometer. The chemical shifts are reported in parts per
million relative to tetramethylsilane as an internal standard and the coupling constant J in hertz.
The reaction was monitored by GC and TLC. The products were analyzed by GC-MS and IR.
HRMS was recorded on a micromass ESI TOF (time-of-flight) mass spectrometer.
Experimental procedure for N-nitrosoamide synthesis
In oven–dried 10 mL reaction tube equipped with magnetic stir–bar, N-methylbenzamide 1a (1
mmol, 135 mg) and tert-butyl nitrite (1.5 mmol, 155 mg) were added by syringe. The reaction
mixture was stirred at 29 °C (room temperature) for 1 h. After completion of the reaction, all
volatiles were removed under vacuum. The yellow colored oil N-nitrosoamide product 2a was
purified by column chromatography (silica gel, 40−200 mesh) and confirmed by NMR. In gram
ACS Paragon Plus Environment

Page 19 of 47
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
scale synthesis, the N-methylbenzamide 1a (10 mmol, 1.35 g) and tert-butyl nitrite (1.5 mmol,
1.55 g) were added by syringe in oven–dried 100 mL round bottom flask. The reaction mixture
was stirred at 29 °C (room temperature) for 1.25 h. After completion of the reaction, all volatiles
were removed under vacuum. The 1.36 g (83%) of yellow colored oily N-nitrosoamide product
2a was observed.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental procedure for acid synthesis
In oven–dried 10 mL reaction tube equipped with, magnetic stir–bar, N-methoxybenzamide 3a (1
mmol, 151 mg) and tert-btutyl nitrite (1.5 mmol, 155 mg) were added by syringe in 3 mL of
water. The reaction mixture was stirred at 29 °C (room temperature) for 35 min. The colorless
solid benzoic acid product 4a was purified by column chromatography (silica gel, 40−200 mesh).
In gram scale carboxylic acid synthesis, the N-methoxybenzamide 3a (10 mmol, 1.35 g) and
tert-butyl nitrite (1.5 mmol, 1.55 g) were added drop wise in 100 mL round bottom flask at the
cool condition. The reaction mixture was stirred at 29 °C (room temperature) for 45 minutes.
After completion of the reaction, all volatiles were removed under vacuum. The 1.06 g (87%) of
benzoic acid product 4a was observed.
Experimental procedure for benzocoumarin synthesis
In oven–dried 10 mL reaction tube equipped with, magnetic stir–bar, 2-phenyl, N-
methoxybenzamide 5a (1 mmol, 227 mg) and tert-butyl nitrite (1.5 mmol, 155 mg) was added by
syringe. The reaction mixture was stirred at 40 °C for 18 h. After completion of the reaction, all
the volatiles were removed under vacuum. The colorless solid benzocoumarin product 6a was
purified by column chromatography (silica gel, 40−200 mesh). In gram scale benzocoumarin
synthesis, the 2-phenyl, N-methoxybenzamide 5a (6 mmol, 1.36 g) and tert-butyl nitrite (9
mmol, 0.93 g) was added drop wise in 100 mL round bottom flask at the cool condition for 1 h.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 47
1
2
3
4
5
6
7
8
9
Next, reaction was stirred to 29 °C (room temperature) for 18 h. After completion of the reaction,
all the volatiles were removed under vacuum. The 0.7 g (61%) of benzocoumarin product 6a was
observed.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Experimental procedure for Ru(II)/PEG-400 catalyzed isocoumarin synthesis and catalyst
recyclability
In a 15 mL Schlenk tube, N-methoxybenzamide 3a (0.50 mmol, 76 mg) and tert-butyl nitrite (0.8
mmol, 78 mg) were added by syringe. The reaction mixture was stirred at 29 °C (room
temperature) for 35 minutes, followed by added diphenylacetylene 7a (1 mmol, 178 mg),
[RuCl2(p-cymene)]2 (3 mol%, 18 mg), Cu(OAc)2 (0.25 mmol, 45 mg), and AgSbF6 (5 mmol, 17
mg). To the same mixture 4 mL PEG-400 was added and the reaction mixture was stirred at 60
°C for 12 h. After completion of the reaction, the reaction mixture was cooled to room
temperature. Next, 7-8 mL of diethyl ether was added in the same Schlenk tube and was shaken
for 2-3 minutes. The upper layer containing product mixture was transferred to 150 mL round
bottom flask and the process was repeated for 3-4 times. All volatiles were removed from the
product mixture under vacuum. The colorless solid isocoumarin product 8aa was purified by
column chromatography (silica gel, 40−200 mesh). In the recyclability study, the lower layer of
o
PEG-400 containing catalytic system was heated at 40-50 C for 10 minutes to remove the
miscible diethyl ether and transferred back to the Schlenk tube containing stirred mixture of N-
methoxybenzamideand tert-butyl nitrite for the next cycle.
