One-pot synthesis of triazines as potential agents affecting cell differentiation

Monatshefte für Chemie - Chemical Monthly

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ORIGINAL PAPER

One-pot synthesis of triazines as potential agents affecting cell

differentiation

Thomas Linder¹Michael Schnu¨rch¹

Marko D. Mihovilovic¹

•

Received: 8 April 2018 / Accepted: 23 April 2018

Ó The Author(s) 2018

Abstract

This paper outlines the synthesis of a number of structural analogs of 3-[(4,6-diphenoxy-1,3,5-triazin-2-yl)amino]benzoic

acid which represent compounds with potential cardiogenetic activity. A one-pot protocol was developed for swift

functionalization of the 1,3,5-triazine core without the need of isolating intermediates. The developed route starts from

readily available 2,4,6-trichloro-1,3,5-triazine, displacing the chlorine atoms sequentially by aryloxy, arylamino, or aryl-

thio moieties to enable access to molecules with three different substituents of this type in good yields. To facilitate

puriﬁcation, tert-butyl, methyl, and ethyl ester derivatives of the target compounds were initially synthesized. The tert-

butyl esters could be readily hydrolyzed to the desired compounds, while reduction of the methyl and ethyl esters gave the

corresponding benzylic alcohols in high yields, thereby expanding the substrate scope for future relevant cell assays.

Graphical abstract

Keywords Cell differentiation Á Triazine Á One-pot synthesis Á Nucleophilic substitution

Introduction

Cardiovascular diseases are among the most important

causes of death globally [6] and an estimated average

number of 15 years of life are lost because of a myocardial

infarction [7]. As about 34% of the patients experiencing a

coronary attack will die due to this event, these ﬁg-

ures point out the importance of new methods for cardiac

repair. Apart from replacement by tissue transplant, the

restoration by activation of resident (cardiac) stem cells or

regeneration by the formation of cardiomyocytes from

progenitor or stem cells has been given much attention

[8–10]. This is particularly important in the case of

renewing dead cardiomyoblasts in the wage of a condition

such as myocardial infarction, because the mammalian

(i.e., human) heart responds to tissue damage by scarring

rather than regeneration [11]. Human embryonic stem cells

have shown the potential to develop into cardiomyocytes

in vitro. One approach is gene therapy, which involves the

use of viral vectors for genetic manipulation and makes it

During the development of animals and humans from a

zygote to a multicellular biological system, the organism

needs to grow by cell ﬁssion and dedicate newly formed

cells to particular purposes. The process that converts those

cells of the early stages of life (the embryonic stem cells) to

specialized tissue is known as cell differentiation. Apart

from a merely biological interest, the subject is of great

importance to the medical sciences, as it promises to hold

the key for replacing damaged or lost tissue and organs

[1–5].

& Michael Schnu¨rch

michael.schnuerch@tuwien.ac.at

1

Institute of Applied Synthetic Chemistry, TU Wien,

Getreidemarkt 9/163, 1060 Vienna, Austria

123

T. Linder et al.

difﬁcult to achieve approval by health regulating bodies for

clinical use [12, 13]. Similarly, the use of viruses to obtain

induced pluripotent stem (iPS) cells from differentiated

cells for reprogramming also raises safety issues, while the

efﬁciency of plasmids for this purpose is extremely low

[14]. The use of small organic molecules to trigger cell

differentiation represents an alternative, which could be

carried out ex vivo and the so-formed cardiomyocytes

subsequently implanted.

dependent on the concentration at which it is applied, as

well as the developmental stage of the cell at the time of

exposure.

More important to this work, however, is the ﬁnding that

retinoids generally inhibit cell proliferation and promote

cardiac differentiation of stem cells [26]. While applying

small molecules for heart muscle formation is a promising

approach, applying retinoic acid itself to stem cells has

multiple issues. Given its polyoleﬁnic structure, it is rather

reactive in the presence of oxygen and light [27]. It is also

isomerized under physiological conditions and enters the

metabolism of the cell [28]. As indicated above, this nat-

ural compound also fulﬁlls many other roles in cell bio-

chemistry and responses of the cell exposed to it depend

crucially on the concentration and the state of cell, because

its interaction is unlikely to be limited to one target only

[29, 30]. This aggravates screening and makes the avail-

ability of synthetic retinoids highly desirable.

In 2004, a screen with mouse embryonic carcinoma P19

cells showed that certain 2-pyrimidinamines, termed car-

diogenols A–D (Fig. 1) up-regulated the expression of an

artiﬁcial gene containing the promoter for the atrial natri-

uretic factor (ANF) [15]. This is a polypeptide hormone,

synthesized and excreted primarily by cardiomyocytes, and

therefore considered a cardiac-speciﬁc marker protein

[16, 17]. Considerable research has been conducted in our

group to substantiate the cardiogenetic potential of these

molecules, as well as ﬁnding new ones with promising

results in the relevant biological screens (as exempliﬁed in

Fig. 2 top) [18–20].

Recently, it was determined that the heterocyclic com-

pound 3-[(4,6-diphenoxy-1,3,5-triazin-2-yl)amino]benzoic

acid (DTAB, compound 4a, Fig. 3) is an RARb and RARc

selective ligand, activating retinoic acid signaling [31].

This compound served as a starting point for the present

work, in which a method was developed which enables the

preparation of compounds with this scaffold from 2,4,6-

trichloro-1,3,5-triazine in a sequential, one-pot fashion

(Fig. 3), making use of the step-wise reactivity of the

chloride substitution process.

Retinoic acid, which is an active metabolite of retinol

(vitamin A) and occurs naturally in the all-trans (atRA) and

9-cis form (Fig. 2 bottom), has been shown to take part in a

multitude of physiological functions, notably during the

development of the organism and the proliferation of cells

[21].

Among these are the inhibition of the serotonin-acti-

vated proliferation of aortic smooth muscle cells in primary

culture (as shown in dogs) and inhibition of cell prolifer-

ation in cultivated chick embryonic vascular smooth mus-

cle cells [22, 23], to the extent that retinoids, such as atRA,

have been used clinically for anti-cancer treatments and

therapies in dermatology [24]. On the other hand, there

have been indications that retinoic acid may enhance,

rather than suppress, proliferation of smooth muscle cells

[25]. Examples like these illustrate that the physiological

effects of retinoic acid are very complex and highly

Although not strictly analogous to the pyrimidine

compounds shown in Figs. 1 and 2, this addition of a

nitrogen atom to the core ring structure (by shifting from

the pyrimidine to the 1,3,5-triazine heterocycle) extends

the scaffold range in a logical bioisosteric modiﬁcation and

complements the previous studies already conducted in the

area of cardiogenesis in our group.

Fig. 1 Cardiogenols and Shz-1 as literature-known compounds with cardiomyogenic activity

123

One-pot synthesis of triazines as potential agents affecting cell differentiation

Fig. 2 Examples of compounds with cardiomyogenic activity. Top: synthesized in our group. MK 142 could be shown to produce beating heart

muscle cells from W4 embryonic stem cells. Bottom: Retinoic acid isomers

Fig. 3 Parent literature

compound and the envisioned

synthetic route

2,4,6-Trichloro-1,3,5-triazine (cyanuric chloride, 1) is

an electron-poor heterocycle and behaves as a heterocyclic

Results and discussion

acid chloride analog, with its reactive chlorine atoms being

easily substituted in S_NAr reactions. Therefore, it can serve

as starting material for (differently) substituted 1,3,5-

trazines, where the substituents are linked via nucleophilic

heteroatoms, such as oxygen, nitrogen, and sulfur.

Symmetrically trisubstituted triazines can be prepared by

protic or Lewis acid- or base-catalyzed cyclotrimerization

of nitriles or acid-catalyzed cyclocondensation of imidic

esters (Scheme 1) [32].

1,3,5-Triazines with three different substituents are

accessible by condensation of acylamidines (themselves

prepared from amides and amide acetals) with other

amidines (Scheme 1) [28].

To gain experience with nucleophilic aromatic substi-

tution on the 1,3,5-triazine scaffold, a known procedure to

produce 2-phenoxy-4,6-dichloro-1,3,5-triazine (2a) was

repeated [33]. In this procedure, 2,4,6-trichloro-1,3,5-

123

T. Linder et al.

Scheme 1

triazine was combined with one equivalent of phenol and

N,N-diisopropylethylamine (DIPEA) in THF at 0 °C

(Scheme 2 top). While the authors state that no puriﬁcation

was required (short of removing the amine hydrochloride

by ﬁltration) to afford 2a in 92% yield, GC–MS analysis

revealed that about 10% of the disubstituted triazine 3a was

formed, as well. Although this could be removed by re-

crystallization, such a byproduct ratio would have a neg-

ative impact on the one-pot procedure in which three

sequential nucleophilic replacements were aimed at with-

out any work-up of intermediates. Thus, on repetition of

this synthesis, the reaction temperature was lowered to -

15 °C initially and the reaction time was extended to allow

for complete conversion, which avoided formation of

byproduct and gave 2a in 95% without further puriﬁcation

(Scheme 2 top).

This reaction proceeds swiftly in the beginning, with the

appearance of the hydrochloride salt after a few minutes.

Since combining the two components under basic condi-

tions is noticeably exothermic, it was decided to add the

phenolic compounds as THF solutions to ensure the

reproducibility of byproduct suppression. Disubstituted 3a

was prepared in this way, adding two equivalents in suc-

cession. After the amount of the mono-substituted inter-

mediate 2a had decreased to less than 2% (GC–MS), the

reaction mixture was worked up and gave 3a in 78% after

puriﬁcation (Scheme 2 bottom).

In general, neither of these two intermediates is very

stable; they decompose visibly if stored at room

Scheme 2

123

One-pot synthesis of triazines as potential agents affecting cell differentiation

temperature for a period of a few months. Unlike the actual

target trisubstituted triazines, the disubstituted compounds

are also attacked by DMSO, which precludes direct NMR

shift comparison in the same solvent, because the latter are

generally not soluble enough in, e.g., CDCl₃(trichlorotri-

azine itself reacts vigorously with DMSO, by attack of the

oxygen) [34]. This actually speaks in favor of a method

which omits isolation and puriﬁcation of such reactive

intermediates and makes a one-pot protocol all the more

appealing.

both electron-rich(er) and electron-poor(er) phenoxy sub-

stituents have to be incorporated at the triazine core, then

the order of addition of the two phenols is important: the

electron-richer(er) has to be added prior to the electron-

poor(er). Knowing this, the ﬁnal step of the sequence could

be investigated.

A preliminary experiment showed that 3-aminobenzoic

acid reacts with 3a under much the same conditions

(DIPEA as the base) as in the preparation of 2a and 3a to

give the parent literature compound 4a (DTAB,

Scheme 4).

An unexpected behavior occurred when two different

aryloxy residues were attempted to be incorporated into the

triazine scaffold. In the ﬁrst step, 4-chlorophenol (an

electron-deﬁcient phenol) was reacted with starting mate-

rial 1, and the reaction was checked for completion by TLC

and GC–MS. Then, with addition of phenol in the second

step, three products emerged (Scheme 3): in addition to

expected 3b, compounds 3c and 3a were also detected, in

the approximate ratio of 8:2:1. A very similar product

distribution was obtained when 2- or 3-chlorophenol was

used in step one. By contrast, starting from puriﬁed 2a and

reacting it with 4-chlorophenol under the same conditions,

almost none of the undesired products were formed (ratio

of 97:2:1).

As a somewhat troubling property, it was found that

none of these trisubstituted triazine compounds (with or

without the presence of a carboxylic acid function) could

be detected in either GC or GC–MS analysis, limiting

reaction control to TLC analysis. In general, the triaziny-

laminobenzoic acids were crystalline materials, sparingly-

to-moderately soluble in common organic solvents (e.g.,

very low solubility in CHCl₃, MeOH, Et₂O, MeCN; best

solubility was found with 1,4-dioxane). It, therefore,

appeared promising to prepare a variety of these com-

pounds in one pot by starting from trichlorotriazine,

incorporating ﬁrst two different phenoxy substituents and

subsequently adding the amine compound.

These ﬁndings can be readily explained by looking at

the electronic features of the applied phenols. Owing to the

electron-withdrawing substituent, chlorophenol(s) can also

serve as a leaving group and remain present in the reaction

mixture after replacement by phenol. In this displacement

reaction, 2a is formed as an intermediate. Both 2b and 2a

can then form substitution products with either phenol

(added to the mixture for the second step) or chlorophenol

(liberated in the displacement) and, hence, lead to the

observed product distribution. This has two implications: if

While the reaction itself worked as expected, a severe

puriﬁcation problem occurred: as chromatographic sepa-

ration of carboxylic acids was not feasible, re-crystalliza-

tion remained the only means of puriﬁcation. Because the

step-wise reactivity of trichlorotriazine in the nucleophilic

substitution was neither fully selective, nor complete,

unwanted other triazinyl benzoic acids, mostly those with

two identical aryloxy substituents, were also obtained.

These persisted in the 5–10% range as judged by HPLC

analysis after re-crystallization from various solvents

Scheme 3

123

T. Linder et al.

Scheme 4

(CHCl₃/n-hexane, toluene, and EtOH). Therefore, target

compounds could not be puriﬁed to a satisfactory degree.

In light of these puriﬁcation issues, carboxylic acids

were masked as their methyl (and, in one case, ethyl)

esters, i.e., retaining the one-pot protocol but using an alkyl

aminobenzoate in the third substitution step (Scheme 5).

This opened the possibility for chromatographic separation.

To reduce disubstitution in the ﬁrst nucleophilic dis-

placement even further, the solutions containing the phe-

nols and the base were also cooled to the reaction

temperature (- 35 °C) prior to dropwise addition (at the

reported temperature of 0 °C [20, 35], the reaction is less

selective, as stated above). In general, care needs to be

taken as to drive the reaction as far to completion as pos-

sible, however, without losing selectivity. This is why the

reaction times tended to be very long (up to 47 h), while

the reaction temperature was not taken beyond ? 40 °C.

The results are summarized in Scheme 5.

Compounds 5e, 5f, and 5h were ﬁrst puriﬁed by re-

crystallization. As this did not eliminate byproducts com-

pletely (i.e., differently substituted triazines; impurities in

the 1–5% range), subsequent column chromatography was

applied for ﬁnal puriﬁcation, but the overall decrease in

yield was signiﬁcantly larger than the amount of impurity

initially present (Scheme 5, yields before column are in

parentheses).

To evaluate the importance of a carboxylic functional

group on the aniline moiety in positions 3 and 4 for bio-

logical activity, two more compounds were prepared

devoid of this functionality. Since the two phenoxy sub-

stituents were identical, two equivalents of phenol were

used in one go rather than adding them sequentially as in

the cases above (Scheme 6). Being a good nucleophile,

thiophenol was also incorporated well into the triazine ring.

While 6 is a known compound [36, 37], a literature

reference to 7 could not be found. It offers the possibility of

another linking group besides NH and S, by oxidation of

the sulﬁde to the sulfoxide (SO) or the sulfone (SO₂). This

could be used if one wishes to reverse the role of this part

of the molecule in hydrogen bonding, switching it from a

hydrogen donor to an acceptor.

The reactions, which were carried out using readily

available phenols proceeded very well in most cases.

Various electron-rich and -poor phenols were used to

investigate the scope of this method, also beyond common

pharmacophores such as chloro and methoxy substituents.

As for the performance of the reaction, there is no signif-

icant difference in yields of compounds bearing electron

donating p-tert-butyl and p-methoxy, versus electron-

withdrawing p-, m-, o-chloro, p-cyano, and m-nitro sub-

stituents. One exception is compound 5l: the second

nucleophilic substitution with 5-bromo-2-hydroxyben-

zaldehyde was not complete, even after 46 h, and consid-

erable amount of the starting material was recovered by

column chromatography. In addition, puriﬁcation was

plagued with separating this compound from byproducts as

it showed great tailing on the column. Therefore, after two

chromatographic runs, only 15% could be obtained. By

contrast, more electron-rich aldehydes, such as vanillin

(leading to 5j and 5k), worked quite well and difﬁculties

with the use of the 3-aminobenzoate in the third step did

not arise, probably owing to the low temperature

conditions.

Next, the obtained benzoic ester products had to be

hydrolyzed to the corresponding carboxylic acids. Since

methyl and ethyl esters are usually best cleaved by irre-

versible base hydrolysis, this was attempted ﬁrst. However,

in all the attempts and seemingly irrespective of tempera-

ture (- 20 to ? 50 °C), the hydroxide ion attacked the

electron-deﬁcient triazine carbon bonded to the phenoxy

substituents and released the phenol, preferentially the

more electron-deﬁcient one. This process also consumed

the amount of base available, leaving unhydrolyzed ester

behind. In addition, a variation of hydroxide-promoted

hydrolysis in a non-aqueous environment did not bring the

desired results [38].

On the other hand, the model compounds proved inert

towards acid hydrolysis, short of exceptionally harsh con-

ditions leading to its destruction. Since all attempts to

cleave the methyl esters proved to be futile, the use of

alternative esters was considered.

123

One-pot synthesis of triazines as potential agents affecting cell differentiation

Scheme 5

123

T. Linder et al.

Scheme 6

The tert-butyl ester group is well known to be readily

cleaved by acid, because the stable tert-butyl carbenium

ion can act as a leaving group on protonation of the adja-

cent oxygen atom [39]. Moreover, no water is required in

this process, the only byproduct is gaseous isobutene

(formed by elimination from the carbenium ion) and this

deprotection can be carried out under mild conditions. For

this reason, 3-tert-butylaminobenzoate was used in a one-

pot sequence analogously to the synthesis of the methyl

esters (Scheme 7).

the compound solely in formic acid (with some sonication

to aid dissolution) and stir the solution at slightly elevated

temperatures (40–50 °C). A large excess of formic acid

(4 cm³for, e.g., 0.1 mmol) was used to make sure that the

intermediately formed and very strongly electrophilic tert-

butyl cation would not be likely to react with either the

starting material or the product (as is sometimes the case)

[44] in, e.g., an electrophilic aromatic substitution reaction

of the carbocycles, before it is eliminated to isobutene. In

all but one case (compound 4j), the cleavage reaction was

complete within 1 h.

In an overall view, this reaction produced somewhat

lower yields and appeared to be slower (Scheme 7) than

the synthesis of the corresponding methyl esters. The tert-

butyl group was stable on silica during chromatography.

Work-up had to include an aqueous extraction step with

diluted hydrochloric acid to remove the 3-tert-buty-

laminobenzoate, which was used in slight excess (1.15

equivalents), because this material had very similar R_f

values to products 8a–8j. This operation was carried out

quickly to avoid ester cleavage prior to chromatographic

separation—even though the corresponding carboxylic acid

was eventually desired, because only the ester could be

puriﬁed chromatographically. The solution containing the

product was then treated with NaHCO₃solution (for neu-

tralization) and brine before evaporation and column

chromatography. The compounds also turned out to be

generally more soluble and less inclined to crystallize than

the corresponding methyl esters because of the non-polar

tert-butyl group, although crystalline materials could be

obtained in all cases.

