Selective access to 3-cyano-1 H -indoles, 9 H -pyrimido[4,5- b ]indoles, or 9 H -Pyrido[2,3- b ]indoles through copper-catalyzed one-pot multicomponent cascade reactions

Article abstract of DOI:10.1021/acs.joc.5b00239

Novel and selective synthetic approaches toward indole derivatives via copper-catalyzed one-pot multicomponent cascade reactions of 1-bromo-2-(2,2-dibromovinyl)benzenes with aldehydes and aqueous ammonia are presented. Intriguingly, the concentration of a

Full text of DOI:10.1021/acs.joc.5b00239

Article
pubs.acs.org/joc
Selective Access to 3‑Cyano‑1H‑indoles, 9H‑Pyrimido[4,5‑b]indoles,
or 9H‑Pyrido[2,3‑b]indoles through Copper-Catalyzed One-Pot
Multicomponent Cascade Reactions
Bin Li, Shenghai Guo, Ju Zhang, Xinying Zhang,* and Xuesen Fan*
School of Environment, School of Chemistry and Chemical Engineering, Collaborative Innovation Center of Henan Province for
Green Manufacturing of Fine Chemicals, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education, and
Henan Key Laboratory for Environmental Pollution Control, Henan Normal University, Xinxiang, Henan 453007, P. R. China
S
* Supporting Information
ABSTRACT: Novel and selective synthetic approaches
toward indole derivatives via copper-catalyzed one-pot multi-
component cascade reactions of 1-bromo-2-(2,2-
dibromovinyl)benzenes with aldehydes and aqueous ammonia
are presented. Intriguingly, the concentration of ammonia, the
molar ratio of reagents, and the structural features of the
aldehyde substrate serve as key factors in controlling the
selective formation of 3-cyano-1H-indoles, 9H-pyrimido[4,5-
b]indoles, or 9H-pyrido[2,3-b]indoles. Compared with liter-
ature procedures, the synthetic approaches reported herein have advantages such as readily available starting materials, mild
reaction conditions, and divergent reaction patterns toward different products with easily tunable selectivity.
of 2-(2-haloalkenyl)aryl halides with anilines, amides, or
carbamates to afford a series of N-functionalized indoles.12
Meanwhile, multicomponent reactions (MCRs) in which three
or more different starting materials undergo sequential
transformations in the same vessel to form multiple C−C
and/or C−heteroatom bonds are rapidly prevailing.13 Com-
pared with step-by-step operations, this protocol is advanta-
geous because it obviates the need to isolate and purify the
intermediates. In particular, copper-catalyzed MCRs with C−N
bond formation as a key step have turned out to be a powerful
tool for the construction of N-fused heterocycles.14 In this
regard, we have developed some efficient syntheses of N-
heterocycles through Cu-catalyzed MCRs by using aqueous
ammonia as a cheap nitrogen source.15 As a continuation of our
study in this field, we have discovered a new synthetic approach
toward indole-related heterocycles through Cu-catalyzed one-
pot MCRs of 1-bromo-2-(2,2-dibromovinyl)benzenes16 with
aldehydes and aqueous ammonia. In this approach, different
reaction modes of the same starting materials can be realized in
a controllable manner through tuning of the concentration of
ammonia and the dosage of reagents to give 3-cyano-1H-
indoles or 9H-pyrimido[4,5-b]indoles/9H-pyrido[2,3-b]-
indoles.
INTRODUCTION
■
Indole and its derivatives are attracting tremendous attention
because of their wide range of medicinal activities, frequent
occurrence in natural products, and multiple uses in organic
synthesis.1−4 Among them, 3-cyanoindoles5 and pyrimido[4,5-
b]indoles6 show remarkable biological significance and have
therefore been used as key building blocks in the construction
of medicinal and functional materials.7 In addition, 9H-
pyrimido[4,5-b]indoles can act as extended purine bases to
form unnatural nucleosides, which were successfully utilized as
probes in studying single-nucleotide polymorphism typing and
hole transport through DNA and to build DNA logic gates in
nucleic acid chemistry.8 To date, a number of synthetic
strategies toward 3-cyanoindoles9 or pyrimido[4,5-b]indoles10
have been developed. While those pioneering methods are
generally efficient and reliable, they usually start from substrates
that already have an indole scaffold. Moreover, some of those
syntheses require harsh reaction conditions and necessitate
toxic reagents and multistep processes. Therefore, the develop-
ment of simple synthetic methods in which both the indole
framework and the cyano/pyrimidine unit are constructed
simultaneously via a one-pot procedure featuring facile
operation and easily accessible starting materials remains an
attractive but still challenging task.
Transition-metal-catalyzed cascade cyclization of ortho-
functionalized (2-bromovinyl)benzenes has recently evolved
as a direct and efficient approach toward substituted indoles.
For example, Lautens has reported an elegant strategy leading
to 2-substituted indoles via Pd-catalyzed tandem C−N/C−C
coupling of 2-(2,2-dibromovinyl)anilines.11 Willis revealed a
Cu−diamine complex-catalyzed tandem C−N bond formation
RESULTS AND DISCUSSION
■
Initially, treatment of 1-bromo-2-(2,2-dibromovinyl)benzene
(1a) (0.5 mmol), benzaldehyde (2a) (1 mmol), and aqueous
Received: February 1, 2015
© XXXX American Chemical Society
A
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a
Table 1. Optimization Study on the Formation of 3-Cyano-1H-indole (4a) and 9H-Pyrimido[4,5-b]indole (5a)
b
Yield (%)
entry
mL of 3
catalyst
CuI
additive (equiv)
solvent (mL)
4a
15
5a
1
2
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
0.75
3
−
DMF (3)
DMF (3)
DMF (3)
DMF (3)
DMF (3)
DMF (3)
DMF (2)
DMF (1.5)
DMF (0.75)
DMF (3)
DMSO (1.5)
NMP (1.5)
DMF (1.5)
DMF (1.5)
DMF (3)
DMF (3)
DMF (3)
DMF (1.5)
DMF (6)
21
CuI
1,10-phen (0.2)
19
15
22
26
32
56
62
25
52
60
53
58
32
22
16
trace
trace
5
24
3
CuI
L-Proline (0.2)
24
4
CuI
DABCO (A) (0.2)
PivOH (B) (1)
A (0.2) + B (1)
A (0.2) + B (1)
A (0.2) + B (1)
A (0.2) + B (1)
A (0.2) + B (1)
A (0.2) + B (1)
A (0.2) + B (1)
A (0.2) + B (1)
A (0.2) + B (1)
A (0.2) + B (1)
A (0.2) + B (1)
A (0.2) + B (1)
A (0.2) + B (1)
A (0.2) + B (1)
30
5
CuI
24
6
CuI
30
7
CuI
13
8
CuI
CuI
trace
13
9
10
11
12
13
14
15
CuI
trace
trace
trace
trace
trace
35
1.5
1.5
1.5
1.5
1
CuI
CuI
CuBr
Cu(OAc)2
CuI
c
16
1
CuI
42
c
17
0.5
0.25
1
CuI
CuI
55
c
18
35
c
19
CuI
47
a
b
c
Reaction conditions: 0.5 mmol of 1a, 1 mmol of 2a, and 0.05 mmol of catalyst at 80 °C under air in a sealed tube for 24 h. Isolated yields. With
1.5 mmol of 2a for 30 h.
ammonia (3) (26%, 1.5 mL) with CuI (0.05 mmol) in DMF (3
mL) at 80 °C for 24 h gave 2-phenyl-1H-indole-3-carbonitrile
(4a) in 15% yield and 2,4-diphenyl-9H-pyrimido[4,5-b]indole
(5a) in 21% yield (Table 1, entry 1). To improve the efficiency,
several ligands including 1,10-phenanthroline (1,10-phen), L-
proline, and 1,4-diazabicyclo[2.2.2]octane (DABCO) were
tried (entries 2−4). Among them, DABCO showed a positive
effect in raising the yields of both 4a and 5a (entry 4). Next,
inspired by the fact that pivalic acid (PivOH) has frequently
been used as an additive to facilitate Cu-catalyzed coupling
reactions,17 we tried PivOH in the reaction of 1a, 2a, and 3. As
expected, addition of PivOH did indeed improve the reaction,
but the yields were still not satisfactory (entry 5). Gratifyingly,
using a combination of DABCO (0.2 equiv) with PivOH (1
equiv) gave better yields of both 4a and 5a than using DABCO
or PivOH alone, although the selectivity was only marginal
(entry 6). In following studies, we were pleased to find that in
the presence of CuI (0.1 equiv), DABCO (0.2 equiv), and
PivOH (1 equiv), reducing the amount of solvent (DMF)
amplified the selectivity for 4a significantly (entry 7), and 1.5
mL of DMF was found to be the most optimal (entry 8;
concentration of ammonia ≈ 7 M, 1a:2a:3 molar ratio = 1:2:42;
condition A). Notably, when the other conditions were kept
unchanged, halving the amounts of both aqueous ammonia 3
and DMF (concentration of ammonia ≈ 7 M, 1a:2a:3 molar
ratio = 1:2:21) resulted in reduced yield and selectivity (entry
9). On the other hand, doubling the amounts of both 3 and
DMF (concentration of ammonia ≈ 7 M, 1a:2a:3 molar ratio =
1:2:84) did not improve the reaction further (entry 10). Next,
other solvents such as DMSO and 1-methyl-2-pyrrolidinone
(NMP) were screened, and they were less effective than DMF
in mediating this reaction (entries 11 and 12). Studies with
CuBr or Cu(OAc)2 as the catalyst resulted in decreased yields
(entries 13 and 14). In further optimization, it was revealed that
the selectivity of this MCR could be changed in the opposite
direction to favor the formation of 5a when the amount of
ammonia was reduced from 1.5 to 1 mL in the presence of 3
mL of DMF (entry 15). The selectivity could be amplified by
increasing the amount of 2a from 1 to 1.5 mmol (entry 16) and
by reducing the amount of 3 from 1 to 0.5 mL (entry 17;
concentration of ammonia ≈ 2 M, 1a:2a:3 molar ratio = 1:3:14;
condition B). It was also found that decreasing the amounts of
3 and DMF to 0.25 and 1.5 mL (entry 18; concentration of
ammonia ≈ 2 M, 1a:2a:3 molar ratio = 1:3:7) or increasing
them to 1 and 6 mL (entry 19, concentration of ammonia ≈ 2
M, 1a:2a:3 molar ratio = 1:3:28) resulted in reduced yields of
5a.
With the optimized conditions in hand, we then examined
the scope of 1 and 2 for the synthesis of 3-cyanoindoles under
condition A (Table 1, entry 8). First, diversely substituted
benzene substrates 1 were evaluated with 2a and 3. The results
listed in Table 2 show that various R1, including hydrogen,
chloro, fluoro, trifluoromethyl, methyl, and methoxy, were well-
tolerated (entries 1−8). It was also found that the electronic
nature of these substituents did not affect the efficiency in an
obvious way. Next, the effect of varying the aldehyde substrate
2 was tested by treating different aldehydes 2 with 1a and 3
(entries 9−24). Aryl-substituted aldehydes bearing various
functional groups (from alkyl or alkoxyl to halides) on the aryl
ring underwent this tandem reaction smoothly to afford the
desired 3-cyanoindoles 4i−q in reasonably good yields. The
position of the substituent on the aryl ring had little effect on
the efficiency, as representatively demonstrated by a methyl
group (entries 13−15). With 1-naphthoaldehyde and thio-
phene-2-carboxaldehyde, 4r and 4s were obtained in 68% and
45% yield, respectively. It is noteworthy that aliphatic aldehydes
B
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Table 2. Substrate Scope for the Synthesis of 3-Cyanoindoles
4
Table 3. Substrate Scope for the Synthesis of 9H-
Pyrimido[4,5-b]indoles 5
a
18
,
a
b
entry
R1
R2
product
yield (%)
b
entry
R1
R2
product
yield (%)
1
2
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4a
62
64
63
61
59
56
58
53
66
71
65
63
57
64
61
62
68
68
45
42
51
54
49
61
60
63
57
63
62
55
62
52
65
52
53
1
2
H
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
5a
5b
5c
5d
5e
5f
55
56
54
58
57
54
50
47
58
61
63
47
48
53
51
52
46
40
52
48
46
4-F
5-F
4-Cl
4b
4c
4-F
5-F
4-Cl
3
3
4
4d
4e
4
5
4-CF3
5
4-CF3
6
5-CH3
4f
6
5-CH3
7
4-CH3O
4g
4h
4i
7
4-CH3O
5g
5h
5i
8
4,5-OCH2O-
8
4,5-OCH2O-
9
H
3-FC6H4
9
H
3-FC6H4
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
H
4-ClC6H4
4j
10
11
12
13
14
15
16
17
18
19
20
21
H
4-ClC6H4
5j
H
4-BrC6H4
4k
4l
H
4-BrC6H4
5k
5l
H
4-CF3C6H4
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
3,4-(CH3O)2C6H3
1-naphthyl
H
4-CF3C6H4
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
1-naphthyl
2-thienyl
H
4m
4n
4o
4p
4q
4r
H
5m
5n
5o
5p
5q
5r
5s
5t
H
H
H
H
H
H
H
H
H
H
H
2-thienyl
4s
4-Cl
4-CF3
5-CH3
4-ClC6H4
H
CH3
4t
4-CH3OC6H4
4-CH3OC6H4
H
CH3CH2
4u
4v
5u
H
CH3CH2CH2
(CH3)2CHCH2
C6H5CH2CH2
4-CH3OC6H4
4-CH3OC6H4
CH3CH2CH2
4-ClC6H4
a
Reactions were run with 1 (0.5 mmol), 2 (1.5 mmol), CuI (0.05
mmol), DABCO (0.1 mmol), PivOH (0.5 mmol), and 3 (26%, 0.5
mL) in DMF (3 mL) at 80 °C under air in a sealed tube for 30 h.
