New serinolic amino-s-triazines by chemoselective amination of cyanuric chloride and their (pro)diastereomerism in restricted rotational phenomena

Article abstract of DOI:10.2478/s11532-012-0015-4

The highly chemoselective preparation of new elaborated N-unsymmetrically substituted chlorodiamino-s-triazines and melamines, seen as building-blocks for iterative synthesis, is reported. It consisted of amination of cyanuric chloride with commercial C-2

Full text of DOI:10.2478/s11532-012-0015-4

Cent. Eur. J. Chem. • 10(4) • 2012 • 1119-1136
DOI: 10.2478/s11532-012-0015-4
Central European Journal of Chemistry
New serinolic amino-s-triazines
by chemoselective amination of cyanuric
chloride and their (pro)diastereomerism
in restricted rotational phenomena
Research Article
Oana Moldovan1,2, Pedro Lameiras3, Eric Henon3, Flavia Popa1,2,
Agathe Martinez3, Dominique Harakat3, Carmen Sacalis1,
Yvan Ramondenc2, Mircea Darabantu1*
1“Babes-Bolyai” University, Department of Organic Chemistry,
400028 Cluj-Napoca, Romania
2University and INSA of Rouen, IRCOF – LCOFH,
UMR 6014 CNRS COBRA, 76821 Mont Saint-Aignan Cedex, France
3University of Reims Champagne-Ardenne, ICMR - LIS,
UMR 6229, BP 1039, 51687 Reims, France
Received 4 December 2011; Accepted 23 January 2012
Abstract:
The highly chemoselective preparation of new elaborated N-unsymmetrically substituted chlorodiamino-s-triazines and melamines,
seen as building-blocks for iterative synthesis, is reported. It consisted of amination of cyanuric chloride with commercial
C-2-substituted 2-aminopropane-1,3-diols (“serinols”), playing the role as “open-chain” unit and enantiopure (1S,2S)-2-amino-1-
(4-nitrophenyl)propane-1,3-diols (“p-nitrophenylserinols”) based amino-1,3-dioxanes (“closed-chain” unit). Issued from
the restricted rotation about C(s-triazine)-N(exocyclic) partial double bonds, seen as axes of (pro)diastereomerism, a global
four-component rotational equilibrium involving the title compounds is discussed based on DFT computation and (VT) NMR data.
Depending on π-deficiency of the s-triazine core, an (un)synchronised deblocking of the generated rotational diastereomers was
observed. They are discussed as influence of intra- vs. intermolecular NH…OH (dynamic) interactions occurring in the “open-chain”
unit and the anancomeric, axial vs. equatorial, amino-anchorage of the “closed-chain” unit.
Keywords: Amino-s-triazines • NMR • Restricted rotation • Serinols
© Versita Sp. z o.o.
1. Introduction
we considered two series of new N-substituted amino-s-
triazines, I and II (Scheme 1), possessing:
Following our recent findings in the synthesis [1-5],
i) A serinolic “open-chain” unit of type C-2-substituted
structure [1-5] and use [6-8] of N-substituted 2,4,6- 2-aminopropane-1,3-diol, SER-NH
2 (a-c).
triamino-s-triazines (melamines) by exploiting the
versatilenucleophilicityofC-substituted2-aminopropane-
1,3-diols (serinols) [9,10] against cyanuric chloride, we
now report new results in a combined synthetic-structural
approach.
Thus, since both theoretic [11] and / or synthetic [12]
advances in dendrimers’chemistry called attention on the
diversity of peripheral groups providing a plethora of sites
for further nanoscale manipulation of these architectures,
ii)
A
“closed-chain” unit of type O,O-masked
p-nitrophenylserinol as anancomeric (4S,5S)-amino-
1,3-dioxane containing the primary amino group in axial
D-NH2 (ax) or in equatorial D-NH2 (eq) position[9,10].
Although amination of cyanuric chloride is a standard
synthetic protocol, the dendritic-iterative facet of this
methodology was reviewed just recently by Simanek
et al. [13-15]. Conversely, to a detailed conformational
analysis in this class of elaborated amino-s-triazines
* E-mail: darab@chem.ubbcluj
darabantu@cluj.astral.ro
1119

New serinolic amino-s-triazines by chemoselective amination
of cyanuric chloride and their (pro)diastereomerism
in restricted rotational phenomena
SER-NH2 (a-c)
R1 NH2
R2
axial
NH2
5
anchorage
O2N
O2N
N
N
O
O
O
D-NH2 (ax)
4
SER-HN
N
NH-D (ax or eq)
OH OH
equatorial
anchorage
NMe2
R1 = Me (a, "Methylserinol")
Et (b, "Ethylserinol")
Series I : D-NH (ax)
Series II : D-NH (eq)
Series I and II : SER-NH (a-c)
R2 = Cl, piperazin-1-yl
5
O
CH2NH2
D-NH2 (eq)
2
4
CH2OH (c, TRIS)
p-nitrophenylserinolic "closed-chain" unit
Serinolic "open-chain" unit
Scheme 1. Targeted series of amino-s-triazines.
attention was paid also very recently only [16] by the and synthesis of compounds D-NH2 (ax), D-NH2 (eq)
sameauthorsinspiteofthewellestablishedphenomena, [1,9,10,27-30] and 1a-c [2] we reported elsewhere.
as early as 1971 [17,18], namely the restricted rotations
about the C(s-triazine)-N(exocyclic) partial double bonds
[19-26] governing, overall, the stereo-dynamism of
these structures.
2.2. Procedures
Typical procedure for the synthesis of compounds 2a-c
and 3a-c. Preparation of compound 2c (Scheme 3)
To anh. K2CO3 (1.512 g, 100%, 10.944 mmol)
suspended in anh. THF (100 mL), solid 2-amino-
2-(hydroxymethyl)propane-1,3-diol (TRIS, 1.325 g,
10.944 mmol) was added with vigorous stirring. The
resulting suspension was cooled at -15°C when cyanuric
chloride (2.018 g, 10.944 mmol) as clear anh. THF
(25 mL) solution was injected rapidly. The reaction
mixture was let gently to reach room temperature and
was kept as such for additional 24 hrs. with stirring. After
this period, TLC monitoring indicated the intermediate
2,4-dichloro-6-{[1,3-dihydroxy-2-(hydroxymethyl)prop-
2-yl]amino}-s-triazine 1c as a single spot (acetone:
ligroin 2:1, Rf = 0.80). Freshly prepared (4S,5S)-
Consequently, the aim of the present work is
to describe the clean and efficient access to new
N-substituted amino-s-triazines, series
I
and II
(Scheme 1), together with their stereochemistry focused
on rotational Ar-N< aspects.
2. Experimental procedure
2.1. General
Melting points are uncorrected; they were carried out
on ELECTROTHERMAL® instrument. Conventional
NMR spectra were recorded on a Bruker® AM300
1
5-amino-4-(4-nitrophenyl)-1,3-dioxane
D-NH2 (ax)
instrument operating at 300 and 75 MHz for H and
13C nuclei respectively. VT NMR experiments were
performed on a Bruker® DMX500 instrument. All NMR
spectra were measured in anhydrous commercially
available deuterated solvents. The 13C NMR description
of compounds exhibiting frozen rotamers at room
temperature was made by considering them as one
global structure. Multiple δC values for the same-labelled
position means mixture of rotamers. Some specific
abbreviations were used: bd (broad doublet) bdd (broad
doublet of doublets, bq (broad quartet), bm (broad
multiplet), p-NPh (p-nitrophenyl).TLC was performed by
using aluminium sheets with silica gel 60 F254 (Merck®);
flash column chromatography was conducted on Silica
gel Si 60 (40–63 µm, Merck®). All visualisations were
realised in UV at 254 nm. IR spectra were performed
on a Perkin-Elmer® Paragom FT-IR spectrometer. Only
relevant absorptions are listed [throughout in cm-1: weak
(w), medium (m) or (s) strong]. Microanalyses were
performed on a Carlo Erba® CHNOS 1160 apparatus.
Mass spectra (MS) were recorded on a Bruker® Esquire
Instrument. Specific rotations were measured on a
POLAMAT® Karl-Zeiss Jena instrument. Analytical data
(2.452 g, 100%, 10.944 mmol) and anh. K2CO3
(1.512 g, 100%, 10.944 mmol) were added and the
reaction mixture was heated at reflux (65°C) for 12 h.
(TLC monitoring, toluene : iPrOH 2:1, Rf = 0.80). When
D-NH2 (ax) and 1c were detected in small traces only,
the reaction mixture was cooled at room temperature.
Minerals were filtered off and well washed with anh.
THF. The organic filtrate was evaporated under reduced
pressure to dryness to provide 5.222 g crude product.
This was purified by column chromatography on silica
gel (toluene : iPrOH 2:1) affording 4.110 g compound 2c
(84% yield with respect to cyanuric chloride).
2-Chloro-6-{[1,3-dihydroxy-2-(methyl)prop-2-yl]
amino}-4-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-
yl]amino}-s-triazine 2a (80%) yellowish powder, mp
i
107-118°C (column chromatography, toluene : PrOH,
2:1). [Found: C 45.98, H 5.11, N 18.80; C17H21ClN6O6
(440.12) requires: C 46.32, H 4.80, N 19.06%]. Rf 0.86
(66% toluene/iPrOH). IR νmax. (KBr) 3320 (s), 2946 (m),
2867 (m), 1581 (s), 1520 (s), 1411 (m), 1347 (s), 1242
(m), 1175 (s), 1094 (s), 1027 (s), 966 (m), 852 (m), 804
(s), 744 (m), 711 (m), 592 (w) cm-1. 1H NMR (500 MHz,
1120