N-methyl-N-nitrosobenzamide (2a)20a
Yellow oil. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20 v/v)
mixture as eluent. Isolated yield: 97% (159 mg). 1H NMR (400 MHz, CDCl3) δ 7.73 (d, J = 7.5
ACS Paragon Plus Environment

Page 21 of 47
The Journal of Organic Chemistry
1
2
3
4
5
Hz, 2H), 7.53 (t, J = 7.3 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 3.25 (s, 3H). 13C{1H}NMR (101 MHz,
CDCl3) δ 172.8, 132.7, 132.5, 130.7, 128.1, 26.8. IR (ATR) ν (cm−1) 1704, 1495, 1342, 961.
6
7
8
9
N,4-dimethyl-N-nitrosobenzamide (2b)19
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Yellow oil. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20 v/v)
mixture as eluent. Isolated yield: 96% (167 mg). 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 8.0
Hz, 2H), 7.23 (d, J = 7.9 Hz, 2H), 3.24 (s, 3H), 2.38 (s, 3H). 13C{1H}NMR (101 MHz, CDCl3) δ
172.5, 143.4, 130.9, 129.8, 128.8, 26.8, 21.5. IR (ATR)ν (cm−1) 1698, 1497, 1339, 1160, 959.
4-(tert-butyl)-N-methyl-N-nitrosobenzamide (2c)
Yellow oil. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20 v/v)
mixture as eluent. Isolated yield: 94% (206 mg). 1H NMR (400 MHz, CDCl3) δ 7.72 (d, J = 8.3
Hz, 2H), 7.47 (d, J = 8.4 Hz, 2H), 3.25 (s, 3H), 1.32 (s, 9H). 13C{1H}NMR (101 MHz, CDCl3) δ
172.4, 156.2, 130.9, 129.8, 125.1, 35.0, 31.0, 26.8. IR (ATR)ν (cm−1) 1701, 1497, 1335, 1167,
960, 804. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C12H16N2O2Na 243.1103; found
243.1104.
4-methoxy-N-methyl-N-nitrosobenzamide (2d)19
Yellow oil. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20 v/v)
mixture as eluent. Isolated yield: 89% (172 mg). 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.3
Hz, 2H), 6.90 (d, J = 8.3 Hz, 2H), 3.80 (s, 3H), 3.22 (s, 3H). 13C{1H}NMR (101 MHz, CDCl3) δ
171.5, 163.2, 133.4, 124.6, 113.5, 55.4, 27.0. IR (ATR)ν (cm−1) 1688, 1497, 1255, 1159, 1020,
958.