Isolated yields.
H
4w
4x
H
4-F
4y
b
5-F
4z
5-F
4aa
4bb
4cc
4dd
4ee
4ff
4gg
4hh
4ii
4-Cl
4-Cl
4-Cl
4-CF3
4-CF3
5-CH3
4-CH3O
4,5-OCH2O-
In further studies, the scope of the aldehyde substrates was
extended to acetaldehyde. To our surprise, the reaction of
acetaldehyde with 1a and 3 under condition B afforded 2-
methyl-9H-pyrido[2,3-b]indole (6a) rather than the expected
2,4-dimethyl-9H-pyrimido[4,5-b]indole. Literature searching
revealed that the pyrido[2,3-b]indole scaffold, also known as
α-carboline,19−21 has been found in numerous natural products
and synthetic compounds with an array of biological activities.
Thus, the development of practical methods for the synthesis of
pyrido[2,3-b]indoles would enable the facile preparation of
families of biologically significant compounds. Hence, our study
continued with an exploration of the scope and generality of
this new entry into pyrido[2,3-b]indole derivatives. The results
listed in Table 4 show that not only acetaldehyde but also
propionaldehyde, butyraldehyde, 3-methylbutanal, and 3-
phenylpropanal were also compatible substrates to react with
1a and 3, giving α-carbolines 6a−e in moderate yields. Notably,
with acetaldehyde a monosubstituted 9H-pyrido[2,3-b]indole
was obtained (entry 1), while the other aldehydes gave 2,3-
disubstituted α-carboline analogues (entries 2−5). Next,
propionaldehyde was used as a model substrate to react with
different 1 and 3. Compounds 1 substituted with either
electron-withdrawing or electron-donating groups took part in
this reaction readily (entries 6−10), allowing for a highly
convenient preparation of α-carboline derivatives.
4-CH3OC6H4
CH3CH2CH2
4-CH3OC6H4
CH3CH2CH2
4-CH3OC6H4
CH3CH2CH2
CH3CH2CH2
a
Reactions were run with 1 (0.5 mmol), 2 (1 mmol), CuI (0.05
mmol), DABCO (0.1 mmol), PivOH (0.5 mmol), and 3 (26%, 1.5
mL) in DMF (1.5 mL) at 80 °C under air in a sealed tube for 24 h.
b
Isolated yields.
were also found to be suitable for this reaction, giving 2-alkyl-3-
cyanoindoles (entries 20−24). In further studies, different 1
were allowed to react with various 2 and 3. Promisingly, all of
these substrates were compatible with this reaction and give 3-
cyanoindoles bearing diverse functional groups (entries 25−
35).
Having established a general method for the synthesis of 3-
cyanoindoles 4, we moved on to study the substrate scope for
the synthesis of 9H-pyrimido[4,5-b]indoles 5 from the reaction
of 1 with 2 and 3 under condition B (Table 1, entry 17). It was
found that diversely substituted 1-bromo-2-(2,2-dibromovinyl)-
benzenes 1 reacted smoothly with various aryl aldehydes 2 and
aqueous ammonia 3 to give a series of 9H-pyrimido[4,5-
b]indoles 5 irrespective of the electronic and steric nature of
the substituents (Table 3, entries 1−21).
Interestingly, the reaction was also found to be suitable for an
α,β-unsaturated aldehyde. Thus, treatment of 1-bromo-2-(2,2-
dibromovinyl)benzenes 1 with cinnamaldehyde and aqueous
C
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(condition B), III first undergoes an intramolecular C−N
coupling to give 2-bromoindole (IX), which then undergoes an
aryl amination to give 2-aminoindole (X). Nucleophilic
addition of X onto imine XI, formed in situ from the
condensation of 2a with 3, affords XII. Subsequent
condensation of XII with 2a gives imine XIII, and then
nucleophilic cyclization of XIII occurs to afford tetrahydro-1H-
pyrimido[4,5-b]indole (XIV). Finally, oxidative aromatization
of XIV gives 5a as the final product (Scheme 3).
As for the formation of 6a, it should start with the reaction of
1a with 3 under condition B to give intermediates III, IX, and
X sequentially. Meanwhile, self-aldol condensation of acetalde-
hyde gives but-2-enal (XV) as another key intermediate.
Michael addition of X toward XV affords the adduct XVI, which
then undergoes an intramolecular aldol-type reaction to
sequentially give XVII and XVIII. Finally, oxidative dehydro-
genation of XVIII affords 6a (Scheme 4).
The proposed mechanisms for the formation of 4a, 5a, and
6a as shown in Schemes 2−4 were partially confirmed by the
following experiments. First, III,11a IX,11b and 2-benzyl-5-
phenylpent-2-enal were prepared. Then III was treated with 2a
and 3 under condition A. From this reaction, 4a was obtained
in a yield of 76% (Scheme 5). This result is consistent with that
obtained by using 1a as a starting material and might be
considered as positive evidence for the proposed reaction
mechanism, in which III is considered to be a key intermediate
for the formation of 4a.
Table 4. Substrate Scope for the Synthesis of 9H-Pyrido[2,3-
b]indoles 6
a
,
18
b
entry
R1
R3
product
yield (%)
1
2
H
H
H
H
H
H
6a
6b
6c
6d
6e
6f
38
43
46
42
52
46
47
49
41
44
CH3
3
CH3CH2
(CH3)2CH
C6H5CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
CH3CH2
4
5
6
5-F
7
4-Cl
6g
6h
6i
8
4-CF3
9
4-CH3O
4,5-OCH2O-
10
6j
a
Reactions were run with 1 (0.5 mmol), 2 (1.5 mmol), CuI (0.05
mmol), DABCO (0.1 mmol), PivOH (0.5 mmol), and 3 (26%, 0.5
mL) in DMF (3 mL) at 80 °C in a sealed tube under air for 30 h.
b
Isolated yields.
ammonia under condition B afforded 2-phenyl-9H-pyrido[2,3-
b]indole (6k) in 50% yield (Scheme 1)
Scheme 1. Formation of 6k from the Reaction of
Cinnamaldehyde
Second, III was treated with 2a and 3 under condition B to
give 5a in 68% yield (Scheme 6). This result showed that III
might be a key intermediate for the formation of 5a.
Third, IX was treated with 2a and 3 under condition B to
give 5a in a yield of 80% (Scheme 7). This result is positive in
supporting the proposed mechanism, in which IX is considered
to be a key intermediate in the formation of 5a.
Fourth, 2-benzyl-5-phenylpent-2-enal was treated 1a and 3
under condition B to give 6e in a yield of 57% (Scheme 8).
This result is consistent with that obtained using 3-phenyl-
propanal as the starting material and should be considered as
positive evidence for the mechanism, in which an α,β-
unsaturated aldehyde is considered to be a key intermediate
for the formation of 6.
On the basis of the above results and our previous studies,15
a plausible pathway for the formation of 4a is proposed in
Scheme 2. First, Cu(I)-catalyzed aryl amination of 1a with 3
Scheme 2. Plausible Mechanism for the Formation of 4a
Finally, 2-benzyl-5-phenylpent-2-enal was treated with IX
and 3 under condition B. From this reaction, 6e was obtained
in a yield of 73% (Scheme 9). This result is consistent with that
obtained by using 1a and 3-phenylpropanal as the starting
materials and should be considered as positive evidence for the
proposed reaction mechanism, in which both IX and an α,β-
unsaturated aldehyde are considered to be key intermediates for
the formation of 6.
In order to showcase the applicability of the method for the
synthesis of 4-cyanoindoles developed herein, a larger-scale
preparation of 2-(4-methoxyphenyl)-1H-indole-3-carbonitrile
(4p) was carried out. Thus, 1a (5 mmol) was treated with 4-
methoxybenzaldehyde (10 mmol) and aqueous ammonia (26%,
15 mL) in the presence of CuI (0.5 mmol), DABCO (1 mmol),
and PivOH (5 mmol) in DMF (15 mL) at 80 °C in a sealed
vessel under air for 24 h. This reaction afforded 4p in 48%
yield.
In summary, we have developed some novel strategies for the
preparation of indole-related heterocycles, including 1H-indole-
3-carbonitriles, 9H-pyrimido[4,5-b]indoles, and 9H-pyrido[2,3-
b]indoles. These protocols show some notable features. First,
both the indole framework and the cyano/pyrimidine/pyridine
with the assistance of DABCO and PivOH affords 2-(2,2-
dibromovinyl)aniline (III). At a high concentration of 3
(condition A), III undergoes two sequential intermolecular
vinyl aminations to afford intermediates IV and V, respectively.
In the next stage, condensation of V with 2a gives imine VI.
Subsequent intramolecular nucleophilic addition in VI affords
intermediate VII, and oxidative dehydrogenation of VII affords
VIII. Finally, elimination of NH3 from VIII affords 4a.
On the other hand, it is suggested that the initial step in the
formation of 5a also involves a Cu(I)-catalyzed aryl amination
of 1a to give intermediate III. At a lower concentration of 3
D
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Scheme 3. Plausible Mechanism for the Formation of 5a
Scheme 4. Plausible Mechanism for the Formation of 6a
Scheme 5. Formation of 4a from the Reaction of III, 2a, and
3 under Condition A
Scheme 8. Formation of 6e from 1a, α,β-Unsaturated
Aldehyde, and 3 under Condition B
Scheme 9. Formation of 6e from IX, α,β-Unsaturated
Aldehyde, and 3 under Condition B
Scheme 6. Formation of 5a from the Reaction of III, 2a, and
3 under Condition B
Scheme 7. Formation of 5a from the Reaction of IX, 2a, and
3 under Condition B
carbonitriles or 9H-pyrimido[4,5-b]indoles/9H-pyrido[2,3-b]-
indoles could be obtained as dominant products from the same
starting materials simply by tuning the concentration of
ammonia and the molar ratio of the reagents. Moreover, the
reactions are realized under mild conditions, and the substrates
are readily available and generally broad in scope. With all of
these advantages, the methods developed herein should find
wide application in the synthesis of relevant heterocyclic
compounds. Further study to gain deeper insight into the
reaction mechanisms is currently underway.
unit are constructed simultaneously through the formation of
multiple C−N and C−C bonds. Second, either 1H-indole-3-
E
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Article
129.8, 130.9, 137.8, 147.6. HRMS: calcd for C16H10F3N2 287.0796 [M
+ H], found 287.0812.
6-Methyl-2-phenyl-1H-indole-3-carbonitrile (4f). Eluent: petrole-
EXPERIMENTAL SECTION
■
1. General Methods. 1-Bromo-2-(2,2-dibromovinyl)benzenes 1
were prepared through the reaction of 2-bromobenzaldehydes with
carbon tetrabromide according to a literature procedure.22 Other
reagents and solvents were purchased from commercial suppliers and
used without further purification. 1H and 13C NMR spectra were
recorded at 400 and 100 MHz, respectively. Chemical shifts (in ppm)
were referenced to tetramethylsilane in CDCl3 or DMSO-d6. 13C
NMR spectra were calibrated with CDCl3 (δ = 77.00 ppm) or DMSO-
d6 (δ = 39.50 ppm). Multiplicities are indicated as follows: s (singlet);
d (doublet); t (triplet); m (multiplet); dd (doublet of doublets); td
(triplet of doublets); br s (broad singlet), etc. Coupling constants are
given in hertz. High-resolution mass spectrometry (HRMS) was
performed in ESI mode using a MicrOTOF mass spectrometer. The
conversion of starting materials was monitored by thin-layer
chromatography (TLC) using silica gel plates (silica gel 60 F254,
0.25 mm), and components were visualized by observation under UV
light (254 and 365 nm).
um ether/ethyl acetate (5:1). White solid (64 mg, 56%), mp 248−250
1
°C. H NMR (400 MHz, DMSO-d6): δ 2.42 (s, 3H), 7.07 (d, J = 8.4
Hz, 1H), 7.32 (s, 1H), 7.49−7.53 (m, 2H), 7.60 (t, J = 7.6 Hz, 2H),
7.95 (d, J = 7.6 Hz, 2H), 12.41 (s, 1H). 13C NMR (100 MHz, DMSO-
d6): δ 21.8, 81.7, 112.8, 117.6, 118.5, 124.2, 126.6, 127.3, 129.8, 130.0,
130.2, 133.9, 136.4, 144.7. HRMS: calcd for C16H13N2 233.1078 [M +
H], found 233.1075.
