"transition-metal-free" synthesis of carbazoles by photostimulated reactions of 2′-halo[1,1′-biphenyl]-2-amines

Article abstract of DOI:10.1021/jo5024393

An efficient and simple protocol for the preparation of a series of 9H-carbazoles by photostimulated S_RN1 substitution reactions is presented. Substituted 9H-carbazoles were synthesized in low to excellent yields (up to 96%) through an intramolecular C-N bond formation of 2′-halo[1,1′-biphenyl]-2-amines by the photoinitiated S_RN1 mechanism under mild and "transition-metal-free" conditions. The biphenylamines used as substrates were obtained with isolated yields ranging from 21% to 84% by two approaches: (A) the cross-coupling Suzuki-Miyaura reaction and (B) the radical arylation of anilines. Some key aspects of the proposed mechanism were evaluated at the B3LYP/6-311+G? level.

Full text of DOI:10.1021/jo5024393

Subscriber access provided by - Access paid by the | UCSF Library
Article
“Transition-Metal Free” Synthesis of Carbazoles by
Photostimulated Reactions of 2'-Halo-[1,1'-biphenyl]-2-amines
Walter Damian Guerra, Roberto Arturo Rossi, Adriana Beatriz Pierini, and Silvia Maricel Barolo
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo5024393 • Publication Date (Web): 09 Dec 2014
Downloaded from http://pubs.acs.org on December 12, 2014
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 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
“
Transition-Metal Free” Synthesis of Carbazoles by Photostimulated
Reactions of 2'-Halo-[1,1'-biphenyl]-2-amines
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
Walter D. Guerra, Roberto A. Rossi, Adriana B. Pierini,* and Silvia M. Barolo*
INFIQC, Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad
Nacional de Córdoba, Ciudad Universitaria, 5000 Córdoba, Argentina.
RECEIVED DATE (to be automatically inserted after your manuscript is
accepted if required according to the journal that you are submitting your paper to)
CORRESPONDING AUTHOR FOOTNOTE (Phone number: (+54) 351-5353867, e-mail:
adriana@fcq.unc.edu.ar and sbarolo@fcq.unc.edu.ar
X
R2
R2
Transition
Metal-free
Z
Z
R3
R3
hυ
ET
N
1
R HN
1
R
14 Examples
up to 96 % yield
X= Cl or Br
Z= CH or N
Abstract: An efficient and simple protocol for the preparation of a series of 9H-carbazoles
by photostimulated S 1 substitution reactions is presented. Substituted 9H-carbazoles
RN
were synthesized from low to excellent yields (up to 96%) through an intramolecular C-N
bond formation of 2'-halo-[1,1'-biphenyl]-2-amines by the photoinitiated S 1 mechanism
RN
under mild and “transition-metal free” conditions. The biphenyl amines used as substrates
were obtained with isolated yields ranging from 21% to 84% by two approaches: A) the
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 2 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
cross-coupling Suzuki-Miyaura reaction, and B) the radical arylation of anilines. Some key
aspects of the proposed mechanism were evaluated at the B3LYP/6-311+G* level.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Introduction
Carbazole and its derivatives are an important type of nitrogen containing aromatic
1,2
3
heterocycles with various pharmacological activities such as anticancer, antimicrobial,
4
5
6
antipsychotic, antimitotic and antioxidant. For example, the anti-inflammatory properties
7
8
of carbazomycin B and the antitumor properties of ellipticine derivatives have been
9
10
reported. Also, carvedilol and carazolol have been identified for their potential as
multiple-action antihypertensive compounds. There are also many applications of these
11
heteroaromatic compounds in materials science.
Given the remarkable importance of functionalized carbazoles and their derivatives
across many fields, the development of mild and efficient preparative protocols continues
to be a challenging endeavor in synthetic organic chemistry.
Representative synthetic protocols involving intramolecular C-N coupling are
summarized in scheme 1 such as: A) Transition-metal-catalyzed sequential C-C and C-N
12
bond formation using N-acetylated o-bromoanilines and o-substituted iodoarenes; B)
1
3
Rhodium-catalyzed carbazole formation from biaryl azides; C) Metal catalyzed or
1
4,15
transition-metal free intramolecular C-H amination of N-substituted aminobiphenyls;
D)
1
6
One-pot Rh(III) catalyzed C-H amination of non-protected 2-aminobiaryls; E) Benzyne-
mediated cyclization of N-protected and halogenated diarylamines using magnesium
17
bis(dialkyl amides) as a base; F) Transition-metal free cyclization of 2-nitrobiaryls with
1
8
PhMgBr.
ACS Paragon Plus Environment

Page 3 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
R
H N
2
I
NO2
Br
N3
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) Pd
F)
B)
Rh
C)
H
H
PhMgBr
E)
N
H
NHR
NHP
Benzyne
Pd or Metal
free
D) Rh
H
Br
NH2
H
Scheme 1. Intramolecular C-N coupling strategies for the synthesis of carbazoles.
Despite the numerous useful synthetic procedures to prepare these compounds,
several limitations still need to be overcome. Most of these procedures involve elevated
temperatures, catalytic amounts of metal complexes (Pd or Rh), long reaction times, iodo-
or bromo- arenes as starting material, or harsh reaction conditions. A practical, efficient and
general route to carbazoles by C-N bond formation from chloro arenes would be desirable
in view of the importance and applicability of these heterocycles.
The radical nucleophilic substitution mechanism (S 1) is a chain process that
RN
involves radicals and radical anions as intermediates as shown in scheme 2. The scope of
this mechanism has increased considerably and nowadays serves as an important synthetic
19
strategy.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 4 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 2. The S 1 Mechanism.
RN
The initiation step is an electron transfer (ET) from a suitable donor (e.g., the
nucleophile or a base) to afford the radical anion of the substrate. This ET could also follow
a concerted dissociative step to directly afford radicals and the anion of the leaving group
20
(
dissociative electron transfer or DET). In some systems this ET is spontaneous, but in
others light is required to induce the reaction. Electrons [(from dissolved alkali metals in
liquid ammonia, or from a cathode) or inorganic salts (e.g., Fe(II) or SmI )] also can initiate
2
1
9
the reaction.
Several nucleophiles, such as carbanions and anions derived from heteroatoms can
be used to form new C-C or C-heteroatom bonds in good yields; the reaction is also
compatible with many substituents. An interesting feature is the possibility to obtain
heterocycles by intramolecular ring closure of compounds bearing both the leaving group
19
and the nucleophilic center in an adequate relative position.
The intramolecular S 1 reaction has been used to synthesize by “C-C bond
RN
2
1
22
23
formation” 9H-carbazoles, phenanthridines and benzophenanthridines, carbolines,
24
25
bractazonine alkaloid, 1-phenyl-indanes and tetralin derivatives, and aporphine and
2
6
homoaporphine alkaloids. The cyclization of N-(2-halophenyl)phenyl acetamides to
ACS Paragon Plus Environment

