Halogen Bond-Assisted Electron-Catalyzed Atom Economic Iodination of Heteroarenes at Room Temperature

Article abstract of DOI:10.1021/acs.joc.9b00174

A halogen bond-assisted electron-catalyzed iodination of heteroarenes has been developed for the first time under atom economic condition at room temperature. The iodination is successful with just 0.55 equiv of iodine and 0.50 equiv of peroxide. The kinetic study indicates that the reaction is elusive in the absence of a halogen bond between the substrate and iodine. The formation of a halogen bond, its importance in lowering the activation barrier for this reaction, the presence of radical intermediates in a reaction mixture, and the regioselectivity of the reaction have been demonstrated with several control experiments, spectroscopic analysis, and quantum chemical calculations. Allowing the formation of the halogen bond may offer a new strategy to generate the reactive radical intermediates and to enable the otherwise elusive electron-catalyzed reactions under mild reaction conditions.

Full text of DOI:10.1021/acs.joc.9b00174

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Article
Halogen Bond–Assisted Electron–Catalyzed Atom
Economic Iodination of Heteroarenes at Room Temperature
Imran Kazi, Somraj Guha, and Govindasamy Sekar
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00174 • Publication Date (Web): 01 May 2019
Downloaded from http://pubs.acs.org on May 1, 2019
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Halogen Bond–Assisted Electron–Catalyzed Atom Economic Iodination of
Heteroarenes at Room Temperature
Imran Kazi, Somraj Guha and Govindasamy Sekar*
Department of Chemistry, Indian Institute of Technology Madras, Chennai – 600 036,
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Tamil Nadu, INDIA
E-mail: gsekar@iitm.ac.in
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ABSTRACT
A halogen bond–assisted electron–catalyzed iodination of heteroarenes has been developed for
the first time under atom economic conditions at room temperature. The iodination is
successful with just 0.55 equivalent of iodine and 0.50 equivalent of peroxide. The kinetic
study indicates that the reaction is elusive in absence of halogen bond between the substrate
and iodine. The formation of halogen bond, its importance in lowering the activation barrier
for this reaction, the presence of radical intermediates in reaction mixture and the
regioselectivity of the reaction have been demonstrated with several control experiments,
spectroscopic analysis and quantum chemical calculations. Allowing the formation of halogen
bond may offer a new strategy to generate the reactive radical intermediates and to enable the
otherwise elusive electron–catalyzed reactions under mild reaction conditions.
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INTRODUCTION
Halogen bond (XB) refers to the attractive noncovalent interaction between an electrophilic
1
halogen atom (XB donor) and a Lewis base (XB acceptor). Several studies on XB were related
to solid state chemistry but recently, its application has been realized in the field of crystal
2
a
2b
2c
2d,e
engineering, medicinal chemistry, self-assembly and supramolecular chemistry.
In
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addition to this, XB has emerged as an important tool in the field of organic synthesis. In the
last few years, XB has been employed for activation of functional groups,3a,b synthesis of
recyclable catalysts,3c photoactivation of halides to generate radical intermediates3d and
transformation of gaseous compounds to easily–handleable condensed–phase liquid reagents.3e
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Figure 1. Concept of employing XB–assisted electron–catalyzed reaction for regioselective
iodination of various heteroarenes under mild condition.
As the part of our on–going research on the effect of halogen bonds on the reactivity of
4
halogen(I) reagents and in situ–generated halogen(I) intermediates, we have observed that the
XB between the Lewis base and halogen(I) center assists the electron transfer (ET) from the
former to the latter to generate radical species.4c This observation was also reported by
5
Roshokha and coworkers in 2014. They demonstrated that XB significantly lowers the
activation barrier for the electron transfer (ET) from donor (Lewis base) to acceptor (halogen(I)
center). Thus, we envisaged that XB can be an efficient tool to modulate the electron transfer
processes in organic synthesis.
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The electron transfer (ET) process is the crucial initiation step for synthetically important
radical–molecule reactions. The radical–molecule reaction is a reaction between radicals and
6
close–shell molecules such as unimolecular radical substitution reactions (SRN1), base-
promoted homolytic aromatic substitutions (BHAS),7 transition-metal-free Heck-type
reactions, radical cross-dehydrogenative coupling reactions via BHAS9 and alkoxy
carbonylation of aryl halides.10 According to Studer and Curran, these reactions can be
mechanistically generalized as ‘electron- catalyzed reactions’.11 A general and simplified
mechanistic pathway for an electron-catalyzed reaction is depicted in Figure 1A (‘electron as
catalyst’ view).
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As the radicals are very reactive species, these reactions generally proceed smoothly (chain
reaction) once the radical and radical anion intermediates are formed in the reaction mixture.
The main challenge for these reactions is to initiate the generation of radical anion by ET
process and to control the selectivity of the reaction (favoring one pathway among several other
competitive pathways). In general, to initiate this ET process, harsh conditions such as high
t
temperature, stoichiometric amount of base (such as KO Bu), or stoichiometric amount of
1
1
peroxide are required. We hypothesized that the XB–assisted ET might be employed to
generate the reactive radical intermediates and to initiate an electron–catalyzed radical–
molecule reaction under mild reaction conditions. Moreover, this radical molecule reactions
1
2
are helpful for radical C–H activation or radical cross coupling reaction. Herein, for the first
time, we demonstrate how halogen bond enables the electron–catalyzed iodination of hetero
arenes at room temperature utilizing only semi-stoichiometric amount of iodine and peroxide
as oxidant. The reaction is elusive under the same reaction conditions when halogen bond is
absent between the substrate and iodine.
Due to the presence of weak carbon–iodine bond, heteroaryl halides are one of the most
important structural precursors in synthetic organic chemistry and often used as starting
1
3
materials for transition metal-catalyzed cross-coupling reactions and nucleophilic aromatic
substitution.14 Recently, few procedures have reported the regioselective iodination of
quinolines with I
2
/TBHP15a,b and K
2
S
2
O
8
/Ce(NO
3
)
/NaI.15c Unfortunately, in both the cases the
3
reactions were carried out under harsh conditions and in presence of costly metal catalysts.
RESULTS AND DISCUSSION
To initiate our study, we have chosen isoquinoline 1a as a model substrate in the presence of
molecular iodine. The initial reaction was carried out by 1 equiv. of isoquinoline 1a and 1.1
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Table 1. Optimization for regioselective iodination of isoquinolinea
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Oxidant
Solvent
(mol %)
Temp
( C)
Time
(h)
Yield
(%)
Entry I
2
(equiv.)
b
o
c
(equiv.)
1
2
1.1
1.1
-
-
Pyd
130
rt
36
36
24
23
24
30
23
23
24
21
24
24
64e
35
73
74
73
70
73
74
42
92
85
75
-
3
1.1
TBHP (1.0)
TBHP (1.0)
TBHP (1.0)
TBHP (1.0)
TBHP (0.6)
TBHP (0.5)
TBHP (0.3)
TBHP (0.5)
TBHP (0.5)
TBHP (0.5)
-
rt
4
0.60
0.55
0.50
0.55
0.55
0.55
0.55
0.55
0.55
-
rt
5
-
rt
6
-
rt
7
-
rt
8
-
rt
9
-
rt
10
AcOH (10)
rt
1
1
1
2
HCO
2
H (10)
H (10)
rt
EtCO
2
rt
CF
3
CO
10)
2
H
1
3
0.55
TBHP (0.5)
rt
24
73
(
1
1
1
4
5
6
0.55
0.55
0.55
0.55
0.55
TBHP (0.5)
TBHP (0.5)
TBHP (0.5)
MeOH (10)
EtOH (10)
rt
rt
22
22
18
24
24
78
79
94
63
16
H
2
H
2
H
2
O (10)
rt
rt
17
H
2
O
2
(0.5)
O (10)
1
8
DTBP (0.5)
O (10)
rt
a
b
c
d
Reaction conducted in 1 mmol scale. TBHP in decane used. Isolated yield. 3 equiv. of pyridine was
e
used. Oxygen balloon was used.
equiv. of molecular iodine in the presence of 3 equiv. of pyridine as a solvent under oxygen
o
atmosphere yielded 64% of 4-iodoisoquinoline 2a at 130 C in 36 h (Table 1, entry 1). The
reaction provided 35% yield of iodinated product at room temperature in absence of solvent
(Entry 2). When the reaction was performed in the presence of 1.0 equiv. of TBHP in decane,
7
3% of product was isolated at room temperature (Entry 3). We did not observe any reduced
yield of iodinated product by decreasing the loading of iodine from 1.1 equiv. to 0.55 equiv.
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(
Entry 4–6). Similarly, by screening the amount of TBHP, it was inferred that 0.50 equiv. of
TBHP was adequate for the reaction (Entry 7–9). Further, a range of solvent were examined to
improve the yield of 2a (Entry 10–16) and the results are summarized in Table 1. Finally, it
was observed that 10 mol% of H
6).16a To improve the efficiency of the reaction, various oxidants were screened (Entry 17–
18). In case of H , the yield of C-3 iodinated isoquinoline was reduced to 63% (entry 17).
2
O gave the best yield of 94% of the isolated product (Entry
1
1
1
1
1
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0
1
2
O
2
The reaction provided very poor yield when DTBP (Di-tertbutyl peroxide) was used as an
oxidant (Entry 18).
Table 2. Scope of the iodination of quinoline derivatives.a
Time
(h)
Yield
(%)
Entry
1
Substrate
Product
18
94
2
3
4
5
6
33
30
48
36
72
90
74
65b
71b
62b
48b
54b
46b
7
8
9
72
72
72
a
b
16b
Isolated yield. 2 equiv. of pyridine was used.