Puriﬁcation was not required; work-up was limited to

adding diethyl ether after concentrating the reaction pro-

duct to dryness and to remove the solvent again in vacuo to

aid evaporation of the formic acid. Thus, the desired car-

boxylic acids 4a–4k were obtained in quantitative yields

(Scheme 8).

From the viewpoint of biological activity, it is interest-

ing to compare the changes that occur when the carboxylic

acid function—common to all structures so far, except 6

and 7—is replaced by another group. The hydroxyl func-

tional group of a benzylic alcohol represents such a change;

it is also polar and capable of hydrogen bonding. These

compounds were obtained by reducing the corresponding

methyl and ethyl esters, since the tert-butyl group of

compounds in Scheme 7 would be quite resistant to

hydride attack. Usually, such a transformation is accom-

plished by a highly reactive complex metal hydride, nota-

bly lithium aluminium hydride. Since it was already

obvious that strong nucleophiles are not tolerated very well

due to the reactivity of the C–O bond of the substituted

triazines, a less aggressive method would be highly sought-

after. Based on the higher electronegativity of boron (2.0 of

B vs. 1.6 of Al), the frequently used sodium borohydride is

a less reactive reducing agent but usually falls short of

transforming esters accordingly. However, additional

reactivity can be gained by changing the counter-ion to

lithium, which offered the prospect of having just the right

reductive power to accomplish the task. Literature sug-

gested that the reactivity of the borohydride has been

enhanced by the addition of lithium chloride [45], and fast

As indicated above, the tert-butyl group can be removed

easily under moderately strong acidic conditions. The

classic removal condition involves the use of triﬂuoroacetic

acid [40] (pK_A= 0.23) [41], but formic acid [42] (pK_A-

= 3.77) [43] can also be used. This is, therefore, a milder

method, which is compatible with a large number of

functional groups. First, formic acid, dissolved in CH₂Cl₂

was tried at room temperature, but this did not advance the

reaction. However, upon heating to 40 °C, the reaction

proceeded as observed by TLC after several hours. Finally,

it proved a very simple and effective operation to take up

123

One-pot synthesis of triazines as potential agents affecting cell differentiation

Scheme 7

reductions with this reagent have been performed by

microwave irradiation [46]. Moreover, it has been reported

that reducible groups, such as NO₂and CN, can be pre-

served under lithium borohydride conditions [47].

after 18 h. Higher temperature (75 °C, and then 90 °C)

only led to compound decomposition as indicated by

multiple spots on TLC. Since also other related conditions

did not lead to the desired reduction in acceptable amounts,

another reducing agent had to be considered. Based on the

idea that increased steric bulk may prevent the hydride ion

from attacking the electrophilic triazine carbons,

diisobutylaluminium hydride was tried under standard

conditions in anhydrous CH₂Cl₂under argon at - 70 °C.

To test the reduction, compounds 5c–5e were used again

(Scheme 9). An initial attempt to carry out such a reduction

of 5e using 1.1 equivalents of NaBH₄in the presence of 2.0

equivalents of LiCl by the conventional heating at 65 °C in

anhydrous THF did not bring about this transformation

123

T. Linder et al.

Scheme 8

Although a large excess of this reagent (up to 5.1 equiva-

lents) had to be used to complete the reaction relatively

quickly (around 1–3 h), the desired conversion could be

completed with good yields (Scheme 10). Most

importantly, no phenols were detected, and puriﬁcation

was only needed to remove some residual starting material

that had escaped TLC analysis (due to its low concentra-

tion) during the reaction. However, triazinyl benzoic esters

123

One-pot synthesis of triazines as potential agents affecting cell differentiation

Scheme 9

Scheme 10

123

T. Linder et al.

bearing nitro and cyano groups were not attempted,

because these functions are both readily reduced, as well.

capillary column BGB 5 (30 m 9 0.32 mm ID) and

applying the following standardized temperature proﬁle:

2 min at 100 °C/ramp 18 °C min^-1until 280 °C/5 min at

280 °C. Electron ionization was used (70 eV); all fragment

signals (m/z) at/over mass 100 and at/over 10% relative

intensity are indicated. NMR spectroscopy: NMR spectra

were recorded from DMSO-d₆or CDCl₃solutions on a

Bruker AC 200 (200 MHz) or a Bruker Avance UltraShield

(400 MHz) spectrometer (as indicated), and chemical shifts

are reported in ppm relative to the nominal residual solvent

signals [51]: CDCl₃: d = 7.26 ppm (¹H), d = 77.16 ppm

(¹³C); DMSO-d₆: d = 2.50 (¹H), d = 39.52 (¹³C). DEPT-

135 or J-modulation pulse sequences (APT) were used to

aid in the multiplet assignment in the ¹³C spectra.

Conclusion

In this work, it was demonstrated that derivates of the

triazine compound DTAB, 4a, bearing three different

substituents, can be prepared in a one-pot protocol. How-

ever, if carboxylic acids akin to DTAB are desired, sepa-

ration problems emerge; and it is, therefore, necessary to

mask the carboxylic function to facilitate puriﬁcation. The

compounds in question are still labile toward nucleophiles

(hydroxide, hydride, and methoxide), which prevents

smooth basic hydrolysis of methyl esters and their reduc-

tion to the corresponding benzylic alcohols with lithium or

sodium borohydride. Still, they can be converted using the

more sterically demanding diisobutylaluminium hydride in

good yields. In addition, the triazine scaffold is inert

toward acid, which allows the facile and operationally

simple acid-promoted cleavage of tert-butyl esters of the

corresponding carboxylic acids, affording the latter quan-

titatively. Biological results have been recently disclosed in

a patent application [48, 49].

Numbering of the atoms in the synthesized products

parallels the priority of the individual cycles of the mole-

cules, as inferred from systematic nomenclature. Therefore,

the hydrogen and carbon positions belonging to the ring

with the highest priority are referred to as H1, H2, H3,…

and C1, C2, C3,…, respectively. The numbers designate

the order of the atoms within a particular ring system. The

atoms in the second ring are indicated with one prime (H1’,

H2’, H3’,… and C1’, C2’, C3’,…), in the next ring with

two primes, etc. However, the core 1,3,5-triazine cycle is

given highest priority in all cases. This is done regardless

that a compound may actually bear its name-giving func-

tional group on one of the lower priority rings, as the sufﬁx

…acid implies for the example, as shown in Fig. 4.

In addition, all compounds are drawn in such a way that

they follow the ’, ’’, ’’’ order of the second, third, and

fourth ring in the clockwise manner as shown. Identiﬁed

signals were marked with an asterisk (*) when assignment

was equivocal.

Experimental

Chemicals: Unless otherwise noted, chemicals were pur-

chased from commercial suppliers and used without further

puriﬁcation. DIBAL-H solution in n-hexane was reaction-

titrated according to a literature procedure (39) and the

content of active DIBAL-H was determined by standard ¹H

NMR spectroscopy [50]. Dry solvents were obtained by

passing pre-dried material through a cartridge containing

activated alumina (solvent dispensing system) and stored

under N₂. Microwave reactions were performed using a

Biotage Initiator 2.5 laboratory microwave device. Chro-

matography: Flash column chromatography was performed

on Merck silica gel 60 (40–63 lm). Separations were

carried out either using a Bu¨chi Sepacore system (MPLC)

or by hand column (as noted). For thin-layer chromatog-

raphy (TLC), aluminium backed Merck silica gel 60 with

ﬂuorescence indicator F₂₅₄was used. For preparative TLC,

Analtech Uniplate silica gel GF (20 9 20 cm, 1000 lm)

glass-backed plates with ﬂuorescence indicator UV254

were used. Distillation: Kugelrohr distillation was carried

out using a Bu¨chi GKR-51 apparatus. Melting points were

determined using a Koﬂer-type Leica Galen III micro hot

stage microscope or a Stanford Research Systems MPA100

OptiMelt Automatic Melting Point System. Data are given

in 0.5 °C intervals. GC–MS: GC–MS runs were performed

on a Thermo Finnigan Focus GC/DSQ II using a standard

NMR characteristics of 2,4,6-trisubstitued 1,3,5-

triazines

While 2,4,6-trisubstituted 1,3,5-triazines present rather

ordinary proton NMR spectra, a noteworthy aspect became

apparent in ¹³C spectra: carbons C4 and C6, such as in

compound 5c, (Fig. 5; i.e., those adjacent to the aryloxy

groups) appeared at low ﬁeld in the 170–173 ppm range

relative to TMS. They gave rather broad and also low

Fig. 4 Explanation of code for peak assignment

123

One-pot synthesis of triazines as potential agents affecting cell differentiation

hindered internal rotation at room temperature (Fig. 6,

bottom). To elucidate the situation further, the simpler

compound 6 was also subjected to ¹³C NMR-measurement

at 120 °C. The effect was particularly prominent in the

case of carbon positions C4 and C6; they showed up as two

broad signals at 171.8 and 172.3 ppm at room temperature,

but also coalesced at 171.5 ppm as a sharp peak, making it

very plausible that rotation around the C2–N bond was

slowed down at room temperature. This can be explained

by considering the highly electron-deﬁcient triazine and the

appropriate resonance contributor as in Fig. 7. C4 and C6

then adopt different relative conformations, i.e., cis and

trans to carbons C2’ and C6’, respectively, as the C2–N

bond displays partial double bond character. These con-

formations are stable long enough that carbon nuclei C4

and C6 become magnetically different and are visible on

the NMR time scale as separate signals.

Fig. 5 Compound 5c, an example for unexpected ¹³C NMR behavior

intensity signals (Fig. 6 top) or were not discernable as

distinct peaks, in which case they emerged only as a small

bulge in the spectrum. This is true for the magnetic ﬁeld

strength of the instrument that was used to measure most of

the samples (4.7 T, corresponding to 200 MHz of proton

resonance frequency).

In many cases, the total number of carbon signals of the

triazine compounds bearing two aryloxy and one pheny-

lamino moiety showed more carbon signals than was

expected. What is more, additional peak splitting was

observed when the same sample was measured using

higher resolution and ﬁeld strength (400 MHz, compound

5c, Fig. 6 middle vs. top).

In addition, if these two carbons are also chemically

unequal, the two stable conformers become different

rotamers, and the expected two signals split into four (as

with 5c, Figs. 6, 8). There is no cis/trans isomerism of this

sort regarding carbon C2 itself, and this nucleus is, there-

fore, unaffected by peak splitting.

Thus, it seemed that in solution different long-lived (on

the NMR time scale) conformers were present to give rise

to more signals than expected. To test this hypothesis,

high-temperature ¹³C spectra (at 120 °C) were recorded.

Indeed, under such conditions, fewer carbon signals were

There are no additional peaks in the spectra of com-

pounds where the NH is replaced by some other atom, such

as sulfur in 7. It, therefore, appears evident that the hin-

dered rotation around this carbon–nitrogen bond is

responsible for this isomerism as observed with compounds

like 5c.

observed, conﬁrming that the compound must experience

Fig. 6 ¹³C NMR of compound 5c, recorded under different conditions

123

T. Linder et al.

Fig. 7 Low- versus high-

temperature NMR of compound

6

Fig. 8 Rotamers of compound 5c

2,4-Dichloro-6-phenoxy-1,3,5-triazine (2a, C₉H₅Cl₂N₃O)

2,4,6-Trichloro-1,3,5-triazine (1.225 g, 6.64 mmol, 1.00

equiv.), dissolved in 14 cm³THF, was cooled to - 15 °C

(ice/salt bath), and then, 0.858 g DIPEA (6.64 mmol, 1.00

equiv.) and 0.625 g phenol (6.64 mmol, 1.00 equiv.) were

added slowly while stirring. The reaction was kept at that

temperature for 30 min, after that the temperature was

raised to 0 °C and stirring was continued for another

3.75 h. Then, the mixture was warmed to r. t. within

30 min. The formed DIPEA-hydrochloride was removed

by ﬁltration and washed with additional THF

(2 9 10 cm³). The solution was evaporated to give the

solid crude product. It was again dissolved in 100 cm³

EtOAc and this organic solution was washed with saturated

NaHCO₃solution (2 9 100 cm³), 100 cm³5% KHSO₄,

and 100 cm³brine. After drying over Na₂SO₄, the solvent

was removed and the product dried in vacuo without fur-

ther puriﬁcation. Yield: 1.521 g (95%); appearance: col-

orless solid; m.p.: 115–116 °C (lit.: 111.5–113.8 °C) [52];

R_f= 0.50 (hexane/EtOAc, 5:1); ¹H NMR (CDCl₃,

200 MHz): d = 7.13–7.23 (m, 2H, H2’ & H6’), 7.28–7.39

(m, 1H, H4’), 7.41–7.53 (m, 2H, H3’ & H5’) ppm; ¹³C

NMR (CDCl₃, 50 MHz): d = 121.1 (d, C2’ & C6’), 127.1

(d, C4’), 130.1 (d, C3’ & C5’), 151.2 (s, C1’), 171.3 (s,

C6), 173.2 (s, C2 & C4) ppm; GC–MS (EI, 70 eV): t_R-

= 8.08 min; m/z (%) = 243 (M^?, 10), 241 (M^?, 15), 208

(32), 206 (100), 143 (11).

2,4-Dichloro-6-(4-chlorophenoxy)-1,3,5-triazine

(2b, C₉H₄Cl₃N₃O) The reaction was performed in an 8 cm³

glass vial, using a cryo or thermo block. 2,4,6-Trichloro-

triazine (369 mg, 2.00 mmol, 1.00 equiv.) was dissolved in

3.0 cm³THF and cooled to - 35 °C. DIPEA (349 mg,

2.70 mmol, 1.35 equiv.) was added to 257 mg

4-chlorophenol (2.00 mmol, 1.00 equiv.), dissolved in

1.6 cm³THF; the mixture was also cooled to - 35 °C,

before this solution was added slowly to the trichlorotri-

azine solution while stirring. To ensure complete transfer,

another 1.6 cm³of THF, cooled to - 35 °C, was used to

ﬂush all phenol into the reaction mixture. Stirring was

continued at this temperature for 3 h, then at r. t. for 27 h.

H₂O (10 cm³) was then added to the reaction mixture and

the compound was extracted with EtOAc (2 9 10 cm³),

123

One-pot synthesis of triazines as potential agents affecting cell differentiation

followed by washing with 10 cm³brine. The solution was

concentrated in vacuo and the compound [53] was puriﬁed

by column chromatography (MPLC, 90 g silica, 90 cm³

min^-1ﬂow rate, LP with 2% EtOAc), and ﬁnally dried in

vacuo. Yield: 243 mg (44%); appearance: colorless solid;

m.p.: 105–108 °C; R_f= 0.51 (hexane/EtOAc, 5:1); ¹H

NMR (CDCl₃, 200 MHz): d = 7.03–7.17 (m, 2H, H2’ &

H6’), 7.32–7.46 (m, 2H, H3’ & H5’) ppm; ¹³C NMR

(CDCl₃, 50 MHz): d = 122.5 (d, C2’ & C6’), 130.1 (d, C3’

& C5’), 132.6 (s, C4’), 149.5 (s, C1’), 171.0 (s, C6), 173.2

(s, C2 & C4) ppm; GC–MS (EI, 70 eV): t_R= 9.16 min; m/z

(%) = 277 (M^?, 12), 275 (M^?, 15), 244 (10), 242 (62), 241

(12), 240 (100), 177 (15), 111 (24).

Synthesis of (4,6-disubstituted-1,3,5-triazin-2-

yl)aminobenzoic acids 4a–4k—general

procedure A

The reaction was performed in an 8 cm³glass vial, using a

thermo block. Formic acid (4.0 cm³) was added to 1,1-

dimethylethyl aminobenzoate (1.00 equiv.). This mixture

was brieﬂy sonicated until the starting material was dis-

solved and stirred at the speciﬁed temperature until TLC

showed complete conversion. The content of the reaction

vial was transferred to a round bottom ﬂask and the vial

was ﬂushed with a few cm³of CH₂Cl₂. Then, the solvents

were removed under reduced pressure, 10 cm³Et₂O was

added to facilitate the removal of residual formic acid, the

solution evaporated again and ﬁnally dried in vacuo.

2-Chloro-4,6-diphenoxy-1,3,5-triazine (3a, C₁₅H₁₀ClN₃O₂)

2,4,6-Trichloro-1,3,5-triazine (1.248 g, 6.77 mmol, 1.00

equiv.), dissolved in 7 cm³THF, was cooled to - 30 °C;

then, a solution of 0.637 g phenol (6.77 mmol, 1.00 equiv.)

and 0.874 g DIPEA (6.77 mmol, 1.00 equiv.) in 7 cm³

THF was added dropwise over 10 min while stirring. The

reaction was kept at - 35 to - 30 °C for another 30 min

and subsequently at 0 °C for 5 h. Then, another solution of

0.637 g phenol (6.77 mmol, 1.00 equiv.) and 0.874 g

DIPEA (6.77 mmol, 1.00 equiv.) in 7 cm³THF was added

dropwise over 15 min and the mixture was warmed slowly

to r. t. After 48 h, the reaction temperature was raised to

50 °C and stirring was continued for 4.5 h. The formed

DIPEA-hydrochloride was removed by ﬁltration and

washed with additional THF (30 cm³). The solution was

evaporated to give the solid crude product. It was again

dissolved in 100 cm³EtOAc and this organic solution was

washed with Na₂CO₃solution, 0.5 M HCl, as well as brine

(2 9 100 cm³for each) and subsequently dried over Na_2-

SO₄. The solvent was removed and the crude material was

re-crystallized from n-hexane/toluene (35 cm³/7 cm³),

collected by ﬁltration, washed with 20 cm³n-hexane, and

dried in vacuo. Yield: 1.584 g (78%); appearance: color-

less crystals; m.p.: 120.5–121 °C (lit.: 119–121 °C) [54];

R_f= 0.39 (hexane/EtOAc, 5:1); ¹H NMR (CDCl₃,

200 MHz): d = 7.10–7.19 (m, 4H, H2’ & H6’ & H2’’ &

H6’’), 7.22–7.32 (m, 2H, H4’ & H4’’), 7.34–7.46 (m, 4H,

H3’ & H5’ & H3’’ & H5’’) ppm; ¹³C NMR (CDCl₃,

50 MHz): d = 121.2 (d, C2’ & C6’), 126.5 (d, C4’), 129.7

(d, C3’ & C5’), 151.3 (s, C1’), 172.4 (s, C4 & C6), 173.8

(s, C2) ppm; GC–MS (EI, 70 eV): t_R= 11.45 min; m/z

(%) = 301 (M^?, 11), 300 (M^?, 10), 299 (M^?, 33), 298

(16), 264 (57), 208 (32), 207 (11), 206 (100), 180 (12), 145

(15), 140 (10), 138 (31), 121 (20).