5-Methoxy-2-phenyl-1H-indole-3-carbonitrile (4g).9a Eluent: pe-
troleum ether/ethyl acetate (5:1). White solid (72 mg, 58%), mp
246−248 °C. 1H NMR (400 MHz, DMSO-d6): δ 3.82 (s, 3H), 6.91−
6.93 (m, 1H), 7.06 (d, J = 2.4 Hz, 1H), 7.44 (d, J = 8.8 Hz, 1H), 7.51
(t, J = 7.2 Hz, 1H), 7.60 (t, J = 7.6 Hz, 2H), 7.95 (d, J = 7.2 Hz, 2H),
12.49 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 55.9, 81.6, 100.1,
114.1, 114.8, 117.7, 127.2, 129.6, 129.8, 130.0, 130.2, 130.9, 145.0,
156.0. MS: m/z 249 [M + H]+.
6-Phenyl-5H-[1,3]dioxolo[4,5-f ]indole-7-carbonitrile (4h). Eluent:
petroleum ether/ethyl acetate (5:1). White solid (69 mg, 53%), mp
264−266 °C. 1H NMR (400 MHz, DMSO-d6): δ 6.04 (s, 2H), 7.02 (s,
1H), 7.06 (s, 1H), 7.47 (t, J = 7.2 Hz, 1H), 7.57 (t, J = 7.6 Hz, 2H),
7.89 (d, J = 7.6 Hz, 2H), 12.40 (s, 1H). 13C NMR (100 MHz, DMSO-
d6): δ 82.2, 93.6, 97.4, 101.6, 123.0, 126.8, 128.5, 129.7, 129.8, 130.1,
131.0, 143.2, 145.0, 146.4. HRMS: calcd for C16H11N2O2 263.0820 [M
+ H], found 263.0829.
2-(3-Fluorophenyl)-1H-indole-3-carbonitrile (4i). Eluent: petrole-
um ether/ethyl acetate (5:1). White solid (78 mg, 66%), mp 271−272
°C. 1H NMR (400 MHz, DMSO-d6): δ 7.24−7.41 (m, 3H), 7.56 (d, J
= 8.0 Hz, 1H), 7.63−7.69 (m, 2H), 7.75−7.78 (m, 1H), 7.84 (d, J =
8.0 Hz, 1H), 12.67 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 82.5,
113.2, 114.0, 114.2, 117.08, 117.13, 117.3, 119.0, 122.7, 123.5, 123.6,
124.7, 128.6, 131.8, 131.9, 132.0, 136.0, 143.42, 143.44, 161.6, 164.0.
HRMS: calcd for C15H9FN2Na 259.0648 [M + Na], found 259.0657.
2-(4-Chlorophenyl)-1H-indole-3-carbonitrile (4j). Eluent: petrole-
um ether/ethyl acetate (5:1). White solid (89 mg, 71%), mp 287−289
°C. 1H NMR (400 MHz, DMSO-d6): δ 7.23−7.33 (m, 2H), 7.54 (d, J
= 7.6 Hz, 1H), 7.63 (d, J = 7.6 Hz, 1H), 7.69 (d, J = 8.8 Hz, 2H), 7.97
(d, J = 9.2 Hz, 2H), 12.64 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
δ 82.2, 113.1, 117.2, 118.9, 122.6, 124.6, 128.63, 128.65, 129.1, 129.9,
135.1, 136.0, 143.8. HRMS: calcd for C15H10ClN2 253.0532 [M + H],
found 253.0526.
2. General Procedure for the Preparation of 3-Cyanoindoles
4. To a tube containing a solution of 1-bromo-2-(2,2-dibromovinyl)-
benzene (1a) (170 mg, 0.5 mmol) in DMF (1.5 mL) were added CuI
(9.5 mg, 0.05 mmol), DABCO (11.2 mg, 0.1 mmol), PivOH (51 mg,
0.5 mmol), benzaldehyde (2a) (106 mg, 1 mmol), and aqueous
ammonia (3) (26%, 1.5 mL). The tube was sealed, and the mixture
was stirred at 80 °C under an atmosphere of air for 24 h. After the
reaction mixture was cooled to room temperature, the reaction was
quenched with H2O, and the resulting mixture was extracted with ethyl
acetate. The combined organic layers were washed with brine and then
dried over anhydrous Na2SO4. The solvent was evaporated under
vacuum, and the crude product was purified by column chromatog-
raphy on silica gel using petroleum ether/ethyl acetate (5:1) as the
eluent to give 2-phenyl-1H-indole-3-carbonitrile (4a) (68 mg, 62%).
Other 3-cyanoindoles (4b−ii) were obtained in a similar manner.
2-Phenyl-1H-indole-3-carbonitrile (4a).9d Eluent: petroleum
ether/ethyl acetate (5:1). White solid (67 mg, 62%), mp 233−234
1
°C. H NMR (400 MHz, CDCl3): δ 7.26−7.33 (m, 2H), 7.44−7.53
(m, 4H), 7.74−7.76 (m, 1H), 7.90 (q, J = 8.0 Hz, 2H), 9.14 (s, 1H).
13C NMR (100 MHz, CDCl3): δ 83.9, 111.8, 117.0, 119.6, 122.5,
124.4, 126.9, 128.9, 129.4, 130.1, 135.1, 144.8. MS: m/z 219 [M +
H]+.
5-Fluoro-2-phenyl-1H-indole-3-carbonitrile (4b).9d Eluent: petro-
leum ether/ethyl acetate (5:1). White solid (76 mg, 64%), mp 248−
2-(4-Bromophenyl)-1H-indole-3-carbonitrile (4k). Eluent: petro-
leum ether/ethyl acetate (5:1). White solid (96 mg, 65%), mp 301−
302 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.30 (dd, J1 = 8.8 Hz, J2 =
2.0 Hz, 1H), 7.53−7.56 (m, 2H), 7.60−7.63 (m, 3H), 7.95 (d, J = 7.6
Hz, 2H), 12.78 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 81.7,
114.8, 116.7, 118.0, 124.5, 127.2, 127.5, 129.4, 129.8, 130.7, 134.5,
146.6. HRMS: calcd for C15H9BrN2Na 318.9847 [M + Na], found
318.9838.
1
249 °C. H NMR (400 MHz, DMSO-d6): δ 7.14 (t, J = 9.2 Hz, 1H),
7.38 (d, J = 9.2 Hz, 1H), 7.53 (d, J = 6.4 Hz, 2H), 7.60 (t, J = 7.2 Hz,
2H), 7.95 (d, J = 7.2 Hz, 2H), 12.66 (s, 1H). 13C NMR (100 MHz,
DMSO-d6): δ 82.2, 103.9, 104.1, 112.6, 112.9, 114.5, 114.6, 117.0,
127.5, 129.3, 129.4, 129.6, 129.8, 130.6, 132.6, 146.7, 157.7, 160.1. MS:
m/z 237 [M + H]+.
6-Fluoro-2-phenyl-1H-indole-3-carbonitrile (4c). Eluent: petrole-
um ether/ethyl acetate (5:1). White solid (77 mg, 63%), mp 274−276
°C. 1H NMR (400 MHz, DMSO-d6): δ 7.11 (t, J = 9.2 Hz, 1H), 7.31
(d, J = 9.2 Hz, 1H), 7.51−7.54 (m, 1H), 7.59−7.65 (m, 3H), 7.94 (d, J
= 7.6 Hz, 2H), 12.68 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ
82.0, 99.2, 99.5, 111.0, 111.3, 117.1, 120.2, 120.3, 125.3, 127.4, 129.6,
129.8, 130.5, 136.0, 136.1, 146.11, 146.14, 159.1, 161.5. HRMS: calcd
for C15H10FN2 237.0828 [M + H], found 237.0822.
5-Chloro-2-phenyl-1H-indole-3-carbonitrile (4d). Eluent: petro-
leum ether/ethyl acetate (5:1). White solid (77 mg, 61%), mp 284−
286 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.29 (d, J = 8.0 Hz, 1H),
7.53−7.55 (m, 2H), 7.59−7.62 (m, 3H), 7.95 (d, J = 8.0 Hz, 2H),
12.76 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 81.7, 114.8, 116.8,
118.0, 124.5, 127.2, 127.6, 129.4, 129.8, 130.8, 134.5, 146.6. HRMS:
calcd for C15H10ClN2 253.0532 [M + H], found 253.0538.
2-(4-(Trifluoromethyl)phenyl)-1H-indole-3-carbonitrile (4l). Elu-
ent: petroleum ether/ethyl acetate (5:1). White solid (90 mg, 63%),
1
mp 260−262 °C. H NMR (400 MHz, DMSO-d6): δ 7.25−7.36 (m,
2H), 7.58 (d, J = 8.0 Hz, 1H), 7.65−7.67 (m, 1H), 7.99 (d, J = 8.4 Hz,
2H), 8.17 (d, J = 8.4 Hz, 2H), 12.78 (s, 1H). 13C NMR (100 MHz,
DMSO-d6): δ 83.2, 113.3, 117.0, 119.1, 122.8, 123.0, 124.9, 125.8,
126.65, 126.68, 126.72, 126.76, 128.1, 128.6, 133.6, 136.2, 143.1.
HRMS: calcd for C16H9F3N2Na 309.0616 [M + Na], found 309.0619.
2-(o-Tolyl)-1H-indole-3-carbonitrile (4m).9d Eluent: petroleum
ether/ethyl acetate (5:1). White solid (66 mg, 57%), mp 181−183
1
°C. H NMR (400 MHz, DMSO-d6): δ 2.35 (s, 3H), 7.27 (t, J = 7.2
Hz, 1H), 7.33 (t, J = 8.0 Hz, 1H), 7.56 (d, J = 8.0 Hz, 1H), 7.59−7.67
(m, 3H), 7.94−7.63 (m, 1H), 8.01−8.02 (m, 1H), 12.70 (s, 1H). 13C
NMR (100 MHz, DMSO-d6): δ 82.6, 113.3, 117.1, 119.0, 122.7, 124.8,
126.1, 126.3, 127.0, 128.6, 130.2, 131.8, 134.5, 136.1, 143.3. MS: m/z
233 [M + H]+.
2-Phenyl-5-(trifluoromethyl)-1H-indole-3-carbonitrile (4e). Elu-
ent: petroleum ether/ethyl acetate (5:1). White solid (84 mg, 59%),
1
2-(m-Tolyl)-1H-indole-3-carbonitrile (4n).9d Eluent: petroleum
ether/ethyl acetate (5:1). White solid (74 mg, 64%), mp 248−250
°C. 1H NMR (400 MHz, CDCl3): δ 2.43 (s, 3H), 7.26−7.30 (m, 3H),
7.40 (t, J = 8.0 Hz, 1H), 7.45−7.47 (m, 1H), 7.69−7.70 (m, 1H),
mp 321−323 °C. H NMR (400 MHz, DMSO-d6): δ 7.54−7.65 (m,
4H), 7.73 (d, J = 8.0 Hz, 1H), 7.93 (s, 1H), 7.98 (d, J = 7.2 Hz, 2H).
13C NMR (100 MHz, DMSO-d6): δ 82.8, 114.2, 116.1, 116.17, 116.21,
116.6, 120.70, 120.73, 123.0, 123.3, 123.9, 126.7, 127.6, 128.2, 129.3,
F
DOI: 10.1021/acs.joc.5b00239
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
7.75−7.77 (m, 1H), 9.06 (s, 1H). 13C NMR (100 MHz, CDCl3): δ
21.3, 83.9, 111.6, 116.8, 119.6, 122.4, 124.0, 124.3, 127.4, 128.9,
129.30, 129.35, 130.9, 134.9, 139.3, 144.9. MS: m/z 233 [M + H]+.
2-(p-Tolyl)-1H-indole-3-carbonitrile (4o).9d Eluent: petroleum
ether/ethyl acetate (5:1). White solid (71 mg, 61%), mp 288−290
°C. 1H NMR (400 MHz, CDCl3): δ 2.41 (s, 3H), 7.26−7.32 (m, 4H),
7.44−7.46 (m, 1H), 7.73−7.80 (m, 3H), 9.06 (s, 1H). 13C NMR (100
MHz, CDCl3): δ 21.4, 83.3, 111.7, 119.4, 122.4, 124.2, 126.6, 126.7,
128.9, 130.1, 135.0, 140.4, 145.1. MS: m/z 233 [M + H]+.
1H NMR (400 MHz, CDCl3): δ 3.10 (t, J = 7.2 Hz, 2H), 3.27 (t, J =
7.2 Hz, 2H), 7.18 (d, J = 6.8 Hz, 2H), 7.21−7.32 (m, 6H), 7.65−7.69
(m, 1H), 8.33 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 29.4, 35.2,
85.3, 111.4, 116.1, 119.1, 122.1, 123.5, 126.8, 127.5, 128.4, 128.8,
134.5, 139.8, 147.9. MS: m/z 247 [M + H]+.
5-Fluoro-2-(4-methoxyphenyl)-1H-indole-3-carbonitrile (4y). Elu-
ent: petroleum ether/ethyl acetate (5:1). White solid (80 mg, 60%),
1
mp 257−259 °C. H NMR (400 MHz, DMSO-d6): δ 3.83 (s, 3H),
7.07−7.17 (m, 3H), 7.33 (d, J = 8.0 Hz, 1H), 7.48−7.50 (m, 1H), 7.91
(d, J = 8.8 Hz, 2H). 13C NMR (100 MHz, DMSO-d6): δ 55.9, 81.0,
103.6, 103.9, 112.0, 112.3, 114.2, 114.3, 115.2, 117.3, 122.1, 129.0,
129.5, 129.6, 132.6, 147.0, 157.7, 160.0, 161.2. HRMS: calcd for
C16H11FN2ONa 289.0753 [M + Na], found 289.0749.
2-(4-Methoxyphenyl)-1H-indole-3-carbonitrile (4p).9d Eluent: pe-
troleum ether/ethyl acetate (5:1). White solid (77 mg, 62%), mp
280−282 °C. 1H NMR (400 MHz, DMSO-d6): δ 3.84 (s, 3H), 7.16−
7.29 (m, 4H), 7.52 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.93−
7.95 (m, 2H), 12.43 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 55.9,
80.7, 112.9, 115.2, 117.8, 118.6, 122.2, 122.3, 124.0, 128.88, 128.93,
135.9, 145.4, 161.0. MS: m/z 249 [M + H]+.
