A New One-Pot Three-Component Synthesis of 4-Aryl-6-cycloamino-1,3,5-triazin-2-amines under Microwave Irradiation

SYNTHESIS

0

3

9

-

7

8

1

4

3

7

-

2

1

0

X

Georg Thieme Verlag KG Rüdigerstraße 14, 70469 Stuttgart

2021, 53, A–L

paper

A

en

M. S. Shahari et al.

Paper

Synthesis

A New One-Pot Three-Component Synthesis of 4-Aryl-6-cyclo-

amino-1,3,5-triazin-2-amines under Microwave Irradiation

Muhammad Syafiq Bin Shahari^a

Ahmad Junaid^b

Edward R. T. Tiekink^c

R

CHO

1) EtOH, HCl (1 equiv), 55 min

2) aq NaOH (2 equiv), 20 min

N

NH

N

X

Anton V. Dolzhenko*^a,d

0

-0

0

1

-

5

0

5

9

-

2

7

6

+

NH

microwave irradiation, 140 °C

N

NH₂

N

NH₂

X

H

^aSchool of Pharmacy, Monash University Malaysia, Jalan Lagoon

Selatan, Bandar Sunway, Selangor Darul Ehsan 47500,

Malaysia

21 examples

up to 71% yield

o n e - p o t

anton.dolzhenko@monash.edu

antileukemic

properties

^bDepartment of Medicinal Chemistry and Molecular Pharma-

cology, Purdue University, West Lafayette, Indiana 47907, USA

^cResearch Centre for Crystalline Materials, School of Medical

and Life Sciences, Sunway University, 5 Jalan Universiti, Bandar

Sunway, Selangor Darul Ehsan 47500, Malaysia

^dSchool of Pharmacy and Biomedical Sciences, Curtin Health

Innovation Research Institute, Faculty of Health Sciences, Cur-

tin University, GPO Box U1987 Perth, Western Australia 6845,

Australia

for R = Ph, X = o-phenylene:

GI₅₀= 1.95 μM (Jurkat T cells)

m i c r o w a v e

anton.dolzhenko@curtin.edu.au

Dedicated to the memory of Professor Boris Syropyatov (6 Nov 1940 – 24 Oct 2020)

Corresponding Author

Received: 14.01.2021

Accepted after revision: 26.02.2021

Published online: 26.02.2021

The 1,3,5-triazine ring of these drugs is decorated in posi-

tions 2, 4, and 6 with two substituted amino groups and a

(het)aryl moiety. The inhibitors of Bruton’s tyrosine ki-

nase¹²and lysophosphatidic acid acyltransferase ^13–15and

recently reported¹⁶highly potent and selective agents tar-

geting triple-negative breast cancer share a similar 4-

DOI: 10.1055/a-1401-2795; Art ID: ss-2021-z0019-op

Abstract A new method for the fast synthesis of diverse 4-aryl-6-cy-

cloamino-1,3,5-triazin-2-amines was developed. The synthesis is per-

formed under microwave irradiation in a one-pot manner from cy-

anoguanidine, aromatic aldehydes, and cyclic amines. Their three-

component reaction in the presence of hydrochloric acid produced di-

hydrotriazines, which were then converted (without isolation) into the

targeted compounds via aromatic dehydrogenation in the presence of

alkali. The reaction tolerated various aromatic aldehydes (including het-

erocyclic) and cyclic amines. Crystal structures of two representative 4-

aryl-6-morpholino-1,3,5-triazin-2-amines were established by X-ray

crystallography. The results of preliminary biological screening identi-

fied potent antileukemic activity for 6-[3,4-dihydroisoquinolin-2(1H)-

yl]-4-phenyl-1,3,5-triazin-2-amine.

(het)aryl-6-arylamino-1,3,5-triazin-2-amine

scaffold.

Structurally related compounds with 6-aralkylamino sub-

stitution demonstrated potent inhibition of tryptophan hy-

droxylase¹⁷and an effective positive allosteric modulation

of G protein-coupled receptor 68 (GPR68).^18,19The inhibi-

tors of phosphoinositide 3-kinase²⁰and ligands for H₄hista-

mine receptors^21,22were found among 4-aryl-6-cycloami-

no-1,3,5-triazin-2-amines, while similar 4-aralkyl-6-cy-

cloamino-1,3,5-triazin-2-amines are selectively bound to 5-

HT₆serotonin receptors.²³

Key words triazines, multicomponent reactions, microwave-assisted

The pharmacological investigation of 4-aryl-6-cycloam-

ino-1,3,5-triazin-2-amines 1 possessing different substitu-

tion patterns would open opportunities for the identifica-

tion of new potent bioactive agents. However, existing

methods for the preparation of these compounds are limit-

ed and do not allow fast synthesis of sufficiently diverse

molecules.

One of the methods for the synthesis of 4-aryl-6-cy-

cloamino-1,3,5-triazin-2-amines 1 utilizes cyanuric chlo-

ride, which is involved in a sequential nucleophilic substi-

tution with cyclic amines (e.g., morpholine) and then am-

monia; the Suzuki cross-coupling of the resulting

intermediate with arylboronic acids concludes this ap-

proach (Scheme 1, Route 1).²⁰

synthesis, dehydrogenative aromatization, antiproliferative activity

1,3,5-Triazines have been one of the most widely used

classes of herbicides for the last half-century.¹In veterinary

medicine, triazines (including 1,3,5-triazines toltrazuril and

ponazuril) form a well-established class of antiprotozoal

drugs.²In the contemporary design of new bioactive com-

pounds with potential therapeutic applications, the 1,3,5-

triazine ring has also proven to be a privileged scaffold.^3–5

Despite a wide range of biological activities reported for

1,3,5-triazines, achievements in the development of anti-

cancer agents based on this skeleton were particularly im-

portant.^6,7Recently approved anticancer drugs include

1,3,5-triazines Enasidenib^8,9and Gedatolisib^10,11(Figure 1).

Georg Thieme Verlag KG, Rüdigerstraße 14, 70469 Stuttgart, Germany

B

M. S. Shahari et al.

Paper

Synthesis

O

N

CF₃

N

O

N

Me

N

O

N

F₃C

N

O

H

N

H

NMe₂

OH

H

Enasidenib

Gedatolisib

OMe

Cl

MeO

OMe

NH₂

N

O

N

F

O

Me

Br

Et

Me

HO

N

Me

N

NH₂

N

NH₂

N

H

N

H

N

NH₂

H

Lisophosphatidic acid acyltransferase β inhibitors

Bruton's kinase inhibitor

Selective triple-negative breast cancer cell

growth inhibitor

NH₂

HO₂C

HO

F

N

Me

N

NH₂

N

NH₂

H

N

NH₂

H

PhO

Positive allosteric modulators of GPR68

Tryptophan hydroxylase

inhibitor

Cl

OH

Ar

N

X

N

NH₂

N

NH₂

N

NH₂

N

NH₂

Y

N

O

Me

5-HT₆serotonin receptor ligand

Me

1

Phosphoinositide 3-kinase

inhibitor

H₄histamine receptor ligand

Figure 1 Selected bioactive 1,3,5-triazines

Another general approach for the synthesis of 1 relies

on the reactions of biguanides, derived from cyanoguani-

dine and cyclic amines, with different reagents (Scheme 1,

Route 2). The reaction of biguanides with benzoin is highly

sensitive to pH and substrate structure,²⁴making the scope

of this method for the preparation of 4-aryl-6-cycloamino-

1,3,5-triazin-2-amines limited. The condensation of bigua-

nides with carboxylic acid derivatives, for example, esters in

the presence of strong bases, is the most common method

for the synthesis of 1.²⁵Recently, N,N-dimethyl-substituted

amides were employed in the imidazolium-catalyzed reac-

tion with biguanides resulting in the triazine ring closure.²⁶

However, this reaction was more applicable to DMF as a

one-carbon inserting synthon and only one 4-aryl deriva-

tive was prepared by this method.²⁶Benzyl alcohols were

reported to react with biguanides under the ruthenium²⁷or

graphene oxide²⁸catalysis affording 4-aryl-6-cycloamino-

1,3,5-triazin-2-amines 1. Being more general in scope,

these methods suffer from relatively long reaction time

(heating for up to 30 h in the second step).