O. Moldovan et al.
[D6]DMSO, 353 K): δH 1.12 (3H, s, Me), 3.48-3.57 (4H, (35), 455.1 [M++H] (100), 438.2 (11), 437.2 (54), 419.2
m, CH2OH), 4.03 (1H, d, JH,H=11.0 Hz, H-6-a, D-NH), (41). [α]D25=-34 (0.5% DMSO).
2
2
4.14 (1H, d, JH,H=11.5 Hz, H-6-e, D-NH), 4.37 (1H, d,
2-Chloro-6-{[1,3-dihydroxy-2-(hydroxymethyl)prop-
3JH,H=9.0 Hz, H-5-e, D-NH), 4.50 (2H, bs, OH), 5.00 (1H, 2-yl]amino}-4-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-
d, 2JH,H=6.0 Hz, H-2-a, D-NH), 5.23 (1H, d, 2JH,H=6.0 Hz, 5-yl]amino}-s-triazine 2c (84%) yellowish powder, mp
i
H-2-e, D-NH), 5.28 (1H, s, H-4-a, D-NH), 6.41, 6.51 200-205°C (column chromatography, toluene : PrOH,
(1H, 2×bs, SER-NH), 7.01 (1H, bs, D-NH), 7.66 (2H, d, 2:1). [Found: C 45.01, H 4.39, N 18.59; C17H21ClN6O7
3JH,H=8.5 Hz, H-2, -6, p-NPh), 8.14 (2H, d, 3JH,H=7.0 Hz, (456.12) requires: C 44.69, H 4.63, N 18.40%]. Rf 0.80
H-3, -5, p-NPh) ppm; 13C NMR (125 MHz, [D6]DMSO, (66% toluene/iPrOH). IR νmax. (KBr) 3369 (s), 2950 (m),
298 K): δC 18.7, 18.8, 19.0, 19.4 (Me), 49.3, 49.5, 49.8 2865 (m), 1586 (s), 1519 (s), 1418 (m), 1387 (m), 1347
(C-5, D-NH), 58.8, 59.0 (C-2, SER-NH), 63.4, 63.5, (s), 1243 (m), 1175 (s), 1096 (s), 1026 (s), 967 (m), 852
1
63.6, 63.7, 63.8 (CH2-OH), 69.7, 70.1, 70.2, 70.5 (C-6, (w), 804 (m), 743 (m), 711 (m), 593 (w) cm-1. H NMR
D-NH), 77.9, 78.2, 78.4, 78.8 (C-4, D-NH), 93.88, 93.94, (500 MHz, [D6]DMSO, 353 K): δH 3.66 (6H, bs, CH2OH),
2
94.0, 94.2 (C-2, D-NH), 123.3, 123.5, 123.6, 123.8 (C-2, 4.05 (1H, bd, JH,H=9.5 Hz, H-6-a, D-NH), 4.14 (1H, d,
-6, p-NPh), 127.4, 127.5, 127.6, 127.9 (C-3, -5, p-NPh), 2JH,H=11.5 Hz, H-6-e, D-NH), 4.36 (1H, bs, H-5-e, D-NH),
2
146.7, 146.76, 146.78 (C-1, p-NPh), 147.17, 147.21, 4.36, 4.53 (3H, 2×bs, OH), 5.00 (1H, d, JH,H=6.0 Hz,
2
147.24 (C-4, p-NPh), 164.9, 165.1, 165.3, 165.4, 165.6 H-2-a, D-NH), 5.23 (1H, d, JH,H=6.0 Hz, H-2-e, D-NH),
(C-4, -6, s-triazine), 167.76, 167.82, 167.9, 168.2 (C-2, 5.27 (1H, bs, H-4-a, D-NH), 6.24, 6.30 (1H, 2×bs, SER-
s-triazine) ppm. MS (ESI+), m/z (rel. int. %) 463.1 NH), 7.01 (1H, bs, D-NH), 7.65 (2H, d, 3JH,H=8.0 Hz, H-2,
3
[M+Na+] (7.5), 443.1 [M++2H] (38), 441.3 [M++H] (100), -6, p-NPh), 8.14 (2H, bd, JH,H=7.0 Hz, H-3, -5, p-NPh)
315.1 (10). [α]D25=-46 (0.5% DMSO).
ppm; 13C NMR (75 MHz, [D6]DMSO, 298 K): δC 49.2,
2-Chloro-6-{[1-hydroxy-2-(hydroxymethyl)but-2-yl] 49.3, 49.7 (C-5, D-NH), 59.4, 59.6, 60.1 (C-2, SER-NH),
amino}-4-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5- 62.1, 62.3, 62.4 (CH2OH), 69.9, 70.3 (C-6, D-NH), 78.0,
yl]amino}-s-triazine 2b (66%) yellowish powder, mp 78.1, 78.6 (C-4, D-NH), 93.8 (C-2, D-NH), 123.2, 123.4
i
97-102°C (column chromatography, toluene : PrOH, (C-2, -6, p-NPh), 127.4, 127.6, 127.7 (C-3, -5, p-NPh),
2:1). [Found: C 47.35, H 5.25, N 18.79; C18H23ClN6O6 146.6 (C-1, p-NPh), 147.1 (C-4, p-NPh), 164.9, 165.0,
(454.14) requires: C 47.53, H 5.10, N 18.48%]. Rf 0.83 165.2, 165.4 (C-4, -6, s-triazine), 167.6, 167.8 (C-2,
(66% toluene/iPrOH). IR νmax. (KBr) 3372 (s), 2972 (m), s-triazine) ppm. MS (CI, isobutane) m/z (rel. int. %) 513
2864 (m), 1587 (s), 1521 (s), 1414 (m), 1346 (s), 1242 [M+ +iBuH-2H] (20), 495 [M+K+] (9), 457 [M+] (100), 421
(m), 1175 (s), 1095 (s), 1028 (s), 966 (m), 852 (m), (10), 225 (11),140(10). [α]D25=-36 (0.5% DMSO).
1
804 (m), 745 (w), 711 (m), 582 (w) cm-1. H NMR (500
2-Chloro-6-{[1,3-dihydroxy-2-(methyl)prop-2-yl]
3
MHz, [D6]DMSO, 353 K): δH 0.72 (3H, t, JH,H=7.3 Hz, amino}-4-{{[(2R,4S,5S)-5-(dimethylamino)-4-(4-
3
CH3), 1.70 (2H, bq, JH,H=7.2 Hz, CH2-CH3), 3.50 (2H, nitrophenyl)-1,3-dioxan-2-yl]methyl}amino}-s-triazine
2
2
d, JH,H=11.0 Hz, CH2-OH), 3.59 (2H, bd, JH,H=8.5 Hz, 3a (83%) yellow powder, mp 126-134°C (column
CH2OH), 4.02 (1H, d, 2JH,H=11.0 Hz, H-6-a, D-NH), 4.14 chromatography, toluene : EtOH, 1:5). [Found: C 47.95,
(1H, d, 2JH,H=11.5 Hz, H-6-e, D-NH), 4.37 (3H, bs, H-5-e H 5.51, N 19.39; C20H28ClN7O6 (497.18) requires: C
D-NH, OH), 5.00 (1H, d, JH,H=6.5 Hz, H-2-a, D-NH), 48.24, H 5.67, N 19.69%]. Rf 0.80 (17% toluene/EtOH).
5.23 (1H, d, JH,H=6.0 Hz, H-2-e, D-NH), 5.28 (1H, s, IR νmax. (KBr) 3382 (s), 3276 (s), 2941 (m), 2878 (m),
2
2
H-4-a, D-NH), 6.31, 6.43 (1H, 2×bs, SER-NH), 7.02 (1H, 1587 (s), 1521 (s), 1462 (m), 1412 (m), 1349 (s), 1153
3
bs, D-NH), 7.65 (2H, d, JH,H=7.5 Hz, H-2, -6, p-NPh), (m), 1113 (m), 1057 (s), 852 (w), 804 (m), 753 (w), 709
3
1
8.14 (2H, bd, JH,H=6.0 Hz, H-3, -5, p-NPh) ppm; 13C (m), 571 (w) cm-1. H NMR (500 MHz, [D6]DMSO, 353
NMR (125 MHz, [D6]DMSO, 303 K): δC 7.8, 7.9 (CH3), K): δH 1.27 (3H, s, Me), 2.23 (6H, s, NMe2), 2.88 (1H,
3
22.1, 22.5, 23.0, 23.1 (CH2-CH3), 49.3, 49.37, 49.4, 49.9 dd as t, JH,H=3.0 Hz, H-5-e, D-NH), 3.52 (2H, bs, CH2-
(C-5, D-NH), 60.9 (C-2, SER-NH), 61.2, 61.3, 61.4, 61.5 NH), 3.60 (4H, bs, CH2OH), 3.98 (1H, dd, 3JH,H=2.0 Hz,
2
(CH2OH), 70.07, 70.1, 70.2, 70.5 (C-6, D-NH), 78.2, 2JH,H=12 Hz, H-6-a, D-NH), 4.46 (1H, d, JH,H=12.0 Hz,
78.4, 78.5, 78.8 (C-4, D-NH), 93.89, 93.94 (C-2, D-NH), H-6-e, D-NH), 4.52 (2H, bs, OH), 5.01 (1H, dd as t,
3
123.2, 123.3, 123.4, 123.6, (C-2, -6, p-NPh), 127.6, 3JH,H=4.3 Hz, H-2-a, D-NH), 5.20 (1H, d, JH,H=2.0 Hz,
127.7, 127.9, 128.0 (C-3, -5, p-NPh), 146.7, 146.8, (C-1, H-4-a, D-NH), 6.45, 6.58 (1H, 2×bs, SER-NH), 7.48 (1H,
p-NPh), 147.1, 147.17, 147.22 (C-4, p-NPh), 164.7, bs, CH2NH), 7.66 (2H, d, 3JH,H=8.5 Hz, H-2, -6, p-NPh),
164.99, 165.04, 165.3, 165.4, 165.7 (C-4, -6, s-triazine), 8.17 (2H, d, 3JH,H=9.0 Hz, H-3, -5, p-NPh) ppm; 13C NMR
167.8 (C-2, s-triazine) ppm. MS (ESI+), m/z (rel. int. %) (125 MHz, [D6]DMSO, 298 K): δC 18.8, 19.0 (CH3), 43.8
493.1 [M+K+] (9), 477.1 [M+Na+] (18), 457.1 [M++2H] (NMe2), 44.3, 44,4, 44,8 (CH2NH), 58.46, 58.51 (C-5,
1121

New serinolic amino-s-triazines by chemoselective amination
of cyanuric chloride and their (pro)diastereomerism
in restricted rotational phenomena
D-NH), 58.98, 59.04 (C-2, SER-NH), 63.5, 63.6, 63.6, (m), 1113 (m), 1054 (s), 1014 (m), 852 (w), 804 (m),
1
63.9 (CH2OH), 64.4, 64.6 (C-6, D-NH), 80.05, 80.12, 710 (m), 597 (w) cm-1. H NMR (500 MHz, [D6]DMSO,
80.3 (C-4, D-NH), 99.0, 99.2, 99.5 (C-2, D-NH), 123.3 353 K): δH 2.28 (6H, s, NMe2), 2.97 (1H, bs, H-5-e,
(C-2, -6, p-NPh), 127.1 (C-3, -5, p-NPh), 146.7 (C-1, D-NH), 3.53 (2H, s, CH2-NH), 3.72 (6H, s, CH2OH), 4.01
p-NPh), 148.8, 148.9 (C-4, p-NPh), 165.0, 165.3, 165.6, (1H, d, 2JH,H=11.5 Hz, H-6-a, D-NH), 4.42 (3H, bs, OH),
165.85, 165.91 (C-4, -6, s-triazine), 167.88, 167.93, 4.49 (1H, d, 2JH,H=12.5 Hz, H-6-e, D-NH), 5.03 (1H, bs,
168.4 (C-2, s-triazine) ppm. MS (ESI+), m/z (rel. int. %) H-2-a, D-NH), 5.24 (1H, bs, H-4-a, D-NH), 6.31, 6.40
537.2 [M+K+] (2), 520.1 [M+Na+] (3.5), 500.2 [M++3H], (1H, 2×bs, SER-NH), 7.60 (1H, bs CH2NH), 7.68 (2H,
3
3
498.1 [M++H] (100), 462.2 (7), 273.2 (7), 208.0 (11), d, JH,H=8.5 Hz, H-2, -6, p-NPh), 8.18 (2H, d, JH,H=8.5
182.2 (17). [α]D25=+147 (0.5% DMSO). Hz, H-3, -5, p-NPh) ppm; 13C NMR (75 MHz, [D6]DMSO,
2-Chloro-6-{[1-hydroxy-2-(hydroxymethyl)but-2- 298 K): δC 43.7 (NMe2), 44.2, 44.6 (CH2NH), 58.5 (C-5,
yl]amino}-4-{{[(2R,4S,5S)-5-(dimethylamino)-4-(4- D-NH), 59.6, 60.0, 60.2 (C-2, SER-NH), 62.4, 62.5
nitrophenyl)-1,3-dioxan-2-yl]methyl}amino}-s-triazine (CH2OH), 64.4, 65.3, 67.4 (C-6, D-NH), 80.5 (C-4,
3b (42%) yellow powder, mp 110-115°C (column D-NH), 99.2 (C-2, D-NH), 123.2 (C-2, -6, p-NPh), 126.9
chromatography, Et2O : EtOH : H2O, 0.5:8:1). [Found: C (C-3, -5, p-NPh), 146.7 (C-1, -4, p-NPh), 165.2, 165.7
48.98, H 5.81, N 19.39; C21H30ClN7O6 (511.19) requires: (C-4, -6, s-triazine), 167.7, 168.2 (C-2, s-triazine) ppm.
C 49.27, H 5.91, N 19.15%]. Rf 0.73 (5% Et2O/84% MS (CI, isobutane), m/z (rel. int. %) 514 [M++H] (25) 278
EtOH/H2O). IR νmax. (KBr) 3275 (s), 2971 (m), 2881 (m), (5), 178 (100), 140 (18), 116(11), 104 (21), 87 (18). [α]
1591 (s), 1521 (s), 1464 (m), 1411 (s), 1349 (s), 1154
25=+157 (0.5% DMSO).
D
(m), 1117 (m), 1059 (s), 852 (w), 802 (m), 752 (w), 708
Typical procedure for the synthesis of compounds
1
(m), 570 (w) cm-1. H NMR (500 MHz, [D6]DMSO, 353 4a-c and 5a-c. Preparation of compound 4c
3
K): δH 0.779, 0.784 (3H, 2×t, JH,H=7.5 Hz, CH3), 1.79 (Scheme 3)
(2H, q, 3JH,H=7.3 Hz, CH2CH3), 2.27 (6H, s, NMe2), 2.97
At room temperature and with vigorous stirring,
(1H, bs, H-5-e, D-NH), 3.51-3.54 (2H, m, CH2-OH), 3.56 anh. K2CO3 (0.604 g, 4.377 mmol) was suspended in a
(2H, dd as t, 3JH,H=3.0 Hz, CH2NH), 3.67 (2H, 2×d as t, solution obtained by dissolving anh. piperazine (1.504 g,
2JH,H=11.0, 12.5 Hz, CH2OH), 4.00 (1H, d, 2JH,H=11.5 Hz, 17.508 mmol) in anh. THF (125 mL). To this suspension,
H-6-a, D-NH), 4.49 (1H, d, 2JH,H=12.5 Hz, H-6-e, D-NH), chlorodiamino-s-triazine 2c (2.000 g, 4.377 mmol) was
4.53 (2H, bs, OH), 5.01 (1H, dd as t, 3JH,H=4.5 Hz, H-2-a, added portionwise (5 equal portions, 0.400 g 2c / portion,
D-NH), 5.24 (1H, bs, H-4-a, D-NH), 6.39, 6.47 (1H, each 2 h.). After each addition and within 2 hours, TLC
2×bs, SER-NH), 7.50 (1H, bs, CH2NH), 7.67 (2H, d, monitoring indicated the completion of the reaction as
3JH,H=8.5 Hz, H-2, -6, p-NPh), 8.17 (2H, d, 3JH,H=9.0 Hz, follows: total consumption of 2c (toluene : iPrOH = 2:1,
H-3, -5, p-NPh) ppm; 13C NMR (125 MHz, [D6]DMSO, Rf = 0.8, visualisation in UV 254 nm) and formation
303 K): δC 7.9, 7.96, 8.01, 8.1 (CH3), 22.2, 22.3, 22.6, of 4c (EtOH : aq. NH3 25% = 9:1, Rf = 0.76, double
23.0, 23.1 (CH2-CH3), 43.8 (NMe2), 44.2, 44.4, 44.8 visualisation: UV 254 nm then I2 bath). After addition,
(CH2NH), 58.6 (C-5, D-NH), 60.9, 61.0, 61.1, 61.2, (C-2, the reaction mixture was stirred at room temperature for
SER-NH), 61.46, 61.51, 61.65, 61.71 (CH2OH), 64.4, 24 hrs. Minerals were filtered off and well-washed with
64.6 (C-6, D-NH), 80.0, 80.1, 80.3 (C-4, D-NH), 99.1, anh. THF. The combined THF solution was evaporated
99.3, 99.6 (C-2, D-NH), 123.4 (C-2, -6, p-NPh), 127.1 under reduced pressure to yield 2.900 g crude material
(C-3, -5, p-NPh), 146.8 (C-1, p-NPh), 148.6, 148.8 (C-4, which was separated by column chromatography on
p-NPh), 165.0, 165.2, 165.6, 165.8, 165.9, 166.0, (C-4, silica gel (EtOH : aq. NH3 25% = 9:1, Rf = 0.76, double
-6, s-triazine), 167.3, 167.9, 168.3 (C-2, s-triazine) ppm. visualisation: UV 254 nm then I2 bath). The isolated 4c,
MS (ESI+), m/z (rel. int. %) 515.4 [M++4H] (8), 514.4 2.267 g was taken with anh. THF (2 mL) then diethyl
[M++3H], 512.4 [M++H] (100), 498.4 (4). [α]D25=+128 ether was added and the resulting fine yellow suspension
(0.5% DMSO).
was stirred at room temperature for 1 hr. After cooling at
2-Chloro-6-{[1,3-dihydroxy-2-(hydroxymethyl)prop- -20°C for 12 h, filtering off, washing with could diethyl
2-yl]amino}-4-{{[(2R,4S,5S)-5-(dimethylamino)-4-(4- ether and drying, 1.910 g pure 4c was obtained (86%
nitrophenyl)-1,3-dioxan-2-yl]methyl}amino}-s-triazine yield with respect to 2c).
3c (95%) yellow powder, mp 138-140°C (column
1-{6-{[1,3-Dihydroxy-2-(methyl)prop-2-yl]amino}-4-
chromatography, ligroin : acetone, 1:4). [Found: C {[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-yl]amino}-s-
47.08, H 5.55, N 19.38; C20H28ClN7O7 (513.17) requires: triazin-2-yl}-piperazine 4a (80%) yellowish powder, mp
C 46.74, H 5.49, N 19.08%]. Rf 0.80 (20% ligroin/ 123-133°C (column chromatography, EtOH : aq. NH3
acetone). IR νmax. (KBr) 3369 (s), 2945 (m), 2878 (m), 25% 9:1). [Found: C 51.55, H 5.80, N 23.03; C21H30N8O6
1583 (s), 1520 (s), 1412 (m), 1348 (s), 1299 (m), 1154 (490.23) requires: C 51.42, H 6.16, N 22.84%]. Rf 0.77
1122