Page 5 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
afford 1-methyl-3-phenylindolin-2-one has been performed under microwave (MW)
2
7
heating. The syntheses of benzo-fused heterocycles bearing from six- to nine-membered
rings have been reported to proceed in good to excellent yields. This procedure involves 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
the key step the photostimulated S 1 reaction of ketone enolate anions linked by a bridge
RN
2
8
to a pendant haloarene.
Furthermore, some examples of C-heteroatom bond formation were reported in
29
cyclization reactions of aromatic amines with ortho-dihaloaromatic compounds. Even
though the intramolecular S 1 reaction has proved to be a successful tool to synthesize
RN
heterocycles, there are only a few reports of C-N bond formation within the intramolecular
2
2a,30
approach.
On this basis, we studied a new synthetic strategy that involved, first, the
construction of compounds such as 2'-halo-[1,1'-biphenyl]-2-amines bearing both the
leaving group and the precursor of the anion centre on nitrogen in the same molecule. In a
second phase, the strategy includes as key step the formation of a new C-N bond by
intramolecular “transition-metal free” photostimulated reaction, to give the 9H-carbazoles.
Also, some relevant electronic and geometric factors of these reactions were examined by
DFT calculations.
Results and Discussion
2
'-Halo-[1,1'-biphenyl]-2-amines (3) used to achieve the synthesis of carbazoles
3
1
were prepared by the cross-coupling Suzuki-Miyaura reaction (method A), or by radical
32
arylation of anilines 5 with arylhydrazines 4 (method B) (Table 1). Most of the
biphenylamines thus obtained have not been described in the literature.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 6 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
The Pd-catalyzed reaction of 2-bromoaniline (1a) with 2-chlorophenylboronic acid
3
3
(
2a) under similar experimental conditions to those reported (method A), afforded 2'-
chloro-[1,1'-biphenyl]-2-amine (3a) in 84% isolated yield (entry 1, Table 1).
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Following the same procedure, the reaction of different anilines with 2-
phenylboronic acids afforded the corresponding mono and di-substituted 2'-chloro-[1,1'-
biphenyl]-2-amines in 36-79% isolated yields (entries 2-3,5-6, 8-9, Table 1).
The substituted 2'-bromo-[1,1'-biphenyl]-2-amines (3c´ and f) were obtained in low
isolated yields (entries 4 and 7, Table 1) from 2-(bromophenyl)hydrazine (4) and 4-
substituted anilines 5a-b following the previously reported regioselective radical arylation
3
2
of anilines with arylhydrazines (Table 1, method B).
a
Tabla 1. Preparation of 2'-halo-[1,1'-biphenyl]-2-amines (3a-h).
substrate
substrate
b
entry
method
product (% )
(1 or 4)
(2 or 5)
ACS Paragon Plus Environment

Page 7 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
2
3
4
5
6
7
8
9
1a (Y=Br, R =H)
2a (R =H)
A
A
A
B
A
3a (84)
3b (49)
3c (36)
3c´ (31)
3d(60)
3e(17)
1
2
1b (Y=Br, R =4-Me)
2a (R =H)
1
2
1c (Y=Br, R =4-OMe)
2a (R =H)
1
2
4
5a (R =OMe)
3
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
1d (Y=Br, R =4-CN)
2a (R =H)
1
2
c
1e (Y=Cl, R =4-CF )
2a (R =H)
A
B
A
A
1
3
2
4
5b (R =COOEt)
3
3f (27)
3g (79)
3h(39)
1g (Y=Br, R =4,6-di-Me) 2a (R =H)
1
2
1d (Y=Br, R =4-CN)
2b (R =CF )
1
2
3
a
Method A: 5 mol % Pd(PPh ) Cl , 10 mol % PPh as ligand, NaHCO as base in DME-water (1:1) at 120°C
3
2
2
3
3
for 3h. Method B: 15 equiv of aniline, 5 equiv of MnO and NaHCO as base (the latter when the hydrazine
2
3
b
c
hydrochloride is used) in MeCN at rt for 2h. Isolated yields. 2 mol % Pd(OAc) , 4 mol % XPhos in dioxane
2
34
at 80ºC for 18h.
Utilizing the cross-coupling Suzuki-Miyaura reaction, 2-(2-chlorophenyl)pyridin-3-
amine (3i) was prepared (30% isolated yield) by reaction of 2-chloro-3-nitro-pyridine (1i)
35
with 2-chlorophenylboronic acid (2a) followed by chemical reduction (scheme 3).
Scheme 3. Synthesis of 2-(2-chlorophenyl)pyridin-3-amine (3i).
The Pd-catalyzed reaction of polycyclic aromatic compounds to afford more complex
precursors was also examined. Within this goal, 1-(2-chlorophenyl)naphthalen-2-amine (3j)
was obtained (21% isolated yield, scheme 4).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 8 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Scheme 4. Synthesis of 1-(2-chlorophenyl)naphthalen-2-amine (3j).
The scope of the S 1 reaction of the previously reported substrates (3a-f) to achieve
RN
the synthesis of various substituted carbazoles was further explored. The overall
experimental details and the results obtained are presented in Table 2.
After 180 min of irradiation, the reaction of 2'-chloro-[1,1'-biphenyl]-2-amine (3a)
in DMSO at 40 ºC with excess t-BuOK (2 equiv) afforded the 9H-carbazol (6a) in 57%
yield, together with 13% of the reduced product [1,1'-biphenyl]-2-amine (7a) (entry 1,
Table 2). Similar results were obtained in liquid ammonia as solvent at -33 ºC (entry 2,
Table 2).
A similar yield of 6a (43%) was obtained at shorter reaction times (60 min of
irradiation, entry 3, Table 2). There was no reaction under dark conditions which excludes a
benzyne mechanism (entry 4, Table 2). Besides, the photostimulated reaction was partially
1
9c
inhibited by m-dinitrobenzene (m-DNB), a strong electron-acceptor (entry 5, Table 2).
Also, the effect of the base was evaluated by carrying out the photostimulated
reaction in the absence of t-BuOK (entry 6, Table 2). Under these conditions traces of 6a
were observed indicating the importance of the base to form the anion of the substrate and
to initiate the reaction.
Table 2. Photostimulated reactions of 2'-halo-[1,1'-biphenyl]-2-amines (3a-f).
ACS Paragon Plus Environment