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With the optimized reaction conditions (Table 1, entry 16) in hand, the scope of regioselective
iodination of various quinoline derivatives and 7-azaindoles were investigated. Substrates with
both electron–donating and electron–withdrawing groups were well tolerated during the
iodination reaction. Unsubstituted Isoquinoline and quinoline moieties were regioselectively
iodinated in excellent yields (Table 2, 2a–b). Good to excellent yields were observed with
quinoline moiety having electron-donating groups (2c–2e). In contrast, the presence of
Table 3. Scope of the iodination of amino-quinoline.a
0
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Time Yield
Entry
1
Substrate
Product
(h)
(%)
4
92b
2
3
4
3
78
82
83
1.5
1.5
5
6
7
6
85
84
82
81
10
12
13
8
a
b
16b
Isolated yield. 5 equiv. of pyridine was used.
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Table 4. Scope of the iodination of substituted 7-azaindoles.a
1
1
1
1
1
1
1
1
1
1
2
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2
2
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6
0
1
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9
0
1
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9
0
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9
0
1
2
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9
0
1
2
3
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9
0
Time Yield
Entry
1
Substrate
Product
(h)
(%)
6
91
2
3
4
5
6
3.5
3
86
82
81
81
80
73
1.5
4
4
7
8
9
5
22
9
75
86
81
0
1
1
0
1
10
26
aIsolated yield.16b
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electron- withdrawing group at the quinoline ring decreased the yield of the product (2f–2g).
For 8-substituted quinoline molecule, a decrease in the yield was observed owing to the steric
hindrance near the donor nitrogen atom (2h and 2i).
Quinoline moiety bearing amino functional group underwent iodination and generated the
desired products in very good yields under the optimized reaction conditions (Table 3). The 8-
aminoquinolines gave the corresponding C-5 iodinated products in good to excellent yields
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(2j–2m). The structure of the productwas established by single-crystal XRD analysis of 2j
(CCDC no. 1871694).17a The 6-aminoquinolines and 5-aminoisoquinolines were also
transformed to C-5 and C-8 iodinated products respectively in high yield under the optimized
reaction conditions (2n–2q).
The substrate scope of the reaction with various substituted 7-azaindoles was examined under
the optimized conditions and the results have been described in Table 4. Generally, 7-azaindole
containing electron-donating groups on the pyrrole ring were well tolerated and delivered the
corresponding C-3 iodinated products in good to excellent yields (4a–4f). A slight decrease in
the yield was observed for N-benzyl and N-phenyl 7-azaindole (4g and 4h). The electron-
withdrawing group containing 7-azaindoles were well tolerated and provided the
corresponding C-3 iodinated products in good yields (4i and 4j).When ethyl carboxylate
containing group was subjected to the reaction condition even trace amount of product was not
observed (4k).
Further, the synthetic application of 4-iodoisoquinoline has been manifested by the carbon-
carbon bond formation reaction with styrene to give 6 which acts as an important precursor in
organic synthesis (Scheme 1a).18a Similarly, when 4-iodoisoquinoline was treated with
phenylboronic acid it was readily converted to 8 in presence of Pd(OAc) /DABCO system
2
(Scheme 1b).18b
Scheme 1. Synthetic transformation of 4-iodoisoquinoline.
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The exceptional mild conditions of this new iodination process propelled us to do the well–
thought–out mechanistic investigations and to check our hypothesis on halogen bond–assisted
electron–catalyzed pathway. To verify the presence of halogen-bonding interaction between
isoquinoline and molecular iodine, UV-Vis experiment was performed in hexane (Figure 2A).19
An absorption band corresponding to the free iodine in hexane was observed near 522 nm.
When UV-Vis absorption spectrum of 1a (40 equivalents) and iodine (1 equivalent) was
1
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0
A)
B)
C)
E)
D)
Figure 2. A) UV-Vis experiment of 1a (green line), iodine (blue line) and 1a+iodine (red line)
in hexane at 40 equivalents for 1a and 1 equivalent for iodine (path length = 1 cm). B) UV-Vis
spectra of 1a (40 equivalents) + iodine (1 equivalent) in hexane (path length = 1 cm) where 40
equivalents isoquinoline in hexane as blank. C) Optimized structure with DFT using ωB97X-
D functional and 6-311G(d,p) for C,H; 6-311+G(d,p) for N; aug-cc-pVTZ-PP for I in hexane
(
IEFPCM). D) Difference in total electron density between the excited state (corresponding to
λ=312 nm) and ground state mapped with electrostatic potential (isovalue = 0.0001). E) UV-
Vis spectra for titration of 1 equivalent I with isoquinoline (0 equivalent to 26 equivalents) in
2
hexane and of 1 equivalent I
equivalents in hexane.
2
+ 1 equivalent TBHP with isoquinoline (0 equivalent to 26
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recorded in hexane, the band near 522 nm completely disappeared and two new bands emerged
with the maxima at 420 nm (blue-shifted band, BS) and at 325 nm (charge–transfer band, CT)
(Figure 2A). In figure 2B, CT band merged with the broad absorption band of isoquinoline 1a
at 325 nm. To solve this problem, UV-Vis spectrum of the mixture of 40 equivalents 1a and 1
equivalent iodine was recorded in hexane with 40 equivalents solution of 1a in hexane as blank.
Due to this, the absorption band of 1a was completely cancelled out and the new CT band
clearly emerged with maxima at 325 nm. This experimental result supported the formation of
XB interaction between 1a and iodine and is corroborated with the literature reports (Figure
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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7
8
9
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8
9
0
1
2
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4
5
6
7
8
9
0
2
B).19
The Density Functional Theory calculations gave evidence of the formation of halogen bond
between isoquinoline and iodine. The distance between the nitrogen atom and the iodine atom
of XB complex 1a and I is 2.62 Å which is lesser than the sum of Van der Waals radii of N
2
and I (3.53 Å) and higher than the sum of covalent radii of N and I (2.10 Å) (Figure 2C).17a
The TD–DFT calculation was also performed to realize the nature of CT transition which is an
important component of halogen bond.17a,22f The calculation predicted the presence of two
absorption maxima at λ=417 nm with low oscillator strength (f = 0.022) and at λ=312 nm with
high oscillator strength (f = 0.061). These two values corroborated with the experimentally
observed BS band at λ=420 nm with low absorbance and CT band at λ=325 nm with high
absorbance.17a
Further insight into the CT transition was obtained by visualizing the difference between the
total electron density of the excited state (corresponding to λ=312 nm) and total electron density
of the ground state.17a,20 The blue region indicates a positive difference in electron density (i.e.
the electron density in excited state is higher than the electron density in ground state). The red
region indicates a negative difference in electron density (i.e. the electron density in excited
state is lower than the electron density in ground state). It is clear from figure 2D that electron
moves from 1a (electron-donor) to iodine (electron-acceptor) in excited state correspond to CT
transition.
Next, we tried to find how the oxidizing agent affects the XB interaction between 1a and iodine.
For this purpose, we compared the binding constant for the XB interaction between 1a and
iodine in the presence and absence of TBHP. The binding constants were calculated using UV-
Vis titration of iodine with increasing concentration of 1a in the presence and absence of TBHP.
The data was fitted (1:1 model) using Bindfit.17a,21
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The binding constant for the XB interaction between the iodine and 1a was found to be K =
1
-1
-1
160.90 M in presence of TBHP and K = 149.49 M in absence of TBHP (Figure 2E). This
2
experiment clearly showed that the oxidizing agent does not significantly affect the halogen–
bonding interaction between iodine and 1a. Thus we anticipated that, in our system, TBHP
could not oxidize iodine to the more electrophilic hypoiodite (iodine(I)) or iodate (iodine(V))
1
1
1
1
1
1
1
1
1
1
2
2
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2
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2
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8
9
0
2
2
which are capable of forming stronger XB bonds. In fact, the oxidation of iodine in the
presence of peroxides is associated with the undesired Bray–Liebhafsky oscillatory reaction
which is responsible for the excess consumption of peroxides.22b,23 We assume that the
formation of a stable halogen–bonded complex between 1a and iodine under solvent–free
condition prevents the background Bray–Liebhafsky reaction and thus helps to reduce the
amount of terminal oxidant required for the reaction.
A)
B)
C)
D)
E)
Figure 3. A) (i) Yield versus time profile of heteroarenes iodination reaction; y-axis: yield of
1
2
j and 2ja in %, x-axis: time in min. yields were determined by H NMR spectroscopy. (ii) The
role of halogen bond in electron transfer for isoquinoline system. B) Mechanistic probe by
controlled experiments. C). Identifying the regioselectivity with molecular orbital analysis with
DFT using ωB97X-D functional and 6-311G(d,p) for C,H; 6-311+G(d,p) for N; aug-cc-pVTZ-
PP for I in Vacuum. D). Thermodynamic stability of various radical intermediates with DFT
using ωB97X-D functional and 6-311G(d,p) for C,H; 6-311+G(d,p) for N; aug-cc-pVTZ-PP
1
7b a
17a
for I in Vacuum.
Energy of both the isomers (R and S) were calculated. The most stable
isomers were taken to obtain the energy differences. E) A plausible mechanistic pathway for
iodination of isoquinoline.
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6
To investigate the role of XB in the iodination process, a kinetic study of the reaction was
performed (Figure 3A (i)). The rate of the iodination of 8-aminoquinoline 1j was significantly
faster than the rate of the iodination of 1-naphthylamine 1ja. A significant difference in the rate
of the reaction was observed when 8-aminoquinoline (blue line) and 1-naphthylamine (red line)
were treated under optimized conditions (0.55 equiv. of iodine, 0.5 equiv. of TBHP, 10 mol%
0
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9
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4
5
6
7
8
9
0
of H O and 5 equiv. pyridine). This kinetic study strongly indicated that the formation of
2
halogen bond between 1a and iodine is responsible for the success of this iodination process.
Later, we compare the reactivity of naphthalene and isoquinoline under optimized conditions.
In case of naphthalene, even trace amount of iodinated compound was not observed (Figure
3
A (ii)). This result also indicated that the XB interaction between the substrate and iodine is
crucial for the success of the reaction.
