Acid mediated coupling of aliphatic amines and nitrosoarenes to indoles

Article abstract of DOI:10.1039/c9cc09616g

Traditionally, amines react with nitrosoarenes to provide the corresponding imines or azo compounds. Herein, we report an acid mediated annulation reaction of aliphatic amines and nitrosoarenes to provide indole derivatives. The elusive direct annulation of aliphatic amines and nitrosoarenes via simultaneous C-C and C-N bond formation was achieved under metal free conditions. This conceptually novel method for indole synthesis does not require pre-functionalization steps for the new C-C and C-N bond formation. The method has been applied for an elegant synthesis of nor-neocryptolepine and neocryptolepine.

Full text of DOI:10.1039/c9cc09616g

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DOI: 10.1039/C9CC09616G
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Acid Mediated Coupling of Aliphatic Amines and Nitrosoarenes to
Indoles
Subhra Kanti Roy, Anisha Purkait, Sk Md Tarik Aziz and Chandan K. Jana*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
Traditionally, amines reacts with nitrosoarenes to provide and azoxy-arene.6l Herein, we report the first example of an acid
corresponding imines or azo compounds. Here in, we report an acid mediated direct annulation reaction of nitrosoarenes and
mediated annulation reaction of aliphatic amines and aliphatic amines to provide indoles under metal and oxidant
nitrosoarenes to provide indole derivatives. The elusive direct free simple conditions (Scheme 1c).
annulation of aliphatic amines and nitrosoarenes via C-C and C-N Despite the limitation related to the lack of availability of aryl
bond formation were achieved under metal free conditions. This hydrazines,8 Fischer indole synthesis, which works via a simple
conceptually novel method for indole synthesis does not require condensation of arylhydrazines and enolizable carbonyl
pre-functionalizations steps for the new C-C and C-N bond compounds, was found to be an extremely beneficial method
formation. The method has been applied for an elegant synthesis for the preparation of natural and unnatural indole derivatives.9
of nor-neocryptolepine and neocryptolepine.
This is mostly because of its operational simplicity and
involvement of readily accessible substrates (e.g. aldehydes and
ketones) (Scheme 2a). More importantly, this method works
with carbonyl compounds as the abundant source of C2-C3 unit
without requiring pre-functionalization. Saturated aliphatic
amines are as abundant as the carbonyl compounds. Therefore,
the synthesis of indoles directly starting from aliphatic amines
would be impactful. A wide variety of C-H functionalization
reactions of aliphatic amines are known.10,11 Surprisingly, to the
best of our knowledge, synthesis of indole using saturated
Indole moieties are ubiquitous in biologically active natural
products, pharmaceuticals, and agro-chemicals (Scheme 1a).1
Therefore, varieties of synthetic strategies have been
developed for the synthesis of indole derivatives.2 Nucleophilic,
electrophilic, and radical cyclization reactions involving suitably
functionalized aniline derivatives are the major ways of indole
ring formation. The indole synthesis via sigmatropic
rearrangements is another common approach.2 A large number
of metal catalyzed annulation reactions of aniline derivatives
with alkyne and alkene have been developed for indole
synthesis.3,4 Except for aniline derivatives, 2-nitrostyrene
derivatives were also reacted under various reducing conditions
to provide the corresponding indole derivatives.3,4
Nitrosoarenes were used in a wide variety of reactions, such as
pericyclic reaction, aldol reaction, annulation reactions, and C-
H functionalization reaction due to their ready availability.5,6
Metal catalyzed annulation reactions of nitrosoarenes with
alkynes or N-hydroxy allenylamines have also been reported
recently to provide indole derivatives (Scheme 1b).7 However,
reaction of nitrosoarene with alkyl and aryl amines are well
known to provide the corresponding azo derivatives (Scheme
1b).5a On the other hand benzyl amines undergo oxidation in
the presence of nitrosoarene to provide corresponding imines
aliphatic amines have not been known yet.
