Metal-Free Thermal Activation of Molecular Oxygen Enabled Direct α-CH2-Oxygenation of Free Amines

Article abstract of DOI:10.1021/acs.joc.7b02630

Direct oxidation of α-CH₂ group of free amines is hard to achieve due to the higher reactivity of amine moiety. Therefore, oxidation of amines involves the use of sophisticated metallic reagents/catalyst in the presence or absence of hazardous oxidants under sensitive reaction conditions. A novel method for direct C-H oxygenation of aliphatic amines through a metal-free activation of molecular oxygen has been developed. Both activated and unactivated free amines were oxygenated efficiently to provide a wide variety of amides (primary, secondary) and lactams under operationally simple conditions without the aid of metallic reagents and toxic oxidants. The method has been applied to the synthesis of highly functionalized amide-containing medicinal drugs, such as O-Me-alibendol and -buclosamide.

Full text of DOI:10.1021/acs.joc.7b02630

Subscriber access provided by READING UNIV
Article
Metal Free Thermal Activation of Molecular Oxygen
Enabled Direct #-CH2-Oxygenation of Free Amines
Santanu Ghosh, and Chandan K. Jana
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02630 • Publication Date (Web): 28 Nov 2017
Downloaded from http://pubs.acs.org on November 29, 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 24
The Journal of Organic Chemistry
1
2
3
4
5
6
Metal Free Thermal Activation of Molecular Oxygen Enabled Direct
αꢀCH2ꢀOxygenation of Free Amines
7
8
9
Santanu Ghosh and Chandan K. Jana*
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
Department of Chemistry, Indian Institute of Technology Guwahati, Guwahati, India, 781039
Eꢀmail: ckjana@iitg.ernet.in
Abstract: Direct oxidation of αꢀCH2 group of free amines is hard to achieve due to the higher reactivity
of amine moiety. Therefore, oxidation of amines involves the use of sophisticated metallic reaꢀ
gents/catalyst in the presence or absence of hazardous oxidants under sensitive reaction conditions. A
novel method for direct CꢀH oxygenation of aliphatic amines through a metal free activation of molecuꢀ
lar oxygen has been developed. Both activated and unactivated free amines were oxygenated efficiently
to provide a wide variety of amides (primary, secondary) and lactams under operationally simple condiꢀ
tions without the aid of metallic reagents and toxic oxidants. The method has been applied to the syntheꢀ
sis of highly functionalized amide containing medicinal drugs, such as OꢀMeꢀalibendol and –
buclosamide.
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
Introduction:
Amides and lactams are ubiquitously found as the core structural unit of both natural and synꢀ
thetic molecules which are relevant to advanced materials and medicines.1 Conventional methꢀ
ods for the amide synthesis utilize coupling reaction of carboxylic acids or its activated derivaꢀ
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 24
1
2
3
4
5
6
7
8
9
tives with amines in the presence of expensive coupling reagents which produce a stoichiometric
amount of byproducts.2 To avoid this drawback, amidation reactions using catalytic amounts of
coupling reagents have been developed.3 Additionally, conversions of alcohol and aldehyde,4,5
oximes and nitrile,6 αꢀketo acids, and αꢀbromo nitroalkanes7 to amides were developed as alterꢀ
native direct methods. However, relatively less number of examples were known for the direct
oxidation of αꢀmethylene group of free amines to corresponding amides because of the higher
reactivity of the amine moiety. The known examples primarily involve metalꢀbased reaꢀ
gents/catalysts or hazardous inorganic and organic oxidants (Scheme 1, eq 1).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 1. Synthesis of amides and lactams via direct oxygenation of amines.
Molecular oxygen would be a viable substitute of hazardous inorganic or organic oxidants.
However, photochemical or metal mediated activation is generally required to activate kinetically
inert oxygen before its reaction with other organic molecules.10 Therefore, in some cases, molecꢀ
ular oxygen acts as the viable oxidant only in the presence of sophisticated metallic reagents/
catalysts.9 Importantly, αꢀoxygenation of free amines to amides is generally hard to achieve due
to the associated side reactions producing corresponding imines and nitriles, and thus protection
of amine moiety is required before oxidation reaction.11 Therefore, the development of novel
2
ACS Paragon Plus Environment

Page 3 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
methodology for direct oxygenation of amines that work under the conditions free of metallic
reagents/catalysts and hazardous oxidants avoiding undesired side reaction would be of particuꢀ
lar importance. Here in, we report the first example of oneꢀstep, metal free and operationally
simple direct oxygenation of free aliphatic amines to amides and lactams using molecular oxyꢀ
gen as the source of amide oxygen (eq 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
A biomimetic domino aminationꢀoxygenation strategy for direct conversion of aldehydes to
amides has been developed recently by our group (eq 3).5 An azomethine ylide related to 1a,5, 12
which was formed from aldehyde and fluorenyl amine, reacted with molecular oxygen/air to
provide the corresponding amide. We anticipated the formation of an iminium ion 1b/zwitterion
1c from the reaction of an aliphatic amine with the suitable ketone or its derivatives (eq 4).12
Subsequent reaction of intermediate zwitterion 1c with molecular oxygen could furnish desired
amides. In this way, direct αꢀoxygenation of free amines to amides can be achieved under metal
and oxidant free conditions without forming undesired side products, such as imines and nitriles.
Results and Discussion:
We began our investigation with a reaction of benzylamine and 9ꢀfluorenone (2a) in the presꢀ
ence of molecular oxygen (Table 1). However, the expected benzamide (3) was not formed (entry
3
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 24
1
2
3
4
5
6
7
8
9
1). Similarly, the reactions in the presence of various other carbonyl compounds were also found
to be unsuccessful in providing the desired benzamide (SI, Table s1). Interestingly, benzylamine
reacted with 9ꢀfluorenone in the presence of Bronsted acid and molecular oxygen to provide the
desired amide with maximum 40% isolated yield (entry 2). This indicated that the initial imine
formation from the amine and carbonyl compound is crucial in achieving the αꢀoxygenation of
amines. We then decided to use 9Hꢀfluorenꢀ9ꢀimine (2b) instead of 9ꢀfluorenone to facilitate the
imine formation via transimination reaction with benzylamine. Expectedly, the desired benꢀ
zamide was isolated with 62% yield from the reaction of benzylamine with 9Hꢀfluorenꢀ9ꢀimine
in refluxing toluene for 4 h under oxygen environment (entry 3). An increase in the yield to 70%
was observed upon an increase in the reaction time to 12 h (entries 4, 5, 7). Further improvement
of the yield was not observed employing other reaction conditions using different solvents, temꢀ
perature, etc. Slightly lower yield was obtained from the reaction in the presence of air as comꢀ
pared to the reaction carried out in the presence of oxygen (entry 13).
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: Screening of reaction conditions.a
entry conditions
Isolated yield (%)
1
2a, oxygen, toluene, RT, 24 h
0
2b
3
2a, oxygen, amberlystꢀ15, toluene, reflux, 24 h
2b, oxygen, toluene, reflux, 4 h
40
62
4
ACS Paragon Plus Environment