Recently, we developed a new method for the synthesis

of 6,N²-diaryl-1,3,5-triazin-2,4-diamines 3 via a one-pot

three-component condensation, followed by the Dimroth

rearrangement and dehydrogenative aromatization of the

dihydrotriazine intermediates 2 (Scheme 2).²⁹This method

was efficiently applied to a wide range of substrates and af-

forded compounds with significant anticancer activity.³⁰

The three-component synthesis of dihydrotriazines 4 has

not been reported. Moreover, secondary amines and all ali-

phatic amines failed to afford dihydrotriazines in earlier at-

tempts³¹to involve them in the three-component reaction

with cyanoguanidine and aldehydes. Nevertheless, we de-

C

M. S. Shahari et al.

Paper

Synthesis

Route 1

Cl

Ar

N

Cl

N

Cl

N

ArB(OH)₂

O

NH

NH₃

Na₂CO₃, Pd(PPh₃)₄

N

NH₂

N

Cl

N

Cl

N

NH₂

O

(ref. 20)

Ph

O

Ph

OH

Route 2

Ph

NH NH

N

NH

(ref. 24)

N

H

NH₂

NH

N

NH₂

N

H

NH₂

Ar

N

NH NH

N

reagents/catalysts

O

NH

N

H

NH₂

N

NH₂

O

Reagents/catalysts

ArCO₂Et, NaOMe

Ref.

25

26

27

28

ArC(=O)NH₂, imidazole HCl

ArCH₂OH, tBuOK, RuCl₂(COD)

ArCH₂OH, KOH, graphene oxide

Scheme 1 Reported methods for the synthesis of 4-aryl-6-cycloamino-1,3,5-triazin-2-amines

cided to attempt performing the three-component synthe-

sis of 4 under microwave irradiation also suggesting that

upon heating in the presence of a base, these intermediates

would undergo dehydrogenative aromatization to afford

the desired triazines 1 (Scheme 2). Performing both of

these transformations in a one-pot manner would make

this method more practical for the fast synthesis of diverse

4-aryl-6-cycloamino-1,3,5-triazin-2-amines 1. Microwave

irradiation has demonstrated a great utility in the multi-

component reactions³²and for the preparation of 1,3,5-tri-

azines³³improving the efficiency of synthetic procedures.

Herein we report the development of a new method for the

synthesis of 4-aryl-6-cycloamino-1,3,5-triazin-2-amines 1

via the proposed approach under microwave irradiation.

For the trial reaction and the subsequent condition opti-

mization, we utilized the model reaction of cyanoguanidine

with p-tolualdehyde and morpholine under controlled mi-

crowave irradiation in a Monowave 400 reactor (Anton Paar,

Austria) (Table 1). Replicating the reaction conditions from

our protocol developed earlier for the synthesis of 6,N²-dia-

ryl-1,3,5-triazin-2,4-diamines 3,²⁹we were delighted to ob-

serve the formation of the desired product 1f, which was

easily isolated by simple filtration in 37% yield (Table 1, en-

try 2). Changing the solvent from EtOH to MeOH or PrOH

resulted in lower yields (entries 1 and 3). Attempts to in-

crease or decrease the reaction temperature also had a neg-

ative impact on yields of 1f (entries 4 and 5) and further op-

timization was continued at 140 °C using EtOH as a reaction

Ar²

CHO

Ar¹

NaOH

Ar¹NH₂

HCl

N

.

(ref. 29)

HCl

+

Ar¹

NH

N

NH₂

H₂N

N

NH₂

N

H

N

NH₂

2

3

H

Ar

CHO

HCl

NaOH

X

N

NH

N

.

+

HCl

NH

(this work)

N

NH₂

NH

N

NH₂

X

N

NH₂

4

1

H

Scheme 2 One-pot three-component synthesis of 6,N²-diaryl-1,3,5-triazin-2,4-diamines 3 and proposed synthesis of 4-aryl-6-cycloamino-1,3,5-triaz-

in-2-amines 1

D

M. S. Shahari et al.

Paper

Synthesis

medium. It was found that an increase in the duration of the

first step benefited the reaction outcome improving the

yield to 44% in 55 minutes (entry 6). Further improvement

to 48% yield was achieved extending the duration of the

second step to 20 minutes (entry 7). The longer duration of

the second step resulted in lower yields, probably due to the

gradual degradation of the product under the reaction con-

ditions (entries 8 and 9). The addition of another equivalent

of p-tolualdehyde at any of the steps did not improve the re-

action outcome (entries 10 and 11). At the same time, the

base appeared to play a critical role in the second step. The

detrimental effect to the reaction outcome was observed

when sodium hydroxide was applied in the second step in

the quantity equimolar to hydrochloric acid added in the

first step (entry 12). Heating without microwave irradiation

under otherwise similar conditions using a Monowave 50

reactor resulted in some decrease in the yield of 1f (entry

13). Therefore, microwave conditions allowing isolation of

1f in 48% yield (entry 7) were used for the exploration of

the reaction scope (more detailed optimization results are

available in Supporting Information Table S1). It should be

also noted that unlike in the synthesis of N²-aryl analogues

3,³⁴we were unable to isolate intermediate 4 after the first

step.

In the exploration of the method scope, different aro-

matic aldehydes and cyclic amines were examined. The re-

action of cyanoguanidine and morpholine with benzalde-

hydes tolerated various substituents in the aldehyde aro-

matic ring (Scheme 3). Moreover, heteroaromatic aldehyde

was also successfully involved in the reaction affording 1p

in 53% yield.

Examining the scope of cyclic amines for the reaction,

we found that in the three-component reaction with cy-

anoguanidine and benzaldehyde, morpholine could be re-

placed by pyrrolidine, piperidines, N-methylpiperazine, or

tetrahydroisoquinoline thus affording corresponding 6-cy-

cloamino-4-phenyl-1,3,5-triazin-2-amines 1q–u (Scheme

4).

The proposed mechanism for the synthesis of 1 is out-

lined in Scheme 5. In the first step, the addition of a cyclic

amine to the acid-activated nitrile group of cyanoguanidine

is followed by the reaction of the formed biguanide 5 with

an aldehyde resulting in the dihydrotriazine ring closure

and formation of the intermediate 4. In the presence of al-

kali, it converts into the N-Mannich base 6, which under-

goes dehydrogenative aromatization resulting in the forma-

tion of 1. It is proposed that the aromatization involves ini-

tial ring-opening by the alkali, oxidation to the N-

acylbiguanide 7, recyclization to 8, and subsequent dehy-

dration affording the desired product 1.