Page 9 of 52
The Journal of Organic Chemistry
1
2
3
4
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
biphenylamine
products
a
b
-
c
entry
1
recovered
%)
conditions
yields %
6
Cl %
3
R
(
7
13(9)
9
a
a
a
a
a
a
b
c
H
H
---
---
12
84
50
92
---
---
---
---
---
---
hυ, 3h
hυ, 3h
hυ, 1h
dark, 1h
hυ, 1h
hυ, 1h
hυ, 3h
hυ, 3h
hυ, 3h
hυ, 3h
hυ, 3h
hυ, 3h
a
a
a
a
a
a
b
c
c
d
e
f
57(41)
57(45)
90
95
80
d
2
3
4
H
43
18
H
--
--- <10
31
e
5
H
19
<3
4
7
f
6
H
<10
7
8
Me
OMe
OMe
CN
CF3
COOEt
63(48)
(29)
9(<5)
(20)
93
90
83
82
90
90
g
9
c´
d
e
34(30) 30(15)
1
0
1
(79)
83(72)
66(47)
---
---
---
1
g
12
f
a
The reactions were run in 5 mL of DMSO (40 ºC) with 1 equiv of substrate and 2 equiv of t-BuOK
and irradiated for the specific time. Irradiation was conducted in a photochemical reactor equipped with two
b
Philips HPI-T 400 W lamps of metallic iodide (air and water refrigerated). Yields were determined by CG
c
(
internal standard method). Isolated yields are given in parentheses. Halide anions were determined
d
potentiometrically. The reaction was run in 200 ml of liquid ammonia (-33 ºC), with 1 equiv of substrate and
e
f
2
g
equiv of t-BuOK. 30 mol % of m-DNB with respect to the substrate was added. In the absence of t-BuOK.
Bromide as leaving group.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 10 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
Low to very good yields of mono-substituted carbazoles were obtained by reaction
of compounds 3b-f (entries 7-12, Table 2). The anions of 3b, c and c´ afforded carbazoles
6b-c in 34-63% together with the corresponding reduced products 7b-c (entries 7-9, Table
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
). Meanwhile, anions from 3d-f gave specifically the carbazoles in higher yields (66-83%)
entries 10-12, Table 2).
Extension of the procedure to synthesize more complex carbazoles and even δ-
(
carboline is presented in Table 3. The reaction of the anion of 3g and 3j gave both,
disubstituted carbazoles 6g, j (49% and 53% yields, respectively) together with the reduced
products 7g, j (26%) (entries 1 and 4; Table 3).
-
On the other hand, 3h gave only the carbazole 6h (70% isolated yield, entry 2,
Table 3). Moreover, the δ–carboline 6i was obtained in 71% yields uncontaminated by the
reduced product (entry 3, Table 3).
As can be seen in general, biphenylamines with electron donating group (EDG) like
Me or OMe gave both, cyclized and reduced products, meanwhile biphenylamines
containing electron-withdrawing groups (EWG) like CN, COOEt or CF gave only the
3
carbazole.
a
Table 3. Synthesis of di-susbstituted and polycyclic carbazoles (6g-j).
c
yields %
b
-
d
entry
biphenylamines
products
Cl %
6
7
1
49 (44)
26 (15)
96
ACS Paragon Plus Environment

Page 11 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
2
70
85
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
3
4
71 (58)
80
95
53
26
a
The reactions were run in 5 mL of DMSO (40 ºC), with 1 equiv of substrate and 2 equiv of t-BuOK and
irradiated (180 min). Irradiation was conducted in a photochemical reactor equipped with two Philips HPI-T
b
c
4
00 W lamps of metallic iodide (air and water refrigerated). In all cases conversion was complete. Yields
d
determined by CG (internal standard method). Isolated yields are in brackets. Chloride anions were
determined potentiometrically.
The partial inhibition of the irradiated reaction in the presence of m-DNB (Table 2,
entry 5), and the lack of formation of 6a (9H-carbazole) under dark conditions (Table 2,
entry 4) provided evidence that the present cyclization could proceed via the SRN1
mechanism.
-
We propose that in the presence of excess t-BuOK the anion 3 is formed. The
initiation step of these reactions would be the photoinduced ET from an adequate electron
36
- •-
source, such as t-BuOK, to yield the respective radical dianions (3 ) (scheme 5) which
.
-
.-
could dissociate to afford the distonic radical anion 3 . Moreover, 3 could be formed by a
•-
-
-
concerted dissociative ET (DET). An additional ET from 6 to 3 will afford 6 and radical
- •-
dianion (3 ) , which could propagate the reaction. Upon acidification of the reaction media
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 12 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
and work up, product 6 was formed. Calculations supporting key steps of the proposed
mechanism will be further discuss.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
DET
-Cl
R
Cl
R
ET
-Cl
3
HN
HN
3
3
O
R
R
3
ET
N
H
N
H
6
6
Scheme 5. Mechanism proposed for the formation of carbazole.
Based on the successful syntheses of substituted and polycyclic 9H-carbazoles and
δ-carboline, via S 1 reactions of halo-biphenylamines, we explored the synthesis of N-
RN
phenyl-9H-carbazoles as possible future substrates. Within this goal the N-phenyl-[1,1'-
biphenyl]-2-amines 9a-c were prepared in low yields by reaction of iodobenzene (8) with
the corresponding 2'-halo-[1,1'-biphenyl]-2-amines (3a,b,c´) under Buchwald-Hartwig
3
7,38
conditions (scheme 6).
in Table 4.
The synthesis of carbazoles from compounds 9a-c is presented
ACS Paragon Plus Environment