(a) Relevant examples of bioactive natural and synthetic indole derivatives
Me
Cl
N
OMe
OMe
OMe
N
Antidepressant
O
N
N
Cl
N
N
N
Br
H
N
N
BPR0L075
(anticancer)
2
N
MeO
Neocryptolepine
(+)-Perophoramidine
H
(b) traditional reactions of amines with nitrosoarenes
O
N
N
R
N
R
Ar
+
Ar
+
NH2
R = alkyl and Aryl
O
N
N
Ar
Ar
Ar'
N
Ar'
+
Ar
N
O
Ar'
(c)
NH2
this work
: annulation reaction of amines with nitrosoarenes
O
simultaneous
R
N
R
H
H+
C-C & C-N bond formation
metal free
H
R
+
N
R
NHR
operationally simple
broad scope
R2
31 examples, up to 71%
R2
H
Scheme 1. Relevant bioactive indole containing molecules and reactions of amines
with nitrosoarenes.
In continuation of our interest on the amine functionalization,
we anticipated that amines 1 could be reacted with the
nitrosoarenes to provide N-amino hydroxylamine 2 (Scheme
2b).12 Dehydration followed by isomerization would produce
a. Department of Chemistry, IIT Guwahati, India, 781039,
E-mail: ckjana@iitg.ac.in
† Footnotes relating to the title and/or authors should appear here.
Electronic Supplementary Information (ESI) available: [details of any supplementary
information available should be included here]. See DOI: 10.1039/x0xx00000x
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hydrazine derivative 3 which could provide desired indole 4 via as 3, 5-di-NO2-benzoic acid, 2, 5-di-Cl-benzoic acid, 4-Cl-benzoic
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DOI: 10.1039/C9CC09616G
[3,3]-sigmatropic rearrangement-annulation cascades. The acid, TFA and acetic acid, etc (see ESI, Table S1, entry 11-18).
major challenge would be to avoid the facile and simple However, the yield of the desired product did not improve. We
oxidation of amines to imines 5 via elimination of arylhydroxyl realized that the formation of azoxybenzene via thermal
amine 6.13
disproportionation of nitrosobenzene leads to the decrease in
the formation of the desired product. The reaction was
performed with slow addition of nitrosobenzene to minimize
the formation of undesired azoxybenzene (Table 1, entry 7-10).
The best result was obtained from the reaction of THQ with
nitrosobenzene added portion wise over a period of 2 h in the
presence of 4-NO2-benzoic acid in refluxing toluene (70%, Table
1, entry 7). Interestingly, the reaction in the absence of acid did
not provide the desired product 9.
(a) precursors for C2-C3 unit in Indole synthesis
R
R
ArNHNH2
limited
R
R
R
?
(
)
R/H
R
O
H/R
abundant
not used
NHR
N
N
H
H
abundant
widely used
(b) mechanistic hypothesis for using amines as C2-C3 unit in Indole synthesis
R
R
R
dehydration
R
R
N
sigmatropic
rearrangement
R
R
isomerization
Ar
O
R
NR
NR
HN
annulation
N
NHR
N
2
H
4
HO
Ar
Ar
1
3
Major challange
R
H
N
H2N
HO
Ar
oxidation
to imines
R2
R
NR
6
O
5
R2
N
R1
Scheme 2. Reaction design: scope and challenges.
4-NO2PhCO2H (1 equiv.)
R1
R
+
R
N
toluene, reflux
18 h
N
H
H
10
11
12a-v
Table 1. Optimization of reaction conditions.
H2N
H2N
H2N
H2N
O
N
R
X
RO
conditions
N
H
+
N
N
H
H
N
H
12a
12b
12c
12d
12e
, R = Me, 59%
, R = Et, 61%
, R = npr, 54%
, R = ipr, 64%
, R = tBu,67%
7
8
9
N
12f
, X = F, 69%
, X = Cl, 71%
, X = Br, 59%
12i
, R = Me, 50%
12j, R = CF3, 60%
H
12g
12a
x-ray of
12h
entry
1a
conditions (equiv.)