The NMR spectroscopic data for the prepared com-

pounds support proposed structure 1. In the ¹³C NMR spec-

tra of 1, the three downfield signals at 164.4–169.7 ppm

confirm the formation of an electron-deficient aromatic

1,3,5-triazine ring.

Due to extended conjugation, the triazine and a phenyl

ring directly attached to it are coplanar. This results in a sig-

nificant downfield shift of the H NMR spectra signals at-

tributed to phenyl protons located in ortho-positions to the

triazine and experiencing its anisotropic effect.

1

The electron-deficient nature of the triazine ring results

in significant delocalization of electrons from the adjacent

amino groups. The protons of the primary amino group in

1

position 2 are therefore deshielded and their signal in H

NMR spectra appear at 6.71–7.01 ppm. The electron delo-

calization of the cycloamino nitrogen atom is particularly

visible in the NMR spectra of 1q, which possesses a relative-

ly more rigid pyrrolidine ring. This delocalization implies a

partial double bond character of the C–N bond connecting

Table 1 Optimization of Reaction Conditions for the Synthesis of

4-(4-Methylphenyl)-6-morpholino-1,3,5-triazin-2-amine (1f) under

Microwave Irradiation^a

Me

(i) solvent, HCl (concd), MW

(ii) aq NaOH, MW

CHO

+

N

O

NH

N

NH

N

NH₂

O

N

NH₂

1f

H

Entry

Solvent

Temp (°C)

Reaction time (min) Yield (%)^b

(i) (ii)

1

2

MeOH

EtOH

PrOH

EtOH

140

130

150

140

20

15

33

37

9

20

55

15

20

25

60

20

3

4

28

31

44

48

46

41

33

26

6

5

6

7

8

9

10^c

11^d

12^e

13^f

33

^aThe reactions were performed in a Monowave 400 microwave reactor

(Anton Paar, Austria) using cyanoguanidine (2.5 mmol), p-tolualdehyde

(2.5 mmol), morpholine (2.5 mmol), and concd HCl (2.5 mmol) in 2 mL of

the specified solvent in step (i) and addition of 1 mL of aq 5 N NaOH in step

(ii).

^bIsolated yield calculated on the basis of cyanoguanidine.

^cThe reaction was carried out using 5 mmol of p-tolualdehyde.

^dAnother 2.5 mmol of p-tolualdehyde was added to the reaction mixture in

step (ii).

^eAq 5 N NaOH (0.5 mL, 2.5 mmol) was used in step (ii).

^fThe reaction was performed in a Monowave 50 reactor (Anton Paar,

Austria) without microwave irradiation.

E

M. S. Shahari et al.

Paper

Synthesis

R

CHO

1) EtOH, HCl (1 equiv), MW, 140 °C, 55 min

2) aq NaOH (2 equiv), MW, 140 °C, 20 min

N

NH

+

N

NH₂

Cl

N

NH₂

O

NH

O

H

1

F

N

NH₂

N

NH₂

N

NH₂

N

NH₂

O

1a (35%)

1b (31%)

1c (35%)

tBu

1d (36%)

Me

NMe₂

Me

N

NH₂

N

NH₂

N

NH₂

N

NH₂

O

1e (32%)

1f (48%)

1g (53%)

1h (18%)

OMe

OCF₃

OPh

OBn

N

NH₂

N

NH₂

N

NH₂

N

NH₂

1i (45%)

1j (26%)

1k (55%)

1l (40%)

OBn

OMe

MeO

OMe

S

N

NH₂

N

NH₂

N

NH₂

N

NH₂

1p (53%)

1m (71%)

1n (37%)

1o (41%)

Scheme 3 Scope of aromatic aldehydes for the synthesis of 4-aryl-6-morpholino-1,3,5-triazin-2-amines 1a–p

the rings. In ¹H and ¹³C NMR spectra of 1q, the restricted ro-

tation around this bond manifests in individual signals for

magnetically non-equivalent atoms of the opposite sides of

the symmetrical pyrrolidine ring.

triazine ring and due to restricted rotation become magnet-

ically non-equivalent. Therefore, in the ¹H NMR spectrum of

1s, these protons give two independent signals downfield-

shifted to 4.72–4.81 ppm (Δ ≈ 1.7–1.8 from the signals of

the same protons in 4-methylpiperidine³⁶) due to the

anisotropic effect of the triazine ring. The axial protons at

the same carbon atoms are significantly less affected (Δ ≈

0.3 ppm). At higher temperatures (35 °C), two broad signals

of the equatorial -CH coalesce into a single peak still sug-

gesting slow rotation around the C–N bond between the

triazine and piperidine rings due to the lone pair delocal-

ization (Figure 2). Upon further heating, the signal of the

1

The H NMR spectrum of 1s also confirms the substan-

tial delocalization of the lone pair of the piperidine nitrogen

over the triazine ring. The methyl group in position 4 of the

piperidine ring stabilizes its chair conformation with sub-

stituents occupying equatorial positions. The chemical

shifts and coupling for the signals of the remaining protons

also confirm the chair conformation of the piperidine³⁵in

1s. Additionally, the equatorial protons at carbon atoms ad-

jacent to the piperidine nitrogen occur in the plane of the

F

M. S. Shahari et al.

Paper

Synthesis

Ph

1) EtOH, HCl (1 equiv), MW, 140 °C, 55 min

2) aq NaOH (2 equiv), MW, 140 °C, 20 min

CHO

N

NH

+

N

X

N

NH₂

X

NH

N

NH₂

H

1

Ph

N

Ph

N

NH₂

N

NH₂

N

NH₂

1r (10%)

1s (9%)

Me

Ph

1q (14%)

Ph

N

NH₂

N

NH₂

N

1t (34%)

1u (38%)

Me

Scheme 4 Scope of cyclic amines for the synthesis of 4-phenyl-6-cycloamino-1,3,5-triazin-2-amines 1q–u

NH₂

O

NH⁺

N

HN

Ar

HN

NH

N

HN

NH

H⁺

H

HO

N

H

N

X

HN

N

H

+

X

Ar

H₂O

Ar

5

HN

X

NH₂

^–N

HO

N

HO^–

N

HN

N

^–O

Ar

N

H

N

H

N

H

N

X

H

Ar

6

4

– H⁺, – 2 e^–

NH₂

N

HN

N

O

HO

– H₂O

Ar

N

H

N

H

N

Ar

X

Ar

8

1

7

Scheme 5 Proposed mechanism for the synthesis of 4-aryl-6-cycloamino-1,3,5-triazin-2-amines 1

equatorial -CH transforms into the expected doublet with

²J_gem= –13 Hz. Due to the 1,4-substitution of the piperidine

ring in 1s, its chair conformation remains stable at these

temperatures.

ship. The (benzyloxy)phenyl residue is twisted as seen in

the dihedral angle between the rings of 79.47(4)°. The ter-

minal ring lies in a position orientated towards the bay re-

gion of the molecule defined by the triazine and two con-

nected rings, and is orthogonal to the central plane forming

a dihedral angle of 88.80(3)°. Within the ring, the C–N bond

lengths span a relatively narrow range, that is, 1.3293(14) Å

for C4–N5 to 1.3546(14) Å for C2–N3, consistent with con-

siderable delocalization of -electron density over the ring;

the exocyclic C2–N2 bond [1.3429(14) Å] lies within this

range.