Page 5 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
4
2b, oxygen, toluene, reflux, 8 h
67
70
65
70
25
65
70
70
69
57
48
72
15
5
5
2b, oxygen, toluene, reflux, 12 h
2b, oxygen, toluene, 80 oC, 24 h
2b, oxygen, toluene, reflux, 24 h
2b, oxygen, toluene, reflux, 24 h
2b, oxygen, benzene, reflux, 24 h
2b, oxygen, Et3N, toluene, reflux, 12 h
2b, oxygen, xylene, reflux, 12 h
2b, oxygen, xylene, 110 oC, 12 h
2b, toluene 110 oC, 12 h
6
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
8c
9
10d
11
12
13e
14d, e 2b, toluene 110 oC, Et3N, 12 h
15
16
17
2b, oxygen, tBuOK, toluene, reflux, 12 h
2b, oxygen, DCM, reflux, 24 h
2b, oxygen, toluene, RT, 24 h
aAmine (0.56 mmol) was reacted with 2 (0.56 mmol) in air or oxygen atmosphere. Use of 50
b
mol% of the 2a provided only 35% yield. Catalytic (20 mol%) amount of 2b was used. dReacꢀ
c
e
tions were carried out in the presence of 20 mol% of triethylamine. Reactions were performed
in the presence of an air balloon.
Next, the best conditions were used to investigate the substrate scope of this novel amidation
reaction (Scheme 2). Arylmethylamines having electron donating as well as electron withdrawꢀ
ing groups at different positions of aryl moiety provided the desired benzamides 5aꢀp with good
5
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 24
1
2
3
4
5
6
7
8
9
to moderate yields. Amines containing heteroaryl group like picolylamine or 2ꢀamino furan also
reacted smoothly to afford corresponding amides 5q and 5r, respectively. Importantly, selective
αꢀoxygenation of amines occurred to provide the corresponding amides while other reactive hetꢀ
eroꢀfunctional groups (e.g, –OR, ꢀBr, ꢀF, ꢀCl, ꢀNMe2) remained unreacted.
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 2. Scope of oxygenation of primary aromatic and aliphatic amines.
O
2b
9-fluorenone
+
R
NH2
R
NH2
O2, toluene
reflux, 12-60 h
R= aryl, alkyl
5a-r, 6a-f
aromatic amides
5a, R = OMe, 70%
O
NH2
O
NH2
O
NH2
R
5b, R = Cl, 70%
5c, R = Me, 64%
5d, R = OCF3, 60%
5e, R = NMe2, 65%
5f, R = F, 58%
R
5g, R = CF3, 52%
5h, R = Cl, 60%
5i, R = F, 55%
5j, R = Br, 50%
5k, R = OMe, 55%
R
O
NH2
O
NH2
O
NH2
O
NH2
O
NH2
Cl
OMe MeO
OMe
Cl
OMe
5l, 65%
OMe
5m, 60%
Cl
5n, 54%
Cl
5p, 50%
5o, 60%
aliphatic amides
O
6a, n = 5, 40%
O
6b, n = 7, 48%
6c, n = 9, 55%
6d, n = 11, 54%
6e, n = 13, 53%
6f, n = 15, 51%
NH2
O
N
O
NH2
( )n
NH2
5q, 57 %
5r, 70 %
The scope of direct CꢀH oxygenation of unactivated aliphatic primary amines was tested next.
Accordingly, the long chain aliphatic primary amines with varying chain lengths were reacted to
obtain corresponding amides 6aꢀf. Higher reaction time (60 h) was required to obtain the amides
with moderate to good yields.
6
ACS Paragon Plus Environment

Page 7 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
Scheme 3. Scope in oxidation of secondary acyclic and cyclic amines.
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
With the success in oxygenation of primary amines, reactions using secondary amines were
carried out to examine the generality of this method (Scheme 3). Oxidation of cyclic and acyclic
aliphatic secondary amines occurred smoothly to yield corresponding secondary benzamides 7aꢀf
and lactams 7gꢀj, respectively. A longer reaction time (24 h) of secondary amines as compared to
that of primary benzylamines was necessary for good conversion due to the reduced reactivity of
sterically demanding secondary amines. However, Nꢀsubstituted benzamides 7aꢀf were isolated
with slightly lower yields as compared to lactams. Interestingly, αꢀCꢀH oxygenation of pyrroliꢀ
dine was achieved using 9ꢀfluorenone to obtain γꢀlactam with 60% isolated yield (SI, Table s2).
However, better yields of the lactams were obtained using 9Hꢀfluorenꢀ9ꢀimine (2b). Tetrahydroiꢀ
soquinoline gave the highest yield (82%) of the desired lactam.
To demonstrate the synthetic utility of this method, a reaction of benzylamine was carried out
in gram scale (1.8 g) under optimized conditions to afford the desired benzamides in grams quanꢀ
7
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 24
1
2
3
4
5
6
tity (1.1 g). 9ꢀfluorenone, which was produced (with 88%) as the only by product, can be easily
separated via simple washing and recycled after its conversion to 9Hꢀfluorenꢀ9ꢀimine.
7
8
9
Different mechanistic possibilities, which are shown in scheme 4a, may be operative for the diꢀ
rect conversion of amines to corresponding amides and lactams. Direct oxidation of amines 8 by
molecular oxygen followed by reaction of resulting imines 9 (via 10) under oxidizing conditions
may lead to corresponding amides 11.13 Conversion of imines 9 to corresponding nitriles 12 and
its subsequent hydrolysis could also be another pathway for formation of amide 13. These mechꢀ
anistic possibilities can be eliminated as the reaction of only benzylamine under optimized conꢀ
ditions did not produce the desired amide (Scheme 4b, eq 5). On the other hand, the reaction of
preformed imine 17a under the same reaction conditions provided the desired benzamide with
60% yield (eq 6). However, the yield of benzamide increased to 72% when the reaction was carꢀ
ried out in the presence of catalytic amount of triethylamine. Therefore, the reaction proceeded
through the imine/iminum ion 14 which could be formed from the condensation of amine 8 and
9Hꢀfluorenꢀ9ꢀimine (2b). Amine assisted deprotonation of 14 to form the azomethine anion/ylide
15 which subsequently reacted with molecular oxygen to provide the peroxide intermediate
16.12g Related 1,2,4ꢀdioxazolidine were known to be prepared from the reaction of αꢀ
hydroperoxyꢀamine with carbonyl compounds and from the reaction of carbonyl oxide with
imine.14 Thermal disintegration of peroxide 16 provided the desired amide/lactam and 9ꢀ
fluorenone.5, 14 Interestingly, imine 17b derived from benzaldehyde and benzylamine did not
provide the desired amides under the standard conditions (eq 7). Therefore, easy formation of
azomethine anion/ylide 15 and its enhanced stability due to the aromatic nature of fluorenyl aniꢀ
on turned out to be crucial for this transformation.
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
8
ACS Paragon Plus Environment

