One-step synthesis of 2-amino-5h-pyrimido[5,4-b]indoles, substituted 2-(1,3,5-triazin-2-yl)-1h-indoles, and 1,3,5-triazines from aldehydes

Article abstract of DOI:10.1002/ejoc.201200276

An efficient one-step synthesis of 2-amino-5H-pyrimido[5,4-b]indoles through a copper-catalyzed cascade reaction between 3-haloindole-2-carbaldehydes and guanidine hydrochloride is described. In contrast, the base-mediated reactions of either 3-haloindole-2-carbaldehydes or substituted indole-2-carbaldehydes with substituted amidine hydrochlorides in DMSO result in the formation of 2-(1,3,5-triazin-2-yl)-1H-indole derivatives in one step in excellent yields. Studies toward exploring the utility of the method demonstrate that even substituted benzaldehydes undergo a similar reaction to efficiently yield 2,4,6-trisubstituted 1,3,5-triazines. A plausible mechanism for the formation of substituted 1,3,5-triazines identifies the role of DMSO as an oxidant during the reaction. The synthesis of 2-amino-5H-pyrimido[5,4-b]indoles from 3-haloindole-2-carbaldehyde and guanidine hydrochloride is described. In contrast, 3-haloindole-2-carbaldehydes or indole-2-carbaldehydes react with substituted amidine hydrochlorides to give 2-(1,3,5-triazin-2-yl)-1H-indole derivatives in excellent yields. The latter protocol was used to prepare 2,4,6-trisubstituted 1,3,5-triazines.

Full text of DOI:10.1002/ejoc.201200276

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DOI: 10.1002/ejoc.201200276
One-Step Synthesis of 2-Amino-5H-pyrimido[5,4-b]indoles, Substituted
2-(1,3,5-triazin-2-yl)-1H-indoles, and 1,3,5-Triazines from Aldehydes[‡]
Subhasish Biswas[a] and Sanjay Batra*[a]
Keywords: Nitrogen heterocycles / Fused-ring systems / Synthetic methods / Copper
Anefficientone-stepsynthesisof2-amino-5H-pyrimido[5,4-b]-
indoles through a copper-catalyzed cascade reaction be-
tween 3-haloindole-2-carbaldehydes and guanidine hydro-
chloride is described. In contrast, the base-mediated reac-
tions of either 3-haloindole-2-carbaldehydes or substituted
indole-2-carbaldehydes with substituted amidine hydro-
chlorides in DMSO result in the formation of 2-(1,3,5-triazin-
2-yl)-1H-indole derivatives in one step in excellent yields.
Studies toward exploring the utility of the method demon-
strate that even substituted benzaldehydes undergo a similar
reaction to efficiently yield 2,4,6-trisubstituted 1,3,5-tri-
azines. A plausible mechanism for the formation of substi-
tuted 1,3,5-triazines identifies the role of DMSO as an oxi-
dant during the reaction.
action between guanidine and N-acetylindole-3-one.[8,9]
These routes, however, result in 5H-pyrimido[5,4-b]indoles
which are either substituted at the 4-position or both the 2-
and 4-positions simultaneously.
Introduction
Fused indoles constitute one of the largest family of or-
ganic compounds, as they are represented in numerous nat-
ural alkaloids, pharmaceuticals, and agrochemicals.[1] Ow-
ing to their significant relevance, there is continued interest
in the development of newer approaches to the syntheses
of fused indoles.[2] Amongst these approaches, transition-
metal-catalyzed processes have proved complementary to
the conventional protocols and have allowed the reactions
to be performed under relatively mild conditions. In an on-
going project in our lab, we have successfully employed sub-
stituted indole-2-carbaldehydes and their derivatives to such
protocols to synthesize indole-fused pyridine, diazocine,
quinoxaline, and benzodiazepine.[3] More recently, we re-
ported a facile and efficient synthesis of pyrazolo[4,3-d]-
pyrimidines through a copper-catalyzed cascade reaction
between 4-iodopyrazole-3-carbaldehydes and substituted
amidines.[4] Essentially, to extend the scope of this protocol,
we envisage that reacting guanidine or substituted amidines
with 3-haloindole-2-carbaldehydes under identical condi-
tions should lead to 2-substituted 5H-pyrimido[5,4-b]-
indoles (Figure 1), which is the core framework of com-
pounds associated with a variety of biological properties
such as PDE inhibition, ionotropic and chronotropic activi-
ties, and benzodiazepine receptor binding activity.[5–7] The
general routes to this core involve either the condensation
of formamide with 3-aminoindole-2-carboxylate or the re-
Figure 1. Retrosynthetic analysis for the synthesis of substituted
5H-pyrimido[5,4-b]indoles.
It is worthwhile to mention that there exists only one
report describing the preparation of 2-substituted 5H-pyr-
imido[5,4-b]indoles, achieved in 8–10 steps (Figure 2).[7] De-
spite this, we decided to test our protocol for the synthesis
of 2-substituted 5H-pyrimido[5,4-b]indoles. Although the
reaction of 3-haloindole-2-carbaldehydes with guanidine
hydrochloride gave the expected 5H-pyrimido[5,4-b]indol-2-
amines, it was surprising to discover that a similar reaction
with substituted amidines resulted in substituted 2-(1,3,5-
triazin-2-yl)-1H-indoles. Furthermore, copper was not es-
sential for both reactions, although the formation of 2-
amino-5H-pyrimido[5,4-b]indoles was facilitated by its
presence. As the formation of the 2-(1,3,5-triazin-2-yl)-1H-
indoles did not involve a halo group at the 3-position of the
indole, the methodology was successful with simple substi-
tuted indole-2-carbaldehydes, and the application of the
method was extended to substituted benzaldehydes. A lit-
erature search for a similar precedence revealed that substi-
tuted benzaldehydes have been treated with benzamidine
hydrochloride under basic conditions to give substituted
1,3,5-dihydrotriazines.[10] Studies into a plausible mecha-
nism for the formation of the 1,3,5-triazines emphasized the
[‡] CDRI Communication No. 8236
[a] Medicinal and Process Chemistry Division, CSIR – Central
Drug Research Institute,
P. O. Box 173, Lucknow 226001, India
Fax: +91-522-2623405, -2623938
E-mail: batra_san@yahoo.co.uk
s_batra@cdri.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201200276.
