Convergent Versus Divergent Three-Step Synthesis of the First (4-Aminophenoxy)alkanoic Acid-Based Tripodal Melamines

Article abstract of DOI:10.1080/00397911.2015.1041048

Starting from N-(4-hydroxyphenyl)acetamide (Paracetamol, convergent approach) or from cyanuric chloride in reaction with 4-aminophenol (divergent approach), two synthetic routes toward novel tripodal N-substituted melamines as s-triazine derivatives of (4-aminophenoxy)acetic acid or of 4-(4-aminophenoxy)butyric acid are comparatively defined. The key steps consist of Williamson etherification of N-masked forms of 4-aminophenol and acidic hydrolysis of the N- and/or O-protected (4-aminophenoxy)alkanoic segments.

Full text of DOI:10.1080/00397911.2015.1041048

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Convergent Versus Divergent Three-
Step Synthesis of the First (4-
Aminophenoxy)alkanoic Acid–Based
Tripodal Melamines
Cristina Morara, Lavinia Costa, Pedro Lameirasb, Cyril Antheaumec &
Mircea Darabantua
a BABES-BOLYAI University, Faculty of Chemistry and Chemical
Engineering, Department of Chemistry, Cluj-Napoca, Romania
b University of Reims Champagne-Ardenne, ICMR, Reims, France
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c University of Strasbourg, Faculty of Pharmacy, Illkirch, France
Accepted author version posted online: 22 Apr 2015.Published
online: 22 Apr 2015.
To cite this article: Cristina Morar, Lavinia Cost, Pedro Lameiras, Cyril Antheaume &
Mircea Darabantu (2015): Convergent Versus Divergent Three-Step Synthesis of the First
(4-Aminophenoxy)alkanoic Acid–Based Tripodal Melamines, Synthetic Communications:
An International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI:
10.1080/00397911.2015.1041048
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1041048
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Synthetic Communications1, 0: 1–8, 2015
Copyright © Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397911.2015.1041048
CONVERGENT VERSUS DIVERGENT THREE-STEP
SYNTHESIS OF THE FIRST (4-AMINOPHENOXY)
ALKANOIC ACID–BASED TRIPODAL MELAMINES
Cristina Morar,1 Lavinia Cost,1 Pedro Lameiras,2
Cyril Antheaume,3 and Mircea Darabantu1
1BABES-BOLYAI University, Faculty of Chemistry and Chemical
Engineering, Department of Chemistry, Cluj-Napoca, Romania
2University of Reims Champagne-Ardenne, ICMR, Reims, France
3University of Strasbourg, Faculty of Pharmacy, Illkirch, France
GRAPHICAL ABSTRACT
Abstract Starting from N-(4-hydroxyphenyl)acetamide (Paracetamol, convergent
approach) or from cyanuric chloride in reaction with 4-aminophenol (divergent approach),
two synthetic routes toward novel tripodal N-substituted melamines as s-triazine
derivatives of (4-aminophenoxy)acetic acid or of 4-(4-aminophenoxy)butyric acid are
comparatively defined. The key steps consist of Williamson etherification of N-masked
forms of 4-aminophenol and acidic hydrolysis of the N- and=or O-protected (4-
aminophenoxy)alkanoic segments.
Keywords (4-Aminophenoxy)acetic acid; 4-(4-aminophenoxy)butyric acid; melamine;
Williamson etherification
INTRODUCTION
The use of the first N-substituted 2,4,6-triamino-1,3,5-triazines (melamines)
based on D- or L-alanine in construction of luminescent enantiomorphic three-
dimensional (3D) metal–organic frameworks has been recently reported.[1] This
innovative approach in organic material domain prompted other authors[2] to
enlarge this novel class of tripodal compounds by using the microwave-assisted
Received April 6, 2015.
Address correspondence to Mircea Darabantu, PBABES-BOLYAI University, Faculty of
Chemistry and Chemical Engineering, Department of Chemistry, 11 Arany János st., 400028 Cluj-
Napoca, Romania. E-mail: darab@chem.ubbcluj.ro, m.darabantu@upcmail.ro
1