O. Moldovan et al.
(90% EtOH/aq. NH3 25%). IR νmax. (KBr) 3400 (s), 2922 D-NH), 93.9, 94.0 94.1 (C-2, D-NH), 123.2, 123.5 (C-2,
(m), 2855 (s), 1548(s), 1501 (s), 1444 (s), 1346 (s), -6, p-NPh), 127.3, 127.6 (C-3, -5, p-NPh), 147.0, 147.1
1274 (m), 1174 (m), 1106 (m), 1056 (m), 1027 (m), 875 (C-1, -4, p-NPh), 164.5 (C-2, s-triazine), 165.4, 165.6
(w), 852 (w), 810 (m), 744 (w),711 (m), 583 (w) cm-1. (C-4, -6, s-triazine) ppm. MS (ESI+), m/z (rel. int. %)
1H NMR (500 MHz, [D6]DMSO, 363 K): δH 1.21 (3H, s, 505.3 [M++H] (100), 403.2 (25), 224.0 (12), 208.0 (37).
Me), 2.65 (4H, t, 3JH,H=5.0 Hz, H-3, -5, Piperazine), 3.47 [α]D25=+42 (0.5% DMSO).
2
3
(2H, d, JH,H=10.5 Hz, CH2OH), 3.48 (4H, t, JH,H=5.0
1-{6-{[1,3-Dihydroxy-2-(hydroxymethyl)prop-2-yl]
2
Hz, H-2, -6, Piperazine), 3.56 (2H, d, JH,H=10.5 Hz, amino}-4-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-yl]
CH2OH), 4.02 (1H, d, 2JH,H=11.0 Hz, H-6-a, D-NH), 4.11 amino}-s-triazin-2-yl}-piperazine 4c (86%) yellowish
(1H, dd, 3JH,H=1.5 Hz, 2JH,H = 11.5 Hz, H-6-e, D-NH), 4.41 powder, mp 146-157°C (column chromatography,
3
(1H, d, JH,H = 9.0 Hz, H-5-e, D-NH), 4.54 (3H, bs, OH, EtOH : aq. NH3 25% 9:1). [Found: C 50.11, H 5.88, N
Pip-NH), 5.00 (1H, d, 2JH,H=6.5 Hz, H-2-a, D-NH), 5.225 21.90; C21H30N8O7 (506.22) requires: C 49.80, H 5.97,
2
(1H, s, H-4-a, D-NH), 5.230 (1H,d, JH,H=5.5 Hz, H-2-e, N 22.12%]. Rf 0.71 (90% EtOH/aq. NH3 25%). IR νmax.
D-NH), 5.43 (1H, s, SER-NH), 5.49 (1H, d, 3JH,H=9.5 Hz, (KBr) 3392 (m), 2943 (m), 2856 (m), 1549 (s), 1504 (s),
3
D-NH), 7.62 (2H, d, JH,H=9.0 Hz, H-2, -6, p-NPh), 8.11 1446 (m), 1346 (s), 1273 (m), 1174 (m), 1105 (m), 1025
(2H, d, 3JH,H=8.5 Hz, H-3, -5, p-NPh) ppm; 13C NMR (125 (m), 872 (w), 852 (w), 809 (m), 744 (w), 711 (w), 584
MHz, [D6]DMSO, 298 K): δC 19.2 (Me), 44.2, 44.3 (C-2, (w) cm-1. 1H NMR (500 MHz, [D6]DMSO, 353 K): δH 2.65
3
-6, Piperazine), 45.8, 45.9, 46.0 (C-3, -5, Piperazine), (3H, t, JH,H=4.8 Hz, H-3, -5, Piperazine), 2.68 (1H, s,
48.8, 48.9 (C-5, D-NH), 57.9 (C-2, SER-NH), 64.6, 64.9 Pip-NH), 3.46 (4H, t, 3JH,H=5.0 Hz, H-2, -6, Piperazine),
(CH2OH), 70.5, 70.6, 70.8, 71.0 (C-6, D-NH), 78.5, 78.6, 3.30 (3H, bs, OH), 3.62 (6H, s, CH2OH), 4.02 (1H, d,
2
78.9, 79.0 (C-4, D-NH), 93.9, 94.0, 94.1 (C-2, D-NH), 2JH,H=11.0 Hz, H-6-a, D-NH), 4.11 (1H, JH,H=11.0 Hz,
123.2, 123.5 (C-2, -6, p-NPh), 127.4, 127.6 (C-3, -5, H-6-e, D-NH), 4.40 (1H, bd, 3JH,H = 7.5 Hz, H-5-e, D-NH),
2
p-NPh), 147.0, 147.1 (C-1, -4, p-NPh), 164.17, 164.22, 5.00 (1H, d, JH,H=6.5 Hz, H-2-a, D-NH), 5.22 (1H, s,
2
164.3, 164.5 (C-2, s-triazine), 165.3, 165,4 (C-4, -6, H-4-a, D-NH), 5.23 (1H, d, JH,H=5.5 Hz, H-2-e, D-NH),
s-triazine) ppm. MS (ESI+), m/z (rel. int. %) 491.2 [M++H] 5.43 (1H, s, SER-NH), 5.61 (1H, d, 3JH,H=9.5 Hz, D-NH),
(100), 403.2 (22), 208.0 (29). [α]D25=+28 (0.5% DMSO). 7.63 (2H, d, JH,H=9.0 Hz, H-2, -6, p-NPh), 8.12 (2H, d,
3
1-{6-{[1-Hydroxy-2-(hydroxymethyl)but-2-yl]amino}- 3JH,H=8.0 Hz, H-3, -5, p-NPh) ppm; 13QC NMR (75 MHz,
4-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-yl]amino}-s- [D6]DMSO, 298 K): δC 43.9 (2C, C-2, -6, Piperazine),
triazin-2-yl}-piperazine 4b (84%) yellowish powder, mp 45.4 (2C, C-3, -5, Piperazine), 48.8 (1C, C-5, D-NH),
125-130°C (column chromatography, EtOH : aq. NH3 61.0, 61.3 (4C, C-2, CH2OH, SER-NH), 70.5, 70.7 (1C,
25% 9:1). [Found: C 51.99, H 6.22, N 21.95; C22H32N8O6 C-6, D-NH), 78.4, 78,8 (1C, C-4, D-NH), 93.9 (1C,
(504.24) requires: C 52.37, H 6.39, N 22.21%]. Rf 0.66 C-2, D-NH), 123,1, 123,3 (2C, C-2, -6, p-NPh), 127.1,
(90% EtOH/aq. NH3 25%). IR νmax. (KBr) 3401 (s), 2966 127.4 (2C, C-3, -5, p-NPh), 146.9 (2C, C-1, -4, p-NPh),
(m), 2856 (s), 1552 (s), 1500 (s), 1445 (s), 1346 (s), 1174 164.2 (1C, C-2, s-triazine), 165.0, 165.2, 165.4, 165.5
(m), 1106 (m), 1061 (m), 1026 (m), 873 (w), 852 (w), 809 (2C, C-4, -6, s-triazine) ppm. MS (DCI positive, 200
(m), 744 (w), 710 (w), 583 (w) cm-1. 1H NMR (500 MHz, eV, isobutane), m/z (rel. int. %) 563 [M++iBuH-2 H] (9),
3
[D6]DMSO, 363 K): δH 0.74 (3H, t, JH,H = 7.3 Hz, CH3), 507 [M++H] (100), 489 (10), 477 (10), 404 (10),282 (5),
1.73, 1.74 (2H, 2×q, JH,H=7.5 Hz, CH2CH3), 2.69 (4H, 225 (10), 115 (8), 104 (20), 87 (75). [α]D25=+24 (0.5%
3
3
t, JH,H=5.0 Hz, H-3, -5, Piperazine), 3.49-3.51 (6H, m, DMSO).
CH2OH, H-2, -6, Piperazine), 3.56 (2H, d, 2JH,H=10.5 Hz,
1-{6-{[1,3-Dihydroxy-2-(methyl)prop-2-yl]amino}-
CH2OH), 4.02 (1H, d, 2JH,H=11.5 Hz, H-6-a, D-NH), 4.12 4-{{[(2R,4S,5S)-5-(dimethylamino)-4-(4-nitrophenyl)-
(1H, dd, 3JH,H=1.5 Hz, 2JH,H = 11.5 Hz, H-6-e, D-NH), 4.41 1,3-dioxan-2-yl]methy}lamino}-s-triazin-2-yl}-piperazine
3
(1H, d, JH,H = 9.0 Hz, H-5-e, D-NH), 4.54 (3H, bs, OH, 5a (71%) yellow powder, mp 118-123°C (column
2
Pip-NH), 5.00 (1H, d, JH,H=6.5 Hz, H-2-a, D-NH), 5.23 chromatography, EtOH : aq. NH3 25% 9:1). [Found: C
2
(1H, d, JH,H=5.5 Hz, H-2-e, D-NH), 5.24 (1H, s, H-4a, 52.88, H 7.07, N 22.85; C24H37N9O6 (547.29) requires:
D-NH), 5.35 (1H, s SER-NH), 5.52 (1H, d, 3JH,H=9.5 Hz, C 52.64, H 6.81, N 23.02%]. Rf 0.57 (90% EtOH/aq.
3
D-NH), 7.62 (2H, d, JH,H=8.0 Hz, H-2, -6, p-NPh), 8.10 NH3 25%). IR νmax. (KBr) 3295 (s), 2932 (s), 2860 (s),
3
(2H, d, JH,H=8.5 Hz, H-3, -5, p-NPh) ppm; 13C NMR 1670 (m), 1548 (s), 1516 (s), 1444 (s), 1348 (s), 1296
(125 MHz, [D6]DMSO, 298 K): δC 8.1 (CH3), 23.4, 23.46, (m), 1151 (m), 1113 (m), 1055 (m), 1016 (m), 852 (m),
1
23.54 (CH2CH3), 43.5, 44.0 (C-2, -6, Piperazine), 45.45, 809 (m), 710 (m), 668 (w), 572 (w) cm-1. H NMR (500
45.55, 45.64, 45.7 (C-3, -5, Piperazine), 48.8, 48,9 (C-5, MHz, [D6]DMSO, 353 K): δH 1.27 (3H, s, Me), 2.23 (6H,
D-NH), 60.2 (C-2, SER-NH), 62.5, 62.9 (CH2OH), 70.5, s, NMe2), 2.69 (4H, t, 3JH,H=4.8 Hz, H-3, -5, Piperazine),
3
70,6 70.8, 70.9 (C-6, D-NH), 78.5, 78.95, 79.04 (C-4, 2.86 (1H, dd as t, JH,H=2.8 Hz, H-5-e, D-NH), 3.496
1123