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S. Biswas, S. Batra
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role of DMSO (dimethyl sulfoxide) as an oxidant, which
was confirmed experimentally. These unusual results
prompted us to present the results of this study.
Figure 2. Synthesis of 5H-pyrimido[5,4-b]indol-2-amine.
Scheme 1. Reagents and conditions: (i) Guanidine hydrochloride
(2, 1.0 equiv.), CuI (0.1 equiv.), l-proline (0.2 equiv.), Cs2CO3
(2.0 equiv.), DMSO (2 mL), 90 °C, 12 h; (ii) formamidine acetate
(3, 1.0 equiv.), CuI (0.1 equiv.), l-proline (0.2 equiv.), Cs2CO3
(2.0 equiv.), DMSO (2 mL), 90 °C, 12 h; (iii) acetamidine hydro-
chloride (4, 1.0 equiv.), CuI (0.1 equiv.), l-proline (0.2 equiv.),
Cs2CO3 (2.0 equiv.), DMSO (2 mL), 90 °C, 12 h; (iv) benzamidine
hydrochloride (5, 1.0 equiv.), CuI (0.1 equiv.), l-proline (0.2 equiv.),
Cs2CO3 (2.0 equiv.), DMSO (2 mL), 90 °C, 12 h.
Results and Discussion
The sequence began with several substituted 3-haloind-
ole-2-carbaldehydes 1 (X = I), which were prepared as pre-
viously reported.[3b] Because we knew the optimized condi-
tions for the anticipated coupling reaction,[4] we simulta-
neously investigated the reaction of 3-haloindole-2-carbal-
dehyde 1 with guanidine hydrochloride (2), formamidine
acetate (3), acetamidine hydrochloride (4), and benzamidine
hydrochloride (5). These reactions were performed under
the standardized conditions of CuI, l-proline, and Cs2CO3
in DMSO at 90 °C (Scheme 1). The reaction between 1 and
1.0 equiv. of guanidine hydrochloride (2) resulted in the for-
mation of a single product as evident from the TLC analy-
sis. In contrast, the reaction with 1.0 equiv. of formamidine
acetate (3) produced a mixture of products. However, the
reaction with 1.0 equiv. of either acetamidine hydrochloride
(4) or benzamidine hydrochloride (5) resulted in a mixture
of two products. The product obtained from the reaction
with guanidine hydrochloride (2) was characterized spectro-
Figure 3. Ortep diagram for 9 at 35% probability level.
Studies Related to the Synthesis of 2-Amino-5H-
pyrimido[5,4-b]indoles
Encouraged by the success of the copper-catalyzed reac-
scopically as the expected 2-amino-5H-pyrimido[5,4-b]ind- tion of guanidine hydrochloride (2) with 3-iodoindole-2-
ole (6). The mixture resulting from the reaction with acet- carbaldehyde (1) to afford a single product, we examined
amidine hydrochloride (4) was purified, yielding two solid its optimization and scope for the first phase of the study.
products. The spectroscopic characterization of one of the As a consequence, the reaction was screened for varying
products, isolated in 45% yield, led us to establish its struc- copper sources, ligands, bases, and solvents.
ture as indole-2-carbaldehyde (8). Notably, the spectro-
As indicated in Table 1, among the different copper
scopic data of the second product, obtained in 34% yield, sources examined, CuI salts were found to be better than
differed from that of the anticipated 2-methyl 5H-pyrim- CuII salts, and the yields were good with CuI (Table 1, En-
ido[5,4-b]indole (7). On the basis of the data, the structure tries 1–5). In terms of the ligands which were evaluated,
was tentatively assigned as 2-(4,6-dimethyl-1,3,5-triazin-2- that is, l-proline, ethylenediamine, N,NЈ-dimethylethyl-
yl)-1H-indole (9). Nevertheless, to secure an unambiguous enediamine, N,NЈ-tetramethylethylenediamine, cyclohex-
structure of the product, a single crystal was prepared from anediamine (cis/trans mixture), and 1,10-phenanthroline,
its DMSO solution and subjected to X-ray crystallographic 1,10-phenanthroline afforded 6 in 68% yield (Table 1, En-
analysis. The result proved the structure to be 2-(4,6-di- tries 1, 6–10). We investigated other bases, namely K2CO3
methyl-1,3,5-triazin-2-yl)-1H-indole (9) which remains hith- and K3PO4, but Cs2CO3 gave the best yields (Table 1, En-
erto unreported in the literature (Figure 3).[11] In a similar tries 10–12). Additionally, we realized that DMSO was the
fashion to the reaction with 4, benzamidine hydrochloride most suitable solvent for the reaction, giving rise to product
(5) also gave a mixture of 8 (42%) and 2-(4,6-diphenyl- 6 (Table 1, Entries 10, 13–15). Inferior results were pro-
1,3,5-triazin-2-yl)-1H-indole (10, 36%).
duced when the reaction was conducted in other solvents
2
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5H-Pyrimido[5,4-b]indole and 1,3,5-Triazine Derivatives
[DMF (dimethylformamide), toluene, dioxane). Although yields than the ones without substituents or with a halo
the control experiment in which neither a copper source nor group on the phenyl ring (Table 2, Entries 8 and 9). Chang-
a ligand (Table 1, Entry16) were used was successful, the ing the iodo to a bromo group at the 3-position of indole
rate was sluggish, and the reaction required 52 h to reach resulted in products with relatively low yields (Table 2, En-
completion as compared to 12 h in the presence of copper. tries 2 and 3). To assess the significance of copper in the
The other control experiment performed in the presence of protocol, all of the reactions were performed in the absence
CuI but absence of the ligand was also successful, but the of copper and the ligand. In each case, though the reaction
yield of the product was relatively low (Table 1, Entry 17).
was successful, the time required for completion increased,
and the isolated yields were comparatively less (see Sup-
porting Information).