Page 9 of 24
The Journal of Organic Chemistry
1
2
3
4
Scheme 4. (a) Proposed mechanism. (b) Controlled and labelling experiments.
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
Alternatively, imine/iminum ion 14 or its regioisomer could participate in an Alderꢀene reacꢀ
tion with singlet oxygen to produce corresponding hydroperoxides which could subsequently
react directly or through the formation of 16 to provide the desired amide.15 However, the reacꢀ
tion of imine 17b in the presence of either 2a or 2b did not produce the desired amide under
9
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 24
1
2
3
4
5
6
7
8
standard reaction condition (eq 7). Moreover, the desired amide was formed with 68% from a
reaction which was carried out without exposing the reaction mixture to the light (eq 8). Thereꢀ
fore, these observations are unsupportive to the singletꢀoxygenꢀene reaction pathway.
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
pꢀChlorobenzylamine and 2b were reacted under standard reaction conditions in the presence
18
of H2O18 to identify the source of amide oxygen (eq 9). Expectedly, the formation of Oꢀamide
was not observed which supported our proposed mechanism that the amide oxygen has been inꢀ
corporated from molecular O2 and not from H2O. Incorporation of 31% 18O into 9ꢀfluorenone
occurred through the partial hydrolysis of 9Hꢀfluorenꢀ9ꢀimine in the presence of H218O.
Scheme 5. Application in syntheses of medicinal drugs and their derivatives.
10
ACS Paragon Plus Environment

Page 11 of 24
The Journal of Organic Chemistry
1
2
3
4
(a) (i) Me2SO4, K2CO3, acetone, reflux, 12 h, 90%, (ii) 2ꢀaminoethanol, 4 Å MS, DCM, rt, 12
5
6
o
h, 85%, (iii) NaCNBH3, MeOH, 40 C, 4 h, 95%; (b) (i) Me2SO4, K2CO3, acetone, reflux, 12 h,
7
8
80%, (ii) nꢀbutylamine, 4 Å MS, DCM, rt, 12 h, 88%, (iii) NaCNBH3, MeOH, 40 oC, 4 h, 90%;
9
o
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
(c) (i) 2ꢀphenylethanamine, 4 Å MS, DCM, rt, 12 h, 88%; (ii) NaCNBH3, MeOH, 40 C, 4 h,
90%; (d) (i) Me2SO4, K2CO3, acetone, reflux, 12 h, 78%; (ii) 2ꢀphenylethanamine, 4 Å MS,
o
DCM, rt, 12 h, 85%, (iii) NaCNBH3, MeOH, 40 C, 4 h, 90%. eYields based on recovered startꢀ
ing materials.
Amide functionality in medicinal drugs is generally installed via condensation of the correꢀ
sponding carboxylic acid derivatives with the amines. The overall synthetic sequence involve the
use of toxic oxidants and coupling reagents.16 We applied this novel strategy for the direct conꢀ
version of amines to amides under metal and toxic oxidant free conditions for the synthesis of the
analogues of amide containing medicinal drugs (Scheme 5). OꢀMeꢀalibendol 19a and –
buclosamide 19b were obtained readily from the reaction of respective secondary amines 18a
and 18b, which were prepared from commercially available aldehydes. Similarly, a derivative of
bezafibrate 19c and synthetic precursor 19d for glibenclamide were prepared from benzyl amines
18c and 18d, respectively.
Conclusion:
In summary, we have developed a conceptually novel method for direct αꢀoxidation of free aliꢀ
phatic amines to amides and lactams without the aid of metallic reagents and toxic oxidants. αꢀ
C(sp3)ꢀH oxygenation was achieved through a metal free thermal activation of molecular oxyꢀ
gen. The reaction is operationally simple, efficient and applicable to a broad class of primary
amines (activated benzyl or unactivated alkyl amines), cyclic and acyclic secondary amines. The
11
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 24
1
2
3
4
elegant syntheses of highly functionalized Nꢀalkyl benzamide moieties of medicinal drugs using
5
6
this method showed its synthetic potential.
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
Experimental Section:
General: All reactions involving airꢀ or moistureꢀsensitive reagents or intermediates were carꢀ
ried out in ovenꢀdried glassware under an argon atmosphere. Commercial grade dichloromethane
(CH2Cl2), xylene, benzene and toluene were distilled over CaH2 before use. All other solvents
and reagents were purified according to standard procedures or were used as received from Alꢀ
drich, Acros, Merck and Spectrochem. H, 13C NMR spectroscopy: Varian Mercury plus 400
1
MHz, Bruker 600 MHz, Jeol 400 MHz (at 298 K). Chemical shifts, δ (in ppm), are reported relaꢀ
tive to TMS δ (1H) 0.0 ppm, δ (13C) 0.0 ppm) which was used as the inner reference. Otherwise,
the solvents residual proton resonance and carbon resonance (CHCl3, δ (1H) 7.26 ppm, δ (13C)
77.2 ppm; CD3OD, (1H) 3.31 ppm, δ (13C) 49.0 ppm) were used for calibration. Column chromaꢀ
tography: Merck or Spectrochem silica gel 60ꢀ120 under gravity. MS (ESIꢀHRMS): Mass spectra
were recorded on an Agilent AccurateꢀMass QꢀTOF LC/MS 6520, and peaks are given in m/z (%
of basis peak).
General procedure for the synthesis of aryl amides from primary benzylamines (I):
Primary amine (0.56 mmol) was added to a solution of 9Hꢀfluorenꢀ9ꢀimine (1 equiv) in toluene
(2 mL) and the mixture was refluxed for 12 h. After the disappearance of the starting material
indicated from TLC, solvent was evaporated in vacuum and crude product was subjected to silica
gel chromatography (EtOAc: hexane, 1:1) to afford the analytically pure amides.
12
ACS Paragon Plus Environment