The structural assignments were further confirmed by

X-ray crystallography data for two representative com-

pounds 1l and 1n; their molecular structures are illustrated

in Figure 3. In 1l, the six atoms comprising the triazine ring

are planar, exhibiting a root-mean-square (r.m.s.) deviation

= 0.0074 Å. The pendent phenyl ring is inclined to the cen-

tral plane [N3C3/C6 dihedral angle = 26.77(5)°] and the di-

hedral angle between the triazine ring and the best plane

through the morpholine ring (chair conformation) of

5.89(7)° is indicative of approximately co-planar relation-

The molecular structure of 1n (Figure 3b) presents simi-

lar features to that of 1l. The r.m.s. deviation for the six at-

oms comprising triazine ring = 0.0090 Å. The dihedral an-

G

M. S. Shahari et al.

Paper

Synthesis

for C2–N3, and, again, as for 1l, there is no pattern of alter-

nating short and long C–N bonds within the triazine ring;

the C2–N2 bond length is 1.3366(16) Å.

Me

H

N

Ph

H

N

In the molecular packing of 1l, amine-N–H···N(triazine)

hydrogen bonding assembles centrosymmetrically-related

molecules into dimeric aggregates through eight-mem-

bered {···HNCN}₂supramolecular synthons (Figure 4a). Geo-

metric parameters characterizing the key interatomic con-

tacts are given in the caption of Supporting Information

Figure S1. The aggregates thus formed are linked into a su-

pramolecular tape, approximately along [1 3 0], by amine-

N–H···O(ether) hydrogen bonds. The connections between

tapes to form a layer in the ab-plane are -stacking interac-

tions between triazine and C41-phenyl rings as detailed in

Supporting Information Figure S1; layers stack along the c-

axis without directional interactions between them.

1s

H₂N

Figure 2 Restricted rotation around the C–N bond between the tri-

azine and piperidine rings in 1s: signals of the equatorial -CH of piperi-

dine in dynamic ¹H NMR spectra

Figure 4 Supramolecular association sustained by conventional hydro-

gen bonds in 1l and 1n: (a) the supramolecular tape in the crystal of 1l

and (b) supramolecular layer in the crystal of 1n (non-participating hy-

drogen atoms have been omitted for clarity). The N–H···O and N–H···N

hydrogen bonds are represented by orange and blue dashed lines, re-

spectively.

Figure 3 Molecular structures of (a) 1l and (b) 1n showing atom label-

ing scheme and 70% anisotropic displacement parameters

A more complicated expansion of supramolecular asso-

ciation is evident in the crystal of 1n whereby each mole-

cule is connected to four symmetry-related molecules by

conventional hydrogen bonding. Thus, the hydrogen bonds

prominent in the molecular packing are amine-N–

H···O(morpholine) and amine-N–H···N(triazine), and lead to

the formation of a two-dimensional array in the ac-plane

(Figure 4b); see the caption of Supporting Information Fig-

ure S2 for geometric details. Additional stabilization to the

gles between the central plane and the attached phenyl

[11.28(5)°] and morpholine [5.10(5)°; chair conformation]

rings indicate, to a first approximation, co-planar relation-

ships. The molecule has the shape of the letter U. Within

the triazine ring, significant delocalization of -electron

density is indicated as the range of C–N bond lengths is less

than for 1l, that is, 1.3318(16) Å for C4–N3 to 1.3529(16) Å

H

M. S. Shahari et al.

Paper

Synthesis

layer is afforded by morpholine-C–H···O(methoxy) and

morpholine-C–H···(phenyl) contacts. The layers stack

along the b-axis with the directional interactions to consol-

idate the three-dimensional packing being methyl-C–

H···O(methoxy) and -stacking interactions between tri-

azine and C41-phenyl rings; a view of the unit-cell contents

is shown in Supporting Information Figure S2.

Austria) microwave reactor operating at maximal microwave power

up to 850 W at 140 °C for 55 min. After cooling to rt, aq 5 N NaOH (1

mL) was added to the mixture and irradiation was continued for an-

other 20 min at 140 °C. After cooling, the precipitated product was fil-

tered, washed with H₂O, and recrystallized from an appropriate sol-

vent affording desired products 1.

6-Morpholino-4-phenyl-1,3,5-triazin-2-amine (1a)

The prepared compounds were screened for antiprolif-

erative activity against a Jurkat-T cell line at 10 M. The

most potent compound identified in the screening was 6-

[3,4-dihydroisoquinolin-2(1H)-yl]-4-phenyl-1,3,5-triazin-

2-amine (1u), which was further tested at several concen-

trations (Supporting Information, Figure S3) to estimate the

50% growth inhibition (GI₅₀) value. Typical antileukemic

drugs mercaptopurine, methotrexate, and cytarabine were

used as positive controls. It was found that 1u inhibited cell

proliferation in a concentration-dependent manner demon-

strating the GI₅₀value of 1.95 ± 0.25 M. Being more potent

than mercaptopurine (GI₅₀= 11.12 ± 4.89 M), 1u was less

effective than methotrexate (GI₅₀= 0.37 ± 0.03 M) and cy-

tarabine (GI₅₀= 0.29 ± 0.01 M). Nevertheless, these results

indicate that the search for new antileukemic agents among

4-aryl-6-cycloamino-1,3,5-triazin-2-amines could be fruit-

ful.

In conclusion, we have developed a new method for the

fast one-pot synthesis of diverse 4-aryl-6-cycloamino-

1,3,5-triazin-2-amines. This method is based on two pro-

cesses: (1) acid-catalyzed three-component condensation

of cyanoguanidine, aromatic aldehydes, and cyclic amines

and (2) dehydrogenative aromatization in the presence of a

base. Overall, the method was found to be rather general,

with similar efficacy applicable to various aldehydes and

cyclic amines. The main advantage of the method is the po-

tential for quick and convenient access to structurally di-

verse 4-aryl-6-cycloamino-1,3,5-triazin-2-amines for their

biological evaluations. Preliminary data from the antileuke-

mic screening of prepared 4-aryl-6-cycloamino-1,3,5-triaz-

in-2-amines were promising. Further investigations are un-

der way and the results will be reported in due course.

White solid; yield: 224 mg (35%); mp 119–121 °C (EtOH) (Lit.³⁷mp

121–123 °C.

¹H NMR (300 MHz, DMSO-d₆):  = 3.63–3.67 (4 H, m, CH₂OCH₂), 3.80

(4 H, br s, CH₂NCH₂), 6.94 (2 H, br s, NH₂), 7.43–7.55 (3 H, m, H-3′, H-

4′, and H-5′), 8.28–8.32 (2 H, m, H-2′ and H-6′).

¹³C NMR (75 MHz, DMSO-d₆):  = 43.1 (CH₂NCH₂), 65.9 (CH₂OCH₂),

127.7 (2 C), 128.1 (2 C), 131.2, 136.8, 164.9 (C-6), 167.1 (C-2), 169.6

(C-4).