Table 1. Results of the study for optimization of reaction of 3-iodo-
indole-2-carbaldehyde (1) with guanidine hydrochloride (2).[a]
Table 2. Scope of the copper-catalyzed cascade process for the syn-
thesis of 2-amino-5H-pyrimido[5,4-b]indoles.[a]
Entry Cu cat.
Ligand
Base
Solvent Yield [%][b]
1
2
3
4
5
6
7
8
CuI
A
A
A
A
A
B
C
D
E
F
F
F
F
F
F
–
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
Cs2CO3 DMSO
K2CO3 DMSO
52
47
43
11
08
46
54
57
41
68
55
42
58
48
34
46[c]
59
CuBr
Cu2O
CuSO4
Cu(OAc)2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
9
10
11
12
13
14
15
16
17
K3PO4
DMSO
CuI
CuI
CuI
–
Cs2CO3 DMF
Cs2CO3 toluene
Cs2CO3 dioxane
Cs2CO3 DMSO
Cs2CO3 DMSO
CuI
–
[a] Reagents and conditions: under nitrogen atmosphere, 3-iodo-
indole-2-carbaldehyde (1, 1.1 mmol), guanidine hydrochloride (2,
2.2 mmol), Cu salt (0.11 mmol), ligand (0.22 mmol), base
(2.2 mmol), solvent (2 mL), temperature (90 °C), time (12 h).
[b] Isolated yields. [c] Reaction completed in 52 h.
The scope of the copper-catalyzed cascade synthesis of
the 5H-pyrimido-[5,4-b]-indol-2-amine derivatives from the
reactions of substituted 3-haloindole-2-carbaldehydes 1
with guanidine hydrochloride (2) was tested under the opti-
mized conditions (10 mol-% CuI, 20 mol-% of 1,10-phen-
anthroline, and 2.0 equiv. of Cs2CO3 in DMSO under nitro-
gen). As shown in Table 2, most of the substrates afforded
products in moderate to good yields. In line with an obser-
vation made in our previous studies,[3] here too we found
that the reaction with N-Boc-protected indoles produced N-
deprotected products in less time, but the yields were rela-
tively low in comparison to the reaction with the unprotec-
ted indoles (compare Table 1, Entry 10 and Table 2, En-
[a] Reagents and conditions: under nitrogen atmosphere,
1
(1.1 mmol), 2 (1.1 mmol), CuI (0.11 mmol), 1,10-phenanthroline
(0.22 mmol), Cs2CO3 (2.2 mmol), DMSO (2 mL), temperature
(90 °C). [b] Time of completion. [c] Isolated yields. [d] Isolated yield
obtained in the presence of copper salt and without ligand.
Studies Related to the Synthesis of 2,4,6-Trisubstituted
1,3,5-Triazines
Having studied the transformation of 3-haloindole-2-
tries 1–5). In general, the substrates with electron-donating carbaldehydes to 2-amino-5H-pyrimido[5,4-b]indoles, we
substituents on the phenyl ring of the indole gave better turned our attention to its reactions with substituted amid-
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ine hydrochlorides. As mentioned earlier, it was reported were isolated in 72–89% yields (Table 3). In contrast to the
that benzamidine hydrochloride (2.0 equiv.) was treated literature, it is worthwhile to mention that we detected no
with substituted benzaldehydes to furnish 1,3,5-dihydrotri- cases of 1,3,5-dihydrotriazine formation during our studies.
azines which were oxidized in the presence of sodium sulfite
or sodium thionite to obtain substituted 1,3,5-triazines
(Scheme 2).[9]
Scheme 4. Reagents and conditions: (i) acetamidine hydrochloride
(4, 2.0 equiv.), Cs2CO3, DMSO, 90 °C, 12 h; (ii) benzamidine hy-
drochloride (5, 2.0 equiv.), Cs2CO3, DMSO, 90 °C, 12 h.
Scheme 2. Reported method[10] for the synthesis of substituted
1,3,5-triazines from substituted benzaldehydes.
Table 3. Scope of base-mediated transformation of indole-2-carbal-
dehyde to substituted 2-(1,3,5-triazin-2-yl)-1H-indoles.[a]
From our initial results of the reaction with substituted
amidines, it was evident that no cross-coupling reaction in-
volving the iodine at the 3-position of the indole was occur-
ring, and formation of the substituted 1,3,5-triazine would
require 2.0 equiv. of the substituted amidine hydrochloride.
Henceforth, in a representative study, the reaction between
3-iodoindole-2-carbaldehyde (1) and acetamidine hydro-
chloride (4) was investigated systematically. Accordingly,
first 1 was treated with 2.0 equiv. of acetamidine hydrochlo-
ride under the optimized conditions both with CuI and in
the absence of the copper source. It was satisfying to note
that under these conditions the reaction gave the identical
product in comparable yields, which was identified as ex-
pected 9 (Scheme 3). Furthermore, by using 2.0 equiv. of 4,
we did not observe the formation of indole-2-aldehyde (8).
A similar reaction of 3-iodoindole-2-carbaldehyde with
2.0 equiv. of benzamidine hydrochloride (5) also proceeded
smoothly affording the corresponding substituted triazine
10 in excellent yields. Nevertheless, formation of 9 and 10
suggested that under the reaction conditions deiodination
invariably occurs.
Scheme 3. Reagents and conditions: (i) acetamidine hydrochloride
(4, 2.0 equiv.), (A) CuI (0.1 equiv.), Cs2CO3 (2.0 equiv.), 1,10-phen-
anthroline (0.2 equiv.), DMSO (2 mL), 90 °C, and 12 h or
(B) Cs2CO3 (2.0 equiv.), DMSO (2 mL), 90 °C, and 12 h; (ii) benz-
amidine hydrochloride (5, 2.0 equiv.), A or B (same as above).