N,3-dimethyl-N-nitrosobenzamide (2e)
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 47
1
2
3
4
Yellow oil. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20 v/v)
5
6
mixture as eluent. Isolated yield: 91% (161 mg). 1H NMR (400 MHz, CDCl3) δ 7.56 – 7.51 (m,
7
8
13
2H), 7.37 – 7.30 (m, 2H), 3.26 (s, 3H), 2.38 (s, 3H). C{1H}NMR (101 MHz, CDCl3) δ 173.0,
9
138.0, 133.3, 132.7, 131.1, 128, 127.9, 26.8, 21.2. IR (ATR)ν (cm−1) 1700, 1503, 1342, 1163,
970, 727. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C9H10N2O2Na 201.0634; found
201.0634.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3,4-dimethoxy-N-methyl-N-nitrosobenzamide (2f)
Yellow oil. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (70:30 v/v)
mixture as eluent. Isolated yield: 83% (185 mg). 1H NMR (400 MHz, CDCl3) δ 7.37 – 7.34 (m,
2H), 6.86 (d, J = 8.3 Hz, 1H), 3.88 (s, 3H), 3.85 (s, 3H), 3.27 – 3.15 (m, 3H). 13C{1H}NMR (101
MHz, CDCl3) δ 171.5, 152.9, 148.5, 125.8, 124.6, 113.5, 109.9, 55.98, 55.9, 27.1. IR (ATR)ν
(cm−1) 1695, 1597, 1493, 1341, 1243, 1132, 988, 746. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C10H12N2O4Na 247.0690; found 247.0689.
N-methyl-N-nitroso-2-naphthamide (2g)
Yellow oil. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20 v/v)
1
mixture as eluent. Isolated yield: 93% (199 mg). H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H),
7.85 (dt, J = 19.1, 7.6 Hz, 4H), 7.54 (dt, J = 14.8, 7.2 Hz, 2H), 3.34 (s, 3H). 13C{1H}NMR (101
MHz, CDCl3) δ 172.8, 135.0, 132.5, 132.1, 129.9, 129.3, 128.5, 127.9, 127.7, 126.9, 126.3, 27.0.
IR (ATR)ν (cm−1) 1704, 1479, 1335, 1155, 1002, 921, 781, 754. HRMS (ESI-TOF) m/z: [M +
Na]+ Calcd for C12H10N2O2Na 237.0654; found 237.0634.
N,2-dimethyl-N-nitrosobenzamide (2h)
ACS Paragon Plus Environment

Page 23 of 47
The Journal of Organic Chemistry
1
2
3
4
Yellow oil. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20 v/v)
5
6
mixture as eluent. Isolated yield: 84% (149 mg). 1H NMR (400 MHz, CDCl3) δ 7.35 (d, J = 8.2
7
8
13
Hz, 2H), 7.29 – 7.18 (m, 2H), 3.25 (s, 3H), 2.29 (s, 3H). C{1H}NMR (101 MHz, CDCl3) δ
9
174.5, 136.1, 133.9, 130.6, 130.6, 128.4, 125.4, 26.0, 19.7. IR (ATR)ν (cm−1) 1707, 1502, 1340,
1167, 956, 735. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C9H10N2O2Na 201.0632; found
201.0634.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-methyl-N-nitroso-[1,1'-biphenyl]-2-carboxamide (2i)
Yellow oil. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20 v/v)
mixture as eluent. Isolated yield: 82% (196 mg). 1H NMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.5
Hz, 1H), 7.59 – 7.52 (m, 1H), 7.45 (dd, J = 13.1, 7.5 Hz, 2H), 7.36 – 7.20 (m, 5H), 2.91 (s, 3H).
13C{1H}NMR (101 MHz, CDCl3) δ 175.1, 141.3, 140.1, 133.8, 131.0, 129.6, 128.7, 128.5,
128.2, 127.7, 127.3, 25.7. IR (ATR)ν (cm−1) 1707, 1504, 1344, 1167, 962, 742. HRMS
(ESI-TOF) m/z: [M + Na]+ Calcd for C14H12N2O2Na 263.0792; found 263.0791.
N,4-dimethyl-N-nitrosobenzamide (2j)
Yellow oil. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20 v/v)
1
mixture as eluent. Isolated yield: 85% (168 mg). H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H),
7.61 (d, J = 7.7 Hz, 1H), 7.51 (dd, J = 8.0, 1.0 Hz, 1H), 7.38 (t, J = 7.9 Hz, 1H), 3.26 (s, 3H).
13C{1H}NMR (101 MHz, CDCl3) δ 171.6, 134.3, 134.2, 132.4, 130.5, 129.4, 128.7, 26.8. IR
(ATR)ν (cm−1) 1701, 1496, 1340, 1144, 971, 777, 734. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd
for C8H7ClN2O2Na 221.0091; found 221.0088.