Anal. Calcd for C₁₃H₁₅N₅O: C, 60.69; H, 5.88; N, 27.22. Found: C, 60.54;

H, 5.93; N, 27.07.

4-(3-Fluorophenyl)-6-morpholino-1,3,5-triazin-2-amine (1b)

White solid; yield: 215 mg (31%); mp 143–144 °C (EtOH).

¹H NMR (300 MHz, DMSO-d₆):  = 3.63–3.68 (4 H, m, CH₂OCH₂), 3.80

(4 H, br s, CH₂NCH₂), 7.03 (2 H, br s, NH₂), 7.37 (1 H, ddt, J = 0.9, 2.7,

8.5 Hz, H-4′), 7.53 (1 H, ddd, J = 6.0, 8.0, 8.0 Hz, H-5′), 8.01 (1 H, ddd,

J = 1.4, 2.7, 10.6 Hz, H-2′), 8.14 (1 H, ddd, J = 1.2, 1.2, 7.8 Hz, H-6′).

¹³C NMR (75 MHz, DMSO-d₆):  = 43.1 (CH₂NCH₂), 65.9 (CH₂OCH₂),

114.0 (d, J = 22.9 Hz), 118.0 (d, J = 21.1 Hz), 123.7 (d, J = 3.0 Hz), 130.2

(d, J = 7.5 Hz), 139.6 (d, J = 7.5 Hz), 162.1 (d, J = 242.2 Hz), 164.8 (C-6),

167.1 (C-2), 168.5 (d, J = 3.1 Hz, C-4).

Anal. Calcd for C₁₃H₁₄FN₅O: C, 56.72; H, 5.13; N, 25.44. Found: C,

56.55; H, 5.20; N, 25.32.

4-(4-Fluorophenyl)-6-morpholino-1,3,5-triazin-2-amine (1c)

White solid; yield: 239 mg (35%); mp 186–187 °C (EtOH).

¹H NMR (300 MHz, DMSO-d₆):  = 3.63–3.67 (4 H, m, CH₂OCH₂), 3.79

(4 H, br s, CH₂NCH₂), 6.96 (2 H, br s, NH₂), 7.29 (2 H, dd, J = 8.8, 8.8 Hz,

H-3′ and H-5′), 8.35 (2 H, dd, J = 5.9, 8.7 Hz, H-2′ and H-6′).

¹³C NMR (75 MHz, DMSO-d₆):  = 43.1 (CH₂NCH₂), 65.9 (CH₂OCH₂),

115.0 (2 C, d, J = 21.6 Hz), 130.1 (2 C, d, J = 8.9 Hz), 133.3 (d, J = 2.2 Hz),

164.1 (d, J = 248.3), 164.8 (C-6), 167.1 (C-2), 168.7 (C-4).

Anal. Calcd for C₁₃H₁₄FN₅O: C, 56.72; H, 5.13; N, 25.44. Found: C,

56.59; H, 5.20; N, 25.32.

4-(4-Chlorophenyl)-6-morpholino-1,3,5-triazin-2-amine (1d)

Yellowish solid; yield: 264 mg (36%); mp 203–204 °C (EtOH) (Lit.³⁸mp

198–201 °C).

¹H NMR (300 MHz, DMSO-d₆):  = 3.63–3.67 (4 H, m, CH₂OCH₂), 3.79

(4 H, br s, CH₂NCH₂), 6.99 (2 H, br s, NH₂), 7.54 (2 H, d, J = 8.7 Hz, H-3′

and H-5′), 8.30 (2 H, d, J = 8.7 Hz, H-2′ and H-6′).

¹³C NMR (75 MHz, DMSO-d₆):  = 43.1 (CH₂NCH₂), 65.9 (CH₂OCH₂),

128.2 (2 C), 129.5 (2 C), 135.7, 136.0, 164.8 (C-6), 167.1 (C-2), 168.7

(C-4).

Melting points (uncorrected) were determined on a Stuart SMP40 au-

tomatic melting point apparatus. ¹H and ¹³C NMR spectra were re-

corded on a Bruker Fourier NMR spectrometer (300 MHz) using

DMSO-d₆as a solvent and TMS as an internal reference. Microwave-

assisted reactions were carried out in the closed vessel focused single

mode using a Monowave 400 microwave synthesizer (Anton Paar,

Austria) monitoring reaction temperature by the equipped IR sensor.

The control experiment using conventional heating was performed in

a Monowave 50 (Anton Paar, Austria) reactor.

Anal. Calcd for C₁₃H₁₄ClN₅O: C, 53.52; H, 4.84; N, 24.01. Found: C,

53.39; H, 4.97; N, 23.94.

4-Aryl-6-cycloamino-1,3,5-triazin-2-amines 1; General Procedure

To a solution of cyanoguanidine (0.21 g, 2.5 mmol), (het)arylaldehyde

(2.5 mmol), and cyclic amine (2.5 mmol) in EtOH (2 mL) in a 10 mL

seamless pressure vial was added concd HCl (0.21 mL, 2.5 mmol). The

reaction mixture was irradiated in the Monowave 400 (Anton Paar,

4-(3-Methylphenyl)-6-morpholino-1,3,5-triazin-2-amine (1e)

White solid; yield: 216 mg (32%); mp 151–152 °C (EtOH).

I

M. S. Shahari et al.

Paper

Synthesis

¹H NMR (300 MHz, DMSO-d₆):  = 2.39 (3 H, s, CH₃), 3.64–3.69 (4 H,

m, CH₂OCH₂), 3.82 (4 H, br s, CH₂NCH₂), 6.97 (2 H, br s, NH₂), 7.32–

7.40 (2 H, m, H-4′ and H-5′), 8.10–8.17 (2 H, m, H-2′ and H-6′).

4-[4-(Trifluoromethoxy)phenyl]-6-morpholino-1,3,5-triazin-2-

amine (1j)

White solid; yield: 220 mg (26%); mp 141–142 °C (EtOH).

¹³C NMR (75 MHz, DMSO-d₆):  = 21.0 (CH₃), 43.1 (CH₂NCH₂), 66.0

(CH₂OCH₂), 125.0, 128.0, 128.2, 131.8, 136.8, 137.2, 164.9 (C-6), 167.1

(C-2), 169.7 (C-4).

¹H NMR (300 MHz, DMSO-d₆):  = 3.64–3.67 (4 H, m, CH₂OCH₂), 3.79

(4 H, br s, CH₂NCH₂), 7.04 (2 H, br s, NH₂), 7.46 (2 H, d, J = 8.9 Hz, H-3′

and H-5′), 8.40 (2 H, d, J = 8.9 Hz, H-2′ and H-6′).

¹³C NMR (75 MHz, DMSO-d₆):  = 43.1 (CH₂NCH₂), 65.9 (CH₂OCH₂),

119.9 (q, J = 257.4 Hz, OCF₃), 120.4 (2 C), 129.8 (2 C), 136.0, 150.4 (q,

J = 1.5 Hz), 164.8 (C-6), 167.1 (C-2), 168.5 (C-4).

Anal. Calcd for C₁₄H₁₇N₅O: C, 61.98; H, 6.32; N, 25.81. Found: C, 61.85;

H, 6.45; N, 25.69.