[a] Reagents and conditions: 8 (1.4 mmol), substituted amidine hy-
drochloride 4/5 (2.8 mmol), Cs2CO3 (2.8 mmol), DMSO (2 mL),
temperature (90 °C). [b] Isolated yields.
Consequently, as an obvious step, we next investigated
the success of the protocol with indole-2-carbaldehyde.
Therefore, indole-2-carbaldehyde (8) was treated with aceta-
midine hydrochloride (4) or benzamidine hydrochloride (5)
Because 1,3,5-triazines are an important class of com-
in the presence of Cs2CO3 in DMSO at 90 °C, and as ex- pounds having significant antibacterial,[12] pesticidal,[13]
pected, these reactions afforded 1,3,5-triazines 9 and 10 in and optoelectronic,[14] properties, we considered investiga-
75% and 86% yields, respectively (Scheme 4). Next, the ting the extension of our method to simple benzaldehydes.
generality of the methodology was evaluated by subjecting Therefore, different benzaldehydes 11 were treated with
several indole-2-carbaldehydes to similar reactions. It was acetamidine hydrochloride and benzamidine hydrochloride
satisfying to note that in each case the substituted triazines in the presence of Cs2CO3 in DMSO at 90 °C in a parallel
4
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5H-Pyrimido[5,4-b]indole and 1,3,5-Triazine Derivatives
fashion. It was a delight to discover that all of the reactions 1,3,5-triazine, thereby suggesting the role of DMSO as an
proceeded smoothly to furnish the respective substituted oxidant during the reaction (Figure 4). Furthermore, to
1,3,5-triazines 12 and 13 in good to excellent isolated yields provide chemical evidence to this effect, a representative
(Table 4).
study of 2,4,6-triphenyl-1,3,5-dihydrotriazine (14) was
heated at 90 °C in DMSO in either the presence or absence
of Cs2CO3. Under both conditions, it was observed that the
transformation of 14 to 2,4,6-triphenyl-1,3,5-triazine (13)
occurred, though the reaction was comparatively faster in
the presence of the base (Scheme 5).
Table 4. Scope of base-mediated transformation of substituted
benzaldehyde to 2,4,6-trisubstituted 1,3,5-triazines.[a]
Table 5. Scope of the base and solvent in the reaction[a] of benzal-
dehyde and benzamidine hydrochloride.
Entry
Base
Solvent
Yield [%]
Yield [%]
13
14
1
2
3
4
5
6
7
8
9
10
Et3N
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
toluene
MeCN
DMF
68
64
63
72
70
65
–
–
–
–
–
–
–
–
–
DBU[b]
DABCO[b]
Na2CO3
K2CO3
K3PO4
–
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
81
82
85
76[c]
water
[a] Reagents and conditions: benzaldehyde (11, 1.0 mmol), benz-
amidine hydrochloride (5, 2.0 mmol), base (2.2 mmol), solvent
(2 mL), temperature (90 °C). [b] DBU = 1,8-diazabicyclo[5.4.0]-
undec-7-ene, DABCO = 1,4-diazabicyclo[2.2.2]octane. [c] Reaction
completed in 36 h.
[a] Reagents and conditions: 11 (2.8 mmol), substituted amidine hy-
drochloride (5.6 mmol), Cs2CO3 (5.6 mmol), DMSO (2 mL), tem-
perature (90 °C). [b] Isolated yields.
However, mechanistic considerations and a different re-
sult from the literature for the reaction of benzaldehyde
with benzamidine hydrochloride warranted an investigation
into the reaction conditions. Therefore, in a model study,
the reaction between benzaldehyde 11 and benzamidine hy-
drochloride (5) was carried out using different bases and
solvents (Table 5). In the first set of experiments, DMSO as
the solvent was kept constant, and the bases were altered
to include both organic and inorganic bases. All of the reac-
tions were performed at 90 °C (Table 5, Entries 1–6). In
each case, 2,4,6-triphenyl-1,3,5-triazine (13) was isolated in
good yields. In the second set of experiments, the base was
maintained as Cs2CO3, and different solvents including
MeCN, DMF, PhMe, and H2O were examined (Table 5,
Entries 7–10,). Notably, in each case, the isolated product
was identified to be 2,4,6-triphenyl-1,3,5-dihydrotriazine
(14) instead of 1,3,5-triazine 13. From the results of this
study, it was evident that the reaction proceeds in the re-
ported fashion, affording the 1,3,5-dihydrotriazine first
Figure 4. Plausible mechanism for the formation of 1,3,5-triazines
from aldehyde.
Scheme 5. Reagents and conditions: (i) Cs2CO3 (2.0 equiv.), DMSO
which then gets converted into the 2,4,6-trisubstituted (2 mL), 90 °C, 6 h; (ii) DMSO (2 mL), 90 °C, 24 h.
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2 H, Ar), 7.72–7.76 (m, 1 H, Ar), 8.89 (s, 1 H, Ar), 11.45 (br. s, 1
Conclusions
H, N) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 105.3, 105.7,
In summary, we have developed a one-step synthesis for 111.6, 111.7, 111.9, 112.0, 115.6, 121.6, 122.8, 133.9, 151.1, 158.7,
162.4, 167.1 ppm. MS (ESI): m/z = 203.3 [M + H]+. HRMS (ESI):
2-amino-5H-pyrimido[5,4-b]indoles from 3-haloindole-2-
carbaldehydes. The synthesis of this indole-fused system
calcd. for C10H8FN4 [M + H]+ 203.0733; found 203.0728.
was achieved under basic conditions, though the presence
of copper and a ligand facilitated the rate of reaction and
the formation of the product. In contrast, upon reaction
with similar substrates, the substituted amidines gave sub-
stituted 2-(1,3,5-triazin-2-yl)-1H-indoles through a cascade
sequence. On the basis of the results, this methodology was
extended to direct the transformation of simple benzalde-
hydes into 2,4,6-trisubstituted 1,3,5-triazines. The role of
DMSO as an oxidant to assist the transformation of 1,3,5-
dihydrotriazine to 1,3,5-triazine was demonstrated.