2
C. MORAR ET AL.
Scheme 1. Targeted (4-aminophenoxy)acetic– (n ¼ 1) and 4-(4-aminophenoxy)butyric acid– (n ¼ 3) based
tripodal melamines A and B.
amination of 2,4,6-trichloro-1,3,5-triazine (cyanuric chloride) with various
unprotected natural amino acids (L-aspartic, L-glutamic, glycine, L-valine, etc.).
These syntheses provided C3-symmetrical polycarboxylate ligands seen as structural
directing units in metal–organic frameworks.
In line with these findings and following up our previous work on the synthesis
and structure of highly elaborated melamines,[3] we became interested in the prep-
aration of two new (4-aminophenoxy)alkanoic acid–based tripodal melamines, A
and B (Scheme 1).
Our interest was motivated as well by the lack of data concerning (i)
preparation of the apparently implicit precursors, (4-aminophenoxy)acetic acid[4]
and, mainly, 4-(4-aminophenoxy)butyric acid[5] against, (ii) bioimpact of their
various derivatives,[4e,6] and (iii) potential use of the tripodal compounds A and B
as new meta-trivalent dendritic cores.
DISCUSSION
Targeting the N-substituted tripodal melamines A and B, we envisaged two
synthetic routes, designed hereafter as the convergent and divergent routes.
The convergent route is depicted in Scheme 2.
Thus, starting from N-(4-hydroxyphenyl)acetamide (Paracetamol) 1, our
strategy implied the access to precursors (4-aminophenoxy)alkanoic acids 4a and
4b via their hydrochlorides 3a and 3b respectively. (4-Aminophenoxy)acetic acid
hydrochloride 3a was prepared in two steps, I and II, both inspired by Bezwada’s
recently patented protocol.[4e] Williamson etherification of Paracetamol 1 upon treat-
ment with ethyl bromoacetate (step I, 90% yield; lit. 80%[4e]) followed by the double
acidic hydrolysis of the resulting amidoester 2a (step II, 92% yield; lit. 77.6%[4e]
)
afforded the desired 3a with a global yield of 83% (lit. 62%[4e]). Alternative methods
in synthesis of 3a, for example, Williamson etherification of 1 with ethyl chloroacetate
(20% yield, our result), sodium cloroacetate,[4d,6d] or bromoacetate[4f] gave poor or no
results. We isolated the free amine 4a of 3a by manipulating the insolubility in water
of 4a in such a way that its contamination with potassium chloride was avoided
(global yield 1 → 4a, 67%).
To produce 4-(4-aminophenoxy)butyric acid 4b,[5] we initially planned the
regioselective Csp3-O ring opening of c-butyrolactone in reaction with sodium
phenoxide of 1 in similar conditions with those already reported for sodium
4-nitrophenoxide.[5b] In our hands no reaction occurred, and the starting N-(4-
hydroxyphenyl)acetamide 1 was recovered. Therefore, we had to move our interest,
once again, towards Williamson methodology, based on the expected similar

(4-AMINOPHENOXY)ALKANOIC ACID–BASED MELAMINES
3
Scheme 2. Three-step (I–III) convergent route towards (4-aminophenoxy)acetic– (n ¼ 1) and 4-(4-amino-
phenoxy)butyric acid– (n ¼ 3) based tripodal melamines A and B.
reactivity of 1 in comparison with N-(4-hydroxybenzyl)acetamide.[6a] We thus
obtained the amidoester 2b (step I) in a clean reaction with good yield. However,
the double acidic hydrolysis of 2b (step II), carried out in identical conditions as
1
for 2a, resulted in a crude reaction mixture whose H NMR spectrum revealed,
besides formation of 3b, its contamination either with the hydrochloride of 4-amino-
phenol 3d (20%, issued from the supplementary cleavage of the Ar-O-C linkage) or
with the intermediate 3c (10%, Fig. S1). 1H NMR monitoring of the process revealed
the reaction reaching completion within 2 h, a much shorter time in comparison with
2a (Scheme 2). As for 4a, the free amine 4b of 3b was isolated simply by modulating its
insolubility in water against that of potassium chloride. To conclude, the overall yield
(1 → 4b) of the synthesis was 39%.
In the final step III, we realised the one-pot triple anchorage of (4-aminophe-
noxy)alkanoic segments on s-triazine starting directly from hydrochlorides 3a and
3b. If so, our option was mandatory to the use of an efficient proton scavenger able
not only to generate in situ the corresponding free amines of 4a and 4b but also to
neutralize their carboxylic groups as well as the resulted HCl during aminations.
DIPEA failed to accomplish this triple task; that is, the reaction did not reach
completion (with thin-layer chromatographic, TLC, monitoring). The situation was
similar in the presence of single anhydrous K2CO3 or AcONa. Only the equimolar