Page 13 of 52
The Journal of Organic Chemistry
1
2
3
4
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
Scheme 6. Preparation of N-phenyl-[1,1'-biphenyl]-2-amines 9a-c.
Excellent isolated yields of N-phenyl carbazoles 10a-c (87 - 96%) were obtained by
photostimulated reaction of 9a-c either in liquid ammonia or DMSO (entries 1-4, Table 4).
Interestingly, under the same experimental conditions a simple modification of the starting
material (N-phenyl substitution) improved significantly the yield of the reaction. For
example, 3a afforded 9H-carbazole in 57% yield meanwhile its corresponding N-phenyl
derivative 9a gave the cyclic compound in 93% (entry 1, Table 1 vs. entry 2, Table 4).
Also, it is important to notice that while 3a afforded cyclization and reduction, cyclization
was the only reaction obtained with 9a, b and c (entries 1, 7 and 9, Table 1 vs. entries 2-4,
Table 4).
a
Table 4. Synthesis of N-phenyl-carbazoles (9a-c).
-
-
N-phenyl-
Yield
Cl /Br
entry
Product
c
%
d
biphenylamine
%
b
1
96
93
95
97
2
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 14 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
3
4
87
90
87
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
87
a
The reactions were run in 5 mL of DMSO (40 ºC), with 1 equiv of substrate and 2 equiv of t-BuOK
and irradiated for 3 hours. Irradiation was conducted in a photochemical reactor equipped with two Philips
b
HPI-T 400 W lamps of metallic iodide (air and water refrigerated). The reaction was run in 200 ml of liquid
c
ammonia (-33 ºC), with 1 equiv of substrate and 2 equiv of t-BuOK and irradiated for 3 hours. Isolated
d
yields. Halide anions were determined potentiometrically.
To extend the application of the methodology developed to obtain N-phenyl-
carbazoles, we evaluated the reactivity of a phenanthrene-9-amine in this system. When the
photostimulated reaction was carried out with 10-(2-chlorophenyl)-N-phenylphenanthren-9-
amine (11), 9-phenyl-9H-dibenzo[a,c]carbazole (12) was obtained in 55% yield together
with 9H-dibenzo[b,d]phenanthro[9,10-f]azepine (13) in 38 % yield (scheme 7). It is
important to notice that 13 is the product corresponding to the C-C coupling. This C-C
coupling was not observed in the reactions of 9a-c (entries 1-4, Table 4).
ACS Paragon Plus Environment

Page 15 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
N
Cl
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
2(55%)
t-BuOK, hν
+
HN
DMSO
-Cl
11
NH
1
3(38%)
Scheme 7. Intramolecular photostimulated reactions of 10-(2-chlorophenyl)-N-
phenylphenanthren-9-amine (11).
In order to rationalize our experimental results, a computational study with the
39
B3LYP DFT functional and the 6-311+G* basis set was carried out. The solvent effect
4
0
was included with the continuum solvent model (PCM). Key mechanistic intermediates
and reactive pathways presented in Scheme 5 were studied for the anions of 3a, 9a and 11.
1
9c
-
In relation to the different initiation steps that could be in play, ET form t-BuO to
36
the substrate in its excited state has been proposed in other systems. The thermodynamic
-
-
of the ET from t-BuO to the S state of 3a was evaluated with TD-DFT as exothermic,
1
indicating it is as a feasible initiation pathway under our experimental conditions (excess t-
-
-
41
BuO ). Another possibility being ET from S to S of 3a (see Supporting Information).
1
0
-
•-
With respect to the species formed, the calculations failed to locate (3 ) as a
stationary species of the dianionic surface. This result indicates that, upon recipient of an
-
•-
electron, 3a dissociates into the distonic radical anion 3a and chloride anion (scheme 8).
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 16 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
•-
The most stable conformer of the intermediate 3a has a dihedral angle equal to 0 degrees
0
between the two phenyl subunits. This high-energy intermediate may rotate around the
•-
Cphenyl-Cphenyl bond to give the less stable intermediate 3a180 (dihedral=180 degree) with an
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
activation energy of 4.59 kcal/mol. Based on the calculated energy difference between both
•-
conformers 3a0 prevails (91%) under conformational equilibrium at 318 K. This
conformer is responsible to follow the cyclization reactive pathway to afford the C-N cyclic
•-
radical anion 6a . This pathway is pursued by crossing a low activation energy barrier
(Ea=4.55 kcal/mol).
Scheme 8. Stationary points evaluated on the potential energy surface of C-N cyclization
-
for 3a by ET.
ACS Paragon Plus Environment

Page 17 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
•-
Cyclization of 3a as well as its reduction by hydrogen abstraction from the solvent
0
(
DMSO) (scheme 9) were calculated as exothermic processes in -36.92 and -6.67 kcal/mol,
respectively; this meaning both reactions may occur under our experimental conditions.
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 9. Hydrogen abstraction by 3a from the solvent.
•-
-
Important to point out is that the ET from 6a to 3a is calculated as exothermic by
-
31.54 kcal/mol (scheme 10). This exothermic reaction clearly demonstrated that the
energetics for an efficient propagation of the proposed mechanistic cycle (scheme 5) are
reasonable.
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 18 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
•-
-
Scheme 10. ET from 6a to 3a .
-
A similar energy profile was calculated for 9a . This anion affords, after DET, the
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
•-
•-
distonic radical anion 9a (scheme 11). The Ea
of 9a was calculated to be 3.03
0
cyclization
0
•-
kcal/mol, which is 1.5 kcal/mol lower than Eacyclization of 3a0 (without N-phenyl
•-
substitution). Moreover, the activation energy for C -C
rotation of 9a is higher than
aryl
phenyl
0
•-
•-
•-
Earotation of 3a . Assuming 9a and 3a have similar Ea for hydrogen abstraction from the
0
0
0
•-
-
solvent, the lower Eacyclization of 9a indicates this is the preferred reaction path for 9a and
0
thus explains the cyclization specificity observed experimentally for the N-phenyl
substituted compounds.
ACS Paragon Plus Environment

Page 19 of 52
The Journal of Organic Chemistry
1
2
3
4
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
Scheme 11. Stationary points evaluated on the potential energy surface of C-N
-
cyclization for 9a by ET.
-
-
The differences in C-N vs C-C regiochemistry in the cyclization of 9a and 11 were
also examined (scheme 12). As seen from the scheme, the C-N coupling of the reactive
•-
•-
•-
•-
intermediates 9a and 11 to form 10a and 12 occurs with similar EaC-N cyclization. On the
•-
•-
other hand, C-C cyclization is favored for 11 with respect to 9a by ≈9 kcal/mol (Ea
C-C
•
-
•-
(11 )=6.84 kcal/mol; Ea
(9a )=15.99 kcal/mol).
cyclization
C-C cyclization
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 20 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
•
-
•-
Scheme 12. Evaluation of C-N vs. C-C cyclization for 9a and 11 by ET.
•-
•-
Inspection of the minimum energy geometries of 9a and 11 shows they bear a
similar distance from N to the radical center (CRadical Center-N distance=2.4Å, Figure 1). On
the other hand, they differ in the distances of the radical center to the closest anionic carbon
•-
•-
(CRadical Center-Cortho-N distances being 4.1Å and 3.8Å for 9a and 11 , respectively, Figure
•-
1
). The greater proximity between the reactive centers in 11 may be responsible for its
lower activation energy to follow the C-C cyclization route and thus, to afford the
corresponding observed azepine (C-C product). This product is other evidence that favors
the proposed mechanism with radical anions intermediates, in which coupling between a
radical and different positions of an anionic system can occur.
ACS Paragon Plus Environment

