Regioselective Nitration of N-Alkyl Anilines using tert-Butyl Nitrite under Mild Condition

Article abstract of DOI:10.1021/acs.joc.8b02377

Regioselective ring nitration of N-alkyl anilines is reported using tert-butyl nitrite. The reactions proceed efficiently with a wide range of substrates providing synthetically useful N-nitroso N-alkyl nitroanilines in excellent yields which can be easily converted into N-alkyl phenylenediamines and N-alkyl nitroanilines using Zn-AcOH and HCl/MeOH, respectively.

Full text of DOI:10.1021/acs.joc.8b02377

Subscriber access provided by University of Winnipeg Library
Article
Regioselective nitration of N-alkyl anilines
using tert-butyl nitrite under mild condition
Priyanka Chaudhary, Surabhi Gupta, Nalluchamy Muniyappan,
Shahulhameed Sabiah, and Jeyakumar Kandasamy
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02377 • Publication Date (Web): 12 Dec 2018
Downloaded from http://pubs.acs.org on December 12, 2018
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 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 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.
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 48
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Regioselective nitration of N-alkyl anilines using tert-butyl
nitrite under mild condition
Priyanka Chaudhary,a Surabhi Gupta,a Nalluchamy Muniyappan,b Shahulhameed
Sabiahb and Jeyakumar Kandasamya*
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
aDepartment of chemistry, Indian Institute of Technology (BHU), Varanasi, Uttar Pradesh-221005;
bDepartment of chemistry, Pondicherry University, Pondicherry-605014
NO2
NO2
"Denitrosation"
R2
H
N
R2
H
HCl,
O
O
N
N
N
R1
R1
NO
CH3CN, 80 oC
3-6 h
CH3OH
R2
R1
R1=H, Alkyl
N-Alkyl Nitroanilines
N-Nitroso N-alkyl nitroanilines
R2=Benzyl/alkyl
Zn, AcOH
CH3OH
"Denitrosation
followed by reduction"
‡ Direct nitration of N-alkyl aniline
‡ Metal-Free nitration
‡ 70%-91% Yield
NH2
H
‡ 43 Examples
N
R1
R2
N-Alkyl o-phenylenediamines
Abstract: Regioselective ring nitration of N-alkyl anilines is reported using tert-butyl nitrite.
The reactions proceed efficiently with a wide range of substrates providing synthetically useful
N-nitroso N-alkyl nitroanilines in excellent yields which can be easily converted into N-alkyl
phenylenediamines and N-alkyl nitroanilines using Zn-AcOH and HCl/MeOH, respectively.
Introduction
Nitroarenes are not only important starting materials but also structural motifs of many bioactive
molecules and natural products.1 In fact, nitroaromatic compounds play an important role in
chemical industry to generate various consumer products.2 In this context, nitroanilines were
found widespread applications in organic synthesis as building blocks.1-2 N-Alkyl nitroanilines
are the direct source of mono-N-alkylated phenylenediamines that are used extensively in the
preparation of various bioactive molecules and heterocycles such as benzimidazoles,
benzotriazoles, benzodiazepines, etc. (Figure 1).3 N-Alkyl nitroanilines are typically prepared
through a multistep synthesis from corresponding anilines involving protection and deprotection
steps. Alternatively, these compounds have been prepared from corresponding nitro aryl halides
through SNAr reaction with different amines.1 However, unlike anilines, only limited number
functionalized nitro aryl halides are commercially available while some of them are expensive.
1
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 48
1
2
3
4
5
6
7
8
9
Despite having many methods for the nitration of N-protected anilines (i.e. N-acyl and N-
sulfonyl anilines),4 nitration of N-alkyl anilines is as yet unexplored. Nevertheless, development
of such protocols will allow a short and quick access to N-alkyl nitroanilines. In 1908, Tingle et
al. made a brief study on the direct nitration of N-alkyl anilines by using the classical nitration
methods.5 This study demonstrated that N-alkyl anilines behave similarly to unprotected anilines6
and provide tarry oxidation products as well as inconsistent regio-nitrated products for different
N-alkyl substituents. For example, nitration of N-methylaniline provides m-nitro N-methylaniline
while N-ethylaniline provides p-nitro N-ethylaniline in the presence of HNO3/H2SO4.5
R1
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
R1
N
N
O
N
N
H
R1
HN
H
O2N
R1
N
N
R1
R
N
H
N
R1
H2N HN
R1
N
N
R1=Alkyl and Benzyl
N
N
O
N
R1
Figure 1. Synthetic importance of nitroanilines.
Scheme 1. Developed approaches for the synthesis of N-alkyl nitroanilines and N-alkyl
phenylenediamines.
H
R1
N
NH2
Zn/AcOH
R1
R1
R1
MeOH
H
NO
N-alkyl
N
N
o-phenylenediamines
NO2
t-BuONO
CH3CN
H
R1
HCl/MeOH
N
R2
R2
NO2
R1= H, Alky, Aryl
R2 = H, Alkyl, Aryl, halogens, etc.
R1
N-alkyl
o-nitroanilines
tert-Butyl nitrite (TBN) is a radical nitrating agent that has been explored in different organic
transformations.7 An efficient transformation of anilines to corresponding aryl azides was
2
ACS Paragon Plus Environment

Page 3 of 48
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
successfully demonstrated by Moses et al. using TBN and TMS-N3.7b Subsequently, nitration of
phenols,7c alkenes,7d alkynes,7e sulfonanilides4a and acetanilides4b were achieved using TBN.
Recently, N-nitrosation of amides using tert-butyl nitrite was demonstrated by Bhanage et al.
under mild condition.7f tert-Butyl nitrite is an efficient nitrogen transfer reagent that has been
employed as a source of nitrogen in many organic reactions.7g-i It is an acid-free reagent which
produces tert-butanol as the only by-product, hence attracted many organic chemists. In the last
few years, our research group has focused on the chemistry of N-nitrosamines8 and recently
demonstrated the N-nitrosation of secondary amines,8a oxidative dimerization of thioamides8d
and triazolation of o-phenylenediamines8e using tert-butyl nitrite under mild condition. In this
context, here we disclose tert-butyl nitrite mediated ring nitration of N-alkyl anilines under
catalyst and acid free conditions. This reaction provides N-nitroso N-alkyl nitroanilines in
excellent yields which can be easily converted into N-alkyl phenylenediamines and N-alkyl
nitroanilines in a single step using Zn-AcOH/MeOH and HCl/MeOH respectively (Scheme 1).
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 conditions.a,b
Bn NO
N
Bn
NO
Bn
H
N
N
N
O
O
NO2
+
Solvent, Temp.
OCH3
OCH3
OCH3
2a
2aa
1aa
Temp.
(oC)
S.No. Solvent
Time
Yield (%)b
TBN
(eq.)
2a
>95
89
2aa
ndc
ndc
no solvent
CH3CN
RT
RT
1
2
1.0
1.0
10 min
10 min
RT
RT
94
ndc
ndc
3
4
CH3CN
CH3CN
2.0
3.0
10 min
10 min
>97
RT
RT
RT
5
6
7
CH3CN
CH3CN
CH3CN
3.0
3.0
3.0
30 min
3 h
84
63
29
11
31
71
12 h
8
DCE
3.0
3.0
3.0
RT
RT
RT
12 h
12 h
12 h
64
59
75
30
35
20
9
1,4-dioxane
THF
10
ndc
80
11
12
RT
50
MeOH
94
13
3.0
3.0
12 h
3 h
CH3CN
CH3CN
13
80
15
89
3.0
3 h
14
CH3CN
4.0
80
1 h
ndc
94
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 48
1
2
3
4
5
aReaction conditions: Aniline 1aa (1.0 mmol) and TBN were stirred in acetonitrile (8 mL).
bIsolated yields. cNot detected in TLC.
6
7
8
9
Results and Discussion
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-Methoxy N-benzyl aniline (1aa) was chosen as the model substrate for the optimization study
and subjected for ring nitration in the presence of different equiv. of tert-butyl nitrite (TBN).
Initially, the reaction was attempted with 1.0 to 3.0 equiv. TBN under solvent free condition as
well as in acetonitrile for 10 minutes at room temperature. All these reactions provided N-
nitrosamine 2a as the only product. However, when the reaction was allowed to stir for longer
time with 3.0 equiv. of tert-butyl nitrite, formation of a new product was observed along with N-
nitrosamine 2a. It is noteworthy that the yield of new product was increased subsequently with
the time. For instance, at 10 mins, the N-nitrosamine 2a was observed as the only product, but
after 30 mins the new product was formed in 11 % yield which was subsequently increased to
71% after 12 h (Table 1, entries 2-7). To our delight, the resulting product has been identified as
N-nitroso N-benzyl 2-nitro 4-methoxyaniline (2aa) through NMR and Mass.
4
ACS Paragon Plus Environment