8-Bromo-5H-pyrimido[5,4-b]indol-2-amine: Table 2, Entry 6. Brown
solid (0.144 g from 0.3 g), Rf = 0.40 (EtOAc/hexanes, 1:1, v/v), m.p.
Ͼ 250 °C (EtOAc). IR (KBr): ν
= 3423 (NH) cm–1. 1H NMR
˜
max
(300 MHz, [D6]DMSO): δ = 6.64 (br. s, 2 H, NH2), 7.38–7.47 (m,
2 H, Ar), 8.13 (s, 1 H, Ar), 8.93 (s, 1 H, Ar), 11.57 (br. s, 1 H,
NH) ppm. 13C NMR (50 MHz, [D6]DMSO): δ = 103.5, 112.8,
121.8, 123.3, 125.5, 126.9, 137.1, 151.2, 162.5, 167. ppm. MS (ESI):
m/z = 263.3 [M + H]+. HRMS (ESI): calcd. for C10H7BrN4 [M +
H]+ 262.9932; found 262.9936.
8-Methoxy-5H-pyrimido[5,4-b]indol-2-amine: Table 2, Entry 8.
Brown solid (0.147 g from 0.3 g), Rf = 0.34 (EtOAc/hexanes, 1:1,
v/v), m.p. Ͼ 250 °C (EtOAc). IR (KBr): ν
= 3435 (NH) cm–1.
˜
max
1H NMR (300 MHz, [D6]DMSO): δ = 3.79 (s, 3 H, OCH3), 6.44
(br. s, 2 H, NH2), 6.88 (d, J = 7.7 Hz, 1 H, Ar), 7.23 (d, J = 8.4 Hz,
1 H, Ar), 7.51 (s, 1 H, Ar), 8.85 (s, 1 H, Ar) 11.23 (br. s, 1 H,
NH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 55.6, 103.4, 111.7,
112.9, 121.3, 132.0, 150.4, 154.3, 158.3, 162.0, 167.2 ppm. MS
(ESI): m/z = 215.2 [M + H]+. HRMS (ESI): calcd. for C11H11N4O
[M + H]+ 215.0933; found 215.0929.
Experimental Section
General Methods: The melting points were measured using capil-
lary tubes with a Precision melting point apparatus containing sili-
con oil. The IR spectroscopic data were recorded with a Perkin–
Elmer RX I FTIR spectrophotometer. H and 13C NMR spectra
1
were recorded with either a Bruker DPX-200 or a Bruker Avance
DRX-300 FT spectrometer, using TMS as an internal standard
(chemical shifts in δ). The ESI-MS data were recorded with a
MICROMASS Quadro-II LCMS system. The HRMS spectra were
recorded as ESI-HRMS with an Agilent 6520 Q-TOF, LC-MS/MS
mass spectrometer. The room temperatures varied between 20 and
35 °C. All of the solvents and chemicals were used as procured
from the suppliers.
7,8-Dimethoxy-5H-pyrimido[5,4-b]indol-2-amine: Table 2, Entry 9.
Brown solid (0.148 g from 0.3 g), Rf = 0.24 (EtOAc/hexanes, 1:1,
v/v), m.p. Ͼ 250 °C (EtOAc). IR (KBr): ν
= 3415 (NH) cm–1.
˜
max
1H NMR (300 MHz, [D6]DMSO): δ = 3.80 (s, 3 H, OCH3), 3.81
(s, 3 H, OCH3), 6.37 (br. s, 2 H, NH2), 6.91 (s, 1 H, Ar), 7.54 (s, 1
H, Ar), 8.76 (s, 1 H, Ar), 11.26 (br. s, 1 H, NH) ppm. 13C NMR
(50 MHz, [D6]DMSO): δ = 55.7, 56.2, 95.6, 103.6, 106.4, 112.3,
132.0, 144.6, 148.1, 148.2, 157.7, 160.7 ppm. MS (ESI): m/z = 245.2
[M + H]+. HRMS (ESI): calcd. for C12H13N4O2 [M + H]+
245.1039; found 245.1042.
General Procedure for the Preparation of 5H-Pyrimido[5,4-b]indol-
2-amines, Exemplified by 5H-Pyrimido[5,4-b]indol-2-amine (6): To a
solution of 3-iodoindole-2-carbaldehyde (0.3 g, 1.1 mmol) and
guanidine hydrochloride (0.21 g, 2.2 mmol) in DMSO (2 mL) were
added CuI (0.021 g, 0.11 mmol), 1,10-phenanthroline (0.025 g,
0.22 mmol), and Cs2CO3 (0.72 g, 2.2 mmol). The reaction mixture
was heated at 90 °C for the mentioned time in a sealed tube under
nitrogen. Thereafter, water (50 mL) and ethyl acetate (25 mL) were
added, and the reaction mixture was filtered through a bed of Ce-
lite. The layers were separated, the aqueous layer was extracted
with ethyl acetate (2ϫ20 mL). The combined organic layers were
washed with brine (35 mL), dried with anhydrous Na2SO4, and
concentrated under vacuum. Column chromatography of the crude
product over basic alumina (EtOAc/hexanes, 1:1) furnished the
General Procedure for the Preparation of 2-(4,6-Dimethyl-1,3,5-tri-
azin-2-yl)-1H-indoles as Exemplified by 2-(4,6-Dimethyl-1,3,5-tri-
azin-2-yl)-1H-indole (9): To a solution of 3-iodoindole-2-carbal-
dehyde (0.3 g, 1.1 mmol) and acetamidine hydrochloride (0.21 g,
2.2 mmol) in DMSO (2 mL) was added Cs2CO3 (0.72 g, 2.2 mmol),
and the reaction mixture was heated at 90 °C for the mentioned
time in a sealed tube under nitrogen. Thereafter, water (50 mL) and
ethyl acetate (25 mL) were added, and the reaction mass and the
organic layers were separated. The aqueous layer was extracted
with ethyl acetate (2ϫ20 mL). The combined organic layers were
washed with brine (35 mL), dried with anhydrous Na2SO4, and
concentrated under vacuum. Column chromatography of the crude
product product over silica gel (60–120 mesh, EtOAc/hexanes, 1:4)
furnished the pure 2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1H-indole (9)
as a yellow solid (0.183 g, 74%).