6-Fluoro-2-(4-methoxyphenyl)-1H-indole-3-carbonitrile (4z). Elu-
ent: petroleum ether/ethyl acetate (5:1). White solid (84 mg, 63%),
1
mp 283−285 °C. H NMR (400 MHz, DMSO-d6): δ 3.84 (s, 3H),
2-(3,4-Dimethoxyphenyl)-1H-indole-3-carbonitrile (4q). Eluent:
petroleum ether/ethyl acetate (5:1). White solid (94 mg, 68%), mp
220−222 °C. 1H NMR (400 MHz, DMSO-d6): δ 3.84 (s, 3H), 3.87 (s,
3H), 7.18−7.26 (m, 2H), 7.28−7.30 (m, 1H), 7.52 (d, J = 8.0 Hz,
1H), 7.56−7.60 (m, 3H), 12.44 (s, 1H). 13C NMR (100 MHz,
DMSO-d6): δ 56.11, 56.15, 80.8, 110.7, 112.6, 112.8, 117.9, 118.6,
120.3, 122.2, 122.4, 124.1, 128.8, 135.8, 145.6, 149.4, 150.7. HRMS:
calcd for C17H14N2O2Na 301.0953 [M + Na], found 301.0971.
2-(Naphthalen-1-yl)-1H-indole-3-carbonitrile (4r).9d Eluent: pe-
troleum ether/ethyl acetate (5:1). White solid (91 mg, 68%), mp
266−268 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.29−7.38 (m, 2H),
7.58−7.64 (m, 3H), 7.69−7.30 (m, 2H), 7.79−7.81 (m, 1H), 7.86−
7.89 (m, 1H), 8.08−8.10 (m, 1H), 8.16 (d, J = 8.4 Hz, 1H), 12.71 (s,
1H). 13C NMR (100 MHz, DMSO-d6): δ 85.6, 113.2, 116.8, 118.9,
122.5, 124.2, 125.5, 125.9, 127.1, 127.8, 127.9, 128.1, 129.1, 129.4,
130.8, 131.2, 133.8, 136.0, 145.4. MS: m/z 269 [M + H]+.
7.06−7.11 (m, 3H), 7.17 (d, J = 8.8 Hz, 1H), 7.26−7.29 (m, 1H),
7.57−7.61 (m, 1H), 7.90 (d, J = 8.8 Hz, 2H), 12.53 (s, 1H). 13C NMR
(100 MHz, DMSO-d6): δ 55.9, 80.8, 99.0, 99.3, 110.7, 110.9, 115.2,
117.3, 119.8, 119.9, 122.0, 125.3, 128.8, 135.8, 136.0, 146.29, 146.32,
158.9, 161.1, 161.3. HRMS: calcd for C16H11FN2ONa 289.0753 [M +
Na], found 289.0746.
6-Fluoro-2-propyl-1H-indole-3-carbonitrile (4aa). Eluent: petro-
leum ether/ethyl acetate (5:1). White solid (57 mg, 57%), mp 113−
1
115 °C. H NMR (400 MHz, CDCl3): δ 1.02 (t, J = 7.2 Hz, 3H),
1.78−1.87 (m, 2H), 2.92 (t, J = 7.2 Hz, 2H), 6.98−7.03 (m, 1H),
7.07−7.09 (m, 1H), 7.55−7.58 (m, 1H), 8.68 (s, 1H), 13C NMR (100
MHz, CDCl3): δ 13.6, 22.0, 29.4, 85.2, 98.0, 98.3, 110.6, 110.8, 116.0,
119.8, 119.9, 123.9, 134.5, 134.6, 149.5, 159.1, 161.5. HRMS: calcd for
C12H11FN2Na 225.0804 [M + Na], found 225.0815.
5-Chloro-2-(4-chlorophenyl)-1H-indole-3-carbonitrile (4bb). Elu-
ent: petroleum ether/ethyl acetate (5:1). White solid (90 mg, 63%),
2-(Thiophen-2-yl)-1H-indole-3-carbonitrile (4s).9d Eluent: petro-
leum ether/ethyl acetate (5:1). White solid (50 mg, 45%), mp 206−
1
mp 332−333 °C. H NMR (400 MHz, DMSO-d6): δ 7.30−7.33 (m,
1H), 7.55 (d, J = 8.4 Hz, 1H), 7.64 (s, 1H), 7.70 (d, J = 8.4 Hz, 2H),
7.96 (d, J = 9.2 Hz, 2H), 12.82 (s, 1H). 13C NMR (100 MHz, DMSO-
d6): δ 82.0, 114.8, 116.5, 118.1, 124.7, 127.3, 128.2, 129.2, 129.7,
129.9, 134.5, 135.4, 145.2. HRMS: calcd for C15H9Cl2N2 287.0143 [M
+ H], found 287.0152.
1
208 °C. H NMR (400 MHz, CDCl3): δ 7.13−7.16 (m, 1H), 7.25−
7.26 (m, 2H), 7.42−7.44 (m, 2H), 7.68−7.71 (m, 1H), 7.78 (d, J = 3.6
Hz, 1H), 9.56 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 83.3, 111.7,
119.3, 122.5, 124.4, 127.41, 127.43, 128.4, 128.6, 129.6, 131.4, 135.1,
139.3. MS: m/z 225 [M + H]+.
2-Methyl-1H-indole-3-carbonitrile (4t).9d Eluent: petroleum ether/
5-Chloro-2-(4-methoxyphenyl)-1H-indole-3-carbonitrile (4cc).
Eluent: petroleum ether/ethyl acetate (5:1). White solid (87 mg,
1
ethyl acetate (5:1). White solid (33 mg, 42%), mp 166−168 °C. H
1
62%), mp 288−290 °C. H NMR (400 MHz, DMSO-d6): δ 3.87 (s,
NMR (400 MHz, CDCl3): δ 2.63 (s, 3H), 7.22−7.26 (m, 2H), 7.35−
7.37 (m, 1H), 7.64−7.66 (m, 1H), 8.59 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 13.0, 85.7, 111.2, 116.3, 118.9, 122.0, 123.4, 127.6, 134.6,
144.5. MS: m/z 157 [M + H]+.
3H), 7.20 (d, J = 8.4 Hz, 2H), 7.30 (d, J = 9.2 Hz, 1H), 7.54 (d, J = 8.8
Hz, 1H), 7.61 (s, 1H), 7.94 (d, J = 8.4 Hz, 2H), 12.65 (s, 1H). 13C
NMR (100 MHz, DMSO-d6): δ 55.8, 80.6, 114.5, 115.4, 117.0, 117.8,
121.8, 124.1, 127.0, 129.1, 130.0, 134.4, 146.8, 161.3. HRMS: calcd for
C16H11ClN2ONa 305.0458 [M + Na], found 305.0462.
2-Ethyl-1H-indole-3-carbonitrile (4u). Eluent: petroleum ether/
1
ethyl acetate (5:1). White solid (43 mg, 51%), mp 117−118 °C. H
5-Chloro-2-propyl-1H-indole-3-carbonitrile (4dd). Eluent: petro-
leum ether/ethyl acetate (5:1). White solid (60 mg, 55%), mp 159−
NMR (400 MHz, CDCl3): δ 1.43 (t, J = 7.6 Hz, 3H), 3.00 (q, J = 7.6
Hz, 2H), 7.22−7.28 (m, 2H), 7.40−7.42 (m, 1H), 7.65−7.67 (m, 1H),
8.94 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 13.3, 21.0, 84.0, 111.5,
116.5, 118.9, 122.0, 123.4, 127.7, 134.6, 150.5. HRMS: calcd for
C11H11N2 171.0922 [M + H], found 171.0921.
1
161 °C. H NMR (400 MHz, CDCl3): δ 1.01 (t, J = 7.2 Hz, 3H),
1.78−1.87 (m, 2H), 2.92 (t, J = 7.2 Hz, 2H), 7.19 (d, J = 8.8 Hz, 1H),
7.29 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 9.41 (s, 1H). 13C NMR (100
MHz, CDCl3): δ 13.6, 22.4, 29.5, 84.8, 112.4, 115.8, 118.5, 123.7,
127.8, 129.1, 133.0, 150.3. HRMS: calcd for C12H11ClN2Na 241.0509
[M + Na], found 241.0519.
2-Propyl-1H-indole-3-carbonitrile (4v). Eluent: petroleum ether/
1
ethyl acetate (5:1). White solid (50 mg, 54%), mp 115−117 °C. H
NMR (400 MHz, CDCl3): δ 1.03 (t, J = 7.2 Hz, 3H), 1.79−1.88 (m,
2H), 2.94 (t, J = 7.2 Hz, 2H), 7.24−7.26 (m, 2H), 7.38 (d, J = 5.2 Hz,
1H), 7.66−7.68 (m, 1H), 8.83 (s, 1H). 13C NMR (100 MHz, CDCl3):
δ 13.7, 22.5, 29.5, 85.0, 111.4, 116.5, 119.0, 122.0, 123.4, 127.7, 134.6,
149.1. HRMS: calcd for C12H13N2 185.1078 [M + H], found
185.1086.
2-(4-Methoxyphenyl)-5-(trifluoromethyl)-1H-indole-3-carboni-
trile (4ee). Eluent: petroleum ether/ethyl acetate (5:1). White solid
1
(98 mg, 62%), mp 306−308 °C. H NMR (400 MHz, DMSO-d6): δ
3.83 (s, 3H), 7.16 (d, J = 8.0 Hz, 2H), 7.53 (d, J = 8.8 Hz, 1H), 7.66
(d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.93 (d, J = 8.4 Hz, 2H), 12.78 (s,
1H). 13C NMR (100 MHz, DMSO-d6): δ 55.9, 81.6, 113.8, 115.3,
115.8, 115.9, 116.8, 120.41, 120.44, 121.5, 122.9, 123.2, 124.0, 126.7,
128.3, 129.2, 137.6, 147.6, 161.4. HRMS: calcd for C17H11F3N2ONa
339.0721 [M + Na], found 339.0726.
2-Isobutyl-1H-indole-3-carbonitrile (4w). Eluent: petroleum
ether/ethyl acetate (5:1). White solid (48 mg, 49%), mp 116−117
1
°C. H NMR (400 MHz, CDCl3): δ 1.01 (d, J = 6.4 Hz, 6H), 2.09−
2.16 (m, 1H), 2.82 (d, J = 7.2 Hz, 2H), 7.22−7.28 (m, 2H), 7.37−7.39
(m, 1H), 7.66−7.68 (m, 1H), 8.62 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 22.3, 29.2, 36.6, 85.8, 111.3, 116.4, 119.0, 122.0, 123.4,
127.6, 134.5, 148.2. HRMS: calcd for C13H14N2Na 221.1055 [M +
Na], found 221.1043.
2-Propyl-5-(trifluoromethyl)-1H-indole-3-carbonitrile (4ff). Elu-
ent: petroleum ether/ethyl acetate (5:1). White solid (65 mg, 52%),
mp 171−173 °C. 1H NMR (400 MHz, CDCl3): δ 1.04 (t, J = 7.2 Hz,
3H), 1.82−1.92 (m, 2H), 2.98 (t, J = 7.6 Hz, 2H), 7.48−7.52 (m, 2H),
7.94 (s, 1H), 9.29 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 13.6, 22.3,
29.6, 85.6, 112.0, 115.7, 116.47, 116.51, 116.55, 120.2, 120.3, 123.3,
2-Phenethyl-1H-indole-3-carbonitrile (4x).9d Eluent: petroleum
ether/ethyl acetate (5:1). White solid (75 mg, 61%), mp 125−126 °C.
G
DOI: 10.1021/acs.joc.5b00239
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The Journal of Organic Chemistry
Article
124.4, 124.7, 126.0, 127.1, 136.1, 151.2. HRMS: calcd for
C13H11F3N2Na 275.0772 [M + Na], found 275.0783.
6-Chloro-2,4-diphenyl-9H-pyrimido[4,5-b]indole (5d). Eluent:
petroleum ether/ethyl acetate (10:1). White solid (103 mg, 58%),
1
mp 289−291 °C. H NMR (400 MHz, DMSO-d6): δ 7.48−7.67 (m,
2-(4-Methoxyphenyl)-6-methyl-1H-indole-3-carbonitrile (4gg).
Eluent: petroleum ether/ethyl acetate (5:1). White solid (85 mg,
9H), 7.98 (d, J = 5.6 Hz, 2H), 8.53 (d, J = 5.6 Hz, 2H), 12.69 (s, 1H).
13C NMR (100 MHz, DMSO-d6): δ 108.8, 114.0, 120.7, 121.4, 125.3,
127.8, 128.4, 129.1, 129.27, 129.30, 130.8, 130.9, 138.1, 138.3, 138.7,
158.0, 160.3, 160.5. HRMS: calcd for C22H15ClN3 356.0954 [M + H],
found 356.0958.
1
65%), mp 251−253 °C. H NMR (400 MHz, DMSO-d6): δ 2.41 (s,
3H), 3.83 (s, 3H), 7.04 (d, J = 8.4 Hz, 1H), 7.16 (d, J = 9.2 Hz, 2H),
7.29 (s, 1H), 7.46 (d, J = 8.8 Hz, 1H), 7.91 (d, J = 8.8 Hz, 2H), 12.26
(s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 21.8, 55.9, 80.5, 112.6,
115.2, 117.9, 118.3, 122.4, 124.0, 126.7, 128.8, 133.5, 136.3, 144.9,
160.9. HRMS: calcd for C17H14N2ONa 285.1004 [M + Na], found
285.1001.