4
C. MORAR ET AL.
Scheme 3. Proposed acid–base rational synthesis of N-substituted melamines A and B (step III, Scheme 2).
tandem K2CO3=AcONa gave the desired results (Scheme 2) as suggested by the
stoichiometric equations proposed in Scheme 3.
Indeed, in the end of aminations, both melamine A and B precipitated at pH 5
upon dilution with ice. We also observed the positive effect of butanone as cosolvent,
previously noticed by Negoro and Kawata[7a,7b] in the case of triple amination of
cyanuric chloride by 4-aminophenol (see later discussion).
In summary, the global yield (I–III) of the synthesis of melamine A was 76%,
but for B it was 47% (Figs. S14–19).
The divergent route is depicted in Scheme 4.
The known 4-aminophenol-based melamine 5 was obtained (step I) according to
the Negoro and Kawata protocol (91% yield; lit. 95%[7a,7b]). We note the failure to
prepare compound 5 in alternative conditions, that is, in refluxing acetone (3–48 h)
in the presence of an excess of 4-aminophenol[7c,7d] or anhydrous K2CO3 as proton
scavengers.[7e] In our hands, these protocols gave multicomponent crude reaction
mixtures, disclosing an incomplete triple amination. The next steps were mandatory
in addition to manipulations in triplicate. Williamson etherification of 5 (step II)
occurred with satisfactory and very similar yields, 6a against 6b. From all new com-
pounds discussed in the present work, only the melamine triester 6b required purifi-
cation by column chromatography. In the final step (III), compounds 6a and 6b
were successfully hydrolyzed in both variants, acidic (route III-a) or basic (route
Scheme 4. Three-step (I–III) divergent route toward (4-aminophenoxy)acetic– (n ¼ 1) and 4-(4-
aminophenoxy)butyric acid– (n ¼ 3) based tripodal melamines A and B.

(4-AMINOPHENOXY)ALKANOIC ACID–BASED MELAMINES
5
III-b), in very clean processes. No degradation of the 4-phenoxybutyric segment was
observed during triple acidolysis of melamine triester 6b.
By applying the divergent route, melamine A was obtained with 47% (I–IIIa)
and 43% (I–IIIb) global yields. In turn, 36% (I–IIIa) and 48% (I–IIIb) were the glo-
bal yields in the case of melamine B.
CONCLUSIONS
N-(4-Hydroxyphenyl)acetamide (paracetamol) was
a promising starting
material for a convergent three-step expeditious synthesis of two novel tripodal
N-substituted melamines as s-triazine derivatives of (4-aminophenoxy)acetic acid
(76% overall yield) and 4-(4-aminophenoxy)butyric acid (47% overall yield). Alter-
natively, starting from cyanuric chloride in with reaction 4-aminophenol (divergent
approach), the same two N-substituted tripodal-melamines were available with over-
all yields ranging between 36 and 48%. Regardless, the crucial steps of the three-step
strategy (convergent versus divergent) consisted of (i) Williamson etherification(s) of
N-masked forms of 4-aminophenol and (ii) acidic hydrolysis of (4-aminophenoxy)
alkanoic motifs during their N-, O-chemoselective deprotection.
EXPERIMENTAL
Melting points were measured on an Electrothermal instrument and are not cor-
rected. NMR spectra were recorded on Bruker AV 400, 500, or AV 600 instruments
operating at 400, 500, or 600 MHz for 1H and at 100, 125, or 150 MHz for 13C nuclei
respectively. All chemical shifts (d values) are given in parts per million (ppm); all
homocoupling patterns (nJH,H values) are given in hertz. Thin-layer chromatography
(TLC) was performed using aluminium sheets with silica gel 60 F254 (Merck); column
chromatography was conducted on silica gel Si 60 (40–63 µm, Merck). IR spectra were
recorded on a Bruker FT-IR Vector 22 Spectrometer. Microanalyses were performed
on a Carlos Erba CHNOS 1160 apparatus. Gas chromatography–mass spectrometry
(GC-MS) analysis was carried out on a Schimadzu GC-MS QP-2010 Plus instrument
equipped with a column HP-5MS under electron-impact (EI) ionization (70 eV). Mass
spectra were measured on a LTQ ORBITRAP XL (Thermo Scientific) instrument,
which was externally calibrated using the manufacturer’s electrospray ionization
(ESI, þ) calibration mix. The samples were introduced into the spectrometer by
direct infusion. All solvents and reagents were of analytical grade and required no
purification prior to use.
Typical Procedure for Preparation of the Tripodal Melamines A and B
by Convergent Route (III, Scheme 2): Preparation of Compound B
At 0–5°C, in a solution containing cyanuric chloride (0.075 g, 0.41 mmol)
dissolved in butanone (3.60 mL), a water (1.70 mL) solution obtained by dissolving
4-(4-aminophenoxy)butyric acid hydrochloride 3b (0.296 g, 1.28 mmol) and
anhydrous K2CO3 (0.177 g, 1.28 mmol) was injected dropwise with vigorous stirring.
After 30 min, anhydrous AcONa (0.105 g, 1.28 mmol) dissolved in water (0.30 mL)
was added as the temperature ranged between 5 and 10 °C. After additional 30 min