Page 21 of 52
The Journal of Organic Chemistry
1
2
3
4
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
-
.
Figure 1. Relevant C-N and C-C distances in energy-minimized conformers of 9a
-.
and 11 .
Conclusions
In summary, we report our studies on photostimulated intramolecular S 1 reactions
RN
using different 2'-halo-[1,1'-biphenyl]-2-amines as staring material. These reactions
constitute a new, simple and efficient C–N protocol to obtain mono and di-substituted 9H-
carbazoles and also 9-phenyl-9H-carbazoles. The approach does not involve the use of
transition metals or drastic reaction conditions, and a variety of substituents are tolerated
under the reaction conditions employed. The methodology compares fairly well with the
2
1
approach based on C-C cyclization. Moreover, we found that a simple modification of the
starting material (N-phenyl substitution) under identical reaction conditions increased the
yields significantly (87-96%). This is an interesting possibility not feasible with the C-C
cyclization approach.
Considering the good yields, the low cost, availability and/or simplicity of starting
materials, and the short time and mild reaction conditions of the procedures, we
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 22 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
demonstrated that this can be a valuable alternative to access to 9H-carbazoles in a novel
approach.
The computational calculations seem to be a successful approach to study the
conformational equilibrium of anions and distonic radical anions as well as the energetic of
their C-N cyclization. The calculations also explain the experimentally observed
regiochemistry of C-C vs. C-N cyclization for the N-phenanthryl system.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Experimental Section
Computational Procedure. All calculations were performed with the Gaussian09
program. The conformers obtained were refined with complete geometry optimization
39
within the B3LYP DFT functional with the 6-311+G* basis set. The geometries thus
found were used as starting points for the evaluation of the reaction profiles by using the
distinguished coordinate scan. The effect of DMSO as solvent was evaluated through
40
Tomasi’s Polarized Continuum Model (PCM) as implemented in Gaussian09. The
inclusion of the solvent in the calculations is a requisite to evaluate valence radical anions.
The B3LYP functional and the 6-311+G* basis set have been previously tested for similar
42
systems. The characterization of stationary points was done by Hessian matrix
calculations. The energy informed for TSs, anions and radical anions includes zero-point
corrections. The single excited stated (S ) of anion 3a was calculated with TD DTF the
1
B3LYP functional and the 6-311+G* basis set. The energy of S was calculated including
1
the PCM contribution under the StateSpecific approach.
General Considerations. Gas chromatographic analyses were performed using a gas
chromatograph with a flame ionization detector, and equipped with the following columns:
ACS Paragon Plus Environment

Page 23 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
1
2
5 m x 0.20 mm x 0.25 ꢀm column and 15 m × 0.25 mm × 0.25 ꢀm column. H NMR
13
(
400.16 MHz), C NMR (100.63 MHz) spectra were obtained in DMSO-d and CDCl as
6 3
solvents. Coupling constants are given in Hz and chemical shifts are reported in δ values in
ppm. Data are reported as followed: chemical shift, multiplicity (s = singlet, s br = broad
singlet, d = doublet, t = triplet, dd = double doublet, dt = double triplet, ddd = double
double doublet, m = multiplet), coupling constants (Hz), and integration. Gas
Chromatographic/Mass Spectrometer analyses were carried out on a GC/MS spectrometer
equipped with a 30 m × 0.25 mm × 0.25 ꢀm column. Irradiation was conducted in a reactor
equipped with two Philips HPI-T 400 W lamps of metallic iodide (cooled with water).
Potentiometric titration of halide ions where performed in a pHmeter using an Ag/Ag+
electrode. Melting points were performed with an electrical instrument. The high resolution
mass (HRMS) of pure products were recorded on a TOF equipment, operated with an ESI
source operated in (positive/negative) mode, using nitrogen as nebulizing and drying gas
and sodium formiate 10 mM as internal calibrate instrument. Materials: 2-bromoaniline, 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
bromo-4-mtehyl-aniline,
trifluoromethyl)aniline,
2-bromo-4,6-di-methyl-aniline,
2-chloro-3-nitropyridine, 4-methoxyaniline,
2-chloro-4-
ethyl 4-
(
aminobenzoate, 2-(bromophenyl)hydrazine hydrochloride, (2-chlorophenyl)boronic acid, 2-
chloro-5-(trifluoromethyl)phenylboronic acid, t-BuOK, t-BuONa, Cs CO , Pd(PPh ) Cl ,
2
3
3 2
2
PPh , NaHCO , MnO , Pd(OAc) , 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl
3
3
2
2
(
XPhos), bis-[2-(diphenylphosphino)phenyl]ether (DPEphos), iodobenzene, 1,3-
dinitrobenzene, iron powder (Fe(0)), were commercially available and used as received
from the supplier. 4-Amino-3-bromobenzonitrile, 2-bromo-4-methoxyaniline, 1-
bromonaphthalen-2-amine and 10-bromophenanthren-9-amine were obtained by reported
4
3
methods. DMSO was stored under molecular sieves (4 Å). Toluene, dimethoxyethane
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 24 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
(
DME) and dioxane were distilled from Na-benzophenone and stored under N atmosphere.
2
All solvents were analytical grade. Silica gel (0.063−0.200 mm) was used in column
chromatography.
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
Representative Procedure for synthesis of 2'-halo-[1,1'-biphenyl]-2-amines
Method A: The following procedure is representative for biphenylamines 3a-c, d-e, g-j. A
solution of 2-bromoaniline (86 mg, 0.5 mmol), 2-chlorophenylboronic acid (93.6 mg, 0.6
mmol), Pd(PPh ) Cl (17.5 mg, 0.025 mmol), PPh (13.1 mg, 0.05 mmol) and NaHCO
3
2
2
3
3
(126 mg, 1.5 mmol) in DME (2 mL) was stirred at room temperature for 5 min. H O (2
2
mL) was added, and the resulting mixture was slightly degassed, sealed, and stirred at
120ºC for 2 h. After being cooled to room temperature, the mixture was extracted with
Et O or EtOAc. The extracts were combined, dried over Na SO , and filtered. After
2
2
4
removal of volatile components from the filtrate, the resulting crude product was purified
by column chromatography on silica gel eluting with petroleum ether/EtOAc (100:0 →
8
0:20 %). Dark yellow crystals of 2'-chloro-[1,1'-biphenyl]-2-amine (3a) was isolated in
3
3
1
8
4% yield (88 mg, 0.433 mmol), m.p.: 51-53 ºC (lit 52-53ºC). H NMR (400 MHz,
CDCl ): δ 7.52-7.49 (m, 1H), 7.35-7.29 (m, 3H), 7.21 (br. ddd, J = 7.2, 6.4, 1.6 Hz, 1H),
3
7
.05 (dd, J = 7.5, 1.5 Hz, 1H), 6.84 (td, J = 7.5, 1.1 Hz, 1H), 6.79 (dd, J = 8.0, 0.8 Hz, 1H),
13
3.55 (br.s, 2H). C NMR (100 MHz, CDCl ): δ 143.9, 138.1, 134.0, 132.0, 130.5, 130.0,
3
+
1
29.3, 129.19, 127.3, 125.5, 118.5, 115.7. GC-MS (EI) m/z 205 (10), 203 (22) [M ], 169
(14), 168 (98), 167 (100), 140 (6), 139 (11), 84 (25).
2'-Chloro-5-methyl-[1,1'-biphenyl]-2-amine (3b). Prepared by the general procedure A and
purified by column chromatography on silica gel eluting with petroleum ether/EtOAc
1
(100:0 → 70:30 %). Dark yellow oil was obtained in 49% yield (53 mg, 0.245 mmol). H
ACS Paragon Plus Environment