2,4-Diphenyl-6-(trifluoromethyl)-9H-pyrimido[4,5-b]indole (5e).
Eluent: petroleum ether/ethyl acetate (10:1). White solid (110 mg,
57%), mp 317−319 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.53−7.54
(m, 3H), 7.56−7.71 (m, 3H), 7.76 (d, J = 8.8 Hz, 1H), 7.81−7.83 (m,
1H), 8.02−8.05 (m, 3H), 8.54−8.57 (m, 2H), 12.98 (s, 1H). 13C
NMR (100 MHz, DMSO-d6): δ 109.2, 113.3, 119.10, 119.14, 119.2,
121.5, 121.8, 123.9, 124.5, 126.6, 128.4, 128.5, 129.1, 129.30, 129.33,
131.0, 131.1, 132.0, 138.2, 138.6, 141.7, 158.6, 160.6, 160.9. HRMS:
calcd for C23H15F3N3 390.1218 [M + H], found 390.1200.
5-Methoxy-2-propyl-1H-indole-3-carbonitrile (4hh). Eluent: pe-
troleum ether/ethyl acetate (5:1). White solid (55 mg, 52%), mp
125−127 °C. 1H NMR (400 MHz, CDCl3): δ 1.02 (t, J = 7.2 Hz, 3H),
1.77−1.86 (m, 2H), 2.90 (t, J = 7.2 Hz, 2H), 3.86 (s, 3H), 6.86−6.89
(m, 1H), 7.10 (s, 1H), 7.24 (d, J = 8.8 Hz, 1H), 8.37 (s, 1H). 13C
NMR (100 MHz, CDCl3): δ 13.6, 22.3, 29.3, 55.7, 85.1, 100.6, 112.0,
113.8, 116.5, 128.4, 129.2, 148.8, 155.9. HRMS: calcd for C13H15N2O
215.1184 [M + H], found 215.1202.
6-Propyl-5H-[1,3]dioxolo[4,5-f ]indole-7-carbonitrile (4ii). Eluent:
petroleum ether/ethyl acetate (5:1). White solid (60 mg, 53%), mp
172−173 °C. 1H NMR (400 MHz, CDCl3): δ 1.01 (t, J = 7.6 Hz, 3H),
1.74−1.83 (m, 2H), 2.86 (t, J = 7.6 Hz, 2H), 5.96 (s, 2H), 6.81 (s,
1H), 7.02 (s, 1H), 8.36 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 13.6,
22.5, 29.4, 85.1, 92.4, 97.9, 101.0, 116.5, 121.8, 129.2, 144.4, 145.6,
147.2. HRMS: calcd for C13H13N2O2 229.0977 [M + H], found
229.0986.
3. General Procedure for the Preparation of 9H-Pyrimido-
[4,5-b]indoles 5. To a tube containing a solution of 1-bromo-2-(2,2-
dibromovinyl)benzene (1a) (170 mg, 0.5 mmol) in DMF (3 mL)
were added CuI (9.5 mg, 0.05 mmol), DABCO (11.2 mg, 0.1 mmol),
PivOH (51 mg, 0.5 mmol), benzaldehyde (2a) (159 mg, 1.5 mmol),
and aqueous ammonia (3) (26%, 0.5 mL). The tube was sealed, and
the mixture was stirred at 80 °C under an atmosphere of air for 30 h.
After the reaction mixture was cooled to room temperature, the
reaction was quenched with H2O, and the resulting mixture was
extracted with ethyl acetate. The combined organic layers were washed
with brine and then dried over anhydrous Na2SO4. The solvent was
evaporated under vacuum, and the crude product was purified by
column chromatography on silica gel using petroleum ether/ethyl
acetate (10:1) as the eluent to give 2,4-diphenyl-9H-pyrimido[4,5-
b]indole (5a) (88 mg, 55%). Other 9H-pyrimido[4,5-b]indoles (5b−
u) were obtained in a similar manner.
7-Methyl-2,4-diphenyl-9H-pyrimido[4,5-b]indole (5f). Eluent: pe-
troleum ether/ethyl acetate (10:1). White solid (90 mg, 54%), mp
1
269−271 °C. H NMR (400 MHz, DMSO-d6): δ 2.46 (s, 3H), 7.01
(d, J = 8.0 Hz, 1H), 7.37 (s, 1H), 7.53 (d, J = 7.6 Hz, 3H), 7.65−7.70
(m, 4H), 8.01 (d, J = 6.4 Hz, 2H), 8.54 (d, J = 6.4 Hz, 2H), 12.42 (s,
1H). 13C NMR (100 MHz, DMSO-d6): δ 22.0, 109.5 112.4, 116.9,
122.1, 122.7, 128.2, 129.0, 129.2, 129.3, 130.5, 130.6, 138.0, 138.6,
139.1, 140.1, 157.8, 158.9, 159.5. HRMS: calcd for C23H18N3 336.1500
[M + H], found 336.1471.
6-Methoxy-2,4-diphenyl-9H-pyrimido[4,5-b]indole (5g). Eluent:
petroleum ether/ethyl acetate (10:1). White solid (88 mg, 50%), mp
299−301 °C. 1H NMR (400 MHz, DMSO-d6): δ 3.68 (s, 3H), 7.14−
7.17 (m, 1H), 7.27 (s, 1H), 7.49−7.55 (m, 4H), 7.65−7.71 (m, 3H),
8.02 (d, J = 7.2 Hz, 2H), 8.54 (d, J = 6.0 Hz, 2H), 12.38 (s, 1H). 13C
NMR (100 MHz, DMSO-d6): δ 55.8, 105.8, 109.4, 113.2, 116.5, 119.8,
128.3, 129.0, 129.1, 129.4, 130.6, 130.7, 134.2, 138.6, 138.8, 154.4,
157.8, 159.6, 159.7. HRMS: calcd for C23H18N3O 352.1450 [M + H],
found 352.1458.
7,9-Diphenyl-5H-[1,3]dioxolo[4,5-f ]pyrimido[4,5-b]indole (5h).
Eluent: petroleum ether/ethyl acetate (10:1). White solid (86 mg,
1
47%), mp 324−326 °C. H NMR (400 MHz, DMSO-d6): δ 6.05 (s,
2H), 7.09 (d, J = 6.0 Hz, 2H), 7.48−7.54 (m, 3H), 7.63−7.69 (m,
3H), 7.95 (d, J = 7.6 Hz, 2H), 8.51 (d, J = 6.8 Hz, 2H), 12.41 (s, 1H).
13C NMR (100 MHz, DMSO-d6): δ 93.6, 101.1, 101.8, 109.8, 111.9,
128.1, 129.0, 129.16, 129.20, 130.35, 130.40, 135.4, 138.7, 139.0,
143.2, 148.5, 157.1, 158.2, 158.3. HRMS: calcd for C23H16N3O2
366.1241 [M + H], found 366.1228.
2,4-Diphenyl-9H-pyrimido[4,5-b]indole (5a).10g Eluent: petroleum
ether/ethyl acetate (10:1). White solid (88 mg, 55%), mp 299−301
°C. 1H NMR (400 MHz, DMSO-d6): δ 7.18 (t, J = 7.2 Hz, 1H), 7.47−
7.58 (m, 5H), 7.66 (d, J = 7.2 Hz, 3H), 7.81 (d, J = 7.6 Hz, 1H), 8.01
(d, J = 6.4 Hz, 2H), 8.55 (d, J = 6.0 Hz, 2H), 12.56 (s, 1H). 13C NMR
(100 MHz, DMSO-d6): δ 109.4, 112.4, 119.3, 121.2, 122.3, 128.0,
128.3, 129.0, 129.3, 129.4, 130.5, 130.7, 138.6, 139.1, 139.6, 157.7,
159.6, 159.9. MS: m/z 322 [M + H]+.
6-Fluoro-2,4-diphenyl-9H-pyrimido[4,5-b]indole (5b). Eluent: pe-
troleum ether/ethyl acetate (10:1). White solid (94 mg, 56%), mp
295−297 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.35−7.45 (m, 2H),
7.52−7.60 (m, 4H), 7.66−7.71 (m, 3H), 7.99 (d, J = 5.6 Hz, 2H),
8.53−8.55 (m, 2H), 12.61 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
δ 107.7, 108.0, 109.3, 113.6, 113.7, 115.6, 115.9, 119.8, 119.9, 128.4,
129.1, 129.27, 129.34, 130.8, 130.9, 136.1, 138.4, 138.7, 156.3, 158.3,
160.3, 160.4. HRMS: calcd for C22H15FN3 340.1250 [M + H], found
340.1242.
7-Fluoro-2,4-diphenyl-9H-pyrimido[4,5-b]indole (5c). Eluent: pe-
troleum ether/ethyl acetate (10:1). White solid (91 mg, 54%), mp
301−302 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.04−7.08 (m, 1H),
7.33−7.35 (m, 1H), 7.52−7.56 (m, 3H), 7.65−7.68 (m, 3H), 7.77−
7.80 (m, 1H), 8.00 (d, J = 5.6 Hz, 2H), 8.54 (d, J = 6.0 Hz, 2H), 12.67
(s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 99.0, 99.2, 109.16,
109.22, 109.4, 116.1, 123.9, 124.0, 128.4, 129.1, 129.26, 129.30, 130.6,
130.8, 138.4, 138.8, 140.5, 140.6, 158.4, 159.3, 159.8, 161.0, 163.5.
HRMS: calcd for C22H15FN3 340.1250 [M + H], found 340.1248.
2,4-Bis(3-fluorophenyl)-9H-pyrimido[4,5-b]indole (5i). Eluent:
petroleum ether/ethyl acetate (10:1). White solid (103 mg, 58%),
1
mp 239−241 °C. H NMR (400 MHz, DMSO-d6): δ 7.19−7.23 (m,
1H), 7.32−7.37 (m, 1H), 7.47−7.56 (m, 2H), 7.58−7.61 (m, 2H),
7.70−7.82 (m, 3H), 7.86 (d, J = 7.6 Hz, 1H), 8.21−8.24 (m, 1H), 8.38
(d, J = 7.6 Hz, 1H), 12.65 (s, 1H). 13C NMR (100 MHz, DMSO-d6):
δ 109.8, 112.6, 114.5, 114.7, 116.0, 116.2, 117.3, 117.46, 117.54, 117.7,
118.9, 121.5, 122.4, 124.3, 125.5, 128.4, 131.1, 131.2, 131.3, 131.4,
139.8, 140.9, 141.0, 141.1, 141.2, 157.6, 158.0, 158.5, 161.6, 161.8,
164.0, 164.2. HRMS: calcd for C22H14F2N3 358.1156 [M + H], found
358.1142.
2,4-Bis(4-chlorophenyl)-9H-pyrimido[4,5-b]indole (5j).10g Eluent:
petroleum ether/ethyl acetate (10:1). White solid (118 mg, 61%), mp
1
319−320 °C. H NMR (400 MHz, DMSO-d6): δ 7.21 (t, J = 7.6 Hz,
1H), 7.52 (t, J = 7.6 Hz, 1H), 7.58−7.61 (m, 3H), 7.74 (d, J = 8.4 Hz,
2H), 7.81 (d, J = 8.4 Hz, 1H), 8.04 (d, J = 8.0 Hz, 2H), 8.53 (d, J = 8.4
Hz, 2H), 12.59 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 109.6,
112.5, 119.1, 121.5, 122.5, 128.2, 129.1, 129.4, 130.0, 131.2, 135.4,
135.6, 137.3, 137.7, 139.7, 157.7, 158.3, 158.8. MS: m/z 390 [M +
H]+.
2,4-Bis(4-bromophenyl)-9H-pyrimido[4,5-b]indole (5k).10g Elu-
ent: petroleum ether/ethyl acetate (10:1). White solid (150 mg,
63%), mp 301−302 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.22 (t, J
= 7.6 Hz, 1H), 7.52 (t, J = 8.0 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.74
(d, J = 8.0 Hz, 2H), 7.81 (d, J = 8.4 Hz, 1H), 7.88 (d, J = 8.4 Hz, 2H),
7.97 (d, J = 8.0 Hz, 2H), 8.46 (d, J = 8.8 Hz, 2H), 12.60 (s, 1H). 13C
H
DOI: 10.1021/acs.joc.5b00239
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NMR (100 MHz, DMSO-d6): δ 109.6, 112.6, 119.1, 121.5, 122.5,
124.1, 124.6, 128.3, 130.3, 131.5, 132.1, 132.3, 137.7, 138.0, 139.8,
157.7, 158.4, 158.9. MS: m/z 478 [M + H]+.
156.5, 157.8. HRMS: calcd for C18H12N3S2 334.0472 [M + H], found
334.0460.
6-Chloro-2,4-bis(4-chlorophenyl)-9H-pyrimido[4,5-b]indole (5s).
Eluent: petroleum ether/ethyl acetate (10:1). White solid (110 mg,
52%), mp 324−326 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.53−7.59
(m, 4H), 7.67 (s, 1H), 7.75 (d, J = 8.4 Hz, 2H), 8.02 (d, J = 8.8 Hz,
2H), 8.49 (d, J = 8.0 Hz, 2H), 12.73 (s, 1H). 13C NMR (100 MHz,
DMSO-d6): δ 108.8, 114.1, 120.3, 121.5, 125.5, 128.0, 129.1, 129.4,
130.0, 131.2, 135.7, 135.8, 137.0, 137.3, 138.2, 157.9, 158.8, 159.3.