Finally, the presence of radical intermediates was checked for the reaction mixture. The radical
trapping experiment was carried out with radical scavenger 2,2,6,6-tetramethyl-1-
piperidinyloxy (TEMPO) and 2,6-Di-tert-butyl-4-methylphenol (BHT) and no product
formation was observed (Figure 3B). This indicates that the reaction proceeds via radical
pathway. The reason behind the regio–selectivity of this iodination process was rationalized by
several quantum chemical calculations performed with DFT following reported literature.20
Firstly, we examined the energies of the frontier orbitals of 1a and iodine radical (I•) in order
to identify the interacting orbitals of 1a and I• during the reaction. It was observed that the
SOMO of I• interacts with the HOMO of 1a as they are closer in energy than the other
combinations (Figure 3C(i)). The Natural Population Analysis (NPA) of 1a with DFT showed
that the C–4 position has the largest contribution to HOMO (coefficient=0.48) among the three
carbons in heterocyclic ring of 1a.17a Thus, kinetically, the addition of I• to 1a is favorable at
C–4 position (Figure 3C(ii)). Next, the thermodynamic stability of three possible radical
intermediates which can be formed by the addition of I• to 1a was examined. It was observed
that the total energy of the intermediate 10 and 11 is higher than the total energy of intermediate
9
(Figure 3D). Therefore, the formation of the intermediate 9 (corresponding to C–4 iodination
product) is thermodynamically more stable than the formation of other two intermediates 10
and 11 (corresponding to C–3 and C–1 iodination products respectively). Hence, both the
kinetically–controlled and thermodynamically–controlled pathways lead to the formation of
intermediate 9 which further transformed to the product 2a.
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A plausible reaction pathway for the regioselective iodination of isoquinoline is depicted in
Figure 3E. The reaction pathway is initiated by an XB assisted ET to iodine from isoquinoline
-
(
step 1). In step 2, 12 dissociates into anion I and iodine radical (I•). In step 3, addition of
iodine radical to isoquinoline takes place to generate the 4-iodo-3,4-dihydroisoquinoline
-
1
1
1
1
1
1
1
1
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7
8
9
0
radical 9. In step 4, 9 is deprotonated by I to provide the radical anion intermediate 14. Finally,
in step 5, the electron transfer from radical anion species 14 to iodine occurs to generate the
intermediate 12 along with 4-iodoisoquinoline. The TBHP oxidizes HI and regenerates
molecular iodine.24
CONCLUSION
In conclusion, for the first time, the halogen–bond has been employed as an efficient tool to
enable an electron–catalyzed regioselective iodination of hetero aryls under mild reaction
conditions. The halogen bond between hetero–aryl substrates (electron–donor) and iodine
(electron–acceptor) lowers the activation energy of the electron–transfer (ET) from the former
to the latter. The mechanistic experiments and the quantum chemical calculations demonstrate
the formation of halogen bond and the presence of radical intermediates in reaction mixture.
The formation of halogen bond is not only helping in a ET under mild condition, it also stops
the unwanted Bray–Liebhafsky reaction and thus helps to reduce the amount of terminal
oxidant required for the reaction. The quantum chemical study shows that both the kinetically-
controlled and thermodynamically–controlled pathways lead to a single regioisomer. This
work shows that halogen–bond assisted electron–transfer can be an efficient tool to generate
the reactive radical intermediates under mild reaction conditions. This result encourages the
new possibilities of exploiting the halogen bond–assisted ET in designing a wide variety of
new electron–catalyzed radical–molecule reactions under transition metal–free conditions.
The advantages of the XB–assisted electron–catalyzed iodination of quinolines and other
heteroarenes can be summarized as follows: (1) The method is highly atom economic and
green. Only 0.55 equiv. of iodine and 0.50 equiv. TBHP is sufficient to drive the reaction to
completion. (2) It precludes the use of transition metal catalysts which are expensive, toxic and
2
5
have a strict limit of level in pharmaceutical products. (3) The reaction proceeds smoothly at
room temperature under solvent free condition. The solvent free reactions reduce the amount
of waste generated from reactions and were designated as one of the top priority in green
chemistry research areas by ACS Green Chemistry Pharmaceutical Roundtable.26
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6
EXPERIMENTAL SECTION
All reactions were carried out in oven dried reaction tubes. TBHP in decane, di-tert-
butyl peroxide, palladium acetate and DABCO were purchased from Sigma-Aldrich chemical
company. Iodomethane, ethylbromide, 1-iodopropane, 1-bromopentane, 1-bromooctane,
benzyl bromide and iodobenzene were purchased from Avra Synthesis Pvt. Ltd. Various
isoquinolines, quinolines and azaindoles were purchased from Alfa Aesar, Sigma-Aldrich,
TCI, Avra synthesis, Spectrochem Pvt. Ltd. and used directly as received. Reactions were
monitored by thin layer chromatography (TLC) using Merck silica gel 60 F254 precoated plates
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
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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
(0.25 mm) and visualized by UV fluorescence quenching using appropriate mixture of ethyl
acetate and hexanes as eluting solvent mixtures. Silica gel for column chromatography (particle
size 100-200 mesh) was purchased from Avra Synthesis Pvt. Ltd. and used for column
1
13
1
chromatography using hexanes and ethyl acetate mixture as eluent. H and C{ H} NMR
1
spectra were recorded on a Bruker 400 0r 500 MHz instrument. H NMR is reported relative
1
3
1
to residual CDCl3 (δ 7.26 ppm) or DMSO-d6 (δ 2.50 ppm). C{ H} NMR is reported relative
to residual CDCl3 (δ 77.16 ppm) or DMSO-d6 (δ 39.52 ppm). Chemical shifts were recorded
in parts per million (ppm) and multiplicities are as indicated: s (singlet,) d (doublet,) t (triplet,)
q (quartet,) quint (quintet), sext (sextet), dd (doublet of doublet,) m (multiplet,) tt (triplet of
triplet,) td (triplet of doublet). Coupling constant, J, are reported in Hertz. Melting points were
recorded on a Guna capillary melting point apparatus and are corrected with benzoic acid as
reference. FTIR spectra were recorded on a JASCO spectrometer and are reported in frequency
of absorption (cm-1) using dry KBr pellet. The UV–Vis spectra was recorded in JASCO V-
6
50 UV-VIS Spectrophotometer. High resolution mass spectra (HRMS) were recorded on Q-
Tof Micro mass spectrometer.
Experimental procedure for synthesis of 4-iodoisoquinoline (2a) from isoquinoline (1a):
Isoquinoline (129 mg, 1 mmol), molecular iodine (140 mg, 0.55 mmol) and 0.5 mmol
TBHP (6M in decane) were taken in an oven dried reaction tube. H
added into the reaction tube and the reaction was stirred at room temperature. After completion
of the reaction, it was quenched with aqueous saturated Na solution (10 mL). The reaction
mixture was extracted with ethyl acetate. The combined organic layer was washed with water
2 X 10 mL) and dried over anhydrous Na SO . The organic layer was evaporated under
2
O (2 μL, 0.1 mmol) was
2
S
2
O
3
(
2
4
reduced pressure to produce crude product which was purified by silica gel column
chromatography (hexanes / ethyl acetate) to give 4-iodoisoquinoline 2a (240 mg, 94% yield).
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Experimental procedure for synthesis of 5-iodoquinolin-8-amine (2j) from 8-
aminoquinoline (1j):
In an oven-dried reaction tube, 8-aminoquinoline (122 mg, 0.5 mmol), molecular iodine
(
70 mg, 0.275 mmol) and 0.25 mmol TBHP (6 M in decane) were taken. Pyridine (121 μL, 1.5
mmol.) and H O (2 μL, 0.1 mmol) were added into the reaction tube and the reaction was stirred
at room temperature. After completion of the reaction, the reaction was quenched with aqueous
saturated Na solution (10 mL). The reaction mixture was extracted with ethyl acetate (15
mL) and water (2 X 10 mL). The combined organic layer was dried over anhydrous Na SO
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
2
2
S
2
O
3
2
4
and evaporated under reduced pressure. The reaction mixture was purified by silica gel column
chromatography (hexanes/ ethyl acetate) to give 5-iodoquinolin-8-amine 2j (124 mg, 92%
yield).
Experimental procedure for synthesis of 3-iodo-7-azaindole (4) from 7-azaindole (3):
7
-Azaindole (59 mg, 0.5 mmol), molecular iodine (70 mg, 0.275 mmol) and 0.25 mmol
TBHP (6M in decane) were taken in an oven dried reaction tube. Pyridine (121 μL, 1.5 mmol)
and H O (2 μL, 0.1 mmol) were added into the reaction tube and the reaction was stirred at
room temperature. After completion of the reaction, the reaction mixture was quenched with
aqueous saturated Na solution (10 mL). The reaction mixture was extracted with ethyl
acetate. The combined organic layer was washed with water (2 X 10 mL) and dried over
anhydrous Na SO . The solvent was removed under reduced pressure to produce crude product
2
2
S
O
2 3
2
4
which was purified by silica gel column chromatography (hexanes / ethyl acetate) to give 3-
iodo-7-azaindole 4a (111 mg, 91% yield).
o
o
27
4
-Iodoisoquinoline (2a): 120 mg, 94% yield; light yellow solid; mp 88–90 C [93-94 C, lit];
1
R
f
= 0.36 (10% ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 7.66 (t, J=8.0 Hz, 1H),
7
.75–7.83 (m, 1H), 7.89 (d, J=7.6 Hz, 1H), 7.99 (d, J=8.4 Hz, 1H), 8.93 (s, 1H), 9.13 (s, 1H);
13
1
C{ H} NMR (100 MHz, CDCl ) δ 97.0, 128.3, 128.5, 129.8, 130.8, 132.1, 137.2, 151.1,
3
-1
+
1
52.7; FTIR (KBr): 754, 950, 1373, 2928 cm ; HRMS (m/z): [M+H] calculated for C
55.9623; found: 255.9595.