4-(4-Methylphenyl)-6-morpholino-1,3,5-triazin-2-amine (1f)

White solid; yield: 324 mg (48%); mp 167–168 °C (EtOH) (Lit.²⁵mp

Anal. Calcd for C₁₄H₁₄F₃N₅O₂: C, 49.27; H, 4.13; N, 20.52. Found: C,

49.13; H, 4.29; N, 20.40.

167 °C).

¹H NMR (300 MHz, DMSO-d₆):  = 2.37 (3 H, s, CH₃), 3.63–3.67 (4 H,

m, CH₂OCH₂), 3.79 (4 H, br s, CH₂NCH₂), 6.92 (2 H, br s, NH₂), 7.27 (2

H, d, J = 8.0 Hz, H-3′ and H-5′), 8.20 (2 H, d, J = 8.2 Hz, H-2′ and H-6′).

¹³C NMR (75 MHz, DMSO-d₆):  = 21.0 (CH₃), 43.1 (CH₂NCH₂), 65.9

(CH₂OCH₂), 127.8 (2 C), 128.7 (2 C), 134.1, 141.0, 164.9 (C-6), 167.1

(C-2), 169.6 (C-4).

6-Morpholino-4-(3-phenoxyphenyl)-1,3,5-triazin-2-amine (1k)

White solid; yield: 480 mg (55%); mp 147–148 °C (EtOH).

¹H NMR (300 MHz, DMSO-d₆):  = 3.62–3.65 (4 H, m, CH₂OCH₂), 3.76

(4 H, br s, CH₂NCH₂), 6.95 (2 H, br s, NH₂), 7.04 (2 H, m, H-6′′ and H-

2′′), 7.13–7.22 (2 H, m, H-4′ and H-4′′), 7.37–7.45 (2 H, m, H-3′′ and H-

5′′), 7.49 (1 H, t, J = 7.9 Hz, H-5′), 7.90 (1 H, dd, J = 1.4, 2.5 Hz, H-2′),

8.09 (1 H, ddd, J = 1.2, 1.4, 7.8 Hz, H-6′).

¹³C NMR (75 MHz, DMSO-d₆):  = 43.1 (CH₂NCH₂), 65.9 (CH₂OCH₂),

117.7 (C-2′), 118.4 (2 C), 121.6, 122.9, 123.4, 129.8, 130.0 (2 C), 139.0,

156.5, 156.7, 164.8 (C-6), 167.1 (C-2), 169.0 (C-4).

Anal. Calcd for C₁₄H₁₇N₅O: C, 61.98; H, 6.32; N, 25.81. Found: C, 61.88;

H, 6.41; N, 25.73.

4-[4-(tert-Butyl)phenyl]-6-morpholino-1,3,5-triazin-2-amine (1g)

White solid; yield: 418 mg (53%); mp 178–179 °C (EtOH).

Anal. Calcd for C₁₉H₁₉N₅O₂: C, 65.32; H, 5.48; N, 20.04. Found: C,

65.19; H, 5.63; N, 19.88.

¹H NMR (300 MHz, DMSO-d₆):  = 1.31 [9 H, s, C(CH₃)₃], 3.63–3.67 (4

H, m, CH₂OCH₂), 3.78 (4 H, br s, CH₂NCH₂), 6.91 (2 H, br s, NH₂), 7.48

(2 H, d, J = 8.6 Hz, H-3′ and H-5′), 8.21 (2 H, d, J = 8.6 Hz, H-2′ and H-

6′).

4-[3-(Benzyloxy)phenyl]-6-morpholino-1,3,5-triazin-2-amine (1l)

Light brown solid; yield: 362 mg (40%); mp 161–162 °C (MeCN).

¹³C NMR (75 MHz, DMSO-d₆):  = 30.9 [C(CH₃)₃], 34.5 [C(CH₃)₃], 43.0

(CH₂NCH₂), 65.9 (CH₂OCH₂), 124.8 (2 C), 127.6 (2 C), 134.1, 153.9,

164.8 (C-6), 167.1 (C-2), 169.6 (C-4).

¹H NMR (300 MHz, DMSO-d₆):  = 3.60–3.69 (4 H, m, CH₂OCH₂), 3.78

(4 H, br s, CH₂NCH₂), 5.17 (2 H, s, OCH₂Ph), 6.97 (2 H, br s, NH₂), 7.18

(1 H, ddd, J = 1.0, 2.6, 8.2 Hz, H-4′), 7.30–7.44 (4 H, m, H-5′, H-3′′, H-4′′

and H-5′′), 7.46–7.51 (2 H, m, H-2′′ and H-6′′), 7.88–7.96 (2 H, m, H-2′

and H-6′).

Anal. Calcd for C₁₇H₂₃N₅O: C, 65.15; H, 7.40; N, 22.35. Found: C, 65.02;

H, 7.53; N, 22.23.

¹³C NMR (75 MHz, DMSO-d₆):  = 43.1 (CH₂NCH₂), 65.9 (CH₂OCH₂),

69.2 (OCH₂Ph), 113.9, 117.7, 120.3, 127.6 (2 C), 127.8, 128.4 (2 C),

129.2, 137.0, 138.4, 158.2, 164.8 (C-6), 167.1 (C-2), 169.4 (C-4).

4-[4-(N,N-Dimethylamino)phenyl]-6-morpholino-1,3,5-triazin-2-

amine (1h)

Yellow solid; yield: 132 mg (18%); mp 209–210 °C (EtOH).

Anal. Calcd for C₂₀H₂₁N₅O₂: C, 66.10; H, 5.82; N, 19.27. Found: C,

65.89; H, 5.96; N, 19.11.

¹H NMR (300 MHz, DMSO-d₆):  = 2.99 (CH₃), 3.62–3.65 (4 H, m,

CH₂OCH₂), 3.76 (4 H, br s, CH₂NCH₂), 6.71 (2 H, br s, NH₂), 6.72 (2 H, d,

J = 9.1 Hz, H-3′ and H-5′), 8.14 (2 H, d, J = 9.0 Hz, H-2′ and H-6′).

¹³C NMR (75 MHz, DMSO-d₆):  = 39.6 [N(CH₃)₂], 43.0 (CH₂NCH₂), 65.9

(CH₂OCH₂), 110.8 (2 C), 123.6, 129.1 (2 C), 152.3, 164.8 (C-6), 166.9

(C-2), 169.6 (C-4).

4-[4-(Benzyloxy)phenyl]-6-morpholino-1,3,5-triazin-2-amine

(1m)

Yellow solid; yield: 641 mg (71%); mp 164–165 °C (EtOH).

¹H NMR (300 MHz, DMSO-d₆):  = 3.61–3.66 (4 H, m, CH₂OCH₂), 3.78

(4 H, br s, CH₂NCH₂), 5.17 (2 H, s, OCH₂Ph), 6.86 (2 H, br s, NH₂), 7.09

(2 H, d, J = 9.0 Hz, H-3′ and H-5′), 7.31–7.51 (5 H, m, OCH₂C₆H₅), 8.25

(2 H, d, J = 8.9 Hz, H-2′ and H-6′).