3-[(4,6-Diphenoxy-1,3,5-triazin-2-yl)amino]benzoic acid (4a,

C₂₂H₁₆N₄O₄) Prepared according to general procedure A

using 46 mg 1,1-dimethylethyl aminobenzoate 8a

(0.10 mmol, 1.00 equiv.); 50 °C for 1 h; compound 4a is

literature-known [31, 55]. Yield: 40 mg (quant.); appear-

ance: off-white solid; m.p.: 267.5–270 °C; R_f= 0.57

(hexane/EtOH, 1:1); ¹H NMR (DMSO-d₆, 200 MHz):

d = 7.14–7.35 (m, 7H), 7.38–7.52 (m, 4H), 7.56 (d,

J₃= 7.7 Hz, 1H), 7.76 (d, J₃= 8.3 Hz, 1H), 8.03 (s, 1H,

H2’), 10.40 (s, 1H, NH), 12.98 (bs, 1H, CO₂H) ppm; ¹³C

NMR (DMSO-d₆, 50 MHz): d = 121.5 (d, C2’), 121.8 (d,

C2’’ & C2’’’ & C6’’ & C6’’’), 124.1 (d, C4’), 124.8 (d,

C6’), 125.7 (d, C4’’ & C4’’’), 128.5 (d, C5’), 129.6 (d, C3’’

& C3’’’ & C5’’ & C5’’’), 131.2 (s, C3’), 138.6 (s, C1’),

151.8 (s, C1’’, C1’’’), 166.2 (s, C2), 167.1 (s, CO₂), 171.8

& 172.2 (bs, C4 & C6, rotamers) ppm.

3-[[4-(4-Chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-

yl]amino]benzoic acid (4b, C₂₂H₁₅ClN₄O₄) Prepared

according to general procedure A using 49 mg 1,1-dime-

thylethyl aminobenzoate 8b (0.10 mmol, 1.00 equiv.);

50 °C for 1 h. Yield: 44 mg (quant.); appearance: beige

solid; m.p.: 244–247 °C; R_f= 0.63 (hexane/EtOH, 1:1); ¹H

NMR (DMSO-d₆, 200 MHz): d = 7.14–7.38 (m, 6H),

7.38–7.63 (m, 5H), 7.72 (d, J₃= 8.4 Hz, 1H), 8.04 (s, 1H,

H2’), 10.42 (s, 1H, NH), 12.91 (bs, 1H, CO₂H) ppm; ¹³C

NMR (DMSO-d₆, 50 MHz): d = 121.5 (d, C2’), 121.8 (d,

C2’’’ & C6’’’), 123.8 (d, C2’’ & C6’’), 124.2 (d, C4’), 124.8

(d, C6’), 125.8 (d, C4’’’), 128.5 (d, C5’), 129.5 (d, C3’’* &

C5’’*), 129.6 (d, C3’’’* & C5’’’*), 129.9 (s, C4’’), 131.2 (s,

C3’), 138.5 (s, C1’), 150.6 (s, C1’’), 151.8 (s, C1’’’), 166.1

(s, C2), 167.0 (s, CO₂), 171.3–172.4 (C4 & C6) ppm.

3-[[4-(3-Chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-

yl]amino]benzoic acid (4c, C₂₂H₁₅ClN₄O₄) Prepared

according to general procedure A using 49 mg 1,1-dime-

thylethyl aminobenzoate 8c (0.10 mmol, 1.00 equiv.);

50 °C for 1 h. Yield: 44 mg (quant.); appearance: off-white

123

T. Linder et al.

solid; m.p.: 227–230 °C; R_f= 0.59 (hexane/EtOH, 1:1); ¹H

NMR (DMSO-d₆, 200 MHz): d = 7.16–7.53 (m, 10H),

7.58 (d, J₃= 7.7 Hz, 1H), 7.75 (d, J₃= 7.9 Hz, 1H), 8.04

(s, 1H, H2’), 10.45 (s, 1H, NH), 12.97 (bs, 1H, CO₂H)

ppm; ¹³C NMR (DMSO-d₆, 50 MHz): d = 120.8 (d, C6’’),

121.5 (d, C2’), 121.8 (d, C2’’’ & C6’’’), 122.4 (d, C2’’),

124.3 (d, C4’), 124.8 (d, C6’), 125.8 (d, C4’’’), 125.9 (d,

C4’’), 128.5 (d, C5’), 129.6 (d, C3’’’ & C5’’’), 131.0 (d,

C5’’), 131.4 (s, C3’), 133.4 (s, C3’’), 138.5 (s, C1’), 151.8

(s, C1’’’), 152.4 (s, C1’’), 166.2 (s, C2), 167.1 (s, CO₂*),

171.3–172.3 (C4 & C6, not resolved) ppm.

J₃= 9.0 Hz, 2H, H3’’ & H5’’), 7.13–7.34 (m, 6H),

7.39–7.51 (m, 2H), 7.56 (d, J₃= 7.6 Hz, 1H), 7.74 (d,

J₃= 8.2 Hz, 1H), 8.04 (s, 1H, H2’), 10.37 (s, 1H, NH),

12.93 (bs, 1H, CO₂H) ppm; ¹³C NMR (DMSO-d₆,

50 MHz): d = 55.5 (q, OCH₃), 114.5 (d, C3’’ & C5’’),

121.5 (d, C2’), 121.8 (d, C2’’’ & C6’’’), 122.7 (d, C2’’ &

C6’’), 124.1 (d, C4’), 124.8 (d, C6’), 125.7 (d, C4’’’), 128.5

(d, C5’), 129.6 (d, C3’’’ & C5’’’), 131.3 (s, C3’), 138.6 (s,

C1’), 145.2 (s, C1’’), 151.8 (s, C1’’’), 156.9 (s, C4’’), 166.2

(s, C2), 167.1 (s, CO₂), 171.3–172.7 (C4 & C6, not

resolved) ppm.

3-[[4-(2-Chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-

3-[[4-(4-Cyanophenoxy)-6-phenoxy-1,3,5-triazin-2-

yl]amino]benzoic acid (4d, C₂₂H₁₅ClN₄O₄) Prepared

according to general procedure A using 49 mg 1,1-dime-

thylethyl aminobenzoate 8d (0.10 mmol, 1.00 equiv.);

50 °C for 1 h. Yield: 44 mg (quant.); appearance: colorless

crystals; m.p.: 249.5–251.5 °C; R_f= 0.60 (hexane/EtOH,

yl]amino]benzoic acid (4g, C₂₃H₁₅N₅O₄) Prepared accord-

ing to general procedure A using 48 mg 1,1-dimethylethyl

aminobenzoate 8g (0.10 mmol, 1.00 equiv.); 45 °C for 1 h.

Yield: 43 mg (quant.); appearance: colorless solid; m.p.:

150 °C (decomp.); R_f= 0.65 (hexane/EtOH, 1:1); ¹H NMR

(DMSO-d₆, 200 MHz): d = 7.16–7.35 (m, 4H), 7.37–7.77

(m, 6H), 7.94 (d, J₃= 8.1 Hz, 2H, H3’’ & H5’’), 8.06 (s,

1H, H2’), 10.48 (s, 1H, NH) ppm, CO₂H not visible; ¹³C

NMR (DMSO-d₆, 50 MHz): d = 108.6 (s, C4’’), 118.5 (s,

CN), 121.66 (d, C2’), 121.76 (d, C2’’’ & C6’’’), 123.3 (d,

C2’’ & C6’’), 124.4 (d, C4’), 124.8 (d, C6’), 125.8 (d,

C4’’’), 128.5 (d, C5’), 129.6 (d, C3’’’ & C5’’’), 131.6 (s,

C3’), 134.0 (d, C3’’ & C5’’), 138.4 (s, C1’), 151.6 (s,

C1’’’), 155.2 (s, C1’’), 166.2 (s, C2), 167.1 (s, CO₂),

170.9–172.2 (C4 & C6, not resolved) ppm.

1

1:1); H NMR (DMSO-d₆, 200 MHz): d = 7.13–7.51 (m,

9H), 7.52–7.75 (m, 3H), 7.99 (s, 1H, H2’), 10.49 (s, 1H,

NH), 12.93 (bs, 1H, CO₂H) ppm; ¹³C NMR (DMSO-d₆,

50 MHz): d = 121.6 (d, C2’), 121.8 (d, C2’’’ & C6’’’),

124.3 (d, C6’’*), 124.8 (d, C6’), 125.8 (d, C4’’’), 126.0 (s,

C2’’), 127.5 (d, C4’’*), 128.5 (d, C5’’*), 128.6 (d, C5’*),

129.7 (d, C3’’’ & C5’’’), 130.3 (d, C3’’), 131.3 (s, C3’),

138.5 (s, C1’), 147.7 (s, C1’’), 151.8 (s, C1’’’), 166.2 (s,

C2), 167.1 (s, CO₂), 171.2–172.5 (C4 & C6, not resolved)

ppm, one d signal missing possibly due to overlap.

3-[[4-[4-(1,1-Dimethylethyl)phenoxy]-6-phenoxy-1,3,5-tri-

azin-2-yl]amino]benzoic acid (4e, C₂₆H₂₄N₄O₄) Prepared

according to general procedure A using 51 mg 1,1-dime-

thylethyl aminobenzoate 8e (0.10 mmol, 1.00 equiv.);

45 °C for 1 h. Yield: 46 mg (quant.); appearance: off-white

solid; m.p.: 245–247 °C; R_f= 0.67 (hexane/EtOH, 1:1); ¹H

NMR (DMSO-d₆, 200 MHz): d = 1.30 (s, 9H, (CH₃)₃),

7.10–7.33 (m, 6H), 7.37–7.51 (m, 4H), 7.57 (d,

J₃= 7.7 Hz, 1H), 7.75 (d, J₃= 8.7 Hz, 1H), 8.05 (s, 1H,

H2’), 10.40 (s, 1H, NH), 12.92 (bs, 1H, CO₂H) ppm; ¹³C

NMR (DMSO-d₆, 50 MHz): d = 31.3 (q, C(CH₃)₃), 34.3

(s, C(CH₃)₃), 121.2 (d, C2’’ & C6’’), 121.6 (d, C2’), 121.8

(d, C2’’’ & C6’’’), 124.1 (d, C4’), 124.8 (d, C6’), 125.7 (d,

C4’’’), 126.3 (d, C3’’ & C5’’), 128.4 (d, C5’), 129.6 (d,

C3’’’ & C5’’’), 131.2 (s, C3’), 138.7 (s, C1’), 148.0 (s,

C4’’*), 149.5 (s, C1’’*), 151.8 (s, C1’’’), 166.2 (s, C2),

167.1 (s, CO₂), 171.6–172.7 (C4 & C6, not resolved) ppm.

3-[[4-(3-Nitrophenoxy)-6-phenoxy-1,3,5-triazin-2-

yl]amino]benzoic acid (4h, C₂₂H₁₅N₅O₆) Prepared accord-

ing to general procedure A using 40 mg 1,1-dimethylethyl

aminobenzoate 8h (0.08 mmol, 1.00 equiv.); 45 °C for 1 h.

Yield: 36 mg (quant.); appearance: beige solid; m.p.:

225–228 °C; R_f= 0.51 (hexane/EtOH, 1:1); ¹H NMR

(DMSO-d₆, 200 MHz): d = 7.16–7.33 (m, 4H), 7.34–7.50

(m, 2H), 7.57 (d, J₃= 7.7 Hz, 1H), 7.63–7.84 (m, 3H),

8.06 (s, 1H, H2’), 8.15 (d, J₃= 7.5 Hz, 1H), 8.22 (m, 1H,

H2’’), 10.49 (s, 1H, NH), 12.83 (bs, 1H, CO₂H) ppm; ¹³C

NMR (DMSO-d₆, 50 MHz): d = 117.5 (d, C2’’), 120.7 (d,

C4’’), 121.5 (d, C2’), 121.8 (d, C2’’’ & C6’’’), 124.4 (d,

C4’), 124.8 ((d, C6’), 125.8 (d, C4’’’), 128.5 (d, C6’’*),

128.9 (d, C5’*), 129.6 (d, C3’’’ & C5’’’), 130.8 (d, C5’’),

131.3 (s, C3’), 138.5 (s, C1’), 148.4 (s, C3’’), 151.8 (s,

C1’’’*), 152.0 (s, C1’’*), 166.2 (s, C2), 167.1 (s, CO₂),

171.2–172.5 (C4 & C6, not resolved) ppm.

3-[[4-(4-Methoxyphenoxy)-6-phenoxy-1,3,5-triazin-2-

3-[[4-(4-Formyl-2-methoxyphenoxy)-6-phenoxy-1,3,5-tri-

azin-2-yl]amino]benzoic acid (4i, C₂₄H₁₈N₄O₆) Prepared

according to general procedure A using 39 mg 1,1-dime-

thylethyl aminobenzoate 8i (0.075 mmol, 1.00 equiv.);

45 °C for 1 h. Yield: 34 mg (quant.); appearance: pale

yellow solid; m.p.: 217.5–220 °C; R_f= 0.62 (hexane/

yl]amino]benzoic acid (4f, C₂₃H₁₈N₄O₅) Prepared accord-

ing to general procedure A using 49 mg 1,1-dimethylethyl

aminobenzoate 8f (0.10 mmol, 1.00 equiv.); 50 °C for 1 h.

Yield: 43 mg (quant.); appearance: off-white solid; m.p.:

233–236.5 °C; R_f= 0.65 (hexane/EtOH, 1:1); ¹H NMR

(DMSO-d₆, 200 MHz): d = 3.77 (s, 3H, OCH₃), 6.97 (d,

1

EtOH, 1:1); H NMR (DMSO-d₆, 200 MHz): d = 3.86 (s,

123

One-pot synthesis of triazines as potential agents affecting cell differentiation

3H, OCH₃), 7.12–7.33 (m, 4H), 7.35–7.75 (m, 7H), 8.00 (s,

1H, H2’), 10.00 (s, 1H, CHO), 10.44 (s, 1H, NH) ppm,

CO₂H not visible; ¹³C NMR (DMSO-d₆, 50 MHz):

d = 56.1 (q, OCH₃), 112.3 (d, C3’’), 121.5 (d, C2’), 121.8

(d, C2’’’ & C6’’’), 123.7 (d, C5’’*), 123.8 (d, C4’*), 124.3

(d, C6’’*), 124.7 (d, C6’), 125.8 (d, C4’’’), 128.5 (d, C5’),

129.7 (d, C3’’’ & C5’’’), 131.4 (s, C3’), 135.1 (s, C4’’),

138.5 (s, C1’), 145.3 (s, C1’’*), 151.70 (s, C2’’*), 151.75

(s, C1’’’*), 166.1 (s, C2), 167.1 (s, CO₂*), 171.2–172.7 (C4

& C6, not resolved), 192.1 (d, CHO) ppm.

Synthesis of methyl and ethyl (4,6-disubstituted-

1,3,5-triazin-2-yl)aminobenzoates—general

procedure B

The reaction was performed in an 8 cm³glass vial, using a

cryo or thermoblock. DIPEA (1.10 equiv.) was added to the

phenolic compound R¹PhOH (1.00 equiv.) dissolved in

0.5 cm³THF. This solution was cooled to - 35 °C and

then added dropwise to a solution of 2,4,6-trichlorotriazine

(1.00 equiv.) in 2.0 cm³THF at - 35 °C while stirring. To

ensure complete transfer, another 0.5 cm³of THF was used

to ﬂush all phenolic compound into the reaction mixture.

Stirring was continued (step 1) at this temperature until

TLC indicated complete conversion or no signiﬁcant

change in reaction composition. Then, DIPEA (1.60 equiv.)

was added to a solution of phenol R²PhOH (1.00 equiv.) in

0.5 cm³THF, and this mixture was added to the reaction.

To ensure complete transfer, another 0.5 cm³of THF was

used to ﬂush all phenolic compounds into the reaction

mixture. Stirring was continued (step 2) and checked by

TLC. Then, DIPEA (1.50 equiv.), followed by alkyl

aminobenzoate (1.15 equiv.), was added directly to the

reaction mixture. The reaction was then continued (step 3)

and checked by TLC. For work-up, 15 cm³CH₂Cl₂was

added to the reaction mixture followed by 15 cm³1 N

HCl_aq, and the compound was extracted. The layers were

separated; the organic phase was washed with water

(2 9 15 cm³) and then concentrated in vacuo. Further

work-up and puriﬁcation procedures are given at the

respective examples.

3-[[4-(4-Formyl-2-methoxyphenoxy)-6-(4-methoxyphe-

noxy)-1,3,5-triazin-2-yl]amino]benzoic acid (4j, C₂₅H₂₀N₄O₇)

Prepared according to general procedure A using 37 mg

1,1-dimethylethyl aminobenzoate 8j (0.068 mmol, 1.00

equiv.); 45 °C for 1.25 h. Yield: 33 mg (quant.); appear-

ance: colorless solid; m.p.: 180–182 °C; R_f= 0.59 (hexane/

1

EtOH, 1:1); H NMR (DMSO-d₆, 200 MHz): d = 3.76 (s,

3H, C4’’’OCH₃), 3.86 (s, 3H, C2’’OCH₃), 6.96 (d,

J₃= 9.1 Hz, 2H, H3’’’ & H5’’’), 7.11–7.29 (m, 3H),

7.42–7.83 (m, 5H), 8.02 (s, 1H, H2’), 10.00 (s, 1H, CHO),

10.42 (s, 1H, NH), 12.92 (bs, 1H, CO₂H) ppm; ¹³C NMR

(DMSO-d₆, 100 MHz): d = 55.9 (q, C4’’’OCH₃), 56.5 (q,

C2’’OCH₃), 112.8 (d, C3’’), 114.9 (d, C3’’’ & C5’’’), 122.4

(d), 123.1 (d, C2’’’ & C6’’’), 124.1 (d), 125.0 (d), 127.6 (d),

135.4 (s, C4’’), 137.9 (s, C1’), 139.7 (s), 145.7 (s, C1’’*),

145.8 (s, C1’’’*), 152.2 (s, C2’’), 157.3 (s, C4’’’), 166.6 (s),

171.4–173.0 (C4 & C6, not resolved), 192.6 (d, CHO)

ppm, one s and two d signals missing possibly due to

overlap.

