Serinolic amino-s-triazines: Iterative synthesis of N-substituted amino-1,3-dioxane derivatives from l-(p-nitrophenyl)serinols and rotational stereochemistry phenomena

FULL PAPER

DOI: 10.1002/ejoc.200700847

Serinolic Amino-s-triazines: Iterative Synthesis of N-Substituted Amino-1,3-

dioxane Derivatives from l-(p-Nitrophenyl)serinols and Rotational

Stereochemistry Phenomena

Marijana Fazekas,^[a]Monica Pintea,^[a]Pedro Lameiras,^[b]Amandine Lesur,^[b]

Camelia Berghian,^[a,b]Ioan Silaghi-Dumitrescu,^[c]Nelly Plé,^[b]and Mircea Darabantu*^[a,b]

Keywords: Amination / Conformation analysis / Molecular modeling / Nitrogen heterocycles / NMR Spectroscopy

We report the first iterative and chemioselective approach

towards the synthesis of highly elaborated N-substituted

2,4,6-triamino-s-triazines (melamines) and precursors, by

[l-(p-nitrophenyl)serinols]. The stereochemistry of the title

compounds is discussed in terms of (pro)diastereomerism

originating from restricted rotation about the newly created

amination of cyanuric chloride with anancomeric and enan- C(s-triazine)–NϽ bonds and supported by NMR and DFT cal-

tiomerically pure primary and tertiary amino-1,3-dioxanes.

The starting nucleophiles were prepared by direct dia-

stereospecific and diastereoselective acetalization of N-sub-

stituted (1S,2S)-2-amino-1-(p-nitrophenyl)propane-1,3-diols

culation data.

Germany, 2008)

1. Introduction

We have previously reported a methodology by which to

access enantiomerically pure primary (IIa) and tertiary (IIb)

5-amino-1,3-dioxanes (Scheme 1) by direct acetalization of

the C-1-substituted serinols (2-aminopropane-1,3-diols),

(1S,2S)-2-amino-1-(p-nitrophenyl)propane-1,3-diol [l-(p-ni-

trophenyl)serinol, Ia] and its N,N-dimethyl analogue Ib, on

treatment with certain nonenolizable (di)carbonyl com-

pounds in strongly acidic media.^[1a–1e]The configurational

stability is excellent, as evidenced by the commercially avail-

able 2,2-dimethyl acetal IIc of phenylserinol [(1S,2S)-2-

amino-1-phenylpropane-1,3-diol, Ic; Scheme 1].^[2]Besides

this stability, primary 5-amino-1,3-dioxane derivatives IIa

manifested useful reactivity with (aryl)(di)aldehydes and

(di)acyl (di)chlorides, yielding not only the expected N-sub-

stituted amides,^[1a–1c]but also new C-, N-substituted isoin-

dolines^[1c,1e]and 1,3-dioxanic Schiff bases.^[1e,1f]

Scheme 1.

methyl)methaneamine, 2-(hydroxymethyl)serinol] anchored,

by Williamson methodology, on diazine and s-triazine skel-

etons.^[3]The coordination capabilities, both in solution and

in the solid state, of the resulting functionalized π-deficient

structures prompted us to investigate the use, described

here, of an enlarged series of O,O-serinolic protected build-

ing blocks based on Ia and Ib – 1,3-dioxanes of type IIa, IIb

(Scheme 1) – as amino nucleophiles with cyanuric chloride

(anchorage by amination).

In continuation of our contributions to serinol chemistry,

we have recently described the synthesis and stereochemis-

try of some protected O-, N-, O-serinolic building blocks,

in the form of the 5-hydroxymethyl-3,7-dioxa-azabicyclo-

[3.3.0]octanes (III, Scheme 1) based on TRIS [tris(hydroxy-

[a] Department of Organic Chemistry, Babes-Bolyai University,

11 Aranyi Jànos St., 400028 Cluj-Napoca, Romania

Fax: +40-264-59-08-18

To the best of our knowledge, there is only one report^[4]

relating to the preparation and antitumor potential of 2,4,6-

triamino-s-triazines (melamines) N-substituted with 1,3-di-

oxan-5-yl motifs as derivatives of C-2-substituted serinols.

However, they were obtained in an inverted two-step strat-

egy consisting of amination of cyanuric chloride followed

by transacetalization.

E-mail: darab@chem.ubbcluj.ro

[b] Institut de Recherche en Chimie Organique Fine (I.R.C.O.F.),

Université de Rouen,

BP 08, 76131 Mont Saint-Aignan, France

[c] Department of Inorganic Chemistry, Babes-Bolyai University,

11 Aranyi Jànos St., 400028 Cluj-Napoca, Romania

Supporting information for this article is available on the

WWW under http://ww w .eurjoc.org or from the author.

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In this context, we note that the exploitation of the tion of the nucleophilicity of the amino group in Ia with

amino group as a selective nucleophile for substitution of a

six-membered saturated heterocycle is mentioned only occa-

sionally in syntheses of amino-s-triazines, and mainly in re-

cent literature relating to dendrimeric melamines,^[5a–5c]4-

aminopiperidine,^[5d,5e]4-(aminomethyl)piperidine,^[5a–5c]and

amino sugars.^[5f]Only isolated interest has been paid to

their intrinsic structural feature of restricted rotational phe-

nomena about the C(s-triazine)–NϽ bonds.^[5d,5e]

respect to formaldehyde, glyoxal, and the diethyl acetal of

aminoacetaldehyde. The conditions shown in Scheme 2

were also required for successful syntheses starting from Ib,

treatment of which with the same carbonyl partners accord-

ing to “classical” procedures (e.g., at reflux in an aromatic

solvent with azeotropic removal of water and PTSA as cata-

lyst) resulted in no reaction.^[2e]

Our synthetic protocol, consisting of a totally dia-

stereospecific and diastereoselective cyclocondensation,

provide access to two types of 5-amino-1,3-dioxanes – “sim-

ple” (1a–d) and “double”, 2,2Ј-dimeric (1e–g) – with yields

exemplifying its overall ease (see Exp. Sect.). Indeed, despite

the harsh conditions, all compounds of the series 1a–d

could be isolated as pure analytical samples by simple

crystallization in routine workups. If 1e and 1g were

prepared directly, by homo-coupling acetalization

(2ϫIb)Ǟ1e, (2ϫIa)Ǟ1g, the disadvantages of the rather

poor yields constantly obtained were offset by the structural

profits gained. However, the cross-coupling acetalization

2. Results and Discussion

2.1. Synthesis and Stereochemistry of Starting Amino-1,3-

dioxanes Based on l-(p-Nitrophenyl)serinols

Our synthesis of 5-amino-1,3-dioxanes (Scheme 1) is

summarized in Scheme 2.

As mentioned above, compounds 1a–d were prepared by

direct acetalization of the enantiomerically pure (1S,2S)-(p-

nitrophenyl)serinols Ia and Ib in concentrated sulfuric acid

(tenfold molar excess) at low temperature. We emphasize (Ia + Ib) directed towards the 5,5Ј-diamino-2,2Ј-bi-1,3-diox-

that only these conditions allowed the complete cancella- ane 1f gave poor selectivity, resulting in a 1e/1f/1g mixture

Scheme 2.

Scheme 3.

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Serinolic Amino-s-triazines: Synthesis and Stereochemistry

(15:46:39 ratio) easily separable by column chromatography ical shifts of 5(Ј)-H-e ranging between 2.93 and 3.01 ppm.

in this order (conversion of Ia 29% and 18% of Ib, yield If an axial C-5(Ј) dimethylamino group was present instead

11% with respect to the desired 1f).

(compounds 1c, 1d, 1e, and 1f), geminal anisochrony at C-

5-Amino-1,3-dioxanes 1a–g were all anancomeric struc- 6(Ј) increased dramatically (∆δ ≈ 0.65 ppm) while shielding

tures^[6]because of their overwhelmingly one-sided confor- of 5-H(Ј)-e was observed (2.67–2.81 ppm).

mational equilibria due to the adoption of an equatorial

Reasonable explanation for these features, provided by

position^[1f]by the p-nitrophenyl (p-nph) ring located at C- manipulation of Dreiding models and by DFT calculations

4(Ј) (A ≈ 11.93 kJmol^–1;^[7]Scheme 3). This A value was (Scheme 3; see later in Section 2.4.2.1., Table 4), involved

greater by far than the A values of the C-5(Ј) amino (5.15– differently correlated rotational preferences of substituents

7.10 kJmol^–1) or C-5(Ј) dimethylamino (6.40–8.80 kJmol^–1) at C-4(Ј) and C-5(Ј). Thus, the equatorial p-nph group at

groups.^[6]

C-4(Ј) was bisectional in the presence of an in-directed axial

1

As a result, all H NMR spectra of compounds 1a–g, C-5(Ј) amino group, developing expected intramolecular hy-

displaying AMX coupling patterns in the C-4(Ј)–C-5(Ј)– drogen bonds with heterocyclic oxygen atoms (not depicted

3

C-6(Ј) sequences with stereospecific J_H,Hvalues of 1.0– in Scheme 3), but was orthogonal if a bulkier axial NMe₂

1

3.0 Hz, and also 2D H–¹H-NOESY experiments, allowed functionality was attached at C-5(Ј). Its methyl groups had

to assign the protons in this region to δ-4(Ј)-H-a Ͼ δ-6(Ј)- an out orientation with respect to the 1,3-dioxane ring.

H-e Ͼ δ-6(Ј)-H-a Ͼ δ-5(Ј)-H-e.^[1f]As expected, they also

confirmed the equatorial C-2,–2’ links between the 1,3-di-

oxane units in dimers 1e–g and the equatorial positions of

2.2. Synthesis of N-Substituted Aminodichloro-s-triazines

Containing the 1,3-Dioxane Motif

the C-2 methylene fragments in the aminomethyl groups of

compounds 1b and 1d (A values up to 7.50 kJmol^–1).^[6]

However, free orientations of amino groups with respect to

Test aminations were directed towards monosubstitution

the equatorial C-2 methylenes of the aminomethyl frag- of chlorine in cyanuric chloride, with the use of the primary

ments in amino-1,3-dioxanes 1b and 1d should be pointed amino-1,3-dioxanes 1a, 1b, and 1g as nucleophiles

out (see inset in Scheme 3). This nuanced discrimination (Scheme 4).

will be implied from here on throughout discussions in ref-

Under the depicted conditions, monomeric (2a) and di-

erence to equatorial vs. axial anchorage on the s-triazine meric (2b and 2c) N-substituted 6-amino-2,4-dichloro-s-tri-

ring after aminations carried out with 1b and 1d as nucleo- azines were prepared simply with good yields in a very clean

philes on treatment with cyanuric chloride.

procedure. Nevertheless, when we attempted to estimate the

In conclusion, no epimerization occurred during acetali- difference in reactivity (if any) between the axial C-5 amino

zations, the initial absolute configurations (1S,2S) of Ia and and the equatorial C-2 aminomethyl groups in 1b, its treat-

Ib again being identifiable as the 4(Ј)S,5(Ј)S units in all of ment with 1 molar equivalent of cyanuric chloride, even un-

the 1a–g series, though being extended to 2(Ј)R,4(Ј)S,5(Ј)S der very mild conditions, provided a polymeric mass from

in 1b, 1d, and 1e–g.

which we finally succeeded in isolating only a crude equi-

Furthermore, ¹H data relating to the 1,3-dioxane rings in molar mixture of precursors of 2c, in the form of the re-

1

1a, 1b, 1g, and 1f, each bearing an axial C-5(Ј) amino gioisomeric derivatives 2d + 2e (relevant H NMR spectro-

group, in CDCl₃indicated a very small geminal aniso- scopic data as shown in Scheme 4). Both 2d and 2e were

chrony of methylene C-6(Ј) (∆δ ≈ 0.06 ppm), with the chem- highly unstable.

Scheme 4.

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M. Darabantu et al.

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We therefore concluded that, in the first amination step,

different locations of the primary amino sites on the rigid

1,3-dioxane ring had no relevance for their competitive nu-

cleophilicity with respect to cyanuric chloride.

2.3. Synthesis of N-Substituted Melamines Containing 1,3-

Dioxane Motifs

Encouraged by the synthetic feasibility described above,

we envisaged a one-pot preparation of N-substituted mela-

mines containing 1,3-dioxane motifs. For this report we li-

mit our discussion to results obtained with amino-1,3-diox-

anes 1a, 1d, and 1f (Scheme 2, Scheme 3), a priori discrimi-

nated by the innate stereochemistry of their axial and/or

equatorial amino sites.

2.3.1. Synthesis of N-Substituted Melamines Containing an

Axial Anchorage of the 1,3-Dioxane Motif to Amino

s-Triazine

Scheme 5.

The chemistry we developed starting from amino-1,3-di- covered in all syntheses (Table 1, Entries 1–3). Reducing the

oxane 1a is presented in Scheme 5, while the results are col- nucleophilicity of 1a by using more polar solvents (thf, 1,4-

lected in Table 1.

dioxane, Entries 4–6), resulted in diminished thermal degra-

All experiments proceeded spot-to-spot in TLC monitor- dation of the reaction mixture and the isolation of signifi-

ing, and were stopped when no more change was observed cant amounts of intermediate 2a (Entries 4, 5). The overall

or when thermal degradation became deleterious.

conversion of 1a was still up to 60%, while the partial con-

In preliminary investigations, performed in toluene versions 1aǞ2a and 1aǞ3a were sensitive to the 1a/cyanu-

(Table 1, Entries 1–3), only double amination occurred, af- ric chloride molar ratio. We finally achieved the production

fording chlorodiamino-s-triazine 3a as the major product of the desired melamine 4a (Entry 6) but with very small

with satisfactory levels of conversion of 1a. This result, ob- levels of conversion, only to rule out this type of structure

tained in the early stage of our study, implied that steric as a target molecule.

hindrance was crucial in the iterative substitution of chlo-

We therefore instead considered the use of triethylamine

rine to give an N-substituted melamine based entirely on (Entries 7–9) both as a toluene-soluble proton scavenger

axial amino nucleophile 1a. Almost exactly the theoretically (equimolar ratio Et₃N/1a) and as a potential nucleophile.^[8]

required quantity of unreacted starting material 1a was re- Indeed, competition between 1a and triethylamine for the

Table 1. Results in the synthesis of compounds 2a, 3a, 3b, and 4a–c with axial anchorage of 1,3-dioxane motifs to amino-s-triazine

(Scheme 5).

Entry

n

1 equiv. base

T [°C]

Partial conversions of 1a (%)^[a]

% Overall

conversion

of 1a

equiv.

2a

3a

4a

3b

4b

4c

1

2

3

4

5

0.30

0.33

0.47

0.48

K₂CO₃/toluene

proton sponge/toluene

K₂CO₃/thf

12 (reflux)

20 (reflux)

20 (70)

26 (reflux)

24 (room temp.)

22 (reflux)

8 (room temp.)

36 (reflux)

24 (–15 to room

temp.)

45

61

58

50

46

45

61

62

72

64

4

22

18

K₂CO₃/1,4-dioxane

6

7

0.33

K₂CO₃/1,4-dioxane

Et₃N/toluene

2

54

4

60

12

40

20

24

52

24 (70)

9 (reflux)

24^[b]

6

44

8

9

0.33

Et₃N/toluene

24 (–10 to room

temp.)

30^[c]

48 (reflux)^[c]

2 (room temp.)

24 (reflux)

12

5

10

12

20

10

24

43

24

Et₃N/1,4-dioxane

14

4

[a] All calculations relate to effective amounts of compound isolated by column chromatography (mainly in Entries 7–9); all values are

averaged from Ϯ0.3 fluctuation. [b] Italics format: partial and corresponding total (overall) conversions of triethylamine. [c] Major thermal

decomposition was observed.

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Serinolic Amino-s-triazines: Synthesis and Stereochemistry

cyanuric chloride took place, the triethylamine being N-de-

Thus, in toluene, triethylamine was the first nucleophile

alkylated to yield melamines 4b and 4c with moderate de- to aminate cyanuric chloride [Equations (1), (2)], followed,

grees of conversion. They were the only products formed in in the last steps of substitution, by 1a [Equations (3), (4),

toluene (Entries 7, 8); meanwhile in 1,4-dioxane (Entry 9), and (5)]. Consistently with overall conversions, primary

intermediates 3a and 3b were also isolated. Although no amino-1,3-dioxane 1a was, on the whole, more nucleophilic

dedicated investigation of this competition chemistry was than triethylamine (Table 1, Entries 7, 8).

carried out, we have been able to formulate some observa-

tions based on separate syntheses (Scheme 6).

(ii) In 1,4-dioxane at reflux, although the nucleophilici-

ties of 1a and triethylamine were diminished, as shown by

the overall conversions, the difference in reactivity between

them was much higher.

Hence, significant amounts of chlorodiamino-s-triazines

3a and 3b were isolated. Compound 3a was not an interme-

diate in the synthesis of 4c (Table 1, Entry 9, Scheme 5),

because on treatment with a large excess of triethylamine

(Scheme 6) over 68 h, only a low level of conversion 3aǞ4c

was observed, suggesting that melamine 4c was formed, as

in toluene, in reactions as depicted in Equations (3) and (5).

2.3.2. Synthesis of N-Substituted Melamines with

Equatorial Anchorage of the 1,3-Dioxane Motif to Amino-

s-triazine

Scheme 6.

The different chemistry we found in the case of the di-

amino-1,3-dioxane 1d is summarized in Scheme 8. Quanti-

tative and qualitative results are collected in Table 2.

(i) In toluene at reflux, the isolated aminodichloro-s-tri-

azine 2a was only quantitatively converted into 3b after 96 h

upon treatment with 4 molar equivalents of triethylamine.

No traces of melamine 4b were detected under these condi-

tions. Neither of the experiments 7 or 8 (Table 1) required

such long duration and excess of triethylamine, suggesting

that 2a was not a precursor of 4b (Scheme 5), and nor was

3a a precursor of 4c. If so, melamines 4c and 4b originated

from two unisolated chloro-s-triazines that were mono- and

diaminated by triethylamine; see Scheme 7, Equations (1)

and (2).

Scheme 8.

The simplest experiment, consisting of treatment of 1d

with 1 molar equivalent of cyanuric chloride (Scheme 8,

Table 2, Entry 1), raised unexpected synthetic and struc-

tural problems. The crude reaction mixture, with very com-

Scheme 7.

Table 2. Results for the synthesis of compounds 2f, 3c, 3d, and 4d (Scheme 8).

Entry

n equiv.

C₃N₃Cl₃

Solvent

Time [h] (T [°C])

Partial conversions 1d (%)^[a]

% Overall conversion of 1d

2f

3c

3d

4d

1

2

3

4

5

6

1.00

0.45

0.33

thf

24 (–20 to room temp.)

24 (room temp.) or 12 (70)

72 (room temp.)

24 (room temp.) or 100 (reflux)

24 (room temp.) or 24 (70)

8 (room temp.) or 36 (reflux)

16

–

37

–

100

89

toluene

1,4-dioxane

71

52

–

42

34

18

19

36

27

20

71

36^[b]

69

–

54

[a] All calculations refer to effective amounts of compound isolated by column chromatography; all values were averaged from Ϯ0.3

fluctuations. [b] Major thermal degradation was observed.