Anal. Calcd for C₁₅H₂₀N₆O: C, 59.98; H, 6.71; N, 27.98. Found: C, 59.87;

H, 6.82; N, 27.85.

4-(4-Methoxyphenyl)-6-morpholino-1,3,5-triazin-2-amine (1i)

Yellowish solid; yield: 325 mg (45%); mp 182–183 °C (EtOH) (Lit.³⁸mp

177–179 °C).

¹³C NMR (75 MHz, DMSO-d₆):  = 43.1 (CH₂NCH₂), 65.9 (CH₂OCH₂),

69.3 (OCH₂Ph), 114.2 (2 C), 127.7 (2 C), 127.8, 128.4 (2 C), 129.3, 129.5

(2 C), 136.7, 160.9, 164.8 (C-6), 167.0 (C-2), 169.2 (C-4).

¹H NMR (300 MHz, DMSO-d₆):  = 3.64–3.68 (4 H, m, CH₂OCH₂), 3.80

(4 H, br s, CH₂NCH₂), 3.83 (3 H, s, OCH₃), 6.88 (2 H, br s, NH₂), 7.02 (2

H, d, J = 9.0 Hz, H-3′ and H-5′), 8.28 (2 H, d, J = 9.0 Hz, H-2′ and H-6′).

Anal. Calcd for C₂₀H₂₁N₅O₂: C, 66.10; H, 5.82; N, 19.27. Found: C,

65.98; H, 5.90; N, 19.13.

4-(3,4-Dimethoxyphenyl)-6-morpholino-1,3,5-triazin-2-amine

(1n)

¹³C NMR (75 MHz, DMSO-d₆):  = 43.1 (CH₂NCH₂), 55.2 (OCH₃), 66.0

(CH₂OCH₂), 113.4 (2 C), 129.2, 129.5 (2 C), 161.8, 164.9 (C-6), 167.1

(C-2), 169.3 (C-4).

White solid; yield: 297 mg (37%); mp 172–173 °C (EtOH).

Anal. Calcd for C₁₄H₁₇N₅O₂: C, 58.52; H, 5.96; N, 24.38. Found: C,

58.39; H, 6.08; N, 24.23.

J

M. S. Shahari et al.

Paper

Synthesis

¹H NMR (300 MHz, DMSO-d₆):  = 3.63–3.67 (4 H, m, CH₂OCH₂), 3.78

(4 H, br s, CH₂NCH₂), 3.81 (3 H, s, OCH₃), 3.82 (3 H, s, OCH₃), 6.87 (2 H,

br s, NH₂), 7.03 (1 H, d, J = 8.6 Hz, H-5′), 7.85 (1 H, d, J = 2.0 Hz, H-2′),

7.93 (1 H, dd, J = 2.0, 8.5 Hz, H-6′).

Anal. Calcd for C₁₄H₁₇N₅: C, 65.86; H, 6.71; N, 27.43. Found: C, 65.73;

H, 6.85; N, 27.28.

4-(4-Methylpiperidino)-6-phenyl-1,3,5-triazin-2-amine (1s)

¹³C NMR (75 MHz, DMSO-d₆):  = 43.1 (CH₂NCH₂), 55.3 (OCH₃), 55.4

(OCH₃), 65.9 (CH₂OCH₂), 110.7, 110.9, 121.3, 129.2, 148.1, 151.5,

164.8 (C-6), 167.0 (C-2), 169.3 (C-4).

White solid; yield: 58 mg (9%); mp >300 °C (EtOH).

¹H NMR (300 MHz, DMSO-d₆):  = 0.93 (3 H, d, J = 6.3 Hz, CH₃), 1.00–

1.11 (2 H, m, CH₂CHMeCH₂-ax), 1.61–1.71 (3 H, m, CHMe, CH₂NCH₂-ax),

2.86 (2 H, br t, J = 12.2 Hz, CH₂CHMeCH₂-eq), 4.72 (1 H, br s, NCH₂-eq),

4.81 (1 H, br s, NCH₂-eq), 6.85 (2 H, br s, NH₂), 7.42–7.53 (3 H, m, H-3′,

H-4′, and H-5′), 8.26–8.31 (2 H, m, H-2′ and H-6′).

Anal. Calcd for C₁₅H₁₉N₅O₃: C, 56.77; H, 6.03; N, 22.07. Found: C,

56.69; H, 6.10; N, 21.98.

¹³C NMR (75 MHz, DMSO-d₆):  = 21.7 (CH₃), 30.6 (2 × CH₂), 33.5

(CHMe), 42.7 (CH₂NCH₂), 127.6 (2 C), 128.0 (2 C), 131.0, 137.1, 164.5

(C-6), 167.2 (C-2), 169.6 (C-4).

4-(3,4,5-Trimethoxyphenyl)-6-morpholino-1,3,5-triazin-2-amine

(1o)

White solid; yield: 358 mg (41%); mp 234–235 °C (EtOH) (Lit.³⁹mp

240 °C).

Anal. Calcd for C₁₅H₁₉N₅: C, 66.89; H, 7.11; N, 26.00. Found: C, 66.78;

H, 7.23; N, 25.83.

¹H NMR (300 MHz, DMSO-d₆):  = 3.64–3.67 (4 H, m, CH₂OCH₂), 3.73

(3 H, s, OCH₃), 3.77 (4 H, br s, CH₂NCH₂), 3.84 (6 H, s, 2 × OCH₃), 6.94 (2

H, br s, NH₂), 7.62 (2 H, s, H-2′ and H-6′).

4-(4-Methylpiperazino)-6-phenyl-1,3,5-triazin-2-amine (1t)

¹³C NMR (75 MHz, DMSO-d₆):  = 43.1 (CH₂NCH₂), 55.8 (2 × OCH₃),

60.0 (OCH₃), 65.9 (CH₂OCH₂), 105.0 (2 C), 132.2, 140.3, 152.5 (2 C),

164.8 (C-6), 167.0 (C-2), 169.2 (C-4).

White solid; yield: 231 mg (34%); mp 173–174 °C (EtOH) (Lit.²²mp

171–174 °C).

¹H NMR (300 MHz, DMSO-d₆):  = 2.21 (3 H, s, NCH₃), 2.32–2.38 [4 H,

m, CH₂N(Me)CH₂], 3.81 (4 H, br s, CH₂NCH₂), 6.92 (2 H, br s, NH₂),

7.42–7.55 (3 H, m, H-3′, H-4′, and H-5′), 8.26–8.31 (2 H, m, H-2′ and

H-6′).

Anal. Calcd for C₁₆H₂₁N₅O₄: C, 55.32; H, 6.09; N, 20.16. Found: C,

55.23; H, 6.22; N, 19.99.

¹³C NMR (75 MHz, DMSO-d₆):  = 42.4 (NCH₃), 45.7 (CH₂NCH₂), 54.3

[CH₂N(Me)CH₂], 127.7 (2C), 128.1 (2C), 131.1, 136.9, 164.7 (C-6),

167.1 (C-2), 169.6 (C-4).

6-Morpholino-4-(thiophen-2-yl)-1,3,5-triazin-2-amine (1p)

Light brown solid; yield: 352 mg (53%); mp 145–146 °C (EtOH).