3-[[4-(4-Cyanophenoxy)-6-(4-methoxyphenoxy)-1,3,5-tri-

azin-2-yl]amino]benzoic acid (4k, C₂₄H₁₇N₅O₅) Prepared

according to general procedure A using 31 mg 1,1-dime-

Ethyl 4-[(4,6-diphenoxy-1,3,5-triazin-2-yl)amino]benzoate

(5a, C₂₄H₂₀N₄O₄) Prepared according to general procedure

using for step 1: 277 mg 2,4,6-trichlorotriazine

(1.50 mmol, 1.00 equiv.), 141 mg phenol (1.50 mmol, 1.00

equiv.), 213 mg DIPEA (1.65 mmol, 1.10 equiv.); - 35 °C

for 6 h; step 2: 141 mg phenol (1.50 mmol, 1.00 equiv.),

310 mg DIPEA (2.40 mmol, 1.60 equiv.); 35 °C for 46 h;

step 3: 285 mg ethyl 4-aminobenzoate (1.73 mmol, 1.15

equiv.), 291 mg DIPEA (2.25 mmol, 1.50 equiv.); 40 °C

for 42 h. After the work-up procedure described in general

procedure B, 1 cm³diethyl ether and 2 cm³LP were added

to induce precipitation and facilitate evaporation to dry-

ness. The crude material was dissolved in a mixture of

reﬂuxing CHCl₃/LP (1: 2, 12 cm³) and 8 cm³n-hexane

was added. After crystallization overnight, the compound

was isolated by ﬁltration, washed with 40 cm³LP, and

dried in vacuo. Yield: 611 mg (95%); appearance: color-

less solid; m.p.: 159–161 °C; R_f= 0.54 (hexane/EtOAc,

2:1); ¹H NMR (DMSO-d₆, 200 MHz): d = 1.28 (t,

J₃= 7.1 Hz, 3H, CH₃), 4.25 (q, J₃= 7.1 Hz, 2H, CH₂),

7.26–7.35 (m, 6H), 7.45–7.57 (m, 6H), 7.63–7.74 (m, 2H),

10.57 (s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆, 50 MHz):

B

thylethyl aminobenzoate 8k (0.06 mmol, 1.00 equiv.);

45 °C for 1 h. Yield: 27 mg (quant.); appearance: colorless

solid; m.p.: 240.5–242.5 °C; R_f= 0.48 (hexane/EtOH,

1:1); ¹H NMR (DMSO-d₆, 200 MHz): d = 3.77 (s, 3H,

OCH₃), 6.97 (d, J₃= 9.0 Hz, 2H, H3’’’ & H5’’’), 7.11–7.33

(m, 3H), 7.46–7.80 (m, 4H), 7.94 (d, J₃= 8.3 Hz, 2H, H3’’

& H5’’), 8.06 (s, 1H, H2’), 10.44 (s, 1H, NH) ppm, CO₂H

not visible; ¹³C NMR (DMSO-d₆, 50 MHz): d = 55.5 (q,

OCH₃), 108.6 (s, C4’’), 114.5 (d, C3’’’ & C5’’’), 118.5 (s,

CN), 121.7 (d, C2’), 122.6 (d, C2’’’ & C6’’’), 123.3 (d, C2’’

& C6’’), 124.4 (d, C4’), 124.9 (d, C6’), 128.6 (d, C5’),

131.4 (s, C3’), 134.2 (d, C3’’ & C5’’), 138.5 (s, C1’), 145.2

(s, C1’’’), 155.2 (s, C1’’), 156.9 (s, C4’’’), 166.2 (s, C2),

167.1 (s, CO₂) ppm, C4 & C6 not visible.

123

T. Linder et al.

1

d = 14.1 (q, CH₃), 60.4 (t, CH₂), 119.4 (d, C2’ & C6’),

121.9 (d, C2’’ & C2’’’ & C6’’ & C6’’’), 123.9 (s, C4’),

125.8 (d, C4’’ & C4’’’), 129.60 (C3’ & C5’), 129.63 (d,

C3’’ & C3’’’ & C5’’ & C5’’’), 143.0 (s, C1’), 151.9 (s, C1’’

& C1’’’), 165.3 (s, CO₂), 166.0 (s, C2), 172.1 (s, C4 & C6,

no rotamers visible individually) ppm.

186.5–188 °C; R_f= 0.48 (hexane/EtOAc, 2:1); H NMR

(DMSO-d₆, 400 MHz): d = 3.82 (s, 3H, CH₃), 7.19–7.36

(m, 6H), 7.41–7.53 (m, 4H), 7.58 (d, J₃= 6 Hz, 1H), 7.76

(bs, 1H), 8.08 (s, 1H, H2’), 10.47 (s, 1H, NH) ppm; ¹³C

NMR (DMSO-d₆, 100 MHz, 120 °C): d = 51.2 (q, CH₃),

120.9 (d), 121.2 (d), 123.5 (d), 124.8 (d), 127.6 (d), 128.6

(d), 128.7 (d), 129.3 (s), 129.9 (s), 138.1 (s, C1’), 150.3 (s,

C1’’), 151.6 (s, C1’’’), 164.5 (s, C2*), 166.1 (s, CO₂*),

171.3 & 171.5 (s, C4 & C6) ppm; one d signal missing

possibly due to overlap.

Methyl 3-[(4,6-diphenoxy-1,3,5-triazin-2-yl)amino]benzoate

(5b, C₂₃H₁₈N₄O₄) Prepared according to general procedure

B

using for step 1: 277 mg 2,4,6-trichlorotriazine

(1.50 mmol, 1.00 equiv.), 141 mg phenol (1.50 mmol, 1.00

equiv.), 213 mg DIPEA (1.65 mmol, 1.10 equiv.); - 35 °C

for 6 h; step 2: 141 mg phenol (1.50 mmol, 1.00 equiv.),

310 mg DIPEA (2.40 mmol, 1.60 equiv.); 35 °C for 46 h;

step 3: 261 mg methyl 3-aminobenzoate (1.73 mmol, 1.15

equiv.), 291 mg DIPEA (2.25 mmol, 1.50 equiv.); 35 °C

for 26 h. After the work-up procedure described in general

procedure B, the compound crystallized; the material was

then dissolved in 10 cm³reﬂuxing chloroform and 10 cm³

n-hexane was added to the boiling mixture, which caused

the compound to precipitate. After crystallization over-

night, the compound was isolated by ﬁltration, washed with

30 cm³LP and dried in vacuo. Yield: 523 mg (84%);

appearance: off-white powder; m.p.: 198–199.5 °C; R_f-

= 0.50 (hexane/EtOAc, 2:1); ¹H NMR (DMSO-d₆,

200 MHz): d = 3.81 (s, 3H, CH₃), 7.18–7.31 (m, 7H),

7.41–7.48 (m, 4H), 7.56 (d, J₃= 7.8 Hz, 1H), 7.75 (d,

J₃= 7.9 Hz, 1H), 8.03 (s, 1H, H2’), 10.42 (s, 1H, NH)

ppm; ¹³C NMR (DMSO-d₆, 50 MHz): d = 52.2 (q, CH₃),

121.2 (d, C2’), 121.8 (d, C2’’ & C2’’’ & C6’’ & C6’’’),

123.9 (d, C4’), 125.1 (d, C6’), 125.7 (d, C4’’ & C4’’’),

128.7 (d, C5’), 129.6 (d, C3’’ & C3’’’ & C5’’ & C5’’’),

130.0 (s, C3’), 138.9 (s, C1’), 151.8 (s, C1’’, C1’’’), 166.0

(s, C2*), 166.2 (s, CO₂*), 171.8 & 172.2 (bs, C4 & C6,

rotamers) ppm.

Methyl 3-[[4-(3-chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-

yl]amino]benzoate (5d, C₂₃H₁₇ClN₄O₄) Prepared according

to general procedure B using for step 1: 277 mg 2,4,6-

trichlorotriazine (1.50 mmol, 1.00 equiv.), 141 mg phenol

(1.50 mmol, 1.00 equiv.), 213 mg DIPEA (1.65 mmol,

1.10 equiv.);

-

35 °C for 6 h; step 2: 193 mg

3-chlorophenol (1.50 mmol, 1.00 equiv.), 310 mg DIPEA

(2.40 mmol, 1.60 equiv.); 35 °C for 46 h; step 3: 261 mg

methyl 3-aminobenzoate (1.73 mmol, 1.15 equiv.), 291 mg

DIPEA (2.25 mmol, 1.50 equiv.); 35 °C for 26 h. After the

work-up procedure described in general procedure B,

approx. 5 cm³LP was added to induce precipitation and

facilitate evaporation to dryness. The crude material was

dissolved in 4 cm³reﬂuxing CHCl₃and 4 cm³n-hexane

was added. After cooling and crystallization were com-

plete, the compound was isolated by ﬁltration, washed with

20 cm³LP, and dried in vacuo. Yield: 600 mg (89%);

appearance: colorless powder; m.p.: 151.5–156 °C; R_f-

= 0.55 (hexane/EtOAc, 2:1); ¹H NMR (DMSO-d₆,

200 MHz): d = 3.81 (s, 3H, CH₃), 7.24–7.51 (m, 10H),

7.58 (d, J₃= 7.8 Hz, 1H), 7.77 (d, J₃= 8.3 Hz, 1H), 8.05

(t, J = 1.6 Hz, 1H, H2’), 10.48 (s, 1H, NH) ppm; ¹³C NMR

(DMSO-d₆, 50 MHz): d = 52.2 (q, CH₃), 120.7 (d, C6’’),

121.3 (d, C2’), 121.8 (d, C2’’’ & C6’’’), 122.4 (d, C2’’),

124.0 (d, C4’), 125.1 (d, C6’), 125.7 (d, C4’’’), 125.9 (d,

C4’’), 128.7 (d, C5’), 129.6 (d, C3’’’ & C5’’’), 130.0 (s,

C3’), 130.9 (d, C5’’), 133.4 (s, C3’’), 138.7 (s, C1’), 151.8

(s, C1’’’), 152.4 (s, C1’’), 166.0 (s, C2*), 166.2 (s, CO₂*),

171.3–172.4 (C4 & C6, not resolved) ppm.

Methyl 3-[[4-(4-chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-

yl]amino]benzoate (5c, C₂₃H₁₇ClN₄O₄) Prepared according

to general procedure B using for step 1: 277 mg 2,4,6-

trichlorotriazine (1.50 mmol, 1.00 equiv.), 141 mg phenol

(1.50 mmol, 1.00 equiv.), 213 mg DIPEA (1.65 mmol,

1.10 equiv.);

-

35 °C for 6 h; step 2: 193 mg

Methyl 3-[[4-(2-chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-

yl]amino]benzoate (5e, C₂₃H₁₇ClN₄O₄) Prepared according

to general procedure B using for step 1: 277 mg 2,4,6-

trichlorotriazine (1.50 mmol, 1.00 equiv.), 141 mg phenol

(1.50 mmol, 1.00 equiv.), 213 mg DIPEA (1.65 mmol,

1.10 equiv.); 35 °C for 6 h; step 2: 193 mg 2-chlorophenol

(1.50 mmol, 1.00 equiv.), 310 mg DIPEA (2.40 mmol,

1.60 equiv.); 35 °C for 46 h; step 3: 261 mg methyl

3-aminobenzoate (1.73 mmol, 1.15 equiv.), 291 mg

DIPEA (2.25 mmol, 1.50 equiv.); 35 °C for 26 h. After the

work-up procedure described in general procedure B,

approx. 5 cm³LP was added to induce precipitation and

facilitate evaporation to dryness. The crude material was

4-chlorophenol (1.50 mmol, 1.00 equiv.), 310 mg DIPEA

(2.40 mmol, 1.60 equiv.); 35 °C for 46 h; step 3: 261 mg

methyl 3-aminobenzoate (1.73 mmol, 1.15 equiv.), 291 mg

DIPEA (2.25 mmol, 1.50 equiv.); 35 °C for 26 h. After the

work-up procedure described in general procedure B,

approx. 5 cm³LP was added to induce precipitation and

facilitate evaporation to dryness. The crude material was

dissolved in 5.5 cm³reﬂuxing CHCl₃and 5.5 cm³n-hex-

ane was added. The solution was brieﬂy sonicated to

facilitate crystallization and the compound was isolated by

ﬁltration, washed with 15 cm³LP and dried in vacuo.

Yield: 546 mg (81%); appearance: colorless powder; m.p.:

123

One-pot synthesis of triazines as potential agents affecting cell differentiation

dissolved in a reﬂuxing mixture of CHCl₃/n-hexane (2: 3,

11 cm³) and more n-hexane (11 cm³) was added. The

solution was brieﬂy sonicated to facilitate crystallization

and the compound was isolated by ﬁltration, washed with

20 cm³LP and dried in vacuo to give 5e (540 mg, 80%). A

fraction of this material (95 mg) was further puriﬁed by

column chromatography (MPLC, 100 g silica, 45 cm³

min^-1ﬂow rate, LP with a gradient of EtOAc 1–12%

within 15 min, then up to 100% EtOAc within 60 min).

Yield: 79 mg (corresponds to 67% yield over 2 puriﬁcation

steps); appearance: slightly off-white powder; m.p.:

& C6’’), 121.3 (d, C2’), 121.8 (d, C2’’’ & C6’’’), 123.9 (d,

C4’), 125.1 (d, C6’), 125.7 (d, C4’’’), 126.3 (d, C3’’ &

C5’’), 128.7 (d, C5’), 129.6 (d, C3’’’ & C5’’’), 130.0 (s,

C3’), 138.9 (s, C1’), 148.0 (s, C4’’*), 149.5 (s, C1’’*),

151.8 (s, C1’’’), 166.0 (s, C2*), 166.2 (s, CO₂*),

171.7–172.5 (C4 & C6, not resolved) ppm.

Methyl 3-[[4-(4-methoxyphenoxy)-6-phenoxy-1,3,5-triazin-

2-yl]amino]benzoate (5g, C₂₄H₂₀N₄O₅) Prepared accord-

ing to general procedure B using for step 1: 277 mg 2,4,6-

trichlorotriazine (1.50 mmol, 1.00 equiv.), 141 mg phenol

(1.50 mmol, 1.00 equiv.), 213 mg DIPEA (1.65 mmol,

1

139–141.5 °C; R_f= 0.48 (hexane/EtOAc, 2:1); H NMR

1.10 equiv.);

-

35 °C for 7 h; step 2: 186 mg

(DMSO-d₆, 200 MHz): d = 3.81 (s, 3H, CH₃), 7.17–7.48

(m, 9H), 7.58 (t, J₃= 8.5 Hz, 2H), 7.69 (bs, 1H), 7.99 (s,

1H, H2’), 10.51 (s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆,

50 MHz): d = 52.2 (q, CH₃), 121.3 (d, C2’), 121.8 (d, C2’’’

& C6’’’), 124.0 (d, C4’), 124.2 (d, C6’’), 125.1 (d, C6’),

125.8 (d, C4’’’), 126.0 (s, C2’’), 127.5 (d, C4’’*), 128.6 (d,

C5’’*), 128.7 (d, C5’*), 129.6 (d, C3’’’ & C5’’’), 130.0 (s,

C3’), 130.3 (d, C3’’), 138.6 (s, C1’), 147.7 (s, C1’’), 151.7

(s, C1’’’), 166.0 (s, C2*), 166.2 (s, CO₂*), 171.2 & 171.6 &

171.9 & 172.2 (s, C4 & C6, 2 pairs of rotamers) ppm.

4-methoxyphenol (1.50 mmol, 1.00 equiv.), 310 mg

DIPEA (2.40 mmol, 1.60 equiv.); 35 °C for 47 h; step 3:

261 mg methyl 3-aminobenzoate (1.73 mmol, 1.15 equiv.),

291 mg DIPEA (2.25 mmol, 1.50 equiv.); 35 °C for

23.5 h. After the work-up procedure described in general

procedure B, the compound was puriﬁed by manual col-

umn chromatography (silica, EtOAc/LP) and dried in

vacuo. Yield: 569 mg (85%); appearance: colorless solid;

1

m.p.: 56–60 °C; R_f= 0.36 (hexane/EtOAc, 2:1); H NMR

(DMSO-d₆, 200 MHz): d = 3.76 (s, 3H, C4’’OCH₃), 3.81

(s, 3H, CO₂CH₃), 6.96 (d, J = 9.0 Hz, 2H, H3’’ & H5’’),

7.13–7.31 (m, 6H), 7.41–7.48 (m, 2H), 7.56 (d,

J₃= 7.9 Hz, 1H), 7.76 (d, J = 7.9 Hz, 1H), 8.04 (s, 1H,

H2’), 10.39 (s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆,

50 MHz): d = 52.1 (q, CO₂CH₃), 55.4 (q, C4’’OCH₃),

114.4 (d, C3’’ & C5’’), 121.1 (d, C2’), 121.7 (d, C2’’’ &

C6’’’), 122.6 (d, C2’’ & C6’’), 123.8 (d, C4’), 125.0 (d,

C6’), 125.6 (d, C4’’’), 128.6 (d, C5’), 129.5 (d, C3’’’ &

C5’’’), 129.9 (s, C3’), 138.8 (s, C1’), 145.2 (s, C1’’), 151.8

(s, C1’’’), 156.8 (s, C4’’), 165.9 (s, C2*), 166.1 (s, CO₂*),

171.7–172.5 (C4 & C6, not resolved) ppm.

Methyl

3-[[4-[4-(1,1-dimethylethyl)phenoxy]-6-phenoxy-

1,3,5-triazin-2-yl]amino]benzoate (5f, C₂₇H₂₆N₄O₄) Pre-

pared according to general procedure B using for step 1:

277 mg 2,4,6-trichlorotriazine (1.50 mmol, 1.00 equiv.),

141 mg phenol (1.50 mmol, 1.00 equiv.), 213 mg DIPEA

(1.65 mmol, 1.10 equiv.); - 35 °C for 6 h; step 2: 225 mg

4-(1,1-dimethylethyl)phenol (1.50 mmol, 1.00 equiv.),

310 mg DIPEA (2.40 mmol, 1.60 equiv.); 35 °C for 46 h;

step 3: 261 mg methyl 3-aminobenzoate (1.73 mmol, 1.15

equiv.), 291 mg DIPEA (2.25 mmol, 1.50 equiv.); 35 °C

for 26 h. After the work-up procedure described in general

procedure B, the solvent was evaporated completely and

the crude material was dissolved in a reﬂuxing mixture of

CHCl₃/n-hexane (1:1, 4.5 cm³) and more n-hexane

(8.5 cm³) was added. The solution was brieﬂy sonicated to

facilitate crystallization and the compound was isolated by

ﬁltration, washed with 60 cm³LP, and dried in vacuo to

give 5f (565 mg, 80%). A fraction of this material

(235 mg) was further puriﬁed by column chromatography

(MPLC, 100 g silica, 45 cm³min^-1ﬂow rate, LP with a

gradient of EtOAc 1 to 12% within 15 min, then up to

100% EtOAc within 60 min). Yield: 194 mg (corresponds

to 66% yield over 2 puriﬁcation steps); appearance: col-

orless solid; m.p.: 85–86 °C; R_f= 0.53 (hexane/EtOAc,

2:1); ¹H NMR (DMSO-d₆, 200 MHz): d = 1.28 (s, 9H,

C(CH₃)₃), 3.82 (s, 3H, OCH₃), 7.14–7.30 (m, 6H),

7.41–7.48 (m, 4H), 7.56 (d, J₃= 7.7 Hz, 1H), 7.76 (d,

J₃= 7.9 Hz, 1H), 8.04 (s, 1H, H2’), 10.41 (s, 1H, NH)

ppm; ¹³C NMR (DMSO-d₆, 50 MHz): d = 31.2 (q,

C(CH₃)₃), 34.2 (s, C(CH₃)₃), 52.2 (OCH₃), 121.2 (d, C2’’

Methyl 3-[[4-(4-cyanophenoxy)-6-phenoxy-1,3,5-triazin-2-

yl]amino]benzoate (5h, C₂₄H₁₇N₅O₄) Prepared according

to general procedure B using for step 1: 277 mg 2,4,6-

trichlorotriazine (1.50 mmol, 1.00 equiv.), 141 mg phenol

(1.50 mmol, 1.00 equiv.), 213 mg DIPEA (1.65 mmol,

1.10 equiv.); - 35 °C for 6 h; step 2: 179 mg 4-hydroxy-

benzonitrile (1.50 mmol, 1.00 equiv.), 310 mg DIPEA

(2.40 mmol, 1.60 equiv.); 35 °C for 46 h; step 3: 261 mg

methyl 3-aminobenzoate (1.73 mmol, 1.15 equiv.), 291 mg

DIPEA (2.25 mmol, 1.50 equiv.); 35 °C for 26 h. After the

work-up procedure described in general procedure B,

approx. 10 cm³LP was added to induce precipitation

(under sonication) and facilitate evaporation to dryness.