Page 13 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
Benzamide4d (3): White solid (47 mg, 70%). 4ꢀMethoxybenzamide 5 (5a): White solid (60 mg,
70%). 4ꢀChlorobenzamide4d (5b): White solid (61 mg, 70%). 4ꢀMethylbenzamide4d (5c):
White solid (49 mg, 65%). 4ꢀ(trifluoromethoxy)benzamide4c (5d): White solid (69 mg, 60%).
4ꢀ(dimethylamino)benzamide5 (5e): White solid (60 mg, 65%). 4ꢀFluorobenzamide8c (5f):
White solid (45 mg, 58%). 4ꢀ(trifluoromethyl)benzamide8f (5g): White solid (53 mg, 50%). 2ꢀ
Chlorobenzamide5 (5h): White solid (52 mg, 60%). 2ꢀFluorobenzamide6g (5i): White solid
(43 mg, 55%). 3ꢀBromobenzamide5 (5j): White solid (56 mg, 50%). 3ꢀMethoxybenzamide8c
(5k): White solid (47 mg, 55%). 3,4ꢀDimethoxybenzamide5 (5l): White solid (66 mg, 65%).
3,4,5ꢀTrimethoxybenzamide5 (5m): White solid (72 mg, 60%). 3,4ꢀDichlorobenzamide17c
(5n): White solid (68 mg, 54%). 2,4ꢀDichlorobenzamide5 (5o): White solid (67 mg, 63%). 1ꢀ
Naphthamide4d (5p): White solid (48 mg, 50%). Picolinamide4d (5q): White solid (38 mg,
56%). Furanꢀ2ꢀcarboxamide 5 (5r): White solid (44 mg, 70%).
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
General procedure for the synthesis of primary aliphatic amides from primary amines (GP
II): Primary amine (0.56 mmol) was added to a solution of 9Hꢀfluorenꢀ9ꢀimine (1 equiv) in toluꢀ
ene (2 mL) and the mixture was refluxed for 60 h. After the disappearance of the starting materiꢀ
al indicated from TLC, solvent was evaporated in vacuum and crude product was subjected to
silica gel chromatography (EtOAc: hexane, 1:1) to afford the analytically pure amides.
Octanamide11c (6a): White solid (32 mg, 40%). Decanamide17e (6b): White solid (46 mg,
48%). Dodecanamide11c (6c): White solid (62 mg, 55%). Tetradecanamide17a (6d): White solid
(69 mg, 54%).
Palmitamide (6e): According to general procedure II, hexadecylamine (0.14 mL, 0.56 mmol)
and 9Hꢀfluorenꢀ9ꢀimine 2b (0.10 g, 0.56 mmol) in toluene (2 mL) were refluxed for 60 h and
13
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 24
1
2
3
4
5
6
7
8
9
column chromatography (silica gel; EtOAc: hexane, 1:1) of the crude product gave 6e as white
solid (76 mg, 53%). Mp 103ꢀ104 oC. 1H NMR (600 MHz, CDCl3) δ = 5.48 (s, 1H), 5.42 (s, 1H),
2.21 (t, J = 7.8 Hz, 2H), 1.65 – 1.60 (m, 2H), 1.33 – 1.24 (m, 24H), 0.87 (t, J = 7.2 Hz, 3H) ppm.
13C NMR (151 MHz, CDCl3) δ = 175.8, 36.2, 32.1, 29.89, 29.87, 29.85, 29.80, 29.7, 29.6, 29.5,
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
13
29.4, 25.7, 22.9, 14.3 ppm. (Reduced numbers of C signals is observed due to overlapping).
HRMS (ESIꢀTOF) m/z: ([M+H]+) calculated for C16H34NO 256.2635; Found 256.2638.
Stearamide (6f): According to general procedure II, octadecylamine (0.15 mL, 0.56 mmol) and
9Hꢀfluorenꢀ9ꢀimine 2b (0.10 g, 0.56 mmol) in toluene (2 mL) were refluxed for 60 h and column
chromatography (silica gel; EtOAc: hexane, 1:1) of crude gave 6f as white solid (82 mg, 51%).
Mp 106ꢀ107 oC. H NMR (600 MHz, CDCl3) δ = 5.51 (s, 1H), 5.42 (s, 1H), 2.21 (t, J = 7.8 Hz,
1
13
2H), 1.65 – 1.60 (m, 2H), 1.34 – 1.22 (s, 28H), 0.88 (t, J = 6.9 Hz, 3H) ppm. C NMR (151
MHz, CDCl3) δ = 175.8, 36.1, 32.1, 29.9, 29.83, 29.78, 29.65, 29.5, 29.4, 25.7, 22.9, 14.3 ppm.
(Reduced numbers of 13C signals is observed due to overlapping). HRMS (ESIꢀTOF) m/z:
([M+H]+) calculated for C18H38NO 284.2948; Found 284.2946.
General procedure for the synthesis of Secondary Amides or lactams from secondary acyꢀ
clic or cyclic amines (III):
Secondary acyclic or cyclic amine (0.56 mmol) was added to a solution of 9Hꢀfluorenꢀ9ꢀimine
(0.56 mmol) in toluene (2 mL) and the mixture was refluxed for 24 h. After the disappearance of
the starting material indicated from TLC, solvent was evaporated in vacuum and crude product
was subjected to silica gel chromatography (silica gel; EtOAc: hexane, 1:1) to afford the analytiꢀ
cally pure amides and lactams.
4ꢀMethoxyꢀNꢀmethylbenzamide5 (7a): White solid (37 mg, 40%).
14
ACS Paragon Plus Environment