Page 25 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
NMR (400 MHz, CDCl ): δ 7.47-7.50 (m, 1H), 7.27-7.33 (m, 3H), 7.00-7.03 (m, 1H), 6.87
3
1
3
(
d, J = 1.6 Hz, 1H), 6.70 (d, J = 8.0 Hz, 1H), 3.43 (br.s, 2H), 2.27 (s, 3H). C NMR (100
MHz, CDCl ): δ 141.3, 138.2, 133.8, 131.9, 130.8, 129.8, 129.7, 129.0, 127.6, 127.2, 125.5,
3
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
13
1
15.7, 20.4. H- C HSQC NMR (CDCl ): δ /δ 7.47-7.50/129.8, 7.27-7.33/131.9, 7.27-
H C
3
1
1
7
.33/129.0, 7.27-7.33/127.2, 7.00-7.05/129.7, 6.87/130.8, 6.70/115.7, 2.27/20.4. H- H
1
13
COSY NMR (CDCl ): δ /δ 7.27-7.33/7.47-7.50, 6.87/7.00-7.03, 6.70-7.00-7.03. H- C
3
H
H
HMBC NMR (CDCl ): δ /δ 7.47-7.50/127.2, 7.27-7.33/138.2, 7.27-7.33/133.8, 7.27-
3
H
C
7.33/131.9, 7.27-7.33/129.8, 7.27-7.33/129.0, 7.27-7.33/125.5, 6.87/141.3, 6.87/138.2,
6
.70/127.6, 6.70/125.5, 2.27/130.8, 2.27/129.7, 2.27/127.6. GC-MS (EI) m/z 219 (10), 217
+
(
55) [M ], 183 (12), 182 (100), 181 (36), 180 (16), 167 (64), 90 (14), 77 (18), 76 (13).
+
+
44
HRMS (TOF, ESI ): calcd for C H ClN (M + H) : 218.0737; Found: 218.0727.
1
3
13
2
'-Chloro-5-methoxy-[1,1'-biphenyl]-2-amine (3c). Prepared by the general procedure A
and purified by column chromatography on silica gel eluting with petroleum ether/1,2-
dichloroethane (50:50 → 0:100 %). Light brown oil was obtained in 39% yield (45.4 mg,
1
0
.195 mmol). H NMR (400 MHz, CDCl ): δ 7.48-7.51 (m, 1H), 7.30-7.35 (m, 3H), 6.82
3
(
dd, J = 8.4, 2.8 Hz, 1H), 6.75 (d, J = 8.4 Hz, 1H), 6.65 (d, J = 2.8 Hz, 1H), 3.76 (s, 3H),
13
3.31 (br.s, 2H). C NMR (100 MHz, CDCl ): δ 152.4, 137.9, 137.4, 133.7, 131.8, 129.9,
3
1
13
1
7
6
6
29.1, 127.2, 126.5, 116.9, 115.6, 115.1, 55.8. H- C HSQC NMR (CDCl ): δ /δ 7.48-
3
H C
.51/129.9, 7.30-7.35/131.8, 7.30-735/129.1, 7.30-735/127.2, 6.75/116.9, 6.65/115.6,
1
1
.82/115.1, 3.76/55.8. H- H COSY NMR (CDCl ): δ /δ 7.30-735/7.48-7.51, 6.75/6.82,
3
H
H
1
13
.65/6.82. H- C HMBC NMR (CDCl ): δ /δ 7.48-7.51/127.2, 7.30-7.35/137.9, 7.30-
3
H
C
7.35/133.7, 7.30-7.35/131.8, 7.30-7.35/129.9, 7.30-7.35/129.1, 7.30-7.35/126.5, 6.82/152.4,
6
.82/137.4, 6.82/115.6, 6.75/152.4, 6.75/133.7, 6.65/152.4, 6.65/137.9, 6.65/137.4,
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 26 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
6
.65/115.1. GC-MS (EI) m/z: 235 (28), 234 (23), 233 (85) [M ], 220 (28), 218 (100), 198
+
(
55), 183 (34), 182 (33), 155 (37), 154 (34). HRMS (TOF, ESI ): calcd for C H ClNO
1
3
13
+
(M + H) : 234.0686; Found 234.0691.
'-Chloro-5-carbonitrile-[1,1'-biphenyl]-2-amine (3d). Prepared by the general procedure
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
A and purified by column chromatography on silica gel eluting with petroleum
ether/EtOAc (100:0 → 60:40 %). White amorphous solid was obtained in 60% yield (68.4
1
mg, 0.3 mmol), m.p.: 90-91 ºC. H NMR (400 MHz, CDCl ): δ 7.50-7.55 (m, 1H), 7.46
3
(dd, J = 8.4, 2.0 Hz, 1H), 7.35-7.40 (m, 2H), 7.33 (d, J =2.0 Hz, 1H), 7.28-7.30 (m, 1H),
1
3
6
1
.76 (d, J = 8.4 Hz, 1H), 4.06 (br.s, 2H). C NMR (100 MHz, CDCl ): δ 147.9, 135.5,
3
1
13
34.7, 133.8, 133.3, 131.7, 130.2, 123.0, 127.6, 124.8, 119.8, 115.0, 100.3. H- C HSQC
NMR (CDCl ): δ /δ 7.50-7.55/130.2, 7.46/133.3, 7.35-7.40/130.0, 7.35-7.40/127.6,
3
H
C
1
1
7
7
.33/134.7, 7.28-7.30/131.7, 6.76/115.0. H- H COSY NMR (CDCl ): δ /δ 7.33/7.46,
H H
3
1
13
.28-7.30/7.50-7.55, 7.28-7.30/7.35-7.40, 6.76/7.46. H- C HMBC NMR (CDCl ): δ /δ
C
3
H
7.50-7.55/135.5, 7.50-7.55/133.8, 7.50-7.55/127.6, 7.46/147.9, 7.46/134.7, 7.46/119.8,
7
7
6
1
.35-7.40/135.5, 7.35-7.40/133.8, 7.35-7.40/131.7, 7.35-7.40/130.2, 7.33/147.9, 7.33/133.3,
.33/119.8, 7.28-7.30/135.5, 7.28-7.30/133.8, 7.28-7.30/130.0, 7.28-7.30/124.8, 6.76/124.8,
+
.76/100.3, 4.06/124.8, 4.06/115.0. GC-MS (EI) m/z: 228 (20) [M ], 194 (12), 193 (100),
+
92 (46), 166 (10), 164 (13), 96 (10), 83 (12). HRMS (TOF, ESI ): calcd for C H ClN Na
1
3
9
2
+
(M + Na) : 251.0346; Found 251.0353.
'-Chloro-5'-(trifluoromethyl)-[1,1'-biphenyl]-2-amine (3e). Prepared by the general
2
procedure A and purified by column chromatography on silica gel eluting with petroleum
ether/EtOAc (100:0 → 90:10 %). Colorless oil was obtained in 17% yield (23 mg, 0.09
1
mmol). H NMR (400 MHz, CDCl ): δ 7.50-7.54 (m, 1H), 7.30-7.39 (m, 3H), 7.15 (d, J =
3
1
3
8
.0 Hz, 1H), 7.06 (dd, J = 8.0, 0.8 Hz, 1H), 7.00 (s, 1H), 3.73 (br.s, 2H). C NMR (100
ACS Paragon Plus Environment