yield (%)
40
H2N
H2N
H2N
H2
N
4-NO2PhCO2H (1.0), toluene, reflux
4-NO2PhCO2H (1.0), toluene, reflux
4-NO2PhCO2H (1.0), toluene, reflux
4-NO2PhCO2H (1.0), toluene, reflux
R
R
2b
3c
4
54
51
58
N
R3
N
N
R3
H
N
H
H
H
, R = NO2, R3 = H
, R = H, R3 = NO2
, R = Et, R3 = H, 33%
, R = H, R3 = Et, 36%
12n
12o
49%, (
12p
, 50%
12l
12m
69%, (
12k
, 55%
12n 12o
:
= 1:1)
12l 12m
:
= 1:1)
Cl
H2N
NH2
H2
N
NH2
5
6
4-Cl-PhCO2H (1.0), toluene, reflux
2-NO2PhCO2H (1.0), toluene, reflux
4-NO2PhCO2H (1.0), toluene, reflux
4-NO2PhCO2H (1.0), toluene, reflux
4-NO2PhCO2H (0.2), toluene, reflux
4-NO2PhCO2H (0.5), toluene, reflux
toluene, reflux
40
28
R
N
N
H
N
H
N
H
H
12s
12t
12u
, R = H, 57%
12r
, 45%
12q
, 60%
12v,
46%
, R = Br, 50%
7d
8e
9d
10d
11
70
, R = Cl, 51%
Scheme 3. Substrates Scope.
68
54
The optimized conditions were then used to test the scope of
this new method for indole synthesis via ring-opening
annulation reaction of tetrahydroquinolines and nitrosoarenes.
The scope of the reactivity of nitrosoarenes was investigated
first. Various nitrosoarene containing different substituents
were reacted with THQ to obtain the corresponding 3-
substituted indoles 12a-v with good to very good yields
(Scheme 3). Alkyl groups, such as Me, Et, nPr, iPr, tBu substituted
nitrosoarenes reacted efficiently with THQ to give
corresponding indoles (12a-e) with good yields. The structure of
12a was confirmed by X-ray crystallography. Similarly, the
reactions of THQ with halogen (e.g. F, Cl, Br) substituted
nitrosoarenes provided corresponding indoles (12f-h) with
good yields. 3, 5-dimethylnitrosobenzene also reacted
smoothly to afford 12k with a moderate yield. However,
regioisomeric indoles with equal amounts were obtained from
the reaction of m-substituted nitrosobenzene. 3-
ethylnitrosobenzene afforded a separable mixture of 12l and
12m with 69% combined yield. On the other hand, an
inseparable mixture of 12n and 12o was isolated from the
reaction of 3-nitro-nitrosobenzene.
60
trace
All reactions were performed with THQ (0.30 mmol), nitrosobenzene (0.60 mmol)
in solvent (4 mL) for 18 h. a1.0 equiv. of nitrosobenzene, b1.0 equiv. of
nitrosobenzene and 1.5 eq. of THQ, c1.5 equiv. of nitrosobenzene was used.
daddition of nitrosobenzene over 2 h and eaddition of nitrosobenzene in toluene
was carried out over 2 h by syringe pump.
According to our anticipation, we started our investigation by
reacting tetrahydroquinoline (THQ, 8), which is commercially
available, with nitrosobenzene 7 in the presence of 4-NO2-
benzoic acid under refluxing toluene. To our delight, expected
3-substituted indole derivative 9 was isolated with 40% after 18
h of reaction. Encouraged by the initial result, different reaction
conditions were examined to increase the yield of the desired
product. An increase in the yield of 9 was observed on the
increase in the relative stoichiometry of nitrosobenzene (Table
1, entry 3, 4). However, a further increase in the amount of
nitrosobenzene to 2.5 equivalent leads to a decrease in the
formation of 9 (see ESI, Table S1, entry 5). Toluene was found
to be the best among the other solvents which were screened
(see ESI, Table S1, entry 6-10). The reaction was carried out in
the presence of various other organic and inorganic acids, such
Next, the reactions of substituted THQ derivative with
nitrosobenzene were investigated to further expand the scope
2 | J. Name., 2012, 00, 1-3
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of this annulation reaction. The reactions with THQ having NOE experiments. Intramolecular trapping of hydVraiezwoAnrtiiculemOniloinne
DOI: 10.1039/C9CC09616G
substituents both in the aromatic and aliphatic ring have been 26 provides direct evidence that the reaction proceeds via 18
studied. Annulation reaction of 8-methyltetrahydroquinoline (Scheme 5b).