Page 5 of 48
The Journal of Organic Chemistry
1
2
3
4
Figure 2. Low temperature NMR studies of compound 2aa.
5
6
7
8
In general, N-nitrosamines exhibit two orientations, (i.e. syn and anti) due to restricted rotation of
the N-N bond. In this context, the compound 2aa shows two isomers in ~3:2 ratio, which are
inseparable in column chromatography (Figure 2, 2aa-I and 2aa-II). It is very interesting to note
that one of the isomer (i.e. 2aa-I or 2aa-II) displays some structural dynamics in solution as seen
in 1H NMR. For instance, the N-benzylic methylene protons (Hc & Hd) of one isomer appeared at
5.2 ppm as singlet while other isomer did not show any signal (for the benzylic methylene
protons) at room temperature. In order to reveal the structural dynamics, 1H NMR was measured
at low temperatures, i.e. 0 °C, -30 °C and -60 °C. To our delight, at 0 °C the benzylic protons
appeared as broad signals at 5.5 ppm and 6.3 ppm (Ha & Hb) that split as doublets at -30 °C and -
60 °C (Figure 2).
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
Nevertheless, a selective denitrosation of the product 2aa using I2/Et3SiH8c gave the N-benzyl 2-
nitro 4-methoxyaniline (4aa) in quantitative yield with the structure confirmed by NMR, Mass
and single crystal XRD (Scheme 2).9
Scheme 2. Denitrosation of N-nitrosamine 2aa.
Bn
ON
I2 (cat.)
Et3SiH
N
NO2
CH2Cl2, rt
95%
OCH3
2aa
CCDC: 1836064
4aa
Understanding the novelty of this transformation, the reaction was further optimized in other
solvents such as DCE, 1,4-dioxane, THF and methanol with 3.0 equiv. TBN for 12 h at room
temperature (Table 1, entries 8-11). However, these solvents provide the desired product 2aa in
a low yield when compared with acetonitrile. In fact, the desired product 2aa was not detected in
methanol. Hence, the reaction was further investigated in acetonitrile at elevated temperatures,
i.e. 50 °C and 80 °C with 3-4 equiv. of TBN (Table 1, entries 12-14). To our delight, the desired
product 2aa was obtained in 94% yield with 4 equiv. of TBN at 80 °C within 1 h time (Table 1,
entry 14).
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 48
1
2
3
4
5
6
7
8
9
Having established the optimized condition, we further investigated the potential application of
this method with different N-alkyl and benzyl anilines (Schemes 3-5). Initially, the ring nitration
of p-substituted N-alkyl and benzyl anilines was studied under optimized condition (Scheme 3).
Anilines bearing electron donating groups (e.g. methyl and methoxy) as well as electron
withdrawing groups (e.g. chlorine and bromine) underwent ring nitration smoothly and gave o-
nitrated products in 72-84% yields within 3 h (Scheme 3, 2ab-2az). It was observed that fluorine
functionalized anilines required slightly longer time i.e. 6 h for the nitration process (Scheme 3,
2ag and 2ao).
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
Scheme 3. Nitration of various p-substituted N-alkyl anilines.a,b
6
ACS Paragon Plus Environment

Page 7 of 48
The Journal of Organic Chemistry
1
2
3
4
R2
H
ON
R2
N
N
NO2
5
TBN (4 equiv.)
6
7
CH3CN, 80 oC
3 h
R1
R1
2ab-2az
8
1ab-1az
9
Bn
ON
Bn
ON
ON
Bn
ON
CH3
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
ON
CH3
N
F
N
CH3
N
ON
N
N
N
NO2
NO2
NO2
NO2
NO2
NO2
Cl
CH3
Cl
CH3
2ab:
OCH3
2ac:
c
2ae:
84%
Br
81%
2af:
83%
82%
2ag:
72%
2ad:
80%
CH3
SCH3
Cl
CH3
OCH3
ON
ON
ON
ON
ON
N
ON
N
N
N
N
N
NO2
NO2
NO2
NO2
NO2
NO2
OCH3
2ak:
OCH3
2aj:
CH3
CH3
CH3
2ah:
OCH3
80%
2al:
2am:
81%
79%
H3C
83%
84%
2ai:
85%
CH3
Br
OCH3
CH3
CH3
Br
CF3
ON
ON
ON
ON
ON
ON
ON
N
N
N
N
N
N
N
NO2
NO2
NO2
NO2
NO2
NO2
NO2
CH3
2an:
F
Cl
Cl
Cl
Cl
Cl
c
2aq:
2ar:
2as:
2at:
79%
80%
83%
81%
2ao:
2ap:
83%
75%
80%
ON
CH3
OCH3
Cl
CH3
ON
N
ON
ON
ON
ON
N
N
N
N
N
NO2
NO2
NO2
NO2
NO2
NO2
Cl
Br
Br
Br
OMe
Cl
2au:
82%
2av:
80%
2aw:
2ax:
2ay:
2az:
83%
82%
83%
82%
aReaction conditions: Aniline (1.0 mmol) and TBN (4.0 equiv.) were stirred in acetonitrile (8
mL) at 80 °C for 3 h. bIsolated yields. cReaction was carried out for 6 h.
It is worth nothing that no influence was observed in the nitration process by the substituents
present on the benzylic ring (Scheme 3, 2ah-2ax). Indeed, the benzylic aromatic ring remained
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 48
1
2
3
4
5
6
7
8
9
intact during the nitration process even in the presence of strong electron donating groups such
as methoxy and thiomethyl, which is an important feature of this protocol (Scheme 3, 2ai, 2al,
2ap and 2aw). In addition, neither over nitrated nor m-nitrated products were observed in the
reaction which increases the scope of this methodology. Moreover, functionalized anilines
bearing sensitive functional groups such as allyl and propargyl underwent nitration smoothly and
gave the desired products 2ay and 2az in >82% yields.
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
Further, the nitration of unsubstituted N-alkyl and N-benzyl anilines (1ba-1bg) was attempted
under optimized condition (Scheme 4). To our delight, the ring nitration proceeds very
efficiently and gave the mono-nitrated products, either ortho or para, but not meta, in 85-91%
yields. It is also interesting to note that irrespective of the substituent present on the amine, un-
substituted anilines provided p-nitro products (2ba-2bg) in high yields in comparison to o-nitro
products (2ba′-2bg′). Similar to unsubstituted anilines, m-functionalized anilines also gave the p-
nitroaniline products 2bh-2bj in high yields along with negligible amounts of o-nitrated products
(Scheme 5).
Scheme 4. Nitration of various unsubstituted N-alkyl anilines.a,b
ON
R
N
ON
R
R
H
N
N
TBN (4.0 eq.)
NO2
+
Acetonitrile
80 oC, 4 h
NO2
2ba-2bg
1ba-1bg
2ba'-2bg'
ON
CH3
ON
Et
ON
Bn
ON
N
N
N
N
Br
NO2
NO2
NO2
NO2
2ba
2ba'
para
ortho
: 62%
: 23%
2bb
2bb'
para 2bd : 67%
ortho 2bd': 21%
para
ortho
: 69%
: 19%
2bc
2bb'
para
ortho
: 72%
: 22%
CH3
ON
ON
ON
N
N
N
F
CH3
NO2
NO2
NO2
2be
2be'
2bg
2bg'
para
ortho
: 69%
: 21%
para
ortho
: 72%
: 19%
2bf
2bf'
para
ortho
:67%
:20%
aReaction conditions: Aniline (1.0 mmol) and TBN (4 .0 equiv.) were stirred in acetonitrile (8
mL) at 80 °C for 4 h. bIsolated yields.
Scheme 5. Nitration of various m-substituted N-alkyl anilines.a,b
8
ACS Paragon Plus Environment

Page 9 of 48
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
ON
Bn
ON
Bn
ON
Bn
N
N
N
Bn
H
N
NO2
+
O2N
TBN (4.0 eq.)
+
R
R
Acetonitrile
80 oC, 4 h
R
R
NO2
2bh-2bj
1bh-1bj
<5%
9
ON
Bn
ON
N
Bn
ON
Bn
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
N
Br
H3CO
H3C
NO2
NO2
2bi
NO2
2bh
: 72%
: 73%
2bj
: 70%
aReaction conditions: Aniline (1.0 mmol) and TBN (4.0 equiv.) were stirred in acetonitrile (8
mL) at 80 °C for 4 h. bIsolated yields.
Having studied the nitration of p-, m- and unsubstituted N-alkyl anilines, nitration of o-
substituted anilines 1bk and 1bl was investigated under optimized condition (Scheme 6).
However, surprisingly, no nitration was observed while corresponding N-nitrosamine was
obtained as the major product.
Scheme 6. Nitration of o-substituted N-alkyl anilines.
H
Bn
ON
Bn
N
ON
Bn
N
N
R1
R2
R1
R2
TBN (4.0 eq.)
R1
R2
CH3CN, 80 oC
4 h
+
1
2
1bk
R = Me = R =H (
)
NO2
<5%
1
2
>90%
1bl
R = R =Me (
)
Having generated a large number of N-nitroso N-alkyl o-nitroanilines, a facile method for the
one-step procedure, i.e. denitrosation of N-nitrosamine followed by reduction of the nitro group,
was sought. Because, such protocols can offer the N-alkyl o-phenylenediamines in three steps,
starting from corresponding anilines. For this investigation, 4-methoxy N-nitroso N-benzyl
nitroaniline (2aa) was chosen as a model substrate and subjected for one-pot reduction with
different reducing agents (Table 2).
Initially the reduction was investigated with mild reducing agents such as Zn/NH4Cl and
Fe/NH4Cl in methanol at room temperature (Table 2, entries 1-2). The Zn/NH4Cl system
provided the desired product in 15% while 10% was obtained with Fe/NH4Cl. Hence, the
reduction was further investigated at 50 °C with Zn/NH4Cl in methanol. The yield of the reaction
is subsequently increased with increase in temperature as well as equivalence of reducing agents
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 48
1
2
3
4
5
6
7
8
9
(Table 2, entries 3-4). However, the reaction did not go for completion under thesis conditions.
Therefore, the reduction was further investigated with Zn/AcOH and Zn/HCl systems (Table 2,
entries 5-8).To our delight, the Zn (4.0 equiv.)/AcOH (1.5 mL) system gave the desired product
3aa in 88% yield within 20 minutes at 50 °C (Table 2, entry 8). In fact, other reducing agents
such as NiCl2/NaBH4 and Raney Ni/H2 were found inferior and gave low yields of the desired
product (Table 2, entries 9-10).
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 2. Optimization of one step reduction of nitroso and nitro group.a,b
ON
H
Bn
Bn
N
N
NO2
NH2
Reagents
MeOH
OCH3
OCH3
3aa
2aa
Metal
(equiv.)
Yield (%)b
S.No.
Additive
Temp.
Time
(oC)
RT
RT
50
NH4Cl (1.0 mL)
NH4Cl (1.0 mL)
NH4Cl (1.0 mL)
1
2
3
Zn (2.0)
Fe (2.0)
Zn (2.0)
1 h
1 h
1 h
15
10
30
4
5
Zn (4.0)
Zn (2.0)
2 h
1 h
NH4Cl (2.0 mL)
AcOH (1.0 mL)
50
50
59
RT
6
Zn (2.0)
1 h
48
HCl (1.0 mL)
RT
50
50
7
Zn (4.0)
AcOH (1.0 mL)
AcOH (1.5 mL)
30 min
20 min
72
8
Zn (4.0)
88
NiCl2 (2.0)
9
NaBH4 (4.0 eq.)
H2 (1 bar)
RT
RT
1 h
3 h
35
Raney Ni
(4 eq.)
10
<10
aReaction conditions: N-nitroso nitroaniline (1 mmol), Methanol (6 mL). bIsolated yields.
Using the optimized condition, reduction of various N-nitroso N-alkyl nitroanilines was
investigated (Scheme 7). All these substrates underwent one-pot reduction smoothly to provide
N-substituted o-phenylenediamines (3aa-3ap) in 78-88% yield within 20 minutes, irrespective of
the substituents present on the substrates. More importantly, chemoselective reduction was
observed with substrates bearing carbon-carbon double and triple bonds (3am and 3an). It is also
10
ACS Paragon Plus Environment