New serinolic amino-s-triazines by chemoselective amination
of cyanuric chloride and their (pro)diastereomerism
in restricted rotational phenomena
3
(2H, dd as t, JH,H=4.5 Hz, CH2NH), 3.504 (2H, d, [M++H] (100), 548.3 (10), 302.2 (15), 281.7 (25), 208.0
2JH,H=10.0 Hz, CH2OH), 3.58 (4H, t, 3JH,H=5.3 Hz, H-2, -6, (13), 143.1 (7). [α]D25=+136 (0.5% DMSO).
2
Piperazine), 3.60 (2H, d, JH,H=10.5 Hz, CH2OH), 3.96
1-{6-{[1,3-Dihydroxy-2-(hydroxymethyl)prop-2-
(1H, dd, 2JH,H=12.5 Hz, 3JH,H=3.0 Hz, H-6-a, D-NH), 4.46 yl]amino}-4-{{[(2R,4S,5S)-5-(dimethylamino)-4-(4-
(1H, d, JH,H=12.0 Hz, H-6-e, D-NH), 4.66 (3H, bs, OH, nitrophenyl)-1,3-dioxan-2-yl]methyl}amino}-s-triazin-2-
Pip-NH), 4.99 (1H, dd as t, 3JH,H=4.8 Hz, H-2-a, D-NH), yl}-piperazine 5c (81%) yellow powder, mp 140-145°C
5.18 (1H, d, JH,H=3.5 Hz, H-4-a, D-NH), 5.55 (1H, s (column chromatography, EtOH : aq. NH3 25% 9:1).
SER-NH), 6.27 (1H, bdd as bt, JH,H=5.5 Hz CH2NH), [Found: C 50.98, H 6.77, N 22.55; C24H37N9O7 (563.28)
7.64 (2H, d, JH,H=8.5 Hz, H-2, -6, p-NPh), 8.16 (2H, d, requires: C 51.15, H 6.62, N 22.37%]. Rf 0.57 (90%
2
3
3
3
3JH,H=8.5 Hz, H-3, -5, p-NPh) ppm; 13C NMR (125 MHz, EtOH/aq. NH3 25%). IR νmax. (KBr) 3298 (s), 2940 (s),
[D6]DMSO, 298 K): δC 19.3 (Me), 43.8 (NMe2), 44.4 (C-2, 2858 (s), 1551 (s), 1515 (s), 1446 (s), 1347 (s), 1297
-6, Piperazine), 45.87, 45.94, 46.03 (C-3, -5, Piperazine, (m), 1151 (m), 1112 (m), 1054 (m), 1015 (m), 852 (m),
1
CH2NH), 58.0 (C-2, SER-NH), 58.5, 58.6 (C-5, D-NH), 809 (m), 710 (w), 578 (w) cm-1. H NMR (500 MHz,
64.4, 64.5, 64.6 (CH2OH), 64.88, 64.92, 65.3 (C-6, [D6]DMSO, 353 K): δH 2.23 (6H, s, NMe2), 2.69 (4H,
3
D-NH), 80.1, 80.2 (C-4, D-NH), 99.8, 99.9 (C-2, D-NH), t, JH,H=4.8 Hz, H-3, -5, Piperazine), 2.86 (1H, dd as t,
123.19, 123.24 (C-2, -6, p-NPh), 127.0 (C-3, -5, p-NPh), 3JH,H=2.8 Hz, H-5-e, D-NH), 3.30 (1H, bs, Pip-NH), 3.50
3
3
146.7 (C-1, p-NPh), 148.9 (C-4, p-NPh), 164.7 (C-2, (2H, dd as t, JH,H=4.8 Hz, CH2NH), 3.57 (4H, t, JH,H
=
s-triazine), 165.9 (C-4, -6, s-triazine) ppm. MS (ESI+), 4.3 Hz, H-2, -6, Piperazine), 3.66 (6H, s, CH2OH), 3.97
m/z (rel. Int. %) 548.3 [M++H] (100), 543.3 (8), 295.2 (1H, dd, 2JH,H=12.5 Hz, 3JH,H=3.0 Hz, H-6-a, D-NH), 4.46
(10), 217.1 (15), 154.1 (10), 120.1 (3). [α]D25= +145 (1H, d, 2JH,H=12.5 Hz, H-6-e, D-NH), 4.65 (3H, bs, OH),
(0.5% DMSO).
5.00 (1H, dd as t, 3JH,H=4.5 Hz, H-2-a, D-NH), 5.19 (1H,
3
1-{6-{[1-Hydroxy-2-(hydroxymethyl)but-2-yl] d, JH,H=3.0 Hz, H-4-a, D-NH), 5.53 (1H, s, SER-NH),
amino}-4-{{[(2R,4S,5S)-5-(dimethylamino)-4-(4- 6.38 (1H, bs, CH2NH), 7.64 (2H, d, JH,H=8.5 Hz, H-2,
nitrophenyl)-1,3-dioxan-2-yl]methyl}amino}-s-tri-azin-2- -6, p-NPh), 8.17 (2H, d, JH,H=8.5 Hz, H-3, -5, p-NPh)
3
3
yl}-piperazine 5b (67%) yellow powder, mp 112-118°C ppm; 13C NMR (75 MHz, [D6]DMSO, 298 K): δC 43.7
(column chromatography, EtOH : aq. NH3 25% 9:1). (NMe2), 44.3 (C-2, -6, Piperazine), 45.8, 46.1, 46.3 (C-3,
[Found: C 53.55, H 7.17, N 22.22; C25H39N9O6 (561.30) -5, Piperazine, CH2NH), 58.4 (C-5, D-NH), 61.3, 61.4
requires: C 53.46, H 7.00, N 22.45%]. Rf 0.70 (90% (C-2, SER-NH), 64.3 (CH2OH), 65.3 (C-6, D-NH), 80.0
EtOH/aq. NH3 25%). IR νmax. (KBr) 3392 (s), 2939 (s), (C-4, D-NH), 99.6 (C-2, D-NH), 123.1 (C-2, -6, p-NPh),
2856 (s), 1553 (s), 1514 (s), 1446 (s), 1348 (s), 1298 126.9 (C-3, -5, p-NPh), 146.5 (C-1, p-NPh), 148.8 (C-4,
(m), 1151 (m), 1113 (m), 1055 (s), 1011 (m), 852 (m), p-NPh), 164.4 (C-2, s-triazine), 165.8 (C-4, -6, s-triazine)
-1
1
710 (m), 573 (w) cm . H NMR (500 MHz, [D6]DMSO, ppm. MS (DCI positive, 200 eV, isobutane), m/z (rel. Int.
3
353 K): δH 0.79, 0.80 (3H, 2×t, JH,H = 7.5 Hz, CH3), %) 620 [M++iBuH-2H] (5),564 [M++1] (65), 449 (28), 380
3
1.80, 1.81 (2H, 2×q, JH,H=7.5 Hz, CH2CH3), 2.23 (6H, (55), 300 (10), 282 (15), 221 (5), 178 (100), 165 (25),
s, NMe2), 2.70 (4H, t, 3JH,H=4.8 Hz, H-3, -5 Piperazine), 148 (10), 104 (45), 87 (35). [α]D25=+137 (0.5% DMSO).
3
2.86 (1H, dd as t, JH,H=2.3 Hz, H-5-e, D-NH), 3.50
3
(2H, dd as t, JH,H=4.5 Hz, CH2NH), 3.51-3.62 (8H, m,
CH2OH, H-2, -6, Piperazine), 3.96 (1H, dd, JH,H=12.5
2
3. Results and discussion
3
2
Hz, JH,H=3.0 Hz, H-6-a, D-NH), 4.46 (1H, d, JH,H=12.5
Hz, H-6-e, D-NH), 4.68 (3H, bs, OH, Pip-NH), 4.99
3.1. Synthesis
Our chemistry is depicted in Schemes 2 and 3.
3
(1H, dd as t, JH,H = 4.8 Hz, H-2-a, D-NH), 5.18 (1H,
d, JH,H=3.0 Hz, H-4-a, D-NH), 5.46 (1H, s SER-NH),
3
Enantiopure
amino-1,3-dioxanes
D-NH2
(ax
6.29 (1H, bdd as bt, 3JH,H=5.5 Hz, CH2NH), 7.64 (2H, d,
3JH,H=8.5 Hz, H-2, -6, p-NPh), 8.16 (2H, d, 3JH,H=9.0 Hz,
H-3, -5, p-NPh) ppm; 13C NMR (125 MHz, [D6]DMSO,
298 K): δC 8.3 (CH3), 23.5, 23.6 (CH2CH3), 43.8 (NMe2),
44.3 (C-2, -6, Piperazine), 45.8, (C-3, -5, Piperazine,
CH2NH), 58.6 (C-5, D-NH), 60.4 (C-2, SER-NH), 62.8,
63.4 (C-6, D-NH), 64.5 (CH2OH), 80.1, 80.3 (C-4, D-NH),
99.8, 100.1 (C-2, D-NH), 123.2 (C-2, -6, p-NPh), 127.0
(C-3, -5, p-NPh), 146.7 (C-1, p-NPh), 148.93, 148.95
(C-4, p-NPh), 164.7 (C-2, s-triazine), 165.9, 166.0 (C-4,
-6, s-triazine) ppm. MS (ESI+), m/z (rel. Int. %) 562.3
or eq) were routinely prepared (Scheme 2) by our
diastereospecific “sulphuric acetalisation” method
[1,9,10,27-30] applied to the corresponding (1S,2S)-
2-amino-1-(4-nitrophenyl)propane-1,3-diols (“Threo-p-
nitrophenylserinols” [29]).
Next, the optimised protocol directed to
chlorodiamino-s-triazines 2 and 3 consisted of using
C-2-substituted serinols, SER-NH2 (a-c) (Scheme 1),
as the first amino-nucleophile against cyanuric chloride,
then D-NH2 (ax), in a one-pot synthesis. Indeed, in
series 2, the inverted employ of serinolic reagents
1124