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plex NMR spectra, was an almost polymeric mass from ditional chemical nonequivalence between -(MeN-DX-

which we separated, by column chromatography, the envis- CH₂NH)- units in any of the possible oligomers 3c-1, 3c-2,

aged aminodichloro-s-triazine 2f with a poor degree of con- or 3c-3 (see discussion later in Section 2.4.2.)

version. As observed for 2d and 2e (Section 2.2, Scheme 4),

despite convincing NMR, IR and MS spectra, 2f was un- seen by us as an attractive building block, yielded no im-

stable on storage even for short periods. provement, as the conditions listed in Table 2 so far appear

Attempted optimization of the synthesis of oligomer 3c,

Along with 2f, a stable compound 3c was isolated. Its to be the most promising ones. Interestingly, attempted par-

m/z (%) (MALDI) = 942.5 (100) [M]⁺was consistent with tial demethylation of the C-5 dimethylamino groups in

an oligomeric structure containing two N-mono-demethyl- amino-1,3-dioxanes 1c and 1f (Scheme 2, Scheme 3) gave

ated 1d and three chloro-s-triazine fragments. We deduced negative results. Surprisingly, 1c was completely inert to cy-

that 2f was, in fact, just a precursor of the more stable 3c, anuric chloride even in toluene at reflux; meanwhile 1f, un-

and on treatment with cyanuric chloride, 1d was coupled der conditions identical to those used for 1d, yielded only a

with both amino nucleophilic sites (Scheme 8). Hence, three polymeric mass. Like it or not, at this point of our study,

possible formulations of oligomer 3c (3c-1, 3c-2, and 3c-3) we had to consider the equimolar treatment of cyanuric

were considered (Scheme 9). We assigned 3c-1 as the correct chloride with 1d to be best avoided as unpromising because

1

structure of 3c on the basis of the comparative H NMR of its modest results.

spectroscopic data below.

Thus, in order to speed up the first amination step, we

(i) Firstly, we figured the chemical shift of the NH proton opted to start further experiments at room temperature in

in 2f in CDCl₃(6.33 ppm, broad dd as a triplet) to be in- the presence of an excess of nucleophile 1d (Table 2, En-

dicative, in an AMX coupling pattern, of a CH₂NH group tries 2–6).

Accordingly, N-substituted chlorodiamino-s-triazine 3d

and N-substituted melamine 4d, constructed exclusively

from 1d, were prepared with moderate to good overall levels

of conversion. On the whole, the syntheses of 3d and 4d

showed higher reactivity of the sterically unconstrained

equatorial C-2 aminomethyl site in 1d in the second and

third steps of s-triazinic chlorine substitution than of its

own axial C-5 dimethylamino component and of the axial

C-5 amino of 1a (Section 2.3.1.). As shown in Table 2,

melamine 4d was the single product in only one of the ex-

periments (Entry 4), when the lowest observed conversion

of 1d (36%) was the result of thermal degradation of the

reaction mixture during the long reflux time (100 h). Re-

gardless of the solvent polarity, the data in Table 2 also

demonstrate complete replacement of s-triazine chlorines

linked to a dichloro-s-triazine, since in 3c the same type of

resonance was at 6.26 ppm. We next observed, however,

that protons of NH groups linked to a monochloro-s-tri-

azine, as in 3d, (Scheme 8), were also situated in the 5.62–

6.33 ppm region, precluding a definite diagnosis for 3c in

CDCl₃.

(ii) Fortunately, in [D₆]DMSO, a strong hydrogen bond

acceptor solvent,^[9f]the NH proton signals were very dif-

ferently shifted downfield, to 7.73–8.06 ppm in 3d but to

9.48 ppm in 3c. The peripheral s-triazine rings in 3c were

thus far greater deshielding influences than the central s-

triazine unit in 3d, most probably due to the two chlorine

substituents. In addition, in aminodichloro-s-triazine 2a

(Scheme 4), the δ(NH) value in [D₆]DMSO was also very

comparable (9.41 ppm).

One must also observe that -(MeN-DX-CH₂NH) units by nucleophile 1d to be difficult, especially in the final step

were chemically equivalent only in 3c-1 and 3c-2. Neverthe- (3dǞ4d) of substitution. In all manipulations 2–6

less, this feature was irrelevant for the purpose of this analy- (Table 2), TLC monitoring detected only mixtures of com-

sis, since 3c was expected to be a mixture of frozen rotamers pounds 3d, 4d, and unreacted 1d, the last of which was re-

about the C(s-triazine)–N(exocyclic) bonds, causing ad- covered by column chromatography.

Scheme 9.

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Serinolic Amino-s-triazines: Synthesis and Stereochemistry

2.3.3. Synthesis of N-Substituted Dimeric Melamines with

1,3-Dioxane Motifs

due to lpNǞπ(s-triazine) conjugation, only minor atten-

tion had been paid until now to a specific conformation^[5-

d,5e,9a]

defining the environment of the nitrogen atom in-

For this discussion, we finished the synthetic explora-

tions by preparing dimeric melamines with piperazine as a

nucleophilic linker between two identical N,NЈ-symmetri-

cally disubstituted chlorodiamino-s-triazines 3a, 3d, and 3e

(Scheme 10).

volved in this partial double bond. The results of our itera-

tive syntheses provided evidence of the importance of loca-

tion, axial or equatorial, of the amino site in an anancom-

eric 1,3-dioxane in the second and third amination steps of

cyanuric chloride. We therefore considered it to be of inter-

est to complete this study with a stereochemical examina-

tion focused on the nature of rotational phenomena, mainly

about the newly created C(s-triazine)–N(axial vs. equato-

rial) bonds, seen as (pro)stereogenic axes in the title com-

pounds. For this purpose, the variety in the new family of

amino-s-triazines presented its simplest classification, based

on the increasing number of 1,3-dioxane motifs (1 to 3) N-

monosubstituting through their exocyclic nitrogen atoms.

2.4.1. N-Substituted Amino-s-triazines Containing a Single

1,3-Dioxane Motif

A NMR investigation in this series provided the perti-

nent commenting data collected in Table S1 (axial anchor-

age; Scheme 11) and Table S2 (equatorial anchorage;

Scheme 12).

Scheme 10.

The synthesis of compound 5a under the conditions illus-

trated was relatively straightforward. In contrast, toluene

was not an appropriate solvent for the dimerization 3dǞ5b

due to thermal degradation. In 1,4-dioxane, however, al-

though the reaction proceeded very slowly (over 4 d) as

shown by spot-to-spot TLC monitoring, dimeric melamine

5b could be routinely prepared.

Special consideration was paid to the dimeric amino-1,3-

dioxane 1f Me₂N-DX-DX-NH₂as starting material. We

thus set out directly only for double amination of cyanuric

chloride by 1f, inspired by the already established restrictive

behavior of its simpler analogues, the monomeric H₂N-DX

1a (steric hindrance) and Me₂N–DX–CH₂NH₂1d (demeth-

ylation). Although difficulty was expected, chlorodiamino-

s-triazine 3e was obtainable under milder conditions than

those used for 3a (Scheme 5, Table 1) or 3d (Scheme 8,

Table 2). Next, 3e underwent dimerization through the pi-

perazine linker to give 5c in moderate yield, due mainly to

thermal decomposition. In attempts to avoid this (e.g., by

replacing 1,4-dioxane with thf), TLC monitoring identified

5c as a component of complex reaction mixtures, unpromis-

ing for successful separation by chromatographic methods.

All members of series 5a–c could be chromatographed

on silica gel, providing stable pure analytical samples with

clean and convincing IR, NMR, and MS spectra.

Scheme 11.

Scheme 12.

Compounds 2a–c, 3b, and 4b (Scheme 11) each possessed

a s-triazinylamino group in an axial C-5(Ј) position in the

rigid 1,3-dioxane ring, as demonstrated by the magnitudes

of stereospecific ⁿJ_H,H(n = 2, 3) values of the AMX systems

in the sequence C-5(Ј)–C-6(Ј), assigned as 5(Ј)-H-e–6(Ј)-H-

2.4. Rotational Stereochemistry Phenomena in N-

Substituted Amino-s-triazines Containing 1,3-Dioxane

Motifs

3

e–6(Ј)-H-a. The magnitude of J_H,Hcoupling (9.1–10.0 Hz)

N(Ј)H:5(Ј)-H-e suggested a rather trans relationship be-

In previous structural approaches involving N-substi- tween these protons, and hence some limited rotation about

tuted amino-s-triazines and directed towards investigation the axial ϾC-5(Ј)–N(Ј)Ͻ bond. We considered a steric im-

of restricted rotation about C(s-triazine)–NϽ bonds,^[5a,5b,9]pediment innate to the adjacent equatorial and bisectional

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C-4(Ј) p-nph ring to be responsible for this preferred geome- rise to diastereomerism about the stereogenic C-6(s-tri-

try. From here on we refer to the arrangement of the axial azine)–N(axial) axis and prodiastereomerism about the pro-

C-5(Ј) s-triazinylamino substituent, also bisecting the 1,3- stereogenic C-4(s-triazine)–N(Et)₂axis (Figure 1).

1

dioxane ring, as s-trans-out.

Its H NMR spectrum thus displayed two environments,

Indeed, the strongly π-deficient N-substituted amino- blocked rotamers 3b-anti (major) and 3b-syn (minor). The

dichloro-s-triazines 2a–c, with increased order of the C- s-triazine chlorine and DX ring were used as references for

6(Ј)(s-triazine)–N(Ј)(axial) bond dictating restricted rota- anti and syn descriptors. The anti-3b/syn-3b ratio was calcu-

tion about this axis, revealed prodiastereomerism, since the lated from the resonances of protons 5-H-e and NH and

s-triazine carbons C-2(Ј) and -4(Ј) were diastereotopic (∆δ from the QC NMR spectrum. Indeed, the QC NMR spec-

= 0.5–0.6 ppm). As a result, coplanarity between the ϾC- trum of 3b (75 MHz) showed the methyl and methylene car-

5(Ј)–N(Ј)H sequences and s-triazine rings, imposed by the bons in the NEt₂groups to be diastereotopic: 13.2 and

lpN(Ј)(axial)Ǟπ(s-triazine) conjugation, was expected. 13.4 ppm (Me in anti-3b), 13.1 and 13.6 ppm (Me in syn-

This should more readily accommodate the s-trans-out ar- 3b), and 41.8. 41.9 ppm (methylene in both anti- and syn-

rangement of the amino-s-triazine fragment with the pres- 3b). The diastereomers of 3b, anti vs. syn, were then differ-

ence at C-4(Ј) of the bulky equatorial and bisectional p-nph entiated, account being taken of a reasonable dipolar inter-

substituent. That is, in series 2a–c, both steric and electronic action between their two differently substituted aromatic

requirements were met in conjunction to generate frozen rings, but placed appropriately: (i) equatorial benzene by

rotational prodiastereomerism.

the strongly electron-withdrawing nitro group, and (ii) s-

Compounds 2a–c were not amenable to ¹³C DNMR trans-out s-triazine by the strongly electron-releasing dieth-

monitoring^[9b–9d]since some decomposition occurred upon ylamino group. Rotamer anti-3b was thus predicted to be

heating in [D₆]DMSO, obscuring the relevant signals for stabilized by the opposite orientations of these two dipole

dynamic phenomena.

moments, and hence dominant.

Appropriate changes thus having been made, the N,NЈ-

Additional observations supporting our rotameric as-

unsymmetrically disubstituted chlorodiamino-s-triazine 3b signments were (i) the shifting of the mixture’s anti/syn

at room temperature showed two hindered rotations giving composition in CDCl₃vs. [D₆]DMSO (Table S1), (ii) the de-

1

Figure 1. H DNMR spectra of compound 3b ([D₆]DMSO on 400 MHz timescale, Table S1).

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Serinolic Amino-s-triazines: Synthesis and Stereochemistry

shielding influence of s-triazine chlorine’s dipole moment as references; Scheme 13) were used to depict the three rot-

1

on some relevant H chemical shifts^[1c,10]such as δ(5-H-e, amerism terms that we encountered in this series of N,NЈ-

3b-syn) Ͼ δ(5-H-e, 3b-anti) but δ(NH, 3b-anti) Ͼ δ(NH, 3b- symmetrically disubstituted diamino-s-triazines.^[9f]

syn) (Table S1 in the Supporting Information, Figure 1),

and (iii) the weak N(CH₂CH₃)/3-, 5-H (p-nph) correlation

1

found in the 2D H–¹H-NOESY chart for the major dia-

stereomer.

1

As can be seen in Figure 1, the H DNMR spectra of 3b

(298–353 K) revealed that this compound existed at 353 K

only in a slow exchange status between unequally populated

sites (partially deblocked structure).^[6]We explained this dy-

namic behavior on the basis of electronic, rather than steric,

factors operating in the ground state of 3b: namely the in-

creased bond order of the C(s-triazine)–NϽ links as two

lpNǞπ(s-triazine) conjugations reinforced by the electron-

withdrawing s-triazine chlorine. We also ruled out the alter-

native hypothesis that a crowded rotational transition state

(steric factor) of 3b could in fact be responsible for the spec-

tral changes shown in Figure 1 since the more congested

molecule melamine 4c was completely deblocked at 353 K

(see Section 2.4.2.2.)

To our surprise, at 298 K, prodiastereomerism was also

present in melamine 4b, since despite its lowest π-deficiency

Scheme 13.

in the discussed series, this molecule was still a blocked rot-

amer. Nevertheless, it appeared to us that the prodia-

stereomerism of 4b involved only the C-6(s-triazine)–N(ax-

2.4.2.1. Analysis of Frozen Equilibria

ial) bond, illustrated by diastereotopicity as ∆δ (s-triazine

At room temperature, each of 3a, 3c–e, and 4c (Table 3)

C-2 vs. C-4) = 0.3 ppm (Table S1), because all four N(Et) exists as a rotameric mixture (frozen equilibria) of three

groups were ¹H and ¹³C chemically equivalent (i.e., as a possible diastereomers about two C(s-triazine)–N(exo-

single A₂X₃¹H coupling pattern. We therefore concluded cyclic) bonds, two stereogenic axes, anti-anti (a-a), syn-syn

that frozen rotamerism in the ground state of 4b was some- (s-s) and anti-syn (a-s).^[9f,10]Despite the complicated NMR

what residual and most probably due to steric obstruction spectra, their abundances could be established, since well

1

promoted by the equatorial C-4 p-nph group and not to separated H signals of what from here on are named “in-

any noteworthy lpN(axial)Ǟπ(s-triazine) conjugation.

dicative protons”, isochronous in each of the rotamers (a-

In compounds 2c, 2f, and 3c (Scheme 12, Table S2) a a) and (s-s) but equally intense and anisochronous (syn vs.

(2,4-dichloro-s-triazin-6-yl)aminomethyl fragment was anti) in rotamers (a-s) were exhibited. Usually, N(Ј)H pro-

linked to the 1,3-dioxanic ring at C-2(Ј) in an equatorial tons played the basic indicative role (compounds 3a, 3d, 3e

position.

and 4c; see later discussion).

NMR spectroscopic data relating to this anchorage

Distinction between (a-a) and (s-s) rotamers in chlorodi-

showed the features we expected: ¹H diastereotopicity in the amino-s-triazines 3a, 3c, 3e, and 3d by direct NMR experi-

equatorial C-2⁽Ј⁾methylene group and prodiastereomerism mentation was not possible. Therefore, in the case of dif-

due to the C-6(Ј) (s-triazine)–N(Ј)H partial double bonds ferently anchored – double axial (3a) and double equatorial

(prostereogenic axis), as well as the ¹³C implying dia- (3d) – compounds we applied computational methods, both

stereotopicity across the s-triazine carbons C-2(Ј) and -4(Ј). in gas phase and in solution (chloroform). The results are

3

We note the smaller J_H,Hvalue (5.5–6.4 Hz) between collected in Table 4.

protons CH₂and NH, denoting the lack of any constraint

The lowest-energy gas-phase conformers generated by

to rotation about the CH₂–NH bond, which is believed to SpartanЈ04 with the MMFF force field were thus subjected

be independent of the equatorial anchorage.

to full geometry optimization at the B3LYP/6-31G(d) level

of theory by use of the same package.^[11]Further, the effect

of solvent was taken into account by performing SCRF sin-

gle-point calculation at the gas-phase optimum geometries

2.4.2. N,NЈ-Symmetrically Disubstituted Diamino-s-

triazines Containing Two 1,3-Dioxane Motifs

The stereochemistry of restricted rotational phenomena in the COSMO^[11e]model implemented in NWChem.^[12]

about C(s-triazine)–N(Ј)Ͻ bonds in the title compounds 3a,

Initial inspection of calculated stereoisomers (Table 4)

1

3c–e, and 4c was analyzed by starting from H NMR spec- confirmed our earlier NMR basic conformation considera-

troscopic data (Table 3), DFT calculations (Table 4) and, tions about anancomeric serinolic 1,3-dioxanes (Section

fortuitously, assignments already made in the case of sim- 2.1., Scheme 3) connected to a s-triazinyl moiety by substi-

pler structures in Section 2.4.1. The descriptors syn and anti tution through the axial C-5 amino group in 3a (bisectional

(1,3-dioxane ring and s-triazine substituent R¹= Cl, NEt₂s-trans-out arrangement, Section 2.4.1, Scheme 11) or

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1

Table 3. Relevant H NMR spectroscopic data for N,NЈ-symmetrically disubstituted diamino-s-triazines 3a, 3c–e, and 4c containing two

1,3-dioxane motifs (Scheme 13).

[a] Averaged values determined from signals of the depicted indicative protons. [b] Doublets (³J_H,H= 9.0–9.8 Hz) in 3a, 3e, and 4c;

overlapped doublets of doublets as triplets (³J_H,Haround 6.0 Hz) in 3c and 3d with clear connectivities in 2 D ¹H–¹H-COSY charts:

N(Ј)H:5(Ј)-H-e in 3a, 3e and N(Ј)H/CH₂in 3d.

1

Table 4. Relative energies (∆E, kJmol^–1) of the blocked rotamers of compounds 3a and 3d vs. their H NMR abundance (Scheme 13).

Compound

Gas phase^[a]relative energy (∆E [kJmol^–1])

Solution (CHCl₃) relative energy (∆E [kJmol^–1])^[b]

1

assigned H NMR abundance (CDCl₃) (%)^[c]

Rotamer

(a-a)

(a-s)

(s-s)

(a-a)

(a-s)

(s-s)

3a

4.12

1.55

0.00

2.89

31

0.69

35

0.00

34

3d

0.00

9.00

4.57

0.00

63

8.84

27

5.72

10

[a] Spartan, B3LYP/6-31G(d) implemented in Gaussian 98. [b] (COSMO model) Single-point calculations on the Spartan geometries run at

B3LYP/6-31G(d) within NWChem. [c] Percentages corrected for symmetry starting from abundance of rotamers (a-s) ϵ (s-a) twice favored

with respect to (a-a) and (s-s); e.g., for 3a, percentages deduced from ¹H NMR spectrum were: 23% (a-a), 52% (a-s ϵ s-a), 25% (a-a)

(Table 3); ratios corrected for symmetry: 23 (a-a)/26 (a-s or s-a)/25 (s-s) respectively; corrected abundances: 31% (a-a), 35% (a-s), 34% (s-s).