The crude material was dissolved in 16 cm³reﬂuxing

CHCl₃and 16 cm³n-hexane was added. After cooling and

crystallization were complete, the compound was isolated

by ﬁltration, washed with 20 cm³LP, and dried in vacuo to

give 5h (569 mg, 86%). A fraction of this material

(223 mg) was further puriﬁed by column chromatography

123

T. Linder et al.

(MPLC, 100 g silica, 45 cm³min^-1ﬂow rate, LP with a

gradient of EtOAc 1 to 12% within 17 min, then up to

100% EtOAc within 60 min). Yield: 183 mg (corresponds

to 71% yield over 2 puriﬁcation steps); appearance: col-

orless solid; m.p.: 116.5–120 °C; R_f= 0.40 (hexane/

EtOAc, 2:1); ¹H NMR (DMSO-d₆, 200 MHz): d = 3.82 (s,

3H, CH₃), 7.24–7.31 (m, 4H), 7.41–7.60 (m, 5H), 7.71 (bs,

1H), 7.94 (d, J₃= 8.1 Hz, 2H, H3’’ & H5’’), 8.03 (s, 1H,

H2’), 10.50 (s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆,

50 MHz): d = 52.1 (q, CH₃), 108.5 (s, C4’’), 118.4 (s, CN),

121.2 (d, C2’), 121.7 (d, C2’’’ & C6’’’), 123.2 (d, C2’’ &

C6’’), 124.0 (d, C4’), 125.1 (d, C6’), 125.7 (d, C4’’’), 128.6

(d, C5’), 129.5 (d, C3’’’ & C5’’’), 129.9 (s, C3’), 134.0 (d,

C3’’ & C5’’), 138.5 (s, C1’), 151.7 (s, C1’’’), 155.1 (s,

C1’’), 165.8 (s, C2*), 166.0 (s, CO₂*), 170.9–172.3 (C4 &

C6, not resolved) ppm.

Methyl

3-[[4-(4-formyl-2-methoxyphenoxy)-6-phenoxy-

1,3,5-triazin-2-yl]amino]benzoate (5j, C₂₅H₂₀N₄O₆) Pre-

pared according to general procedure B using for step 1:

277 mg 2,4,6-trichlorotriazine (1.50 mmol, 1.00 equiv.),

141 mg phenol (1.50 mmol, 1.00 equiv.), 213 mg DIPEA

(1.65 mmol, 1.10 equiv.); - 35 °C for 6 h; step 2: 228 mg

vanillin (1.50 mmol, 1.00 equiv.), 310 mg DIPEA

(2.40 mmol, 1.60 equiv.); 40 °C for 46 h; step 3: 261 mg

methyl 3-aminobenzoate (1.73 mmol, 1.15 equiv.), 291 mg

DIPEA (2.25 mmol, 1.50 equiv.); 40 °C for 24 h. After the

work-up procedure described in general procedure B,

2 cm³diethyl ether was added, followed by approx 5 cm³

LP to induce crystallization and facilitate evaporation to

dryness. As re-crystallization from chloroform/n-hexane

was not successful, the compound was puriﬁed via column

chromatography (MPLC, 90 g silica, 45 cm³min^-1ﬂow

rate, CH₂Cl₂with a gradient of EtOAc (1 to 4% within

60 min) and dried in vacuo. Yield: 545 mg (77%);

appearance: colorless crystals; m.p.: 79–82 °C; R_f= 0.24

(hexane/EtOAc, 2:1); ¹H NMR (DMSO-d₆, 200 MHz):

d = 3.80 (s, 3H, CO₂CH₃), 3.85 (s, 3H, C2’’OCH₃),

7.17–7.30 (m, 4H), 7.40–7.70 (m, 7H), 7.99 (s, 1H, H2’),

10.00 (s, 1H, CHO), 10.46 (s, 1H, NH) ppm; ¹³C NMR

(DMSO-d₆, 50 MHz): d = 52.1 (q, CO₂CH₃), 56.0 (q,

C2’’OCH₃), 112.1 (d, C3’’), 121.2 (d, C2’), 121.7 (d, C2’’’

& C6’’’), 123.5 (d, C5’’*), 123.7 (d, C4’*), 123.9 (d,

C6’’*), 125.0 (d, C6’), 125.7 (d, C4’’’), 128.6 (d, C5’),

129.5 (d, C3’’’ & C5’’’), 129.9 (s, C3’), 135.0 (s, C4’’),

138.6 (s, C1’), 145.2 (s, C1’’*), 151.68 (s, C2’’*), 151.76

(s, C1’’’*), 165.8 (s, C2*), 166.0 (s, CO₂*), 171.2–172.4

(C4 & C6, not resolved), 191.9 (d, CHO) ppm.

Methyl

3-[[4-(3-nitrophenoxy)-6-phenoxy-1,3,5-triazin-2-

yl]amino]benzoate (5i, C₂₃H₁₇N₅O₆) Prepared according to

general procedure B using for step 1: 277 mg 2,4,6-

trichlorotriazine (1.50 mmol, 1.00 equiv.), 141 mg phenol

(1.50 mmol, 1.00 equiv.), 213 mg DIPEA (1.65 mmol,

1.10 equiv.); - 35 °C for 6 h; step 2: 209 mg 3-nitrophe-

nol (1.50 mmol, 1.00 equiv.), 310 mg DIPEA (2.40 mmol,

1.60 equiv.); 40 °C for 46 h; step 3: 261 mg methyl

3-aminobenzoate (1.73 mmol, 1.15 equiv.), 291 mg

DIPEA (2.25 mmol, 1.50 equiv.); 40 °C for 24 h. After the

work-up procedure described in general procedure B,

approx. 5 cm³diethyl ether was added to induce precipi-

tation and facilitate evaporation to dryness. The crude

material was dissolved in 8 cm³reﬂuxing CHCl₃and

8 cm³n-hexane was added. The solution was brieﬂy son-

icated to facilitate crystallization and the compound was

isolated by ﬁltration and washed with 60 cm³LP. The

compound had to be re-crystallized a second time by dis-

solving it in 17 cm³reﬂuxing CHCl₃and adding 17 cm³n-

hexane. After complete crystallization, the material was

isolated by ﬁltration, washed with 25 cm³LP and dried in

vacuo. Yield: 474 mg (69%); appearance: colorless pow-

der; m.p.: 165–176 °C; R_f= 0.34 (hexane/EtOAc, 2:1); ¹H

NMR (DMSO-d₆, 200 MHz): d = 3.80 (s, 3H, CH₃),

7.21–7.29 (m, 4H), 7.39–7.46 (m, 2H), 7.57 (d,

J₃= 7.5 Hz, 1H), 7.68–7.80 (m, 3H), 8.05 (s, 1H, H2’),

8.14 (d, J₃= 7.3 Hz, 1H), 8.21 (s, 1H, H2’’), 10.51 (s, 1H,

NH) ppm; ¹³C NMR (DMSO-d₆, 50 MHz): d = 52.1 (q,

CH₃), 117.4 (d, C2’’), 120.6 (d, C4’’), 121.2 (d, C2’), 121.7

(d, C2’’’ & C6’’’), 123.9 (d, C4’), 125.1 (d, C6’), 125.7 (d,

C4’’’), 128.6 (d, C6’’*), 128.7 (d, C5’*), 129.4 (d, C3’’’ &

C5’’’), 129.9 (s, C3’), 130.7 (d, C5’’), 138.5 (s, C1’), 148.3

(s, C3’’), 151.7 (s, C1’’’*), 151.9 (s, C1’’*), 165.8 (s, C2*),

166.1 (s, CO₂*), 171.1–172.3 (C4 & C6, not resolved)

ppm.

Methyl

3-[[4-(4-formyl-2-methoxyphenoxy)-6-(4-

(5k,

methoxyphenoxy)-1,3,5-triazin-2-yl]amino]benzoate

C₂₆H₂₂N₄O₇) Prepared according to general procedure B

using for step 1: 277 mg 2,4,6-trichlorotriazine

(1.50 mmol, 1.00 equiv.), 186 mg 4-methoxyphenol

(1.50 mmol, 1.00 equiv.), 213 mg DIPEA (1.65 mmol,

1.10 equiv.); - 35 °C for 7 h; step 2: 228 mg vanillin

(1.50 mmol, 1.00 equiv.), 310 mg DIPEA (2.40 mmol,

1.60 equiv.); 40 °C for 47 h; step 3: 261 mg methyl

3-aminobenzoate (1.73 mmol, 1.15 equiv.), 291 mg

DIPEA (2.25 mmol, 1.50 equiv.); 40 °C for 23.5 h. After

the work-up procedure described in general procedure B,

the was compound was puriﬁed via column chromatogra-

phy (MPLC, 90 g silica, 30–35 cm³min^-1ﬂow rate,

CH₂Cl₂with a gradient of EtOAc 1 to 20%). Mixed frac-

tions were also obtained, which were re-submitted to

another chromatographic puriﬁcation (MPLC, 40 g silica,

35 cm³min^-1ﬂow rate, CH₂Cl₂with 4% EtOAc) and

dried in vacuo. Yield: 674 mg (90%); appearance: color-

less solid; m.p.: 79–82 °C; R_f= 0.18 (hexane/EtOAc, 2:1);

¹H NMR (DMSO-d₆, 200 MHz): d = 3.76 (s, 3H,

123

One-pot synthesis of triazines as potential agents affecting cell differentiation

C4’’’OCH₃), 3.80 (s, 3H, CO₂CH₃*), 3.84 (s, 3H,

C2’’OCH₃*), 6.95 (d, J₃= 9.0 Hz, 2H, H3’’’ & H5’’’),

7.13–7.26 (m, 3H), 7.45–7.74 (m, 5H), 8.00 (s, 1H, H2’),

10.00 (s, 1H, CHO), 10.44 (s, 1H, NH) ppm; ¹³C NMR

(DMSO-d₆, 50 MHz): d = 52.1 (q, CO₂CH₃), 55.4 (q,

C4’’’OCH₃), 56.1 (q, C2’’OCH₃), 112.2 (d, C3’’), 114.4 (d,

C3’’’ & C5’’’), 121.3 (d, C2’), 122.6 (d, C2’’’ & C6’’’),

123.6 (d, C5’’*), 123.8 (d, C4’*), 124.0 (d, C6’’*), 125.1 (d,

C6’), 128.7 (d, C5’), 130.0 (s, C3’), 135.0 (s, C4’’), 138.7

(s, C1’), 145.2 (s, C1’’*), 145.3 (s, C1’’’*), 151.7 (s, C2’’),

156.9 (s, C4’’’), 166.0 (s, C2*), 166.2 (s, CO₂*), 171.5 &

172.3 (bs, C4 & C6), 192.0 (d, CHO) ppm.

213 mg DIPEA (1.65 mmol, 1.10 equiv.); - 35 °C for 7 h;

step 2: 179 mg 4-hydroxybenzonitrile (1.50 mmol, 1.00

equiv.), 310 mg DIPEA (2.40 mmol, 1.60 equiv.); 40 °C

for 47 h; step 3: 261 mg methyl 3-aminobenzoate

(1.73 mmol, 1.15 equiv.), 291 mg DIPEA (2.25 mmol,

1.50 equiv.); 40 °C for 23.5 h. After the work-up procedure

described in general procedure B, the solvent was evapo-

rated completely and the crude material was dissolved in a

reﬂuxing mixture of CHCl₃/cyclohexane (4:1, 7.5 cm³) and

more cyclohexane (18 cm³) was added. After cooling and

crystallization were completed, the compound was isolated

by ﬁltration, washed with 25 cm³LP, and dried in vacuo.

The material had to be puriﬁed further by column chro-

matography (MPLC, silica, short column, neat CH₂Cl₂,

20 cm³min^-1ﬂow rate, switching to 30 cm³min^-1after

1 h, adding 2% EtOAC after 1 h 20 min and switching to

40 cm³min after the appearance of the product peak (1 h

35 min)). The solvent was evaporated; TLC analysis

revealed a byproduct still present. Thus, the compound was

submitted to a second short column (MPLC, silica, 25 cm³

min^-1ﬂow rate, CH₂Cl₂with 2% EtOAc, increasing

gradually to 10% with the appearance of the product peak),

and dried in vacuo. Yield: 617 mg (88%); appearance:

colorless powder; m.p.: 132–134.5 °C; R_f= 0.29 (hexane/

EtOAc, 2:1); ¹H NMR (DMSO-d₆, 200 MHz): d = 3.76 (s,

3H, C4’’’OCH₃), 3.82 (s, 3H, CO₂CH₃), 6.96 (d,

J₃= 9.0 Hz, 2H, H3’’’ & H5’’’), 7.17 (d, J₃= 9 Hz, 2H),

7.28 (t, J₃= 7.9 Hz, 1H), 7.50 (d, J₃= 8.6 Hz, 2H), 7.58

(d, J₃= 7.8 Hz, 1H), 7.63–7.82 (m, 1H), 7.94 (d,

J₃= 8.3 Hz, 2H, H3’’ & H5’’), 8.05 (s, 1H, H2’), 10.47 (s,

1H, NH) ppm; ¹³C NMR (DMSO-d₆, 50 MHz): d = 52.1

(q, CO₂CH₃), 55.4 (q, C4’’’OCH₃), 108.6 (s, C4’’), 114.5

(d, C3’’’ & C5’’’), 118.5 (s, CN), 121.3 (d, C2’), 122.6 (d,

C2’’’ & C6’’’), 123.2 (d, C2’’ & C6’’), 124.1 (d, C4’), 125.2

(d, C6’), 128.7 (d, C5’), 130.0 (s, C3’), 134.1 (d, C3’’ &

C5’’), 138.7 (s, C1’), 145.2 (s, C1’’’), 155.2 (s, C1’’), 156.9

(s, C4’’’), 165.9 (s, C2*), 166.1 (s, CO₂*), 171.2 & 171.6 &

172.1 & 172.5 (s, C4 & C6, 2 pairs of rotamers) ppm.

Methyl 3-[[4-(4-bromo-2-formylphenoxy)-6-(4-methoxyphe-

noxy)-1,3,5-triazin-2-yl]amino]benzoate (5l, C₂₅H₁₉BrN₄O₆)

Prepared according to general procedure B using for step 1:

277 mg 2,4,6-trichlorotriazine (1.50 mmol, 1.00 equiv.),

186 mg 4-methoxyphenol (1.50 mmol, 1.00 equiv.),

213 mg DIPEA (1.65 mmol, 1.10 equiv.); - 35 °C for 6 h;

step

2:

302 mg

5-bromo-2-hydroxybenzaldehyde

(1.50 mmol, 1.00 equiv.), 310 mg DIPEA (2.40 mmol,

1.60 equiv.); 40 °C for 46 h; step 3: 261 mg methyl

3-aminobenzoate (1.73 mmol, 1.15 equiv.), 291 mg

DIPEA (2.25 mmol, 1.50 equiv.); 40 °C for 24 h. After the

work-up procedure described in general procedure B, the

compound was puriﬁed via column chromatography

(MPLC, 90 g silica, 35 cm³min^-1ﬂow rate, CH₂Cl₂with

1% EtOAc, gradually increasing to 3% over the course of

the separation), which gave 263 mg (32%) of still signiﬁ-

cantly contaminated material. Thus, 46 mg of the material

were submitted to another chromatographic puriﬁcation

(MPLC, 105 g silica, 50 cm³min^-1ﬂow rate, LP/EtOAc,

4:1) and then dried in vacuo. Yield: 22 mg (corresponds to

15% yield over 2 puriﬁcation steps); appearance: colorless

solid; m.p.: 180 °C (decomp.); R_f= 0.31 (hexane/EtOAc,

2:1); ¹H NMR (DMSO-d₆, 200 MHz): d = 3.76 (s, 3H,

OCH₃), 3.82 (s, 3H, OCH₃), 6.96 (d, J₃= 8.9 Hz, 2H),

7.10–7.34 (m, 3H), 7.43 (d, J₃= 8.5 Hz, 1H), 7.53–7.81

(m, 2H), 7.89–8.10 (m, 3H), 10.00 (s, 1H, CHO), 10.45 (s,

1H, NH) ppm; ¹³C NMR (DMSO-d₆, 50 MHz): d = 52.2

(q, CO₂CH₃), 55.4 (q, C4’’’OCH₃), 114.4 (d, C3’’’ &

C5’’’), 118.9 (s, C4’’), 121.3 (d, C2’), 122.6 (d, C2’’’ &

C6’’’), 124.1 (d, C4’), 125.1 (d, C6’), 126.2 (d, C6’’*),

128.7 (d, C5’), 129.8 (s, C2’’), 130.0 (s, C3’), 132.5 (d,

C3’’*), 138.2 (d, C5’’*), 138.6 (s, C1’), 145.2 (s, C1’’’),

151.7 (s, C1’’), 156.9 (s, C4’’’), 165.9 (s, C2*), 166.0 (s,

CO₂*), 171.5–172.5 (C4 & C6, not resolved), 188.4 (d,

CHO) ppm.

Synthesis of 2,4,6-trisubstitued 1,3,5-triazines—

general procedure C

The reaction was performed in an 8 cm³glass vial, using a

cryo or thermo block. DIPEA (523 mg, 4.05 mmol, 2.70

equiv.) was added to 282 mg phenol (3.00 mmol, 2.00

equiv.), dissolved in 1.0 cm³THF, and this solution was

then added dropwise to a solution of 277 mg 2,4,6-

trichlorotriazine (1.50 mmol, 1.00 equiv.) in 2.5 cm³THF

at - 35 °C while stirring. To ensure complete transfer,

another 0.5 cm³of THF was used to ﬂush all phenol into

the reaction mixture. Stirring was continued at - 35 °C for

2 h, then at r. t. for 70 h (step 1) until TLC indicated

complete conversion or no signiﬁcant change in reaction

Methyl

3-[[4-(4-cyanophenoxy)-6-(4-methoxyphenoxy)-

1,3,5-triazin-2-yl]amino]benzoate (5m, C₂₅H₁₉N₅O₅) Pre-

pared according to general procedure B using for step 1:

277 mg 2,4,6-trichlorotriazine (1.50 mmol, 1.00 equiv.),

186 mg 4-methoxyphenol (1.50 mmol, 1.00 equiv.),

123

T. Linder et al.

(DMSO-d₆, 50 MHz): d = 121.4 (d, C2’ & C2’’ & C6’ &

C6’’), 125.9 (d, C4’ & C4’’), 126.3 (s, C1’’’), 129.2 (d,

C3’’’ & C5’’’), 129.5 (d, C3’ & C3’’ & C5’ & C5’’), 129.7

(d, C4’’’), 134.8 (d, C2’’’ & C6’’’), 151.3 (s, C1’ & C1’’),

170.6 (s, C2 & C4), 184.8 (s, C6) ppm.

composition. Then, 291 mg DIPEA (2.25 mmol, 1.50

equiv.) was added directly to the reaction mixture, fol-

lowed by nucleophile PhXH (1.73 mmol, 1.15 equiv.). The

reaction was continued at r. t. for 24 h (step 2) and checked

by TLC. For work-up, 15 cm³CH₂Cl₂was added to the

reaction mixture, followed by 15 cm³1 N HCl_aqand the

compound was extracted. The layers were separated, the

organic phase washed with water (2 9 15 cm³) and then

concentrated in vacuo. Further work-up and puriﬁcation

procedures are given at the respective examples.