O. Moldovan et al.
NH2
5
R3 = H
O
O
p-NPh
O2N
N(R3)2
4
(4S,5S) D-NH2 (ax) (80%)
1
i - iv
2
NMe2
5
OH OH
(1S,2S): R3 = H, Me
p-NPh: p-NitroPhenyl
O
R3 = Me
O
CH2NH2
p-NPh
2
4
(2R,4S,5S) D-NH2 (eq) (84%)
i) 10 eq. H2SO4 (c 96%) / 0oC; ii) 1 eq. H2CO / 0oC [® D-NH2 (ax)] or 1 eq.
H2N-CH2-CH(OR4) (R4 = Me, Et) [® D-NH2 (eq)]; iii) 0oC ® r.t. / 24 h.; iv)
aq. NH3 (c 25%) / 0oC / pH=9
Key
Scheme 2. Synthesis of p-nitrophenylserinols based amino-1,3-dioxanes as „closed-chain” unit by „sulphuric acetalisation“.
Scheme 3. Synthesis of targeted N-substituted amino-s-triazines.
produced lower yields, e.g., in the case of 2c from 84% crowded environment of the axial C-5 dimethylamino
(Scheme 3) to 55%. We note that, targeting series 3, group in D-NH2 (eq).
previous findings of us [1] evidenced, unsurprisingly
The chemoselective attachment of the third
[31-39], the (non)-selective interaction between nucleophile was accomplished based on our previously
equimolar amounts of cyanuric chloride and amino-1,3- reported procedure [2,3], the portionwise addition, at
dioxane D-NH2 (eq) as side oligomerisations and C-5-N- room temperature, of chlorodiamino-s-triazines 2a-c
demethylation, both with low yield. Therefore, the single and 3a-c to a four fold molar amount of piperazine.
option we had was employed, yet again, of SER-NH2 Melamines 4a-c and 5a-c were purified by column
(a-c) as the first nucleophiles, followed by D-NH2 (eq).
chromatography on partially deactivated silica gel. No
In the last context, one can observe the milder dimeric by products were detected, presumably because
conditions in the synthesis of compounds 3a-c vs. of the transannular effect of piperazine favouring its
2a-c. They were inspired mainly from Kolesinska’s et mono-N-substitution, as previously noticed by Lai et al.
al. recent report [39] demonstrating the high reactivity, [40,41] and independently observed by us [1-3].
even at room temperature, of some less π-deficient than
Compounds 4a-c and 5a-c can be seen as novel
1a-c N-substituted 2,4-dichloro-6-amino-s-triazines building-blocks for further iterative synthesis taking
with respect to elaborated tertiary amines. In our case, into account the presence of the remaining free NH
however, the clean selective evolution of the subsequent functionality of piperazine, a widely recognised linker in
aminations, 1a-c → 3a-c, we explained by the sterically melamines’ dendritic synthesis [2,3,12,40-51].
1125

New serinolic amino-s-triazines by chemoselective amination
of cyanuric chloride and their (pro)diastereomerism
in restricted rotational phenomena
3.2. Rotational stereochemistry phenomena
previously detailed the utility of this “step by step
Starting from the well-known herbicide ATRAZINE® approach” [1-3].
1
(2-chloro-4-ethylamino-6-isopropylamino-s-triazine)
analysis [17,18], the lpN(exocyclic) π(deficient dynamism is listed in Tables 1 and 2.
s-triazine) delocalisation determining restricted rotation
On 1H 500 MHz timescale, rotameric species
The relevant H NMR data associating this stereo-
→
about the partial double bonds C(s-triazine)-N(exocyclic) were displayed accurately by the SER-NH signals of
thus created, is an already well documented feature compounds 2a-c (all four species) and, in part, by 3a-c
in amino-s-triazines. The assignment of the resulted (three species). On 13C 125 MHz timescale, the four
rotamers is a quite difficult task, both in solution and in stereoisomers were more convincing by detection of
solid state [19-26]. Besides investigations by NMR on four sets of peaks for almost all relevant C-environments
the tandem time-temperature scales, computational (see Experimental procedure).
methods [19,25] including DFT approaches by us
Themixturescontentswerecalculatedandcorrelated
[1-3,52] are also of interest. Usually, preceding studies based on 1H integrals of the best separated “amide like”
focused on N-(un)symmetrically substituted melamines protons D-NH (H-α, -β, -γ and -ε) and SER-NH (H-α’, -β’,
by means of (VT) NMR at low temperature [22-26]. -γ’ and -ε’) (Supplementary Fig. 1).
Apart from ATRAZINE®, minor attention was paid
to
N,N’-substituted-2-chloro-4,6-diamino-s-triazines 1H,1H-NOESY chart of compound 2a (Scheme 5;
The individual assignment started from the 2D-
[19-22]. To our knowledge, it was limited to the dynamic Supplementary Fig. 2) exhibiting two dipolar interactions
behaviour, upon heating, of symmetric 2-chloro-4,6- between the proton SER-NH (6.46 ppm, signal H-γ’)
bis(N,N-dialkylamino) derivatives.
and those of p-nitrophenyl ring of the axially anchored D
Therefore, some characteristics defining our (ax) counterpart, hence a “trans” relationship between
N-unsymmetrically substituted amino-s-triazines are the N,N’-ligands in a (SER-s-D-a) (16.5%) arrangement
mandatory.
(Scheme 4). Then, the alternative “trans” orientation
The serinolic “open-chain” N-ligands SER (a-c), of the N,N’-ligands of 2a, (SER-a-D-s), was deduced
containing a variable number of geminal hydroxymethyl reasonably, since its incidence was comparable (19.5%,
groups, wereaprioriseenasthemostOHsolvatedmotifs Scheme 4).
ofthemoleculeswhilethe“closed-chain”N-ligands,D(ax
The major rotamer 2a (a-a) was preliminarily
or eq), had anancomeric 1,3-dioxanic skeletons due to established by considering the two close SER-NH
the overwhelmingly one-sided conformational equilibria, δNH values of protons H-α’ and H-β’, in their anti local
by the adoption of an equatorial position by the C-4-p- environment: 6.74 ppm in 2a (SER-a-D-s, H-β’) and 6.86
nitrophenyl group [53,54]. Moreover, the anchorage of ppm in 2a (a-a, H-α’) (Table 1). If so, mutatis-mutandis,
our “sugar like” D N-ligands to amino-s-triazine was in the syn location, rotamers 2a (SER-s-D-a) and 2a
different, axial in 2a-c and 4a-c but equatorial in 3a-c (s-s), δNH of the same type of protons were also much
and 5a-c.
related, 6.46 ppm (signal H-γ’) and 6.41 ppm (signal
Sincewenormallyexpectedtheirrotationalbehaviour H-ε’) respectively.
to be dependent on the π-deficiency of s-triazine core,
Although compound 2a was the single one in both
our exploration followed its decreasing nature, from series 2 and 3 for which the nature of rotamerism could
chlorodiamino-derivatives 2- and 3a-c to melamines 4- be deduced from a NOESYExperiment, our investigation
and 5a-c.
was not quite in a testis unus testis nullus situation.
Thus, extrapolation of the above result to the
entire series 2 disclosed, for the SER “open-chain”
N-ligands (signals H-α’, -β’, -γ’, -ε’), the magnitude of
their NH chemical shifts being modulated by the strong
3.2.1. N,N’-unsymmetrically substituted 2-chloro-4,6-
diamino-s-triazines
3.2.1.1. Analysis of frozen equilibria: assignment of rotamers
As expected, at room temperature, each compound in dipole moment of the bond (C-2, s-triazine)-Cl causing
series 2 and 3 was a non-statistic mixture of blocked deshileding in its local proximity as δNH (anti) > δNH (syn)
rotational diastereomers about the partial double bonds [55]. This previously deduced, by us, “dipole rule”
C(-4, -6, s-triazine)-N(exocyclic) (Scheme 4). Since [1,2,52] did not fit, however, for the δNH values in the
the latter were two axes of diastereomerism [1,2], a D-NH (ax) fragment (Table 1).
topologically idealised model predicted a frozen four-
Therefore, in order to further support these findings
component global equilibrium. Each of them can and to predict the rotameric occurrence in series 3,
be generated by a single rotation / local equilibrium computational methods were performed in the case of
and originates from two independent pathways. We compounds 2a and 3a (Table 3). Thus, by optimisation of
1126

O. Moldovan et al.
Cl
Cl
2
3a-c
ε+(β+γ)
N
N
4
N
N
Content of frozen rotamers (%) (298 or 303 K)
(a-a) (SER-a-D-s) (SER-s-D-a) (s-s)
SER
D (eq)
SER
H-γ
6
N
N
N
N
N
N
H-ε'
H-ε
H-γ'
(SER-s-D-a)
2a-c
D (ax or eq)
Axial anchorage of D (ax) N-ligand
(s-s)
2a-c, 3a-c
(β+γ), (β'+γ')
2a
2b
62
19.5
19.5
23
2
8
7
16.5
16
18
3a-c
ε'+(β'+γ')
56.5
α'+(β'+γ')
2c 52
Cl
Cl
Equatorial anchorage of D (eq) N-ligand
2a-c
α+(β+γ)
N
N
N
N
3a
3b
3c
19
15
22
19
18
21
62
67
57
-
-
-
H-β'
H-α'
D (ax or eq)
H-α
N
N
N
N
N
N
SER
H-β
SER
(a-a)
D (ax)
(SER-a-D-s)
i) the chlorine atom and SER or D N-ligand are used as reference for a (anti) or s (syn) stereochemical descriptors.
ii) NH-α('), -β('), -γ('), -ε(') : the best 1H NMR separated signals, used for calculation of rotameric content and kinetic parameters (Tables 1, 2, 4 and 5).
Key
Scheme 4. Rotational diastereomers of N,N’-unsymmetrically substituted 2-chloro-4,6-diamino-s-triazines 2a-c and 3a-c, their abundances
and sequential interconversion.
Temperature Gradients (TG) applied to 1H NMR NH
Cl
signals provided additional information.
N
N
As recently recommended by Simanek et al. [16],
even if this parameter is usually applied to peptides and
proteins [56], it is generally accepted and indicative that
if the NH TG of our “amide like” protons is more negative
than -4 ppb/K in a hydrogen bond acceptor solvent
[22,56], such as [D6]DMSO, the NH group was exposed
to solvent and not involved in intramolecular hydrogen
bonds. Conversely, a TG less negative than -4 ppb K-1
indicates the NH protons being, at room temperature,
involved in intramolecular hydrogen bonding (see
example of TGs calculation in SM-3).
If so, in complete accord with DFT calculation, the
major species 2 (a-a) and 3 (s-s) were the most D- (or
SER-N)H…O=SMe2 solvated (Tables 1 and 2). On the
whole, TG D-NH (ax) values were slightly greater than
TG D-NH (eq). In contrast, TGs of SER-NH (a-c) were
much less negative than TGs of D-NH (ax or eq). We
explained this situation by the intramolecular ability of
geminal hydroxymethyl groups to partially associate
the adjacent NH, i.e., >C(CH2OH)n…HN< (n = 2, 3).
Indeed, TRIS as SER-NH (c, n = 3) derivatives 2c and
3c exhibited the less negative TGs.
4
7.44 ppm
(HOH2C)2(H3C)C
H-γ
6
N
N
N
H
O2N
6.46 ppm
O
H-γ'
H
O
H
H
H
H
2a (D-a-SER-s)
Scheme 5. 2D-1H,1H-NOESY result
(on 500 MHz timescale in [D6]DMSO).
for
compound
2a
their rotational diastereomers (a-a) and (s-s) at B3LYP/6-
311++G** level of theory and taking into account the
effect of solvent (DMSO), we found that:
i) In compounds 2a-c, in fully agreement with 1H NMR
data, the frozen arrangement (a-a) was major whereas
rotamers 2a-c (s-s) should be the minor ones.
ii) In contrast, in series 3, if the 1,3-dioxanic N-ligand
was equatorially anchored to amino-s-triazine, rotamers
3a-c (s-s) were, this time, the prevailing species.
iii) Bond orders C(s-triazine)-N[D (ax) or (eq), SER
(a-c)] being almost identical (1.22 – 1.25), the electronic
factors we saw responsible neither for the opposite
dominant incidence of certain rotamer, 2a-c (a-a)
against 3a-c (s-s), nor for their subsequent rotational
activation.
Regardless of the type of D N-ligand linkage
(Tables 1 and 2), in each series, the most polar
stereoisomers, hence the highest solvated, were the
major ones, displaying the most deshielded indicative
protons, SER-NH and D-NH, as well. Surprisingly,
in spite of conflicting dominance of the major type of
rotamer, 2 (a-a) vs. 3 (s-s), overall, the rotameric content
and hierarchy were similar in the two series (Scheme 4),
including the “dipole rule” in the SER-NH δNH sequence.
3.2.1.2. Analysis of dynamic equilibria: steric factors against
solvation effects
Whensubmittedtoprogressivelyincreasedtemperatures
up to 80oC, our molecules reached complete mobility
about the bonds C(s-triazine)-N[D (ax) or (eq)] only.
As shown in Fig. 1 and Tables 1 and 2 (see also
Supplementary Figs. 3 and 4), the typical 1H NMR final
appearance in both series was consistent with a slow
freely rotational motion of the D (ax or or eq) N-ligand
(one NH broad singlet) meanwhile, for the SER N-ligand,
1127