(a) proposed mechanism
with nitrosoarene afforded corresponding indole 12q with 60%
HO
O
N
N
-H2
O
N
H
8
yield. 4-substituted THQ derivatives also gave the
corresponding indoles with good to moderate yields (12s-12v).
Indoline reacted with nitrosoarenes under the standard
condition to afford N-aminoaryl indole derivative.14
N
N
N
N
N
NH
OH
trapped
18
- H+
7
15
17
16
H2
N
[3,3]
N
NH2
The annulation reaction of acyclic secondary amines with
nitrosoarenes was then investigated to increase the scope
further. Accordingly, various N-phenyl β-arylethylamines 13
were reacted with different nitrosobenzene in the presence of
4-NO2PhCOOH to obtain the desired 3-arylindoles 14a-h with
moderate yields (Scheme 4). Similarly, N-phenyl- α,β-
diarylethylamines reacted smoothly with nitrosobenzene to
afford corresponding 2,3-diarylindole 14h. Interestingly, the
significant increase in the yield of 14 (36-45% to 41-57%) was
observed when N-alkyl 3-pyridyl amine (13a-c) was used instead
of N-alkyl phenyl amine. However, dialkyl amines failed to
provide the desired indole under this conditions.
N
HN
N
N
H
H
N
H
21
20
19
9
(b) identification of intermediates
OH
OH
N
PhNO
X
+
NH
N
NBA, toluene
reflux, 18 h
H
7
22
8
NOE
NaBH3CN, AcOH
MeOH, rt, 2.5 h
CH3MgBr
toluene, 70 oC, 12 h
H
N
N
conc. HCl, 12 h
N
H
OH
HN
H
O
NOE
24
, 42%
23
H
PhNO, NBA
N
H
N
H
OH
H
N
toluene, reflux
18 h
N
OH
HN
H
N
27
, 52%
HN
O
HN
Ph
25
, 50%
26
Ph
H
R1
O
N
X
Scheme 5. Mechanistic studies and proposed mechanism.
R2
4-NO2PhCO2
H
R1
R2
R
R
+
toluene, reflux
38 h
N
H
N
H
13
X = N or CH
10
14a-h
(a) synthesis of neocryptolepine and its derivative via intramolecular amination of indole
H2
OMe
Me
N
R
R
CH3
I
Et
I2, Cs2CO3
14a
14b
14c
14d
N
N
R
THF, reflux
12h
CH3CN, rt
4h
N
N
Me
N
N
R
R
R
N
H
H
H
H
X= N, 57%
X= CH, 45% (62%)
X= N, 47%
X= CH, 38% (52%)
neocryptolepine
(R =H,), 74%
, R= CH3, 71%
N
X= N, 50%
X= CH, 41%
N
H
X= N, 49%
X= CH, 36%
28a
, R = H, 74%
H
9
,
12k
29a,
29b
28b,
R= CH3, 69%
OMe
OMe
OMe
(b) Other derivatization
3,5-(CF3 2-PhNCS
THF, 0 oC to rt, 12 h
H2
N
OMe
)
4-Cl-PhCHO
iPr
tBu
NH
14e
14f
14g
R
N
TFA, DCM,
rt, 1h
H
14h
N
H
N
H
N
H
N
H
N
KOH,
toluene
150 oC, 24 h
H
9
,
12b
BnHN
R
X= CH, 43%
X= N, 44%
X= N, 36%
X= CH, 35% (62%)
X= CH, 41% (60%)
H
N
HN
X= CH, 39% (53%)
PhCH2OH
30a,
30b,
R = H, 92%
R = Et, 89%
Cl
N
Scheme 4. Reaction with acyclic amines to 3-aryl and 2,3-diaryl indoles. The yields
based on recovered starting material is provided in parenthesis.
CF3
H
S
R
31
, R = H, 97%
N
32
, R = H, 77%
F3C
H
Scheme 6. Synthetic elaborations: preparation of neocryptolepine and its
derivatives.