9
H
7
NI:
2
o
o
27
3
-Iodoquinoline (2b): 115 mg, 90% yield; light yellow solid; mp 60–62 C [60-62 C, lit];
1
R
f
= 0.34 (5% ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 7.53–7.59 (m, 1H),
1
3
1
7.68–7.76 (m, 2H), 8.06 (d, J=8.4 Hz, 1H), 8.51–8.55 (m, 1H), 9.03 (d, J=2.4 Hz, 1H); C{ H}
NMR (100 MHz, CDCl
3
) δ 89.9, 126.9, 127.5, 129.6, 130.0, 130.2, 143.9, 146.4, 155.7; FTIR
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1
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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
-1
+
(
KBr): 749, 938, 1573, 3056 cm ; HRMS (m/z): [M+H] calculated for C
9
H
7
NI: 255.9623;
found: 255.9633.
o
3
1
3
-Iodo-6-methylquinoline (2c): 100 mg, 74% yield; light yellow solid; mp 106–108 C [112-
o
15a
1
13 C, lit];
R
f
= 0.18 (5% ethyl acetate in hexanes); H NMR (400 MHz, CDCl
=2.0 Hz, J =8.8 Hz, 1H), 7.94 (d, J=8.8 Hz, 1H), 8.42 (d, J=1.6
) δ 21.8, 89.9, 125.7, 129.2,
3
) δ 2.53 (s,
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
H), 7.44 (s, 1H), 7.55 (dd, J
1
2
1
3
1
Hz, 1H), 8.94–8.96 (m, 1H); C{ H} NMR (100 MHz, CDCl
3
-1
1
30.1, 132.5, 137.6, 143.2, 145.0, 154.8; FTIR (KBr): 814, 1021, 1570, 2925 cm ; HRMS
+
(m/z): [M+H] calculated for C10
H NI: 269.9780; found: 269.9775.
9
o
3
1
3
8
-Iodo-6-methoxyquinoline (2d): 93 mg, 65% yield; light yellow solid; mp 108–110 C [116-
o
15a
1
17 C, lit];
R
f
= 0.25 (5% ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 3.92 (s,
H), 6.92–6.96 (m, 1H), 7.34–7.40 (m, 1H), 7.97 (d, J=9.2 Hz, 1H), 8.41–8.46 (m, 1H), 8.85–
13
1
.90 (m, 1H); C{ H} NMR (100 MHz, CDCl ) δ 55.7, 90.7, 104.2, 123.0, 131.0, 131.2, 142.5,
3
-1
+
142.7, 153.1, 158.4; FTIR (KBr): 822, 1024, 1219, 1489, 2922 cm ; HRMS (m/z): [M+H]
calculated for C10 NOI: 285.9729; found: 285.9745.
H
9
6
-Butyl-3-iodoquinoline (2e): 110 mg, 71% yield; pale yellow liquid; R
f
= 0.21 (5% ethyl
1
acetate in hexanes); H NMR (400 MHz, CDCl
1.67 (quint, J=7.2 Hz, 2H), 2.78 (t, J=7.6 Hz, 2H), 7.44 (s, 1H), 7.56 (dd, J
Hz, 1H), 7.95 (d, J=8.4 Hz, 1H), 8.42–8.46 (m, 1H), 8.95 (d, J=1.6 Hz, 1H); C{ H} NMR
100 MHz, CDCl ) δ 14.1, 22.4, 33.4, 35.7, 89.9, 125.1, 129.3, 130.1, 131.8, 142.5, 143.3,
145.2, 154.8; FTIR (KBr): 805, 1067, 1493, 2956 cm ; HRMS (m/z): [M+H] calculated for
15NI: 312.0249; found: 312.0231.
3
) δ 0.94 (t, J=7.2 Hz, 3H), 1.32–1.43 (m, 2H),
1
=1.2 Hz, J =8.8
2
1
3
1
(
3
-1
+
C H
13
o
6
-Chloro-3-iodoquinoline (2f): 87 mg, 60% yield; light yellow solid; mp 120–122 C [118-
o
15a
1
1
19 C, lit];
R
f
= 0.24 (2% ethyl acetate in hexanes); H NMR (400 MHz, CDCl ) δ 7.62–
3
1
3
1
7.69 (m, 2H), 7.98 (d, J=8.8 Hz, 1H), 8.43 (s, 1H), 8.98–9.02 (m, 1H); C{ H} NMR (100
MHz, CDCl ) δ 91.2, 125.5, 130.4, 131.1, 131.2, 133.4, 142.8, 144.8, 156.0; FTIR (KBr): 827,
3
-1
+
9
2
00, 1074, 1570 cm ; HRMS (m/z): [M+H] calculated for C
89.9226.
9
H
6
NClI: 289.9234; found:
o
3-Iodo-8-methoxyquinoline (2g): 77 mg, 54% yield; light yellow solid; mp 110–112 C [116-
o
15a
1
1
3
17 C, lit] ; R
f
= 0.18 (15% ethyl acetate in hexanes); H NMR (400 MHz, CDCl ) δ 4.01 (s,
3
H), 6.99 (d, J=7.6 Hz, 1H), 7.19 (d, J=8.4 Hz, 1H), 7.40 (t, J=8.0 Hz, 1H), 8.43 (d, J=1.6 Hz,
1
3
1
1H), 8.95 (d, J=2.0 Hz, 1H); C{ H} NMR (100 MHz, CDCl ) δ 56.2, 91.1, 108.2, 118.6,
3
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28.0, 131.1, 138.4, 143.6, 154.4, 155.7; FTIR (KBr): 758, 1118, 1261, 1559, 2960 cm-1;
1
+
HRMS (m/z): [M+H] calculated for C10
H
9
NOI: 285.9729; found: 285.9728.
o
8
0
4
-Ethoxy-3-iodoquinoline (2h): 69 mg, 46% yield; light yellow solid; mp 120–122 C; R =
f
1
.33 (15% ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 1.58–1.64 (m, 3H), 4.28–
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
.34 (m, 2H), 7.06 (d, J=6.4 Hz, 1H), 7.23–7.28 (m, 1H), 7.43–7.47 (m, 1H), 8.48–8.50 (m,
1
3
1
1H), 9.04–9.06 (m, 1H); C{ H} NMR (100 MHz, CDCl
3
) δ 14.8, 64.5, 90.9, 109.2, 118.4,
-1
1
28.0, 131.3, 138.6, 143.7, 154.5, 155.0; FTIR (KBr): 754, 1115, 1557, 2980 cm ; HRMS
+
(
m/z): [M+H] calculated for C11H11NOI: 299.9885; found: 299.9856.
o
3
-Iodo-8-nitroquinoline (2i): 72 mg, 48% yield; light yellow solid; mp 116–118 C [121-122
o
28
1
C, lit] ; R
f
= 0.34 (15% ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 7.64 (t, J=7.6
Hz, 1H), 7.93 (d, J=8.0 Hz, 1H), 8.06 (d, J=7.2 Hz, 1H), 8.63–8.67 (m, 1H), 9.15–9.20 (m,
13
1
1
H); C{ H} NMR (100 MHz, CDCl
3
) δ 92.2, 124.4, 126.5, 130.5, 131.1, 137.8, 143.9, 158.1;
+
FTIR (KBr): 767, 1086, 1342, 1527, 1628, 3034; HRMS (m/z): [M+H] calculated for
C
9
H
6
N
2
O
2
I: 300.9474; found: 300.9478.
o
o
5
-Iodoquinolin-8-amine (2j): 124 mg, 92% yield; yellow solid; mp 126–128 C [123-124 C,
2
9
1
lit]; R
f
= 0.36 (5% ethyl acetate in hexanes); H NMR (400 MHz, CDCl ) δ 5.08 (s, 2H), 6.72
3
(d, J=8.0 Hz, 1H), 7.42–7.47 (m, 1H), 7.82 (d, J=8.0 Hz, 1H), 8.24–8.29 (m, 1H), 8.69–8.73
13
1
(
m, 1H); C{ H} NMR (100 MHz, CDCl
45.1, 148.0; FTIR (KBr): 778, 820, 1498, 3313 cm ; HRMS (m/z): [M+H] calculated for
I: 270.9732; found: 270.9708.
3
) δ 81.1, 111.4, 123.1, 130.2, 138.1, 139.2, 140.2,
-1
+
1
C
9
H
8
N
2
o
5
-Iodo-N-methylquinolin-8-amine (2k): 111 mg, 78% yield; yellow solid; mp 82–84 C; R =
f
1
0
.43 (2% ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 3.01 (d, J=5.2 Hz, 3H), 6.26
=1.6
) δ
(
s, 1H), 6.42 (d, J=8.0 Hz, 1H), 7.41–7.46 (m, 1H), 7.88 (d, J=8.4 Hz, 1H), 8.26 (dd, J
1
13
1
Hz, J
2
=8.4 Hz, 1H), 8.65 (dd, J
1
=1.2 Hz, J
2
=4.0 Hz, 1H); C{ H} NMR (100 MHz, CDCl
3
3
1
0.0, 78.6, 105.9, 123.0, 129.8, 138.6, 139.1, 140.2, 146.8, 147.3; FTIR (KBr): 778, 1356,
-1
+
518, 1573, 2987, 3400 cm ; HRMS (m/z): [M+H] calculated for C10
H
10
2
N I: 284.9888;
found: 284.9881.
N-Ethyl-5-iodoquinolin-8-amine (2l): 122 mg, 82% yield; yellow liquid; R
f
= 0.41 (2% ethyl
) δ 1.40 (t, J=7.2 Hz, 3H), 3.27–3.37 (m, 2H),
.18 (s, 1H), 6.43 (d, J=8.0 Hz, 1H), 7.40–7.46 (m, 1H), 7.85 (d, J=8.0 Hz, 1H), 8.25 (d, J=8.4
1
acetate in hexanes); H NMR (400 MHz, CDCl
3
6
1
3
1
Hz, 1H), 8.62–8.68 (m, 1H); C{ H} NMR (100 MHz, CDCl ) δ 14.6, 37.9, 78.4, 106.3, 122.9,
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1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
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5
5
5
5
5
5
5
5
5
6
29.9, 138.6, 139.1, 140.2, 145.8, 147.2; FTIR (KBr): 797, 1148, 1377, 1579, 2969, 3315 cm-
1
1
+
; HRMS (m/z): [M+H] calculated for C11
H
12
2
N I: 299.0045; found: 299.0023.