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Serinolic Amino-s-triazines: Synthesis and Stereochemistry

through the equatorial C-2 aminomethyl group in 3d (Sec-

In contrast, while identically based on a double axial

tion 2.4.1, Schemes 12 and 13).

connection to an s-trans-out diamino-s-triazine unit, only in

Next, the statistical content of rotamers of compound 3a CDCl₃were both compounds 3a and 3e roughly statistical

1

in CDCl₃, deduced from its H NMR spectrum (Table 3), mixtures of rotamers. In [D₆]DMSO, the rotational equilib-

was also predicted by calculation (Table 4), since the differ- rium of 3a was somewhat shifted as 3a (a-a, 23Ǟ34%), 3a

ence between their relative energies was sufficiently small (a-s, 52 ≈ 53%), 3a (s-s, 25Ǟ13%); meanwhile, for 3e, rota-

(0.69–0.16 kcalmol^–1). A definite environment (a-a) vs. (s- mer 3e (a-a) became noticeably dominant (23Ǟ61%), fol-

s) energetic diagnosis of double axial anchored compound lowed by 3e (a-s, 43Ǟ29%) and 3e (s-s, 34Ǟ10%). In ad-

3a by calculations was thus precluded.

dition, in the case of 3a, important π–π interactions such

Computation on the doubly equatorially anchored com- as A.S.I.S. (Aromatic Solvent-Induced Shifts) phenomena^[13]

pound 3d determined its rotamer 3d (a-a) to be the most involving its (a-a) rotamer (23% in CDCl₃) were assumed

stable. The orientation of its two N(Ј)H protons was in the to play a major role in [D₆]benzene (53%, Figure S1 in the

direction of the C-2-s-triazine chlorine (R¹= Cl, Table 3), Supporting Information).

1

allowing us the following indirect H NMR assignment of

Melamine 4c showed a dramatic influence of the solvent

syn:anti rotamerism in this class of chlorodiamino-s-tri- in rotamerism. In CDCl₃, the 2D ¹H–¹H-NOESY chart

azines.

(Figure S2, Table 3) showed rotamer 4c (s-s) greatly pre-

As in the case of the simpler chlorodiamino-s-triazine 3b dominating (88%) over 4c (a-s, 12%).

(Figure 1, Section 2.4.1), we considered the strong dipole

In [D₆]DMSO, equal abundance of 4c (s-s, 40%) and 4c

moments induced by the s-triazine chlorine^[5c,10]in 3a, 3c, (a-s, 40%) was found (Table 3).

3d, and 3e to be a useful discriminating factor in the NMR

2.4.2.2. Analysis of Dynamic Equilibria

spectra, causing, along with the s-triazine N-1 and -3 hydro-

gen-bonding lone pairs, the deshielding of protons N(Ј)H

1

When explored by H DNMR, run in [D₆]DMSO on a

[or N(Ј)Me groups of 3c] in rotamers (a-a) in comparison 400 MHz timescale with heating (298–353 K), the behavior

with (s-s) and in the anti site of rotamers (a-s) against the of our N,NЈ-symmetrically disubstituted diamino-s-tri-

syn (a-s) counterpart. To resume, in CDCl₃, we assigned azines containing two 1,3-dioxane motifs (Table 3) showed

signals located as δN(Ј)H(a-a) ≈ δN(Ј)H(a-s) Ͼ δN(Ј)H(s-a) varied effects of electronic factors vs. steric factors.

≈ δN(Ј)H(s-s) to be doubly indicative of (i) rotamer assign-

Compound 3c remained a rigid structure with respect to

ment and (ii) composition calculation. Subsequently, con- all C(s-triazine)–NH (or –NMe) bonds (Table 3). We ex-

sistently with the specific s-trans-out orientation of the axial plained this rotational stability in two different ways, as

C-5(Ј) s-triazinylamino fragment bisecting the 1,3-dioxane (i) electronic influence at peripheral level, but (ii) steric fac-

ring (Section 2.4.1, Scheme 11), the 5(Ј)-H-e protons in tors in the central part of the oligomer. Thus, the highly π-

chlorodiamino-s-triazines 3a, 3c, 3e in CDCl₃were also deficient terminal dichloro-s-triazines units reinforced the

doubly indicative (Table 3). Since they were s-trans coupled local conjugations lpN(exocyclic)Ǟπ(s-triazine), hence the

with the N(Ј)H protons (Scheme 13, Table 3, Table 4 and bond order of these connections. In contrast, steric hin-

2D ¹H–¹H-COSY charts), with regard to recognition of drance to rotation as represented by the double s-trans-out

rotamerism, the same deshielding influence of the s-triazine relationship in the central bis(methylamino)-s-triazinediyl

chlorine was expected, and indeed found, in CDCl₃, as linker (R²= Me, Table 3) substituted with two axial C-5(Ј)

δ[5(Ј)-H-e, (a-a)] Ͻ δ[5(Ј)-H-e, (s-s)] and δ[5(Ј)-H-e, (a-s)] Ͻ anacomeric 1,3-dioxane motifs and additionally crowded at

δ[5(Ј)-H-e, (a-s)].

As one can see in Table 3, other well separated signals – ively prevailed in the transition vs. ground state of 3c.

p-nph, 6(Ј)-H-e, 2(Ј)-H-a, Me and 5(Ј)-H-e (in solvents When the temperature was increased, compound 3a and

C-4(Ј) by the equatorial and orthogonal p-nph rings decis-

other than CDCl₃) – were also indicative but only for check- its dimeric analogue 3e reached only a slow exchange status

ing rotameric calculation. In other NMR solvents (Table 3), between unequal populated sites (Table 3, Figure S3, com-

1

calculation of the rotameric distribution was also made by pound 3a).^[14]The H DNMR transformations of the DX-

starting from the assumption that the most strongly down- NH rings in 3a were almost the same as those of the inner

field shifted location of NH protons referred to environ- DX-NH ones in 3e. Indeed, in 3e the peripheral Me₂N-DX

ment (a-a); then, different but equally intense signals re- rings in the dimeric 1,3-dioxane sequence Me₂N-DX-DX-

vealed, whenever possible, the two sites, anti vs. syn, in rota- NH were normally freely rotating about the equatorial C-

mers (a-s) etc.

2–C-2Ј bonds with an expected s-trans (antiperiplanar) pre-

The rotameric distribution in the series of N,NЈ-symmet- ferred orientation of protons 2-H-a and 2(Ј)-H-a

rically disubstituted diamino-s-triazines containing two 1,3- (Scheme 3).^[6]

dioxane motifs was strongly dependent on the type of

anchorage to central s-triazine unit and solvent (Table 3).

In comparison with 3c, the sterically less congested tran-

sition states of 3a and 3e, involving the same double axial

The rotameric abundance of the less crowded compound s-trans-out arrangement (Scheme 13) of the central but

3d, in which the two 1,3-dioxane fragments were attached smaller diamino-s-triazinediyl unit (R²= H, Table 3), was,

by equatorial linkages, were less sensitive to various sol- however, just a partial explanation for this evolution, as we

vents. The same, almost zero, influence of solvent modifica- had to deduce from the analysis of the last two items in this

tion was manifested by the oligomeric compound 3c.

series, 3d and 4c.

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Indeed, 3d could be deblocked almost completely at 3a ≈ 3e Ͼ 3d as progressively diminished steric hindrance in

353 K (Figure S3), demonstrating the relevance, in rota- the transitions states associated with rotations about these

tional phenomena, of its far less crowded transition state junctions.

involving two equatorial arrangements about the C(s-tri-

azine)–N(Ј)Ͻ partial double bonds.

2.4.3. N,NЈ,NЈЈ-Trisubstituted Triamino-s-triazines

Containing 1,3-Dioxane Motifs – Melamines and Dimeric

Melamines

Compound 3d was considered appropriate for estimation

of its free enthalpy of activation to rotation (∆G^϶) by appli-

cation of Eyring Equations (6) and (7).^[14]

The rotational behavior of N,NЈ,NЈЈ-symmetrically tri-

substituted melamines 4a (Scheme 5) and 4d (Scheme 8),

containing 1,3-dioxane motifs, and in the dimeric 5a–c

k_c≈ k_–c= 2.22 ∆ν [s^–1]

(6)

(7)

∆G^϶= 19.14 T_c(10.32 + log T_c/k_c) [Jmol^–1]

1

(Scheme 10) was analyzed by H DNMR, their two types

where T_c[K] is the coalescence temperature, ∆ν [Hz] is the of anchorage, axial or equatorial, to amino-s-triazine being

frequency separation between two analyzed signals at room kept in mind.

temperature belonging, in the absence of exchange, to two

Relevant ¹H NMR supporting data for melamines 4a

equally populated sites, and k_c(s^–1) is the rate constant of and 4d are collected in Table 5.

the first-order exchange dynamic process occurring at T_c.

At room temperature, on a 300 MHz timescale in CDCl₃,

As in the case of N-substituted chlorodiamino-s-triazines melamine 4a consisted of a statistic mixture of two predict-

with open-chain serinolic motifs^[10]we had to simplify the able frozen rotamers about bonds I–III: “asymmetric” and

problem considerably by considering rotational equilibria “propeller”.^[9f,10]Their ratio was established from the sig-

of 3d to be limited to a simple topomerization 3d (a-s) p nals of protons N(Ј)(ЈЈ)H, again indicative, since involved in

3d (s-a) presumably via rotamer 3d (a-a) (Table 3). Further- similar steric relations seen in axial monoanchored (Section

more, in Equations (6) and (7) we cautiously used^[9,14]the 2.4.1.) or doubly anchored compounds (Section 2.4.2). On

resonances of “mobile protons” N(Ј)H (Figure S3) and ob- increasing the temperature in [D₆]DMSO on a 400 MHz ¹H

tained ∆ν = 24 Hz, k_c= 53 s^–1, and hence ∆G^϶

=

NMR timescale to 353 K, this triple axial anchored struc-

71.10 kJmol^–1(T_c= 343 K). We note that in Equation (7), ture could not be totally deblocked, exhibiting two unas-

the value of k_cwas multiplied by 2, since rotamers of type signable diastereomers and therefore named simply 4a-

(a-s) ϵ (s-a) were statistically twice favored.^[9f,14]

major and 4a-minor.

The barrier to rotation in 3d was plausible, since it was

In contrast, at 298 K in CDCl₃, melamine 4d (Table 5)

1

smaller than those previously reported for two more was a slow rotational molecule on the H NMR 300 MHz

lpNǞπ conjugated and crowded 2-chloro-4,6-bis(dialkyl- timescale and free rotating on the ¹³C NMR 75 MHz time-

amino)-s-triazines with normal chains (nBu, 74.22 kJmol^–1, scale. Its blocked rotamers, 4d (asymmetric) and 4d (propel-

n-octyl 75.17 kJmol^–1) but significantly higher if the alkyl ler), could be detected only in [D₆]benzene or [D₆]DMSO

chain was branched (iPr, 65.33 kJmol^–1).^[8c]

in slightly different occurrence. In [D₆]DMSO, clean ¹H

¹H DNMR analysis of melamine 4c (Figure S3) gave in- DNMR transformation of 4d into a free rotating molecule,

formation concerning the electronic influence of substitu- suitable for kinetic calculations with the aid of the Eyring

ents in rotational phenomena. Formally, 4c derived from 3a Equation, was observed (Table S3). Three barriers to rota-

by replacement of the s-triazine electron acceptor chlorine tion – ∆G^϶

[kJmol^–1] – about the C(s-triazine)–NH

I–III

with a strong donor diethylamino group. A significant bonds I–III in 4d could be estimated^[9f]from the chemical

lower double bond character of its C(s-triazine)–N(Ј)Ͻ shifts corresponding to the three broad singlets of the

bonds was expected, and indeed, 4c became an almost N(Ј)(ЈЈ)H protons in rotamer 4d asymmetric (298 K,

freely rotating structure at 353 K, with some remaining de- Table 5).

coalescences in the N(Ј)H–5(Ј)-H-e–6(Ј)-H-a zones. Calcu-

We related the decreasing magnitudes of the ∆G^϶

Ͼ

III

lations based on the Eyring Equation with use of protons ∆G^϶Ͼ ∆G^϶values (Table 5, Table S3) to progressively

II

I

N(Ј)H (∆ν = 58 Hz, k_c= 129 s^–1, T_c= 328 K) gave a rota- diminished steric hindrance III Ͼ II Ͼ I in the three transi-

tional barrier about the C(s-triazine)–N(Ј)(axial) bonds as tion states of 4d when each R–NH- group rotates out of

∆G^϶= 65.44 kJmol^–1. ¹H NMR resolution of the Et₂N plane about bonds III, II, and I, respectively.^[9f]They all

group was poor, preventing us from ascertaining the rotam- were higher than the ∆G^϶value for melamine 4c

erism about the C(s-triazine)–N(Et₂) bond. Hence, in mela- (65.44 kJmol^–1, Section 2.4.2.2.). We thus again concluded

mine 4c, despite its steric relationships between diamino-s- that the effect of electron-donor substituents, reducing the

triazine and 1,3-dioxane rings being identical to those in 3a double bond character of C(s-triazine)–NϽ linkages either

and 3e (Scheme 13), favorable electronic factors dominated to a lesser (in 4d) or a greater degree (in 4c), prevailed over

steric hindrance, determining a low energetic level of the steric hindrance in the corresponding transition states,

rotational transition state.

which were more congested in 4c than in 4d.

We therefore finished by defining the “versatile effect of

However, the possibility that additional solvation in [D₆]-

electronic against steric factors” in this series as (i) 3c Ͼ 3a DMSO might have a greater stabilizing effect on the ground

≈ 3e Ͼ 3d Ͼ 4c in decreasing order of double bond charac- state^[9f]of the more basic 4d over 4c was also considered.

ter of their C(s-triazine)–NϽ linkages, and (ii) 3c Ͼ 4c Ͼ This solvation might not only increase the magnitude of all

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Serinolic Amino-s-triazines: Synthesis and Stereochemistry

Table 5. Relevant ¹H NMR spectroscopic data for N,NЈ,NЈЈ-symmetrically trisubstituted melamines containing 1,3-dioxane motifs at-

tached through axial (4a) or equatorial anchorages (4d).

3

[a] Doublets with J_H,H= 8.6–9.9 Hz. [b] Assignment based on the equal intensities of doublets located at δ = 5.52 and 5.62 ppm,

1

which normally belong to the asymmetric rotamer. [c] Assignments deduced from the 2 D H–¹H-COSY chart as N(Ј)(ЈЈ)H:5(Ј)(ЈЈ)-H-e.

[d] Assignment based on the equal intensities of doublets located at δ = 5.60 and 5.78 ppm, which normally belong to the asymmetric

rotamer.

1

∆G^϶barriers in 4d vs. 4c, but also their significantly greater the same H timescale conditions, the equatorially quadru-

values in relation to a ∆G^϶value of 60.90Ϯ0.84 kJmol^–1ply anchored compound 5b, like melamine 4d, was a par-

previously obtained from reported molecular mechanics in tially deblocked molecule since, except for the four protons

the case of 2,4,6-tris(cyclohexylamino)-s-triazine,^[9a]with an N(Ј)H (two distinct broad singlets at δ = 5.29 and

authentic equatorial orientation of amino-s-triazine group 5.79 ppm), unique signals were detected for all other iden-

against cyclohexane ring.

tically numbered nuclei. In addition, the QC NMR spec-

NMR analyses of the dimeric melamines 5a–c were run trum of 5b was also consistent with a single mediated struc-

at room temperature in CDCl₃(300 MHz timescale) and ture.

then in [D₆]DMSO at higher temperature (298–353 K on

In [D₆]DMSO at room temperature, we observed that all

400 MHz timescale). Their evolutions were compared (Fig- compounds 5a–c were partially frozen mixtures of better

ure 2).

solvated rotamers exhibiting a great number of overlapped

At 298 K in CDCl₃, the axially quadruply anchored 5a ¹H multiplets. Indeed, with increasing temperature (Fig-

and 5c showed only ¹H broad multiplets. It was not possible ure 2), diverse modifications were revealed.

to establish whether this appearance was due to a slow mo-

At 353 K, the quadruply axially anchored dimeric mela-

tion mediating unequal populations or simply to over- mine 5a still displayed outstanding decoalescence in the

lapped signals belonging to an exacerbated number of rota- zones 3(Ј)-H–5(Ј)-H (p-nph) and NH–5(Ј)-H-e–6(Ј)-H-a, so

tional conformers [we had previously shown that seven ro- it was not completely deblocked.

tational diastereomers are possible in linearly connected

double melamines of type 5a–c, due to six restricted rota- the inner 1,3-dioxane rings A of dimer 5c. They were as-

tions about C(s-triazine)-NϽ partial double bonds^[10]].

signed as slowly rotating at 353 K; meanwhile the periph-

Similar ¹H DNMR transformations were observed for

On the 75 MHz timescale, 5a and 5c showed some resid- eral 1,3-dioxane rings B indicated their fast-exchange status

ual frozen rotamerism, as more than one ¹³C line was re- about the equatorial bonds C-2–C-2-(Ј). We note that dis-

corded for some homo- or enantiotopic positions, with re- crimination between the two environments A vs. B of 5c

spect to a freely rotating structure (see Exp. Sect.). Under was not possible at 298 K.

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2485

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1

Figure 2. H NMR spectra of compounds 5a–c (353 K, on 400 MHz timescale, [D₆]DMSO).

1

When the above H DNMR results for 5a and 5c were

(ii) a greater ability of the diethylamino group in 4c to

compared with those provided by the simpler melamine 4c accommodate the transition state, by simple rotation out of

(free-rotating structure at 353 K; Figure S3, Section 2.4.2.2.) plane of the s-triazine ring, than the chair–chair flipping

we concluded that this different behavior could be caused by: piperazine linker in 5a and 5c, or

(i) better solvation in [D₆]DMSO of 5a and 5c, stabilizing

(iii) a greater electron-donating effect of the diethylamino

their ground states,

group as a free open-chain substituent, reducing the s-tri-

2486

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Eur. J. Org. Chem. 2008, 2473–2494

Serinolic Amino-s-triazines: Synthesis and Stereochemistry

a Perkin–Elmer^®Paragom FT-IR spectrometer. Only relevant ab-

sorptions 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 as fol-

lows: FAB Spectra on a JEOL^®AX 500 instrument fitted with a

DEC DA 5000 computer, and ionization was produced with a

FAB JEOL^®Cannon (fascicle of Xenon accelerated under 4 kV/

10 µA). MALDI Spectra were acquired on a Micromass TOF-

SpecE MALDI^®Instrument fitted with a time of flight analyzer

and a nitrogen pulsed laser (337 nm). ESI spectra were measured

on a Bruker^®Esquire Instrument with ion trapping in electrospray

mode. Computational details: the lowest-energy gas-phase con-

formers generated by SpartanЈ04 with the MMFF force field were

subjected to full geometry optimization at the B3LYP/6-31G(d)^[11]

level of theory by use of the same package. Further, the effect of

solvent (chloroform) was taken into account by performing SCRF

single-point calculations at the gas-phase optimum geometries with

the COSMO^[11e]model implemented in NWChem.^[12]The synthesis

and stereochemistry of compound 1a and related derivatives we

discussed in detail elsewhere.^{[1a,1c,1d,1f,2a]}

azine π-deficiency, in relation to its inclusion in a six-mem-

bered saturated diaza-heterocycle.

1

As expected, very clean H DNMR evolution, encoun-

tered earlier in the spectra of the doubly equatorially an-

chored compound 3d (Figure S3) and the triply equatorially

anchored melamine 4d (Table 5; Table S2 in the Supporting

Information) also occurred upon heating the quadruply

equatorially anchored compound 5b (Figure 2).

3. Conclusion

Amination of cyanuric chloride with anancomeric

amino-1,3-dioxane obtained by complete diastereospecific

and diastereoselective acetalization of two enantiomerically

pure l-p-nitrophenylserinols yielded N-substituted amino-s-

triazines in moderate to good yields. When double or triple

amination was carried out, quantitative results essentially

depended on the orientation of the nucleophilic site with

respect to the 1,3-dioxane ring, an axial C-5 amino group

being less reactive than an equatorial C-2 aminomethyl one.