Based on the experimental results, a plausible mechanism for
the acid mediated direct annulation of saturated aliphatic
amines with nitrosoarenes has been depicted in scheme 5.
Bronsted acid mediated protonation activated nitrosoarene 7
for nucleophilic addition. Amine 8 reacted with activated
nitrosoarene 15 to provide the hydroxylamine intermediate 16.
Acid assisted dehydration of 16 provided azonium ion 17 which
on subsequent isomerization gave the corresponding
hydrazonium ion 18. The ene-hydrazine 19 produced via
3-(2-aminobenzyl)- indole derivative obtained from the
reaction of THQs and nitrosoarenes were then derivatized in a
varied way to provide natural product and different bioactive
molecules (Scheme 6). Iodine mediated intramolecular C2-
amination of indoles 9 and 12k followed by oxidation of
resulting dihydroquinolines provided biologically important
indoloquinolines 28a and 28b. Nor-neocryptolepine16 28a and
its derivative 28b was further N-methylated with CH3I to obtain
neocryptolepine 29a17 (74%) and its derivative 29b (71%),
respectively. The azepinoindole derivatives are an important
class of compounds which exhibits several bioactivities such as
anti-proliferative, anti-inflammatory, etc.18 Reaction of 4-Cl-
benzaldehyde with indole 9 and 12b in the presence of 2% TFA
in dichloromethane at room temperature afforded
corresponding benzazepinindole derivatives 30a and 30b with
excellent yields. The primary amine moiety of 9 was reacted
with thiocyanate to obtain the thiourea 31 with excellent yield.
Similarly, selective N-benzylation of primary amine gave the
corresponding N-benzyl derivative 32.
isomerization
of
18
underwent
[3,3]-sigmatropic
rearrangement to provide the aniline derivative 20.
Intramolecular cyclization of 20 followed by aromatization
driven elimination of aminoaryl moiety gave the observed
indole 9. The reaction of acyclic amines also proceeds through
similar intermediates, as shown in scheme 5a.
To validate our mechanistic proposal, we performed a reaction
in the presence of 2-naphthol for trapping the hydrazonium
intermediate 18. However, the expected C-alkylated naphthol
22 or oxazine could not be identified. Interestingly, the reaction
of amino alcohol 25, which was prepared in two steps starting
from cinchonine,15 with nitrosobenzene provided the oxazine
27 instead of the corresponding indole derivative. The relative
stereochemistry of oxazine 24 and 27 were assigned based on
In summary, we have developed an original method for
synthesis of indole via a simultaneous functionalization of arene
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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and J. R. de Alaniz, Chem. Sci., 2018, 9, 8748. (l) Y. M. Wu, L. Y.
moiety of nitrosoarene and aliphatic amines. Diversely
substituted indoles were prepared by an acid mediated simple
condensation reaction of aliphatic amines and nitrosoarenes
without the aid of metallic reagents/catalyst and oxidant.
Additionally, an elegant method for the synthesis of
neocryptolepine and its derivatives have been developed using
this simple indole forming reaction. Mechanistic studies
suggested that the reaction proceeds via [3, 3] sigmatropic
rearrangement involving ene-hydrazine intermediate. This
method will be widely used for indole synthesis because it
involves readily available starting materials, simple conditions,
and it does not require pre-functionalizations for the new C-C
and C-N bond formation.
View Article Online
Ho, C. H. Cheng, J. Org. Chem. 1985, 50, 392.
DOI: 10.1039/C9CC09616G
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We acknowledge Science and Engineering Research Board
(SERB), New Delhi (CRG/2019/000330) for funding.
Notes and references
‡ Footnotes relating to the main text should appear here.
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4 | J. Name., 2012, 00, 1-3
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ChemComm
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Journal Name
COMMUNICATION
View Article Online
DOI: 10.1039/C9CC09616G
TOC
Synthesis of indoles from the reaction of amines and
nitrosoarenes
O
R
N
R
R
H+
R
+
NHR2
N
R1
R1
H
simultaneous C-C & C-N bond formation
31 examples
up to 71%
metal-free; operationally simple; broad scope
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 5
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