5
-Iodo-N-propylquinolin-8-amine (2m): 130 mg, 83% yield; yellow liquid; R
f
= 0.38 (2%
) δ 1.07 (t, J=7.2 Hz, 3H), 1.79 (sext,
J=7.6 Hz, 2H), 3.20–3.29 (m, 2H), 6.28 (s, 1H), 6.43 (d, J=8.0 Hz, 1H), 7.39–7.45 (m, 1H),
1
ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
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
1
3
1
7.85 (d, J=8.4 Hz, 1H), 8.24 (d, J=8.4 Hz, 1H), 8.62–8.67 (m, 1H); C{ H} NMR (125 MHz,
CDCl ) δ 11.9, 22.5, 45.2, 78.2, 106.3, 122.9, 129.9, 138.6, 139.1, 140.2, 145.9, 147.2; FTIR
3
-1
+
(
KBr): 736, 1146, 1374, 1577, 2961 cm ; HRMS (m/z): [M+H] calculated for C12
H
14
2
N I:
3
13.0202; found: 313.0201.
o
5
-Iodoquinolin-6-amine (2n): 115 mg, 83% yield; yellow solid; mp 122–124 C; Rf= 0.15
1
(
25% ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 4.60 (s, 2H), 7.20 (d, J=8.8 Hz,
1
H), 7.31–7.37 (m, 1H), 7.86 (d, J=8.8 Hz, 1H), 8.20 (d, J=8.4 Hz, 1H), 8.58–8.63 (m, 1H);
1
3
1
C{ H} NMR (100 MHz, CDCl
3
) δ 81.0, 120.2, 122.9, 130.9, 131.4, 137.9, 143.9, 146.1,
-1
+
1
47.1; FTIR (KBr): 755, 922, 1550, 3186, 3306 cm ; HRMS (m/z): [M+H] calculated for
I: 270.9732; found: 270.9744.
C
9
H
8
N
2
o
N-Ethyl-5-iodoquinolin-6-amine (2o): 125 mg, 84% yield; yellow solid; mp 102–104 C; R =
f
1
0.38 (25% ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 1.37 (t, J=6.8 Hz, 3H),
3
1
.33–3.41 (m, 2H), 4.67 (s, 1H), 7.20 (d, J=9.2 Hz, 1H), 7.30–7.35 (m, 1H), 7.95 (d, J=8.8 Hz,
13
1
H), 8.17–8.22 (m, 1H), 8.57 (dd, J
1
=1.2 Hz, J =4.0 Hz, 1H); C{ H} NMR (100 MHz,
2
CDCl
97, 933, 1151, 1608, 2967 cm ; HRMS (m/z): [M+H] calculated for C11
found: 299.0059.
3
) δ 15.2, 39.2, 82.1, 116.5, 122.9, 131.1, 131.6, 138.0, 143.5, 146.6, 146.7; FTIR (KBr):
-1
+
7
H
12
2
N I: 299.0045;
5
-Iodo-N-propylquinolin-6-amine (2p): 128 mg, 82% yield; yellow liquid; R = 0.09 (5%
f
1
ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 1.05 (t, J=7.2 Hz, 3H), 1.74 (sext,
J=7.2 Hz, 2H), 3.25–3.33 (m, 2H), 4.76 (s, 1H), 7.20 (d, J=9.2 Hz, 1H), 7.29–7.35 (m, 1H),
13
1
7
.95 (d, J=9.2 Hz, 1H), 8.19 (d, J=8.8 Hz, 1H), 8.54–8.60 (m, 1H); C{ H} NMR (100 MHz,
CDCl ) δ 11.7, 22.9, 46.3, 82.1, 116.6, 122.9, 131.0, 131.6, 138.0, 143.5, 146.5, 146.6; FTIR
(KBr): 799, 1140, 1346, 1609, 2960 cm ; HRMS (m/z): [M+H] calculated for C12
3
-1
+
H
14
2
N I:
3
13.0201; found: 313.0215.
o
8
-Iodoisoquinolin-5-amine (2q): 125 mg, 84% yield; yellow solid; mp 138–140 C; R = 0.38
f
1
(20% ethyl acetate in hexanes); H NMR (400 MHz, DMSO-d6) δ 6.23 (s, 2H), 6.70 (d, J=8.4
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Hz, 1H), 7.83 (d, J=8.0 Hz, 1H), 7.90 (d, J=6.0 Hz, 1H), 8.46 (d, J=5.6 Hz, 1H), 9.10 (s, 1H);
1
3
1
C{ H} NMR (100 MHz, DMSO-D6) δ 78.0, 112.5, 115.4, 126.9, 128.2, 139.2, 141.9, 145.4,
-1
+
1
55.4; FTIR (KBr): 779, 817, 1460, 1500, 3303 cm ; HRMS (m/z): [M+H] calculated for
I: 270.9732; found: 270.9715.
C
9
H
8
N
2
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
o
o
3
-Iodo-7-azaindole (4a): 111 mg, 91% yield; light pink solid; mp 194–196 C [201-204 C,
30
1
lit]; R
=4.8 Hz, J
NMR (100 MHz, DMSO-D6) δ 54.5, 116.6, 122.1, 128.2, 130.6, 143.9, 148.1; FTIR (KBr):
f
= 0.09 (5% ethyl acetate in hexanes); H NMR (400 MHz, DMSO-d6) δ 7.15 (dd,
1
3
1
J
1
2
=8.0 Hz, 1H), 7.65–7.71 (m, 2H), 8.23–8.26 (m, 1H), 12.09 (s, 1H); C{ H}
-1
+
7
57, 960, 1406, 1579, 3401 cm ; HRMS (m/z): [M+H] calculated for C
7
H
6
N
2
I: 244.9576;
found: 244.9586.
o
3
-Iodo-1-methyl-7-azaindole (4b): 111 mg, 86% yield; white solid; mp 126–128 C [117-119
o
31
1
C, lit]; R
f
= 0.44 (20% ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 3.90 (s, 3H),
7.13 (dd, J
1
=4.4 Hz, J =8.0 Hz, 1H), 7.28 (s, 1H), 7.70 (dd, J =1.2 Hz, J =8.0 Hz, 1H), 8.32–
2
1
2
1
3
1
8
1
2
.36 (m, 1H); C{ H} NMR (100 MHz, CDCl
3
) δ 31.6, 52.9, 116.5, 123.2, 129.3, 133.1, 144.1,
-1
+
47.6; FTIR (KBr): 754, 929, 1569 cm ; HRMS (m/z): [M+H] calculated for C
58.9732; found: 258.9726.
8
H
8
2
N I:
o
3-Iodo-1-ethyl-7-azaindole (4c): 112 mg, 82% yield; light yellow solid; mp 63–65 C; R
f
=
1
0
.29 (5% ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 1.47 (t, J=7.2 Hz, 3H), 4.35
=1.6 Hz, J =8.0 Hz, 1H), 8.33
=4.8 Hz, 1H); C{ H} NMR (100 MHz, CDCl ) δ 15.9, 39.8, 53.0, 116.6,
(
q, J=7.2 Hz, 2H), 7.10–7.15 (m, 1H), 7.33 (s, 1H), 7.70 (dd, J
1
2
1
3
1
(dd, J
1
=1.6 Hz, J
2
3
-1
123.3, 129.3, 131.5, 143.9, 144.0, 147.0; FTIR (KBr): 766, 927, 1309, 1564, 2977 cm ; HRMS
+
(
m/z): [M+H] calculated for C
9
H
10
2
N I: 272.9889; found: 272.9861.
3
-Iodo-1-propyl-7-azaindole (4d): 116 mg, 81% yield; pale yellow liquid; R
f
= 0.18 (2% ethyl
) δ 0.94 (t, J=7.2 Hz, 3H), 1.89 (sext, J=7.6
Hz, 2H), 4.26 (t, J=7.2 Hz, 2H), 7.10–7.14 (m, 1H), 7.32 (s, 1H), 7.70 (dd, J =1.6 Hz, J =8.0
=4.8 Hz, 1H); C{ H} NMR (100 MHz, CDCl ) δ 11.5, 23.9,
6.7, 52.9, 116.6, 123.2, 129.3, 132.2, 143.9, 147.3; FTIR (KBr): 774, 935, 1348, 1596, 2964
1
acetate in hexanes); H NMR (400 MHz, CDCl
3
1
2
13
1
Hz, 1H), 8.32 (dd, J
1
=1.2 Hz, J
2
3
4
-1
+
cm ; HRMS (m/z): [M+H] calculated for C10
H
12
N I: 287.0045; found: 287.0063.
2
3
-Iodo-1-pentyl-7-azaindole (4e): 127 mg, 81% yield; light pink liquid; R
f
= 0.27 (2% ethyl
) δ 0.88 (t, J=6.8 Hz, 3H), 1.27–1.39 (m, 4H),
.81–1.90 (m, 2H), 4.28 (t, J=7.6 Hz, 2H), 7.09–7.14 (m, 1H), 7.31 (s, 1H), 7.70 (dd, J =1.6
1
acetate in hexanes); H NMR (400 MHz, CDCl
3
1
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2
2
2
2
2
2
2
3
3
3
3
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3
3
3
3
4
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4
4
4
4
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4
4
5
5
5
5
5
5
5
5
5
5
6
13
1
Hz, J
2
=8.0 Hz, 1H), 8.33 (dd, J
1
=1.2 Hz, J
2
=4.4 Hz, 1H); C{ H} NMR (100 MHz, CDCl
3
) δ
14.0, 22.4, 29.1, 30.3, 45.0, 52.9, 116.5, 123.2, 129.2, 132.1, 143.9, 147.3; FTIR (KBr): 766,
-1
+
9
3
36, 1309, 1563, 2957 cm ; HRMS (m/z): [M+H] calculated for C12
15.0341.