In competitive aminations, however, a rigid axial C-5amino

group was more effective than triethylamine.

Restricted rotations about the C(s-triazine)–N(exocyclic)

bonds were found in all compounds under consideration.

The highest double bond character of this linkage was

shown by N-substituted aminodichloro-s-triazines with 1,3-

dioxane motifs, regardless of the axial or equatorial natures

of their attachment. In N-substituted doubly and triply an-

chored structures, specifically assignable frozen rotamerism

(syn/anti or “asymmetric/propeller”) was basically influ-

enced by the nature of anchorage, solvents, and substitu-

ents. The dynamic behavior of these new N-substituted

amino-s-triazines revealed, on the whole, higher rotational

ability in the equatorially constructed compounds.

Typical Procedure for the Synthesis of Compounds 1a–g (Scheme 2).

Simultaneous Preparation of Compounds 1e–g by Cross Acetaliza-

tion Between l-(p-Nitrophenyl)serinols Ia and Ib: Glyoxal monohy-

drate (1.83 g, 24.06 mmol) was suspended in concd. sulfuric acid

(96%, 24.56 g, 13.35 mL, 240.60 mmol) with vigorous stirring

and then cooled at 0 °C. Finely powdered (1S,2S)-2-amino-1-(p-

nitrophenyl)propane-1,3-diol (Ia, as hydrochloride, 6.00 g,

24.06 mmol) was added portionwise (5ϫ1.20 g, each 3 h) at 0 °C.

The reaction mixture was diluted with additional concd. sulfuric

acid (96%, 24.56 g, 13.35 mL, 240.6 mmol) at 0 °C. Finely pow-

dered

(1S,2S)-2-(dimethylamino)-1-(4-nitrophenyl)propane-1,3-

diol (Ib) (5.80 g, 24.06 mmol) was finally added, and the reaction

mixture was stirred and allowed to reach room temperature grad-

ually overnight. The mixture was carefully poured into dichloro-

methane (300 mL) and aq. NH₃(1:1, 200 mL of 25% aq. NH₃and

200 g of ice). The organic layer was recovered, filtered, washed with

water (50 mL) to neutrality, dried with CaCl₂, and evaporated in

vacuo. The resulted crude solid (3.70 g) was separated by flash col-

umn chromatography on silica gel (eluent MeOH/dichloromethane,

3:1, v/v) to yield the following three fractions: 1e (0.40 g), 1f

(1.20 g), and 1g (1.00 g). Each fraction was additionally crystallized

from ether.

Experimental Section

General: Melting points are uncorrected; they were carried out on

an ELECTROTHERMAL^®instrument. Conventional NMR spec-

tra were recorded on a Bruker^®AM 300 instrument operating at

300 and 75 MHz for ¹H and ¹³C nuclei, respectively. ¹H DNMR

spectra were performed on a Bruker^®AM 400 instrument op-

erating at 400 and 100 MHz for ¹H and ¹³C nuclei, respectively,

with 10 K increases in temperature for each step. All NMR spectra

were measured in commercially available anhydrous deuteriated

solvents. No SiMe₄was added; chemical shifts were measured

against the solvent peak. All chemical shifts (δ values) are given

throughout in ppm; all coupling patterns (ⁿJ_H,Hvalues) are given

throughout in Hz. NMR descriptions of compounds exhibiting

three or more frozen rotamers at room temperature have been done

by considering each compound as one overall structure. Multiple

values of chemical shifts and coupling constants for the same lab-

(2R,4S,5S)-5-Amino-2-(aminomethyl)-4-(4-nitrophenyl)-1,3-dioxane

(1b): Yield 65% (6.60 g, 26.00 mmol 1b starting from 8.48 g,

40.00 mmol, Ia), yellow crystalline powder, R_f(75% MeOH/dichlo-

romethane) = 0.20; m.p. 101–102 °C (direct crystallization from

Et₂O/ligroin, 1:1). [α]²_D⁰= +25.0 (0.5% thf); +85.3 (0.2% MeOH).

¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 1.37 (br. s, 4 H, 2ϫNH₂),

3

2.93 (ddd, J_H,H= 1.8, 1.8, 1.8 Hz, 1 H, 5-H-e), 2.96 (d, J_H,H

=

2

3

4.5 Hz, 2 H, CH₂NH₂), 4.12 (dd, J_H,H= 11.6, J_H,H= 1.8 Hz, 1

H, 6-H-a), 4.16 (dd, ²J_H,H= 11.6, ³J_H,H= 1.8 Hz, 1 H, 6-H-e), 4.76

(dd, ³J_H,H= 4.5, 4.5 Hz, 1 H, 2-H-a), 5.01 (s, 1 H, 4-H-a), 7.49 (d,

3

³J_H,H= 8.9 Hz, 2 H, 2-, 6-H, p-nph), 8.23 (d, J_H,H= 8.9 Hz, 2 H,

3-, 5-H, p-nph) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 46.0

(1 C, CH₂NH₂), 50.1 (1 C, C-5), 73.1 (1 C, C-6), 80.5 (1 C, C-4),

103.0 (1 C, C-2), 124.1 (2 C, C-2, -6, p-nph), 126.8 (2 C, C-3, -5,

p-nph), 146.8 (1 C, C-1, p-nph), 147.7 (1 C, C-4, p-nph) ppm. IR

1

eled H or ¹³C position means a mixture of rotamers, as described

(KBr): ν = 3378 (s), 2980 (m), 2918 (m), 2857 (m), 1606 (m), 1515

˜

in Tables 3, 4, and 5. Abbreviations used: br. d (br. doublet), br. dd

(br. doublet of doublets), br. t (br. triplet,) and br. m (br. multiplet).

TLC was performed on aluminium sheets coated with silica gel

60 F₂₅₄(Merck^®); flash column chromatography was conducted on

silica gel Si 60 (40–63 µm, Merck^®). IR spectra were measured on

(s), 1350 (s), 1145 (m), 1092 (m), 1053 (s), 1018 (s), 903 (m), 874

(s), 810 (m), 741 (s), 710 (m), 623 (w), 526 (w) cm^–1. MS (EI): m/z

(%) = 252.8 (7) [M]⁺, 218.0 (78), 188.0 (98), 164.1 (100), 119.9 (73).

C₁₁H₁₅N₃O₄(253.26): calcd. C 52.17, H 5.97, N 16.59; found C

51.89, H 6.22, N 16.65.

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2487

M. Darabantu et al.

FULL PAPER

(4S,5S)-5-(Dimethylamino)-4-(4-nitrophenyl)-1,3-dioxane (1c): Yield

70% (7.00 g, 28.00 mmol 1c starting from 9.60 g, 40.00 mmol Ib),

yellow crystalline powder, R_f(75% MeOH/dichloromethane) =

0.50; m.p. 131–132 °C (direct crystallization from Et₂O/ligroin,

1:1). [α]²_D⁰= +115.0 (1% CDCl₃). ¹H NMR (400 MHz, CDCl₃,

25 °C): δ = 2.01 [s, 6 H, N(CH₃)₂], 2.74 (s, 1 H, 5-H-e), 3.93 (dd,

²J_H,H= 12.4, ³J_H,H= 2.7 Hz, 1 H, 6-H-a), 4.55 (d, ²J_H,H= 12.4 Hz,

(100), 311 (Ͻ5), 180 (Ͻ5), 135 (30). C₂₄H₃₀N₄O₈(502.52): calcd. C

57.36, H 6.02, N 11.15; found C 57.41, H 5.77, N 10.85.

(2R,2ЈR,4S,4ЈS,5S,5ЈS)-5-Amino-5Ј-(dimethylamino)-4,4Ј-bis(4-ni-

trophenyl)-2,2Ј-bi-1,3-dioxane (1f): Yield 11% (1.20 g, 2.53 mmol 1f

starting from Ia hydrochloride, 6.00 g, 24.06 mmol and Ib 5.80 g,

24.06 mmol), yellow crystalline powder, R_f(75% MeOH/dichloro-

methane) = 0.50; m.p. 134–135 °C (flash column chromatography;

methanol/dichloromethane, 3:1). [α]²_D⁰= –3.18 (1% MeOH). ¹H

NMR (300 MHz, CDCl₃, 25 °C): δ = 1.42 (br. s, 2 H, NH₂), 2.2 [s,

6 H, N(CH₃)₂], 2.68 (s, 1 H, 5Ј-H-e), 2.90 (s, 1 H, 5-H-e), 3.95 (dd,

2

3

1 H, 6-H-e), 4.96 (d, J_H,H= 6.2 Hz, 1 H, 2-H-a), 5.03 (d, J_H,H

=

3

3.0 Hz, 1 H, 4-H-a), 5.28 (d, ³J_H,H= 6.2 Hz, 2-H-e), 7.54 (d, J_H,H

3

= 8.6 Hz, 2 H, 2-, 6-H, p-nph), 8.21 (d, J_H,H= 8.6 Hz, 2 H, 3-, 5-

H, p-nph) ppm. ¹³C NMR (100 MHz, CDCl₃, 25 °C): δ = 43.9 [2

C, N(CH₃)₂], 60.2 (1 C, C-5), 65.3 (1 C, C-6), 81.0 (1 C, C-4), 94.1

(1 C, C-2), 123.3 (2 C, C-2, -6, p-nph), 126.3 (2 C, C-3, -5, p-nph),

3

2

²J_H,H= 12.4, J_H,H= 2.3 Hz, 1 H, 6Ј-H-a), 4.09 (d, J_H,H

=

2

11.3 Hz, 1 H, 6-H-a), 4.15 (d, J_H,H= 11.3 Hz, 6-H-e), 4.58 (d,

²J_H,H= 12.4 Hz, 1 H, 6Ј-H-e), 4.84 (d, ³J_H,H= 4.1 Hz, 2-H-a), 4.91

147.4 (1 C, C-1, p-nph), 147.8 (1 C, C-4, p-nph) ppm. IR (KBr): ν

3

˜

(d, J_H,H= 4.1 Hz, 2Ј-H-a), 4.99 (s, 1 H, 4-H-a), 5.06 (d, J_H,H

=

= 3000 (s), 2943 (s), 2834 (s), 2784 (s), 1609 (s), 1517 (s), 1475 (s),

1348 (s), 1316 (s), 1299 (s), 1165 (s), 1080 (s), 1040 (s), 1010 (s),

982 (s), 962 (s), 896 (m), 849 (s), 822 (s), 722 (s), 708 (s), 692 (m),

583 (m) cm^–1. MS (CI, isobutane): m/z (%) = 253 (100) [M + 1]⁺,

209 (Ͻ10), 193 (Ͻ10). C₁₂H₁₆N₂O₄(252.27): calcd. C 57.13, H

6.39, N 11.10; found C 56.88, H 6.11, N 10.96.

3

2.6 Hz, 1 H, 4Ј-H-a), 7.40, 7.43 (2ϫd, J_H,H= 9.0, 9.0 Hz, 4 H,

2-, 2Ј-, 6-, 6Ј-H, p-nph), 8.08, 8.11 (2ϫd, ³J_H,H= 9.0, 9.0 Hz, 4 H,

3-, 3Ј-, 5-, 5Ј-H, p-nph) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C):

δ = 44.1 [2 C, N(CH₃)₂], 50.1 (1 C, C-5), 59.6 (1 C, C-5Ј), 65.3 (1

C, C-6Ј), 73.4 (1 C, C-6), 80.4 (1 C, C-4), 81.1 (1 C, C-4Ј), 100.2 (1

C, C-2Ј), 100.5 (1 C, C-2), 123.6, 124.1 (4 C, C-2, -2Ј, -6, -6Ј, p-

nph), 126.7, 126.8 (4 C, C-3, -3Ј, -5, -5Ј, p-nph), 146.4, 147.2 (2 C,

(2R,4S,5S)-2-(Aminomethyl)-5-(dimethylamino)-4-(4-nitrophenyl)-

1,3-dioxane (1d): Yield 84% (9.45 g, 33.60 mmol 1d starting from

9.60 g, 40.00 mmol Ib), yellow crystalline powder, R_f(75% MeOH/

dichloromethane) = 0.25; m.p. 91–92 °C (direct crystallization from

C-1, -1Ј, p-nph), 147.4, (2 C, C-4, -4Ј, p-nph) ppm. IR (KBr): ν =

˜

3378 (m), 2931 (m), 2865 (m), 2789 (m), 1604 (m), 1518 (s), 1464

(w), 1348 (s), 1149 (m), 1108 (m), 1058 (m), 1014 (m), 852 (m), 742

(m), 712 (m) cm^–1. MS (EI): m/z (%) = 474.0 (42) [M]⁺, 279.9 (12),

240.3 (26), 222.0 (100), 204.3 (23), 157.8 (17). C₂₂H₂₆N₄O₈

(474.47): calcd. C 55.69, H 5.52, N 11.81; found C 55.88, H 5.61,

N 12.15.

Et₂O/ligroin 1:1). [α]²_D⁰

=

+115.0 (0.3% MeOH). ¹H NMR

(300 MHz, CDCl₃, 25 °C): δ = 1.41 (br. s, 2 H, NH₂), 2.25 [s, 6 H,

N(CH₃)₂], 2.67 (dd, ³J_H,H= 3.0, 3.0 Hz, 1 H, 5-H-e), 2.92 (d, ³J_H,H

2

3

= 4.1 Hz, 2 H, CH₂NH₂), 3.95 (dd, J_H,H= 12.6, J_H,H= 3.0 Hz,

2

3

1 H, 6-H-a), 4.55 (d, J_H,H= 12.6 Hz, 1 H, 6-H-e), 4.77 (dd, J_H,H

(2R,2ЈR,4S,4ЈS,5S,5ЈS)-5,5Ј-Diamino-4,4Ј-bis(4-nitrophenyl)-2,2Ј-

bi-1,3-dioxane (1g): Yield 33% (2.95 g, 6.60 mmol 1 g starting from

8.48 g, 40.00 mmol Ia) yellow crystalline powder, R_f(75% MeOH/

dichloromethane) = 0.25; m.p. 141–142 °C (flash column

chromatography; methanol/dichloromethane 3:1 or direct crystalli-

zation from Et₂O). [α]²_D⁰= –11.5 (1% MeOH). ¹H NMR (300 MHz,

CDCl₃, 25 °C): δ = 1.40 (br. s, 4 H, 2ϫNH₂), 3.01 (s, 2 H, 5-, 5Ј-

3

= 4.1, 4.1 Hz, 1 H, 2-H-a), 5.06 (d, J_H,H= 3.0 Hz, 1 H, 4-H-a),

3

7.50 (d, J_H,H= 8.7 Hz, 2 H, 2-, 6-H, p-nph), 8.17 (d, J_H,H

=

8.7 Hz, 2 H, 3-, 5-H, p-nph) ppm. ¹³C NMR (75 MHz, CDCl₃,

25 °C): δ = 44.1 [2 C, N(CH₃)₂], 46.2 (1 C, CH₂NH₂), 59.6 (1 C,

C-5), 65.3 (1 C, C-6), 81.2 (1 C, C-4), 102.6 (1 C, C-2), 123.6 (2 C,

C-2, -6, p-nph), 126.6 (2 C, C-3, -5, p-nph), 147.3 (1 C, C-1, p-nph),

2

147.8 (1 C, C-4, p-nph) ppm. IR (KBr): ν = 3378 (m), 2937 (m),

˜

H-e), 4.21 (d, J_H,H= 11.5 Hz, 2 H, 6-, 6Ј-H-a), 4.26 (d, J_H,H

=

2862 (m), 2773 (m), 1602 (m), 1516 (s), 1464 (w), 1349 (s), 1148 (s),

1107 (m), 1061 (s), 1048 (s), 1008 (s), 905 (s), 852 (m), 717 (m), 710

(m), 580 (w), 462 (w) cm^–1. MS (EI): m/z (%) = 282.2 (100) [M +

1]⁺, 267.9 (12), 251.1 (19), 223.6 (23), 223 (77), 221 (Ͻ10), 209.1

(Ͻ10), 192.8 (Ͻ10), 178.8 (Ͻ10), 160.8 (Ͻ10), 149.1 (Ͻ10), 126.2

(Ͻ10). C₁₃H₁₉N₃O₄(281.31): calcd. C 55.51, H 6.81, N 14.94;

found C 55.61, H 7.11, N 15.15.

11.5 Hz, 2 H, 6-, 6Ј-H-e), 4.98 (s, 2 H, 2-, 2Ј-H-a), 5.10 (s, 2 H, 4-

3

, 4Ј-H-a), 7.51 (d, J_H,H= 8.6 Hz, 4 H, 2-, 2Ј-, 6-, 6Ј-H, p-nph),

3

8.21 (d, J_H,H= 8.6 Hz, 4 H, 3-, 3Ј-, 5-, 5Ј-H, p-nph) ppm. ¹³C

NMR (75 MHz, CDCl₃, 25 °C): δ = 49.7 (2 C, C-5, -5Ј), 73.1 (2 C,

C - 6 , - 6 Ј ) , 8 0 . 2 ( 2 C , C - 4 , - 4 Ј ) , 1 0 0 . 1 ( 2 C , C - 2 ,

-2Ј), 123.7 (4 C, C-2, -2Ј, -6, -6Ј, p-nph), 126.5 (4 C, C-3, -3Ј, -5,

-5Ј, p-nph), 146.1 (2 C, C-1, -1Ј, p-nph), 147.3 (2 C, C-4, -4Ј, p-

nph) ppm. IR (KBr): ν = 3372 (m), 3313 (m), 3108 (w), 3061 (m),

˜

(2R,2ЈR,4S,4ЈS,5S,5ЈS)-5,5Ј-Bis(dimethylamino)-4,4Ј-bis(4-nitro-

phenyl)-2,2Ј-bi-1,3-dioxane (1e): Yield 33% (3.32 g, 6.60 mmol 1e

starting from 9.60 g, 40.00 mmol Ib), yellow crystalline powder,

R_f(75% MeOH/dichloromethane) = 0.75; m.p. 123–124 °C (flash

column chromatography; methanol/dichloromethane 3:1 or direct

2925 (m), 2866 (m), 1603 (s), 1514 (s), 1458 (m), 1348 (s), 1294 (s),

1250 (m), 1144 (s), 1094 (s), 1041 (s), 1015 (s), 963 (s), 877 (s), 843

(s), 812 (s), 741 (s), 713 (s), 690 (w), 558 (w) cm^–1. MS (CI, isobut-

ane): m/z (%) = 503 (Ͻ5) [M + 56]⁺, 447 (100) [M]⁺, 294 (Ͻ5), 235

(10), 154 (5), 116 (Ͻ5). C₂₀H₂₂N₄O₈(446.42): calcd. C 53.81, H

4.97, N 12.55; found C 54.05, H 5.11, N 12.77.

1

crystallization from Et₂O). [α]²_D⁰= –12.14 (1% MeOH). H NMR

(300 MHz, CDCl₃, 25 °C): δ = 2.35 [s, 12 H, 2ϫN(CH₃)₂], 2.81

3

2

(dd, J_H,H= 3.1, 3.1 Hz, 2 H, 5-, 5Ј-H-e), 4.07 (dd, J_H,H= 12.5,

Typical Procedure for the Synthesis of Compounds 2a–c (Scheme 4).