Page 11 of 48
The Journal of Organic Chemistry
1
2
3
4
5
6
worth mentioning that debenzylation or dehalogenation products were not observed during the
reduction, which indicates the broad scope of this methodology.
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
Scheme 7. Denitrosation followed by reduction of nitro group in N-nitroso N-alkyl
nitroaniline.a,b
R2
N
R2
Zn (4.0 eq.)
NH
NO
AcOH:MeOH (2:3)
R1
NO2
R1
NH2
3aa-3al
50 oC, 20 min
Br
H3C
Bn
Bn
Bn
Bn
NH
NH
NH
NH
NH
NH
NH2
NH2
H3C
3ac
Cl
NH2
3ad
: 82%
F
NH2
NH2
F
NH2
3ab
: 85%
: 83%
3ae
3af
3ag
: 80%
: 79%
: 80%
CH3
H3C
H3C
Cl
Br
F3C
H3C
NH
NH
NH
NH
NH
NH2 Cl
NH
Cl
NH2
H3CO
NH2
Br
NH2
NH2
Cl
NH2
3al:
78%
3ah
: 82%
3ai
: 85%
3am:
79%
3aj
3ak
: 81%
: 80%
Bn
NH
Bn
NH
NH
H2N
CH3
3ao:
H2N
3ap:
Cl
NH2
3an:
78%
76%
78%
aReaction conditions: Substituted N-nitrosamines (1.0 mmol) and Zn (4.0 eq.) were stirred in
AcOH:MeOH (2:3, 7.5 mL) at 50 °C. bIsolated yields.
Denitrosation of N-nitrosamine is one of the important transformations in organic synthesis.8c, 10
In fact, we have recently developed an efficient denitrosation methodology using iodine and
triethylsilane at room temperature which shows a remarkable functional group tolerance.8c In this
study, we have developed another simple and cost effective method using aqueous HCl in
methanol. This method involves the reaction of N-nitrosamines with 25% aqueous HCl in
methanol at 50 °C for 15 min followed by acid-basic work-up to provide the N-alkyl
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 48
1
2
3
4
5
6
7
8
9
nitroanilines (4aa-4ap) in excellent yields (Scheme 8). Although, N-alkyl N-nitroso anilines are
susceptible for Fischer-Hepp rearrangement in the presence of hydrochloric acid, we haven’t
observed any such products during the denitrosation. Perhaps, it is due to the presence of nitro
group on the aryl ring which impede the electrophilic ring nitrosation. Moreover, this method
tolerates different functional groups including allyl (4am) and propargyl (4an)9 groups. It is
notable that N-propargyl o-nitroanilines have been recently used as starting materials for the
preparation of biologically important quinoxaline derivatives.11
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
Scheme 8. Denitrosation of N-nitrosamines using aq. HCl-methanol.a,b
R2
N
R2
NH
NO
25% aq. HCl, MeOH
50 oC, 15 min
R1
NO2
R1
NO2
4aa-4al
Br
Bn
Bn
Bn
Bn
NH
NH
NH
NH
NH
NH
H3C
4ac
NO2
Cl
H3CO
NO2
NO2
NO2
F
NO2
NO2
4aa
4ab
4ad
: 82%
: 85%
: 80%
: 83%
4ae
4af
: 80%
: 79%
CH3
Cl
H3C
F3C
H3C
H3C
H3C
NH
NH
NH
NH
NH
NH
Cl
NO2
Br
NO2
Br
NO2
Cl
NO2 Cl
: 80%
NO2
F
NO2
4ag
4ah
4aj
: 81%
: 80%
: 82%
4ai
4ak
4al:
: 85%
78%
Bn
Bn
NH
NH
NH
NO2
NH
O2N

O2N
CH3
H3CO
Cl
NO2
4ap
: 83%
4ao
: 78%
4am
4an
: 80%
: 85%
CCDC:1835907
aReaction conditions: Substituted N-nitrosamines (1 mmol) and HCl (2 mL) were stirred in the
methanol (5 mL) at 50 °C. bIsolated yields.
Considering the biological importance of benzimidazoles and benzotriazoles1,12 synthesis of 5aa-
5ad was demonstrated using the developed methodology as the key steps (Scheme 9). The N-
benzylated o-phenylenediamine derivatives 3aa and 3ae were generated in three steps from
corresponding anilines in high yields and were subsequently converted into useful
benzimidazoles (5aa and 5ab) and benzotriazoles (5ac and 5ad) using literature procedures.3c,13
12
ACS Paragon Plus Environment

Page 13 of 48
The Journal of Organic Chemistry
1
2
3
4
Scheme 9. Synthesis of benzimidazole and benzotriazoles.
5
6
H
N
Ph
7
8
9
4. TEMPO
N
R
Bn
NH2
NH
R
5aa:
5ab:
R= OMe: 72%
R= F: 55%
1.PhCHO,NaBH4
Overall yield
NH2
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
2.t-BuONO/AcCN
Bn
3. Zn, AcOH
4. NaNO2, AcOH
N
N
N
R
3aa:
3ae:
R= OMe
R= F
R
5ac:
5ad:
R= OMe: 68%
R= F: 50%
Overall yield
The mechanism of ring nitration of N-alkyl anilines with tert-butyl nitrite (TBN) is not clear to
us. However, it is clear from the optimization table that N-nitrosation is the first step after which
ring nitration takes place. To understand the mechanism of first step (i.e. N-nitrosation), 4-
methoxy N-benzyl aniline 1aa was with treated with 1.0 equiv. of TBN in the presence of radical
scavenger TEMPO (Scheme 10, a). N-Nitrosation did not occur which indicates that N-
nitrosation reaction takes place under radical mechanism.
Scheme 10. Control experiments.
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 48
1
2
3
4
5
6
7
8
9
Bn
NO
H
Bn
TBN (1.0 eq.)
N
N
TEMPO (1.5 eq.)
a)
Acetonitrile
10 min
OMe
2a
<5%
OMe
1aa
Bn
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
NO
N
Bn
N
NO2
80 oC
b)
Acetonitrile
4 h
OMe
OMe
2a
4aa
< 5%
NO
Bn
Bn
NO
N
TBN (2.0 eq.)
Acetonitrile
N
NO2
c)
RT, 4 h
OMe
2a
OMe
2aa
45%
TBN (2.0 eq.)
TEMPO (2.5 eq.)
NO
Bn
Bn
NO
N
N
NO2
d)
Acetonitrile
RT, 4 h
OMe
2a
OMe
2aa
< 5%
It is well known that N-nitroso N-alkyl anilines undergo Fischer-Hepp rearrangement in the
presence of acid to provide corresponding p-nitroso N-alkyl anilines.14 On the other hand, Drake
et al. have found that some N-nitroso carbazoles undergo radical dissociation which leads to ring
nitrated products in the presence of air.15 Later, Welzel have reported that diphenyl N-
nitrosamine undergo radical dissociation upon heating which provides a mixture of different
rearranged products.16 Thus, to understand the possible ring nitration mechanism, we have
carried out a few more control experiments (Scheme 10, b-d).
The N-nitrosamine 2a was refluxed in acetonitrile in the absence of TBN under air in order to
understand the possible rearrangements (Scheme 10, b). No reaction was observed while 2a was
recovered in 91% yield which indicates that there is no Fischer-Hepp type rearrangement taking
place. Further, nitration of N-nitrosamine 2a was attempted with 2.0 equiv. of TBN at room
temperature which provides o-nitro compound 2aa in 45% yield in 4 h (Scheme 10, c). However,
no reaction was observed when the nitration of N-nitrosamine 2a was attempted with TBN in the
14
ACS Paragon Plus Environment

Page 15 of 48
The Journal of Organic Chemistry
1
2
3
4
presence of radical scavenger TEMPO (Scheme 10, c). This suggests that similar to N-
5
6
nitrosation, ring nitration is also proceeds through a radical mechanism.
7
8
9
Based on these experiments and literature reports, a plausible reaction mechanism has been
proposed for the N-nitrosation and ring nitration as shown Scheme 11. Initially, tert-butyl nitrite
(TBN) undergoes homolytic cleavage and provides tert-butoxy and nitroso radical.
Subsequently, tert-butoxy radical reacts with aniline 1aa and generates amine radical which
leads to the formation of N-NO bond (2a) (Scheme 11, Step 1). Further, the excess tert-butyl
nitrite provide nitro radical in the presence of air4a,4b,6 which undergoes substitution on the aryl
ring resulting in amine-nitroso (i.e. N-NO) bond cleavage. Subsequently, the abstraction of a
proton by t-butoxy radical would result in the formation of nitro-N-nitrosamine 2aa (Scheme 11,
Step 2).
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
Scheme 11. Plausible mechanism for nitration reaction.
Step 1:
t-BuONO
Bn
Bn
NO
Bn
H
N
N
N
NO
t-BuO
-t-BuOH
OMe
OMe
OMe
1aa
2a
Step 2:
t-BuONO
NO
NO
Bn
Bn
NO
Bn
N
N
air
N
H
NO2
O
t-Bu
NO2
NO2
- (t-BuOH)
OMe
OMe
OMe
2a
2aa
To support the assumption of N-N bond cleavage, nitration of N-acetyl as well as N-benzoyl N-
benzyl 4-methoxyanilines (1bm and 1bn) was attempted with 2.0 equiv. of TBN at 80 °C
(Scheme 12). No nitration on the ring was observed (starting material was recovered in both
cases) as there is no possibility of N-CO bond cleavage even at high temperature.
Scheme 12. Nitration of N-acyl N-alkyl anilines with TBN.
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 48
1
2
3
4
5
6
7
8
9
O
O
Bn
Bn
N
R
N
R
NO2
TBN (2.0 eq.)
Acetonitrile
80 oC, 4 h
OCH3
0%
OCH3
1bm
1bn
R=Me (
R= Ph (
)
)
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
It is also noteworthy that o-substituted N-alkyl anilines (1bk and 1bl) did not undergo nitration
under optimized condition and it provides only the corresponding N-nitroso compounds (Scheme
6). This observation lends further support to the proposed mechanism, because sterically
hindered N-nitrosamines are expected to be more stable where N-N bond cleavage would not
occur easily, hence, no nitration is taking place.
Conclusions
In summary, we have developed a practical method for the regioselective nitration of N-alkyl
anilines using tert-butyl nitrite under metal free condition. The reaction provides synthetically
useful N-nitroso N-alkyl nitroanilines in excellent yields. Simple methods were developed for the
conversion of N-nitroso N-alkyl nitroanilines into N-alkyl phenylenediamines and N-alkyl
nitroanilines using Zn/AcOH and 25% aqueous HCl in methanol respectively. Developed
methodologies were validated by demonstrating the synthesis of benzimidazole and
benzotriazole derivatives in good yields.
Experimental Section
General information
Solvents and chemicals were purchased from commercial sources and used without further
purifications. All the reactions were performed in pressure tube at appropriate temperature under
air. Thin layer chromatography was performed using pre-coated plates obtained from E. Merck
(TLC silica gel 60 F254). The TLC’s were visualized in UV Chamber with 254 nm wavelength
lamp. Purification of the products were performed on silica gel (60-120 mesh) using a mixture of
ethyl acetate and hexane. The melting point of all the synthesized compounds has been detected
through Staurt SMP10 melting point apparatus in the range of 0 °C - 300 °C. FTIR of all the
samples are accomplished on ALPHA BRUKER Eco-ATR fitted out on ZnSe ATR crystal in the
16
ACS Paragon Plus Environment