H
16
2
N I: 315.0358; found:
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
3
-Iodo-1-octyl-7-azaindole (4f): 143 mg, 80% yield; light pink liquid; R = 0.32 (2% ethyl
f
1
acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 0.86 (t, J=6.8 Hz, 3H), 1.21–1.35 (m, 10H),
1
.85 (quint, J=7.6 Hz, 2H), 4.28 (t, J=7.2 Hz, 2H), 7.09–7.14 (m, 1H), 7.31 (s, 1H), 7.70 (dd,
13
1
J
1
=1.6 Hz, J
2
=8.0 Hz, 1H), 8.32 (dd, J
1
=1.6 Hz, J =4.8 Hz, 1H); C{ H} NMR (100 MHz,
2
CDCl
3
) δ 14.2, 22.7, 26.9, 29.2, 29.3, 30.6, 31.9, 45.0, 52.9, 116.5, 123.2, 129.2, 132.1, 143.9,
-1
+
1
47.3; FTIR (KBr): 764, 935, 1309, 1598, 2926 cm ; HRMS (m/z): [M+H] calculated for
I: 357.0828; found: 357.0817.
C
15
H
22
N
2
o
3
-Iodo-1-benzyl-7-azaindole (4g): 122 mg, 73% yield; white solid; mp 96–98 C; R = 0.38
f
1
(5% ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 5.48 (s, 2H), 7.12–7.18 (m, 1H),
1
3
1
7
.20–7.35 (m, 6H), 7.72 (d, J=7.6 Hz, 1H), 8.33–8.38 (m, 1H); C{ H} NMR (100 MHz,
CDCl ) δ 48.2, 54.1, 116.9, 123.2, 127.9, 128.0, 129.0, 129.4, 131.9, 137.2, 144.3, 147.5; FTIR
KBr): 762, 931, 1308, 1566, 2926, 3038 cm ; HRMS (m/z): [M+H] calculated for C14
335.0045; found: 335.0034.
3
-1
+
(
H
12
N I:
2
3
-Iodo-1-phenyl-7-azaindole (4h): 120 mg, 75% yield; yellow liquid; R
f
= 0.18 (2% ethyl
1
acetate in hexanes); H NMR (500 MHz, CDCl
3
) δ 7.22 (dd, J
1
=4.5 Hz, J
2
=7.5 Hz, 1H), 7.36
(
t, J=7.5 Hz, 1H), 7.52 (t, J=7.5 Hz, 2H), 7.62 (s, 1H), 7.71 (d, J=8.0 Hz, 2H), 7.79 (d, J=8.0
1
3
1
Hz, 1H), 8.39 (d, J=4.5 Hz, 1H); C{ H} NMR (125 MHz, CDCl
3
) δ 56.6, 117.7, 120.0, 124.2,
1
1
27.0, 129.6, 129.7, 132.0, 137.8, 138.3, 144.9, 147.2; FTIR (KBr): 762, 979, 1315, 1506,
-1
+
595, 3047 cm ; HRMS (m/z): [M+H] calculated for C13
H
10
N
2
I: 320.9889; found: 320.9892.
o
4-chloro-3-Iodo-7-azaindole (4i): 120 mg, 86% yield; white solid; mp 195 C (decomposed);
1
R
f
= 0.33 (20% ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 7.18 (d, J=5.2 Hz, 1H),
) δ 49.7,
1
3
1
7
.80 (s, 1H), 8.18 (d, J=4.8 Hz, 1H), 12.40 (s, 1H); C{ H} NMR (100 MHz, CDCl
16.4, 117.0, 133.1, 134.9, 143.8, 148.5; FTIR (KBr): 824, 1298, 1392, 1498, 1596, 3010 cm-
3
1
1
+
; HRMS (m/z): [M+H] calculated for C
7
H
5
ClN
2
I: 278.9186; found: 278.9193.
o
5
-bromo-3-Iodo-7-azaindole (4j): 131 mg, 81% yield; white solid; mp 210 C (decomposed);
1
R
f
= 0.38 (20% ethyl acetate in hexanes); H NMR (400 MHz, CDCl ) δ 7.80 (s, 1H), 7.86 (d,
3
1
3
1
J=2.0 Hz, 1H), 8.31 (d, J=2.0 Hz, 1H), 12.35 (s, 1H); C{ H} NMR (100 MHz, CDCl ) δ 53.6,
3
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11.6, 123.8, 129.9, 132.5, 143.9, 146.5; FTIR (KBr): 772, 891, 1275, 1394, 1628, 3114, 3478
-1
+
cm ; HRMS (m/z): [M+H] calculated for C
7
H
5
BrN
2
I: 322.8681; found: 322.8683.
1
4
-Iodonaphthalen-1-amine (2ja): 10% yield after 3 h (yield was determined by HNMR
spectroscopy using 1,3,5-trimethoxybenzene as an internal standard), White solid; R = 0.21
f
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
1
(2% ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 4.59 (br s, 2H), 7.05 (d, J=8.8
1
3
1
Hz, 1H), 7.43–7.51 (m, 2H), 7.67 (d, J=8.8 Hz, 1H), 7.73–7.83 (m, 2H); C{ H} NMR (100
MHz, CDCl ) δ 79.2, 120.1, 121.3, 123.0, 125.9, 126.5, 128.7, 134.1, 135.5, 142.7; FTIR
3
-1
+
(KBr): 789, 1398, 1622, 3048, 3318 cm . HRMS (m/z): [M+H] calculated for C10
9
H NI:
2
69.9780; found: 269.9761.
Synthetic transformation of 4-iodoisoquinoline (2a) to 4-styrylisoquinoline (6)18a
In an oven dried reaction tube equipped with magnetic pellet, 4-iodoisoquinoline (128
mg, 0.5 mmol), styrene (86 μL, 0.75 mmol), Et N (1 mmol) and Pd(OAc) (5 mol%) were
3
2
taken. 2 mL of acetonitrile was added into the reaction tube and the reaction mixture was stirred
o
at 90 C under closed atmosphere. After complete consumption of the starting material, the
reaction was stopped, and cooled to room temperature. Then the reaction mixture was extracted
with ethyl acetate. The combined organic layer was washed with water and dried over
anhydrous Na
2
SO . The organic layer was evaporated under reduced pressure to produce crude
4
product which was purified by silica gel column chromatography (hexanes / ethyl acetate).
(Z/E)-4-Styrylisoquinoline (6): 85 mg (6.7:1), 73% yield; yellow liquid; R = 0.19 (10% ethyl
f
1
acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 7.21 (d, J=8.2 Hz, 1H), 7.30–7.36 (m, 1H),
7
.39–7.45 (m, 2H), 7.59–7.64 (m, 3H), 7.67–7.72 (m, 1H), 7.72–7.78 (m, 1H), 7.99 (d, J=8.4
1
3
1
Hz, 1H), 8.14–8.18 (m, 1H), 8.75–8.77 (m, 1H), 9.17 (s, 1H); C{ H} NMR (100 MHz,
CDCl ) δ 120.6, 122.5, 123.0, 126.9, 127.3, 128.2, 128.3, 128.8, 128.9, 130.6, 133.4, 133.9,
37.2, 140.5, 151.9 (“Z”-isomer value given); FTIR (KBr): 759, 1390, 1501, 1620, 3029 cm ;
3
-1
1
+
HRMS (m/z): [M+Na] calculated for C17
H13NNa: 254.0945; found: 254.0963.
Synthetic transformation of 4-iodoisoquinoline (2a) to 4-phenylisoquinoline (8)18b
4
-Iodoisoquinoline (128 mg, 0.5 mmol), phenylboronic acid (85 mg, 0.7 mmol), Pd(OAc)
2
(5
mol%), DABCO (6 mol%) and K CO (3 equiv.) were taken in an oven dried pressure tube
2
3
equipped with magnetic pellet. 2 mL of acetone was added into the reaction tube and the
o
reaction mixture was stirred at 110 C under closed atmosphere. After complete consumption
of the starting material, the reaction was stopped, and cooled to room temperature and acetone
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was evaporated by rotary evaporator under reduced pressure. Then, water (10 mL) was added
into the reaction mixture. The product was extracted into ethyl acetate and dried over anhydrous
Na
2
SO . The organic layer was evaporated under reduced pressure to produce crude product
4
which was purified by silica gel column chromatography (hexanes/ethyl acetate).
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-Phenylisoquinoline (8): 97 mg, 95% yield; pale yellow liquid; R = 0.15 (5% ethyl acetate in
f
1
hexanes); H NMR (400 MHz, CDCl
3
) δ 7.44–7.54 (m, 5H), 7.59–7.70 (m, 2H), 7.92 (d, J=8.0
1
3
1
Hz, 1H), 8.04 (d, J=4.0 Hz, 1H), 8.49 (s, 1H), 9.26 (s, 1H); C{ H} NMR (100 MHz, CDCl
3
)
δ 124.9, 127.3, 128.0, 128.1, 128.6, 128.7, 130.2, 130.7, 133.4, 134.3, 137.1, 142.9, 152.1;
-1
+
FTIR (KBr): 759, 1390, 1501, 1620, 3029 cm ; HRMS (m/z): [M+H] calculated for C15
06.0969; found: 206.0963.
H12N:
2
Experimental procedure for synthesis of N-methylquinolin-8-amine from 8-
aminoquinoline32
To a solution of 8-aminoquinoline (1 mmol) in DMF (5 mL) was added 1 mmol of K
2
CO .
3
After stirring at room temperature for 30 minutes, 1.2 mmol of iodomethane was added drop
wise. The resulting mixture was stirred at room temperature for 24 hours. After completion of
the reaction, the reaction mixture was quenched with aqueous saturated Na
with ethyl acetate (two times). The combined organic layer was washed with water and dried
with anhydrous Na SO . The organic layer was then concentrated under vacuum and purified
2
S
2
3
O and extracted
2
4
by silica gel column chromatography (hexanes / ethyl acetate).
N-methylquinolin-8-amine (1j): 98 mg, 62% yield; yellow liquid; R = 0.44 (5% ethyl acetate
f
1
in hexanes); H NMR (500 MHz, CDCl
3
) δ 3.05 (s, 3H), 6.14 (s, 1H), 6.65 (d, J=7.5 Hz, 1H),
=1.5 Hz, J =4.0
=4.0 Hz, 1H); C{ H} NMR (125 MHz, CDCl ) δ 30.2, 104.3,
13.8, 121.5, 128.0, 128.7, 136.1, 138.4, 146.0, 146.9.