Page 15 of 24
The Journal of Organic Chemistry
1
2
3
4
5
Nꢀethylꢀ4ꢀmethoxybenzamide5 (7b): Column chromatography (silica gel; EtOAc: hexane, 1:2)
gave 7b as an oil (50 mg, 50%).
6
7
8
9
4ꢀMethoxyꢀNꢀpropylbenzamide5 (7c): Column chromatography (silica gel; EtOAc: hexane,
1:3) gave 7c as an oil (60 mg, 55%).
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
Nꢀbutylꢀ4ꢀmethoxybenzamide5 (7d): Column chromatography (silica gel; EtOAc: hexane, 1:3)
gave 7d as an oil (50 mg, 40%).
4ꢀChloroꢀNꢀmethylbenzamide5 (7e): White solid (48 mg, 50%).
Nꢀ(2ꢀhydroxyethyl)benzamide17f (7f): Column chromatography (silica gel; EtOAc: hexane,
2:1) gave 7f as an oil (50 mg, 54%).
Pyrrolidinꢀ2ꢀone8a (7g): Oil (36 mg, 75%).
Isoindolinꢀ1ꢀone17b (7h): White solid (43 mg, 57%).
3,4ꢀDihydroisoquinolinꢀ1(2H)ꢀone9d (7i): Oil (71 mg, 82%).
3,4ꢀDihydroꢀ6,7ꢀdimethoxyisoquinolinꢀ1(2H)ꢀone17d (7j): Column chromatography (silica gel;
EtOAc: hexane, 2:1) gave 7j as white solid (88 mg, 76%).
2ꢀ(5ꢀallylꢀ2,3ꢀdimethoxybenzylamino)ethanol
(18a):
5ꢀallylꢀ2ꢀhydroxyꢀ3ꢀ
methoxybenzaldehyde (0.28 g, 1.43 mmol), dimethyl sulphate (0.54 g, 4.30 mmol ) and
potassium carbonate (0.59 g, 4.30 mmol) in acetone (5 mL) were refluxed for 12 h. After
completetion of the starting materials (indicated from TLC), solvent was evaporated and residue
was purified by coloum chromatography (silica gel; EtOAc: hexane, 1:20) to afford 5ꢀallylꢀ2,3ꢀ
dimethoxybenzaldehyde as an oil (0.27 g, 90%). Then 5ꢀallylꢀ2,3ꢀdimethoxybenzaldehyde (0.10
15
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 24
1
2
3
4
5
6
7
8
9
g, 0.49 mmol) and ethanolamine (30 mg, 0.49 mmol) were dissolved in dichloromethane (3 mL)
and the mixture was stirred at room temperature for 12 h in the presence of 4Å MS (0.1 g). After
consumption of starting material, molecular sieves were filtered out and the solvent was evapoꢀ
rated to give 2ꢀ(5ꢀallylꢀ2,3ꢀdimethoxybenzylideneamino)ethanol (0.10 g, 85%). 2ꢀ(5ꢀallylꢀ2,3ꢀ
dimethoxybenzylideneamino)ethanol (0.10 g, 0.40 mmol) was treated with sodium cyanoboroꢀ
hydride (51 mg, 0.80 mmol ) in MeOH (3 mL) at 40 °C for 4 h. MeOH was then evaporated and
residue was diluted with EtOAc (10 mL) and brine (10 mL). The mixture was extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed (20 mL of brine and 20 mL of
water), dried (Na2SO4) and concentrated in vaccua. Colum chromatography (silica gel; EtOAc:
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
1
hexane, 1:3) of the residue gave 18a as an oil (94 mg, 95%). H NMR (400 MHz, CDCl3) δ =
6.77 (s, 1H), 6.64 (s, 1H), 5.94 – 5.89 (m, 1H), 5.10 – 5.05 (m, 2H), 3.84 (s, 3H), 3.76 (s, 3H),
13
3.62 – 3.57 (m, 4H), 3.32 (d, J = 6.5 Hz, 2H), 2.63 – 2.60 (m, 2H) ppm. C NMR (151 MHz,
CDCl3) δ = 152.5, 146.1, 137.4, 135.6, 132.4, 122.5, 115.8, 111.6, 60.7, 58.9, 55.7, 54.9, 52.3,
40.1 ppm. HRMS (ESIꢀTOF) m/z: ([M+H]+) calculated for C14H22NO3 252.1594; Found
252.1594.
5ꢀAllylꢀNꢀ(2ꢀhydroxyethyl)ꢀ2,3ꢀdimethoxybenzamide (19a): According to general procedure
III, 2ꢀ(5ꢀallylꢀ2,3ꢀdimethoxybenzylamino)ethanol (18a) (75 mg, 0.30 mmol) and 9Hꢀfluorenꢀ9ꢀ
imine, 2b (80 mg, 0.45 mmol) in toluene (2 mL) were refluxed for 60 h and column chromatogꢀ
raphy (silica gel; EtOAc: hexane, 2:1) of the crude product gave 19a as an oil (30 mg, 38%)
1
along with starting material 18a (23 mg, 30%). H NMR (400 MHz, CDCl3) δ = 8.45 (s, 1H),
7.52 (s, 1H), 6.87 (s, 1H), 6.01 – 5.88 (m, 1H), 5.12 – 5.07 (m, 2H), 3.88 (s, 6H), 3.84 – 3.81 (m,
2H), 3.65 – 3.61 (m, 2H), 3.37 (d, J = 6.8 Hz, 2H) ppm. 13C NMR (151 MHz, CDCl3) δ = 166.7,
16
ACS Paragon Plus Environment