Page 17 of 48
The Journal of Organic Chemistry
1
2
3
4
5
6
range of 500-3000 cm-1. The NMR spectra were recorded on Bruker Avance 500 MHz NMR
spectrometer using CDCl3 or DMSO-d6. HRMS spectra were recorded on UHD Q-TOF (ESI-
TOF) using water’s Quattro Micro V 4.1. For the new compounds, melting point, IR, NMR and
7
8
9
13
HRMS-MASS data has been provided. In proton NMR, TMS is calibrated to 0 ppm and in C
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
NMR CDCl3 peak is calibrated to 77.0 ppm.
General procedure for the synthesis of N-alkyl N-nitroso nitroanilines
N-Alkyl aniline (1.0 mmol, 1.0 equiv.) was allowed to stir in acetonitrile (8 mL) approximately
for 5 min at room temperature to which tert-butyl nitrite (TBN) (0.48 mL, 4.0 equiv.) was added.
The reaction was further allowed to stir for 10 minutes at room temperature and then, kept at pre-
heated oil bath at 80 °C. The progress of the reaction was monitored by TLC. After completion,
the reaction mixture was diluted with ethyl acetate (50 mL) and washed with brine solution. The
organic layer was dried over anhydrous sodium sulphate, concentrated and subjected for column
chromatography (SiO2, eluent: hexane/ethyl acetate) to obtain corresponding pure substituted N-
alkyl N-nitrosamines (2ab-2bj). All the o-nitro N-alkyl N-Nitroso aniline compounds showed
rotamers in ~ 3:2 ratio as observed by 1H NMRs.
N-Nitroso N-benzyl-N-(4-methoxy-2-nitroaniline) (2aa): The compound was obtained as
yellow viscous liquid. (Yield: 269 mg, 94%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 85:15, Rf = 0.38. IR (neat): 3091, 2845,
1525, 1268, 1067, 700 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.59 (d, J = 2.5 Hz, 2H), 7.37 (m,
3H), 7.32–7.26 (m, 3H), 7.12 (m, 4H), 7.00 (dd, J = 8.8, 0.62H), 6.49 (d, J = 9.1 Hz, 0.62H),
6.05-5.38 (brs, 1H), 5.13 (s, 2H), 3.92 (s, 3H), 3.87 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ
160.4, 160.1, 146.4, 145.8, 134.4, 133.6, 130.4, 130.3, 129.2, 129.0 (2C), 128.8, 128.7, 128.1,
127.2, 119.7, 119.4 (2C), 110.6, 110.5, 58.0, 56.2, 56.1, 50.3. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C14H14N3O4 288.0984; Found 288.0982.
N-Nitroso N-methyl 4-methyl 2-nitroaniline (2ab): The compound was obtained as yellow
viscous liquid. (Yield: 157 mg, 81%). The residue was purified by column chromatography in
silica gel eluting with hexane: EtOAc 90:10, Rf = 0.49. IR (neat): 3123, 2783, 1600, 1278, 1056
cm-1. 1H NMR (500 MHz, CDCl3) δ 7.90 (s, 1H), 7.57 (dd, J = 15.1, 8.2 Hz, 1H), 7.41 (d, J = 8.1
Hz, 1H), 7.28 (s, 0.26H), 7.06 (d, J = 8.0 Hz, 2H), 4.21 (s, 0.51H), 3.40 (s, 3H), 2.53 (s, 3H),
13
2.49 (s, 0.54). C{1H} NMR (125 MHz, CDCl3) δ 144.0 (2C), 141.4, 140.6, 135.2, 134.6 (2C),
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 48
1
2
3
4
5
6
133.2, 127.2, 127.0, 125.9, 125.6, 40.5, 35.0, 24.0, 20.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd
for C8H10N3O3 196.0722; Found 196.0720.
7
8
9
N-Nitroso N-methyl 4-methoxy 2-nitroaniline (2ac): The compound was obtained as
yellow viscous liquid. (Yield: 173 mg, 82%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.47. IR (neat): 3023, 2763,
1412, 1268, 1001 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.58 (d, J = 1.6 Hz, 1H), 7.42 (d, J = 8.8
Hz, 1H), 7.28 (dd, J = 8.7, 2.5 Hz, 1H), 7.23 (d, J = 8.7, 0.21H), 7.07 (d, J = 8.7 Hz, 0.19H), 4.18
(s, 0.67H), 3.94 (s, 3H), 3.90 (s, 0.64H), 3.38 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 160.3,
160.0, 146.1, 145.0, 128.8, 128.5, 128.5, 124.2, 120.2, 119.7, 110.5, 110.3, 56.2, 56.1, 40.6, 35.3.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C8H10N3O4 212.0671; Found 212.0670.
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-Nitroso N-methyl 4-chloro 2-nitroaniline (2ad): The compound was obtained as yellow
viscous liquid. (Yield: 172 mg, 80%). The residue was purified by column chromatography in
silica gel eluting with hexane: EtOAc 90:10, Rf = 0.48 IR (neat): 3223, 2343, 1523, 1258, 1008
cm-1. 1H NMR (500 MHz, CDCl3) δ 8.10 (t, J = 2.9 Hz, 1H), 7.76 (dt, J = 13.4, 6.7 Hz, 1H), 7.50
(d, J = 8.5 Hz, 1H), 7.16 (d, J = 8.4 Hz, 0.18H), 4.24 (s, 0.52H), 3.40 (s, 3H). 13C{1H} NMR
(125 MHz, CDCl3) δ 144.3 (2C), 136.2, 135.2, 134.7, 133.3, 134.0 (2C), 128.6, 127.9, 125.9,
125.5, 40.3, 34.7. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C7H7ClN3O3 216.0176; Found
216.0174.
N-Nitroso N-benzyl-N-(4-methyl-2-nitroaniline) (2ae): The compound was obtained as
yellow viscous liquid. (Yield: 227 mg, 84%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 85:15, Rf = 0.39. IR (neat): 3023, 3023,
1560, 1223, 1123, 789 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.09 (dd, J = 11.7, 6.6 Hz, 2H), 7.64
(m 1H), 7.60-7.52 (m, 2H), 7.25 (dd, J = 5.9, 2.0 Hz, 2H), 7.18 (d, J = 7.9 Hz, 1H), 7.10 (d, J =
7.9 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.65 (d, J = 9.3 Hz, 0.51H), 5.94-5.53 (brs, 1H), 5.14 (s,
13
2H), 2.38 (s, 2H), 2.32 (s, 3H). C{1H} NMR (125 MHz, CDCl3) δ 145.8, 145.0, 138.6, 137.9,
134.5, 134.0, 133.5, 131.1, 131.0, 130.4, 130.3, 129.6, 129.5, 129.4, 129.2, 129.1, 128.7, 128.3,
125.6, 125.3, 57.6, 49.6, 21.1, 21.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H14N3O3
272.1035; Found 272.1031.
18
ACS Paragon Plus Environment