Preparation of Compound 2c: Anhydrous potassium carbonate

(0.570 g, 4.14 mmol) was suspended with vigorous stirring in a dry

thf (40 mL) solution containing cyanuric chloride (0.780 g,

³J_H,H= 3.1 Hz, 2 H, 6-, 6Ј-H-a), 4.70 (d, J_H,H= 12.5 Hz, 2 H,

6-, 6Ј-H-e), 5.01 (s, 2 H, 2-, 2Ј-H-a), 5.19 (d, J_H,H= 3.1 Hz, 2 H,

4-, 4Ј-H-a), 7.54 (d, J_H,H= 8.4 Hz, 4 H, 2-, 2Ј-, 6-, 6Ј-H, p-nph),

2

3

8.21 (d, J_H,H= 8.4 Hz, 4 H, 3-, 3Ј-, 5-, 5Ј-H, p-nph) ppm. ¹³C 4.14 mmol), cooled to 0 °C. At this temperature, (2R,4S,5S)-5-

3

NMR (75 MHz, CDCl₃, 25 °C): δ = 43.8 [4 C, 2ϫN(CH₃)₂], 59.3

amino-2-(aminomethyl)-4-(4-nitrophenyl)-1,3-dioxane (1b, 0.500 g,

(2 C, C-5, -5Ј), 65.3 (2 C, C-6, -6Ј), 80.7 (2 C, C-4, -4Ј), 99.8 (2 C, 1.97 mmol) in a dry thf (15 mL) solution was added portionwise

C-2, -2Ј), 123.3 (4 C, C-2, -2Ј, -6, -6Ј, p-nph), 126.2 (4 C, C-3, -3Ј,

-5, -5Ј, p-nph), 147.0 (2 C, C-1, -1Ј, p-nph), 147.3 (2 C, Cq, C-4, -

(2.5 mL each 60 min). The reaction mixture was then allowed to

reach room temperature overnight (about 12 h). After filtering and

4Ј, p-nph) ppm. IR (KBr): ν = 3354 (s), 2934 (w), 2886 (w), 1660 thorough washing of solid residues with dry thf (50 mL), the or-

˜

(s), 1607 (w), 1519 (s), 1472 (m), 1453 (m), 1348 (s), 1214 (w), 1108

ganic filtrate was evaporated under reduced pressure to dryness,

(w), 1076 (m), 1048 (m), 1014 (w), 856 (m), 737 (s), 592 (w) cm^–1. yielding the crude product, which was crystallized by trituration

MS (CI, isobutane): m/z (%) = 463 (Ͻ10) [M – 39]⁺, 445 (30), 329 from ligroin/Et₂O. Yield 0.650 g 2c (60%).

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Eur. J. Org. Chem. 2008, 2473–2494

Serinolic Amino-s-triazines: Synthesis and Stereochemistry

2,4-Dichloro-6-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-yl]amino}-s-

triazine (2a): Yield 75 % (11.10 g, 30.00 mmol 2a starting from

8.92 g, 40.00 mmol 1a) yellowish crystalline powder, R_f(60% lig-

roin/acetone) = 0.80; m.p. 192–193 °C (direct crystallization from

Et₂O/ligroin 1:1). [α]²_D⁰= +39.3 (0.18% DMSO), +20.4 (0.2%

6.2 Hz, 1 H, CH₂NH), 6.64 (d, ³J_H,H= 9.5 Hz, 1 H, C-5-NH), 7.50

3

(d, J_H,H= 8.9 Hz, 2 H, 2-, 6-H, p-nph), 8.19 (d, J_H,H= 8.9 Hz,

2 H, 3-, 5-H, p-nph) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ =

44.4 (1 C, CH₂NH), 49.2 (1 C, C-5), 70.7 (1 C, C-6), 79.1 (1 C, C-

4), 99.7 (1 C, C-2), 124.1 (2 C, C-2, -6, p-nph), 126.8 (2 C, C-3, -

5, p-nph), 143.6 (1 C, C-1, p-nph), 148.1 (1 C, C-4, p-nph), 165.8,

166.6 (2 C, C-6, -6Ј, s-triazine), 168.9, 170.7, 171.2, 171.6 (4 C, C-

1

2

MeOH). H NMR (300 MHz, CDCl₃, 25 °C): δ = 4.08 (dd, J_H,H

3

= 12.0, J_H,H= 1.3 Hz, 1 H, 6-H-a), 4.17 (d, ²J_H,H= 12.0 Hz, 1 H,

2

6-H-e), 4.50 (dd, ³J_H,H= 9.7, 1.3 Hz, 1 H, 5-H-e), 4.96 (d, J_H,H

=

2, -2Ј, -4, -4Ј, s-triazine) ppm. IR (KBr): ν = 3326 (m), 3054 (m),

˜

2

6.4 Hz, 1 H, 2-H-a), 5.05 (s, 1 H, 4-H-a), 5.29 (d, J_H,H= 6.4 Hz, 1752 (m), 1725 (m), 1589 (s), 1555 (s), 1511 (s), 1400 (m), 1349 (s),

3

1 H, 2-H-e), 6.56 (d, J_H,H= 9.7 Hz, 1 H, NH), 7.62 (d, J_H,H

=

1324 (m), 1168 (m), 1105 (w), 1055 (w), 950 (m), 799 (m), 745 (w),

8.9 Hz, 2 H, 2-, 6-H, p-nph), 8.12 (d, ³J_H,H= 8.9 Hz, 2 H, 3-, 5-H,

713 (m), 536 (m) cm^–1. MS (EI): m/z (%) = 550.1 (Ͻ10) [M – 1]⁺,

1

p-nph) ppm. H NMR (400 MHz, [D₆]DMSO, 25 °C): δ = 4.04 (d, 529.0 (10), 528.1 (20), 526.2 (38), 490.3 (75), 476.3 (100), 459.2 (10),

2

3

²J_H,H= 11.3 Hz, 1 H, 6-H-a), 4.13 (dd, J_H,H= 11.3, J_H,H

=

447.3 (18), 433.1 (20), 404.2 (27), 390.1 (13), 386.1 (Ͻ10), 364.9

(11), 338.1 (16), 324.1 (19), 320.1 (35), 290.1 (48), 282.0 (26), 277.8

(15), 250.1 (10), 233.6 (17), 223.1 (27), 204.7 (13), 192.8 (16), 185.0

(38), 166.9 (82), 153.0 (53), 135.7 (22), 124.3 (15), 110.4 (18).

C₁₇H₁₃Cl₄N₉O₄(549.16): calcd. C 37.18, H 2.39, N 22.96; found C

1.1 Hz, 1 H, 6-H-e), 4.42 (dd, ³J_H,H= 9.1, 1.1 Hz, 1 H, 5-H-e), 4.97

2

(d, J_H,H= 6.2 Hz, 1 H, 2-H-a), 5.23 (d, J_H,H= 6.2 Hz, 1 H, 2-H-

e), 5.28 (s, 1 H, 4-H-a), 7.66 (d, J_H,H= 8.8 Hz, 2 H, 2-, 6-H, p-

3

nph), 8.15 (d, J_H,H= 8.8 Hz, 2 H, 3-, 5-H, p-nph), 9.41 (d, J_H,H

= 9.1 Hz, 1 H, NH) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 36.85, H 2.55, N 23.11.

50.2 (1 C, C-5), 70.5 (1 C, C-6), 78.9 (1 C, C-4), 94.9 (1 C, C-2),

124.0 (2 C, C-2, -6, p-nph), 126.8 (2 C, C-3, -5, p-nph), 144.4 (1 C,

C-1, p-nph), 148.0 (1 C, C-4, p-nph), 165.8 (1 C, C-6, s-triazine),

2,4-Dichloro-6-{[(2R,4S,5S)-5-(dimethylamino)-4-(4-nitrophenyl)-

1,3-diox-2-yl]methylamino}-s-trazine (2f): Yield 16 % (0.137 g,

0.32 mmol 2f, starting from 0.565 g, 2.00 mmol 1d), yellowish crys-

talline powder, R_f(66% ligroin/acetone) = 0.55, (66% AcOEt/lig-

roin) = 0.45; m.p. 260 °C (dec., flash column chromatography; lig-

roin/acetone 2:1 or AcOEt/ligroin 2:1). [α]²_D⁰= +57.3 (0.05%

MeOH). ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 2.27 [s, 6 H,

N(CH₃)₂], 2.75 (s, 1 H, 5-H-e), 3.82 (br. dd, 2 H, CH₂NH), 3.99

170.6, 171.1 (2 C, C-2, -4, s-triazine) ppm. IR (KBr): ν = 3305 (s),

˜

1585 (s), 1557 (s), 1410 (s), 1346 (s), 1325 (s), 1240 (s), 1183 (s),

1167 (s), 1103 (s), 1043 (m), 1029 (m), 964 (m), 852 (m), 842 (m),

798 (m), 745 (m), 713 (m), 684 (w), 652 (w), 558 (w) cm^–1. MS (EI):

m/z (%) = 370.7 (40) [M – 1]⁺, 340.7 (25), 310.7 (100), 276.7 (18),

217.8 (40), 189.6 (25), 163.9 (26). C₁₃H₁₁Cl₂N₅O₄(372.17): calcd.

C 41.96, H 2.98, N 18.82; found C 41.77, H 3.18, N 19.05.

2

(d, J_H,H= 12.3 Hz, 1 H, 6-H-a), 4.59 (d, J_H,H= 12.3 Hz, 1 H, 6-

H-e), 5.00 (s, 1 H, 2-H-a), 5.10 (s, 1 H, 4-H-a), 6.33 (br. dd, 1 H,

3

(2R,2ЈR,4S,4ЈS,5S,5ЈS)-5,5Ј-Bis[(2,4-dichloro-s-triazin-6-yl)amino]-

4,4Ј-bis(4-nitrophenyl)-2,2Ј-bi-1,3-dioxane (2b): Yield 82% (0.610 g,

0.82 mmol 2b starting from 0.446 g, 1.00 mmol 1 g), yellowish crys-

talline powder, R_f(75% ligroin/acetone) = 0.50; m.p. 216–218 °C

(direct crystallization from Et₂O/ligroin 1:1). [α]²_D⁰= +75.1 (0.3%

NH), 7.48 (d, J_H,H= 8.3 Hz, 2 H, 2-, 6-H, p-nph), 8.22 (d, J_H,H

= 8.3 Hz, 2 H, 3-, 5-H, p-nph) ppm. ¹³C NMR (75 MHz, CDCl₃,

25 °C): δ = 44.1 [2 C, N(CH₃)₂], 44.8 (1 C, CH₂NH), 59.5 (1 C, C-

5), 65.6 (1 C, C-6), 81.3 (1 C, C-4), 98.9 (1 C, C-2), 123.7 (2 C, C-

2, -6, p-nph), 126.5 (2 C, C-3, -5, p-nph), 146.7 (1 C, C-1, p-nph),

147.5 (1 C, C-4, p-nph), 166.6 (1 C, C-6, s-triazine), 171.0 (2 C, C-

1

2

DMSO). H NMR (300 MHz, CDCl₃, 25 °C): δ = 4.28 (dd, J_H,H

3

2

= 13.0, J_H,H= 1.1 Hz, 2 H, 6-, 6Ј-H-a), 4.33 (dd, J_H,H= 13.0,

2, -4, s-triazine) ppm. IR (KBr): ν = 3229 (s), 3083 (s), 2928 (s),

˜

³J_H,H= 1.5 Hz, 2 H, 6-, 6Ј-H-e), 4.61 (dd, J_H,H= 9.5, 1.3 Hz, 2

3

2875 (s), 1784 (m), 1702 (s), 1609 (s), 1521 (s), 1402 (s), 1349 (s),

1323 (s), 1238 (s), 1146 (s), 1035 (s), 984 (m), 851 (m), 800 (m), 708

(w), 533 (w) cm^–1. MS (CI): m/z (%) = 443.2 [M + 14]⁺, 429.2

[M]⁺(70), 411.1 (17), 223.0 (28), 171.1 (13), 126.6 (17), 125.9 (29).

C₁₆H₁₈Cl₂N₆O₄(429.27) (as a result of product instability no satis-

factory microanalysis could be obtained).

H, 5-, 5Ј-H-e), 5.07 (s, 2 H, 2-, 2Ј-H-a), 5.24 (s, 2 H, 4-, 4Ј-H-a),

3

6.49 (d, J_H,H= 9.5 Hz, 2 H, N-, NЈ-H), 7.52 (d, J_H,H= 8.9 Hz,

3

4 H, 2-, 2Ј-, 6-, 6Ј-H, p-nph), 8.18 (d, J_H,H= 8.9 Hz, 4 H, 3-, 3Ј-,

5-, 5Ј-H, p-nph) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 49.5

(2 C, C-5, -5Ј), 70.5 (2 C, C-6, -6Ј), 79.1 (2 C, C-4, -4Ј), 100.0 (2 C,

C-2, -2Ј), 124.0 (4 C, C-2, -2Ј, -6, -6Ј, p-nph), 126.9 (4 C, C-3, -3Ј,

-5, -5Ј, p-nph), 143.7 (2 C, C-1, -1Ј, p-nph), 148.1 (2 C, C-4, -4Ј, p-

nph), 165.8 (2 C, C-6, 6Ј, s-triazine), 170.7, 171.2 (4 C, C-2, -2Ј,

Typical Procedure for the Synthesis of Compounds 3a–e (Schemes 5–

9). Preparation of Compound 3a (Table 1, Entry 2): Anhydrous po-

tassium carbonate (0.414 g, 3 mmol) was suspended with vigorous

stirring in a dry toluene (25 mL) solution containing cyanuric chlo-

ride (0.184 g, 1 mmol), and fine powdered (4S,5S)-5-amino-4-(4-

nitrophenyl)-1,3-dioxane (1a, 0.673 g, 3 mmol) was then added.

The resulted suspension was heated and kept at reflux until TLC

monitoring indicated no more evolution (20 h). The reaction mix-

ture was cooled to room temperature and filtered, and solid resi-

dues were well washed with dry toluene. The organic filtrate was

evaporated to dryness under reduced pressure, providing the crude

reaction mixture, which was separated by flash column chromatog-

raphy on silica gel. The desired 3a was eluted with ligroin/acetone

(1:1, v/v) to give 3a (0.515 g, 61% conversion of 1a). Complete elu-

tion of the column with pure acetone yielded unreacted 1a (0.170 g,

87% recovery of the unreacted 1a).

-4, -4Ј s-triazine) ppm. IR (KBr): ν = 3400 (m), 2870 (m), 1752 (m),

˜

1579 (s), 1510 (s), 1349 (s), 1327 (s), 1239 (s), 1166 (s), 1110 (s),

1033 (m), 852 (m), 743 (w), 715 (w), 526 (w) cm^–1. MS (FAB+, 3-

nitrobenzyl alcohol): m/z (%) = 743 (30) [M + 1]⁺, 400 (30), 382

(20), 355 (15), 342 (35), 324 (27), 312 (35), 296 (15), 289 (28), 261

(65), 245 (100), 219 (38), 191 (47), 165 (40). C₂₆H₂₀Cl₄N₁₀O₈

(742.32): calcd. C 42.07, H 2.72, N 18.87; found C 41.91, H 2.98,

N 18.77.

(2R,4S,5S)-5-[(2,4-Dichloro-s-triazin-6-yl)amino]-2-[(2,4-dichloro-s-

triazin-6-yl)aminomethyl]-4-(4-nitrophenyl)-1,3-dioxane (2c): Yield

60% (0.650 g, 1.18 mmol 2c, starting from 0.500 g, 1.97 mmol 1b),

yellowish crystalline powder, R_f(60% ligroin/acetone) = 0.80; m.p.

287 °C (dec., direct crystallization from Et₂O/ligroin, 1:1). [α]²_D⁰

=

+55.5 (0.15% MeOH). ¹H NMR (300 MHz, CDCl₃, 25 °C): δ =

2

3

3.81 (ddd, J_H,H= 14.3, J_H,H= 5.5, 6.2 Hz, 1 H, CH₂NH), 3.93 Preparation of Compound 3d (Table 2, Entry 2): Anhydrous potas-

2

3

(ddd, J_H,H= 14.3, J_H,H= 5.5, 6.2 Hz, 1 H, CH₂NH), 4.22 (d, sium carbonate (0.980 g, 7.1 mmol) was suspended with vigorous

2

²J_H,H= 11.7 Hz, 1 H, 6-H-a), 4.26 (d, J_H,H= 11.7 Hz, 1 H, 6-H- stirring in a dry toluene (50 mL) solution containing cyanuric chlo-

e), 4.59 (dd, ³J_H,H= 9.5, 1.3 Hz, 1 H, 5-H-e), 5.10 (dd, ³J_H,H= 4.3,

ride (0.589 g, 3.2 mmol), and finely powdered 1d (2.000 g,

7.1 mmol) was then added. The resulted suspension was kept at

3

4.9 Hz, 1 H, 2-H-a), 5.21 (s, 1 H, 4-H-a), 6.44 (dd, J_H,H= 5.5,

Eur. J. Org. Chem. 2008, 2473–2494

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2489

M. Darabantu et al.

FULL PAPER

3

room temperature for 24 h and was then heated at 70 °C until TLC

monitoring indicated no more change (12 h). The reaction mixture

was cooled to room temperature and filtered, and solid residues

were well washed with dry toluene. The organic filtrate was evapo-

rated to dryness under reduced pressure, providing the crude reac-

tion mixture, which was separated by flash column chromatography

on silica gel (eluent acetone/ligroin, 2:1, v/v) as follows: first frac-

tion 3d (1.700 g, 71% conversion of 1d), then 4d (0.400 g, 18%

conversion of 1d) as the second fraction.

5.25 (s, 1 H, 4-H-a), 6.65, 6.93 (2ϫbs 1 H, NH), 7.65 (d, J_H,H

=

3

8.6 Hz, 2 H, 2-, 6-H, p-nph), 8.10, 8.38 (2ϫd, J_H,H= 8.4, 8.6 Hz,

2 H, 3-, 5-H, p-nph) ppm. QC NMR (75 MHz, CDCl₃, 25 °C) 3b-

anti: δ = 13.2, 13.4 [2 C, N(CH₂CH₃)₂], 41.8, 41.9 [2 C, N(CH₂C-

H₃)₂], 49.4 (1 C, C-5), 70.9 (1 C, C-6), 79.4 (1 C, C-4), 94.8 (1 C,

C-2), 123.8 (2 C, C-2, -6, p-nph), 126.9 (2 C, C-3, -5, p-nph), 145.5

(1 C, C-1, p-nph), 147.7 (1 C, C-4, p-nph), 164.1 (1 C, C-4, s-tri-

azine), 165.3 (1 C, C-6, s-triazine), 169.2 (1 C, C-2, s-triazine) ppm.

QC NMR (75 MHz, CDCl₃, 25 °C) 3b-syn: δ = 13.1, 13.6 [2 C,

N(CH₂CH₃)₂], 41.8 [2 C, N(CH₂CH₃)₂], 48.9 (1 C, C-5), 71.5 (1 C,

C-6), 79.9 (1 C, C-4), 94.8 (1 C, C-2), 123.7 (2 C, C-2, -6, p-nph),

127.0 (2 C, C-3, -5, p-nph), 145.4 (1 C, C-1, p-nph), 147.5 (1 C, C-

4, p-nph), 164.1 (1 C, C-4, s-triazine), 165.8 (1 C, C-6, s-triazine),

2-Chloro-4,6-bis{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-yl]amino}-

s-triazine (3a): Yield 61% (0.515 g, 0.92 mmol 3a, starting from

0.673 g, 3.00 mmol 1a) yellowish crystalline powder, R_f(60% lig-

roin/acetone) = 0.40; m.p. 153.2–155.0 °C (flash column

169.3 (1 C, C-2, s-triazine) ppm. IR (KBr): ν = 3321 (w), 2966 (s),

˜

1

chromatography; ligroin/acetone 1.5:1). [α]²_D⁰= –4.0 (0.5% thf). H

2933 (m), 2961 (w), 1579 (s), 1523 (s), 1439 (s), 1346 (s), 1319 (m),

1262 (s), 1174 (s), 1094 (s), 1024 (s), 851 (w), 802 (s), 710 (w), 690

(w), 585 (w) cm^–1. MS (EI): m/z (%) = 408 (Ͻ1) [M – 1]⁺, 227 (100),

212 (40), 198 (65), 184 (20). C₁₇H₂₁ClN₆O₄(408.84): calcd. C 49.93,

H 5.19, N 20.56; found C 50.11, H 4.95, N 20.22.