7.05 (d, J=8.0 Hz, 1H), 7.34–7.38 (m, 1H), 7.41 (t, J=8.0 Hz, 1H), 8.06 (dd, J
1
2
13
1
Hz, 1H), 8.71 (dd, J
1
=1.5 Hz, J
2
3
1
Experimental procedure for synthesis of N-ethylquinolin-8-amine from 8-
aminoquinoline33
To a solution of 8-aminoquinoline (1 mmol) in DMF (5 mL) was added 1 mmol of K
2
CO .
3
After stirring at room temperature for 30 minutes, 1.5 mmol of ethyl bromide was added drop
wise. The resulting mixture was stirred at room temperature for 36 hours. After completion of
the reaction, the reaction mixture was quenched with aqueous saturated Na
2
S
2
3
O and extracted
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with ethyl acetate (two times). The combined organic layer was washed with water and dried
with anhydrous Na
2
SO . The organic layer was then concentrated under vacuum and purified
4
by silica gel column chromatography (hexanes / ethyl acetate).
N-ethylquinolin-8-amine (1k): 88 mg, 51% yield; yellow liquid; R = 0.31 (1% ethyl acetate
f
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
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5
5
5
5
5
5
5
5
6
0
1
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4
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8
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3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
in hexanes); H NMR (400 MHz, CDCl
3
) δ 1.42 (t, J=7.2 Hz, 3H), 3.36 (q, J=6.8 Hz, 2H), 6.05
(s, 1H), 6.67 (d, J=7.6 Hz, 1H), 7.04 (d, J=8.4 Hz, 1H), 7.32–7.43 (m, 2H), 8.02–8.08 (m, 1H),
1
3
1
8
1
.69–8.74 (m, 1H); C{ H} NMR (100 MHz, CDCl ) δ 14.8, 38.1, 104.7, 113.7, 121.4, 127.9,
3
28.8, 136.1, 138.3, 145.1, 146.9.
Experimental procedure for synthesis of N-propylquinolin-8-amine from 8-
aminoquinoline
To a solution of 8-aminoquinoline (1 mmol) in DMF (5 mL) was added 1 mmol of K
2
CO .
3
After stirring at room temperature for 30 minutes, 1.2 mmol of 1-iodopropane was added drop
wise. The resulting mixture was stirred at room temperature for 36 hours. After completion of
the reaction, the reaction mixture was quenched with aqueous saturated Na
with ethyl acetate (two times). The combined organic layer was washed with water and dried
with anhydrous Na SO . The organic layer was then concentrated under vacuum and purified
2
S
2
3
O and extracted
2
4
by silica gel column chromatography (hexanes / ethyl acetate).
N-propylquinolin-8-amine (1l): 123 mg, 66% yield; yellow liquid; R = 0.38 (1% ethyl acetate
f
1
in hexanes); H NMR (400 MHz, CDCl
3
) δ 1.08 (t, J=7.2 Hz, 3H), 1.76–1.86 (m, 2H), 3.29 (d,
J=7.2 Hz, 1H), 6.14 (s, 1H), 6.67 (d, J=7.6 Hz, 1H), 7.01–7.05 (m, 1H), 7.34–7.37 (m, 1H),
7
.37–7.41 (m, 1H), 8.05 (dd, J
1
=1.6 Hz, J
2
=8.4 Hz, 1H), 8.71 (dd, J
1
=1.6 Hz, J =4.0 Hz, 1H);
2
1
3
1
C{ H} NMR (100 MHz, CDCl
3
) δ 11.9, 22.6, 45.4, 104.6, 113.6, 121.4, 128.0, 128.8, 136.1,
+
1
38.3, 145.1, 146.8. HRMS (m/z): [M+H] calculated for C12
H
15
2
N : 187.1235; found:
187.1245.
Experimental procedure for synthesis of N-ethylquinolin-6-amine from 6-
aminoquinoline34
To a solution of 8-aminoquinoline (1 mmol) in DMF (5 mL) was added 1 mmol of K
2
CO .
3
After stirring at room temperature for 30 minutes, 1.5 mmol of ethyl bromide was added drop
wise. The resulting mixture was stirred at room temperature for 48 hours. After completion of
the reaction, the reaction mixture was quenched with aqueous saturated Na
2
S
2
3
O and extracted
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with ethyl acetate (two times). The combined organic layer was washed with water and dried
with anhydrous Na
2
SO . The organic layer was then concentrated under vacuum and purified
4
by silica gel column chromatography (hexanes / ethyl acetate).
N-ethylquinolin-6-amine (1n): 71 mg, 41% yield; brown liquid; R = 0.27 (30% ethyl acetate
f
0
1
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8
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3
4
5
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
in hexanes); H NMR (500 MHz, CDCl
3
) δ 1.34 (t, J=7.0 Hz, 3H), 3.27 (q, J=7.5 Hz, 2H), 6.69
=3.0 Hz, J =9.0 Hz, 1H), 7.24–7.28 (m, 1H), 7.87 (d, J=9.0 Hz,
H), 7.90–7.94 (m, 1H), 8.60 (dd, J =1.5 Hz, J
) δ 14.8, 38.6, 102.9, 121.5, 121.6, 130.2, 130.4, 133.9, 143.2, 146.1, 146.4.
(d, J=2.5 Hz, 1H), 7.08 (dd, J
1
2
13
1
1
1
2
=4.5 Hz, 1H); C{ H} NMR (125 MHz,
CDCl
3
Experimental procedure for synthesis of N-propylquinolin-6-amine from 6-
aminoquinoline
To a solution of 8-aminoquinoline (1 mmol) in DMF (5 mL) was added 1 mmol of K
2
CO .
3
After stirring at room temperature for 30 minutes, 1.2 mmol of 1-iodopropane was added drop
wise. The resulting mixture was stirred at room temperature for 48 hours. After completion of
the reaction, the reaction mixture was quenched with aqueous saturated Na
with ethyl acetate (two times). The combined organic layer was washed with water and dried
with anhydrous Na SO . The organic layer was then concentrated under vacuum and purified
2
S
2
3
O and extracted
2
4
by silica gel column chromatography (hexanes / ethyl acetate).
N-propylquinolin-6-amine (1o): 106 mg, 57% yield; liquid brown; R = 0.21 (30% ethyl
f
1
acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 1.04 (t, J=7.2 Hz, 3H), 1.65–1.76 (m, 2H),
=2.8 Hz, J =9.2
Hz, 1H), 7.22–7.27 (m, 1H), 7.86 (d, J=9.2 Hz, 1H), 7.91 (d, J=8.4 Hz, 1H), 8.57–8.61 (m,
3.17 (t, J=7.2 Hz, 2H), 3.50–3.90 (m, 1H), 6.67 (d, J=2.4 Hz, 1H), 7.07 (dd, J
1
2
1
3
1
1
1
H); C{ H} NMR (100 MHz, CDCl
3
) δ 11.8, 22.6, 45.8, 102.8, 121.5, 121.6, 130.1, 130.4,
+
34.0, 143.1, 145.9, 146.5. HRMS (m/z): [M+H] calculated for C12
H
15
2
N : 187.1235; found:
187.1232.
Experimental procedure for synthesis of N-methyl-7-azaindole from 7-azaindole35
In a round bottom flask 7-azaindole (1 mmol) and DMF (10 mL) were taken. Then the reaction
o
mixture was cooled down to 0 C and 2 mmol of 60% NaH was added and stirred for 1 hour.
After 1 hour, 1.2 mmol of iodomethane was added and the reaction was continued for 4 hours.
After completion of the reaction, it was quenched with cold water and extracted with ethyl
acetate. Then the combined organic layer was dried with anhydrous Na
2
SO . The organic layer
4
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was then concentrated under vacuum and purified by silica gel column chromatography
(hexanes / ethyl acetate).
N-methyl-7-azaindole (3b): 112 mg, 85% yield; pale yellow liquid; R = 0.14 (5% ethyl acetate
f
1
in hexanes); H NMR (400 MHz, CDCl
3
) δ 3.89 (s, 3H), 6.45 (d, J=3.2 Hz, 1H), 7.03–7.08 (m,
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
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2
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3
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7
8
9
0
1
3
1
1
H), 7.18 (d, J=3.2 Hz, 1H), 7.88–7.93 (m, 1H), 8.32–8.35 (m, 1H); C{ H} NMR (100 MHz,
CDCl ) δ 31.4, 99.4, 115.6, 120.7, 128.9, 129.1, 142.9, 147.9.
3
Experimental procedure for synthesis of N-ethyl-7-azaindole from 7-azaindole36
In a round bottom flask 7-azaindole (1 mmol) and DMF (10 mL) were taken. Then the reaction
o
mixture was cooled down to 0 C and 2 mmol of 60% NaH was added and stirred for 1 hour.
After 1 hour, 1.5 mmol of ethyl bromide was added and the reaction was continued for 8 hours.
After completion of the reaction, it was quenched with cold water and extracted with ethyl
acetate. Then the combined organic layer was dried with anhydrous Na
was then concentrated under vacuum and purified by silica gel column chromatography
hexanes / ethyl acetate).
2
SO . The organic layer
4
(
N-ethyl-7-azaindole (3c): 111 mg, 76% yield; pale yellow liquid; R = 0.14 (5% ethyl acetate
f
1
in hexanes); H NMR (400 MHz, CDCl
3
) δ 1.48 (t, J=6.0 Hz, 3H), 4.35 (q, J=5.6 Hz, 2H), 6.45
=1.6 Hz, J =6.4 Hz,
) δ 15.8, 39.4, 99.5,
(d, J=2.8 Hz, 1H), 7.02–7.06 (m, 1H), 7.23 (d, J=2.4 Hz, 1H), 7.90 (dd, J
1
2
1
3
1
1
1
H), 8.32 (dd, J
1
=1.2 Hz, J
2
=3.6 Hz, 1H); C{ H} NMR (100 MHz, CDCl
3
15.6, 120.8, 127.4, 128.8, 142.8, 147.3.