Synthesis of 1,1-dimethylethyl (4,6-

disubstituted-1,3,5-triazin-2-

yl)aminobenzoates—general procedure D

The reaction was performed in an 8 cm³glass vial, using a

cryo or thermoblock. DIPEA (1.10 equiv.) was added to

phenolic compound R¹PhOH (1.00 equiv.), dissolved in

0.4 cm³THF. This solution was cooled to - 35 °C and

then added dropwise to a solution of 2,4,6-trichlorotriazine

(1.00 equiv.) in 0.7 cm³THF at - 35 °C while stirring. To

ensure complete transfer, another 0.4 cm³of THF was used

to ﬂush all phenolic compounds into the reaction mixture.

Stirring was continued (step 1) until TLC indicated com-

plete conversion or no signiﬁcant change in reaction

composition. Then, DIPEA (1.60 equiv.) was added to a

solution of phenol R²PhOH (1.00 equiv.) in 0.4 cm³THF,

and this mixture added to the reaction. To ensure complete

transfer, another 0.4 cm³of THF was used to ﬂush all

phenolic compounds into the reaction mixture. Stirring was

continued (step 2) and reaction progress was checked by

TLC. Then, DIPEA (1.50 equiv.) was added directly to the

reaction mixture, followed by 1,1-dimethylethyl

3-aminobenzoate (1.15 equiv.). The reaction was then

continued (step 3) and checked by TLC.

4,6-Diphenoxy-N-phenyl-1,3,5-triazin-2-amine (6, C₂₁H₁₆N₄O₂)

Prepared according to general procedure C using for step 1:

277 mg 2,4,6-trichlorotriazine (1.50 mmol, 1.00 equiv.),

282 mg phenol (3.00 mmol, 2.00 equiv.), 523 mg DIPEA

(4.05 mmol, 2.70 equiv.); - 35 °C for 2 h, then r. t. for

70 h; step 2: 161 mg aniline (157 mm³, 1.73 mmol, 1.15

equiv.), 291 mg DIPEA (2.25 mmol, 1.50 equiv.); r. t. for

24 h. After the work-up procedure described in general

procedure A, 2 cm³diethyl ether and 5 cm³LP were added

to induce precipitation and facilitate evaporation to dry-

ness. The crude material was dissolved in a reﬂuxing

mixture of CHCl₃/n-hexane (3:2, 10 cm³) and more n-

hexane (15 cm³) was added; after cooling and complete

crystallization, the compound [21, 49, 50] was isolated by

ﬁltration, washed with 35 cm³LP, and dried in vacuo.

Yield: 452 mg (85%); appearance: colorless solid; m.p.:

156–159 °C; R_f= 0.29 (hexane/EtOAc, 5:1); ¹H NMR

(DMSO-d₆, 200 MHz): d = 6.97 (t, J₃= 7.2 Hz, 1H, H4’),

7.13 (t, J₃= 7.6 Hz, 2H, H3’ & H5’), 7.22–7.37 (m, 6H),

7.39–7.55 (m, 6H), 10.28 (s, 1H, NH) ppm; ¹³C NMR

(DMSO-d₆, 50 MHz): d = 120.4 (d, C2’ & C6’), 121.9 (d,

C2’’ & C2’’’ & C6’’ & C6’’’), 123.2 (d, C4’), 125.7 (d, C4’’

& C4’’’), 128.3 (d, C3’ & C5’) 129.6 (d, C3’’ & C3’’’ &

C5’’ & C5’’’), 138.4 (s, C1’), 151.9 (s, C1’’ & C1’’’), 165.9

(s, C2), 171.8 & 172.3 (s, C4 & C6, rotamers) ppm.

Work-up by general procedure D1 10 cm³CH₂Cl₂was

added to the reaction mixture, followed by 10 cm³water

and the compound was extracted. The layers were sepa-

rated, the aqueous phase was re-extracted with 5 cm³

CH₂Cl₂, and the combined organic fractions concentrated

in vacuo. Further work-up and puriﬁcation procedures are

given at the respective examples.

2,4-Diphenoxy-6-(phenylthio)-1,3,5-triazine (7, C₂₁H₁₅N₃O₂S)

Prepared according to general procedure C using for step 1:

277 mg 2,4,6-trichlorotriazine (1.50 mmol, 1.00 equiv.),

282 mg phenol (3.00 mmol, 2.00 equiv.), 523 mg DIPEA

(4.05 mmol, 2.70 equiv.); - 35 °C for 2 h, then r. t. for

70 h; step 2: 190 mg thiophenol (176 mm³, 1.73 mmol,

1.15 equiv.), 291 mg DIPEA (2.25 mmol, 1.50 equiv.); r. t.

for 24 h. After the work-up procedure described in general

procedure A, the solvent was evaporated completely and

the crude material was dissolved in a reﬂuxing mixture of

CHCl₃/n-hexane (3:2, 8.5 cm³) and more n-hexane

(10 cm³) was added; after cooling and crystallization were

completed, the compound was isolated by ﬁltration and

dried in vacuo. Yield: 405 mg (72%); appearance: color-

less solid; m.p.: 157–161.5 °C; R_f= 0.38 (hexane/EtOAc,

Work-up by general procedure D2 the reaction mixture

was taken up with 15 cm³EtOAc, washed with 1 N HCl_aq.

(2 9 10 cm³), 10 cm³saturated aq. NaHCO₃solution, and

10 cm³brine. The organic phase was concentrated in

vacuo. Further work-up and puriﬁcation are as stated

below. Further work-up and puriﬁcation procedures are

given at the respective examples.

1,1-Dimethylethyl

3-[(4,6-diphenoxy-1,3,5-triazin-2-

yl)amino]benzoate (8a, C₂₆H₂₄N₄O₄) Prepared according

to general procedure D using for step 1: 92 mg 2,4,6-

trichlorotriazine (0.50 mmol, 1.00 equiv.), 47 mg phenol

(0.50 mmol, 1.00 equiv.), 71 mg DIPEA (0.55 mmol, 1.10

equiv.);

-

35 °C for 6 h; step 2: 47 mg phenol

(0.50 mmol, 1.00 equiv.), 103 mg DIPEA (0.80 mmol,

1.60 equiv.); r. t. for 46 h; step 3: 111 mg 1,1-

1

5:1); H NMR (DMSO-d₆, 200 MHz): d = 7.13–7.29 (m,

6H), 7.30–7.46 (m, 7H), 7.46–7.56 (m, 2H) ppm; ¹³C NMR

123

One-pot synthesis of triazines as potential agents affecting cell differentiation

dimethylethyl 3-aminobenzoate (0.58 mmol, 1.15 equiv.),

97 mg DIPEA (0.75 mmol, 1.50 equiv.); r. t. for 43 h.

After the work-up procedure described in general proce-

dure C1, the compound was puriﬁed by column chro-

matography (MPLC, 90 g silica, 45 cm³min^-1ﬂow rate,

CH₂Cl₂/LP, 1: 5 with a gradient of 1–25% EtOAc within

35 min) and dried in vacuo. Yield: 167 mg (73%);

appearance: colorless crystals; m.p.: 208–209 °C; R_f-

= 0.62 (hexane/EtOAc, 2:1); ¹H NMR (DMSO-d₆,

200 MHz): d = 1.51 (s, 9H, (CH₃)₃), 7.14–7.34 (m, 7H),

7.39–7.55 (m, 5H), 7.75 (d, J₃= 8.3 Hz, 1H), 8.02 (s, 1H,

H2’), 10.39 (s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆,

50 MHz): d = 27.7 (q, C(CH₃)₃), 80.6 (s, C(CH₃)₃), 121.3

(d, C2’), 121.8 (d, C2’’ & C2’’’ & C6’’ & C6’’’), 123.7 (d,

C4’), 124.7 (d, C6’), 125.7 (d, C4’’ & C4’’’), 128.4 (d,

C5’), 129.6 (d, C3’’ & C3’’’ & C5’’ & C5’’’), 131.7 (s,

C3’), 138.7 (s, C1’), 151.8 (s, C1’’, C1’’’), 164.6 (s, CO₂),

166.2 (s, C2), 171.8 & 172.2 (bs, C4 & C6, rotamers) ppm.

equiv.); r. t. for 46 h; step 3: 111 mg 1,1-dimethylethyl

3-aminobenzoate (0.58 mmol, 1.15 equiv.), 97 mg DIPEA

(0.75 mmol, 1.50 equiv.); 40 °C for 26 h. After the work-

up procedure described in general procedure C1, the

compound was puriﬁed by column chromatography

(MPLC, 90 g silica, 45 cm³min^-1ﬂow rate, LP/CH₂Cl₂/

EtOAc, 10: 2:1, with an additional 2% Et₃N) and dried in

vacuo. Yield: 186 mg (76%); appearance: colorless solid;

1

m.p.: 187.5–190.5 °C; R_f= 0.64 (hexane/EtOAc, 2:1); H

NMR (DMSO-d₆, 200 MHz): d = 1.52 (s, 9H, (CH₃)₃),

7.13–7.60 (m, 11H), 7.77 (d, J₃= 8.0 Hz, 1H), 8.04 (s, 1H,

H2’), 10.45 (s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆,

50 MHz): d = 27.7 (q, C(CH₃)₃), 80.6 (s, C(CH₃)₃), 120.7

(d, C6’’), 121.3 (d, C2’), 121.7 (d, C2’’’ & C6’’’), 122.3 (d,

C2’’), 123.8 (d, C4’), 124.7 (d, C6’), 125.6 (d, C4’’’), 125.8

(d, C4’’), 128.4 (d, C5’), 129.5 (d, C3’’’ & C5’’’), 130.8 (d,

C5’’), 131.7 (s, C3’), 133.4 (s, C3’’), 138.6 (s, C1’), 151.8

(s, C1’’’), 152.4 (s, C1’’), 164.5 (s, CO₂*), 166.1 (s, C2),

171.2–172.2 (C4 & C6, not resolved) ppm.

1,1-Dimethylethyl

3-[[4-(4-chlorophenoxy)-6-phenoxy-

1,3,5-triazin-2-yl]amino]benzoate (8b, C₂₆H₂₃ClN₄O₄) Pre-

pared according to general procedure D using for step 1:

92 mg 2,4,6-trichlorotriazine (0.50 mmol, 1.00 equiv.),

47 mg phenol (0.50 mmol, 1.00 equiv.), 71 mg DIPEA

(0.55 mmol, 1.10 equiv.); - 35 °C for 6 h; step 2; 64 mg

4-chlorophenol (0.50 mmol, 1.00 equiv.), 103 mg DIPEA

(0.80 mmol, 1.60 equiv.); r. t. for 46 h; step 3: 111 mg 1,1-

dimethylethyl 3-aminobenzoate (0.58 mmol, 1.15 equiv.),

97 mg DIPEA (0.75 mmol, 1.50 equiv.); 40 °C for 26 h.

After the work-up procedure described in general proce-

dure C1, the compound was puriﬁed by column chro-

matography (MPLC, 90 g silica, 45 cm³min^-1ﬂow rate,

CH₂Cl₂) and dried in vacuo. Yield: 217 mg (89%);

appearance: off-white solid; m.p.: 172.5–174 °C; R_f= 0.61

(hexane/EtOAc, 2:1); ¹H NMR (DMSO-d₆, 200 MHz):

d = 1.53 (s, 9H, (CH₃)₃), 7.14–7.37 (m, 6H), 7.39–7.58 (m,

5H), 7.73 (d, J₃= 8.1 Hz, 1H), 8.04 (s, 1H, H2’), 10.42 (s,

1H, NH) ppm; ¹³C NMR (DMSO-d₆, 50 MHz): d = 27.8

(q, C(CH₃)₃), 80.7 (s, C(CH₃)₃), 121.3 (d, C2’), 121.8 (d,

C2’’’ & C6’’’), 123.77 (d, C2’’ & C6’’), 123.85 (d, C4’),

124.8 (d, C6’), 125.7 (d, C4’’’), 128.4 (d, C5’), 129.4 (d,

C3’’* & C5’’*), 129.6 (d, C3’’’* & C5’’’*), 129.9 (s, C4’’),

131.7 (s, C3’), 138.6 (s, C1’), 150.6 (s, C1’’), 151.8 (s,

C1’’’), 164.6 (s, CO₂), 166.1 (s, C2), 171.5–172.4 (C4 &

C6, not resolved) ppm.

1,1-Dimethylethyl

3-[[4-(2-chlorophenoxy)-6-phenoxy-

1,3,5-triazin-2-yl]amino]benzoate (8d, C₂₆H₂₃ClN₄O₄) Pre-

pared according to general procedure D using for step 1:

92 mg 2,4,6-trichlorotriazine (0.50 mmol, 1.00 equiv.),

47 mg phenol (0.50 mmol, 1.00 equiv.), 71 mg DIPEA

(0.55 mmol, 1.10 equiv.); - 35 °C for 6 h; step 2: 64 mg

2-chlorophenol (0.50 mmol, 1.00 equiv.), 103 mg DIPEA

(0.80 mmol, 1.60 equiv.); r. t. for 46 h; step 3: 111 mg 1,1-

dimethylethyl 3-aminobenzoate (0.58 mmol, 1.15 equiv.),

97 mg DIPEA (0.75 mmol, 1.50 equiv.); 40 °C for 26 h.

After the work-up procedure described in general proce-

dure C1, the compound was puriﬁed by column chro-

matography (MPLC, 90 g silica, 45 cm³min^-1ﬂow rate,

LP/CH₂Cl₂/EtOAc, 80: 8: 1, with an additional 2% Et₃N)

and dried in vacuo. Yield: 189 mg (77%); appearance:

colorless crystals; m.p.: 191–192 °C; R_f= 0.63 (hexane/

EtOAc, 2:1); ¹H NMR (DMSO-d₆, 200 MHz): d = 1.52 (s,

9H, (CH₃)₃), 7.11–7.56 (m, 10H), 7.56–7.79 (m, 2H), 7.99

(s, 1H, H2’), 10.48 (s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆,

50 MHz): d = 27.7 (q, C(CH₃)₃), 80.6 (s, C(CH₃)₃), 121.3

(d, C2’), 121.7 (d, C2’’’ & C6’’’), 123.8 (d, C4’), 124.2 (d,

C6’’), 124.7 (d, C6’), 125.7 (d, C4’’’), 125.9 (s, C2’’), 127.4

(d, C4’’*), 128.4 (d, C5’’*), 128.5 (d, C5’*), 129.5 (d, C3’’’

& C5’’’), 130.2 (d, C3’’), 131.6 (s, C3’), 138.4 (s, C1’),

147.7 (s, C1’’), 151.7 (s, C1’’’), 164.5 (s, CO₂), 166.1 (s,

C2), 171.2 & 171.6 & 171.8 & 172.2 (C4 & C6, 2 pairs of

rotamers) ppm.

1,1-Dimethylethyl

3-[[4-(3-chlorophenoxy)-6-phenoxy-

1,3,5-triazin-2-yl]amino]benzoate (8c, C₂₆H₂₃ClN₄O₄) Pre-

pared according to general procedure D using for step 1:

92 mg 2,4,6-trichlorotriazine (0.50 mmol, 1.00 equiv.),

47 mg phenol (0.50 mmol, 1.00 equiv.), 71 mg DIPEA

(0.55 mmol, 1.10 equiv.); - 35 °C for 6 h; step 2: 64 mg

3-chlorophenol (0.50 mmol, 1.00 equiv., puriﬁed by

Kugelrohr distillation), 103 mg DIPEA (0.80 mmol, 1.60

1,1-Dimethylethyl 3-[[4-[4-(1,1-dimethylethyl)phenoxy]-6-

phenoxy-1,3,5-triazin-2-yl]amino]benzoate (8e, C₃₀H₃₂N₄O₄)

Prepared according to general procedure D using for step 1:

92 mg 2,4,6-trichlorotriazine (0.50 mmol, 1.00 equiv.),

47 mg phenol (0.50 mmol, 1.00 equiv.), 71 mg DIPEA

(0.55 mmol, 1.10 equiv.); - 35 °C for 7 h; step 2: 75 mg

123

T. Linder et al.

4-(1,1-dimethylethyl)phenol (0.50 mmol, 1.00 equiv.),

103 mg DIPEA (0.80 mmol, 1.60 equiv.); 40 °C for 47 h;

step 3: 111 mg 1,1-dimethylethyl 3-aminobenzoate

(0.58 mmol, 1.15 equiv.), 97 mg DIPEA (0.75 mmol, 1.50

equiv.); 40 °C for 43 h. After the work-up procedure

described in general procedure C1, the compound was

puriﬁed by column chromatography (MPLC, 90 g silica,

45 cm³min^-1ﬂow rate, LP/CH₂Cl₂, 5:1, with a gradient of

EtOAc from 1 to 25% in 35 min) and dried in vacuo.

Yield: 170 mg (67%); appearance: colorless solid; m.p.:

139–141 °C; R_f= 0.75 (hexane/EtOAc, 2:1); ¹H NMR

(DMSO-d₆, 200 MHz): d = 1.31 (s, 9H, C4’’C(CH₃)₃),

1.52 (s, 9H, CO₂C(CH₃)₃), 7.10–7.35 (m, 6H), 7.37–7.58

(m, 5H), 7.78 (d, J₃= 7.3 Hz, 1H), 8.03 (s, 1H, H2’), 10.39

(s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆, 50 MHz):

d = 27.8 (q, CO₂C(CH₃)₃), 31.3 (q, C4’’C(CH₃)₃), 34.3 (s,

C4’’C(CH₃)₃), 80.7 (s, CO₂C(CH₃)₃), 121.2 (d, C2’’ &

C6’’*), 121.3 (d, C2’*), 121.8 (d, C2’’’ & C6’’’), 123.7 (d,

C4’), 124.7 (d, C6’), 125.7 (d, C4’’’), 126.2 (d, C3’’ &

C5’’), 128.4 (d, C5’), 129.6 (d, C3’’’ & C5’’’), 131.6 (s,

C3’), 138.7 (s, C1’), 148.0 (s, C4’’*), 149.5 (s, C1’’*),

151.8 (s, C1’’’), 164.6 (s, CO₂), 166.2 (s, C2), 171.4–172.3

(C4 & C6, not resolved) ppm.