Page 19 of 48
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N-Nitroso N-benzyl-N-(4-chloro-2-nitroaniline) (2af): The compound was obtained as
yellow viscous liquid. (Yield: 241 mg, 83%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.42. IR (neat): 3234, 3123,
1523, 1134, 1000, 973 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.04 (s, 1H), 8.03 (s, 1H), 7.57 (d, J
= 6.6 Hz, 1H), 7.46 (d, J = 10.4 Hz, 4H), 7.36 (m, 4H), 7.27 (m, 4H), 7.17-7.06 (m, 3H), 6.56 (t,
J = 8.5 Hz, 0.65H), 6.00–5.66 (brs, 1H), 5.12 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 146.1,
145.0, 136.3, 135.3, 134.5, 134.1, 133.9, 133.6, 133.1, 132.9, 132.2, 130.1, 129.1 (2C), 128.9
(2C), 128.6, 128.3, 125.9, 125.7, 57.7, 49.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C13H11ClN3O3 292.0489; Found 292.0487.
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-Nitroso N-benzyl-N-(4-fluoro-2-nitroaniline) (2ag): The compound was obtained as yellow
viscous liquid. (Yield: 198 mg, 72%). The residue was purified by column chromatography in
silica gel eluting with hexane: EtOAc 90:10, Rf = 0.52. IR (neat): 3223, 3034, 1458, 1178, 1087
cm-1. 1H NMR (500 MHz, CDCl3) δ 7.40–7.35 (dd, J = 7.7, 2.8 Hz, 10H), 7.31–7.28 (m, 3H),
7.26–7.22 (m, 2H), 7.17–7.10 (m, 2H), 6.64 (d, J = 8.8, 0.65H), 6.06–5.41 (brs, 1H), 5.14 (s,
2H). 13C{1H} NMR (125 MHz, CDCl3) δ 161.9 (d, JC-F = 255.0 Hz), 161.4 (d, JC-F = 255.0 Hz),
146.4 (d, JC-F = 7.9 Hz), 145.5 (d, JC-F = 8.4 Hz), 133.9, 133.1, 130.9 (d, JC-F = 8.6 Hz), 130.7 (d,
JC-F = 4.0 Hz), 130.4 (d, JC-F = 8.5 Hz), 129.1, 129.0, 128.8 (2C), 128.7, 128.2, 126.7 (d, JC-F
=
4.0 Hz), 121.2 (d, JC-F = 22.2 Hz), 120.8 (d, JC-F = 22.2 Hz), 113.4 (d, JC-F = 27.5 Hz), 113.3 (d,
JC-F = 27.5 Hz), 57.7, 49.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C13H11FN3O3 276.0784;
Found 276.0782.
N-Nitroso N-(4-methylbenzyl)-N-(4-methyl-2-nitroaniline) (2ah): The compound was
obtained as yellow viscous liquid. (Yield: 233 mg, 83%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 85:15, Rf = 0.43. IR (neat): 3267, 3156,
1523, 1278, 1007, 985 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.87 (d, J = 2.9 Hz, 2H), 7.43 (d, J =
8.1 Hz, 1H), 7.32 (d, J = 10.6 Hz, 2H), 7.24 (d, J = 8.0 Hz, 3H), 7.18 (d, J = 7.8 Hz, 2H), 7.10
(dd, J = 11.4, 8.0 Hz, 0.54H), 7.03 (d, J = 8.0 Hz, 11H), 6.53 (d, J = 8.0 Hz, 3H), 6.01–5.46 (brs,
1H), 5.10 (s, 2H), 2.48 (s, 3H), 2.43 (s, 2H), 2.37 (s, 2H), 2.32 (s, 3H). 13C{1H} NMR (125 MHz,
CDCl3) δ 145.3, 144.6, 141.3, 140.6, 138.5, 137.7, 134.6, 134.2, 131.8, 131.1, 130.4, 129.5,
129.3 (2C), 129.0, 128.7 (2C), 128.2, 125.8, 125.6, 57.5, 49.6, 21.0, 20.9, 20.9, 20.8. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C15H16N3O3 286.1192; Found 286.1191.
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 48
1
2
3
4
5
6
7
8
9
N-Nitroso N-(4-methoxybenzyl)-N-(4-methoxy-2-nitroaniline) (2ai): The compound was
obtained as yellow viscous liquid. (Yield: 253 mg, 80%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 85:15, Rf = 0.40, IR (neat): 3123, 2783,
1600, 1278, 1056 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.54 (d, J = 2.9 Hz, 2H), 7.23 (d, J = 8.6
Hz, 2H), 7.13–6.92 (m, 5H), 6.86 (d, J = 11.2 Hz, 2H), 6.78 (d, J = 7.9 Hz, 2H), 6.51 (d, J = 8.8
Hz, 0.68H), 6.49 (s, 2H), 5.94–5.32 (brs, 1H), 5.03 (s, 2H), 3.87 (s, 3H), 3.82 (s, 2H), 3.78 (s,
2H), 3.74 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 160.3, 160.1, 159.8, 159.3, 146.4, 145.8,
130.6, 130.5, 130.4, 130.1, 127.0, 126.1, 125.5, 122.9, 119.6, 119.3, 114.3, 114.1 (2C), 110.6,
57.5, 56.2, 56.1, 55.2, 55.2, 49.7. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H16N3O5
318.1090; Found 318.10989.
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-Nitroso N-(4-methylbenzyl)-N-(4-methoxy-2-nitroaniline) (2aj): The compound was
obtained as yellow viscous liquid. (Yield: 255 mg, 85%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 85:15, Rf = 0.38. IR (neat): 3864, 2921,
1705, 1525, 1115, 830 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.87 (s, 1H), 7.42 (dd, J = 8.1, 1.2
Hz, 1H), 7.37–7.20 (m, 1H), 7.07 (dd, J = 13.1, 8.4 Hz, 3H), 6.89 (d, J = 8.6 Hz, 1H), 6.85–6.76
(m, 2H), 6.50 (d, J = 8.0 Hz, 0.59H), 5.90–5.42 (brs, 1H), 5.08 (s, 2H), 3.82 (s, 2H), 3.78 (s, 3H),
2.49 (s, 3H), 2.43 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 159.8, 159.3, 145.4, 144.7, 141.3,
140.7, 134.6, 134.2, 131.8, 130.5, 130.3, 128.9, 128.6, 128.1, 126.1, 125.9, 125.7, 125.4, 114.2,
114.0, 57.3, 55.2, 55.1, 49.3, 20.9 (2C). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C15H16N3O4
302.1141; Found 302.1140.
N-Nitroso N-(4-bromobenzyl)-N-(4-methoxy-2-nitroaniline) (2ak): The compound was
obtained as yellow viscous liquid. (Yield: 307 mg, 84%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 85:15, Rf = 0.39. IR (neat): 3234, 3012,
1456, 1130, 1090 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 10.0 Hz, 1H), 7.75 (d, J = 8.5
Hz, 1H), 7.65 (d, J = 10.4 Hz, 0.58H), 7.32–7.23 (m, 2H), 7.09 (d, J = 8.5 Hz, 2H), 7.05 (d, J =
8.5 Hz, 1H), 6.90 (d, J = 8.6 Hz, 1H), 6.81 (d, J = 8.6 Hz, 2H), 6.49 (d, J = 8.4 Hz, 0.58H), 5.71–
13
5.43 (brs, 1H), 5.08 (s, 2H), 3.83 (s, 2H), 3.79 (s, 3H). C{1H} NMR (125 MHz, CDCl3) δ
160.0, 159.5, 146.2, 145.2, 137.0, 136.5, 133.4, 130.5, 130.4, 130.3, 129.7, 129.5, 128.7, 128.5,
125.7, 125.0, 123.8, 122.7, 114.4, 114.2, 57.2, 55.2 (2C), 49.0. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C14H13BrN3O3 366.0089; Found 366.0086.
20
ACS Paragon Plus Environment

Page 21 of 48
The Journal of Organic Chemistry
1
2
3
4
5
6
N-Nitroso N-(4-thiomethylbenzyl)-N-(4-methyl-2-nitroaniline) (2al): The compound was
obtained as yellow viscous liquid. (Yield: 250 mg, 79%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 85:15, Rf = 0.42. IR (neat): 3203, 2783,
7
8
9
1
1600, 1259, 1116 cm-1. H NMR (500 MHz, CDCl3) δ 7.88 (s, 1H), 7.43 (d, J = 8.0 Hz, 1H),
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
7.33 (d, J = 8.0 Hz, 0.57H), 7.30–7.23 (m, 2H), 7.22 (d, J = 8.1 Hz, 1H), 7.15 (d, J = 8.1 Hz,
2H), 7.10 (d, J = 8.1 Hz, 1H), 7.05 (d, J = 8.0 Hz, 2H), 6.53 (d, J = 8.0 Hz, 0.55), 5.89–5.45 (brs,
13
1H), 5.09 (s, 2H), 2.49 (s, 5H), 2.46 (s, 3H), 2.43 (s, 2H). C{1H} NMR (125 MHz, CDCl3) δ
145.3, 144.6, 141.4, 140.8, 139.5, 138.6, 134.6, 134.2, 131.8, 130.6, 130.0, 129.6, 129.3, 128.7,
128.3, 128.0, 126.3 (2C), 125.9, 125.7, 57.3, 49.4, 20.9, 15.3. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C15H16N3O3S 318.0912; Found 318.0911.
N-Nitroso N-(4-chlorobenzyl)-N-(4-methyl-2-nitroaniline) (2am): The compound was
obtained as yellow viscous liquid. (Yield: 247 mg, 81%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.49. IR (neat): 3380, 2923,
1524, 1346, 1081, 794 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.88 (s, 2H), 7.44 (d, J = 8.0 Hz, 1H),
7.33 (d, J = 8.3 Hz, 2H), 7.30–7.23 (m, 4H), 7.07 (t, J = 7.6 Hz, 3H), 6.51 (d, J = 8.0 Hz, 0.52H),
5.86–5.46 (brs, 1H), 5.08 (s, 2H), 2.48 (s, 3H), 2.42 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ
145.4, 144.6, 141.6, 141.0, 134.7 (2C), 134.3, 134.0, 132.8, 132.0, 131.7, 130.5, 130.2, 129.1,
128.9, 128.6, 128.2, 127.8, 126.1, 125.9, 57.0, 49.2, 21.0 (2C). HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C14H13ClN3O3 306.0645; Found 306.0643.
N-Nitroso N-(3-bromobenzyl)-N-(4-methyl-2-nitroaniline) (2an): The compound was
obtained as yellow viscous liquid. (Yield: 302 mg, 83%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.45. IR (neat): 3834, 2925,
1700, 1524, 1346, 1069, 793 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.91 (s, 1H), 7.49 (dd, J =
19.2, 10.0 Hz, 2H), 7.42 (d, J = 7.9 Hz, 1H), 7.38–7.24 (m, 3H), 7.21–7.06 (m, 3H), 6.55 (d, J =
8.0 Hz, 0.42H), 5.91-5.49 (brs, 1H), 5.09 (s, 2H), 2.51 (s, 3H), 2.45 (s, 2H). 13C{1H} NMR (125
MHz, CDCl3) δ 145.4, 144.6, 141.7, 141.0, 136.7, 135.9, 134.8, 134.4, 132.0, 131.9, 131.8,
131.6, 131.2, 130.5, 130.3, 130.1, 128.7, 128.2, 127.9, 127.7, 127.3, 126.1, 125.9, 122.9, 122.7,
119.5, 57.1, 49.3, 21.0 (2C). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H13BrN3O3 350.0140;
Found 350.0147.
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 48
1
2
3
4
5
6
7
8
9
N-Nitroso N-(4-methylbenzyl)-N-(4-fluoro-2-nitroaniline) (2ao): The compound was
obtained as yellow viscous liquid. (Yield: 216 mg, 75%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.52. IR (neat): 3023, 2793,
1406, 1238, 986 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.82 (dd, J = 10.8, 3.0 Hz, 1H), 7.35 (dd, J
= 12.8, 5.9 Hz, 1H), 7.26–7.17 (m, 4H), 7.10 (d, J = 7.8 Hz, 2H), 7.01 (d, J = 7.9 Hz, 2H), 6.61
(dd, J = 8.8, 5.0 Hz, 0.64H), 6.05–5.34 (brs, 1H), 5.10 (s, 2H), 2.38 (s, 2H), 2.33 (s, 3H).
13C{1H} NMR (125 MHz, CDCl3) δ 161.0 (d, JC-F = 262.0 Hz), 161.5 (d, JC-F = 253.0 Hz), 146.5
(d, JC-F = 7.5 Hz), 145.5 (d, JC-F = 8.7 Hz),, 138.8, 138.1, 131.1 (d, JC-F = 8.5 Hz), 130.9, 130.8
(d, JC-F = 3.7 Hz), 130.7 (d, JC-F = 8.5 Hz), 130.1, 129.7, 129.5, 129.1 128.9, 126.9 (d, JC-F = 3.7
Hz), 121.2 (d, JC-F = 22.2 Hz), 120.8 (d, JC-F = 22.2 Hz), 113.5 (d, JC-F = 27.5 Hz), 113.4 (d, JC-F
= 26.2 Hz), 57.6, 49.7, 21.1, 21.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H13FN3O3
290.0941; Found 290.0939.
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-Nitroso N-(4-chlorobenzyl)-N-(4-methoxy-2-nitroaniline) (2ap): The compound was
obtained as yellow viscous liquid. (Yield: 256 mg, 80%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.51. IR (neat): 3023, 2983,
1412, 1118, 1009, 978 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.57 (d, J = 8.4 Hz, 1H), 7.34 (d, J =
8.5 Hz, 1H), 7.31–7.28 (m, 1H), 7.27–7.23 (m, 1H), 7.17–7.13 (m, 2H), 7.08 (d, J = 8.3 Hz, 1H),
7.04 (dd, J = 8.8, 2.9 Hz, 2H), 6.55 (d, J = 8.8 Hz, 0.54H), 5.93–5.40 (brs, 1H), 5.07 (s, 2H),
3.92 (s, 3H), 3.86 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 160.4, 160.1, 146.3, 145.6, 134.6,
133.9, 132.8, 132.1, 130.5, 130.3, 130.1, 129.9, 129.0, 128.8, 126.8, 122.6, 119.6, 119.4, 110.7,
110.7, 57.1, 56.1, 56.0, 49.5. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H13ClN3O4
322.0595; Found 322.0593.
N-Nitroso N-(4-methylbenzyl)-N-(4-chloro-2-nitroaniline) (2aq): The compound was
obtained as yellow viscous liquid. (Yield: 244 mg, 80%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.53. IR (neat): 3723, 3012,
1435, 1278, 1012, 786 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 14.1 Hz, 1H), 7.59 (d, J
= 10.9 Hz, 1H), 7.49 (d, J = 10.8 Hz, 0.64H), 7.24 (d, J = 8.0 Hz, 1H), 7.21–7.16 (m, 3H), 7.11
(d, J = 7.9 Hz, 2H), 7.01 (d, J = 8.0 Hz, 2H), 6.57 (d, J = 8.5 Hz, 0.65H), 6.02–5.48 (brs, 1H),
5.11 (s, 2H), 2.38 (s, 2H), 2.33 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 146.7, 145.1, 138.8,
138.2, 136.3, 135.3, 134.0, 133.5, 133.0, 130.8, 130.2, 130.0, 129.7, 129.6, 129.2, 129.1, 128.7,
22
ACS Paragon Plus Environment