4-chloro-N-methyl-N-nitrosobenzamide (2k)19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 47
1
2
3
4
5
6
7
8
9
Yellow oil. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20 v/v)
mixture as eluent. Isolated yield: 89% (176 mg). 1H NMR (400 MHz, CDCl3) δ 7.78 – 7.57 (m,
2H), 7.54 – 7.22 (m, 2H), 3.24 (s, 3H). 13C{1H}NMR (101 MHz, CDCl3) δ 171.7, 138.9, 132.2,
130.9, 128.5, 26.8. IR (ATR)ν (cm−1) 1708, 1588, 1488, 1397, 1342, 1164, 963, 804.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-bromo-N-methyl-N-nitrosobenzamide (2l)
Yellow solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20 v/v)
mixture as eluent. Isolated yield: 85% (206 mg). mp 86 – 88 oC. 1H NMR (400 MHz, CDCl3) δ
7.65 – 7.58 (m, 2H), 7.58 – 7.47 (m, 2H), 3.23 (s, 3H). C{1H}NMR (101 MHz, CDCl3) δ
13
171.8, 132.2, 131.4, 131.1, 127.5, 26.8. IR (ATR)ν (cm−1) 1708, 1582, 1497, 1394, 1160, 1069,
946. HRMS (ESI-TOF) m/z: [M + Na]+ Calcd for C8H7BrN2O2Na 264.9579; found 264.9583.
N-methyl-4-nitro-N-nitrosobenzamide (2m)19
Yellow solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (70:30 v/v)
mixture as eluent. Isolated yield: 67% (140 mg). 1H NMR (400 MHz, CDCl3) δ 8.40 – 8.20 (m,
2H), 7.89 (d, J = 8.4 Hz, 2H), 3.34 – 3.25 (m, 3H). C{1H}NMR (101 MHz, CDCl3) δ 171.4,
13
149.7, 138.4, 131.4, 123.3, 26.7. IR (ATR)ν (cm−1) 1711, 1514, 1488, 1346, 1167, 960.
N-benzyl-N-nitrosobenzamide (2n)19
Yellow oil. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20 v/v)
mixture as eluent. Isolated yield: 62% (148 mg). 1H NMR (400 MHz, CDCl3) δ 7.82 – 7.75 (m,
2H), 7.57 (dd, J = 10.7, 4.1 Hz, 1H), 7.47 (t, J = 7.5 Hz, 2H), 7.36 – 7.24 (m, 5H), 5.13 (s, 2H).
13C{1H}NMR (101 MHz, CDCl3) δ 172.9, 134.6, 132.9, 132.6, 130.7, 128.7, 128.5, 128.2,
127.9, 42.9. IR (ATR)ν (cm−1) 1698, 1497, 1346, 1159, 951, 800.
N-methyl-N-nitrosocinnamamide (2s)
ACS Paragon Plus Environment

Page 25 of 47
The Journal of Organic Chemistry
1
2
3
4
Yellow solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20 v/v)
5
6
7
8
o
1
mixture as eluent. Isolated yield: 96% (182 mg). mp = 100 – 102 C. H NMR (400 MHz,
CDCl3) δ 7.97 (d, J = 15.8 Hz, 1H), 7.80 (d, J = 15.8 Hz, 1H), 7.63 – 7.55 (m, 2H), 7.38 (d, J =
4.7 Hz, 3H), 3.17 (s, 3H). 13C{1H}NMR (101 MHz, CDCl3) δ 168.5, 147.2, 134.3, 130.9, 128.9,
128.6, 115.5, 25.8. IR (ATR)ν (cm−1) 1695, 1624, 1475, 1206, 1023, 956. HRMS (ESI-TOF)
m/z: [M + H]+ Calcd for C10H12N2O2 191.0742; found 191.0813.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
N-methyl-N-nitroso-3-phenylpropiolamide (2t)
Yellow oil. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20 v/v)
1
mixture as eluent. Isolated yield: 91% (171 mg). H NMR(400 MHz, CDCl3) δ 7.73 – 7.67 (m,
2H), 7.42 – 7.31 (m, 3H), 3.13 (s, 3H). C{1H}NMR (101 MHz, CDCl3) δ166.0, 147.8, 136.9,
13
133.1, 131.1, 128.7, 127.4, 118.3, 114.5, 25.6. IR (ATR)ν (cm−1) 1702, 1490, 1027. HRMS
(ESI-TOF) m/z:[M + Na]+ Calcd for C10H8N2NaO2211.0477; found 211.0478.