HRMS: calcd for C22H13Cl3N3 424.0175 [M + H], found 424.0167.
2,4-Bis(4-methoxyphenyl)-6-(trifluoromethyl)-9H-pyrimido[4,5-
b]indole (5t). Eluent: petroleum ether/ethyl acetate (10:1). White
solid (108 mg, 48%), mp 316−318 °C. 1H NMR (400 MHz, DMSO-
d6): δ 3.83 (s, 3H), 3.89 (s, 3H), 7.07 (d, J = 8.0 Hz, 2H), 7.22 (d, J =
7.6 Hz, 2H), 7.70 (d, J = 8.4 Hz, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.98
(d, J = 8.4 Hz, 2H), 8.12 (s, 1H), 8.48 (d, J = 8.4 Hz, 2H), 12.62 (s,
1H). 13C NMR (100 MHz, DMSO-d6): δ 55.8, 55.9, 108.1, 113.0,
114.4, 114.6, 115.0, 118.9, 119.5, 121.6, 124.0, 126.8, 130.1, 130.8,
130.9, 132.2, 141.4, 158.7, 160.2, 160.7, 161.6, 161.8. HRMS: calcd for
C25H19F3N3O2 450.1429 [M + H], found 450.1423.
2,4-Bis(4-(trifluoromethyl)phenyl)-9H-pyrimido[4,5-b]indole (5l).
Eluent: petroleum ether/ethyl acetate (10:1). White solid (107 mg,
47%), mp 315−317 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.22 (t, J
= 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.61 (d, J = 8.4 Hz, 1H), 7.77
(d, J = 8.4 Hz, 1H), 7.90 (d, J = 8.0 Hz, 2H), 8.05 (d, J = 8.0 Hz, 2H),
8.23 (d, J = 8.0 Hz, 2H), 8.71 (d, J = 7.6 Hz, 2H), 12.72 (s, 1H). 13C
NMR (100 MHz, DMSO-d6): δ 110.3, 112.6, 118.8, 121.6, 122.6,
125.9, 126.0, 126.20, 126.23, 127.8, 128.0, 128.6, 128.8, 128.9, 130.2,
134.1, 140.0, 142.1, 142.7, 148.6, 157.6, 157.9, 158.4, 162.3. HRMS:
calcd for C24H14F6N3 458.1092 [M + H], found 458.1077.
2,4-Di-o-tolyl-9H-pyrimido[4,5-b]indole (5m).10g Eluent: petrole-
um ether/ethyl acetate (10:1). White solid (84 mg, 48%), mp 212−
1
214 °C. H NMR (400 MHz, CDCl3): δ 2.31 (s, 3H), 2.62 (s, 3H),
6.14 (d, J = 7.6 Hz, 1H), 7.06 (t, J = 7.6 Hz, 1H), 7.21 (t, J = 8.0 Hz,
1H), 7.25−7.26 (m, 1H), 7.37−7.51 (m, 6H), 7.55 (d, J = 7.2 Hz,
1H), 7.92 (d, J = 7.2 Hz, 1H), 12.86 (s, 1H). 13C NMR (100 MHz,
CDCl3): δ 19.6, 20.6, 111.1, 111.8, 119.3, 121.1, 122.1, 126.1, 126.3,
127.4, 128.9, 129.0, 129.2, 130.5, 130.7, 131.2, 135.9, 137.0, 137.9,
138.8, 139.6, 156.8, 160.7, 162.9. MS: m/z 350 [M + H]+.
2,4-Bis(4-methoxyphenyl)-7-methyl-9H-pyrimido[4,5-b]indole
(5u). Eluent: petroleum ether/ethyl acetate (10:1). White solid (91
1
2,4-Di-m-tolyl-9H-pyrimido[4,5-b]indole (5n). Eluent: petroleum
mg, 46%), mp 296−298 °C. H NMR (400 MHz, DMSO-d6): δ 2.45
ether/ethyl acetate (10:1). White solid (92 mg, 53%), mp 230−231
(s, 3H), 3.83 (s, 3H), 3.89 (s, 3H), 7.00 (d, J = 8.4 Hz, 1H), 7.07 (d, J
= 8.8 Hz, 2H), 7.21 (d, J = 8.0 Hz, 2H), 7.33 (s, 1H), 7.75 (d, J = 8.0
Hz, 1H), 7.98 (d, J = 8.8 Hz, 2H), 8.47 (d, J = 8.8 Hz, 2H), 12.27 (s,
1H). 13C NMR (100 MHz, DMSO-d6): δ 22.0, 55.7, 55.8, 108.5,
112.3, 114.3, 114.6, 117.3, 122.0, 122.5, 129.8, 130.4, 130.9, 131.5,
137.4, 139.8, 158.0, 158.6, 159.4, 161.2, 161.5. HRMS: calcd for
C25H22N3O2 396.1712 [M + H], found 396.1699.
1
°C. H NMR (400 MHz, DMSO-d6): δ 2.42 (s, 3H), 2.47 (s, 3H),
7.16−7.20 (m, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.40−7.51 (m, 3H), 7.56
(t, J = 7.6 Hz, 2H), 7.77−7.79 (m, 3H), 8.33−8.35 (m, 2H), 12.50 (s,
1H). 13C NMR (100 MHz, DMSO-d6): δ 21.53, 21.66, 109.4, 112.4,
119.4, 121.2, 122.3, 125.6, 126.4, 127.9, 128.87, 128.93, 129.1, 129.8,
131.0, 131.4, 138.1, 138.5, 138.6, 139.1, 139.6, 157.7, 159.9, 160.0.
HRMS: calcd for C24H20N3 350.1657 [M + H], found 350.1669.
2,4-Di-p-tolyl-9H-pyrimido[4,5-b]indole (5o).10g Eluent: petrole-
um ether/ethyl acetate (10:1). White solid (89 mg, 51%), mp 312−
314 °C. 1H NMR (400 MHz, DMSO-d6): δ 2.38 (s, 3H), 2.47 (s, 3H),
7.17 (t, J = 7.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 2H), 7.47−7.50 (m, 3H),
7.56 (d, J = 8.8 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1H), 7.91 (d, J = 7.6 Hz,
2H), 8.43 (d, J = 8.0 Hz, 2H), 12.44 (s, 1H). 13C NMR (100 MHz,
DMSO-d6): δ 21.5, 21.6, 109.1, 112.3, 119.5, 121.1, 122.3, 127.8,
128.3, 129.3, 129.6, 129.7, 136.0, 136.3, 139.5, 140.2, 140.4, 157.8,
159.7, 160.0. MS: m/z 350 [M + H]+.
4. General Procedure for the Preparation of 9H-Pyrido[2,3-
b]indoles 6. To a tube containing a solution of 1-bromo-2-(2,2-
dibromovinyl)benzene (1a) (170 mg, 0.5 mmol) in DMF (3 mL)
were added CuI (9.5 mg, 0.05 mmol), DABCO (11.2 mg, 0.1 mmol),
PivOH (51 mg, 0.5 mmol), acetaldehyde (66 mg, 1.5 mmol), and
aqueous ammonia (3) (26%, 0.5 mL). The tube was sealed, and the
mixture was stirred at 80 °C under an atmosphere of air for 30 h. After
the mixture was cooled to room temperature, the reaction was
quenched with H2O, and the resulting mixture was extracted with ethyl
acetate. The combined organic layers were washed with brine and then
dried over anhydrous Na2SO4. The solvent was evaporated under
vacuum, and the crude product was purified by column chromatog-
raphy on silica gel using petroleum ether/ethyl acetate (10:1) as the
eluent to give 2-methyl-9H-pyrido[2,3-b]indole (6a) (35 mg, 38%).
Other 9H-pyrido[2,3-b]indoles (6b−j) were obtained in a similar
manner.
2,4-Bis(4-methoxyphenyl)-9H-pyrimido[4,5-b]indole (5p).10g Elu-
ent: petroleum ether/ethyl acetate (10:1). White solid (99 mg, 52%),
1
mp 311−313 °C. H NMR (400 MHz, DMSO-d6): δ 3.83 (s, 3H),
3.89 (s, 3H), 7.08 (d, J = 8.8 Hz, 2H), 7.17 (t, J = 7.2 Hz, 1H), 7.22 (d,
J = 8.8 Hz, 2H), 7.44−7.48 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.87 (d,
J = 8.4 Hz, 1H), 7.99 (d, J = 8.8 Hz, 2H), 8.48 (d, J = 8.4 Hz, 2H),
12.40 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 55.7, 55.8, 108.4,
112.2, 114.3, 114.5, 119.6, 121.0, 122.2, 127.5, 129.9, 130.9, 131.1,
131.4, 139.3, 157.8, 159.3, 159.7, 161.2, 161.6. MS: m/z 382 [M +
H]+.
2-Methyl-9H-pyrido[2,3-b]indole (6a).23 Eluent: petroleum ether/
1
ethyl acetate (10:1). White solid (34 mg, 38%), mp 205−206 °C. H
NMR (400 MHz, CDCl3): δ 2.88 (s, 3H), 7.02 (d, J = 5.2 Hz, 1H),
7.30 (t, J = 7.2 Hz, 1H), 7.50 (t, J = 7.2 Hz, 1H), 7.56 (d, J = 7.6 Hz,
1H), 8.12 (d, J = 8.0 Hz, 1H), 8.38 (d, J = 8.8 Hz, 1H), 10.46 (s, 1H).
13C NMR (100 MHz, CDCl3): δ 23.0, 111.8, 115.1, 120.8, 121.0,
127.4, 129.4, 129.6, 131.0, 138.4, 149.3, 151.7. MS: m/z 183 [M +
H]+.
2,4-Bis(naphthalen-1-yl)-9H-pyrimido[4,5-b]indole (5q). Eluent:
petroleum ether/ethyl acetate (10:1). White solid (97 mg, 46%), mp
305−306 °C. 1H NMR (400 MHz, DMSO-d6): δ 6.81 (d, J = 8.0 Hz,
1H), 6.97 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 8.0 Hz, 2H), 7.52−7.55 (m,
2H), 7.58 (t, J = 7.6 Hz, 2H), 7.65 (t, J = 7.6 Hz, 1H), 7.75−7.78 (m,
2H), 7.88 (d, J = 7.2 Hz, 1H), 7.99−8.02 (m, 1H), 8.05 (d, J = 8.4 Hz,
1H), 8.11 (d, J = 8.4 Hz, 1H), 8.17−8.21 (m, 2H), 8.88−8.90 (m,
1H), 12.68 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 111.5, 112.1,
119.1, 121.0, 122.6, 123.6, 125.4, 125.57, 125.62, 125.9, 126.1, 126.2,
126.8, 127.0, 127.3, 128.4, 128.50, 128.52, 129.2, 129.9, 130.7, 131.5,
133.8, 134.2, 135.9, 137.2, 138.7, 157.0, 159.8, 162.4. HRMS: calcd for
C30H20N3 422.1657 [M + H], found 422.1642.
2,4-Bis(thiophen-2-yl)-9H-pyrimido[4,5-b]indole (5r). Eluent: pe-
troleum ether/ethyl acetate (10:1). White solid (67 mg, 40%), mp
317−319 °C. 1H NMR (400 MHz, DMSO-d6): δ 7.21−7.24 (m, 1H),
7.28 (t, J = 7.6 Hz, 1H), 7.38−7.40 (m, 1H), 7.50−7.57 (m, 2H), 7.74
(d, J = 5.6 Hz, 1H), 7.95 (d, J = 4.8 Hz, 1H), 7.99−8.00 (m, 1H), 8.13
(d, J = 4.0 Hz, 1H), 8.28 (d, J = 8.0 Hz, 1H), 12.59 (s, 1H). 13C NMR
(100 MHz, DMSO-d6): δ 107.6, 112.4, 119.3, 121.5, 122.4, 128.0,
128.7, 128.8, 128.9, 129.8, 130.6, 131.2, 139.5, 142.3, 144.1, 152.9,
2-Ethyl-3-methyl-9H-pyrido[2,3-b]indole (6b). Eluent: petroleum
ether/ethyl acetate (10:1). White solid (45 mg, 43%), mp 214−216
°C. 1H NMR (400 MHz, CDCl3): δ 1.39 (t, J = 7.6 Hz, 3H), 2.50 (s,
3H), 3.02 (q, J = 7.2 Hz, 2H), 7.22−7.24 (m, 1H), 7.43 (t, J = 7.6 Hz,
1H), 7.50 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 8.0 Hz, 1H), 8.09 (s, 1H),
9.88 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 13.5, 19.0, 29.0, 111.0,
114.2, 119.7, 120.6, 121.2, 122.1, 126.0, 130.0, 138.6, 150.8, 158.8.
HRMS: calcd for C14H15N2 211.1235 [M + H], found 211.1240.
3-Ethyl-2-propyl-9H-pyrido[2,3-b]indole (6c). Eluent: petroleum
ether/ethyl acetate (10:1). White solid (55 mg, 46%), mp 173−175
°C. 1H NMR (400 MHz, CDCl3): δ 1.06 (t, J = 7.2 Hz, 3H), 1.35 (t, J
= 7.2 Hz, 3H), 1.80−1.90 (m, 2H), 2.85 (q, J = 8.0 Hz, 2H), 2.98 (t, J
= 8.0 Hz, 2H), 7.25 (t, J = 7.2 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.49
(d, J = 7.6 Hz, 1H), 8.02 (d, J = 7.2 Hz, 1H), 8.13 (s, 1H), 9.75 (s,
1H). 13C NMR (100 MHz, CDCl3): δ 14.3, 15.8, 23.5, 25.5, 37.2,
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111.0, 114.6, 119.8, 120.6, 121.3, 126.2, 128.7, 138.6, 150.4, 156.9.