Page 23 of 48
The Journal of Organic Chemistry
1
2
3
4
5
6
126.9, 125.8, 125.6, 57.5, 49.3, 21.1 (2C). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C14H13ClN3O3 306.0645; Found 306.0643.
7
8
9
N-Nitroso N-(4-bromobenzyl)-N-(4-chloro-2-nitroaniline) (2ar): The compound was
obtained as yellow viscous liquid. (Yield: 305 mg, 83%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf= 0.52. IR (neat): 3875, 3393,
2319, 1615, 1502, 1139, 789 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.95 (s, 1H), 7.53 (d, J = 8.5
Hz, 1H), 7.42 (t, J = 9.2 Hz, 2H), 7.32 (d, J = 8.1 Hz, 1H), 7.15 (s, 1H), 7.10 (d, J = 8.5 Hz, 1H),
6.91 (d, J = 8.1 Hz, 2H), 6.54 (d, J = 8.5 Hz, 0.50H), 5.73–5.37 (brs, 1H), 4.98 (s, 2H). 13C{1H}
NMR (125 MHz, CDCl3) δ 146.1, 145.0, 136.5, 135.6, 134.3, 133.8, 133.0, 132.8, 132.3, 132.2,
132.1, 130.8, 130.4, 129.8, 128.9, 128.8, 126.1, 125.8, 123.2, 122.4, 57.0, 49.0. HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C13H10BrClN3O3 369.9594; Found 369.9594.
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-Nitroso N-(4-isopropylbenzyl)-N-(4-chloro-2-nitroaniline) (2as): The compound was
obtained as yellow viscous liquid. (Yield: 269 mg, 81%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 85:15, Rf = 0.42. IR (neat): 3021, 2456,
1538, 1214, 744, 668 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.07 (dd, J = 9.4, 1.8 Hz, 1H), 7.60
(dd, J = 8.5, 1.7 Hz, 1H), 7.50 (dd, J = 8.4, 1.6 Hz, 0.61H), 7.26 (dd, J = 14.4, 8.7 Hz, 6), 7.18
(dd, J = 16.7, 8.2 Hz, 3H), 7.04 (d, J = 7.9 Hz, 2H), 6.59 (d, J = 8.5 Hz, 0.58H), 5.91–5.46 (brs,
1H), 5.11 (s, 2H), 2.93 (dd, J = 12.8, 6.0 Hz, 1H), 2.88 (dd, J = 13.8, 6.9 Hz, 1H), 1.27 (d, J =
13
6.9 Hz, 6H), 1.23 (d, J = 6.9 Hz, 6H). C{1H} NMR (125 MHz, CDCl3) δ 149.8, 149.1, 136.3,
135.3, 134.0, 133.5, 133.1, 131.2, 130.4, 130.2, 129.3, 129.1 (2C), 128.6, 127.1, 127.0, 126.9,
125.8, 125.7, 115.6, 57.5, 49.5, 47.0, 33.8, 33.7, 29.6, 23.8, 23.8. HRMS (ESI-TOF) m/z:
[M+H]+ Calcd for C16H17ClN3O3 334.0958; Found 334.0956.
N-Nitroso
N-(4-trifluoromethanebenzyl)-N-(4-chloro-2-nitroaniline)
(2at):
The
compound was obtained as yellow viscous liquid. (Yield: 283 mg, 79%). The residue was
purified by column chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.55. IR
(neat): 3741, 3023, 1600, 1348, 1015, 986 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.09 (d, J = 2.3
Hz, 1H), 7.67 (t, J = 5.4 Hz, 1H), 7.60 (s, 2H), 7.54 (t, J = 11.1 Hz, 1H), 7.27 (s, 2H), 7.21 (d, J =
13
8.5 Hz, 1H), 6.65 (d, J = 8.5 Hz, 0.43H), 6.07–5.56 (brs, 1H), 5.19 (s, 2H). C{1H} NMR (125
MHz, CDCl3) δ 146.1, 145.0, 138.0, 137.2, 136.7, 135.7, 134.3, 133.8, 132.8, 131.1 (q, JC-F
=
32.7 Hz), 130.5 (q, JC-F = 32.7 Hz), 129.7, 129.4, 128.8 (2C), 128.6, 127.1, 126.2, 126.1 (q, JC-F
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 48
1
2
3
4
5
6
= 3.7 Hz), 125.9, 125.8 (q, JC-F = 3.7 Hz), 124.8 (2C, q, JC-F = 271.5 Hz), 115.4, 57.0, 49.2.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd. for C14H11ClF3N3O3 360.0363; Found 360.0360.
7
8
9
N-Nitroso N-(2-methylbenzyl)-N-(4-chloro-2-nitroaniline) (2au): The compound was
obtained as yellow viscous liquid. (Yield: 250 mg, 82%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.49. IR (neat): 3721, 2429,
1349, 1214, 744 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 14.8 Hz, 1H), 7.52 (dd, J =
40.1, 8.5 Hz, 2H), 7.35–7.23 (m, 2H), 7.21 (d, J = 14.8 Hz, 1H), 7.14 (m, 4H), 6.92 (d, J = 7.6
Hz, 1H), 6.49 (d, J = 8.5 Hz, 0.64H), 5.94–5.61 (brs, 1H), 5.16 (s, 2H), 2.38 (s, 2H), 2.22 (s, 3H).
13C{1H} NMR (125 MHz, CDCl3) δ 146.2, 145.2, 137.7, 136.3 (2C), 135.3, 134.0, 133.5, 132.8,
131.5, 131.1, 130.8, 130.7, 130.6, 130.4, 129.2, 129.2, 129.0, 128.9, 128.5, 126.4, 126.4, 125.7,
125.6, 55.5, 47.1, 19.1, 19.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H13ClN3O3
306.0645; Found 306.0643.
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-Nitroso N-(4-methylbenzyl)-N-(4-bromo-2-nitroaniline) (2av): The compound was
obtained as yellow viscous liquid. (Yield: 280 mg, 80%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.48. IR (neat): 3423, 2780,
1412, 1289, 1026, 765 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.89 (d, J = 0.9 Hz, 1H), 7.46–7.35
(m, 4H), 7.34–7.25 (m, 4H), 7.17–7.07 (m, 3H), 6.50 (d, J = 8.1 Hz, 0.55H), 6.92–5.47 (brs, 1H),
5.15 (s, 2H), 2.49 (s, 3H), 2.44 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 145.4, 145.3, 144.7,
141.4, 140.7, 134.6, 134.3, 134.2, 133.6, 131.9, 129.2, 128.9, 128.8, 128.7, 128.4, 128.2, 128.0,
126.0, 125.8, 121.9, 57.8, 49.9, 21.0, 20.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C14H13BrN3O3 350.0140; Found 350.0138.
N-Nitroso N-(4-methoxybenzyl)-N-(4-bromo-2-nitroaniline) (2aw): The compound was
obtained as yellow viscous liquid. (Yield: 296 mg, 82%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 80:10, Rf = 0.49. IR (neat): 3803, 3393,
2916, 1502, 885 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.60 (d, J = 6.9 Hz, 1H), 7.35 (d, J = 8.3
Hz, 1H), 7.28 (dd, J = 14.5, 9.3 Hz, 3H), 7.15 (d, J = 8.8 Hz, 1H), 7.09 (d, J = 8.6 Hz, 3H), 7.04
(d, J = 8.8 Hz, 0.56H), 6.52 (d, J = 8.8 Hz, 0.55H), 6.00–5.36 (brs, 1H), 5.08 (s, 2H), 3.93 (s,
3H), 3.88 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 160.4, 160.2, 146.4, 145.7, 134.7, 134.0,
132.8, 132.1, 130.8, 130.5, 130.4, 130.2, 130.0, 129.1, 128.9, 126.9, 122.7, 119.7, 119.5, 110.7,
24
ACS Paragon Plus Environment