N-methyl-N-nitrosofuran-3-carboxamide (2u)
Yellow oil. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20 v/v)
mixture as eluent. Isolated yield: 86% (132 mg). 1H NMR(400 MHz, CDCl3) δ 8.07 (s, 1H), 7.46
(t, J = 1.5 Hz, 1H), 7.02 – 6.94 (m, 1H), 3.24 (s, 3H). 13C{1H}NMR (101 MHz, CDCl3) δ165.38,
149.76, 143.12, 119.49, 111.70, 26.39. IR (ATR)ν (cm−1) 1704, 1408, 1163, 956, 802. HRMS
(ESI-TOF) m/z:[M + H]+ Calcd for C6H7N2O3 155.0448; found 155.0451.
Benzoic acid (4a)34a
Colourless solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20
1
v/v) mixture as eluent. Isolated yield: 97% (118 mg). H NMR (300 MHz, CDCl3) δ 13.09 (s,
1H), 8.19 (d, J = 7.7 Hz, 2H), 7.66 (t, J = 7.3 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H). C{1H}NMR
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 47
1
2
3
4
(75 MHz, CDCl3) δ 172.8, 133.9, 130.3, 129.4, 128.5. GCMS (EI, 70 eV) m/z (%) 122.00
5
6
(99.86), 105.00 (100), 77.00 (59.51), 51.00 (21.23). IR (ATR)ν (cm−1) 1680, 1449, 1323, 1288,
7
8
704.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4-methylbenzoic acid (4b)34a
Colourless solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20
1
v/v) mixture as eluent. Isolated yield: 96% (130 mg). H NMR(300 MHz, CDCl3) δ 12.42 (s,
1H), 8.05 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 7.9 Hz, 2H), 2.46 (s, 3H). C{1H}NMR (75 MHz,
13
CDCl3) δ 172.5, 144.7, 130.3, 129.2, 126.6, 21.7. GCMS (EI, 70 eV) m/z (%) 136.00 (92.22),
118.00 (100), 91.05 (69.44), 65.00 (19.18). IR (ATR)ν (cm−1)1672, 1404, 1269, 904, 733.
4-(tert-butyl)benzoic acid (4c)34b
Colourless solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20
1
v/v) mixture as eluent. Isolated yield: 96% (170 mg). H NMR (300 MHz, CDCl3) δ 12.27 (s,
1H), 8.10 (d, J = 8.3 Hz, 2H), 7.53 (d, J = 8.6 Hz, 2H), 1.39 (s, 9H). C{1H}NMR (75 MHz,
13
CDCl3) δ 172.6, 157.6, 130.2, 126.6, 125.4, 35.2, 31.1. GCMS (EI, 70 eV) m/z (%) 177.95
(20.42), 163.00 (100), 135.00 (35.34), 115.00 (5.89), 91.00 (24.55), 77.00 (7.42). IR (ATR)ν
(cm−1) 1679, 1419, 1285, 933, 706.
3,4-dimethoxybenzoic acid (4d)34a
Colourless solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (70:30
1
v/v) mixture as eluent. Isolated yield: 89% (161 mg). H NMR (300 MHz, CDCl3) δ 11.50 (s,
1H), 7.80 (dd, J = 8.4, 2.0 Hz, 1H), 7.61 (d, J = 1.9 Hz, 1H), 6.93 (d, J = 8.5 Hz, 1H), 3.97 (d, J
13
= 1.9 Hz, 6H). C{1H}NMR (75 MHz, CDCl3) δ 172.1, 153.8, 148.9, 124.6, 121.7, 112.3,
ACS Paragon Plus Environment

Page 27 of 47
The Journal of Organic Chemistry
1
2
3
4
5
6
110.3, 56.1, 56.0. GCMS (EI, 70 eV) m/z (%) 182.00 (100), 166.95 (35.87), 111.00 (20.02),
95.00 (16.19), 77.00 (19.14). IR (ATR)ν (cm−1) 1669, 1586, 1420, 1234, 758.