HRMS: calcd for C16H19N2 239.1548 [M + H], found 239.1540.
2-Isobutyl-3-isopropyl-9H-pyrido[2,3-b]indole (6d). Eluent: petro-
leum ether/ethyl acetate (10:1). White solid (56 mg, 42%), mp 206−
207 °C. 1H NMR (400 MHz, CDCl3): δ 1.08 (d, J = 6.8 Hz, 6H), 1.40
(d, J = 6.8 Hz, 6H), 2.20−2.28 (m, 1H), 3.19 (d, J = 7.2 Hz, 2H),
3.41−3.48 (m, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H),
7.57 (d, J = 8.0 Hz, 1H), 8.08 (d, J = 8.0 Hz, 1H), 8.46 (s, 1H), 11.00
(s, 1H). 13C NMR (100 MHz, CDCl3): δ 22.6, 24.6, 27.1, 29.0, 37.4,
111.2, 114.8, 119.5, 121.4, 123.0, 125.8, 134.1, 139.1, 143.4, 143.8,
150.7. HRMS: calcd for C18H23N2 267.1861 [M + H], found
267.1846.
3-Benzyl-2-phenethyl-9H-pyrido[2,3-b]indole (6e). Eluent: petro-
leum ether/ethyl acetate (10:1). White solid (94 mg, 52%), mp 200−
202 °C. 1H NMR (400 MHz, DMSO-d6): δ 2.86−2.90 (m, 2H),
3.02−3.06 (m, 2H), 4.11 (s, 2H), 7.11−7.28 (m, 10H), 7.37−7.39 (m,
1H), 7.44 (d, J = 7.2 Hz, 1H), 8.04 (d, J = 7.6 Hz, 1H), 8.27 (s, 1H),
11.63 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 35.3, 37.4, 38.4,
111.6, 113.7, 119.6, 120.9, 121.2, 125.3, 126.2, 126.4, 126.5, 128.73,
128.74, 128.87, 128.89, 130.7, 139.4, 141.5, 142.4, 151.2, 156.7.
HRMS: calcd for C26H23N2 363.1861 [M + H], found 363.1851.
3-Ethyl-7-fluoro-2-propyl-9H-pyrido[2,3-b]indole (6f). Eluent: pe-
troleum ether/ethyl acetate (10:1). White solid (59 mg, 46%), mp
192−194 °C. 1H NMR (400 MHz, CDCl3): δ 1.06 (t, J = 7.2 Hz, 3H),
1.34 (t, J = 7.6 Hz, 3H), 1.64−1.71 (m, 2H), 2.84 (q, J = 7.2 Hz, 2H),
2.96 (t, J = 7.6 Hz, 2H), 6.97 (t, J = 8.8 Hz, 1H), 7.17 (d, J = 9.2 Hz,
1H), 7.90−7.94 (m, 1H), 8.06 (s, 1H), 10.01 (s, 1H). 13C NMR (100
MHz, CDCl3): δ 14.2, 15.8, 23.6, 25.5, 37.3, 97.8, 98.1, 107.7, 108.0,
114.1, 117.7, 121.5, 121.6, 128.1, 129.1, 139.2, 139.4, 148.2, 151.0,
156.6, 160.8, 163.2. HRMS: calcd for C16H18FN2 257.1454 [M + H],
found 257.1475.
NMR (400 MHz, DMSO-d6): δ 7.02 (t, J = 7.6 Hz, 1H), 7.09 (d, J =
5.2 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.51−7.63 (m, 5H), 7.66−7.68
(m, 2H), 8.45 (d, J = 5.2 Hz, 1H), 12.00 (s, 1H). 13C NMR (100
MHz, DMSO-d6): δ 111.8, 112.6, 116.4, 119.6, 120.2, 122.3, 127.0,
128.9, 129.2, 129.3, 139.0, 139.5, 144.7, 146.5, 152.8. MS: m/z 245 [M
+ H]+.
5. Preparation of 2-(2,2-Dibromovinyl)aniline (III).11a
To a flask containing a solution of 2-nitrobenzaldehyde (1.51g, 10
mmol) and CBr4 (4.97 g, 15 mmol) in DCM (50 mL) at 0 °C was
added dropwise a solution of PPh3 (7.86 g, 30 mmol) in DCM (15
mL). Then the mixture was stirred for another 0.5 h, warmed to room
temperature, and stirred for an additional 0.5 h. Next, diethyl ether (50
mL) was added to the reaction mixture, which was then filtered
through a short plug of Celite and washed with diethyl ether (10 mL).
The filtrates were concentrated under vacuum, and EtOH (50 mL)
and SnCl2 (13.3 g, 70 mmol) were added to the crude product. The
suspension was then placed into a preheated oil bath with stirring at
100 °C for 1 h. Upon completion of the reaction as monitored by
TLC, the reaction flask was allowed to cool to room temperature.
After most of the ethanol was removed under vacuum, H2O (30 mL)
and EtOAc (30 mL) were added to the residue. Solid K2CO3 was
carefully added to the resulting mixture until pH was above 10. The
EtOAc layer was separated from the heterogeneous mixture, and the
aqueous phase was extracted with EtOAc. The combined organic
layers were washed with brine and then dried over anhydrous Na2SO4.
The solvent was evaporated under vacuum, and the crude product was
purified by column chromatography on silica gel using petroleum
ether/ethyl acetate (5:1) as the eluent to give 2-(2,2-dibromovinyl)-
aniline (III) (2.3 g, 83% over two steps) as a white solid (mp 41−42
°C). 1H NMR (400 MHz, CDCl3): δ 3.71 (br, s, 2H), 6.71 (d, J = 8.0
Hz, 1H), 6.79 (t, J = 7.6 Hz, 1H), 7.17 (t, J = 7.6 Hz, 1H), 7.31 (d, J =
8.0 Hz, 1H), 7.34 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 92.8,
115.8, 118.4, 121.8, 129.2, 129.7, 134.1, 143.7. MS: m/z 278 [M +
H]+.
6-Chloro-3-ethyl-2-propyl-9H-pyrido[2,3-b]indole (6g). Eluent:
petroleum ether/ethyl acetate (10:1). White solid (64 mg, 47%), mp
214−216 °C. 1H NMR (400 MHz, CDCl3): δ 1.18 (t, J = 7.2 Hz, 3H),
1.31 (t, J = 7.2 Hz, 3H), 1.76−1.85 (m, 2H), 2.84 (q, J = 7.2 Hz, 2H),
3.15 (t, J = 8.0 Hz, 2H), 7.41−7.46 (m, 2H), 7.97 (s, 1H), 8.30 (s,
1H), 10.02 (s, 1H). 13C NMR (100 MHz, CDCl3): δ 14.5, 16.6, 22.4,
23.0, 31.3, 112.1, 114.0, 122.28, 122.30, 125.2, 126.0, 129.5, 137.2,
145.5, 146.9, 151.5. HRMS: calcd for C16H18ClN2 273.1158 [M + H],
found 273.1166.
6. Preparation of 2-Bromoindole (IX).11b
3-Ethyl-2-propyl-6-(trifluoromethyl)-9H-pyrido[2,3-b]indole (6h).
Eluent: petroleum ether/ethyl acetate (10:1). White solid (75 mg,
1
49%), mp 227−229 °C. H NMR (400 MHz, CDCl3): δ 1.05 (t, J =
7.2 Hz, 3H), 1.36 (t, J = 7.6 Hz, 3H), 1.80−1.90 (m, 2H), 2.86 (q, J =
7.6 Hz, 2H), 3.02 (t, J = 8.0 Hz, 2H), 7.57 (d, J = 8.8 Hz, 1H), 7.68 (d,
J = 8.8 Hz, 1H), 8.18 (s, 1H), 8.30 (s, 1H), 10.80 (s, 1H). 13C NMR
(100 MHz, CDCl3): δ 14.1, 15.6, 23.5, 25.4, 37.3, 111.0, 114.1, 118.09,
118.13, 118.17, 118.21, 120.9, 121.8, 122.1, 122.8, 112.9, 128.9, 129.6,
140.3, 151.0, 158.2. HRMS: calcd for C17H18F3N2 307.1422 [M + H],
found 307.1426.
3-Ethyl-6-methoxy-2-propyl-9H-pyrido[2,3-b]indole (6i). Eluent:
petroleum ether/ethyl acetate (10:1). White solid (55 mg, 41%), mp
246−248 °C. 1H NMR (400 MHz, CDCl3): δ 1.06 (t, J = 7.2 Hz, 3H),
1.34 (t, J = 7.6 Hz, 3H), 1.81−1.91 (m, 2H), 2.83 (q, J = 8.0 Hz, 2H),
2.98 (t, J = 8.0 Hz, 2H), 3.91 (s, 3H), 7.09−7.12 (m, 1H), 7.42 (d, J =
8.8 Hz, 1H), 7.49 (s, 1H), 8.20 (s, 1H), 10.06 (s, 1H). 13C NMR (100
MHz, CDCl3): δ 14.1, 15.6, 23.3, 25.1, 35.9, 56.0, 103.7, 112.4, 116.1,
116.3, 121.0, 128.2, 130.7, 133.4, 148.4, 153.8, 154.6. HRMS: calcd for
C17H21N2O 269.1654 [M + H], found 269.1676.
To a tube equipped with a magnetic stir bar were added 2-(2,2-
dibromovinyl)aniline (III) (277 mg, 1 mmol), Pd(OAc)2 (11.2 mg,
0.05 mmol), P(t-Bu)3·HBF4 (17.4 mg, 0.06 mmol), and K2CO3 (276
mg, 2 mmol). The tube was flushed with nitrogen three times, after
which toluene (3 mL) was added and the tube was sealed. The mixture
in the tube was stirred at room temperature for 5 min, and then the
tube was placed into a preheated oil bath at 100 °C. After 14 h of
stirring, the reaction tube was allowed to cool to room temperature.
Then the reaction was quenched with H2O, and the resulting mixture
was extracted with ethyl acetate. The combined organic layers were
washed with brine and then dried over anhydrous Na2SO4. The
solvent was evaporated under vacuum, and the crude product was
purified by column chromatography on silica gel using petroleum
ether/ethyl acetate (5:1) as the eluent to give 2-bromoindole (IX)
(166 mg, 85%) as a white solid (mp 81−83 °C). 1H NMR (400 MHz,
CDCl3): δ 6.69 (s, 1H), 7.25 (d, J = 7.6 Hz, 1H), 7.30−7.37 (m, 2H),
7.71 (d, J = 7.6 Hz, 1H), 7.80 (dr, 1H). 13C NMR (100 MHz, CDCl3):
δ 105.0, 109.1, 110.8, 119.9, 120.8, 122.5, 128.9, 136.6. MS: m/z 196
[M + H]+.
8-Ethyl-7-propyl-5H-[1,3]dioxolo[4,5-b]carbazole (6j). Eluent:
petroleum ether/ethyl acetate (10:1). White solid (62 mg, 44%), mp
265−267 °C. 1H NMR (400 MHz, CDCl3): δ 1.09 (t, J = 7.2 Hz, 3H),
1.36 (t, J = 7.6 Hz, 3H), 1.91−2.01 (m, 2H), 2.85 (q, J = 7.6 Hz, 2H),
3.08 (t, J = 7.6 Hz, 2H), 6.09 (s, 2H), 7.08 (s, 1H), 7.38 (s, 1H), 8.33
(s, 1H), 11.6 (s, 1H). 13C NMR (100 MHz, DMSO-d6): δ 14.5, 16.1,
22.8, 25.3, 36.8, 92.8, 100.4, 101.1, 113.7, 121.1, 127.3, 127.8, 134.6,
142.1, 147.1, 150.5, 154.8. HRMS: calcd for C18H20NO2 282.1494 [M
+ H], found 282.1481.
7. Preparation of 2-Benzyl-5-phenylpent-2-enal.
To a flask containing a solution of 3-phenylpropanal (670 mg, 5
mmol) in CH3CN (20 mL) was added NaOH (80 mg, 2 mmol), then
the mixture was stirred at room temperature for 1.5 h. Upon
2-Phenyl-9H-pyrido[2,3-b]indole (6k).21j Eluent: petroleum ether/
1
ethyl acetate (5:1). White solid (61 mg, 50%), mp 244−246 °C. H
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completion of the reaction, the mixture was concentrated, treated with
saturated aqueous NH4Cl, and extracted with ethyl acetate. The
combined organic layers were washed with brine and then dried over
anhydrous Na2SO4. The solvent was evaporated under vacuum, and
the crude product was purified by column chromatography on silica
gel using petroleum ether/ethyl acetate (50:1) as the eluent to give 2-
benzyl-5-phenylpent-2-enal (550 mg, 88%) as a faint-yellow liquid. 1H
NMR (400 MHz, CDCl3): δ 2.80−2.85 (m, 4H), 3.68 (s, 2H), 6.69 (t,
J = 6.8 Hz, 1H), 7.21−7.41 (m, 10H), 9.52 (s, 1H). 13C NMR (100
MHz, CDCl3): δ 29.7, 31.1, 34.5, 126.2, 126.5, 128.4, 128.5, 128.6,
128.7, 139.2, 140.6, 142.8, 154.9, 194.7. MS: m/z 251 [M + H]+.