Page 25 of 48
The Journal of Organic Chemistry
1
2
3
4
5
6
57.2, 56.2, 56.1, 49.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H13BrN3O4 366.0089;
Found 366.0083.
7
8
9
N-Nitroso N-(4-chlorobenzyl)-N-(4-bromo-2-nitroaniline) (2ax): The compound was
obtained as yellow viscous liquid. (Yield: 305 mg, 83%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.50. IR (neat): 3006, 2983,
1578, 1109, 983 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 2.4 Hz, 3H), 7.63 (dd, J = 8.5,
2.1 Hz, 1H), 7.53 (d, J = 8.1 Hz, 1H), 7.44 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.2 Hz, 2H), 7.19 (d,
J = 8.5 Hz, 1H), 7.02 (d, J = 8.2 Hz, 2H), 6.62 (d, J = 8.5 Hz, 0.50H), 5.91–5.50 (brs, 1H), 5.09
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
13
(s, 2H). C{1H} NMR (125 MHz, CDCl3) δ 146.0, 145.0, 136.5, 135.7, 134.3, 133.7, 133.0,
132.8, 132.3, 132.2, 132.1, 130.8, 130.4, 129.9, 129.0, 128.8, 126.0, 125.8, 123.2, 122.4, 57.0,
49.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C13H10BrClN3O3 369.9594; Found 369.9594.
N-Nitroso N-allyl-N-(4-methoxy-2-nitroaniline) (2ay): The compound was obtained as
yellow viscous liquid. (Yield: 194 mg, 82%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.51. IR (neat): 3403, 2983,
1660, 1278, 1053 cm-1. 1H NMR (500 MHz, CDCl3) δ 7.52 (t, J = 2.7 Hz, 2H), 7.31 (d, J = 8.8
Hz, 1H), 7.18 (dd, J = 9.4, 6.5 Hz, 1H), 7.11 (dd, J = 8.7, 2.8 Hz, 1H), 6.93 (d, J = 8.8 Hz,
0.52H), 6.05–5.98 (m, 0.52H), 5.66–5.57 (m, 1H), 5.25 (d, J = 14.1 Hz, 1H), 5.11 (t, J = 13.7 Hz,
13
3H), 4.44 (d, J = 6.5 Hz, 2H), 3.86 (s, 3H), 3.82 (s, 2H). C{1H} NMR (125 MHz, CDCl3) δ
160.4, 160.1, 146.5, 145.8, 131.5, 129.8, 129.8 (2C), 129.2, 127.2, 123.0, 121.1, 120.4, 119.9,
119.5, 110.5 (2C), 110.4, 56.8, 56.2, 56.1, 49.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C10H12N3O4 238.0828; Found: 238.0823.
N-Nitroso N-propargyl-N-(4-chloro-2-nitroaniline) (2az): The compound was obtained as
yellow viscous liquid. (Yield: 198 mg, 83%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.48. IR (neat): 3423, 2972,
1604, 1171, 1023 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J = 2.3 Hz, 1H), 8.16 (d, J = 2.3
Hz, 0.33H), 7.81 (dd, J = 8.5, 2.4 Hz, 1H), 7.75 (dd, J = 8.4, 2.3 Hz, 0.37H), 7.63 (d, J = 8.5 Hz,
1H), 7.32 (d, J = 8.4 Hz, 0.36H), 5.60–5.91 (brs, 1H), 4.71 (d, J = 2.6 Hz, 2H), 2.50 (t, J = 2.5
13
Hz, 0.32H), 2.29 (t, J = 2.6 Hz, 1H). C{1H} NMR (125 MHz, CDCl3) δ 146.1, 145.0, 137.0,
136.3, 134.5, 134.1, 132.1, 131.2, 130.3 (2C), 125.9, 125.9, 76.2, 75.7, 75.1, 74.4, 43.1, 36.0.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C9H7ClN3O3 240.0176; Found 240.0175.
25
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 48
1
2
3
4
5
6
N-Nitroso N-methyl-N-(4-nitroaniline) (2ba): The compound was obtained as yellow
o
solid. M.p. 100-101 C (Yield: 112 mg, 62%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.48. IR (neat): 3021, 2783,
7
8
9
1156, 1118, 1053 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.37 (d, J = 8.8 Hz, 2H), 7.77 (d, J = 8.9
13
Hz, 2H), 3.48 (s, 3H). C{1H} NMR (125 MHz, CDCl3) δ 146.9, 145.8, 125.2, 117.8, 30.0.
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
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C7H8N3O3 182.0566; Found 182.0563.
N-Nitroso N-methyl-N-(2-nitroaniline) (2ba′): The compound was obtained as yellow viscous
liquid. (Yield: 41 mg, 23%). The residue was purified by column chromatography in silica gel
eluting with hexane: EtOAc 85:15, Rf = 0.45. IR (neat): 3042, 2984, 1293, 1007, 1053 cm-1. 1H
NMR (500 MHz, CDCl3) δ 8.11 (t, J = 6.9 Hz, 1H), 7.82–7.76 (m, 1H), 7.65 (t, J = 7.9 Hz, 1H),
7.55 (d, J = 8.0 Hz, 1H), 7.20 (t, J = 6.1 Hz, 0.26H), 4.25 (s, 0.46H), 3.43 (s, 3H). 13C{1H} (125
MHz, CDCl3) δ 144.3, 144.2, 135.7, 134.7, 134.0, 129.5, 127.5, 126.9, 125.7, 125.2, 118.1,
117.8, 40.4, 34.8. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C7H8N3O3 182.0566; Found
182.0564.
N-Nitroso N-ethyl-N-(4-nitroaniline) (2bb): The compound was obtained as yellow solid.
M.p. 117-120 °C (Yield: 134 mg, 69%). The residue was purified by column chromatography in
silica gel eluting with hexane: EtOAc 90:10, Rf = 0.49. IR (neat): 3231, 2978, 1236, 1008, 987
cm-1. H NMR (500 MHz, CDCl3) δ 8.36 (d, J = 9.2 Hz, 2H), 7.76 (d, J = 9.2 Hz, 2H), 4.10 (q, J
1
= 7.2 Hz, 3H), 1.20 (t, J = 7.2 Hz, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 146.2, 145.8, 125.3,
117.7, 37.9, 11.6. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C8H10N3O3 196.0722; Found
196.0722.
N-Nitroso N-ethyl-N-(2-nitroaniline) (2bb′): The compound was obtained as yellow
viscous liquid. (Yield: 37 mg, 19%). The residue was purified by column chromatography in
silica gel eluting with hexane: EtOAc 80:20, Rf = 0.38. IR (neat): 3256, 2987, 1123, 1007, 965
cm-1. H NMR (500 MHz, CDCl3) δ 8.11 (dd, J = 16.4, 8.2 Hz, 1H), 7.83–7.74 (m, 2H), 7.68–
1
7.59 (m, 1H), 7.51 (d, J = 7.9 Hz, 1H), 7.18 (d, J = 7.8 Hz, 0.50H), 4.72–4.63 (m, 1H), 4.03 (q, J
= 7.2 Hz, 2H), 1.52 (t, J = 7.3 Hz, 1.60H), 1.18 (t, J = 7.2 Hz, 3H). C{1H} NMR (125 MHz,
13
CDCl3) δ 145.1, 134.5, 134.4, 133.7, 130.7, 130.3, 129.5, 128.1, 127.4, 125.8, 125.3, 48.9, 41.9,
13.9, 11.3. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C8H10N3O3 196.0722; Found 196.0722.
26
ACS Paragon Plus Environment