7
8
9
[1,1'-biphenyl]-4-carboxylic acid (4e)34b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Colourless solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20
v/v) mixture as eluent. Isolated yield: 97% (192 mg). 1H NMR (300 MHz, DMSO) δ 8.08 – 7.96
13
(m, 2H), 7.63 – 7.51 (m, 4H), 7.44 – 7.26 (m, 3H). C{1H}NMR(75 MHz, DMSO) δ 168.1,
145.1, 139.9, 130.3, 129.8, 128.9, 128.1, 127.2, 126.9. GCMS (EI, 70 eV) m/z (%) 197.90
(98.48), 181.95 (43.54), 166.90 (56.18), 153.00 (46.96), 121.00 (43.57), 65.00 (100). IR (ATR)ν
(cm−1)1672, 1420, 1286, 932, 746.
2-naphthoic acid (4f)34b
Colourless solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20
1
v/v) mixture as eluent. Isolated yield: 98% (168 mg). H NMR (300 MHz, CDCl3) δ 8.76 (s,
1H), 8.16 (dd, J = 8.6, 1.4 Hz, 1H), 8.02 (d, J = 7.9 Hz, 1H), 7.94 (dd, J = 8.1, 5.3 Hz, 2H), 7.63
(dt, J = 15.6, 6.8 Hz, 2H). 13C{1H}NMR (75 MHz, CDCl3) δ 172.2, 135.9, 132.5, 132.2, 129.6,
128.7, 128.3, 127.8, 126.8, 126.6, 125.4. GCMS (EI, 70 eV) m/z (%) 172.00 (77.62), 155.05
(67.47), 127.05 (100), 102.05 (20.71), 63.00 (57.98). IR (ATR)ν (cm−1) 1682, 1299, 777, 758.
2-methylbenzoic acid (4g)34a
Colourless solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20
v/v) mixture as eluent. Isolated yield: 94% (127 mg). 1H NMR (300 MHz, CDCl3) δ 8.12 (d, J =
7.6 Hz, 1H), 7.54 – 7.45 (m, 1H), 7.33 (dd, J = 10.6, 3.9 Hz, 2H), 2.71 (s, 3H). 13C{1H}NMR (75
MHz, CDCl3) δ 173.6, 141.4, 133.0, 131.9, 131.6, 128.4, 125.9, 22.2. GCMS (EI, 70 eV) m/z
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 47
1
2
3
4
(%) 136.00 (89.61), 118.05 (100), 91.05 (70.42), 65.00 (19.71). IR (ATR)ν (cm−1) 2637, 1673,
5
6
1406, 1270, 739.
7
8
9
4-fluorobenzoic acid (4h)34b
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Colourless solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20
1
v/v) mixture as eluent. Isolated yield: 92% (128 mg). H NMR (400 MHz, DMSO) δ 13.00 (s,
13
1H), 8.09 – 7.85 (m, 2H), 7.25 (dd, J = 12.0, 5.5 Hz, 2H). C{1H}NMR (101 MHz, DMSO) δ
166.8 (s), 166.6 (s), 164.1 (s), 132.5 (d, J = 9.4 Hz), 127.8 (d, J = 2.7 Hz), 116.1 (s), 115.8 (s).
GCMS (EI, 70 eV) m/z (%) 140.00 (82.28), 123.00 (100), 95.00 (57.12), 63.00 (22.77). IR
(ATR) ν (cm−1) 1676, 1602, 1293, 1156, 885, 767.