(d, C6’), 125.7 (d, C4’’’), 128.5 (d, C5’), 129.6 (d, C3’’’ &

C5’’’), 131.7 (s, C3’), 138.7 (s, C1’), 145.2 (s, C1’’), 151.8

(s, C1’’’), 156.9 (s, C4’’), 164.6 (s, CO₂), 166.2 (s, C2),

171.2–172.4 (C4 & C6, not resolved) ppm.

1,1-Dimethylethyl 3-[[4-(4-cyanophenoxy)-6-phenoxy-1,3,5-

triazin-2-yl]amino]benzoate (8g, C₂₇H₂₃N₅O₄) Prepared

according to general procedure D using for step 1: 92 mg

2,4,6-trichlorotriazine (0.50 mmol, 1.00 equiv.), 47 mg

phenol (0.50 mmol, 1.00 equiv.), 71 mg DIPEA

(0.55 mmol, 1.10 equiv.); - 35 °C for 7 h; step 2: 60 mg

4-hydroxybenzonitrile (0.50 mmol, 1.00 equiv.), 103 mg

DIPEA (0.80 mmol, 1.60 equiv.); 40 °C for 47 h; step 3:

111 mg 1,1-dimethylethyl 3-aminobenzoate (0.58 mmol,

1.15 equiv.), 97 mg DIPEA (0.75 mmol, 1.50 equiv.);

40 °C for 43 h. After the work-up procedure described in

general procedure C2, the compound was puriﬁed by col-

umn chromatography (MPLC, silica, 45 cm³min^-1ﬂow

rate, liquid appl. with CH₂Cl₂, LP with a gradient of EtOAc

from 4 to 76% within 80 min) and dried in vacuo. Yield:

81 mg (33%); appearance: white solid; m.p.:

1

176.5–178.5 °C; R_f= 0.49 (hexane/EtOAc, 2:1); H NMR

(DMSO-d₆, 200 MHz): d = 1.53 (s, 9H, (CH₃)₃),

7.17–7.34 (m, 4H), 7.38–7.58 (m, 5H), 7.71 (bs, 1H), 7.94

(d, J₃= 8.5 Hz, 2H, H3’’ & H5’’), 8.04 (s, 1H, H2’), 10.46

(s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆, 50 MHz):

d = 27.8 (q, C(CH₃)₃), 80.7 (s, C(CH₃)₃), 108.5 (s, C4’’),

118.5 (s, CN), 121.3 (d, C2’), 121.8 (d, C2’’’ & C6’’’),

123.2 (d, C2’’ & C6’’), 123.9 (d, C4’*), 124.1 (d, C6’*),

125.8 (d, C4’’’), 128.5 (d, C5’), 129.6 (d, C3’’’ & C5’’’),

131.7 (s, C3’), 134.1 (d, C3’’ & C5’’), 138.5 (s, C1’), 151.7

(s, C1’’’), 155.2 (s, C1’’), 164.5 (s, CO₂), 166.2 (s, C2)

ppm, C4 & C6 not visible.

1,1-Dimethylethyl 3-[[4-(4-methoxyphenoxy)-6-phenoxy-

1,3,5-triazin-2-yl]amino]benzoate (8f, C₂₇H₂₆N₄O₅) Pre-

pared according to general procedure D using for step 1:

92 mg 2,4,6-trichlorotriazine (0.50 mmol, 1.00 equiv.),

47 mg phenol (0.50 mmol, 1.00 equiv.), 71 mg DIPEA

(0.55 mmol, 1.10 equiv.); - 35 °C for 7 h; step 2: 62 mg

4-methoxyphenol (0.50 mmol, 1.00 equiv.), 103 mg

DIPEA (0.80 mmol, 1.60 equiv.); 40 °C for 47 h; step 3:

111 mg 1,1-dimethylethyl 3-aminobenzoate (0.58 mmol,

1.15 equiv.), 97 mg DIPEA (0.75 mmol, 1.50 equiv.);

40 °C for 43 h. After the work-up procedure described in

general procedure C2, 2 cm³diethyl ether and 3 cm³LP

was added and the oily material was sonicated to induce

precipitation. After cooling to 0 °C for 2 h, the precipitate

was collected, and 10 cm³LP was added to the supernatant

to induce crystallization of a second fraction which was

collected by centrifugation. The combined fractions were

puriﬁed by column chromatography (MPLC, silica, 45 cm³

min^-1ﬂow rate, LP with a gradient of Et₂O from 15 to

75% in 80 min) and dried in vacuo. Yield: 167 mg (68%);

appearance: colorless crystals; m.p.: 68–70 °C; R_f= 0.56

(hexane/EtOAc, 2:1); ¹H NMR (DMSO-d₆, 200 MHz):

d = 1.52 (s, 9H, (CH₃)₃), 3.77 (s, 3H, OCH₃), 6.97 (d,

J₃= 9.1 Hz, 2H, H3’’ & H5’’), 7.12–7.34 (m, 6H),

7.38–7.58 (m, 3H), 7.77 (d, J₃= 7.5 Hz, 1H), 8.04 (s, 1H,

H2’), 10.37 (s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆,

50 MHz): d = 27.8 (q, C(CH₃)₃), 55.5 (q, OCH₃), 80.7 (s,

C(CH₃)₃), 114.5 (d, C3’’ & C5’’), 121.2 (d, C2’), 121.8 (d,

C2’’’ & C6’’’), 122.6 (d, C2’’ & C6’’), 123.8 (d, C4’), 124.8

1,1-Dimethylethyl 3-[[4-(3-nitrophenoxy)-6-phenoxy-1,3,5-

triazin-2-yl]amino]benzoate (8h, C₂₆H₂₃N₅O₆) Prepared

according to general procedure D using for step 1: 92 mg

2,4,6-trichlorotriazine (0.50 mmol, 1.00 equiv.), 47 mg

phenol (0.50 mmol, 1.00 equiv.), 71 mg DIPEA

(0.55 mmol, 1.10 equiv.); - 35 °C for 7 h; step 2: 70 mg

3-nitrophenol (0.50 mmol, 1.00 equiv.), 103 mg DIPEA

(0.80 mmol, 1.60 equiv.); 40 °C for 47 h; step 3: 111 mg

1,1-dimethylethyl 3-aminobenzoate (0.58 mmol, 1.15

equiv.), 97 mg DIPEA (0.75 mmol, 1.50 equiv.); 40 °C for

43 h. After the work-up procedure described in general

procedure C2, 1 cm³EtOAc and 9 cm³LP were added and

the oily material sonicated to induce precipitation. The

supernatant was removed by centrifugation and the com-

pound puriﬁed by preparative TLC (LP: EtOAc, 3: 1) and

dried in vacuo. Yield: 83 mg (33%); appearance: yellowish

solid; m.p.: 137–148 °C; R_f= 0.47 (hexane/EtOAc, 2:1);

¹H NMR (DMSO-d₆, 200 MHz): d = 1.51 (s, 9H, (CH₃)₃),

7.16–7.32 (m, 4H), 7.35-7.57 (m, 3H), 7.62-7.84 (m, 3H),

8.04 (s, 1H, H2’), 8.15 (dt, J₃= 7.2 Hz, J₄= 2.0 Hz, 1H),

123

One-pot synthesis of triazines as potential agents affecting cell differentiation

8.22 (s, 1H, H2’’), 10.48 (s, 1H, NH) ppm; ¹³C NMR

(DMSO-d₆, 50 MHz): d = 27.7 (q, C(CH₃)₃), 80.7 (s,

C(CH₃)₃), 117.4 (d, C2’’), 120.7 (d, C4’’), 121.2 (d, C2’),

121.7 (d, C2’’’ & C6’’’), 124.0 (d, C4’), 124.8 (d, C6’),

125.7 (d, C4’’’), 128.5 (d, C6’’*), 128.8 (d, C5’*), 129.6 (d,

C3’’’ & C5’’’), 130.8 (d, C5’’), 131.7 (s, C3’), 138.5 (s,

C1’), 148.4 (s, C3’’), 151.7 (s, C1’’’*), 152.0 (s, C1’’*),

164.5 (s, CO₂), 166.1 (s, C2) ppm, C4 & C6 not visible.

colorless solid; m.p.: 88–106 °C; R_f= 0.30 (hexane/

EtOAc, 2:1); ¹H NMR (DMSO-d₆, 200 MHz): d = 1.52 (s,

9H, (CH₃)₃), 3.76 (s, 3H, C4’’’OCH₃), 3.86 (s, 3H,

C2’’OCH₃), 6.96 (d, J₃= 9.0 Hz, 2H, H3’’’ & H5’’’),

7.10–7.31 (m, 3H), 7.44–7.86 (m, 5H), 8.02 (s, 1H, H2’),

10.01 (s, 1H, CHO), 10.42 (s, 1H, NH) ppm; ¹³C NMR

(DMSO-d₆, 50 MHz): d = 27.7 (q, C(CH₃)₃), 55.4 (q,

C4’’’OCH₃), 56.1 (q, C2’’OCH₃), 80.7 (s, C(CH₃)₃), 112.2

(d, C3’’), 114.5 (d, C3’’’ & C5’’’), 121.2 (d, C2’), 122.6 (d,

C2’’’ & C6’’’), 123.6 (d, C5’’*), 123.8 (d, C4’*), 123.9 (d,

C6’’*), 124.6 (d, C6’), 128.5 (d, C5’), 131.7 (s, C3’), 135.0

(s, C4’’), 138.6 (s, C1’), 145.2 (s, C1’’*), 145.3 (s, C1’’’*),

151.8 (s, C2’’), 156.9 (s, C4’’’), 164.6 (s, CO₂), 166.1 (s,

C2), 192.1 (d, CHO) ppm, C4 & C6 not visible.

1,1-Dimethylethyl

3-[[4-(4-formyl-2-methoxyphenoxy)-6-

phenoxy-1,3,5-triazin-2-yl]amino]benzoate (8i, C₂₈H₂₆N₄O₆)-

Prepared according to general procedure D using for step

1: 92 mg 2,4,6-trichlorotriazine (0.50 mmol, 1.00 equiv.),

47 mg phenol (0.50 mmol, 1.00 equiv.), 71 mg DIPEA

(0.55 mmol, 1.10 equiv.); - 35 °C for 7 h; step 2: 76 mg

vanillin (0.50 mmol, 1.00 equiv.), 103 mg DIPEA

(0.80 mmol, 1.60 equiv.); 40 °C for 47 h; step 3: 111 mg

1,1-dimethylethyl 3-aminobenzoate (0.58 mmol, 1.15

equiv.), 97 mg DIPEA (0.75 mmol, 1.50 equiv.); 40 °C for

43 h. After the work-up procedure described in general

procedure C2, the compound was puriﬁed by column

chromatography (MPLC, 90 g silica, 45 cm³min^-1ﬂow

rate, LP with a gradient of EtOAc from 1 to 40% within

1 h) and dried in vacuo. Yield: 141 mg (55%); appearance:

colorless solid; m.p.: 76–79 °C; R_f= 0.31 (hexane/EtOAc,

2:1); ¹H NMR (DMSO-d₆, 200 MHz): d = 1.51 (s, 9H,

(CH₃)₃), 3.86 (s, 3H, OCH₃), 7.11–7.33 (m, 4H), 7.36–7.55

(m, 4H), 7.56–7.78 (m, 3H), 8.00 (s, 1H, H2’), 10.00 (s,

1H, CHO), 10.43 (s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆,

50 MHz): d = 27.8 (q, C(CH₃)₃), 56.2 (q, OCH₃), 80.8 (s,

C(CH₃)₃), 112.3 (d, C3’’), 121.3 (d, C2’), 121.8 (d, C2’’’ &

C6’’’), 123.6 (d, C5’’*), 123.8 (d, C4’*), 123.9 (d, C6’’*),

124.7 (d, C6’), 125.8 (d, C4’’’), 128.5 (d, C5’), 129.6 (d,

C3’’’ & C5’’’), 131.7 (s, C3’), 135.1 (s, C4’’), 138.6 (s,

C1’), 145.3 (s, C1’’*), 151.70 (s, C2’’*) 151.74 (s, C1’’’*),

164.6 (s, CO₂), 166.1 (s, C2), 192.2 (d, CHO) ppm, C4 &

C6 not visible.

1,1-Dimethylethyl

methoxyphenoxy)-1,3,5-triazin-2-yl]amino]benzoate

3-[[4-(4-cyanophenoxy)-6-(4-

(8k,

C₂₈H₂₅N₅O₅) Prepared according to general procedure D

using for step 1: 92 mg 2,4,6-trichlorotriazine (0.50 mmol,

1.00 equiv.), 62 mg 4-methoxyphenol (0.50 mmol, 1.00

equiv.), 71 mg DIPEA (0.55 mmol, 1.10 equiv.); - 35 °C

for 7 h; step 2: 60 mg 4-hydroxybenzonitrile (0.50 mmol,

1.00 equiv.), 103 mg DIPEA (0.80 mmol, 1.60 equiv.);

40 °C for 47 h; step 3: 111 mg 1,1-dimethylethyl

3-aminobenzoate (0.58 mmol, 1.15 equiv.), 97 mg DIPEA

(0.75 mmol, 1.50 equiv.); 40 °C for 43 h. After the work-

up procedure described in general procedure C2, the

compound was puriﬁed by column chromatography

(MPLC, 90 g silica, 45 cm³min^-1ﬂow rate, LP with a

gradient of EtOAc from 10 to 40% within 1 h) and dried

in vacuo. Yield: 145 mg (57%); appearance: colorless

solid; m.p.: 161–164 °C; R_f= 0.43 (hexane/EtOAc, 2:1);

¹H NMR (DMSO-d₆, 200 MHz): d = 1.53 (s, 9H, (CH₃)₃),

3.77 (s, 3H, OCH₃), 6.98 (d, J₃= 9.0 Hz, 2H, H3’’’ &

H5’’’), 7.11–7.32 (m, 3H), 7.46–7.59 (m, 3H), 7.61–7.84

(m, 1H), 7.94 (d, J₃= 8.4 Hz, 2H, H3’’ & H5’’), 8.05 (s,

1H, H2’), 10.45 (s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆,

50 MHz): d = 27.8 (q, C(CH₃)₃), 55.6 (q, C4’’’OCH₃),

80.8 (s, C(CH₃)₃), 108.5 (s, C4’’), 114.5 (d, C3’’’ & C5’’’),

118.4 (s, CN), 121.3 (d, C2’), 122.6 (d, C2’’’ & C6’’’),

123.2 (d, C2’’ & C6’’), 124.0 (d, C4’), 124.9 (d, C6’),

128.5 (d, C5’), 131.7 (s, C3’), 134.1 (d, C3’’ & C5’’),

138.6 (s, C1’), 145.2 (s, C1’’’), 155.2 (s, C1’’), 156.9 (s,

C4’’’), 164.6 (s, CO₂), 166.1 (s, C2) ppm, C4 & C6 not

visible.

1,1-Dimethylethyl 3-[[4-(4-formyl-2-methoxyphenoxy)-6-(4-

methoxyphenoxy)-1,3,5-triazin-2-yl]amino]benzoate

(8j,

C₂₉H₂₈N₄O₇) Prepared according to general procedure D

using for step 1: 92 mg 2,4,6-trichlorotriazine (0.50 mmol,

1.00 equiv.), 62 mg 4-methoxyphenol (0.50 mmol, 1.00

equiv.), 71 mg DIPEA (0.55 mmol, 1.10 equiv.); - 35 °C

for 6 h; step 2: 76 mg vanillin (0.50 mmol, 1.00 equiv.),

103 mg DIPEA (0.80 mmol, 1.60 equiv.); 40 °C for 45 h;

step 3: 111 mg 1,1-dimethylethyl 3-aminobenzoate

(0.58 mmol, 1.15 equiv.), 97 mg DIPEA (0.75 mmol, 1.50

equiv.); 40 °C for 22 h. After the work-up procedure

described in general procedure C2, the compound was

puriﬁed by column chromatography (MPLC, 105 g silica,

50 cm³min^-1ﬂow rate, LP with a gradient of EtOAc from

20 to 40% within 30 min, then to 100% within 15 min) and

dried in vacuo. Yield: 162 mg (59%); appearance:

Synthesis of (4,6-disubstituted-1,3,5-triazin-2-

yl)aminophenyl methyl alcohols—general

procedure E

The reaction was performed using an 8 cm³vial, using a

mixture of MeOH/liq. N₂for cooling. A vial was charged

with alkyl aminobenzoate 5a–5g (1.00 equiv.) and sealed,

123

T. Linder et al.

[3-[[4-(4-Chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]ami-

no]phenyl]methanol (9c, C₂₂H₁₇ClN₄O₃) Prepared accord-

and the atmosphere changed to argon using standard Sch-

lenk technique. Anhydrous CH₂Cl₂(1.0 cm³) was added

via syringe, stirred at r. t. until the ester was dissolved, and

then cooled in a MeOH/liq. N₂bath. Subsequently, a

solution of diisobutylaluminium hydride (DIBAL-H,

0.86 mmol cm^-3) in n-hexane was added slowly. The

reaction mixture was stirred until TLC indicated complete

conversion (in some cases, more DIBAL-H solution was

added in the course of the reaction). Then, the reaction was

quenched by adding 1.0 cm³1 M HCl_aq., stirred for 5 min,

and then removed from the cooling bath, followed by the

addition of 10 cm³H₂O. After extraction with CH₂Cl₂

(10 cm³, then 2 9 5 cm³), the solvent was removed in

vacuo and the compound was puriﬁed as stated below.

ing to general procedure

E using 34 mg methyl

aminobenzoate 5c (0.075 mmol, 1.00 equiv.), 0.35 cm³

DIBAL-H (0.30 mmol, 4.00 equiv.); - 70 °C for 2.25 h;

then more DIBAL-H (0.05 cm³, 0.045 mmol, 0.60 equiv.);

- 70 °C for 1 h. After work-up as described in general

procedure E, the compound was re-crystallized from

1.5 cm³CHCl₃and 10 cm³n-hexane and dried in vacuo.

Yield: 28 mg (89%); appearance: colorless solid; m.p.:

1

110.5–114 °C; R_f= 0.39 (hexane/EtOAc, 1:1); H NMR

(DMSO-d₆, 200 MHz): d = 4.24–4.34 (m 2H, OCH₂),

5.06–5.16 (m, 1H, OH), 6.97 (d, J₃= 7.0 Hz, 1H), 7.09 (t,

J₃= 7.6 Hz, 1H, H5’), 7.20–7.39 (m, 7H), 7.39–7.57 (m,

4H), 10.24 (s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆,

50 MHz): d = 62.8 (t, CH₂), 118.4 (d, C2’*), 118.9 (d,

C6’*), 121.4 (d, C4’*), 121.8 (d, C2’’’ & C6’’’), 123.9 (d,

C2’’ & C6’’), 125.7 (d, C4’’’), 128.0 (d, C5’), 129.5 (d,

C3’’’* & C5’’’*), 129.6 (d, C3’’* & C5’’*), 129.9 (s, C4’’),

138.0 (s, C1’), 143.0 (s, C3’), 150.7 (s, C1’’), 151.8 (s,

C1’’’), 165.9 (s, C2) ppm, C4 & C6 not visible.