Page 27 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
MHz, CDCl ): δ 144.2, 136.7, 133.6, 131.5, 131.3 (q, J = 32 Hz), 130.9, 130.1, 129.6,
3
1
13
1
28.1, 127.4, 124.1 (q, J = 271 Hz), 111.9 (q, J = 4 Hz), 111.7 (q, J = 4 Hz). H- C HSQC
NMR (CDCl ): δ /δ 7.50-7.54/130.1, 7.30-7.39/130.9, 7.30-7.39/129.6, 7.30-7.39/127.4,
3
H
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
1
1
7
7
7
7
.15/130.9, 7.06/111.7, 7.00/111.9. H- H COSY NMR (CDCl ): δ /δ 7.30-7.39/7.50-
3
H H
1
13
.54, 7.06/7.15, 7.00/7.06. H- C HMBC NMR (CDCl ): δ /δ 7.50-7.54/136.7, 7.50-
3
H
C
.54/133.6, 7.50-7.54/127.4, 7.30-7.39/133.6, 7.30-7.39/131.5, 7.30-7.39/130.1, 7.30-
.39/129.6, 7.30-7.39/128.1, 7.15/144.2, 7.15/136.7, 7.15/131.2, 7.06/128.1, 7.06/111.9,
1
9
7.07/128.1, 7.07/124.1, 7.07/111.7. F (377 MHz, CDCl ): δ -62.85. GC-MS (EI) m/z 271
3
F
+
(
27) [M ], 237 (18), 236 (100), 235 (31), 216 (37), 168 (11), 167 (64), 166 (14), 108 (12).
+
+
HRMS (TOF, ESI ): calcd for C H ClF N (M + H) : 272.0448; Found 272.0458.
1
3
10
3
2
'-Chloro-3,5-dimethyl-[1,1'-biphenyl]-2-amine (3g). Prepared by the general procedure A
and purified by column chromatography on silica gel eluting with petroleum ether/1,2-
dichloroethane (50:50 → 25:75 %). Light yellow crystals were obtained in 79% yield (91.3
1
mg, 0.395 mmol), m.p.: 90-91 ºC. H NMR (400 MHz, CDCl ): δ 7.47-7.50 (m, 1H), 7.27-
3
1
3
7
.32 (m, 3H), 6.94 (br.s, 1H), 6.75 (br.s, 1H), 3.35 (br.s, 2H), 2.25 (s, 3H), 2.20 (s, 3H). C
NMR (100 MHz, CDCl ): δ 139.4, 138.5, 133.9, 132.0, 131.0, 129.9, 128.9, 128.5, 127.2,
3
1
13
127.0, 125.2, 122.6, 20.4, 17.8. H- C HSQC NMR (CDCl ): δ /δ 7.47-7.50/129.9,
3
H
C
7
2
2
7
.27-7.32/132.0, 7.27-7.32/128.9, 7.27-7.32/127.2, 6.94/131.0, 6.75/128.5, 2.25/20.4,
1
1
.22/17.8. H- H COSY NMR (CDCl ): δ /δ 7.27-7.32/7.47-7.50, 6.75/6.94, 2.25/6.94,
3
H
H
1
13
.25/6.75, 2.20/6.94, 2.20/6.75. H- C HMBC NMR (CDCl ): δ /δ 7.47-7.50/127.2,
3
H
C
.27-7.32/138.5, 7.27-7.32/133.9, 7.27-7.32/132.0, 7.27-7.32/129.9, 7.27-7.32/128.9, 7.27-
7.32/125.2, 6.94/139.4, 6.94/128.5, 6.75/139.4, 6.75/131.0, 2.25/131.0, 2.25/128.5,
2
.25/127.0, 2.20/139.4, 2.20/131.0, 2.20/122.6. GC-MS (EI) m/z: 233 (16), 232 (10), 231
ACS Paragon Plus Environment