¹H NMR (300 MHz, DMSO-d₆):  = 3.62–3.66 (4 H, m, CH₂OCH₂), 3.75

(4 H, br s, CH₂NCH₂), 6.96 (2 H, br s, NH₂), 7.16 (1 H, dd, J = 3.7, 5.0 Hz,

H-4′), 7.73 (1 H, dd, J = 1.3, 5.0 Hz, H-5′), 7.88 (1 H, dd, J = 1.2, 3.7 Hz,

H-3′).

Anal. Calcd for C₁₄H₁₈N₆: C, 62.20; H, 6.71; N, 31.09. Found: C, 62.07;

H, 6.82; N, 30.92.

¹³C NMR (75 MHz, DMSO-d₆):  = 43.0 (CH₂NCH₂), 65.9 (CH₂OCH₂),

4-[3,4-Dihydroisoquinolin-2(1H)-yl]-6-phenyl-1,3,5-triazin-2-

amine (1u)

127.9, 129.1, 130.6, 142.7, 164.4 (C-6), 166.1 (C-2), 166.8 (C-4).

Yellowish solid; yield: 290 mg (38%); mp 139–140 °C (EtOH).

Anal. Calcd for C₁₁H₁₃N₅OS: C, 50.18; H, 4.98; N, 26.60. Found: C,

50.06; H, 5.07; N, 26.39.

¹H NMR (300 MHz, DMSO-d₆):  = 2.88 (2 H, br t, J = 6.0 Hz, NCH₂CH₂),

4.01 (1 H, br s, NCH₂CH₂), 4.11 (1 H, br s, NCH₂CH₂), 4.89 (1 H, br s,

NCH₂Ar), 5.02 (1 H, br s, NCH₂Ar), 6.96 (2 H, br s, NH₂), 7.18–7.32 (4 H,

m, NCH₂ArCH₂), 7.45–7.58 (3 H, m, H-3′, H-4′, and H-5′), 8.32–8.37 (2

H, m, H-2′ and H-6′).

¹³C NMR (75 MHz, DMSO-d₆):  = 28.4 (NCH₂CH₂), 40.4 (NCH₂CH₂),

44.9 (NCH₂Ar), 126.0, 126.2, 126.3, 127.7 (2 C), 128.1 (2 C), 131.1,

133.7 (br s), 134.7, 136.9, 164.8 (C-6), 167.1 (C-2), 169.6 (C-4).

6-Phenyl-4-pyrrolidino-1,3,5-triazin-2-amine (1q)

White solid; yield: 87 mg (14%); mp 230–231 °C (EtOH) (Lit.²⁴mp 230

°C).

¹H NMR (300 MHz, DMSO-d₆):  = 1.88–1.94 (4 H, m, CH₂CH₂), 3.44–

3.50 (2 H, m, CH₂NCH₂), 3.58–3.64 (2 H, m, CH₂NCH₂), 6.82 (2 H, br s,

NH₂), 7.42–7.54 (3 H, m, H-3′, H-4′, and H-5′), 8.27–8.32 (2 H, m, H-2′

and H-6′).

¹³C NMR (75 MHz, DMSO-d₆):  = 24.65 (CH₂), 24.73 (CH₂), 45.6

(CH₂N), 45.8 (CH₂N), 127.6 (2 C), 128.0 (2 C), 130.9, 137.1, 163.5 (C-6),

166.9 (C-2), 169.1 (C-4).

Anal. Calcd for C₁₈H₁₇N₅: C, 71.27; H, 5.65; N, 23.09. Found: C, 71.17;

H, 5.76; N, 22.91.

X-ray Crystal Structure Determination

Intensity data for 1l and 1n were measured for colorless crystals (11:

0.07 × 0.17 × 0.19 mm; 1m: 0.10 × 0.15 × 0.18 mm) at 100 K on an

Rigaku/Oxford Diffraction XtaLAB Synergy diffractometer (Dualflex,

AtlasS2) fitted with CuK radiation ( = 1.54178 Å) so that θ (100%

data completeness) = 67.1 and 67.7°, respectively. Data reduction and

Gaussian absorption corrections were by standard methods.⁴¹The

structures were solved by direct methods[^42]and refined (anisotropic

displacement parameters and with C-bound H atoms included in the

riding model approximation) on F².⁴³The N-bound H atoms were re-

fined with N–H = 0.88 ± 0.01 Å. A weighting scheme of the form w =

Anal. Calcd for C₁₃H₁₅N₅: C, 64.71; H, 6.27; N, 29.02. Found: C, 64.55;

H, 6.47; N, 28.90.

6-Phenyl-4-piperidino-1,3,5-triazin-2-amine (1r)

White solid; yield: 61 mg (10%); mp 146–147 °C (EtOH) (Lit.⁴⁰mp

149–151 °C).

¹H NMR (300 MHz, DMSO-d₆):  = 1.46–1.55 (2 H, m, CH₂CH₂CH₂),

1.59–1.66 (4 H, m, CH₂CH₂CH₂), 3.80 (4 H, br s, CH₂NCH₂), 6.84 (2 H, br

s, NH₂), 7.42–7.53 (3 H, m, H-3′, H-4′, and H-5′), 8.26–8.31 (2 H, m, H-

2′ and H-6′).

2

1/[²(F_o²) + (aP)²+ bP], where P = (F_o+ 2F_c)/3), was introduced in

¹³C NMR (75 MHz, DMSO-d₆):  = 24.2 (CH₂), 25.3 (2 × CH₂), 43.4

(CH₂NCH₂), 127.6 (2 C), 128.0 (2 C), 131.0, 137.1, 164.5 (C-6), 167.2

(C-2), 169.5 (C-4).

each case. The molecular structure diagrams showing 70% probability

K

M. S. Shahari et al.

Paper

Synthesis

displacement ellipsoids were generated by ORTEP for Windows⁴⁴and

the packing diagrams with DIAMOND.⁴⁵Additional data analysis was

made with PLATON.⁴⁶

Supporting Information

Supporting information for this article is available online at

https://doi.org/10.1055/a-1401-2795. Su

p

ortingInformationS

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ortingI

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formati

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n

Crystal Data for 1l⁴⁷

C₂₀H₂₁N₅O₂, M = 363.42, triclinic, P1, a = 5.32441(9), b = 9.52388(12), c

= 17.7526(3) Å,  = 90.2806(12),  = 97.7765(14),  = 91.0148(12)°, V

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= 891.77(2) Å³, Z = 2, D_x= 1.353 g cm^–3, F(000) = 384,  = 0.737 mm^–1

,

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Conflict of Interest

The authors declare no conflict of interest.

Funding Information

This work is supported by the Ministry of Higher Education, Malaysia

under Fundamental Research Grant Scheme (Grant no.

FRGS/1/2020/STG04/MUSM/02/2). This work also received partial

support from the School of Pharmacy, Monash University Malaysia

(Bridging Grant 2020). Sunway University Sdn Bhd is thanked for the

financial support of the X-ray crystallography laboratory (Grant no.

STR-RCTR-RCCM-001-2019).

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Article Doi

A New One-Pot Three-Component Synthesis of 4-Aryl-6-cycloamino-1,3,5-triazin-2-amines under Microwave Irradiation

DOI: 10.1055/a-1401-2795

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Article abstract of DOI:10.1055/a-1401-2795

Full text of DOI:10.1055/a-1401-2795

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