New serinolic amino-s-triazines by chemoselective amination
of cyanuric chloride and their (pro)diastereomerism
in restricted rotational phenomena
Table 1. Relevant 1H NMR data of restricted rotation about C(s-triazine)-N(exocyclic) bonds in N,N’-unsymmetrically substituted chlorodiamino-s-
triazines 2a-c (on 500 MHz timescale in [D6]DMSO).
No.
T (K)
N-Ligand data
Rotamer
(SER-a-D-s) (SER-s-D-a)
Discriminating δNH (ppm) values and multiplicity
(a-a)
(s-s)
H-α
H-α’
H-β
H-β’
H-γ
H-γ’
H-ε
H-ε
Temperature Gradients (TG) as (ΔδNH / ΔT ) × 103 (ppb/K)a
c
7.62 (d)b
6.86 (s)
7.52 (d)
6.74 (s)
7.44 (d)
6.46 (s)
-
2a
2b
2c
298
353
δNH
D-NH (ax)
δNH SER-NH (a)
6.41 (bs)
δNH D-NH (ax): 7.01 (bs); SER-NH (a): 6.51 (bs)d, 6.41 (bs)e
TG
TG SER-NH (a)
δNH D-NH (ax)
δNH SER-NH (b)
D-NH (ax)
-11.1
-6.4
-9.3
-6.0
-7.8
-0.9
-
0
303
353
7.62 (d)
6.77 (s)
7.52 (d)
6.64 (s)
7.46 (d)
6.34 (s)
-
6.33 (bs)
δNH D-NH (ax): 7.02 (bs); SER-NH (b): 6.43 (bs)d, 6.31 (bs)e
TG
TG SER-NH (b)
δNH D-NH (ax)
δNH SER-NH (c)
D-NH (ax)
-12.0
-6.8
-10.0
-6.6
-8.8
-0.6
-
-0.4
7.53, 7.52, 7.49d
303
353
6.57 (s)
6.50 (s)
6.27 (s)
6.21 (bs)
δNH D-NH (ax): 7.01 (bs); SER-NH (c) : 6.30 (bs)d, 6.24 (bs)e
TG
D-NH (ax)
-
-
-
-
-
TG SER-NH (c)
-5.4
-5.2
-0.6
aΔδNH = [δNH(T) - δNH(T )] < 0; ΔT = (T – T ) > 0 (K) where T = 353 K and Tr.t. is the room temperature, 298 or 303 K. bDoublet with a typical 3JH,H(ax-NH-
r.t.
H-5-e) = 9.0 – 10.0 Hz in D (ax) N-ligand.r.tc. Rotamers not found on the NH zone of the spectra but detected on 13C NMR time scales (see Experimental
Procedure); in series 2a-c the corresponding abundance was adopted from the SER-NH signal H-ε’ (Scheme 4). dNot assignable as overlapped signals.
e
dSignal considered for calculation of SER-NH TG of rotamer (a-a) (see SM-3). Signal used for calculation of SER-NH TG of rotamers (SER-a-D-s) and
(SER-s-D-a) (see SM-3).
Table 2. Relevant 1H NMR data of restricted rotation about C(s-triazine)-N(exocyclic) bonds in N,N’-unsymmetrically substituted chlorodiamino-s-
triazines 3a-c (on 500 MHz timescale in [D6]DMSO).
No.
T (K)
N-Ligand data
Rotamer
(SER-a-D-s) (SER-s-D-a)
Discriminating δNH (ppm) values and multiplicity
(a-a)
(s-s)
H-α
H-β
H-γ
H-ε
H-α’
H-β’
H-γ’
H-ε’
Temperature Gradients (TG) as (ΔδNH / ΔT ) × 103 (ppb/K)a
b
3a
3b
3c
298
353
δNH
D-NH (eq)
-
7.89 (dd as t)c
6.80 (s)
7.91 (dd as t)
6.82 (s)
8.03 (dd as t)
6.92 (s)
δNH SER-NH (a)
-
δNH D-NH (eq): 7.48 (bs); SER-NH (a): 6.58 (bs)d, 6.45 (bs)e
TG
TG SER-NH (a)
δNH D-NH (eq)
δNH SER-NH (b)
D-NH (eq)
-
-
-
-
-7.5
-6.4
7.88 (dd as t)
6.71 (s)
-7.8
-6.7
7.91 (dd as t)
6.75 (s)
-10.0
-6.2
8.05 (dd as t)
6.83 (s)
298
353
δNH D-NH (eq): 7.50 (bs); SER-NH (b): 6.47 (bs)d, 6.39 (bs)e
TG
TG SER-NH (b)
δNH D-NH (eq)
δNH SER-NH (c)
D-NH (eq)
-
-
-
-
-6.9
-5.8
7.92 (dd as t)
6.56 (s)
-7.5
-6.5
7.94 (dd as t)
6.60 (s)
-10.0
-6.5
8.01 (dd as t)
6.64 (s)
303
353
δNH D-NH (eq): 7.60 (bs); SER-NH (c): 6.40 (bs)d, 6.31 (bs)e
TG
D-NH (eq)
-
-
-6.4
-5.0
-6.8
-5.8
-8.2
-4.8
TG SER-NH (c)
aΔδNH = [δNH(T) - δNH(T )] < 0; ΔT = (T – T ) > 0 (K) where T = 353 K and Tr.t. is the room temperature, 298 or 303 K. bRotamers not found on the NH
r.t.
r.t.
zone of the spectra but detected on 13C NMR time scales (see Experimental Procedure). cDoublet of doublets as triplet with typical 3JH,H(eq-CH2-NH) =
6.0 – 6.6 Hz in D (eq) N-ligand. dSignal considered for calculation of SER-NH TG of rotamer (s-s) (see SM-3). eSignal used for calculation of SER-NH TG
of rotamers (SER-a-D-s) and (SER-s-D-a) (see SM-3).
its two NH broad singlets were symptomatic for a partial
turning “activation”, i.e., a slow exchange between two the two N,N’-ligands were “sufficiently remote” for the
unequally populated sites. relevance of a certain NH signal exposed by each of
i) By intercalation of the s-triazine ring in between,
In our attempt to estimate the temperature dependent them, D-NH (ax and eq, H-α, -β, -γ, -ε) or SER-NH (H-α’,
equilibria in Scheme 4, we had to adapt, like it or not, -β’, -γ’, -ε’), be limited to the rotational behaviour of the
three simplifying hypotheses:
unit to that this signal belongs, D or SER.
1128

O. Moldovan et al.
Table 3. Bond orders (B.O.), dipole moments µ (D), ZPE corrected relative energies ΔH0K (kJ mol-1) and relative free energies ΔG298 (kJ mol-1)
of frozen rotamers (a-a) and (s-s) of compounds 2a and 3a.
B.O.a
D
ΔH0K
ΔG298
B.O.
D
ΔH0K
ΔG298
C(4)-N<
C(6)-N<
C(4)-N<
C(6)-N<
2a (a-a)
2a (s-s)
B3LYP/6-31G* (gas phase)
-
-
5.27
4.84
1.00
0.00
0.00
0.00
-
-
3.52
2.07
0.00
2.93
0.63
3.14
B3LYP/6-311++G* / CPCM / DMSOb
1.23 1.25
1.22
1.24
3a (a-a)
3a (s-s)
B3LYP/6-31G* (gas phase)
-
-
5.10
7.81
2.39
0.00
4.31
1.38
-
-
7.85
0.00
1.38
0.00
0.00
B3LYP/6-311++G* / CPCM / DMSO
1.24 1.25
1.24
1.24
11.63
aWiberg bond order calculated within the NBO (Natural Bonding Orbital) analysis. bThe effect of solvent took into account by using the implicit solvent
method CPCM (Conductor-like Polarizable Continuum Model) implemented in Gaussian 09.
ii) Since species 2a-c (s-s) and 3a-c (a-a) were minor were not “synchronised” at all, deblocking about the
or even not detected on the 1H NMR timescale, we only bond C(s-triazine)-N[D (ax)] occurring first, 2 (s-s) 
neglected their content and not their existence.
2 (SER-s-D-a). We ascertained the result of this early
iii) The consecutive activation of the remaining three “rotational competition” by the crowded anchorage
equilibria (Scheme 4) was considered disclosed by the of the D (ax), due to the steric repulsion between its
1
succession in which coalescences of H NH signals two C-4-eq, -5-ax adjacent aromatic rings, determining
appeared (Supplementary Figs. 3 and 4).
instability of its ground state (Scheme 5). Accordingly,
All hereafter kinetic parameters [57,58] were the corresponding energetic barriers about bond C(s-
calculated comparatively with the use of Shanan- triazine)-N[D (ax)], ΔG≠M and ΔG≠m (Table 4), were the
Atidi algorithm [59], Gutowski-Holm [60] and Eyring smallest found in the present study. Next, since the D
Equations [57]. They are collected in Tables 4 and 5 (ax) N-ligand had already reached rotational mobility,
(see also SM-5).
its more as (OH) solvated SER (a-c) partners had also
The opening (SER-s-D-a)  (SER-a-D-s) (“trans”  to accommodate the above priority by a delayed start
“trans”) global equilibria (Supplementary Figs. 2 and 3) about the bond C(s-triazine)-N[SER (a-c)], 2 (s-s)  2
1
were the first observed and VT H NMR monitored by (SER-a-D-s).
means of coalescences of the pairs of signals D-NH (β +
In contrast, in compounds 3a-c, the same “trans 
γ) and SER-NH (β’+ γ’). They referred to close populated trans” double equilibration, (a-a)  3 (SER-a-D-s) and
sites, (50 ± 5)% and, since initially detected, we believed 3 (a-a)  3 (SER-s-D-a), became active about at the
that they occurred, most likely, via the minor rotamers 2 same time (ΔTC = 0 – 10 K), i.e., the N,N’-ligands formed
(s-s) or 3 (a-a), to reveal their rather predicted “rotational a rotational tandem.
instability”.
In series 2, ΔG≠ values of D (ax) N-ligand were
In series 2, as shown by the very different TC values, smaller than those of D (eq) in series 3, to confirm the
ΔTC (β + γ vs. β’ + γ’) ~ 30 K, the two N,N’-ligands more stable ground state of the latter. On the contrary,
1129