6
C. MORAR ET AL.
of stirring, the reaction mixture was heated at reflux for 16 h (TLC monitoring, eluent
EtOH 100%, visualization in UV at k ¼ 254 nm). After that, the reaction mixture
(pH ¼ 5) was cooled at room temperature and poured in ice (12 g). The resulted
suspension was filtered off to give 0.240 g pure compound B as a light pink powder
(88% yield with respect to cyanuric chloride).
2,4,6-Tris-{4-[3-(carboxy)prop-1-yloxy]}phenylamino-s-triazine (B)
Yield 88% (0.240 g B starting from 0.296 g 3b according to the convergent route,
Scheme 2, III); yield 71% (0.05 g B starting from 0.08 g 6b according to the divergent
route, Scheme 4, by acidic hydrolysis IIIa); yield 95% (0.46 g B starting from 0.55 g 6b
according to the divergent route (Scheme 4) by basic hydrolysis IIIb); light pink
powder, mp 196–198 °C (H2O); [found C, 60.12; H, 5.34; N, 12.61%. C33H36N6O9
(660.25) requires: C, 59.99; H, 5.49; N, 12.72%]; Rf (EtOH 100%) 0.33. nmax.(KBr)
3325 (w), 3580 (w), 3157 (w), 2936 (w), 2870 (w), 1740 (m), 1709 (m), 1662 (m),
1601 (m), 1570 (m), 1511 (s), 1471 (w), 1418 (m), 1354 (m), 1300 (w), 1250 (s), 1230
(s), 1172 (m), 1041 (w), 950 (w), 828 (m), 773 (w), 587 (w) cmꢀ1
.
1H NMR
3
(400 MHz, DMSO-d6, 298 K) dH 1.93 (6 H, tt app. qv., JH,H ¼ 6.7 Hz, b-CH2),
3
3
2.38 (6 H, t, JH,H ¼ 7.4 Hz, a-CH2), 3.95 (6 H, t, JH,H ¼ 6.2 Hz, c-CH2), 6.85
3
(6 H, d, JH,H ¼ 8.8 Hz, H-3,-5, Ar), 7.62 (6 H, br s due to the slow rotation about
the partial double bond C(s-triazine)-NH, H-2,-6, Ar), 8.95 (3 H, br s, NH) ppm.
13C NMR in Jmod (100 MHz, DMSO-d6, 298 K) dC 24.5 (b-CH2), 30.4 (a-CH2),
66.9 (c-CH2), 114.3 (C-3,-5, Ar), 122.2 (C-2,-6, Ar), 133.2 (C-1, Ar), 153.9 (C-4,
Ar), 164.1 (C-2,-4,-6, s-triazine), 174.4 (COO) ppm. MS [APCI (þ), MeCN] m=z
(rel. int.%) 661.26 [M þ 1] (100).
Typical Procedure for Williamson Etherification in Triplicate by
Divergent Route (II, Scheme 4): Preparation of Compound 6a
At room temperature and under a dry nitrogen atmosphere, in a DMF (15 mL)
solution containing compound 5 (1.00 g, 2.49 mmol), anhydrous K2CO3 (4.12 g,
29.88 mmol) was suspended with vigorous stirring. Then, ethyl 4-bromoacetate
(1.31 g, 0.87 mL, 7.84 mmol) was injected dropwise. The reaction mixture was stirred
at room temperature for 72 h (TLC monitoring, eluent hexane=acetone=CH2Cl2
1:1:1 v=v=v, visualization in UV at k ¼ 254 nm). Water (25 mL) and ethyl acetate
(50 mL) were added, and the resulting two layers were separated. The organic laeyer
was washed with water (6 × 25 mL) to completely remove DMF, and then dried over
anhydrous Na2SO4. The organic solution was evaporated under reduced pressure to
dryness. The solid crude residue was triturated from a ethyl acetate = Et2O at ꢀ18°C
to give 0.89 g pure compund 6a (54% yield with respect to 5).
2,4,6-Tris[(4-ethoxycarbonylmethoxy)phenylamino]-s-triazine (6a)
Yield 54% (0.89 g 6a starting from 1.00 g 5), white powder, mp 84–86 °C (ethyl
acetate=Et2O); [found C, 60.05; H, 5.72; N, 12.53%. C33H36N6O9 (660.25) requires C,
59.99; H, 5.49; N, 12.72%]; Rf (hexane=acetone=CH2Cl2 1:1:1 v=v=v) 0.75. nmax.(KBr)
3337 (w), 3195 (w), 3116 (w), 2982 (w), 2920 (w), 1752 (m), 1623 (m), 1576 (m), 1511