pure 5H-pyrimido[5,4-b]indol-2-amine (6) as
(0.138 g, 68%).
a brown solid
5H-Pyrimido[5,4-b]indol-2-amine (6): Table 1, Entry 10. Rf = 0.46
(EtOAc/hexanes, 1:1, v/v), m.p. Ͼ 250 °C (EtOAc). IR (KBr): ν
˜
max
= 3421 (NH) cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 6.49 (br. 2-(4,6-Dimethyl-1,3,5-triazin-2-yl)-1H-indole (9): Scheme 3. Rf
s, 2 H, NH2), 7.14 (t, J = 7.1 Hz, 1 H, Ar), 7.27 (t, J = 7.8 Hz, 1 0.53 (EtOAc/hexanes, 1:4, v/v), m.p. 208–210 °C (diethyl ether). IR
=
1
H, Ar), 7.34 (d, J = 7.8 Hz, 1 H, Ar), 7.89 (d, J = 7.5 Hz, 1 H,
(KBr): ν
= 3401 (NH) cm–1. H NMR (300 MHz, CDCl3): δ =
˜
max
Ar), 8.87 (s, 1 H, Ar), 11.41 (br. s, 1 H, NH) ppm. 13C NMR 2.66 (s, 6 H, 2 CH3), 7.15 (t, J = 7.3 Hz, 1 H, Ar), 7.31 (t, J =
(75 MHz, [D6]DMSO): δ = 105.6, 111.0, 119.2, 120.2, 120.6, 124.7,
137.5, 150.1, 158.0, 162. ppm. MS (ESI): m/z = 185.3 [M +
H]+. HRMS (ESI): calcd. for C10H9N4 [M + H]+ 185.0827; found
185.0822.
7.5 Hz, 1 H, Ar), 7.44 (d, J = 8.2 Hz, 1 H, Ar), 7.60 (d, J = 0.8 Hz,
1 H, Ar), 7.71 (d, J = 8.0 Hz, 1 H, Ar), 9.45 (br. s, 1 H, NH) ppm.
13C NMR (50 MHz, CDCl3 + [D6]DMSO): δ = 25.1, 107.2, 111.9,
119.8, 121.4, 124.2, 127.6, 133.2, 137.5, 164.8, 175.4 ppm. MS
(ESI): m/z = 225.2 [M + H]+. HRMS (ESI): calcd. for C13H13N4
[M + H]+ 225.1141; found 225.1143.
8-Fluoro-5H-pyrimido[5,4-b]indol-2-amine: Table 2, Entry 4. Brown
solid (0.132 g from 0.3 g), Rf = 0.43 (EtOAc/hexanes, 1:1, v/v), m.p.
Ͼ 250 °C (EtOAc). IR (KBr): ν
= 3433 (NH) cm–1. 1H NMR
2-(4,6-Dimethyl-1,3,5-triazin-2-yl)-5-fluoro-1H-indole: Table 3, En-
try 1. Yellow solid (0.320 g from 0.3 g), Rf = 0.51 (EtOAc/hexanes,
˜
max
(300 MHz, [D6]DMSO): δ = 6.59 (br. s, 2 H, NH2), 7.29–7.33 (m,
6
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O20276
/KAP1
Date: 10-05-12 10:17:10
Pages: 9
5H-Pyrimido[5,4-b]indole and 1,3,5-Triazine Derivatives
1:4, v/v), m.p. 219–220 °C (diethyl ether). IR (KBr): ν
1
1
= 3412
(NH) cm–1. H NMR (300 MHz, [D6]DMSO): δ = 7.42 (dd, J =
˜
max
(NH) cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.66 (s, 6 H, 2 CH3), 8.7 Hz, J = 1.8 Hz, 1 H, Ar), 7.58 (d, J = 8.8 Hz, 1 H, Ar), 7.65–
7.07 (dt, 1J = 9.1 Hz, 2J = 2.3 Hz, 1 H, Ar), 7.33–7.39 (m, 2 H, 7.73 (m, 7 H, Ar), 7.96 (s, 1 H, Ar), 8.78 (d, J = 6.7 Hz, 4 H, Ar),
Ar), 7.54 (s, 1 H, Ar), 9.45 (br. s, 1 H, NH) ppm. 13C NMR 12.31 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz, [D6]DMSO): δ =
2
(50 MHz, CDCl3 + [D6]DMSO): δ = 24.6, 104.6, 105.0, 105.3,
106.4, 112.2, 112.7, 127.1, 134.0, 134.5, 156.0, 164.3, 175.0 ppm.
MS (ESI): m/z = 243.2 [M + H]+. HRMS (ESI): calcd. for
C13H12FN4 [M + H]+ 243.1046; found 243.1040.
106.9, 112.8, 114.7, 124.1, 127.3, 128.8, 128.9, 129.6, 133.1, 135.3,
135.5, 136.9, 165.8, 170.9 ppm. MS (ESI): m/z = 427.2 [M + H]+.
HRMS (ESI): calcd. for C23H16BrN4 [M + H]+ 427.0558; found
427.0554.