Experimental procedure for synthesis of N-propyl-7-azaindole from 7-azaindole37
In a round bottom flask 7-azaindole (1 mmol) and DMF (10 mL) were taken. Then the reaction
o
mixture was cooled down to 0 C and 2 mmol of 60% NaH was added and stirred for 1 hour.
After 1 hour, 1.2 mmol of 1-iodopropane was added and the reaction was continued for 3 hours.
After completion of the reaction, it was quenched with cold water and extracted with ethyl
acetate. Then the combined organic layer was dried with anhydrous Na
was then concentrated under vacuum and purified by silica gel column chromatography
hexanes / ethyl acetate).
2
SO
4
. The organic layer
(
N-propyl-7-azaindole (3d): 130 mg, 81% yield; pale yellow liquid R = 0.17 (5% ethyl acetate
f
1
in hexanes); H NMR (400 MHz, CDCl
3
) δ 0.94 (t, J=7.2 Hz, 3H), 1.84–1.96 (m, 2H), 4.26 (t,
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J=7.2 Hz, 2H), 6.44 (d, J=3.2 Hz, 1H), 7.01–7.07 (m, 1H), 7.21 (d, J=3.2 Hz, 1H), 7.90 (d,
13
1
J=7.6 Hz, 1H), 8.29–8.35 (m, 1H); C{ H} NMR (100 MHz, CDCl
3
) δ 11.5, 23.8, 46.4, 99.3,
1
15.6, 120.7, 128.1, 128.8, 142.8, 147.6.
Experimental procedure for synthesis of N-pentyl-7-azaindole from 7-azaindole37
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In a round bottom flask 7-azaindole (1 mmol) and DMF (10 mL) were taken. Then the reaction
o
mixture was cooled down to 0 C and 2 mmol of 60% NaH was added and stirred for 1 hour.
After 1 hour, 1.5 mmol of 1-bromopentane was added and the reaction was continued for 4
hours. After completion of the reaction, it was quenched with cold water and extracted with
ethyl acetate. Then the combined organic layer was dried with anhydrous Na
layer was then concentrated under vacuum and purified by silica gel column chromatography
hexanes / ethyl acetate).
2
SO . The organic
4
(
N-pentyl-7-azaindole (3e): 155 mg, 83% yield; pale yellow liquid; R = 0.28 (5% ethyl acetate
f
1
in hexanes); H NMR (400 MHz, CDCl
3
) δ 0.84–0.91 (m, 3H), 1.28–1.41 (m, 4H), 1.80–1.93
(m, 2H), 4.29 (t, J=7.2 Hz, 2H), 6.42–6.46 (m, 1H), 7.00–7.07 (m, 1H), 7.19–7.23 (m, 1H),
13
1
7
3
.90 (d, J=7.6 Hz, 1H), 8.29–8.35 (s, 1H); C{ H} NMR (100 MHz, CDCl ) δ 14.1, 22.5, 29.2,
3
0.3, 44.7, 99.3, 115.6, 120.7, 128.0, 128.8, 142.8, 147.6.
Experimental procedure for synthesis of N-octyl-7-azaindole from 7-azaindole
In a round bottom flask 7-azaindole (1 mmol) and DMF (10 mL) were taken. Then the reaction
o
mixture was cooled down to 0 C and 2 mmol of 60% NaH was added and stirred for 1 hour.
After 1 hour, 1.5 mmol of 1-bromopentane was added and the reaction was continued for 2
hours. After completion of the reaction, it was quenched with cold water and extracted with
ethyl acetate. Then the combined organic layer was dried with anhydrous Na
2
SO . The organic
4
layer was then concentrated under vacuum and purified by silica gel column chromatography
(hexanes / ethyl acetate).
N-octyl-7-azaindole (3f): 207 mg, 90% yield; pale yellow liquid; R = 0.44 (5% ethyl acetate
f
1
in hexanes); H NMR (400 MHz, CDCl
3
) δ 0.86 (t, J=6.4 Hz, 3H), 1.22–1.33 (m, 10H), 1.83–
1
.89 (m, 2H), 4.28 (t, J=7.6 Hz, 2H), 6.44 (d, J=3.2 Hz, 1H), 7.01–7.06 (m, 1H), 7.21 (d, J=3.2
1
3
1
Hz, 1H), 7.89 (dd, J
1
=1.6 Hz, J
2
=8.0 Hz, 1H), 8.32 (dd, J
1
=1.2 Hz, J =4.4 Hz, 1H); C{ H}
2
NMR (100 MHz, CDCl
3
) δ 14.2, 22.7, 27.0, 29.3, 29.4, 30.5, 31.9, 44.7, 99.3, 115.6, 120.7,
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28.1, 128.8, 142.7, 142.8, 147.5. HRMS (m/z): [M+H] calculated for C15
H
23
N : 231.1861;
2
found: 231.1863.
Experimental procedure for synthesis of N-benzyl-7-azaindole from 7-azaindole38
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In a round bottom flask 7-azaindole (1 mmol) and DMF (10 mL) were taken. Then the reaction
o
mixture was cooled down to 0 C and 2 mmol of 60% NaH was added and stirred for 1 hour.
After 1 hour, 1.5 mmol of 1-benzylbromide was added and the reaction was continued for 2
hours. After completion of the reaction, it was quenched with cold water and extracted with
ethyl acetate. Then the combined organic layer was dried with anhydrous Na
layer was then concentrated under vacuum and purified by silica gel column chromatography
hexanes / ethyl acetate).
2
SO . The organic
4
(
o
N-benzyl-7-azaindole (3g): 140 mg, 67% yield; white solid; mp 225–228 C; R = 0.32 (5%
f
1
ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 5.51 (s, 2H), 6.45–6.50 (m, 1H), 7.04–
7
1
1
.10 (m, 1H), 7.15–7.23 (m, 3H), 7.24–7.33 (m, 3H), 7.92 (d, J=8.0 Hz, 1H), 8.32–8.38 (m,
13
1
H); C{ H} NMR (100 MHz, CDCl
28.8, 128.9, 137.9, 143.2, 147.9.
3
) δ 47.9, 100.2, 116.0, 120.6, 127.6 (2C), 127.7, 128.0,
Experimental procedure for synthesis of N-phenyl-7-azaindole from 7-azaindole39
A dried round-bottom flask equipped with a magnetic stirrer bar was charged with CuI (5
mol%) and N-hydroxyphthalimide (10 mol%). To the reaction mixture, sodium methoxide (1.5
equiv.) in DMSO was added. After stirring at room temperature for 30 minutes, a mixture of
iodobenzene and 7-azaindole in DMSO was added to the flask and the reaction mixture was
o
stirred at 110 C. After completion of the reaction, it was cooled to room temperature. Then
the reaction mixture was extracted with ethyl acetate. The combined organic layer was washed
with water and dried over anhydrous Na
2
SO . The organic layer was evaporated under reduced
4
pressure to produce crude product which was purified by silica gel column chromatography
(hexanes / ethyl acetate).
N-phenyl-7-azaindole (3h): 89 mg, 46% yield; pale yellow solid; R = 0.28 (5% ethyl acetate
f
1
in hexanes); H NMR (500 MHz, CDCl
3
) δ 6.63 (d, J=3.5 Hz, 1H), 7.12–7.16 (m, 1H), 7.32–
=1.5 Hz,
) δ 101.7, 116.8, 121.7, 124.1, 126.4, 128.0,
7.37 (m, 1H), 7.51–7.56 (m, 3H), 7.75–7.79 (m, 2H), 7.96–8.00 (m, 1H), 8.39 (dd, J
1
1
3
1
J
2
=4.5 Hz, 1H); C{ H} NMR (100 MHz, CDCl
3
1
29.2, 129.5, 138.6, 143.7, 147.6.
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Experimental procedure for synthesis of Ethyl 1H-pyrrolo[2,3-b]pyridine-1-carboxylate
from 7-azaindole40
In a round bottom flask 7-azaindole (1 mmol) and THF (5 mL) were taken. Then the reaction
o
mixture was cooled down to 0 C and 2 mmol of 60% NaH was added and stirred for 1 hour.
0
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After 1 hour, 1.5 mmol of Ethyl chloroformate was added and the reaction was continued for
2
hours. After completion of the reaction, it was quenched with cold water and extracted with
ethyl acetate. Then the combined organic layer was dried with anhydrous Na SO . The organic
2
4
layer was then concentrated under vacuum and purified by silica gel column chromatography
(hexanes / ethyl acetate).
Ethyl 1H-pyrrolo[2,3-b]pyridine-1-carboxylate (3k): 141 mg, 74% yield; colourless liquid;
1
R
f
= 0.28 (15% ethyl acetate in hexanes); H NMR (400 MHz, CDCl
3
) δ 1.47 (t, J=7.2 Hz, 3H),
4
.54 (q, J=7.2 Hz, 2H), 6.54 (d, J=4.0 Hz, 1H), 7.17–7.22 (m, 1H), 7.72 (d, J=4.0 Hz, 1H),
13
1
7.88 (dd, J
1
=1.2 Hz, J
2
=8.0 Hz, 1H), 8.47–8.52 (m, 1H); C{ H} NMR (100 MHz, CDCl ) δ
3
1
4.5, 63.7, 105.3, 118.8, 123.3, 126.6, 129.4, 145.2, 148.1, 149.9.
AUTHOR INFORMATION
Corresponding Author
E-mail: gsekar@iitm.ac.in
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank DST-SERB, New Delhi (EMR/2017/001700) and IIT Madras (CHY/17-
18/847/RFIR/GSEK) for financial support. Also, we thank DST for funding the
instrumentation facilities. I.K. thanks IIT Madras for a fellowship. S.G. thanks DST, New
Delhi. High-performance computing centre at IIT Madras is gratefully acknowledged for
providing computing facility.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at
DOI:
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Computational details, H and C{ H}NMR spectra for all compounds, X-ray structure and
brief crystal data of compound 2j.
X-ray crystallographic file of compound 2j.
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