[4-[(4,6-Diphenoxy-1,3,5-triazin-2-yl)amino]phenyl]metha-

nol (9a, C₂₂H₁₈N₄O₃) Prepared according to general pro-

cedure

E

using 32 mg ethyl aminobenzoate 5a

(0.075 mmol, 1.00 equiv.), 0.33 cm³DIBAL-H

(0.285 mmol, 3.80 equiv.); - 70 °C for 2.25 h; then more

DIBAL-H (0.05 cm³, 0.045 mmol, 0.60 equiv.); - 70 °C

for 1 h. After work-up as described in general procedure E,

the compound was dried in vacuo and did not require

further puriﬁcation. Yield: 29 mg (quant.); appearance:

colorless powder; m.p.: 152.5–154 °C; R_f= 0.36 (hexane/

EtOAc, 1:1); ¹H NMR (DMSO-d₆, 200 MHz): d = 4.37 (d,

J₃= 5.6 Hz, 2H, CH₂), 5.07 (t, J₃= 5.6 Hz, 1H, OH), 7.04

(d, J₃= 8.5 Hz, 2H, H3’ & H5’), 7.21–7.54 (m, 12H),

10.20 (s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆, 50 MHz):

d = 62.5 (t, OCH₂), 120.0 (d, C2’ & C6’), 121.9 (d, C2’’ &

C2’’’ & C6’’ & C6’’’), 125.7 (d, C4’’ & C4’’’), 126.6 (d,

C3’ & C5’), 129.6 (d, C3’’ & C3’’’ & C5’’ & C5’’’), 137.0

(s, C4’*), 137.4 (s, C1’*), 151.9 (s, C1’’ & C1’’’), 165.8 (s,

C2), 171.7 & 172.4 (s, C4 & C6, rotamers) ppm.

[3-[[4-(3-Chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]ami-

no]phenyl]methanol

(9d,

C₂₂H₁₇ClN₄O₃) Prepared

according to general procedure E using 34 mg methyl

aminobenzoate 5d (0.075 mmol, 1.00 equiv.), 0.45 cm³

DIBAL-H (0.385 mmol, 5.10 equiv.); 70 °C for 1.75 h.

After work-up as described in general procedure E, the

compound was puriﬁed by column chromatography

(MPLC, 8.5 g silica, 8 cm³min^-1ﬂow rate, LP/EtOAc

1:1) and dried in vacuo. Yield: 25 mg (78%); appearance:

colorless oil; R_f= 0.49 (hexane/EtOAc, 1:1); ¹H NMR

(DMSO-d₆, 200 MHz): d = 4.30 (d, J₃= 4.6 Hz, 2H,

OCH₂), 5.11 (t, J₃= 5.4 Hz, 1H, OH), 6.97 (d,

J₃= 7.5 Hz, 1H), 7.10 (t, J₃= 7.7 Hz, 1H, H5’), 7.20–7.41

(m, 7H), 7.41–7.55 (m, 4H), 10.27 (s, 1H, NH) ppm; ¹³C

NMR (DMSO-d₆, 50 MHz): d = 62.7 (t, CH₂), 118.4 (d,

C2’*), 118.9 (d, C6’*), 120.8 (d, C6’’), 121.4 (d, C4’*),

121.7 (d, C2’’’ & C6’’’), 122.3 (d, C2’’), 125.6 (d, C4’’’*),

125.8 (d, C4’’*), 128.0 (d, C5’), 129.5 (d, C3’’’ & C5’’’),

130.9 (d, C5’’), 133.3 (s, C3’’), 138.0 (s, C1’), 142.9 (s,

C3’), 151.8 (s, C1’’’), 152.5 (s, C1’’), 165.9 (s, C2) ppm,

C4 & C6 not visible.

[3-[(4,6-Diphenoxy-1,3,5-triazin-2-yl)amino]phenyl]metha-

nol (9b, C₂₂H₁₈N₄O₃) Prepared according to general pro-

cedure

E using 31 mg methyl aminobenzoate 5b

(0.075 mmol, 1.00 equiv.), 0.33 cm³DIBAL-H

(0.285 mmol, 3.80 equiv.); - 70 °C for 1 h. After work-up

as described in general procedure E, the compound was

dried in vacuo and did not require further puriﬁcation.

Yield: 29 mg (quant.); appearance: colorless powder; m.p.:

49–52 °C; R_f= 0.36 (hexane/EtOAc, 1:1); ¹H NMR

(DMSO-d₆, 200 MHz): d = 4.27 (d, J₃= 5.7 Hz, 2H,

OCH₂), 5.09 (t, J₃= 5.7 Hz, 1H, OH), 6.95 (d,

J₃= 7.3 Hz, 1H), 7.07 (t, J₃= 7.7 Hz, 1H, H5’), 7.20–7.38

(m, 8H), 7.39–7.53 (m, 4H), 10.22 (s, 1H, NH) ppm; ¹³C

NMR (DMSO-d₆, 50 MHz): d = 62.8 (t, CH₂), 118.3 (d,

C2’*), 118.8 (d, C6’*), 121.3 (d, C4’*), 121.8 (d, C2’’ &

C2’’’ & C6’’ & C6’’’), 125.6 (d, C4’’ & C4’’’), 127.9 (d,

C5’), 129.5 (d, C3’’ & C3’’’ & C5’’ & C5’’’), 138.0 (s,

C1’), 142.9 (s, C3’), 151.9 (s, C1’’ & C1’’’), 166.0 (s, C2)

ppm, C4 & C6 not visible.

[3-[[4-(2-Chlorophenoxy)-6-phenoxy-1,3,5-triazin-2-yl]ami-

no]phenyl]methanol (9e, C₂₂H₁₇ClN₄O₃) Prepared accord-

ing to general procedure

E using 34 mg methyl

aminobenzoate 5e (0.075 mmol, 1.00 equiv.), 0.35 cm³

DIBAL-H (0.30 mmol, 4.00 equiv.); - 70 °C for 2 h; then

more DIBAL-H (0.10 cm³, 0.085 mmol, 1.15 equiv.); -

70 °C for 1.75 h. After work-up as described in general

procedure E, the compound was puriﬁed by column chro-

matography (MPLC, 8.5 g silica, 15 cm³min^-1ﬂow rate,

LP/EtOAc 3: 5) and dried in vacuo. Yield: 32 mg (quant.);

123

One-pot synthesis of triazines as potential agents affecting cell differentiation

Acknowledgements Open access funding provided by TU Wien

(TUW). Funding from the Austria Wirtschaftsservice (Uni Invent

Prize: Cardiogenic Drug Candidate) is gratefully acknowledged. .

appearance: colorless solid; m.p.: 52–54 °C; R_f= 0.44

(hexane/EtOAc, 1:1); ¹H NMR (DMSO-d₆, 200 MHz):

d = 4.27 (d, J₃= 5.3 Hz, 2H, OCH₂), 5.09 (t, J₃= 5.6 Hz,

1H, OH), 6.92–7.12 (m, 2H), 7.17–7.53 (m, 10H), 7.63 (d,

J₃= 7.4 Hz, 1H), 10.31 (s, 1H, NH) ppm; ¹³C NMR

(DMSO-d₆, 50 MHz): d = 62.8 (t, CH₂), 118.3 (d, C2’*),

118.8 (d, C6’*), 121.4 (d, C4’*), 121.8 (d, C2’’’ & C6’’’),

124.1 (d, C6’’), 125.7 (d, C4’’’), 125.9 (s, C2’’), 127.4 (d,

C4’’), 127.9 (d, C5’), 128.5 (d, C5’’), 129.5 (d, C3’’’ &

C5’’’), 130.2 (d, C3’’), 137.9 (s, C1’), 142.9 (s, C3’), 147.8

(s, C1’’), 151.7 (s, C1’’’), 165.8 (s, C2) ppm, C4 & C6 not

visible.

Open Access This article is distributed under the terms of the Creative

Commons Attribution 4.0 International License (http://creative

commons.org/licenses/by/4.0/), which permits unrestricted use, dis-

tribution, and reproduction in any medium, provided you give

appropriate credit to the original author(s) and the source, provide a

link to the Creative Commons license, and indicate if changes were

made.

References

1. Wobus AM, Boheler KR (2005) Physiol Rev 85:635

2. Plowright AT, Engkvist O, Gill A, Knerr L, Wang Q-D (2014)

Angew Chem Int Ed 53:4056

3. Pandian GN, Sato S, Anandhakumar C, Taniguchi J, Takashima

K, Syed J, Han L, Saha A, Bando T, Nagase H, Sugiyama H

(2014) ACS Chem Biol 9:2729

4. Davies SG, Kennewell PD, Russell AJ, Seden PT, Westwood R,

Wynne GM (2015) J Med Chem 58:2863

5. Sahara M, Santoro F, Chien KR (2015) EMBO J 34:710

6. World Health Organization (2008) 2008–2013 Action plan for the

global strategy for the prevention and control of noncommuni-

cable diseases. WHO, Geneva

7. Lloyd-Jones D, Adams RJ, Brown TM, Carnethon M, Dai S, De

Simone G, Ferguson TB, Ford E, Furie K, Gillespie C, Go A,

Greenlund K, Haase N, Hailpern S, Ho PM, Howard V, Kissela

B, Kittner S, Lackland D, Lisabeth L, Marelli A, McDermott

MM, Meigs J, Mozaffarian D, Mussolino M, Nichol G, Roger

VL, Rosamond W, Sacco R, Sorlie P, Stafford R, Thom T,

Wasserthiel-Smoller S, Wong ND, Wylie-Rosett J (2010) Cir-

culation 121:e46

8. Boheler KR, Czyz J, Tweedie D, Yang H-T, Anisimov SV,

Wobus AM (2002) Circ Res 91:189

9. Murry CE, Field LJ, Menasche P (2005) Circulation 112:3174

10. Forrester JS, White AJ, Matsushita S, Chakravarty T, Makkar RR

(2009) JACC Cardiovasc Interv 2:1

[3-[[4-[4-(1,1-Dimethylethyl)phenoxy]-6-phenoxy-1,3,5-tri-

azin-2-yl]amino]phenyl]methanol (9f, C₂₆H₂₆N₄O₃) Pre-

pared according to general procedure E using 35 mg

methyl aminobenzoate 5f (0.075 mmol, 1.00 equiv.),

0.45 cm³DIBAL-H (0.385 mmol, 5.10 equiv.); - 70 °C

for 1.5 h. After work-up as described in general procedure

E, the compound was dried in vacuo and did not require

further puriﬁcation. Yield: 33 mg (quant.); appearance:

colorless solid; m.p.: 47–50 °C; R_f= 0.54 (hexane/EtOAc,

1:1); ¹H NMR (DMSO-d₆, 200 MHz): d = 1.31 (s, 9H,

(CH₃)₃), 4.28 (d, J₃= 4.5 Hz, 2H, OCH₂), 5.11 (bs, 1H,

OH), 6.95 (d, J₃= 7.5 Hz, 1H), 7.06 (t, J₃= 7.7 Hz, 1H,

H5’), 7.12–7.21 (m, 2H), 7.22–7.34 (m, 4H), 7.35–7.52 (m,

5H), 10.20 (s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆,

50 MHz): d = 31.2 (q, C(CH₃)₃), 34.2 (s, C(CH₃)₃), 62.8

(t, CH₂), 118.3 (d, C2’*), 118.8 (d, C6’*), 121.1 (d, C2’’*

& C6’’*), 121.3 (d, C4’*), 121.8 (d, C2’’’ & C6’’’), 125.6

(d, C4’’’), 126.2 (d, C3’’ & C5’’), 127.9 (d, C5’), 129.5 (d,

C3’’’ & C5’’’), 138.1 (s, C1’), 142.9 (s, C3’), 147.9 (s,

C4’’*), 149.5 (s, C1’’*), 151.8 (s, C1’’’), 165.9 (s, C2) ppm,

C4 & C6 not visible.

11. Ausoni S, Sartore S (2009) J Cell Biol 184:357

12. Cyranoski D (2007) Nature 450:462

13. Cyranoski D (2008) Nature 452:406

[4-[[4-(4-Methoxyphenoxy)-6-phenoxy-1,3,5-triazin-2-yl]a-

14. Yamanaka S (2009) Cell 137:13

mino]phenyl]methanol

(9g,

C₂₃H₂₀N₄O₄) Prepared

15. Wu X, Ding S, Ding Q, Gray NS, Schultz PG (2004) J Am Chem

Soc 126:1590

16. Boer PH (1993) Exp Cell Res 207:421

according to general procedure E using 33 mg methyl

aminobenzoate 5 g (0.075 mmol, 1.00 equiv.), 0.45 cm³

DIBAL-H (0.385 mmol, 5.10 equiv.); - 70 °C for 1.75 h.

After work-up as described in general procedure E, the

compound was dried in vacuo and did not require further

puriﬁcation. Yield: 31 mg (quant.); appearance: colorless

17. Ruskoaho H (2003) Endocr Rev 24:341

¨

lovic MD (2011) Arkivoc 2011:45

18. Koley M, Konig X, Hilber K, Schnurch M, Stanetty P, Mihovi-

¨

19. Koley M, Mike AK, Heher P, Koenig X, Schon M, Schnurch M,

Hilber K, Weitzer G, Mihovilovic MD (2013) Med Chem Comm

4:1189

1

oil; R_f= 0.32 (hexane/EtOAc, 1:1); H NMR (DMSO-d₆,

20. Mike AK, Koenig X, Koley M, Heher P, Wahl G, Rubi L,

Schnu¨rch M, Mihovilovic MD, Weitzer G, Hilber K (2014) Cell

Physiol Biochem 33:205

21. Gardner DG, Chen S (1999) Life Sci 65:1607

22. Pakala R, Davies PJA, Chandraratna R, Benedict CR (1995) J

Am Coll Cardiol 25:83A

23. Hayashi A, Suzuki T, Tajima S (1995) J Biochem 117:132

24. Miano JM, Topouzis S, Majesky MW, Olson EN (1996) Circu-

lation 93:1886

200 MHz): d = 3.78 (s, 3H, OCH₃), 4.28 (d, J₃= 5.7 Hz,

2H, CH₂), 5.10 (t, J₃= 5.7 Hz, 1H, OH), 6.91–7.52 (m,

13H), 10.18 (s, 1H, NH) ppm; ¹³C NMR (DMSO-d₆,

50 MHz): d = 55.4 (q, OCH₃), 62.8 (t, CH₂), 114.4 (d, C3’’

& C5’’), 118.3 (d, C2’*), 118.8 (d, C6’*), 121.2 (d, C4’*),

121.8 (d, C2’’’ & C6’’’), 122.6 (d, C2’’ & C6’’), 125.6 (d,

C4’’’), 127.9 (d, C5’), 129.5 (d, C3’’’ & C5’’’), 138.1 (s,

C1’), 142.9 (s, C3’), 145.2 (s, C1’’), 151.8 (s, C1’’’), 156.8

(s, C4’’), 165.9 (s, C2) ppm, C4 & C6 not visible.

25. Peclo MM, Printseva OY (1987) Experientia 43:196

123

T. Linder et al.

26. Wobus AM, Kaomei G, Shan J, Wellner M-C, Rohwedel J, Ji G,

Fleischmann B, Katus HA, Hescheler J, Wolfgang-Michael F

(1997) J Mol Cell Cardiol 29:1525

27. Bempong DK, Honigberg IL, Meltzer NM (1995) J Pharmaceut

Biomed 13:285

28. Kojima R, Fujimori T, Kiyota N, Toriya Y, Fukuda T, Ohashi T,

Sato T, Yoshizawa Y, Takeyama K-i, Mano H, Masushige S,

Kato S (1994) J Biol Chem 269:32700

29. Theodosiou M, Laudet V, Schubert M (2010) Cell Mol Life Sci

67:1563

30. Duester G (2008) Cell 134:921

31. Sachidanandan C, Yeh Jing-Ruey J, Peterson QP, Peterson RT

(2008) PLoS ONE 3:e1947

32. Eicher T, Hauptmann S (2003) The chemistry of heterocycles.

Wiley, Weinheim, p 446

33. Goetz RJ, Robertazzi A, Mutikainen I, Turpeinen U, Gamez P,

Reedijk J (2008) J Chem Commun 2008:3384

34. Sun L, Guo Y, Peng G, Li C (2008) Synthesis 2008:3487

35. Sadek H, Hannack B, Choe E, Wang J, Latif S, Garry MG, Garry

DJ, Longgood J, Frantz DE, Olson EN, Hsieh J, Schneider JW

(2008) Proc Natl Acad Sci USA 105:6063

36. Beech WF (1967) J Chem Soc C 1967:466

37. Allington RD, Attwood D, Hamerton I, Hay JN, Howlin B (2002)

J Polym 44:793

42. Chandrasekaran S, Kluge AF, Edwards JA (1977) J Org Chem

42:3972

43. Braude EA, Nachod FC (1955) Determination of organic struc-

tures by physical methods. Academic, New York

44. Wuts PGM (2014) Greene’s protective groups in organic syn-

thesis, 5th edn. Wiley, Hoboken

45. Yang C, Pittman CU Jr (1998) Synth Commun 28:2027

46. Feng J-C, Liu B, Dai L, Yang X-L, Tu S-J (2001) Synth Commun

31:1875

47. Brown HC, Narasimhan S, Choi YM (1982) J Org Chem 47:4702

48. Mihovilovic MD, Schnu¨rch M, Hilber K, Koenig X, Linder T,

Mike A (2013) Triazine derivatives as differentiation accelera-

tors. PCT Int. Appl. WO 2013040622 A1, Mar 28, 2013; Chem

Abstr 158:465140

49. Mihovilovic MD, Schnu¨rch M, Hilber K, Koenig X, Linder T,

Mike A (2012) Triazine derivatives as differentiation accelera-

tors. Austrian Pat. Appl. [Post-Grant] AT 511441 A4, Dec 15,

2012; Chem Abstr 161:269346

50. Hoye TR, Aspaas AW, Eklov BM, Ryba TD (2005) Org Lett

7:2205

51. Gottlieb HE, Kotlyar V, Nudelman A (1997) J Org Chem

62:7512

52. Bruckner H, Wachsmann M (2003) J Chromatogr A 998:73

53. Chaudhari JA, Patel RP, Hathi MV (2007) E-J Chem 4:385

54. von Angerer S (2004) In: Weinreb SM (ed) Product subclass 3:

1,3,5-triazines and phosphorus analogues. Science of synthesis,

vol 17. Georg Thieme Verlag KG, Stuttgart, p 449

55. Spray DC, Campos de Carvalho AC, Mendez-Otero R (2010)

Stem Cells Dev 19:403

38. Theodorou V, Skobridis K, Tzakos AG, Ragoussis V (2007)

Tetrahedron Lett 48:8230

39. Kocienski PJ (1994) Protecting groups, vol 1. Thieme, Stuttgart

40. Wender PA, Schaus JM, White AW (1980) J Am Chem Soc

102:6157

41. Dippy JFJ, Hughes SRC, Rozanski A (1959) J Chem Soc

1959:2492

123

Article Doi

One-pot synthesis of triazines as potential agents affecting cell differentiation

DOI: 10.1007/s00706-018-2212-0

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