The Journal of Organic Chemistry
Page 28 of 52
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
+
(
54) [M ], 197 (13), 196 (100), 195 (38), 194 (24), 182 (11), 181 (76), 180 (40). HRMS
+
+
(
TOF, ESI ): calcd for C H ClN (M + H) : 232.0888; Found 232.0891.
1
4
15
2'-Chloro-5'-(trifluoromethyl)-5-carbonitrile-[1,1'-biphenyl]-2-amine (3h). Prepared by the
general procedure A and purified by column chromatography on silica gel eluting with
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
petroleum ether/ EtOAc (100:0 → 70:30 %). Colorless oil was obtained in 39% yield (57.8
1
mg, 0.195 mmol). H NMR (400 MHz, CDCl ): δ 7.63-7.69 (m, 2H), 7.59-7.60 (m, 1H),
3
7
2
3
1
7
7
7
.50 (dd, J= 8.4, 2.0 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 4.04 (br.s,
1
3
H). C NMR (100 MHz, CDCl ): δ 147.7, 137.9, 136.4, 134.7, 133.8, 130.6, 130.2 (q, J =
3
3 Hz), 128.7 (q, J = 4 Hz), 126.8 (q, J = 4 Hz), 123.4 (q, J = 207 Hz), 123.2, 119.5, 115.3,
1
13
00.7. H- C HSQC NMR (CDCl ): δ /δ 7.63-7.69/130.9, 7.63-7.69/126.8, 7.59-
3
H
C
1
1
.60/128.7, 7.50/133.8, 7.34/134.7, 6.79/115.3. H- H COSY NMR (CDCl ): δ /δ 7.59-
3
H
H
1
13
.60/7.63-7.69, 7.34/7.50, 6.79/7.50. H- C HMBC NMR (CDCl ): δ /δ 7.63-
3
H
C
.69/137.9, 7.63-7.69/136.7, 7.63-7.69/130.2, 7.63-7.69/128.7, 7.63-7.69/123.4, 7.59-
7.60/137.9, 7.59-7.60/126.8, 7.59-7.60/123.4, 7.59-7.60/123.2, 7.50/147.7, 7.50/134.7,
7
6
.50/119.5, 7.34/137.9, 7.34/136.4, 7.34/133.8, 7.34/119.5, 6.79/136.4, 6.79/123.2,
+
.79/110.7. GC-MS (EI) m/z: 298 (17), 296 (52) [M ], 261 (87), 260 (26), 242 (13), 241
+
(100), 192 (71), 191 (19), 164 (18). HRMS (TOF, ESI ): calcd for C H ClF N Na (M +
1
4
8
3
2
+
Na) : 319.0226; Found 319.0234.
2
-(2-Chlorophenyl)pyridin-3-amine (3i). The compound was prepared in an oven-dried
Schlenk tube charged with Pd(OAc) (2.2 mg, 0.01 mmol) and Xphos (10 mg, 0.02 mmol),
2
evacuated, and filled with nitrogen. 1.4-Dioxane (2 mL) was added followed by 2-chloro-3-
nitropyridine (1h) (79 mg, 0.5 mmol) to the flask via syringe. The resulting mixture was
stirred at room temperature and 2-chlorophenylboronic acid (2a, 93.6 mg, 0.6 mmol) was
ACS Paragon Plus Environment

Page 29 of 52
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
added followed by Cs CO (488 mg, 1.5 mmol), added in one portion. The solution was
2
3
heated with stirring to 80ºC for 18 h. After being cooled to room temperature, the mixture
was extracted with EtOAc. The resulting crude was chemically reduced in 2 ml of
ethanol/water (5/2) with 1 equiv of Fe(0) in power and 2 equiv of HCl. The crude was
filtrate over Celite and extracted with EtOAc. The extracts were combined, dried over
Na SO , and filtered. After removal of volatile components from the filtrate, the resulting
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
4
crude product was purified by column chromatography on silica gel eluting with petroleum
ether/EtOAc (100:0 → 50:50 %). Dark brown solid was obtained in 30% yield (31 mg,
1
0
1
.15 mmol), m.p.: 122-123 ºC. H NMR (400 MHz, CDCl ): δ 8.11 (dd, J = 4.8, 1.4 Hz,
3
H), 7.47-7.49 (m, 1H), 7.32-7.41 (m, 3H), 7.11 (dd, J = 8.0, 4.8 Hz, 1H), 7.05 (dd, J = 8.0,
1
3
1.4 Hz, 1H), 3.64 (br.s, 2H). C NMR (100 MHz, CDCl ): δ 143.6, 140.5, 139.5, 137.1,
3
1
13
1
8
33.2, 131.5, 129.9, 129.8, 127.4, 123.8, 122.4. H- C HSQC NMR (CDCl ): δ /δ
H C
3
.11/139.5, 7.47-7.49/129.9, 7.32-7.41/131.3, 7.32-7.41/129.8, 7.32-7.41/127.4,
1
1
7.11/123.81, 7.05/122.4. H- H COSY NMR (CDCl ): δ /δ 7.32-7.41/7.47-7.49,
3
H
H
1
13
7
8
7
7
.11/8.11, 7.05/7.11, 7.05/7.11. H- C HMBC NMR (CDCl ): δ /δ 8.11/143.6,
3
H C
.11/123.8, 8.11/122.4, 7.47-7.49/137.1, 7.47-7.49/133.2, 7.47-7.49/127.4, 7.32-7.41/143.6,
.32-7.41/137.1, 7.32-7.41/133.2, 7.32-7.41/131.3, 7.32-7.41/129.9, 7.32-7.41/129.8,
+
.11/140.5, 7.11/139.5, 7.05/143.6, 7.05/139.5. CG-MS (EI) m/z: 205 (10), 204 (23) [M ],
+
203 (16), 170 (10), 169 (100), 168 (45), 115 (11), 102 (10). HRMS (TOF, ESI ): calcd for
+
45
C H ClN (M + H) : 205.0533; Found 205.0527.
11
10
2
1
-(2-Chlorophenyl)naphthalen-2-amine (3j). Prepared by the general procedure A and
purified by column chromatography on silica gel eluting with petroleum ether: EtOAc
1
(
100:0 → 70:30 %). Brown oil obtained in 21% yield (26.6 mg, 0.105 mmol). H NMR
ACS Paragon Plus Environment