Page 17 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
152.5, 145.9, 136.8, 136.6, 125.8, 122.4, 116.4, 115.9, 62.9, 61.4, 56.1, 42.9, 40.0 ppm. HRMS
(ESIꢀTOF) m/z: ([M+H]+) calculated for C14H20NO4 266.1387; Found 266.1398.
7
8
9
Nꢀ(4ꢀchloroꢀ2ꢀmethoxybenzyl)butanꢀ1ꢀamine (18b): 4ꢀchloroꢀ2ꢀhydroxybenzaldehyde (0.25 g,
1.61 mmol), dimethyl sulphate (0.61 g, 4.84 mmol ) and potassium carbonate (0.67 g, 4.84 mmol
) in acetone (5 mL) were refluxed for 12 h. After completetion of the starting materials (indicated
from TLC), solvent was evaporated and the residue was purified by coloum chromatography
(silica gel; EtOAc: hexane, 1:20) to afford 4ꢀchloroꢀ2ꢀmethoxybenzaldehyde as a white solid
(0.22 g, 80%). Then 4ꢀchloroꢀ2ꢀmethoxybenzaldehyde (0.1 g, 0.59 mmol) and nꢀbutylamine (43
mg, 0.59 mmol) were dissolved in dichloromethane (3 mL) and the mixture was stirred at room
temperature for 12 h in the presence of 4Å MS (0.1 g). After consumption of starting material,
molecular sieves were filtered out and the solvent was evaporated to give Nꢀ(4ꢀchloroꢀ2ꢀ
methoxybenzylidene)butanꢀ1ꢀamine (0.12 g, 88%). Nꢀ(4ꢀchloroꢀ2ꢀmethoxybenzylidene)butanꢀ1ꢀ
amine (0.1 g, 0.44 mmol) was treated with sodium cyanoborohydride (56 mg, 0.89 mmol ) in
MeOH (3 mL) at 40 °C for 4 h . MeOH was evaporated and residue was diluted with EtOAc (10
mL) and brine (10 mL). The mixture was extracted with EtOAc (3 × 20 mL). The combined orꢀ
ganic layers were washed (20 mL of brine and 20 mL of water), dried (Na2SO4) and concentratꢀ
ed in vaccua. Colum chromatography (silica gel; EtOAc: hexane, 1:1) of the residue gave 18b as
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
1
an oil (91 mg, 90%). H NMR (400 MHz, CDCl3) δ = 7.22 (d, J = 2.8 Hz, 1H), 7.16 (dd, J = 8.6,
2.6 Hz, 1H), 6.76 (d, J = 8.8 Hz, 1H), 3.80 (s, 3H), 3.72 (s, 2H), 2.59 – 2.55 (m, 2H), 1.51 – 1.44
13
(m, 2H), 1.37 – 1.30 (m, 2H), 0.89 (t, J = 7.2 Hz, 3H) ppm. C NMR (151 MHz, CDCl3) δ =
156.2, 130.4, 129.5, 127.6, 125.3, 111.3, 55.6, 49.0, 48.8, 32.2, 20.5, 14.0 ppm. HRMS (ESIꢀ
TOF) m/z: ([M+H]+) calculated for C12H19ClNO 228.1150; Found 228.1155.
17
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 24
1
2
3
4
5
6
7
8
9
Nꢀbutylꢀ4ꢀchloroꢀ2ꢀmethoxybenzamide (19b): According to general procedure III: (E)ꢀNꢀ(4ꢀ
chloroꢀ2ꢀmethoxybenzylidene)butanꢀ1ꢀamine (18b) (68 mg, 0.30 mmol) and 9Hꢀfluorenꢀ9ꢀ
imine, 2b (80 mg, 0.45 mmol) in toluene (2 mL) were refluxed for 60 h and column chromatogꢀ
raphy (silica gel; EtOAc: hexane, 2:1) of the crude product gave 19b as an oil (32 mg, 45%)
along with starting material 18a (14 mg, 21%). 1H NMR (400 MHz, CDCl3) δ = 8.17 (d, J = 2.8
Hz, 1H), 7.79 (s, 1H), 7.37 (dd, J = 8.8, 2.8 Hz, 1H), 6.91 (d, J = 8.8 Hz, 1H), 3.95 (s, 3H), 3.48
– 3.43 (m, 2H), 1.63 – 1.56 (m, 2H), 1.44 – 1.38 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H) ppm. 13C NMR
(101 MHz, CDCl3) δ = 164.0, 156.0, 132.2, 132.1, 126.9, 123.3, 112.9, 56.4, 39.7, 31.7, 20.3,
13.9 ppm. HRMS (ESIꢀTOF) m/z: ([M+H]+) calculated for C12H17ClNO2 242.0942; Found
242.0950.
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
Nꢀ(4ꢀchlorobenzyl)ꢀ2ꢀphenylethanamine (18c): 4ꢀchlorobenzaldehyde (0.20 g, 1.43 mmol) and
2ꢀphenylethanamine (0.17 g, 1.43 mmol) were dissolved in dichloromethane (3 mL) and the mixꢀ
ture was stirred at room temperature for 12 h in the presence of 4Å MS (0.20 g). After consumpꢀ
tion of starting material, molecular sieves were filtered out and the solvent was evaporated to obꢀ
tain the imine Nꢀ(4ꢀchlorobenzylidene)ꢀ2ꢀphenylethanamine (0.30 g, 88%). Nꢀ(4ꢀ
chlorobenzylidene)ꢀ2ꢀphenylethanamine (0.10 g, 0.41 mmol) was treated with sodium cyanoboꢀ
rohydride (52 mg, 0.82 mmol) in MeOH (3 mL) at 40 °C for 4 h. MeOH was evaporated and resꢀ
idue was diluted with EtOAc (10 mL) and brine (10 mL). The mixture was extracted with EtOAc
(3 × 20 mL). The combined organic layers were washed (20 mL of brine and 20 mL of water),
dried (Na2SO4) and concentrated in vaccua. Colum chromatography (silica gel; EtOAc: hexane,
1:3) of the residue gave 18c as an oil, (91 mg, 90%).1H NMR (600 MHz, CDCl3) δ = 7.37 – 7.32
13
(m, 4H), 7.29 – 7.26 (m, 5H), 3.81 (s, 2H), 2.96 – 293 (m, 2H), 2.89 – 2.87 (m, 2H) ppm. C
NMR (151 MHz, CDCl3) δ = 140.0, 138.9, 132.6, 129.5, 128.8, 128.6, 128.5, 126.3, 53.1, 50.5,
18
ACS Paragon Plus Environment

Page 19 of 24
The Journal of Organic Chemistry
1
2
3
4
5
36.4 ppm. HRMS (ESIꢀTOF) m/z: ([M+H]+) calculated for C15H17ClN 246.1044; Found
246.1038.
6
7
8
9
4ꢀChloroꢀNꢀphenethylbenzamide (19c): According to general procedure III, Nꢀ(4ꢀ
chlorobenzyl)ꢀ2ꢀphenylethanamine (18c) (73 mg, 0.30 mmol) and 9Hꢀfluorenꢀ9ꢀimine, 2b (80
mg, 0.45 mmol) in toluene (2 mL) were refluxed for 60 h and column chromatography (silica
gel; EtOAc: hexane, 2:1) of the crude product gave 19c as an oil (39 mg, 51%) along with startꢀ
ing material 18c (29 mg 40%). 1H NMR (400 MHz, CDCl3) δ = 7.63 – 7.60 (m, 2H), 7.39 – 7.31
(m, 4H), 7.27 – 7.22 (m, 3H), 6.14 (s, 1H), 3.71 (q, J = 6.8 Hz, 2H), 2.93 (t, J = 6.8 Hz, 2H)
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
ppm. C NMR (101 MHz, CDCl3) δ = 166.5, 138.8, 137.7, 133.1, 128.9, 128.9, 128.9, 128.3,
126.8, 41.3, 35.7 ppm. HRMS (ESIꢀTOF) m/z: ([M+H]+) calculated for C15H15ClNO 260.0837;
Found 260.0836.
Nꢀ(5ꢀchloroꢀ2ꢀmethoxybenzyl)ꢀ2ꢀphenylethanamine (18d): 5ꢀchloroꢀ2ꢀhydroxybenzaldehyde
(0.28 g, 1.77 mmol), dimethyl sulphate (0.67 g, 5.32 mmol ) and potassium carbonate (0.73 g,
5.32 mmol) in acetone (5 mL) were refluxed for 12 h. After completetion of the starting
materials (indicated from TLC), solvent was evaporated and residue was purified by coloum
chromatography (silica gel; EtOAc: hexane, 1:20) to afford 5ꢀchloroꢀ2ꢀmethoxybenzaldehyde as
white solid (0.23 g, 78%). Then 5ꢀchloroꢀ2ꢀmethoxybenzaldehyde (0.12 mg, 0.71 mmol) and
pnenylethanamine (85 mg, 0.71 mmol) were dissolved in dichloromethane (3 mL) and stirred at
room temperature for 12 h in the presence of 4Å MS (0.12 g). After consumption of starting maꢀ
terial, molecular sieves were filtered out and the solvent was evaporated to obtain the imine, Nꢀ
(5ꢀchloroꢀ2ꢀmethoxybenzylidene)ꢀ2ꢀphenylethanamine (0.16 g, 85%). Nꢀ(5ꢀchloroꢀ2ꢀ
methoxybenzylidene)ꢀ2ꢀphenylethanamine (0.15 g, 0.55 mmol) was treated with sodium cyanoꢀ
borohydride (69 mg, 1.10 mmol) in MeOH (3 mL) at 40 °C for 4 h. MeOH was evaporated and
19
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 24
1
2
3
4
5
6
7
8
9
residue was diluted with EtOAc (10 mL) and brine (10 mL). The mixture was extracted with
EtOAc (3 × 20 mL). The combined organic layers were washed (20 mL of brine and 20 mL of
water), dried (Na2SO4) and concentrated in vaccua. Colum chromatography (silica gel; EtOAc:
hexane, 1:2) of the residue gave 18d as an oil (0.14 g, 90%).1H NMR (400 MHz, CDCl3) δ =
7.30 – 7.27 (m, 2H), 7.22 – 7.15 (m, 5H), 6.73 (d, J = 8.8 Hz, 1H), 3.76 (s, 2H), 3.70 (s, 3H),
2.88 – 2.80 (m, 4H) ppm. 13C NMR (151 MHz, CDCl3) δ = 156.1, 139.8, 129.63, 129.58, 128.7,
128.5, 127.8, 126.2, 125.3, 111.3, 55.4, 50.1, 48.7, 36.1 ppm. HRMS (ESIꢀTOF) m/z: ([M+H]+)
calculated for C16H19ClNO 276.1150; Found 276.1157.
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
5ꢀChloroꢀ2ꢀmethoxyꢀNꢀphenethylbenzamide(19d): According to general procedure III, Nꢀ(5ꢀ
chloroꢀ2ꢀmethoxybenzyl)ꢀ2ꢀphenylethanamine (18d) (82 mg, 0.30 mmol) and 9Hꢀfluorenꢀ9ꢀ
imine, 2b (80 mg, 0.45 mmol) in toluene (2 mL) were refluxed for 60 h and column chromatogꢀ
raphy of crude product (silica gel; EtOAc: hexane, 2:1) gave 19d as an oil (38 mg, 44%) along
1
with starting material 18d (23 mg, 28%). H NMR (400 MHz, CDCl3) δ = 8.17 (d, J = 2.8 Hz,
1H), 7.83 (s, 1H), 7.36 – 7.32 (m, 3H), 7.27 – 7.24 (m, 3H), 6.84 (d, J = 8.8 Hz, 1H), 3.78 – 3.75
13
(m, 2H), 3.73 (s, 3H), 2.92 (t, J = 6.8 Hz, 2H) ppm. C NMR (151 MHz, CDCl3) δ = 163.9,
155.9, 139.2, 132.2, 132.0, 128.9, 128.6, 126.7, 126.5, 122.9, 112.7, 56.0, 40.9, 35.5 ppm.
HRMS (ESIꢀTOF) m/z: ([M+H]+) calculated for C16H17ClNO2 290.0942; Found 290.0949.
ASSOCIATED CONTENT
Supporting Information
Additional tables and copies of NMR spectra supplied as Supporting Information.
AUTHOR INFORMATION
Corresponding Author
20
ACS Paragon Plus Environment