4-chlorobenzoic acid (4i)34b
Colourless solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20
1
v/v) mixture as eluent. Isolated yield: 92% (134 mg). H NMR (400 MHz, DMSO) δ 13.06 (s,
13
1H), 7.89 (dd, J = 8.4, 3.7 Hz, 2H), 7.61 – 7.37 (m, 2H). C{1H}NMR (101 MHz, DMSO) δ
166.8, 138.2, 131.5, 131.5, 130.0, 129.1, 129.1. GCMS (EI, 70 eV) m/z (%) 155.95 (46.52),
138.95 (94.28), 110.95 (48.87), 63.00 (100). IR (ATR)ν (cm−1) 1679, 1406, 1311, 1265, 904,
741.
2-iodobenzoic acid (4j)34c
Colourless solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20
1
v/v) mixture as eluent. Isolated yield: 72% (178 mg). H NMR (300 MHz, DMSO) δ 8.78 (s,
1H), 7.86 (dd, J = 7.9, 1.0 Hz, 1H), 7.73 (dd, J = 7.8, 1.7 Hz, 1H), 7.30 (td, J = 7.6, 1.2 Hz, 1H),
13
7.03 (td, J = 7.7, 1.7 Hz, 1H). C{1H}NMR (75 MHz, DMSO) δ 168.2, 141.0, 135.9, 132.3,
130.8, 128.2, 127.9, 93.9. GCMS (EI, 70 eV) m/z (%) 248.00 (7.51), 207.10 (7.97), 164.10
ACS Paragon Plus Environment

Page 29 of 47
The Journal of Organic Chemistry
1
2
3
4
(57.83), 148.15 (100), 120.15 (31.52), 103.10 (45.23). IR (ATR)ν (cm−1) 1672, 1581, 1265,
5
6
1014, 735.
7
8
9
4-cyanobenzoic acid (4k)34a
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Colourless solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (70:30
1
v/v) mixture as eluent. Isolated yield: 87% (128 mg). H NMR (400 MHz, DMSO) δ 13.37 (s,
13
1H), 7.95 (d, J = 4.5 Hz, 2H), 7.85 (d, J = 6.3 Hz, 2H). C{1H}NMR (101 MHz, DMSO) δ
166.4, 135.2, 133.0, 130.3, 118.6, 115.5. GCMS (EI, 70 eV) m/z (%) 147.00 (41.03), 130.00
(100), 102.00 (52.55), 78.00 (35.53), 63.00 (54.52). IR (ATR)ν (cm−1) 1690, 1430, 1287, 932,
768.
4-nitrobenzoic acid (4l)34a
Colourless solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (70:30
v/v) mixture as eluent. Isolated yield: 83% (138 mg). 1H NMR (300 MHz, DMSO) δ 8.23 – 8.15
13
(m, 2H), 8.15 – 8.06 (m, 2H). C{1H}NMR (75 MHz, DMSO) δ 166.3, 150.2, 136.8, 130.8,
123.4. GCMS (EI, 70 eV) m/z (%) 166.90 (55.73), 138.95 (29.77), 121.00 (45.63), 95.00
(33.85), 65.00 (100). IR (ATR)ν (cm−1) 1685, 1539, 1276, 714.
furan-3-carboxylic acid (4m)34a
Colourless solid. Isolated through 40-200 mesh silica gel using pet ether: ethyl acetate (80:20
v/v) mixture as eluent. Isolated yield: 104% (154 mg). 1H NMR (300 MHz, DMSO) δ 7.93 (dd,
J = 1.4, 0.7 Hz, 1H), 7.37 (t, J = 1.7 Hz, 1H), 6.62 (dd, J = 1.9, 0.7 Hz, 1H). 13C{1H}NMR (75
MHz, DMSO) δ 164.7, 147.6, 143.7, 120.0, 109.9. GCMS (EI, 70 eV) m/z (%) 112.05 (90.39),
95.05 (66.02), 78.05 (91.16), 63.00 (100). IR (ATR)ν (cm−1) 1679, 1469, 1293, 1016, 754.
9H-xanthene-9-carboxylic acid (4n)35a
ACS Paragon Plus Environment