New serinolic amino-s-triazines by chemoselective amination
of cyanuric chloride and their (pro)diastereomerism
in restricted rotational phenomena
1
Figure 1. H NMR temperature evolution of compound 3a (on 500 MHz timescale in [D6]DMSO).
rotational barriers of the SER N-ligand in 2a-c were higher ΔG≠m values (2-3 kJ/mol) than 3a-c to suggest
higher with respect to those in 3a-c, presumably because the prevalence of steric factors in the transition states of
of a less crowded transition state when the D N-ligand this local interconversion: compounds 2a and 2b had to
was equatorially positioned.
accommodate a final (a-a) geometry meanwhile 3a-c, a
Additional heating revealed a second type of less crowded (s-s).
equilibration, 2 (a-a)  2 (SER-a-D-s) and 3 (s-s) 
To conclude, in spite of their opposite construction, it
(SER-s-D-a) (Table 5, Supplementary Figs. 2 and 3) was the most stable rotamers, 2a-c (a-a) and 3a-c (s-s),
seen by us as a partial activation of the most stable which could not be completely activated up to 80oC with
rotamers, 2a-c (a-a) and 3a-c (s-s) respectively. Thus, respect to the same partial double bond, C(s-triazine)-
after the first two coalescences, (β + γ) and (β‘ + γ ‘) N[SER (a-c)]. Indeed, equilibria 2 (a-a)  2 (SER-s-D-a)
(Table 4), a subsequent two were observed, [α + (β + and 3 (s-s)  3 (SER-a-D-s), implying rotation of the
1
γ)] in series 2 and [ε + (β + γ)] in series 3. They were SER (a-c) N-ligands, were not VT H NMR observed.
consistent with a single rotation, that of the 1,3-dioxane We deduced, once again, that the high OH solvation
N-ligands about the bonds C(s-triazine)-N[D (ax) or (eq)] combined with a significant NH contribution (expressed
providing final (353 K) broad singlets of protons D-NH, by TG values, Tables 1 and 2) were both responsible for
indicative for a slow free turning motion located in this this SER “residual immobility”.
part of our N,N’-unsymmetrically disubstituted 2-chloro-
4,6-diamino-s-triazines.
3.2.2. N,N’,N”-unsymmetrically substituted melamines
3.2.2.1. Rotational
temperature
Keeping in mind the above findings, analysis of
melamines 4a-c and 5a-c screened the same
structural features as they appeared according to NMR
spectroscopy. Significant 1H NMR data observations are
collected in Table 6.
If so, by considering the normal shifting of these final
equilibria as 2 (SER-a-D-s) → 2 (a-a) but 3 (SER-s-D-a)
→ 3 (s-s) and their consecutive occurrence with respect
to the previous “trans  trans”, a comparison between
ΔG≠m (m → M) values (Table 5) we saw of interest. In
fact, they revealed, this time, the steric influence of the
SER N-ligands, assisting rotation of D-NH (ax or eq)
counterparts. Thus, D (ax) derivatives 2a and 2b had
(pro)diastereomerism
at
room
1130

O. Moldovan et al.
Table 4. Kinetic parameters deduced from VT 1H NMR of compounds 2a-c and 3a-c for the “trans  trans” global equilibria (SER-a-D-s) 
(SER-s-D-a) (see Scheme 4).
No.
Signals considered
Kinetic parameters for rotation of
Relative populations (%)
amino-1,3-dioxanic group (D-NH)
Serinolic group (SER-NH)
“Open-chain” N-ligand
“Closed-chain” N-ligand
b
TC (K)
kC-M
kC-m
ΔG≠M
TC (K)
kC-M
kC-m
(s-1)
ΔG≠M
SER-a-D-s  SER-s-D-a
c
(β + γ)a
ΔG≠m
(β’ + γ’)a
ΔG≠m
β’
β
γ’
γ
(s-1)
(kJ mol-1)
(kJ mol-1)
2a
2b
2c
54
46
323
69.4
88.5
67.93
67.50
353
353
343
249.1
292.5
70.75
70.28
55
56
45
44
323
-
48.0
58.6
68.92
68.38
249.8
305.4
70.74
70.15
-
-
188.3
239.7
69.46
68.77
3a
3b
50
50
318
328
20.0
70.13
313
318
22.2
68.71
45.5
54.5
21.2
25.4
72.26
71.76
31.4
37.6
68.93
68.46
3c
51
49
318
14.5
15.1
70.98
70.87
318
40.3
41.9
68.27
68.17
aSignals providing coalescence (Table 1). bKinetic data for the Major rotamer. cKinetic data for the minor rotamer
Table 5. Kinetic parameters deduced from VT 1H NMR of compounds 2a, 2b and 3a-c for rotation of the “closed-chain” D (ax or eq) N-ligand
(see Scheme 4).
No.
Equilibrium
Kinetic parameters
Signals considered
Relative populations (%)
b
T
C (K)
kC-M
ΔG≠M
ΔG≠m
(SER-a-D-s)

(a-a)
α
α + (β + γ)a
kC-m
β
(s-1)
(kJ mol-1)
2a
2b
24
26
76
74
343
34.4
108.8
74.31
71.02
343
36.3
103.3
74.15
71.17
TC (K)
ε + (β + γ)
kC-M
kC-m
(s-1)
ΔG≠M
ΔG≠m
(SER-s-D-a)

(s-s)
γ
ε
(kJ mol-1)
3a
3b
3c
23.5
21
76.5
79
333
333
333
38.0
123.5
71.78
68.52
38.6
145.1
71.74
68.07
27
73
26.4
71.3
72.80
70.04
aSignals providing coalescence (Table 1). bKinetic data for the Major rotamer. cKinetic data for the minor rotamer
By replacement of the C-2-chlorine atom in [20-26], rotamerism was detectable as classic “slow
s-triazines 2a-c and 3a-c with a bulky, basic and strong exchange status between unequally populated sites”
releasing piperazine unit, we expected that the resulting [57] (Table 6, Fig. 2).
decreased π-deficiency of melamines 4a-c and 5a-c
On 1H timescale, the supporting number of
would diminish the partial double bond character of broad NH singlets exhibited by the D and SER units
their C(s-triazine)-N(exocyclic) junctions to such an (Supplementary Figs. 6a and 7a) did not correlate
extent that the rotational phenomena would have with the number of exchangeable sites because, as a
been obscured. Nevertheless, at room temperature, typical example, the 2D-1H,1H-COSY chart of compound
3
essentially contrasting with other simpler melamines 4c clearly disclosed four times an ax-NH-CH-5-e JH,H
1131

New serinolic amino-s-triazines by chemoselective amination
of cyanuric chloride and their (pro)diastereomerism
in restricted rotational phenomena
Table 6. Relevant (VT) 1H NMR data and Temperature Gradients of melamines 4a-c and 5a-c(on 500 MHz timescale in [D6]DMSO).
No.
Relevant δNH (ppm) values and multiplicity
TGa
TG
D-NH
SER-NH
T (K)
D-NH
SER-NH
Pip-NH
SER-OH
4a
298
TC = 313
363
5.80, 5.70 (bs)
5.59 (bs)
5.49 (d)b
5.56 (bs)
-
4.77 (bs)
-4.8; -3.2
-4.5, -2.5
-2.0
-3.1, -1.4
-2.5, -1.1
-2.9, -0.9
-2.4
-
5.43 (s)
4.54 (bs)
4b
4c
5a
5b
5c
298
TC = 313
363
5.81, 5.68 (bs)
5.65 (bs)
5.55, 5.44 (bs)
5.44 (bs)
4.74 (bs)
-
5.52 (d)
5.35 (s)
4.54 (bs)
298
TC = 313
353
5.92, 5.81 (bs)
5.77 (bs)
5.57, 5.49 (bs)
5.48 (bs)
2.64 (s)
3.45 (s)
-
-5.6, -3.6
-
5.61 (d)
5.43 (s)
2.68 (s)
3.30 (bs)
298
TC = 323
353
6.77, 6.60 (bs)
6.49 (bs)
6.27 (bdd as bt)c
5.71, 5.60 (bs)
5.62 (bs)
4.84 (bs)
-9.1, -6.0
-
5.55 (s)
4.66 (bs)
298
TC = 323
353
6.82, 6.58 (bs)
5.51 (bs)
5.59 (bs)
-
4.77 (bs)
-
-9.6, -5.3
6.29 (bdd as bt)
5.46 (s)
4.68 (bs)
303
TC = 323
353
6.93, 6.80, 6.69 (bs)
5.62 (bs)
-
3.65 (bs)
4.81 (bs)
-
-11.0, -8.4, -6.2
-1.8
6.60 (bs)
-
6.38 (bs)
5.53 (s)
3.00 (bs)
4.65 (bs)
-1
aAs (ΔδNH / ΔT ) × 103 (ppb K ). bDoublet with a typical 3J (ax-NH-CH-5-e) = 9.5 Hz in D (ax) N-ligand of series 4. cBroad doublet of doublets as broad
triplet with a typical 3JH,H(eq-CH2-NH) = 5.5 – 6.0 Hz in D H(e,Hq) N-ligand of series 5.
coupling (Fig. 3; Supplementary Fig. 5). Hence, the two with respect to 4. In this context, the bond C(s-triazine)-
D-NH peaks of 4c referred, in fact, to four environments, N(piperazine) was partial double as well, an authentic
i.e., a “hidden four terms rotational diastereomerism” axis of prodiastereomerism, since either piperazine
about the same bonds C(-4, -6, s-triazine)-N(exocyclic). positions C-α’ vs. -α” or C-β’ vs. -β”, even both, were
That is, although these junctions still remained two axes diastereotopic in the majority of compounds (Fig. 2;
of diastereomerism as they were in chloro-precursors 2 Supplementary Figs. 6b and 7b).
and 3, their discrete nature prevented us to establish
unambiguously a topologic relationship between the order as δC-β > δC-α (Fig. 2) was, in its turn, consistent
rotameric species thus revealed. with the acid-base participation of the Pip-NH sequence
In piperazine N-ligand, the δC values decreasing
As shown in Table 6, in melamines possessing two (vide supra). Moreover, the same C-β > C-αdeshielding
geminal hydroxymethyl groups, protons OH and Pip- in melamines 4c and 5c indicated their piperazine
NH exhibited a unique broad singlet, attributable to a N-ligand being, in these cases, an acid-base partner with
mediatedenvironmentissuedfromarapidintermolecular the traces of water in [D6]DMSO. It is noteworthy that, in
exchange, >C(CH2OH)2  HN-Pip. It follows that, for comparison with the present “monomeric” melamines 4
compounds 4a, 4b, 5a and 5b, one can presume a and 5, previously reported by us C-4(’), -6(’) identically
polymeric acid-base self-assembly, still existent at 80- substituted dimeric melamines with the same N-ligands,
90ºC. In contrast, in the case of melamines 4c and 5c, it SER(a-c) [2], D (ax) or D (eq) [1], the piperazine linker
was very likely that the internal association of their three had all C-positions isochronous and notably located
geminal hydroxymethyl groups prevailed against any upfield, 41.7 – 42.8 ppm.
implication in a similar external affiliation. Accordingly,
only in TRIS (c) based derivatives 4c and 5c, different 3.2.2.2. Reaching the fast free rotational status
δ
NH values, OH and Pip-NH, were located.
Not only that 13C NMR data supported but also shapes of signals D-NH (unique sharp doublet or broad
completed the 1H assignments.
triplet) and SER-NH (unique sharp singlet) (Fig. 2)
As expected, upon heating to 80-90oC, the final line-
Thus, while on 13C timescale at least two sets of showed our melamines becoming a single mediated
peaks for almost all SER or D C-environments were structure, in a fast freely rotating status about all
detected, fewer rotameric sites we observed in series 5 connections C(s-triazine)-N(exocyclic).
1132

O. Moldovan et al.
1
Figure 2. H NMR temperature evolution of compound 4a (on 500 MHz time scale in [D6]DMSO); fast intermolecular acid-base exchanges in
melamines 4a-c and 5a-c on 1H, 13C NMR timescales; (pro)diastereomerism about the bonds C(s-triazine)-N(exocyclic).
Figure 3. Detail from 2D-1H,1H-COSY Chart of compound 4c (on 500 MHz time scale in [D6]DMSO at 298 K).
1133