NMR (300 MHz, CDCl₃, 25 °C): δ = 3.90–4.22 (m, 4 H, 6-, 6Ј-H-

3

a, 6-, 6Ј-H-e), 4.06, 4.28, 4.42 (3ϫd, J_H,H= 8.3, 9.4, 9.8 Hz, 5-,

3

5Ј-H-e, 2 H,), 5.00 (d, J_H,H= 3.0 Hz, 2 H, 4-, 4Ј-H-a), 4.95, 5.00

(2ϫd, ²J_H,H= 6.4 Hz, 2 H, 2-, 2Ј-H-a), 5.25, 5.27, 5.28, 5.33 (4ϫd,

²J_H,H= 5.7, 6.0, 6.4, 6.4 Hz, 2 H, 2-, 2Ј-H-e), 5.75, 5.77, 5.95, 5.97

3

(4ϫd, J_H,H= 9.8, 9.4, 9.4, 9.4 Hz, 2 H, N-, NЈ-H), 7.43–7.48 (m,

2-Chloro-4,6-bis[{(2R,4S,5S)-{2-[(2,4-dichloro-s-triazin-6-yl)amino-

methyl]-4-(4-nitrophenyl)-1,3-dioxan-5-yl}(methyl)amino]-s-triazine

(3c): Yield 37 % (0.242 g, 0.257 mmol 3c, starting from 0.565 g,

4 H, 2-, 2Ј-, 6-, 6Ј-H, p-nph), 8.09–8.15 (m, 4 H, 3-, 3Ј-, 5-, 5Ј-H,

p-nph) ppm. ¹H NMR (400 MHz, [D₆]DMSO, 80 °C): δ = 4.19–

3.79 (br. m, 4 H, 6-, 6Ј-H-a, 6-, 6Ј-H-e), 4.25–4.46 (br. m, 2 H, 5-, 2.000 mmol 1d and 0.395 g, 2.100 mmol cyanuric chloride), yellow-

2

5Ј-H-e), 4.99 (d, J_H,H= 5.2 Hz, 2 H, 2-, 2Ј-H-a), 5.20 (d, J_H,H

=

ish crystalline powder, R_f(66% ligroin/acetone) = 0.75 (66% Ac-

OEt/ligroin) = 0.85; m.p. 111–112 °C (flash column chromatog-

5.2 Hz, 2 H, 2-, 2Ј-H-e), 5.21 (s, 2 H, 4-, 4Ј-H-a), 6.70, 7.06 (br. s

and d, J_H,H= 8.0 Hz, 2 H, N-, NЈ-H), 7.61–7.63 (br. m, 4 H, 2-, raphy; ligroin/acetone 2:1 or AcOEt/ligroin 2:1). [α]²_D⁰= –132.0

2Ј-, 6-, 6Ј-H, p-nph), 7.97–8.09 (br. m, 4 H, 3-, 3Ј-, 5-, 5Ј-H, p- (0.5% thf). ¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 3.22, 3.31

3

nph) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 49.2, 49.3, 49.4,

49.6 (2 C, C-5, -5Ј), 70.5, 70.6, 70.9, 71.1 (2 C, C-6, -6Ј), 79.1, 79.2,

(2 ϫ s, 6 H, 2 ϫ CH₃), 3.90, 3.97 (2 ϫ dd, J_H,H= 14.0, J_H,H=

2

3

2

6.4 Hz, 4 H, 2ϫCH₂NH), 4.34 (d, J_H,H= 12.8 Hz, 2 H, 6-, 6Ј-H-

2

3

79.4 (2 C, C-4, -4Ј), 94.8, 94.9, 95.7 (2 C, C-2, -2Ј), 123.7, 123.8 (4 a), 4.46 (dd, J_H,H= 12.8, J_H,H= 3.4 Hz, 2 H, 6-, 6Ј-H-e), 5.13,

3

C, C-2, -2Ј, -6, -6Ј, p-nph), 126.66, 126.71, 126.9 (4 C, C-3, -3Ј,

-5, -5Ј, p-nph), 142.9, 144.85, 144.94, 145.1 (2 C, C-1, -1Ј, p-nph),

147.85, 147.90 (2 C, C-4, -4Ј, p-nph), 165.2, 165.3, 165.4, 165.8 (2

5.20 (2ϫdd, J_H,H= 4.7, 4.0, 4.7, 4.0 Hz, 2 H, 2-, 2Ј-H-a), 5.30,

3

5.31, 5.707, 5.714 (4ϫd, J_H,H= 3.0, 2.6, 3.6, 3.6 Hz, 2 H, 5-, 5Ј-

3

H-e), 5.36 (d, J_H,H= 3.0 Hz, 2 H, 4-, 4Ј-H-a), 6.26 (dd, J_H,H

=

3

C, C-4, -6, s-triazine), 169.2, 169.4, 169.7 (1 C, C-2, s-triazine) ppm. 6.4, 6.4 Hz, 2 H, N-, NЈ-H), 7.45, 7.49, 7.67 (3ϫd, J_H,H= 8.7,

IR (KBr): ν = 3404 (m), 3315 (m), 2859 (m), 1573 (s), 1519 (s),

1347 (s), 1174 (s), 1105 (w), 1094 (s), 1026 (s), 987 (s), 956 (s), 902

8.7, 9.0 Hz, 4 H, 2-, 2Ј-, 6-, 6Ј-H, p-nph), 8.09, 8.16, 8.22 (3ϫd,

˜

³J_H,H= 8.7, 9.0, 9.0 Hz, 4 H, 3-, 3Ј-, 5-, 5Ј-H, p-nph) ppm. ¹³C

(m), 875 (m), 852 (s), 805 (s), 744 (m), 711 (m), 582 (w), 530 NMR (75 MHz, CDCl₃, 25 °C): δ = 30.7, 34.2, 37.4 (2 C, 2ϫCH₃),

(w) cm^–1. MS (EI): m/z (%) = 558.9 (100) [M]⁺, 540.9 (27), 528.8 44.1, 44.5 (2 C, 2ϫCH₂NH), 50.4 (2 C, C-5, -5Ј), 64.9, 66.2, 70.2

(20), 510.8 (12), 498.8 (7). C₂₃H₂₂ClN₇O₈(559.92): calcd. C 49.34, (2 C, C-6, -6Ј), 79.5 (2 C, C-4, -4Ј), 96.0, 99.5, 101.8, 103.5 (2 C,

H 3.96, N 17.51; found C 49.40, H 4.33, N 17.21.

C-2, -2Ј), 123.8, 124.1, 125.2, 125.9, 126.6 (8 C, CH, p-nph), 143.8

(2 C, C-1, -1Ј, p-nph), 147.9, 148.1, 149.3 (2 C, C-4, -4Ј, p-nph),

165.7 [2 C, 2ϫC-N(CH₃), s-triazine], 166.7 (2 C, 2ϫC-NH, s-tri-

azine), 169.8, 170.5, 170.6, 170.7, 171.6 (5 C, 5 ϫ C-Cl, s-tri-

2-Chloro-4-(diethylamino)-6-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-

5-yl]amino}-s-triazine (3b): Yield 80% (0.327 g, 0.80 mmol 3b start-

ing from 0.372 g, 1.00 mmol 2a, Scheme 6), yellowish crystalline

powder, R_f(66 % ligroin/acetone) = 0.75; m.p. 109–110 °C (flash

column chromatography; ligroin/acetone, 2:1). [α]²_D⁰= –6.25 (0.5%

thf). ¹H NMR (300 MHz, CDCl₃, 25 °C) 3b-anti: δ = 1.01–1.07 [m,

6 H, N(CH₂CH₃)₂], 3.31–3.46 [m, 4 H, N(CH₂CH₃)₂], 4.06 (dd,

azine) ppm. IR (KBr): ν = 3277 (m), 2966 (m), 1745 (m), 1692 (m),

˜

1565 (s), 1521 (s), 1479 (s), 1415 (m), 1349 (s), 1326 (m), 1239 (m),

1175 (m), 1149 (m), 1030 (m), 847 (m), 798 (m), 743 (w), 709 (w),

570 (w), 534 (w) cm^–1. MS (MALDI α-cyano-4-hydroxycinnamic

acid): m/z (%) = calcd. abundances: 948.1 (5), 947.1 (9), 946.1 (36),

945.1 (38), 944.1 (69), 943.1 (41), 942.1 (100), 941.1 (26), 940.1 (58);

found: 948.5 (35), 947.4 (35), 946.6 (50), 945.5 (50), 944.5 (75),

9 4 3 . 6 ( 6 0) , 9 4 2 . 5 ( 1 00 ) [ M ]⁺, 9 4 1 . 4 ( 5 0) , 9 4 0. 6 ( 70).

C₃₃H₃₀Cl₅N₁₅O₈(941.96): calcd. C 42.08, H 3.21, N 22.30; found

C 42.22, H 3.39, N 21.98.

3

2

²J_H,H= 11.7, J_H,H= 1.3 Hz, 6-H-a), 4.20 (d, J_H,H= 11.7 Hz, 1

3

2

H, 6-H-e), 4.42 (d, J_H,H= 9.8 Hz, 1 H, 5-H-e), 4.95 (d, J_H,H

=

2

6.1 Hz, 1 H, 2-H-a), 5.02 (s, 1 H, 4-H-a), 5.27 (d, J_H,H= 6.1 Hz,

3

1 H, 2-H-e), 6.00 (d, J_H,H= 9.8 Hz, 1 H, NH), 7.48 (d, J_H,H

=

3

8.8 Hz, 2 H, 2-, 6-H, p-nph), 8.10 (d, J_H,H= 8.8 Hz, 2 H, 3-, 5-

1

H, p-nph) ppm. H NMR (300 MHz, CDCl₃, 25 °C) 3b-syn (only

3

distinct peaks are listed): δ = 4.16 (d, J_H,H= 11.7 Hz, 1 H, 6-H-

2-Chloro-4,6-bis{[(2R,4S,5S)-5-(dimethylamino)-4-(4-nitrophenyl)-

1,3-dioxan-2-yl]methylamino}-s-triazine (3d): Yield 71 % (1.70 g,

2.52 mmol 3d, starting from 2.00 g, 7.10 mmol 1d), yellowish crys-

talline powder, R_f(66% acetone/ligroin) = 0.80; m.p. 126–127 °C

(flash column chromatography; acetone/ligroin (2:1) then crystalli-

zation from Et₂O). [α]²_D⁰= +189.4 (0.05% DMSO). ¹H NMR

(300 MHz, CDCl₃, 25 °C): δ = 2.24 [s, 12 H, 2ϫN(CH₃)₂], 2.66–

2.71 (m, 2 H, 5-, 5Ј-H-e), 3.58–3.81 (m, 4 H, 2ϫCH₂NH), 3.87–

3.98 (m, 2 H 6-, 6Ј-H-a), 4.51–4.59 (m, 2 H, 6-, 6Ј-H-e), 4.93 (s, 2

3

2

e), 4.53 (d, J_H,H= 9.9 Hz, 1 H, 5-H-e), 4.97 (d, J_H,H= 5.9 Hz, 1

2

3

H, 2-H-a), 5.29 (d, J_H,H= 5.9 Hz, 1 H, 2-H-e), 5.83 (d, J_H,H

=

3

9.9 Hz, 1 H, NH), 7.51 (d, J_H,H= 9.0 Hz, 2 H, 2-, 6-H, p-nph),

8.12 (d, J_H,H= 9.0 Hz, 2 H, 3-, 5-H, p-nph) ppm. ¹H NMR

3

(400 MHz, [D₆]DMSO, 80 °C): δ = 1.03 [t, J_H,H= 7.8 Hz, 6 H,

N(CH₂CH₃)₂], 3.41 [t, ³J_H,H= 7.8 Hz, 4 H, N(CH₂CH₃)₂], 4.05 (br.

2

3

d, J_H,H= 9.8 Hz, 1 H, 6-H-a), 4.14 (dd, J_H,H= 9.8, J_H,H

=

3

2.0 Hz, 1 H, 6-H-e), 4.44 (d, J_H,H= 9.6 Hz, 1 H, 5-H-e), 5.00 (d,

²J_H,H= 6.2 Hz, 1 H, 2-H-a), 5.23 (d, J_H,H= 6.2 Hz, 1 H, 2-H-e), H, 4-, 4Ј-H-a), 4.88–5.08 (m, 2 H, 2-, 2Ј-H-a), 5.62, 6.03, 6.21, 6.36

2

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Eur. J. Org. Chem. 2008, 2473–2494

Serinolic Amino-s-triazines: Synthesis and Stereochemistry

(4ϫdd as br. t, 2 H, N-, NЈ-H), 7.39–7.49 (m, 4 H, 2-, 2Ј-, 6-, 6Ј- (10 mL) solution with vigorous stirring into a dry toluene (50 mL)

H, p-nph), 8.12–8.20 (m, 4 H, 3-, 3Ј-, 5-, 5Ј-H, p-nph) ppm. ¹H

NMR (400 MHz, [D₆]DMSO, 80 °C): δ = 2.21 [s, 12 H, 2ϫN-

solution containing triethylamine (0.563 mL, 0.405 g, 4 mmol) and

(4S,5S)-5-amino-4-(4-nitrophenyl)-1,3-dioxane (1a) (0.897 g,

(CH₃)₂], 2.86 (s, 2 H, 5-, 5Ј-H-e), 3.53 (br. s, 4 H, 2ϫCH₂NH), 4 mmol), cooled to –15 °C. The reaction mixture was then allowed

3.95 (d, ²J_H,H= 11.4 Hz, 2 H, 6-, 6Ј-H-a), 4.43 (d, ²J_H,H= 11.4 Hz,

to reach room temperature (about 24 h) and was then heated at

2 H, 6-, 6Ј-H-e), 5.00 (br. s, 2 H, 2-, 2Ј-H-a), 5.18 (br. s, 2 H, 4-, 70 °C and finally at reflux for an additional 9 h until TLC monitor-

4Ј-H-a), 7.63 (d, ³J_H,H= 8.6 Hz, 4 H, 2-, 2Ј-, 6-, 6Ј-H, p-nph), 7.69 ing indicated no more change. The reaction mixture was cooled to

3

(br. s, 2 H, N-, NЈ-H), 8.14 (d, J_H,H= 8.6 Hz, 4 H, 3-, 3Ј-, 5-, 5Ј- room temperature and filtered, and solid residues were well washed

H, p-nph) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ = 44.1 [4 C,

with dry toluene. The organic filtrate was evaporated to dryness

2ϫN(CH₃)₂], 44.4 (2 C, CH₂NH), 59.5 (2 C, C-5, -5Ј), 65.4 (2 C, under reduced pressure, providing the crude reaction mixture,

C-6, -6Ј), 81.1 (2 C, C-4, -4Ј), 99.5, 99.6 (2 C, C-2, -2Ј), 123.6 (4 C, which was separated by flash column chromatography on silica gel

C-2, -2Ј, -6, -6Ј, p-nph), 126.5 (4 C, C-3, -3Ј, -5, -5Ј, p-nph), 147.25,

147.29 (2 C, C-4, -4Ј, p-nph), 161.1, 166.3, 166.7 (2 C, C-4, -6, s-

(eluent ligroin/acetone 2:1 v/v) as follows: first fraction 4b (0.214 g,

12% conversion of 1a) then 4c (0.477 g, 40% conversion of 1a) as a

triazine), 169.1 (1 C, C-2, s-triazine) ppm. IR (KBr): ν = 3432 (m), second fraction. Complete elution of the column with pure acetone

˜

3268 (m), 2939 (m), 2865 (m), 2789 (m), 1576 (s), 1519 (s), 1464 yielded recovered 1a (0.420 g, 90% recovery of the unreacted 1a).

(m), 1412 (m), 1348 (s), 1153 (m), 1113 (m), 1057 (m), 1013 (m),

2,4,6-Tris{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-yl]amino}-s-tri-

azine (4a): Yield 4 % (0.097 g, 0.13 mmol 4a starting 2.24 g,

10.00 mmol 1a) as a yellowish crystalline powder, R_f(63% ligroin/

852 (m), 806 (m), 709 (m), 587 (w) cm^–1. MS (EI): m/z (%) = 672.9

(100) [M – 1]⁺, 636.9 (Ͻ10), 483.8 (Ͻ10), 221.7 (100).