Page 21 of 24
The Journal of Organic Chemistry
1
2
3
4
* ckjana@iitg.ernet.in
5
6
Notes
7
8
The authors declare no competing financial interest.
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
ACKNOWLEDGMENT
We acknowledge financial support from SERB and CSIR.
REFERENCES
(1) (a) Breneman,C. M., Greenberg A., Liebman, J. F., Eds. The Amide Linkage: Structural Sigꢀ
nificance in Chemistry, Biochemistry, and Materials Science; John Wiley & Sons: New York,
USA, 2002. Selected reports: (b) Asbum, C.; Castro, O. J. Nat. Prod. 1988, 51, 817. (c) Ananꢀ
thanarayanan, V. S.; Tetreault, S.; SaintꢀJean, A. J. Med.Chem. 1993, 36, 1324. (d) Patchett, A. A.
J. Med. Chem. 1993, 36, 2051. (e) Feling, R. H.; Buchanan, G. O.; Mincer, T. J.; Kauffman, C.
A.; Jensen, P. R.; Fenical, W. Angew. Chem. Int. Ed. 2003, 42, 355.
(2) (a) Montalbetti, C. A. G. N.; Falque, V. Tetrahedron 2005, 61, 10827. (b) Valeur, E.; Bradley,
M. Chem. Soc. Rev. 2009, 38, 606. (c) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471.
(3) Lundberg, H.; Tinnis, F.; Selander, N.; Adolfsson, H. Chem. Soc. Rev. 2014, 43, 2714.
(4) For review, see: (a) EkoueꢀKovi, K.; Wolf, C. Chem. Eur. J. 2008, 14, 6302. (b) Allen, C. L.;
Williams, J. M. J. Chem. Soc. Rev. 2011, 40, 3405. for selected reports, see: (c) Owston, N. A.;
Parker, A. J.; Williams, J. M. J. Org. Lett. 2007, 9, 73. (d) Yamaguchi, K.; Kobayashi, H.; Oishi,
T.; Mizuno, N. Angew. Chem. Int. Ed. 2012, 51, 544. (e) Gualtierotti, J.; Schumacher, X.; Fonꢀ
taine, P.; Masson, G.; Wang, Q.; Zhu, J. Chem. Eur. J. 2012, 18, 14812. (f) Vanjari, R.; Guntreddi,
T.; Singh, K. N. Green Chem. 2014, 16, 351. (g) Miyamura, H.; Min, H.; Soule, JꢀF.; Kobayashi,
21
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 24
1
2
3
4
5
6
S. Angew. Chem. Int. Ed. 2015, 54, 7564. (h) Green, R. A.; Pletcher, D.; Leach, S. G.; Brown, R.
C. D. Org. Lett. 2016, 18, 1198.
7
8
(5) Ghosh, S.; Jana, C. K. Org. Lett. 2016, 18, 5788.
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
(6) (a) Yamaguchi, K.; Matsushita, M.; Mizuno, N. Angew. Chem. Int. Ed. 2004, 43, 1576. (b)
Fujiwara, H.; Ogasawara, Y.; Yamaguchi, K.; Mizuno, N. Angew. Chem. Int. Ed. 2007, 46, 5202.
(c) Goto, A.; Endo, K.; Saito, S. Angew. Chem. Int. Ed. 2008, 47, 3607. (d) Ramon, R. S.; Mariꢀ
on, N.; Nolan, S. P. Chem. Eur. J. 2009, 15, 8695. (e) Mitsudome, T.; Mikami, Y.; Mori, H.; Ariꢀ
ta, S.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Chem. Commun. 2009, 22, 3258. (f) Kim, M.;
Lee, J.; Lee, H.ꢀY.; Chang, S. Adv. Synth. Catal. 2009, 351, 1807. (g) Midya, G. C.; Kapat, A.; S.
Maiti, Dash, J. J. Org. Chem. 2015, 80, 4148. (h) Li, Y.; Chen, H.; Liu, J.; Wana, X.; Xu, Q.
Green Chem. 2016, 18, 4865.
(7) (a) Bode, J. W.; Fox, R. M.; Baucom, K. D. Angew. Chem. Int. Ed. 2006, 45, 1248. (b) Carrilꢀ
lo, N.; Davalos, E. A.; Russak, J. A.; Bode, J. W. J. Am. Chem. Soc. 2006, 128, 1452. (c) Sanki,
A. K.; Talan, R. S.; Sucheck, S. J. J. Org. Chem. 2009, 74, 1886. (d) Shen, B.; Makley, D. M.;
Johnston, J. N. Nature, 2010, 465, 1027. (e) Leighty, M. W.; Shen, B.; Johnston, J. N. J. Am.
Chem. Soc. 2012, 134, 15233. (f) Schwieter, K. E.; Johnston, J. N. Chem. Commun. 2016, 52,
152.
(8) Oxidation of protected and unprotected amines. (a) Moriarty, R. M.; Vaid, R. K.; Duncan, M.
P.; Ochiai, M.; Inenaga, M.; Nagao, Y. Tetrahedron Lett, 1988, 29, 6913. (b) Kim, J. W.; Yamaꢀ
guchi, K.; Mizuno, N. Angew. Chem. Int. Ed. 2008, 47, 9249. (c) Wu, X.ꢀF.; Bheeter, C. B.;
Neumann, H.; Dixneuf, P. H.; Beller, M. Chem. Commun. 2012, 48, 12237. (e) Ilangovan, A.;
Satish, G. Org. Lett. 2013, 15, 5726. (f) Poeschl, A.; Mountford, D. M. Org. Biomol. Chem. 2014,
12, 7150. (g) Khusnutdinova, J. R.; BenꢀDavid, Y.; Milstein, D. J. Am. Chem. Soc. 2014, 136,
22
ACS Paragon Plus Environment