2-(4,6-Diphenyl-1,3,5-triazin-2-yl)-5-methoxy-1H-indole:
Entry 7. Yellow solid (0.576 g from 0.3 g), Rf = 0.63 (EtOAc/hex-
anes, 1:4, v/v), m.p. 195–197 °C (hexanes). IR (KBr): ν = 3506
Table 3,
5-Bromo-2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1H-indole: Table 3, En-
try 2. Brown solid (0.301 g from 0.3 g), Rf = 0.50 (EtOAc/hexanes,
˜
1:4, v/v), m.p. 225–226 °C (diethyl ether). IR (KBr): ν
= 3409
˜
max
max
(NH) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.89 (s, 3 H, OCH3),
(NH) cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.66 (s, 6 H, 2 CH3),
7.30–7.40 (m, 2 H, Ar), 7.51 (s, 1 H, Ar), 7.84 (s, 1 H, Ar), 9.48
(br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3 + [D6]DMSO): δ
= 24.4, 105.5, 111.9, 113.4, 122.8, 126.0, 128.4, 134.0, 135.7, 164.0,
174.9 ppm. MS (ESI): m/z = 303.2 [M + H]+. HRMS (ESI): calcd.
for C13H12BrN4 [M + H]+ 303.0245; found 303.0242.
1
2
7.02 (dd, J = 8.9 Hz, J = 2.3 Hz, 1 H, Ar), 7.15 (d, J = 1.9 Hz,
1 H, Ar), 7.41 (d, J = 8.9 Hz, 1 H, Ar), 7.56–7.62 (m, 6 H, Ar),
7.70 (s, 1 H, Ar), 8.73 (d, J = 6.3 Hz, 4 H, Ar), 9.45 (br. s, 1 H,
NH) ppm. 13C NMR (50 MHz, CDCl3): δ = 55.9, 102.7, 107.9,
112.8, 116.9, 128.8, 129.1, 132.7, 133.0, 134.9, 136.1, 154.9, 166.1,
171.5 ppm. MS (ESI): m/z = 379.3 [M + H]+. HRMS (ESI): calcd.
for C24H19N4O [M + H]+ 379.1559; found 379.1562.
2-(4,6-Dimethyl-1,3,5-triazin-2-yl)-5-methoxy-1H-indole: Table 3,
Entry 3. Pale yellow solid (0.344 g from 0.3 g), Rf = 0.48 (EtOAc/
2-(4,6-Diphenyl-1,3,5-triazin-2-yl)-5,6-dimethoxy-1H-indole: Table 3,
Entry 8. Yellow solid (0.525 g from 0.3 g), Rf = 0.53 (EtOAc/hex-
hexanes, 1:4, v/v), m.p. 213-214 °C (diethyl ether). IR (KBr): ν
˜
max
= 3396 (NH) cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.65 (s, 6 H,
2 CH3), 3.87 (s, 3 H, OCH3), 6.99 (d, J = 8.6 Hz, 1 H, Ar), 7.10
(s, 1 H, Ar), 7.33 (d, J = 8.9 Hz, 1 H, Ar), 7.50 (s, 1 H, Ar), 9.37
(br. s, 1 H, NH) ppm. 13C NMR (75 MHz, CDCl3 + [D6]DMSO):
δ = 23.9, 53.8, 100.2, 105.5, 112.1, 114.6, 126.6, 132.3, 132.5, 152.6,
163.7, 174.2 ppm. MS (ESI): m/z = 255.2 [M + H]+. HRMS (ESI):
calcd. for C14H15N4O [M + H]+ 255.1246; found 255.1251.
anes, 1:4, v/v), m.p. 218–220 °C (hexanes). IR (KBr): ν
= 3447
˜
max
(NH) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.93 (s, 6 H, 2
OCH3), 6.91 (s, 1 H, Ar), 7.08 (s, 1 H, Ar), 7.44–7.47 (m, 1 H, Ar),
7.53–7.60 (m, 5 H, Ar), 7.63 (d, J = 1.2 Hz, 1 H, Ar), 8.70 (d, J =
6.3 Hz, 4 H, Ar), 9.43 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 56.1, 56.2, 93.9, 102.6, 108.3, 121.8, 126.6, 128.6,
128.9, 132.5, 132.8, 133.0, 136.3, 146.1, 150.0, 165.7, 171.1 ppm.
MS (ESI): m/z = 409.3 [M + H]+. HRMS (ESI): calcd. for
C25H21N4O2 [M + H]+ 409.1665; found 409.1662.
2-(4,6-Dimethyl-1,3,5-triazin-2-yl)-5,6-dimethoxy-1H-indole: Table 3,
Entry 4. Yellow solid (0.307 g from 0.3 g), Rf = 0.42 (EtOAc/hex-
anes, 1:4, v/v), m.p. 231–232 °C (diethyl ether). IR (KBr): ν
=
˜
max
3391 (NH) cm–1. H NMR (300 MHz, CDCl3): δ = 2.62 (s, 6 H, 2
CH3), 3.94 (s, 6 H, 2 OCH3), 6.88 (s, 1 H, Ar), 7.06 (s, 1 H, Ar),
7.48 (s, 1 H, Ar), 9.36 (br. s, 1 H, NH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 25.7, 56.2, 56.3, 94.0, 102.6, 108.6, 116.5, 121.8, 132.1,
132.5, 133.1, 146.3, 150.3, 176.0 ppm. MS (ESI): m/z = 285.2 [M
+ H]+. HRMS (ESI): calcd. for C15H17N4O2 [M + H]+ 285.1352;
found 285.1355.
1
Supporting Information (see footnote on the first page of this arti-
cle): Spectroscopic details of the compounds in Tables 4 and 2 (con-
1
tinued) and copies of the H and 13C NMR spectra for all of the
compounds are provided.