C₂₉H₃₆ClN₉O₈(674.11): calcd. C 51.67, H 5.38, N 18.70; found C

51.89, H 5.55, N 19.02.

acetone) = 0.45; m.p. 164.4–166.5 °C (flash column chromatog-

raphy; ligroin/acetone 1.7:1). [α]²_D⁰= +4.0 (0.5% thf). ¹H NMR

2-Chloro-4,6-bis{(2R,4S,5S)-2-[(2ЈR,4ЈS,5ЈS)-5Ј-(dimethylamino)- (300 MHz, CDCl₃, 25 °C): δ = 3.77–4.01 (m, 6 H, 6-, 6Ј-, 6ЈЈ-H-a,

3

4Ј-(4Ј-nitrophenyl)-1Ј,3Ј-dioxan-2Ј-yl]-4-(4-nitrophenyl)-1,3-dioxan-

5-ylamino}-s-triazine (3e): Yield 45% (0.360 g, 0.34 mmol 3e, start-

ing from 0.712 g, 1.50 mmol 1f), yellowish crystalline powder,

R_f(55 % ligroin/acetone) = 0.30; m.p. 210–212 °C (flash column

chromatography; ligroin/acetone 1.2:1 then crystallization from

Et₂O). [α]²_D⁰= +4.0 (0.5% thf). ¹H NMR (300 MHz, CDCl₃, 25 °C):

δ = 2.29, 2.30, 2.34 [3ϫs, 12 H, 2ϫN(CH₃)₂], 2.77, 2.81 (2ϫbr. s,

2 H, 2ϫ5Ј-H-e), 4.01–4.28 [br. m, 6 H, 2ϫ(6-H-a, -e), 2ϫ6Ј-H-

6-, 6Ј-, 6ЈЈ-H-e), 4.06, 4.14, 4.26 (s, s, d, J_H,H= 7.9 Hz, 3 H, 5-,

5Ј-, 5ЈЈ-H-e), 4.87–4.92 (m, 6 H, 2-, 2Ј-, 2ЈЈ-H-a, 4-, 4Ј-, 4ЈЈ-H-a),

5.12–5.22 (m, 3 H, 2-, 2Ј, 2ЈЈ-H-e), 5.36, 5.52, 5.62 (3ϫd, J_H,H

3

=

9.9, 9.2, 8.6 Hz, 3 H, N-, NЈ-, NЈЈ-H), 7.36–7.48 (m, 6 H, 2-, 2Ј-,

2ЈЈ-, 6-, 6Ј-, 6ЈЈ-H, p-nph), 7.93–8.08 (m, 6 H, 3-, 3Ј-, 3ЈЈ-, 5-, 5Ј-,

5ЈЈ-H, p-nph) ppm. ¹H NMR (400 MHz, [D₆]DMSO, 80 °C): 4a-

major δ = 3.80 (br. s, 3 H, 6-, 6Ј-, 6ЈЈ-H-a), 4.04 (dd, ²J_H,H= 11.0,

³J_H,H= 1.8 Hz, 3 H, 6-, 6Ј-, 6ЈЈ-H-e), 4.20 (br. s, 3 H, 5-, 5Ј-, 5ЈЈ-

H-e), 4.95 (d, J_H,H= 6.2 Hz, 3 H, 2-, 2Ј-, 2ЈЈ-H-a), 5.15 (s, 3 H,

4-, 4Ј-, 4ЈЈ-H-a), 5.18 (d, J_H,H= 6.2 Hz, 3 H, 3 H, 2-, 2Ј-, 2ЈЈ-H-

e), 5.46 (br. s, 3 H, N-, NЈ-, NЈЈ-H), 7.57 (d, J_H,H= 9.2 Hz, 6 H,

2-, 2Ј-, 2ЈЈ-, 6-, 6Ј-, 6ЈЈ-H, p-nph), 8.01 (d, J_H,H= 9.2 Hz, 6 H,

3

2

a], 4.12, 4.34, 4.49 [3ϫd, J_H,H= 10.8, 9.2, 8.8 Hz, 2 H, 2ϫ5-H-

2

e], 4.66, 4.71 (2ϫd, J_H,H= 13.6 Hz, 2 H, 2ϫ6Ј-H-e), 4.93–5.06

3

[br. m, 4 H, 2ϫ(2-, 2Ј-H-a)], 5.14 [br. m, 4 H, 2ϫ(4-, 4Ј-H-a)],

3

5.68, 5.71, 5.82, 5.97 (4ϫd, J_H,H= 8.8, 8.8, 9.2, 10.8 Hz, 2 H, N-

, NЈ-H), 7.43–7.58 [m, 8 H, 2ϫ(2-, 2Ј-, 6-, 6Ј-H, p-nph)], 8.03–

8.11, 8.18–8.23 [2ϫm, 8 H, 2ϫ(3-, 3Ј-, 5-, 5Ј-H, p-nph)] ppm. H

3-, 3Ј-, 3ЈЈ-, 5-, 5Ј-, 5ЈЈ-H, p-nph) ppm; 4a-minor (only distinct

1

2

peaks are listed): δ = 3.94 (d, J_H,H= 11.0 Hz, 3 H, 6-, 6Ј-, 6ЈЈ-H-

2

NMR (400 MHz, [D₆]DMSO, 80 °C): δ = 2.28 [s, 12 H, 2ϫN(CH₃) a), 4.20 (br. s, 6 H, 6-, 6Ј-, 6ЈЈ-H-e, 5-, 5Ј-, 5ЈЈ-H-e), 4.91 (d, J_H,H

2

3

₂], 2.94 (s, 2 H, 2ϫ5Ј-H-e), 3.92 (d, J_H,H= 12.4 Hz, 2 H, 2ϫ6-

= 6.2 Hz, 3 H, 2-, 2Ј-, 2ЈЈ-H-a), 7.59 (d, J_H,H= 6.8 Hz, 6 H, 2-,

2

3

H-a), 4.05 (d, J_H,H= 10.8 Hz, 2 H, 2ϫ6Ј-H-a), 4.21–4.27 (br. m,

2Ј-, 2ЈЈ-, 6-, 6Ј-, 6ЈЈ-H, p-nph), 8.20 (d, J_H,H= 6.8 Hz, 6 H, 3-,

2 H, 2ϫ6-H-e), 4.30–4.38 (br. m, 2 H, 2ϫ5-H-e), 4.54 (d, ³J_H,H

=

3Ј-, 3ЈЈ-, 5-, 5Ј-, 5ЈЈ-H, p-nph) ppm. ¹³C NMR (75 MHz, CDCl₃,

25 °C): δ = 48.5, 48.9, 49.2, 50.6 (3 C, C-5, -5Ј, -5ЈЈ), 69.9, 70.7,

71.1, 73.1 (3 C, C-6, -6Ј, -6ЈЈ), 79.3, 79.6, 80.5 (3 C, C-4, -4Ј, -4ЈЈ),

94.7 (3 C, C-2, -2Ј, -2ЈЈ), 123.4, 123.8, 124.1 (6 C, C-2, -2Ј, -2ЈЈ,

-6, -6Ј, -6ЈЈ, p-nph), 126.4, 126.8, 126.9, 127.1 (6 C, C-3, -3Ј, -3ЈЈ,

-5, -5Ј, -5ЈЈ, p-nph), 145.3, 145.7, 145.8, 146.0, 147.6 (6 C, C-1,

12.4 Hz, 2 H, 2ϫ6Ј-H-e), 5.07 [s, 4 H, 2ϫ(2-, 2Ј-H-a)], 5.38 (s, 2

H, 2ϫ4Ј-H-a), 5.41 (s, 2 H, 2ϫ4-H-a), 6.53, 6.87 (br. s and d,

³J_H,H= 8.4 Hz, 2 H, N-, NЈ-H), 7.62 [br. s, 4 H, 2ϫ(2-, 6-H, p-

3

nph)], 7.66 [d, J_H,H= 8.8 Hz, 4 H, 2ϫ(2Ј-, 6Ј-H, p-nph)], 8.11–

8.15 [br. d, 4 H, 2ϫ(3-, 5-H, p-nph)], 8.19 [d, ³J_H,H= 8.8 Hz ppm.

4 H, 2 ϫ (3Ј-, 5Ј-H, p-nph)] ppm. ¹³C NMR (75 MHz, CDCl₃, -1Ј, -1ЈЈ, -4, -4Ј, -4ЈЈ, p-nph), 165.2, 165.3 (3 C, C-2, -4, -6, s-tri-

25 °C): δ = 42.7 [4 C, 2ϫN(CH₃)₂], 47.1, 47.2, 47.5 (2 C, 2ϫC-5),

56.5, 58.2 (2 C, 2ϫC-5Ј), 64.3 (2 C, 2ϫC-6Ј), 68.5, 69.3, 69.8 (2

C, 2 ϫC-6), 77.4, 77.7, 77.9 (2 C, 2ϫC-4Ј), 79.8, 80.5 (2 C, 2ϫC-

4), 98.5 (2 C, 2ϫC-2Ј), 99.1 (2 C, 2ϫC-2), 122.25, 122.34 [8 C,

2 ϫ (C-2, -2Ј, -6, -6Ј, p-nph)], 125.3, 125.5 [8 C, 2 ϫ (C-3, -3Ј,

-5, -5Ј, p-nph)], 143.1, 143.3, 143.4 [4 C, 2 ϫ(C-1, -1Ј, p-nph)],

145.7, 145.8, 145.9, 146.4, 146.5 [4 C, 2ϫ(C-4, -4Ј, p-nph)], 163.9,

164.0, 164.3 (2 C, C-4, -6, s-triazine), 167.9, 168.1, 168.4 (1 C, C-

azine) ppm. IR (KBr): ν = 3422 (w), 2856 (w), 1719 (w), 1578 (s),

˜

1518 (s), 1347 (s), 1174 (s), 1094 (m), 1028 (s), 986 (m), 852 (w),

811 (w), 742 (w), 711 (w), 582 (w) cm^–1. MS (FAB+, 3-nitrobenzyl

alcohol): m/z (%) = 748.9 (100) [M + 1]⁺, 613.1 (15), 541.2 (20),

481.1 (15), 460.0 (47), 415.2 (18), 378.1 (33), 351.0 (27).

C₃₃H₃₃N₉O₁₂(747.68): calcd. C 53.01, H 4.45, N 16.86; found C

52.75, H 4.33, N 17.05.

2,4-(Diethylamino)-6-{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-yl]-

amino}-s-triazine (4b): Yield 12%, (0.214 g, 0.48 mmol 4b starting

from 0.897 g, 4.00 mmol 1a) yellowish crystalline powder, R_f(66%

ligroin/acetone) = 0.85; m.p. 75–76 °C (flash column chromatog-

raphy; ligroin/acetone, 2:1). [α]²_D⁰= +6.7 (0.5% thf). ¹H NMR

2, s-triazine) ppm. IR (KBr): ν = 3419 (m), 2971 (m), 2867 (m),

˜

1700 (w), 1605 (s), 1575 (s), 1520 (s), 1415 (w), 1348 (s), 1150 (m),

1110 (s), 1063 (m), 1014 (m), 852 (m), 713 (m), 585 (w) cm^–1. MS

(FAB+, 3-nitrobenzyl alcohol): m/z (%) = 1060.9 (100) [M]⁺, 1015.4

(18), 965.5 (17), 857.9 (19), 838.1 (30), 780.3 (22), 717.8 (23).

C₄₇H₅₀ClN₁₁O₁₆(1060.43): calcd. C 53.23, H 4.75, N 14.53; found

C 52.95, H 4.44, N 14.79.

3

(300 MHz, CDCl₃, 25 °C): δ = 1.06 [t, J_H,H= 6.9 Hz, 12 H,

3

2ϫN(CH₂CH₃)₂], 3.42 [q, J_H,H= 6.9 Hz, 8 H, 2ϫN(CH₂CH₃)₂],

2

3

2

4.04 (dd, J_H,H= 11.3, J_H,H= 1.4 Hz, 1 H, 6-H-a), 4.19 (d, J_H,H

3

Typical Procedure for the Synthesis of Compounds 4a–d (Schemes 5,

6, and 7). Preparation of Compound 4c (Table 1, Entry 7): Cyanuric

chloride (0.247 g, 1.333 mmol) was introduced as a dry toluene

= 11.3 Hz, 1 H, 6-H-e), 4.58 (dd, J_H,H= 10.0, 1.4 Hz, 1 H, 5-H-

e), 4.97 (d, J_H,H= 6.2 Hz, 1 H, 2-H-a), 4.99 (s, 1 H, 4-H-a), 5.28

(d, J_H,H= 6.2 Hz, 1 H, H-2-e), 5.37 (d, J_H,H= 10.0 Hz, 1 H,

2

3

Eur. J. Org. Chem. 2008, 2473–2494

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2491

M. Darabantu et al.

FULL PAPER

NH), 7.53 (d, J_H,H= 8.7 Hz, 2 H, 2-, 6-H, p-nph), 8.10 (d, J_H,H

3

(400 MHz, [D₆]DMSO, 80 °C): δ = 2.21 [s, 18 H, 3ϫN(CH₃)₂],

3

= 8.7 Hz, 2 H, 3-, 5-H, p-nph) ppm. ¹³C NMR (75 MHz, CDCl₃, 2.83 (dd, J_H,H= 3.0, 3.0 Hz, 3 H, 5-, 5Ј, 5ЈЈ-H-e), 3.50 (dd, J_H,H

2

3

25 °C): δ = 13.8 [4 C, 2ϫN(CH₂CH₃)₂], 41.2 [4 C, 2ϫN(CH₂-

CH₃)₂], 48.6 (1 C, C-5), 71.8 (1 C, C-6), 80.0 (1 C, C-4), 94.8 (1 C,

= 5.0, 5.0 Hz, 6 H, 3ϫCH₂NH), 3.92 (dd, J_H,H= 12.4, J_H,H=

3.2 Hz, 3 H, 6-, 6Ј-, 6ЈЈ-H-a), 4.43 (dd, ²J_H,H= 12.4, ³J_H,H= 5.2 Hz,

3

C-2), 123.5 (2 C, C-2, -6, p-nph), 127.1 (2 C, C-3, -5, p-nph), 146.3 3 H, 6-, 6Ј-, 6ЈЈ-H-e), 5.00 (dd, J_H,H= 5.0, 5.0 Hz, 3 H, 2-, 2Ј-,

2ЈЈ-H-a), 5.15 (d, J = 3.6 Hz, 3 H, 4-, 4Ј-, 4ЈЈ-H-a), 6.33 (br. s, 3

-4, s-triazine), 166.1 (1 C, C-6, s-triazine) ppm. IR (KBr): ν = 3330 H, N-, NЈ-, NЈЈ-H), 7.62 (d, J_H,H= 8.8 Hz, 6 H, 2-, 2Ј-, 2ЈЈ-, 6-,

3

(1 C, C-1, p-nph), 147.5 (1 C, C-4, p-nph), 164.5, 164.8 (2 C, C-2,

3

˜

3

(w), 2966 (m), 2930 (m), 2855 (m), 1604 (m), 1567 (s), 1530 (s), 6Ј-, 6ЈЈ-H, p-nph), 8.13 (d, J_H,H= 8.8 Hz, 6 H, 3-, 3Ј-, 3ЈЈ-, 5-,

1502 (s), 1458 (s), 1431 (s), 1374 (s), 1309 (m), 1238 (w), 1176 (s),

1102 (s), 1074 (m), 1027 (m), 989 (m), 852 (m), 812 (s), 747 (w), 44.1 [6 C, 3ϫN(CH₃)₂], 44.3 (3 C, 3ϫCH₂NH), 59.6 (3 C, C-5, -5Ј,

589 (w) cm^–1. MS (CI, isobutane): m/z (%) = 446 (100) [M]⁺, 430

-5ЈЈ), 65.3 (3 C, C-6, -6Ј, -6ЈЈ), 90.5 (3 C, C-4, -4Ј, -4ЈЈ), 100.3 (3 C,

(Ͻ5). C₂₁H₃₁N₇O₄(445.52): calcd. C 56.61, H 7.01, N 22.01; found C-2, -2Ј, -2ЈЈ), 123.6 (6 C, C-2, -2Ј, -2ЈЈ, -6, -6Ј, -6ЈЈ, p-nph), 126.6

5Ј-, 5ЈЈ-H, p-nph) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ =

C 56.88, H 6.79, N 22.25.

(6 C, C-3, -3Ј, -3ЈЈ, -5, -5Ј, -5ЈЈ, p-nph), 147.2 (3 C, C-1, -1Ј, -1ЈЈ,

p-nph), 147.6 (3 C, C-3, -3Ј, -3ЈЈ, -5, -5Ј, -5ЈЈ, p-nph), 166.7 (3 C,

2-(Diethylamino)-4,6-bis{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-

yl]amino}-s-triazine (4c): Yield 40% (0.477 g, 0.80 mmol 4c starting

from 0.897, 4.00 mmol 1a), yellow crystalline powder, R_f(66% lig-

roin/acetone) = 0.45; m.p. 115.3–117.5 °C (flash column

chromatography; ligroin/acetone, 2:1). [α]²_D⁰= +9.9 (0.15% MeOH).

C-2, -4, -6, s-triazine) ppm. IR (KBr): ν = 3400 (m), 2938 (m), 2863

˜

(m), 1602 (s), 1575 (s), 1517 (s), 1464 (m), 1412 (m), 1348 (s), 1152

(m), 1111 (m), 1043 (m), 1013 (m), 852 (m), 753 (w), 709 (m), 586

(w) cm^–1. MS (FAB+, 3-nitrobenzyl alcohol): m/z (%) = 918.0 (100)

[M – 1]⁺, 832.0 (19), 797.1 (15), 766.3 (20), 739.2 (19), 697.0 (65),

588.7 (30), 530.2 (22), 474.4 (47), 413.1 (25). C₄₂H₅₄N₁₂O₁₂

(918.96): calcd. C 54.89, H 5.92, N 18.29; found C 54.77, H 6.15,

N 17.98.

¹H NMR (300 MHz, CDCl₃, 25 °C) 4c (s-s): δ = δ = 0.95 [t, J_H,H

3

= 6.8 Hz, 6 H, N(CH₂CH₃)₂], 3.28 [q, J_H,H= 6.8 Hz, 4 H, 4 H,

2

N(CH₂CH₃)₂], 3.98 (d, J_H,H= 10.9 Hz, 2 H, 6-, 6Ј-H-a), 4.09 (d,

²J_H,H= 10.9 Hz, 2 H, 6-, 6Ј-H-e), 4.38 (d, J_H,H= 9.5 Hz, 2 H,

3

2

5-, 5Ј-H-e), 4.91 (d, J_H,H= 6.0 Hz, 2 H, 2-, 2Ј-H-a), 4.95 (s, 2 H,

Typical Procedure for the Synthesis of Compounds 5a–c (Scheme 10).

Preparation of Compound 5c: Anhydrous potassium carbonate

(0.069 g, 0.500 mmol) was added with vigorous stirring to a dry

1,4-dioxane (25 mL) solution containing 3e (0.530 g, 0.500 mmol)

and anhydrous piperazine (0.021 g, 0.245 mmol). The reaction mix-

ture was heated at reflux until TLC monitoring indicated no more

change (about 56 h). The reaction mixture was cooled to room tem-

perature and filtered, and solid residues were well washed with dry

1,4-dioxane. The organic filtrate was evaporated to dryness under

reduced pressure, providing the crude reaction mixture, which was

purified by flash column chromatography on silica gel (eluent ace-

tone/ligroin, 5:1, v/v) to give 5c (0.300 g, 56% yield).

4-, 4Ј-H-a), 5.22 (d, ²J_H,H= 6.0 Hz, 2 H, 2-, 2Ј-H-e), 5.31 (d, ³J_H,H

3

= 9.5 Hz, 2 H, N-, NЈ-H), 7.45 (d, J_H,H= 8.3 Hz, 4 H, 2-, 2Ј-,

3

6-, 6Ј-H, p-nph), 8.06 (d, J_H,H= 8.3 Hz, 4 H, 3-, 3Ј-, 5-, 5Ј-H, p-

nph) ppm. 4c (a-s) (only distinct signals are listed): δ = 3.87 (dd,

3

2

²J_H,H= 11.5, J_H,H= 1.3 Hz, 2 H, 6-, 6Ј-H-a), 4.24 (d, J_H,H

=

2

11.7 Hz, 1 H, 6-H-e), 4.26 (d, J_H,H= 9.2 Hz, 1 H, 6Ј-H-e), 7.45,

3

7.47 (2ϫd, J_H,H= 7.4 Hz, 4 H, 2-, 2Ј- 6-, 6Ј-H, p-nph), 7.95 (br.

3

s, 2 H, 3-, 5-H, p-nph), 8.18 (d, J_H,H= 8.7 Hz, 2 H, 3Ј-, 5Ј-H, p-

nph) ppm. ¹H NMR (400 MHz, [D₆]DMSO, 80 °C): δ = 0.93 [t,

³J_H,H= 6.8 Hz, 6 H, N(CH₂CH₃)₂], 3.27, 3.33 [2ϫdq, J_H,H

=

2

14.5, ³J_H,H= 6.8 Hz, 4 H, N(CH₂CH₃)₂], 3.93 (d, ²J_H,H= 11.4 Hz,

2

2 H, 6-, 6Ј-H-a), 4.08 (d, J_H,H= 11.4 Hz, 2 H, 6-, 6Ј-H-e), 4.35

3

2

(d, J_H,H= 9.0 Hz, 2 H, 5-, 5Ј-H-e), 4.98 (d, J_H,H= 6.2 Hz, 2 H,

1,4-Bis[4,6-bis{[(4S,5S)-4-(4-nitrophenyl)-1,3-dioxan-5-yl]amino}-s-

triazin-2-yl]piperazine (5a): Yield 80% (0.226 g, 0.20 mmol 5a start-

ing from 0.280 g, 0.50 mmol 3a), yellowish crystalline powder,

R_f(55 % ligroin/acetone) = 0.40; m.p. 222–225 °C (flash column

chromatography; ligroin/acetone 1.25:1). [α]²_D⁰= +3.3 (0.5% thf).