Page 23 of 24
The Journal of Organic Chemistry
1
2
3
4
5
6
2998. (h) Legacy, C. J.; Wang, A.; O’Day, B. J.; M. H. Emmert, Angew. Chem. Int. Ed. 2015, 54,
14907. (i) Griffiths, R. J.; Burley, G. A.; Talbot, E. P. A. Org. Lett. 2017, 19, 870.
7
8
9
(9) (a) Klobukowski, E. R.; Mueller, M. L.; Angelici, R. J.; Woo, L. K. ACS Catal. 2011, 1, 703.
(b) Xu, W.; Jiang, Y.; Fu, H. Synlett 2012, 23, 801. (c) Xu, M.; Zhang, X.ꢀH.; Shao, Y.ꢀL.; Han,
J.ꢀS.; Zhong, P. Adv. Synth. Catal. 2012, 354, 2665. (d) Jin, X.; Kataoka, K.; Yatabe, T.; Yamaguꢀ
chi, K.; Mizuno, N. Angew. Chem. Int. Ed. 2016, 55, 7212. for metal free multiꢀstep reaction see:
(e) Nishinaga, A.; Shimizu, T.; Matsuura, T. J. Chem. Soc. Chem.Commun. 1979, 21, 970. (f)
Rong, H.ꢀJ.; Cheng, Y. F.; Liu, F.ꢀF.; Ren, S.ꢀJ.; Qu, J. J. Org. Chem. 2017, 82, 532.
(10) Bakac, A. Inorg. Chem. 2010, 49, 3584.
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
(11) (a) Tang, R.; Diamond, S. E.; Neary, N.; Mares, F. J. Chem. Soc. Chem. Commun. 1978, 13,
562. (b) Tanaka, K.; Yoshifuji, S.; Nitta, Y. Chem. Pharm. Bull. 1988, 36, 3125. (c) Mori, K.;
Yamaguchi, K.; Mizugaki, T.; Ebitani, K.; Kaneda, K. Chem. Commun. 2001, 5, 461. (d) Zhang,
Y.; Xu, K.; Chen, X.; Hu, T.; Yu, Y.; Zhang. J.; Huang, J. Catal. Commun. 2010, 11, 951.
(12) For selected reactions through related azomethine ylides see: (a) Haldar, S.; Mahato, S.; Jaꢀ
na, C. K. Asian J. Org. Chem. 2014, 3, 44. (b) Zhu, Y.; Buchwald, S. L. Org. Lett. 2014, 16,
5228. (c) Matsumoto, M.; Harada, M.; Yamashita, Y.; Kobayashi, S. Chem. Commun. 2014, 50,
13041. (d) Qian, X.; Ji, P.; He, C.; Zirimwabagabo, JꢀO; Archibald, M. M.; Yeagley, A. A.;
Chruma, J. J. Org. Lett. 2014, 16, 5228. (e) Haldar, S.; Roy, S. K.; Maity, B.; Koley, D.; Jana, C.
K. Chem. Eur. J. 2015, 21, 15290. (f) Wu, Y.; Hu, L.; Li, Z.; Deng, L. Nature 2015, 523, 445. (g)
Liu, J.; Cao, C.ꢀG.; Sun, H.ꢀB., Zhang, X.; Niu, D. J. Am. Chem. Soc. 2016, 138, 13103.
(13) (a) Liu, L.; Zhang, S.; Fu, X.; Yan, C.ꢀH. Chem. Commun. 2011, 47, 10148. (b) Schumperli,
M. T.; Hammond, C.; Hermans, I. ACS Catal. 2012, 2, 1108.
23
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 24
1
2
3
4
5
6
7
8
(14) For related peroxide intermediate see: (a) E. G. E. Hawkins, J. Chem. Soc. 1969, 2663. (b)
McCullough, K. J.; Mori, M.; Tabuchi, T.; Yamakoshi, H.; Kusabayashi, S.; Nojima, M. J. Chem.
Soc., Perkin Trans. 1 1995, 41.
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
(15) Singlet oxygen could be formed in situ in the presence of fluorenyl chromophore as a singlet
sensitizer.
(16) (a) Ruschig, H.; Korger, G.; Nesemann, G. US2923737 A, 1960. (b) Cherkez, S.; Yigal, D.
EP0582441 A1, 1994. (c) Kim, E.; Kim, J. Y.; Rhee, H. Bull. Korean Chem. Soc. 2004, 25, 1720.
(d) Zhao, J.; Li, Z.; Song, S.; Wang, M.; Fu, B.; Zhang, Z. Angew. Chem. Int. Ed. 2016, 55, 5545.
(17) (a) Veitch, G. E.; Bridgwood, K. L.; Ley, S. V. Org. Lett. 2008, 10, 16. (b) Ren, W.; Yaꢀ
mane, M. J. Org. Chem. 2009, 74, 8332. (c) Cao, L.; Ding, J.; Gao, Wang, M.; Z.; Li, J.;Wu, A.
Org. Lett. 2009, 11, 17. (d) Awuah, E.; Capretta, A. J. Org. Chem. 2010, 75, 5627. (e) Martínezꢀ
Asencio, A.; Yus, M.; Ram, D. J. Tetrahedron 2012, 68, 3948. (f) Caldwell, N.; Campbell, P. S.;
Jamieson, C.; Potjewyd, F.; Simpson, I.; Watson, A. J. B. J. Org. Chem. 2014, 79, 9347.
24
ACS Paragon Plus Environment