(4-AMINOPHENOXY)ALKANOIC ACID–BASED MELAMINES
7
(s), 1495 (s), 1418 (s), 1299 (w), 1202 (m), 1083 (w), 1020 (w), 827 (w) cmꢀ1. 1H NMR
3
3
(600 MHz, CDCl3, 298 K) dH 1.29 (9 H, t, JH,H ¼ 7.2 Hz, CH3), 4.26 (6 H, q, JH,H
3
¼ 7.2 Hz, CH2CH3), 4.58 (6 H, s, CH2), 6.83 (6 H, d, JH,H ¼ 9.0 Hz, H-3,-5, Ar),
7.38 (6 H, d, 3JH,H ¼ 9.0 Hz, H-2,-6, Ar), 7.44 (3 H, br s, NH) ppm. 13C NMR in Jmod
(150 MHz, CDCl3, 298 K) dC 14.3 (CH3), 61.5 (CH2CH3), 66.0 (CH2), 115.1 (C-3,-5,
Ar), 122.9 (C-2,-6, Ar), 132.4 (C-1, Ar), 154.4 (C-4, Ar), 163.8 (C-2,-4,-6, s-triazine)
169.1 (COO) ppm. MS [APCI (þ), MeCN] m=z (rel. int. %) 661.26 [M þ 1] (100).
FUNDING
The financial support from a grant provided by the Research Council of
Romania (Project PN-II-ID-PCE-2011-3-0128) is gratefully acknowledged.
SUPPLEMENTAL MATERIAL
Typical) procedures for preparations of compounds 2a, 2b, 3a, 3b, 4a, and 4b
(convergent route) and A, B, and 5 (divergent route); full analytical data of com-
pounds A, 2a, 2b, 3a, 3b, 4a, 4b, 5a, and 6b; 1H NMR monitoring of acidic hydrolysis
of compound 2b; 1H and 13C NMR spectra of compounds 2a, 2b, 3a, 3b, 4a, 4b, A, B,
5, 6a, and 6b; and MS of compounds A and B for this article can be accessed on the
publisher’s website.
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