8. Preparation of 4a from the Reaction of III, 2a, and 3 under
Condition A. To a tube containing a solution of 2-(2,2-
dibromovinyl)aniline (III) (138 mg, 0.5 mmol) in DMF (1.5 mL)
were added CuI (9.5 mg, 0.05 mmol), DABCO (11.2 mg, 0.1 mmol),
PivOH (51 mg, 0.5 mmol), benzaldehyde (2a) (106 mg, 1 mmol), and
aqueous ammonia (3) (26%, 1.5 mL). The tube was sealed, and the
mixture was stirred at 80 °C under an atmosphere of air for 20 h. After
the mixture was cooled to room temperature, the reaction was
quenched with H2O, and the resulting mixture was extracted with ethyl
acetate. The combined organic layers were washed with brine and then
dried over anhydrous Na2SO4. The solvent was evaporated under
vacuum, and the crude product was purified by column chromatog-
raphy on silica gel using petroleum ether/ethyl acetate (5:1) as the
eluent to give 2-phenyl-1H-indole-3-carbonitrile (4a) (82.8 mg, 76%).
9. Preparation of 5a from the Reaction of III, 2a, and 3 under
Condition B. To a tube containing a solution of 2-(2,2-
dibromovinyl)aniline (III) (138 mg, 0.5 mmol) in DMF (3 mL)
were added CuI (9.5 mg, 0.05 mmol), DABCO (11.2 mg, 0.1 mmol),
PivOH (51 mg, 0.5 mmol), benzaldehyde (2a) (159 mg, 1.5 mmol),
and aqueous ammonia (3) (26%, 0.5 mL). The tube was sealed, and
the mixture was stirred at 80 °C under an atmosphere of air for 25 h.
After the mixture was cooled to room temperature, the reaction was
quenched with H2O, and the resulting mixture was extracted with ethyl
acetate. The combined organic layers were washed with brine and then
dried over anhydrous Na2SO4. The solvent was evaporated under
vacuum, and the crude product was purified by column chromatog-
raphy on silica gel using petroleum ether/ethyl acetate (10:1) as the
eluent to give 2,4-diphenyl-9H-pyrimido[4,5-b]indole (5a) (109 mg,
68%).
12. Preparation of 6e from the Reaction of IX, 2-Benzyl-5-
phenylpent-2-enal, and 3 under Condition B. To a tube
containing a solution of 2-benzyl-5-phenylpent-2-enal (188 mg, 0.75
mmol) in DMF (3 mL) were added CuI (9.5 mg, 0.05 mmol),
DABCO (11.2 mg, 0.1 mmol), PivOH (51 mg, 0.5 mmol), 2-
bromoindole (IX) (98 mg, 0.5 mmol), and aqueous ammonia (3)
(26%, 0.5 mL). The tube was sealed, and the mixture was stirred at 80
°C under air for 18 h. After the mixture was cooled to room
temperature, the reaction was quenched with H2O, and the resulting
mixture was extracted with ethyl acetate. The combined organic layers
were washed with brine and then dried over anhydrous Na2SO4. The
solvent was evaporated under vacuum, and the crude product was
purified by column chromatography on silica gel using petroleum
ether/ethyl acetate (10:1) as the eluent to give 3-benzyl-2-phenethyl-
9H-pyrido[2,3-b]indole (6e) (132 mg, 73%).
13. Preparation of 1-Boc-4p.
To facilitate crystallization, 2-(4-methoxyphenyl)-1H-indole-3-carbon-
itrile (4p) was transformed into its Boc derivative 1-Boc-4p. To a flask
containing a solution of 4p (248 mg, 1 mmol) in THF (4 mL) were
added di-tert-butyl dicarbonate (240 mg, 1.1 mmol) and DMAP (12
mg, 0.1 mmol). The mixture was stirred at room temperature for 2 h.
Upon completion of the reaction, the mixture was concentrated. To
the residue were added H2O and ethyl acetate. The organic layer was
separated, washed with brine, and then dried over anhydrous Na2SO4.
The solvent was evaporated under vacuum, and the crude product was
purified by column chromatography on silica gel using petroleum
ether/ethyl acetate (20:1) as the eluent to give tert-butyl 3-cyano-2-(4-
methoxyphenyl)-1H-indole-1-carboxylate (1-Boc-4p) (327 mg, 94%)
as a white solid (mp 125−127 °C). Single crystals of 1-Boc-4p were
grown from chloroform/petroleum ether (4:1) by slow evaporation.
1H NMR (400 MHz, CDCl3): δ 1.35 (s, 9H), 3.88 (s, 3H), 7.03 (dd, J1
= 6.8 Hz, J2 = 2.4 Hz, 2H), 7.37−7.45 (m, 4H), 7.70−7.72 (m, 1H),
8.17−8.19 (m, 1H). 13C NMR (100 MHz, CDCl3): δ 27.4, 55.4, 85.3,
93.3, 113.8, 115.1, 115.4, 119.2, 123.2, 124.3, 125.9, 127.2, 130.4,
135.8, 147.7, 148.9, 160.6. MS: m/z 349 [M + H]+.
10. Preparation of 5a from the Reaction of IX, 2a, and 3
under Condition B. To a tube containing a solution of benzaldehyde
(2a) (159 mg, 1.5 mmol) in DMF (3 mL) were added CuI (9.5 mg,
0.05 mmol), DABCO (11.2 mg, 0.1 mmol), PivOH (51 mg, 0.5
mmol), 2-bromoindole (IX) (98 mg, 0.5 mmol), and aqueous
ammonia (3) (26%, 0.5 mL). The tube was sealed, and the mixture
was stirred at 80 °C under an atmosphere of air for 18 h. After the
mixture was cooled to room temperature, the reaction was quenched
with H2O, and the resulting mixture was extracted with ethyl acetate.
The combined organic layers were washed with brine and then dried
over anhydrous Na2SO4. The solvent was evaporated under vacuum,
and the crude product was purified by column chromatography on
silica gel using petroleum ether/ethyl acetate (10:1) as the eluent to
give 2,4-diphenyl-9H-pyrimido[4,5-b]indole (5a) (128 mg, 80%).
11. Preparation of 6e from the Reaction of 1a, 2-Benzyl-5-
phenylpent-2-enal, and 3 under Condition B. To a tube
containing a solution of 1-bromo-2-(2,2-dibromovinyl)benzene (1a)
(170 mg, 0.5 mmol) in DMF (3 mL) were added CuI (9.5 mg, 0.05
mmol), DABCO (11.2 mg, 0.1 mmol), PivOH (51 mg, 0.5 mmol), 2-
benzyl-5-phenylpent-2-enal (188 mg, 0.75 mmol), and aqueous
ammonia (3) (26%, 0.5 mL). The tube was sealed, and the mixture
was stirred at 80 °C under air for 25 h. After the mixture was cooled to
room temperature, the reaction was quenched with H2O, and the
resulting mixture was extracted with ethyl acetate. The combined
organic layers were washed with brine and then dried over anhydrous
Na2SO4. The solvent was evaporated under vacuum, and the crude
product was purified by column chromatography on silica gel using
petroleum ether/ethyl acetate (10:1) as the eluent to give 3-benzyl-2-
phenethyl-9H-pyrido[2,3-b]indole (6e) (103 mg, 57%).
14. Preparation of 9-Boc-6e.
To facilitate crystallization, 3-benzyl-2-phenethyl-9H-pyrido[2,3-b]-
indole (6e) was transformed into its Boc derivative 9-Boc-6e. To a
flask containing a solution of 6e (180 mg, 0.5 mmol) in THF (2 mL)
were added di-tert-butyl dicarbonate (120 mg, 0.55 mmol) and DMAP
(6 mg, 0.05 mmol). The mixture was stirred at room temperature for 2
h. Upon completion of the reaction, the mixture was concentrated. To
the residue were added H2O and ethyl acetate. The organic layer was
separated, washed with brine, and then dried over anhydrous Na2SO4.
The solvent was evaporated under vacuum, and the crude product was
purified by column chromatography on silica gel using petroleum
ether/ethyl acetate (20:1) as the eluent to give tert-butyl 3-benzyl-2-
phenethyl-9H-pyrido[2,3-b]indole-9-carboxylate (9-Boc-6e) (210 mg,
91%) as a white solid (mp 109−111 °C). Single crystals of 9-Boc-6e
were grown from chloroform/petroleum ether (3:1) by slow
1
evaporation. H NMR (400 MHz, CDCl3): δ 1.79 (s, 9H), 3.09−
3.13 (m, 2H), 3.16−3.20 (m, 2H), 4.07 (s, 2H), 7.09 (d, J = 7.2 Hz,
2H), 7.14 (d, J = 6.8 Hz, 2H), 7.18−7.30 (m, 6H), 7.34 (d, J = 7.2 Hz,
1H), 7.47−7.51 (m, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.92 (s, 1H), 8.39
(d, J = 8.0 Hz, 1H). 13C NMR (100 MHz, CDCl3): δ 28.5, 35.2, 37.6,
K
DOI: 10.1021/acs.joc.5b00239
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The Journal of Organic Chemistry
Article
38.5, 83.7, 116.2, 116.7, 119.9, 122.7, 123.0, 125.8, 126.3, 127.4, 128.3,
128.56, 128.59, 128.7, 128.8, 129.5, 138.2, 140.0, 142.3, 149.8, 150.5,
157.6. MS: m/z 463 [M + H]+.
Miller, D. D. Curr. Med. Chem. 2011, 18, 615. (c) Cacchi, S.; Fabrizi,
G.; Goggiamani, A. Org. Biomol. Chem. 2011, 9, 641.
(6) (a) Traxler, P. M.; Furet, P.; Mett, H.; Buchdunger, E.; Meyer, T.;
Lydon, N. J. Med. Chem. 1996, 39, 2285. (b) Showalter, H. D. H.;
Bridges, A. J.; Zhou, H.; Sercel, A. D.; McMichael, A.; Fry, D. W. J.
Med. Chem. 1999, 42, 5464. (c) Tichy, M.; Pohl, R.; Xu, H. Y.; Chen,
Y. L.; Yokokawa, F.; Shi, P. Y.; Hocek, M. Bioorg. Med. Chem. 2012, 20,
6123.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra and X-ray crystallographic
data (CIF). The Supporting Information is available free of
charge on the ACS Publications website at DOI: 10.1021/
acs.joc.5b00239.
(7) (a) Swain, C. J.; Baker, R.; Kneen, C.; Moseley, J.; Saunders, J.;
Seward, E. M.; Stevenson, G.; Beer, M.; Stanton, J.; Watling, K. J. Med.
Chem. 1991, 34, 140. (b) Kumar, D.; Kumar, N. M.; Chang, K. H.;
Gupta, R.; Shah, K. Bioorg. Med. Chem. Lett. 2011, 21, 5897. (c) Wu,
S.; Wang, L.; Guo, W.; Liu, X.; Liu, J.; Wei, X.; Fang, B. J. Med. Chem.
2011, 54, 2668.
(8) (a) Okamoto, A.; Tanaka, K.; Fukuta, T.; Saito, I. J. Am. Chem.
Soc. 2003, 125, 9296. (b) Okamoto, A.; Tanaka, K.; Nishiza, K.; Saito,
I. Bioorg. Med. Chem. 2004, 12, 5875. (c) Okamoto, A.; Kamei, T.;
Saito, I. J. Am. Chem. Soc. 2006, 128, 658.
AUTHOR INFORMATION
■
Corresponding Authors
*E-mail: xuesen.fan@htu.cn.
*E-mail: xinyingzhang@htu.cn.
Notes
(9) For recent examples of the preparation of 3-cyanoindoles, see:
(a) Swamy, N. K.; Yazici, A.; Pyne, S. G. J. Org. Chem. 2010, 75, 3412.
(b) Yan, G.; Kuang, C.; Zhang, Y.; Wang, J. Org. Lett. 2010, 12, 1052.
(c) Ding, S.; Jiao, N. J. Am. Chem. Soc. 2011, 133, 12374. (d) Peng, J.;
Zhao, J.; Hu, Z.; Liang, D.; Huang, J.; Zhu, Q. Org. Lett. 2012, 14,
4966. (e) Bobko, M. A.; Evans, K. A.; Kaura, A. C.; Shuster, L. E.; Su,
D. S. Tetrahedron Lett. 2012, 53, 200. (f) Zhang, L.; Wen, Q.; Jin, J.;
Wang, C.; Lu, P.; Wang, Y. Tetrahedron 2013, 69, 4236. (g) Yuen, O.
Y.; Choy, P. Y.; Chow, W. K.; Wong, W. T.; Kwong, F. Y. J. Org. Chem.
2013, 78, 3374 and references cited therein. (h) Li, X.; Du, Y.; Liang,
Z.; Li, X.; Pan, Y.; Zhao, K. Org. Lett. 2009, 11, 2643.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the National Natural Science Foundation of
China (Grants 21272058 and 21172057), the Program for
Innovative Research Team in Science and Technology in
University of Henan Province (15IRTSTHN 003), the
Program for Science and Technology Innovation Talents in
Universities of Henan Province (15HASTIT005), and PCSIRT
(IRT 1061) for financial support.
(10) For the preparation of pyrimido[4,5-b]indoles, see: (a) Hyatt, J.
A.; Swenton, J. S. J. Org. Chem. 1972, 37, 3216. (b) Venugopalan, B.;
Desai, P. D.; de Souza, N. J. J. Heterocycl. Chem. 1988, 25, 1633.
(c) Hubschwerlen, C.; Pflieger, P.; Specklin, J.-L.; Gubernator, K.;
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