New serinolic amino-s-triazines by chemoselective amination
of cyanuric chloride and their (pro)diastereomerism
in restricted rotational phenomena
The temperature dependent dynamic behaviour partial double bonds. In chlorodiamino-s-triazines,
needs some comments:
both rotamerism incidence and its deblocking were
i) The NH coalescences occurred almost dictated by i) the global molecular polarity and solvation
simultaneously for D and SER N-ligands. Higher TC of serinolic “open-chain” units then, ii) in a two step
values (+10 K) defined evolution of melamines 5a-c tandem, by the stereochemistry of the “closed-chain”
against 4a-c suggesting a more stable ground states of units amino-anchorage, equatorial or axial, to the
equatorially anchored derivatives (Table 6).
s-triazine core. As an overall result of these influences,
iii) Indeed, examination of TG values revealed the chlorodiamino-s-triazines could completely activated
major contribution of the D N-ligands type of linkage to about the bond C(s-triazine)-N(“closed-chain” unit)
the above dissimilarity. Thus, as a consequence of the only. In the melamines series, an intermolecular acid-
melamines’ diminished π-deficiency, TGs of SER-NH base exchange self-assembled the terms possessing
(a-c) groups notably increased reaching very similar two geminal hydroxymethyl units at the periphery in
values (Tables 1, 2 and 6). They denoted a more partnership with the piperazine NH-termini group.
important serinolic NH…OH internal hydrogen bonding Complete rotational deblocking of melaminic rotamers
than in the chloro-precursors. This fact was common, indicated the major influence of the solvent-“closed-
regardless series 4 or 5. On the contrary, D-NH (ax) chain” unit interactions in stabilizing the ground state of
TGs in melamines 4a-c were by far less negative than equatorially vs. axially connected derivatives.
those of D-NH (eq) in 5a-c (Table 6). The latter had
about the same magnitude as in the corresponding most
π-deficient precursors 3a-c (Table 2). In addition, the
noticeable downfield D-NH resonances in series 5 vs. 4
Acknowledgements
prompted us to conclude that this deshielding was due
to a stronger chelation D (eq)-NH…O=SMe2 favoured by
the sterically less crowded equatorial amino-anchorage.
It was responsible for the higher stabilisation of the
ground state of melamines 5a-c with respect to axially
built 4a-c.
The financial support from Romanian National
Council for Development and Innovation Grant PN-
II-ID-PCE-2011-3-0128 is gratefully acknowledged.
OANA MOLDOVAN thanks for “Investing in people!
Ph.D. scholarship, Project co-financed by the
SECTORAL OPERATIONAL PROGRAM FOR HUMAN
RESOURCES DEVELOPMENT 2007 – 2013 Priority
Axis 1. “Education and training in support for growth and
development of a knowledge based society” Key area of
intervention 1.5: Doctoral and post-doctoral programs
4. Conclusions
A clean and efficient access to highly elaborated in support of research. Contract no.: POSDRU/88/1.5/
enantiopure amino-s-triazines based on (phenyl)serinols S/60185 – “INNOVATIVE DOCTORAL STUDIES IN
was described. The final N,N’N”-unsymmetrically A KNOWLEDGE BASED SOCIETY” Babeş-Bolyai
substituted melamines can be seen as valid building- University, Cluj-Napoca, Romania”. The computational
blocks for iterative synthesis. At room temperature, centre of the University of Reims Champagne-Ardenne
regardless the π-deficiency extent of the s-triazine (ROMEO, http://www.romeo2.fr) is acknowledged for
core, all compounds exhibited a four terms (pro) the CPU time donated.
diastereomerism about the C(s-triazine)-N(exocyclic)
References
[1]
[2]
[3]
M. Fazekas, M. Pintea, P. Lameiras, A. Lesur,
C. Berghian, I. Silaghi-Dumitrescu, N. Plé,
M. Darabantu, Eur. J. Org. Chem. 14, 2473 (2008)
M. Pintea, M. Fazekas, P. Lameiras, I. Cadis,
C. Berghian, I. Silaghi-Dumitrescu, F. Popa, C. Bele,
N. Plé, M. Darabantu, Tetrahedron 64, 8851 (2008)
M. Darabantu, M. Pintea, M. Fazekas, P. Lameiras,
C. Bele, C. Berghian, N. Plé, Heterocyclic Commun.
12, 151 (2006)
[5] M. Pintea, M. Darabantu, M. Fazekas, P. Lameiras,
C. Berghian, I. Delhom, C. Bele, N. Plé, Heterocyclic
Commun. 12, 135 (2006)
[6] V. Lates, D. Gligor, M. Darabantu, L.M. Muresan,
J. Appl. Electrochem. 37, 631 (2007)
C. Berghian, I. Delhom, I. Silaghi-Dumitrescu, [7] C. Bele, M. Darabantu, C.T. Matea, M. Pintea,
N. Plé, A. Turck, Letters in Organic Chemistry 3, 905
(2006)
M. Fazekas, C. Berghian, Buletin USAMV-CN 61,
194 (2005)
[4]
M. Fazekas, M. Darabantu, M. Pintea, P. Lameiras, [8] C. Bele, M. Darabantu, M. Muntean, M. Pintea,
1134

O. Moldovan et al.
[32] R.M. Show, P.J. Ward, J. Chem. Soc. 5446 (1965)
[33] B.I. Stepanov, G.I. Migachev, E.F. Ilina, Zh. Obshch.
Khim. 37, 2140 (1967) (In Russian)
M. Fazekas, C. Berghian, D. Lazar, Buletin USAMV-
CN 60, 1454 (2004)
[9]
M. Darabantu, Curr. Org. Synth. 7, 120 (2010)
M. Darabantu, Curr. Org. Synth. 7, 235 (2010)
D.A. Tomalia, Aldrichimica Acta 37, 39 (2004)
M.B. Steffensen, E.E. Simanek, Angew. Chem. Int.
Ed. 43, 5178 (2004)
[10]
[11]
[12]
[34]
R.M. Show, P.J. Ward, J. Chem. Soc. 12, 1431
(1968)
[35]
G.I. Migachev, E.F. Ilina, B.I. Stepanov, Zh. Obsch.
Khim. 38, 1370 (1968) (In Russian)
[13]
[36] R.M. Show, P.J. Ward, J. Chem. Soc. 6, 596
(1969)
[37] G. Boncic-Caricic, Z.D. Tadic, M.D. Muskatirovic,
J. Serb. Chem. Soc. 59, 929 (1994)
[38] (a) N.D. Reddy, A.J. Elias, N. Ashwani-Vij, J. Chem.
Research (S) 9, 504 (1998); (b) J. Chem. Research
(M) 2033 (1998)
[39] B. Kolesinska, Z.J. Kaminski, Tetrahedron 65, 3573
(2009)
[40] L.-L. Lai, L.-Y. Wang, C.-H. Lee, C.Y. Lin,
K.-L. Cheng, Org. Lett. 8, 1541 (2006)
[41] L.-L. Lai, C.-H Lee, L.-Y Wang, K.L. Cheng, H.-F,
J. Org. Chem. 73, 485 (2008)
[42] W. Zhang, E.E. Simanek, Org. Lett. 2, 843 (2000)
[43] W. Zhang, D.T. Nowlan, L.M. Thomson,
M.W. Lackowski, E.E. Simanek, J. Am. Chem. Soc.
123, 8914, (2001)
[44] W. Zhang, E.E. Simanek, Tetrahedron Lett. 42,
5355, (2001)
[45] W. Zhang, S.O. Gonzalez, E.E. Simanek,
Macromolecules 35, 9015 (2002)
[46] A.P. Umali, E.E. Simanek, Org. Lett. 5, 1245
(2003)
[47] W. Zhang, S.E. Tichy, L.M. Perez, C.G. Maria,
P.A. Lindahl, E.E. Simanek, J. Am. Chem. Soc. 125,
5086 (2003)
[48] E.J. Acosta, Y. Deng, G.N. White, J.B. Dixon,
K.J. Mc Innes, S.A. Senseman, A.S. Frantzen,
E.E. Simanek, Chem. Mater. 15, 2903 (2003)
[49] A.P. Umali, L.H. Crampton, E.E. Simanek, J. Org.
Chem. 72, 9866 (2007)
[50] S. Yooa, S. Yeua, R.L. Sherman, E.E. Simanek,
D.F. Shantza, D.M.J. Ford, Membrane Sci. 334, 16
(2009)
M.B. Steffensen, E. Hollink, F. Kuschel, M. Bauer,
E.E. Simanek, J. Polym. Sci. Part A: Polymer
Chemistry 44, 3411 (2006)
H.L. Crampton, E.E. Simanek, Polym. Int. 56, 489
(2007)
E.E. Simanek, H. Abdou, S. Lalwani, J. Lim,
M. Mintzer, V. J. Venditto, B. Vittur, Proc. R. Soc.
A 466, 1445, (2010)
X.C. Moreno, E.E. Simanek, Macromolecules 41,
4108 (2008)
[14]
[15]
[16]
[17]
[18]
T. Drakenberg, S. Forsen, Chem. Commun. 21, 140
(1971)
S.S. Mirvish, P. Gannett, D.M. Babcook,
D. Williamson, S.C. Chen, D.D. Weisenburger,
J. Agric. Food Chem. 39, 1205 (1991)
I. Willner, J. Rosengaus, Y. Eichen, J. Phys. Org.
Chem. 6, 29 (1993)
A.R. Katritzky, I. Ghiviriga, D.C. Oniciu, A. Barkock,
J. Chem. Soc. Perkin Trans. 2. 4, 785 (1995)
A.R. Katritzky, I. Ghiviriga, P.G. Steel, D.C. Oniciu,
J. Chem. Soc. Perkin Trans. 2. 3, 443 (1996)
I. Ghiviriga, D.C. Oniciu, Chem. Commun. 22, 2718
(2002)
M. Amm, N. Platzer, J. Guilhem, J.P. Bouchet,
J.P. Volland, Magn. Reson. Chem. 36, 587 (1998)
M. Amm, N. Platzer, J.P. Bouchet, J.P. Volland,
Magn. Reson. Chem. 39, 77 (2001)
H.E. Birkett, R.K. Harris, P. Hodgkinson, K. Carr,
M.H. Charlton, J.C. Cherryman, A.M. Chippendale,
R.P. Glover, Magn. Reson. Chem. 38, 504 (2000)
H.E. Birkett, J.C. Cherryman, A.M. Chippendale,
J.O.S. Evans, R.K. Harris, M. James, I.J. King,
G.Mc. Pherson, Magn. Reson. Chem. 41, 324
(2003)
[19]
[20]
[21]
[22]
[23]
[24]
[25]
[26]
[27]
M. Darabantu, C. Maiereanu, G. Plé, C. Berghian,
C. Condamine, Y. Ramondenc, Heterocyclic
Commun. 7, 593 (2001)
[51] S. Lalwani, V.J. Venditto, A. Chouai, E.G. Rivera,
S. Shaunak, E.E. Simanek, Macromolecules 42,
3152 (2009)
[28]
[29]
[30]
[52] F. Popa, P. Lameiras, E. Henon, O. Moldovan,
A. Martinez, C. Batiu, Y. Ramondenc, M. Darabantu,
Can. J. Chem. 89, 1207 (2011)
[53] E.L. Eliel, H.S. Wilen, Stereochemistry of the
Organic Compounds (John Wiley & Sons, New
York, Chichester, Brisbane, Toronto, Singapore,
1994) 221–239, 488–507, 678, 788, 1210
[54] M.J.O. Anteunis, D. Tavernier, F. Borremans,
Heterocycles 4, 293 (1976)
M. Darabantu, G. Plé, S. Mager, C. Puscas,
E. Cotora, Tetrahedron 53, 1909 (1997)
M. Darabantu, S. Mager, G. Plé, C. Puscas,
Heterocycles 41, 2327 (1995)
M. Darabantu, S. Mager, C. Puscas, M. Bogdan,
E. Cotora, G. Plé, I. Bratu, Revue Roumaine de
Chimie 39, 955 (1994) (In French)
[31]
R.C. Galesworthy, R.M. Show, B.C. Smith, J. Chem.
Soc. 1507 (1962)
1135

New serinolic amino-s-triazines by chemoselective amination
of cyanuric chloride and their (pro)diastereomerism
in restricted rotational phenomena
[55] J. Lim, E.E. Simanek, Mol. Pharmaceutics 2, 273 [59] H. Shanan-Atidi, R.H. Bar Eli, J. Phys. Chem. 74,
(2005)
[56] H. Kessler, Angew. Chem. Int. Ed. Engl. 21, 512 [60] H.S. Gutowski, C.H. Holm, J. Chem. Phys. 25, 1228
(1982)
(1956)
[57] H. Friebolin, Basic One- and Two Dimensional [61] C. Berghian, P. Lameiras, L. Toupet, E. Condamine,
961 (1970)
NMR Spectroscopy (VCH Verlagsgesellschaft,
VCH: Weinheim, New York, 1991) 53, 93, 131,
132, 263–291
N. Plé, A. Turck, C. Maiereanu, M. Darabantu,
Tetrahedron, 62, 7319 (2006)
[62] M. Darabantu, C. Maiereanu, I. Silaghi-Dumitrescu,
L. Toupet, E. Condamine, Y. Ramondenc,
C. Berghian, G. Plé, N. Plé, Eur. J. Org. Chem. 12,
2644 (2004)
[58] R.M. Silverstein, F.X. Webster, D.J. Kiemle,
Identification spectrométrique de composes
organiques, 2nd edition (De Boeck & Larcier s.a.,
Bruxelles, 2007) 150-155 (In French)
1136