Acknowledgments
2-(4,6-Diphenyl-1,3,5-triazin-2-yl)-1H-indole (10): Scheme 3. Off-
white solid (0.34 g from 0.3 g), Rf = 0.72 (EtOAc/hexanes, 1:4,
One of the authors (S. B.) gratefully acknowledges the financial
help in the form of fellowship from Council of Scientific and Indus-
trial Research (CSIR), New Delhi. The authors acknowledge the
SAIF division for providing the spectroscopic and analytic data.
We acknowledge the help extended by Prof. Sandeep Verma, of IIT
Kanpur, and we acknowledge his student Ms. Shruti Khanna for
the X-ray analysis of 2-(4,6-dimethyl-1,3,5-triazin-2-yl)-1H-indole
(9).
v/v), m.p. 181–182 °C (hexanes). IR (KBr): νmax = 3465 (NH) cm–1.
˜
1H NMR (300 MHz, CDCl3): δ = 7.18 (t, J = 7.1 Hz, 1 H, Ar),
7.35 (t, J = 7.4 Hz, 1 H, Ar), 7.50–7.63 (m, 7 H, Ar), 7.75 (s, 1 H,
Ar), 7.78 (s, 1 H, Ar), 8.73 (d, J = 6.5 Hz, 4 H, Ar), 9.53 (br. s, 1
H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 108.4, 112.0, 120.9,
122.6, 125.3, 128.7, 128.8, 129.1, 132.7, 134.5, 136.1, 137.6, 166.1,
171.5 ppm. MS (ESI): m/z = 349.2 [M + H]+. HRMS (ESI): calcd.
for C23H17N4 [M + H]+ 349.1453; found 349.1455.
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2-(4,6-Diphenyl-1,3,5-triazin-2-yl)-5-fluoro-1H-indole: Table 3, En-
try 5. Yellow solid (0.566 g from 0.3 g), Rf = 0.71 (EtOAc/hexanes,
1:4, v/v), m.p. 188–190 °C (hexanes). IR (KBr): ν
= 3486
˜
max
(NH) cm–1. 1H NMR (300 MHz, CDCl3): δ = 7.10 (dt, 1J = 9.0 Hz,
2J = 2.3 Hz, 1 H, Ar), 7.37–7.46 (m, 2 H, Ar), 7.56–7.63 (m, 6 H,
Ar), 7.73 (s, 1 H, Ar), 8.73 (d, J = 6.5 Hz, 4 H, Ar), 9.54 (br. s, 1
H, NH) ppm. 13C NMR (75 MHz, CDCl3): δ = 106.6, 106.9, 108.0,
108.1, 112.7, 112.8, 114.1, 114.4, 128.8, 128.9, 129.1, 132.8, 134.1,
135.9, 136.0, 156.8, 160.0, 165.9, 171.5 ppm. MS (ESI): m/z = 367.3
[M + H]+. HRMS (ESI): calcd. for C23H16FN4 [M + H]+ 367.1359;
found 367.1355.
5-Bromo-2-(4,6-diphenyl-1,3,5-triazin-2-yl)-1H-indole: Table 3, En-
try 6. Brown solid (0.493 g from 0.3 g), Rf = 0.68 (EtOAc/hexanes,
1:4, v/v), m.p. 201–202 °C (hexanes). IR (KBr): ν
= 3438
˜
max
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
7

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/KAP1
Date: 10-05-12 10:17:10
Pages: 9
S. Biswas, S. Batra
FULL PAPER
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the refinement, the hydrogens were treated as riding atoms
using the SHELXL default parameters. The crystal data of 2-
(4,6-dimethyl-1,3,5-triazin-2-yl)-1H-indole (crystallized from
DMSO): C13H12N4, M = 224.27, orthorhombic, space group
P21, a = 6.3334(15) Å, b = 9.561(2) Å, c = 18.021(4) Å, α =
90.00, β = 90.00 (7), γ = 90.00, V = 1091.3(4) Å3, Z = 4, Dx =
1.365 gcm–3, μ (Mo-Kα) = 0.086 mm–1, F (000) = 472.0, yellow
block crystals with dimensions 0.22ϫ0.20ϫ0.18 mm, 7140 re-
flections measured (Rint = 0.0376), 2677 unique, wR2 = 0.1926,
conventional R = 0.0614 on F2 values of 2677 reflections with
I Ͼ 2σ(I), (Δ/σ)max = 000), S = 1.063 for all data and 154
parameters. All of these software packages were the integrated
WINGX software package. CCDC-873222 contains the sup-
plementary crystallographic data for this paper. These data can
be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
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[11] Crystals were coated with a light hydrocarbon oil and mounted
in a 100 K dinitrogen stream of a Bruker SMART APEX CCD
diffractometer equipped with a CRYO Industries low-tempera-
ture apparatus. Intensity data were collected using graphite-
monochromated Mo-Kα radiation. The data integration and
reduction were processed with SAINT software. An absorption
correction was applied. The structures were solved by the direct
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Received: March 6, 2012
Published Online: ᭿
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Job/Unit: O20276
/KAP1
Date: 10-05-12 10:17:10
Pages: 9
5H-Pyrimido[5,4-b]indole and 1,3,5-Triazine Derivatives
S. Biswas, S. Batra* .......................... 1–9
One-Step Synthesis of 2-Amino-5H-pyr-
imido[5,4-b]indoles, Substituted 2-(1,3,5-
triazin-2-yl)-1H-indoles, and 1,3,5-Tri-
azines from Aldehydes
The synthesis of 2-amino-5H-pyrimido[5,4-
b]indoles from 3-haloindole-2-carbal-
dehyde and guanidine hydrochloride is de-
scribed. In contrast, 3-haloindole-2-carbal-
dehydes or indole-2-carbaldehydes react
with substituted amidine hydrochlorides to
give 2-(1,3,5-triazin-2-yl)-1H-indole deriva-
tives in excellent yields. The latter protocol
was used to prepare 2,4,6-trisubstituted
1,3,5-triazines.
Keywords: Nitrogen heterocycles / Fused-
ring systems / Synthetic methods / Copper
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