Page 27 of 48
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N-Nitroso N-benzyl-N-(4-nitroaniline) (2bc): The compound was obtained as yellow solid.
M.p. 108-110 °C (Yield: 179 mg, 72%). The residue was purified by column chromatography in
silica gel eluting with hexane: EtOAc 90:10, Rf = 0.50. IR (neat): 3431, 2965, 1266, 1108, 975
cm-1. 1H NMR (500 MHz, CDCl3) δ 8.23 (d, J = 9.2 Hz, 2H), 7.68 (d, J = 9.2 Hz, 2H), 7.32–7.18
(m, 3H), 6.97 (d, J = 7.1 Hz, 2H), 5.21 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 146.4, 145.9,
133.2, 129.1, 128.0, 126.6, 125.2, 118.0, 45.9. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for
C13H12N3O3 258.0879; Found 258.0877.
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-Nitroso N-benzyl-N-(2-nitroaniline) (2bc′): The compound was obtained as yellow
viscous liquid. (Yield: 56 mg, 22%). The residue was purified by column chromatography in
silica gel eluting with hexane: EtOAc 85:15, Rf = 0.44. IR (neat): 3411, 2986, 1136, 975 cm-1. 1H
NMR (500 MHz, CDCl3) δ 7.98 (td, J = 7.7, 1.8 Hz, 1H), 7.58–7.42 (m, 3H), 7.33–7.15 (m, 6H),
7.11–7.00 (m, 2H), 6.54 (dd, J = 7.2, 1.9 Hz, 0.46H), 5.90–5.42 (brs, 1H), 5.07 (s, 2H). 13C{1H}
NMR (125 MHz, CDCl3) δ 146.1, 144.9, 134.5, 134.2, 134.0, 133.6, 133.4, 130.9, 130.4, 129.6,
129.1, 129.1, 128.9, 128.8, 128.6, 128.2, 128.1 (2C), 125.7, 125.4, 57.8, 49.8. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C13H12N3O3 258.0879; Found 258.0878.
N-Nitroso N-(4-bromobenzyl)-N-(4-nitroaniline) (2bd): The compound was obtained as
yellow liquid. (Yield: 225 mg, 67%). The residue was purified by column chromatography in
silica gel eluting with hexane: EtOAc 90:10, Rf = 0.50. IR (neat): 3341, 2865, 1263, 1138, 975
cm-1. 1H NMR (500 MHz, CDCl3) δ 8.30 (d, J = 9.2 Hz, 2H), 7.75 (d, J = 9.2 Hz, 2H), 7.31 (dd,
J = 5.9, 1.5 Hz, 2H), 7.05 (d, J = 8.1 Hz, 2H), 5.28 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ
146.1, 145.9, 132.2, 132.2, 128.3, 125.3, 122.0, 118.0, 45.3. HRMS (ESI-TOF) m/z: [M+H]+
Calcd for C13H11BrN3O3 335.9984; Found 335.9982.
N-Nitroso N-(4-bromobenzyl)-N-(2-nitroaniline) (2bd′): The compound was obtained as
yellow viscous liquid. (Yield: 80 mg, 21%). The residue was purified by column chromatography
in silica gel eluting with hexane: EtOAc 85:15, Rf = 0.43. IR (neat): 3441, 2945, 1345, 1126, 899
cm-1. 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 8.1 Hz, 1H), 7.68 (t, J = 7.7 Hz, 1H), 7.58 (dt, J
= 13.9, 7.4 Hz, 2H), 7.50 (d, J = 8.2 Hz, 1H), 7.41 (d, J = 8.2 Hz, 2H), 7.26 (t, J = 7.1 Hz, 2H),
13
7.03 (d, J = 8.2 Hz, 2H), 6.71 (d, J = 7.2 Hz, 0.38H), 6.95-5.49(brs, 1H), 5.11 (s, 2H). C{1H}
NMR (125 MHz, CDCl3) δ 145.6, 144.7, 134.2, 134.1, 133.8, 133.1, 132.4, 132.0, 131.8, 130.7,
27
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 48
1
2
3
4
5
6
130.5, 130.4, 130.3, 129.7, 128.6, 127.7, 125.7, 125.3, 122.9, 122.1, 57.0, 49.1. HRMS (ESI-
TOF) m/z: [M+H]+ Calcd for C13H11BrN3O3 335.9984; Found 335.9983.
7
8
9
N-Nitroso N-(4-methylbenzyl)-N-(4-nitroaniline) (2be): The compound was obtained as
yellow solid. M.p. 57-58 °C (Yield: 186 mg, 69%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.51. IR (neat): 3421, 2905,
1513, 1356, 789 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 9.2 Hz, 2H), 7.67 (d, J = 9.2
Hz, 2H), 7.03 (d, J = 7.9 Hz, 2H), 6.86 (d, J = 8.0 Hz, 2H), 5.16 (s, 2H), 2.23 (s, 3H). 13C{1H}
NMR (125 MHz, CDCl3) δ 146.5, 145.8, 137.8, 130.2, 129.7, 126.6, 125.1, 118.1, 45.6, 21.0.
HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H14N3O3 272.1035; Found 272.1032.
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-Nitroso N-(4-methylbenzyl)-N-(2-nitroaniline) (2be′): The compound was obtained as
yellow viscous liquid. (Yield: 56 mg, 21%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 85:15, Rf = 0.46. IR (neat): 3445, 3046,
1500, 1136, 790 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.01–7.94 (m, 1H), 7.55 (m, 2H), 7.51–7.42
(m, 2H), 7.18–7.14 (m, 2H), 7.09 (d, J = 7.9 Hz, 1H), 7.00 (d, J = 7.9 Hz, 2H), 6.93 (d, J = 8.0
Hz, 2H), 6.55 (d, J = 9.3 Hz, 0.59H), 5.80–5.35 (brs, 1H), 5.04 (s, 2H), 2.28 (s, 2H), 2.23 (s, 3H).
13C{1H} NMR (125 MHz, CDCl3) δ 150.4, 150.4, 139.1, 138.7, 137.9, 134.6, 134.0, 133.5,
130.4, 130.3, 129.6, 129.5, 129.4 (2C), 129.2, 129.1, 128.7, 128.3, 125.7, 125.3, 57.6, 49.6, 21.1
(2C). HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H14N3O3 272.1035; Found 272.1032.
N-Nitroso N-(4-fluorobenzyl)-N-(4-nitroaniline) (2bf): The compound was obtained as yellow
liquid. (Yield: 194 mg, 67%). The residue was purified by column chromatography in silica gel
eluting with hexane: EtOAc 90:10, Rf = 0.48. IR (neat): 3821, 2985, 1531, 1389, 890 cm-1. 1H
NMR (500 MHz, CDCl3) δ 8.33 (d, J = 9.1 Hz, 2H), 7.81–7.69 (m, 2H), 7.04 (dd, J = 12.0, 6.9
Hz, 4H), 5.26 (s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 162.2 (d, JC-F = 247.7 Hz), 146.2,
145.9, 129.0 (d, JC-F = 3.2 Hz), 128.4 (d, JC-F = 8.2 Hz), 125.2, 118.1, 116.1 (d, JC-F = 21.8 Hz),
45.2. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C13H11FN3O3 276.0784; Found 276.0784.
N-Nitroso N-(4-fluorobenzyl)-N-(2-nitroaniline) (2bf′): The compound was obtained as
yellow viscous liquid. (Yield: 55 mg, 20%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 85:15, Rf = 0.37. IR (neat): 3468, 2890,
1453, 1012, 878 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.07 (d, J = 8.1 Hz, 1H), 7.67 (t, J = 8.5 Hz,
28
ACS Paragon Plus Environment

Page 29 of 48
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1H), 7.63–7.54 (m, 2H), 7.35 (t, J = 8.4 Hz, 4H), 7.29–7.24 (m, 1H), 7.16–7.12 (m, 1H), 7.06 (t,
J = 8.5 Hz, 2H), 6.97 (t, J = 8.6 Hz, 1H), 6.69 (d, J = 5.9 Hz, 0.46H), 5.89-5.55 (brs, 1H), 5.13
(s, 2H). 13C{1H} NMR (125 MHz, CDCl3) δ 162.7 (d, JC-F = 246.0 Hz), 162.3 (d, JC-F = 246.0
Hz), 145.7, 144.8, 134.2, 134.1, 133.7, 131.0 (d, JC-F = 7.5 Hz), 130.6 (d, JC-F = 8.7 Hz), 130.5,
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
129.9 (d, JC-F = 3.7 Hz), 129.7, 129.2 (d, JC-F = 2.5 Hz), 128.7 (d, JC-F = 2.5 Hz), 127.9 (d, JC-F
=
2.5 Hz), 125.7, 125.3, 115.6 (d, JC-F = 21.2 Hz), 115.7 (d, JC-F = 22.5 Hz), 56.9, 49.0. HRMS
(ESI-TOF) m/z: [M+H]+ Calcd for C13H11FN3O3 276.0784; Found 276.0784.
N-Nitroso N-(2-methylbenzyl)-N-(4-nitroaniline) (2bg): The compound was obtained as
yellow liquid. (Yield: 195 mg, 72%). The residue was purified by column chromatography in
silica gel eluting with hexane: EtOAc 90:10, Rf = 0.49. IR (neat): 3737, 2852, 1525, 1115, 905
cm-1. 1H NMR (500 MHz, CDCl3) δ 8.21 (d, J = 9.3 Hz, 2H), 7.62 (d, J = 9.2 Hz, 2H), 7.11 (q, J
= 7.6 Hz, 2H), 6.99 (t, J = 7.3 Hz, 1H), 6.54 (d, J = 7.7 Hz, 1H), 5.13 (s, 2H), 2.26 (s, 3H).
13C{1H} NMR (125 MHz, CDCl3) δ 146.4, 145.8, 134.9, 130.7, 130.4, 127.8, 126.3, 125.2,
125.1, 118.1, 44.4, 19.0. HRMS (ESI-TOF) m/z: [M+H]+ Calcd for C14H14N3O3 272.1035;
Found 272.1033.
N-Nitroso N-(2-methylbenzyl)-N-(2-nitroaniline) (2bg′): The compound was obtained as
yellow viscous liquid. (Yield: 51 mg, 19%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 85:15, Rf = 0.38. IR (neat): 3083, 2895,
1
1898, 1332, 921 cm-1. H NMR (500 MHz, CDCl3) δ 8.09–8.01 (m, 1H), 7.66–7.50 (m, 3H),
7.31–7.19 (m, 3H), 7.18–7.07 (m, 3H), 6.95 (d, J = 7.6 Hz, 1H), 6.61–6.55 (m, 0.55H), 5.95–
5.61 (brs, 1H), 5.19 (s, 2H), 2.37 (s, 2H), 2.22 (s, 3H). 13C{1H} NMR (125 MHz, CDCl3) δ 145.,
145.0, 137.7, 136.2, 134.2, 134.0, 133.5, 131.7, 131.1, 130.9, 130.7, 130.6, 130.6, 130.4, 129.5,
129.2, 129.0, 128.2, 127.8, 126.2, 126.2, 125.5, 125.2, 55.6, 47.3, 19.0, 18.9. HRMS (ESI-TOF)
m/z: [M+H]+ Calcd for C14H14N3O3 272.1035; Found 272.1035.
N-Nitroso N-benzyl-N-(3-methyl-4-nitroaniline) (2bh): The compound was obtained as
yellow viscous liquid. (Yield: 195 mg, 72%). The residue was purified by column
chromatography in silica gel eluting with hexane: EtOAc 90:10, Rf = 0.52. IR (neat): 3821, 2939,
1529, 1131, 811 cm-1. 1H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 9.0 Hz, 1H), 7.53 (d, J = 9.0
Hz, 1H), 7.34-7.26 (m, 3H), 7.07 (d, J = 7.3 Hz, 2H), 5.27 (s, 2H), 2.67 (s, 3H). 13C{1H} NMR
29
ACS Paragon Plus Environment