¹H NMR (300 MHz, CDCl₃, 25 °C): δ = 3.35 (br. s, 8 H, pipera-

zine), 4.00–4.33 [br. m, 8 H, 2ϫ(6-, 6Ј-H-a, -e)], 4.93 [br. s, 8 H,

2ϫ(2-, 2Ј-H-a, 4-, 4Ј-H-a)], 5.22 [br. s, 4 H, 2ϫ(2-, 2Ј-H-e)], 5.42

[br. s, 4 H, 2ϫ(N-, NЈ-H)], 7.42 [br. s, 8 H, 2ϫ(2-, 2Ј-, 6-, 6Ј-H,

p-nph)], 7.93–8.03 [br. m, 8 H, 2ϫ(3-, 3Ј-, 5-, 5Ј-H, p-nph)] ppm.

¹H NMR (400 MHz, [D₆]DMSO, 80 °C): δ = 3.36 (s, 8 H, pipera-

2

2-, 2Ј-H-a), 5.19 (s, 2 H, 4-, 4Ј-H-a), 5.21 (d, J_H,H= 6.2 Hz, 2 H,

2-, 2Ј-H-e), 5.42 (d, ³J_H,H= 9.0 Hz, 2 H, N-, NЈ-H), 7.59 (d, J_H,H

3

= 8.8 Hz, 4 H, 2-, 2Ј-, 6-, 6Ј-H, p-nph), 8.04 (d, ³J_H,H= 8.8 Hz, 4 H,

3-, 3Ј-, 5-, 5Ј-H, p-nph) ppm. ¹³C NMR (75 MHz, CDCl₃, 25 °C): δ

= 13.5 [2 C, N(CH₂CH₃)₂], 41.0 [2 C, N(CH₂CH₃)₂], 48.7 (2 C, C-

5, -5Ј), 71.4 (2 C, C-6, -6Ј), 79.1, 80.8 (2 C, C-4, -4Ј), 94.7 (2 C, C-

2, -2Ј), 123.5 (4 C, C-2, -2Ј, -6, -6Ј, p-nph), 127.0 (4 C, C-3, -3Ј,

-5, -5Ј, p-nph), 146.1 (2 C, C-1, -1Ј, p-nph), 147.5 (2 C, C-4, -4Ј, p-

nph), 164.0 (1 C, C-2, s-triazine), 165.4 (2 C, C-4, -6, s-tri-

azine) ppm. IR (KBr): ν = 3431 (w), 2973 (w), 2859 (w), 1582 (s),

˜

1545 (s), 1502 (s), 1346 (s), 1174 (s), 1106 (m), 1027 (s), 986 (w),

852 (w), 811 (w), 742 (w), 586 (w) cm^–1. MS (EI): m/z (%) = 596.2

(100) [M]⁺, 580 (Ͻ 5), 388.9 (Ͻ 1). C₂₇H₃₂N₈O₈(596.60): calcd. C

54.36, H 5.41, N 18.78; found C 53.99, H 5.33, N 19.05.

2

zine), 3.94 [br. d, J_H,H= 7.6 Hz, 4 H, 2ϫ(6-, 6Ј-H-a)], 4.10 [d,

3

²J_H,H= 10.4 Hz, 4 H, 2ϫ(6-, 6Ј-H-e)], 4.37 [d, J_H,H= 7.6 Hz, 4

2

H, 2ϫ(5-, 5Ј-H-e)], 4.99 [d, J_H,H= 6.0 Hz, 4 H, 2ϫ(2-, 2Ј-H-a)],

2

5.20 [s, 4 H, 2 ϫ (4-, 4Ј-H-a)], 5.22 [d, J_H,H= 6.0 Hz, 4 H,

2,4,6-Tris{[(2R,4S,5S)-5-(dimethylamino)-4-(4-nitrophenyl)-1,3-di-

oxan-2-yl]methylamino}-s-triazine (4d): Yield 36 % (0.165 g,

0.18 mmol 4d starting from 0.422 g, 1.50 mmol 1d) yellowish crys-

talline powder, m.p. 148–150 °C (flash column chromatography;

acetone/ligroin, 2:1, then crystallization from Et₂O). R_f(66% ace-

tone/ligroin) = 0.25. [α]²_D⁰= +49.0 (0.5% DMSO). ¹H NMR

(300 MHz, CDCl₃, 25 °C): δ = 2.23 [s, 18 H, 3ϫN(CH₃)₂], 2.65 (s,

2ϫ(2-, 2Ј-H-e)], 5.58 [d, ³J_H,H= 7.6 Hz, 4 H, 2ϫ(N-, NЈ-H)], 7.59

3

[d, J_H,H= 7.6 Hz, 8 H, 2ϫ(2-, 2Ј-, 6-, 6Ј-H, p-nph)], 8.06 [br. s, 8

H, 2ϫ(3-, 3Ј-, 5-, 5Ј-H, p-nph)] ppm. ¹³C NMR (75 MHz, CDCl₃,

25 °C): δ = 42.8 (4 C, piperazine), 49.0 [4 C, (2ϫC-5, -5Ј)], 71.4 [4

C, (2 ϫC-6, -6Ј)], 79.5, 79.8 [4 C, (2ϫC-4, -4Ј)], 94.7 [4 C, 2ϫ(C-

2, -2Ј)], 123.4 [8 C, 2ϫ(C-2, -2Ј, -6, -6Ј, p-nph)], 127.0 [8 C, 2ϫ(C-

3, -3Ј, -5, -5Ј, p-nph)], 146.0 [4 C, 2ϫ(C-1, -1Ј, p-nph)], 147.6 [4 C,

2ϫ(C-4, -4Ј, p-nph)], 165.5, 165.7 (6 C, C-2, -2Ј, -4, -4Ј, -6, -6Ј, s-

2

3 H, 5-, 5Ј-, 5ЈЈ-H-e), 3.64 (br. s, 6 H, 3ϫCH₂NH), 3.88 (d, J_H,H

= 11.7 Hz, 3 H, 6-, 6Ј-, 6ЈЈ-H-a), 4.53 (d, J_H,H= 11.7 Hz, 3 H,

2

triazine) ppm. IR (KBr): ν = 3414 (w), 2855 (w), 1577 (s), 1520 (s),

˜

6-, 6Ј-, 6ЈЈ-H-e), 4.91 (s, 3 H, 2-, 2Ј-, 2ЈЈ-H-a), 4.99 (s, 3 H, 4-, 4Ј-,

1492 (s), 1442 (s), 1346 (s), 1174 (s), 1095 (m), 1027 (m), 985 (m),

852 (w), 810 (m), 743 (w), 711 (w), 586 (w) cm^–1. MS (FAB+, 3-

nitrobenzylalcohol): m/z (%) = 1132.3 (95) [M+ 1]⁺, 951.9 (20),

723.0 (20), 662.7 (33), 612.4 (25), 550.5 (33), 459.4 (100).

4ЈЈ-H-a), 5.27, 5.84 (2ϫbrs, 3 H, N-, NЈ-, NЈЈ-H), 7.44 (d, ³J =

3

7.0 Hz, 6 H, 2-, 2Ј-, 2ЈЈ-, 6-, 6Ј-, 6ЈЈ-H, p-nph), 8.14 (d, J_H,H

=

7.0 Hz, 6 H, 3-, 3Ј-, 3ЈЈ-, 5-, 5Ј-, 5ЈЈ-H, p-nph) ppm. ¹H NMR

2492

www.eurjoc.org

Eur. J. Org. Chem. 2008, 2473–2494

Serinolic Amino-s-triazines: Synthesis and Stereochemistry

C₅₀H₅₂N₁₆O₁₆(1133.06): calcd. C 53.00, H 4.63, N 19.78; found C

53.33, H 4.81, N 19.96.

5Ј-H, p-nph)] ppm. ¹³QC NMR (75 MHz, CDCl₃, 25 °C): δ = 41.5

(4 C, piperazine), 42.7 [8 C, 4ϫN(CH₃)₂], 46.8 (4 C, 4ϫC-5), 58.2

(4 C, 4ϫC-5Ј), 64.3 (4 C, 4ϫC-6Ј), 69.6, 70.3 (4 C, 4ϫC-6), 77.6,

78.2 (4 C, 4ϫC-4Ј), 79.4, 79.7 (4 C, 4ϫC-4), 98.0 (4 C, 4ϫC-2Ј),

98.8, 99.0 (4 C, 4ϫC-2), 121.9, 122.2 [16 C, 4ϫ(C-2, -2Ј, -6, -6Ј,

p-nph)], 125.3, 125.8 [16 C, 4ϫ(C-3, -3Ј, -5, -5Ј, p-nph)], 144.1,

144.7, 145.9, 146.3 [16 C, 4ϫ(C-1, -1Ј, -4, -4Ј, p-nph)], 163.0, 163.7,

164.1, 164.3 (6 C, C-2, -2Ј, -4, -4Ј, -6, -6Ј, s-triazine) ppm. IR (KBr):

1,4-Bis[4,6-bis{[(2R,4S,5S)-5-(dimethylamino)-4-(4-nitrophenyl)-1,3-

dioxan-2-yl]methylamino}-s-triazin-2-yl]piperazine (5b): Yield 71 %

(0.721 g, 0.53 mmol 5b starting from 1.000 g, 1.48 mmol 3d), yel-

lowish crystalline powder, R_f(100% acetone) = 0.55; m.p. 198–

199 °C (flash column chromatography; acetone then crystallization

from Et₂O). [α]²_D⁰= +222.7 (0.30% DMSO). H NMR (300 MHz,

1

ν = 3428 (m), 2926 (m), 2859 (m), 1607 (s), 1578 (s), 1522 (s), 1492

˜

CDCl₃, 25 °C): δ = 2.27 [s, 24 H, 4ϫN(CH₃)₂], 2.68 [br. s, 4 H,

2 ϫ (5-, 5Ј-H-e)], 3.66–3.73 (br. s, 8 H, piperazine, 8 H,

(s), 1441 (s), 1348 (s), 1148 (m), 1109 (s), 1064 (s), 1012 (s), 851

(m), 810 (m), 712 (m), 583 (w) cm^–1. MS (MALDI+, α-cyano-4-

hydroxycinnamic acid): m/z (%) = 2135.3 (38) [M + 1]⁺, 1894.2

(19), 877.3 (15), 453.4 (42), 212.1 (100). C₉₈H₁₀₈N₂₄O₃₂(2134.07):

calcd. C 55.16, H 5.10, N 15.75; found C 55.33, H 4.88, N 16.05.

2

4ϫCH₂NH), 3.92 [br. d, J_H,H= 11.9 Hz, 4 H, 2ϫ(6-, 6Ј-H-a)],

2

4.56 [d, J_H,H= 11.9 Hz, 4 H, 2ϫ(6-, 6Ј-H-e)], 4.92 [br. s, 4 H,

2ϫ(2-, 2Ј-H-a)], 5.01 [br. s, 4 H, 2ϫ(4-, 4Ј-H-a)], 5.29, 5.79 [br. s,

3

4 H, 2ϫ(N-, NЈ-H)], 7.48 [d, J_H,H= 8.5 Hz, 8 H, 2ϫ(2-, 2Ј-, 6-,

3

6Ј-H, p-nph)], 8.18 [d, J_H,H= 8.5 Hz, 8 H, 2ϫ(3-, 3Ј-, 5-, 5Ј-H,

Supporting Information (see also the footnote on the first page of

this article): Table S1 listing relevant NMR spectroscopic data of

N-substituted amino-s-triazines containing a single 1,3-dioxane

motif by axial anchorage describing the (pro)diastereomerism of

compounds 2a–c, 3b and 4b. Table S2 listing relevant NMR-spec-

troscopic data of N-substituted amino-s-triazines containing a sin-

gle 1,3-dioxane motif by equatorial anchorage describing the (pro)

diastereomerism of compounds 2c, 2f and 3c. Figure S1 illustrating

the dependence on solvent of rotameric distribution of compound

1

p-nph)] ppm. H NMR (400 MHz, [D₆]DMSO, 80 °C): δ = 2.21 [s,

3

24 H, 4ϫN(CH₃)₂], 2.85 [dd, J_H,H= 2.8, 2.8 Hz, 4 H, 2ϫ(5-, 5Ј-

3

H-e)], 3.52 (dd, J_H,H= 5.1, 5.1 Hz, 8 H, 4ϫCH₂NH), 3.67 (br. s,

2

3

8 H, piperazine), 3.94 [dd, J_H,H= 12.4, J_H,H= 2.8 Hz, 4 H,

2

2ϫ(6-, 6Ј-H-a)], 4.43 [d, J_H,H= 12.4 Hz, 4 H, 2ϫ(6-, 6Ј-H-e)],

4.99 [dd, J_H,H= 5.1, 5.1 Hz, 4 H, 2ϫ(2-, 2Ј-H-a)], 5.16 [d, J_H,H

= 3.2 Hz, 4 H, 2ϫ(4-, 4Ј-H-a)], 6.37 [br. s, 4 H, 2ϫ(N-, NЈ-H)],

3

7.62 [d, J_H,H= 8.8 Hz, 8 H, 2ϫ(2-, 2Ј-, 6-, 6Ј-H, p-nph)], 8.14 [d,

³J_H,H= 8.8 Hz, 8 H, 2ϫ(3-, 3Ј-, 5-, 5Ј-H, p-nph)] ppm. ¹³QC NMR

(75 MHz, CDCl₃, 25 °C): δ = 43.4 (4 C, piperazine), 44.1 [8 C,

4ϫN(CH₃)₂], 44.4 (4 C, 4ϫCH₂NH), 59.6 [4 C, 2ϫ(C-5, -5Ј)],

63.4 [4 C, 2 ϫ (C-6, -6Ј)], 81.1 [4 C, 2 ϫ (C-4, -4Ј)], 100.3 [4 C,

2ϫ(C-2, -2Ј)], 123.6 [8 C, 2ϫ(C-2, -2Ј, -6, -6Ј, p-nph)], 126.6 [8 C,

2 ϫ(C-3, -3Ј, -5, -5Ј, p-nph)], 147.3 [4 C, 2 ϫ(C-1, -1Ј, p-nph)],

147.6 [4 C, 2 ϫ (C-4, -4Ј, p-nph)], 165.4 (2 C, C-2, -2Ј, s-tri-

3a. Figure S2 showing the 2D H–¹H-NOESY chart of compound

1

4c as major (s-s) rotamer. Figure S3 describing the ¹H DNMR

evolution of compounds 3a, 3d and 4c. Table S3 listing the ¹H

DNMR data used for calculation of ∆G^϶rotational barriers in the

asymmetric rotamer of melamine 4d.

Acknowledgments

azine),166.6 (4 C, C-4, -4Ј, -6, -6Ј, s-triazine) ppm. IR (KBr): ν =

˜

3434 (m), 2935 (m), 2858 (m), 2787 (m), 1552 (s), 1519 (s), 1441

(s), 1412 (m), 1348 (s), 1279 (m), 1151 (s), 1110 (m), 1054 (s), 1003

(s), 851 (m), 810 (m), 709 (m), 570 (w) cm^–1. MS (MALDI+, α-

cyano-4-hydroxycinnamic acid): m/z (%) = 1361.8 (100) [M]⁺,

1208.7 (50), 1192.7 (20), 1163.6 (17), 1139.7 (40), 986.6 (25), 956.5

(Ͻ10), 917.6 (15), 901.6 (18), 885.7 (12), 837.4 (10). C₆₂H₈₀N₂₀O₁₆

(1361.44): calcd. C 54.70, H 5.92, N 20.58; found C 55.02, H 5.88,

N 20.55.

We wish to thank Dr. Oliver B. Locos for reading the manuscript

and suggesting improvements. Financial supports from the Roma-

nian National Council for Scientific Research (Grants No. 353 and

1482) and the French Agence Universitaire de la Francophonie

(Grant 6313PS571) are gratefully acknowledged.

[1] Methodology restricted, so far, to C-1-(p-nitrophenyl)-substi-

tuted serinols, see: a) M. Darabantu, S. Mager, C. Puscas, M.

Bogdan, E. Cotora, G. Plé, I. Bratu, Rev. Rom. Chim. 1994,

39, 955–965; b) M. Darabantu, S. Mager, C. Puscas, M. Bog-

dan, G. Plé, E. Cotora, D. Kovacs, Rev. Rom. Chim. 1995, 40,

453–461; c) M. Darabantu, S. Mager, C. Puscas, G. Plé, M.

Bogdan, E. Cotora, Rev. Rom. Chim. 1995, 40, 907–915; d) M.

Darabantu, C. Maiereanu, G. Plé, C. Berghian, E. Condamine,

Y. Ramondenc, Heterocycl. Commun. 2001, 7, 593–596; e) M.

Darabantu, G. Plé, S. Mager, C. Puscas, E. Cotora, Tetrahedron

1997, 53, 1909–1922; f) M. Darabantu, G. Plé, S. Mager, L.

Gaina, E. Cotora, A. Mates, L. Costas, Tetrahedron 1997, 53,

1891–1908.

1,4-Bis[4,6-bis{[(2R,4R,5S)-2-[(2ЈR,4ЈS,5ЈS)-5Ј-(dimethylamino)-4Ј-

(4Ј-nitrophenyl)-1Ј,3Ј-dioxan-2Ј-yl]-4-(4-nitrophenyl)-1,3-dioxan-5-

yl]amino}-s-triazin-2-yl]piperazine (5c): Yield 56 %, (0.300 g,

0.14 mmol 5c starting from 0.530 g, 0.50 mmol 3e) yellowish crys-

talline powder, m.p. 234–236 °C (flash column chromatography;

acetone/ligroin 5:1 then crystallization from Et₂O). R_f(83% ace-

1

tone/ligroin) = 0.55. [α]²_D⁰= +8.8 (0.5% thf). H NMR (300 MHz,

CDCl₃, 25 °C): δ = 2.32, 2.36 [2ϫs, 24 H, 4ϫN(CH₃)₂], 2.79 (br.

s, 4 H, 4 ϫ5Ј-H-e), 3.46–3.56 (br. m, 8 H, piperazine), 4.07 (d, ³J_H,H

= 13.3 Hz, 4 H, 4ϫ6Ј-H-a), 4.22 (br. s, 4 H, 4ϫ5-H-e), 4.05–4.48

2

[br. m, 8 H, 4ϫ(6-H-a, -e)], 4.68 (d, J_H,H= 13.3 Hz, 4 H, 2ϫ6Ј-

[2] a) M. Darabantu, S. Mager, G. Plé, C. Puscas, Heterocycles

1995, 41, 2327–2356 and literature cited therein referring to the

synthesis of IIc under strong dehydrating conditions; for other

developments in the use of amino-1,3-dioxanes based on l-

phenylserinol see: b) K. Weinges, K. P. Klotz, H. Droste, Chem.

Ber. 1980, 113, 710–721; c) D. Enders, J. Schankat, Helv. Chim.

Acta 1995, 78, 970–992; d) M. D. Rozwadowska, Tetrahedron

1997, 53, 10615–10622; e) In these “classical” procedures and

essentially depending on the carbonyl electrophile, l-(p-ni-

trophenyl)serinol (Ia, Scheme 1) affords Schiff bases, 1,3-ox-

H-e), 5.02–5.08 [br. m, 8 H, 4 ϫ (2-, 2Ј-H-a)], 5.18 [br. s, 8 H,

4ϫ(4-, 4Ј-H-a)], 5.42 [br. s, 4 H, 2ϫ(N-, NЈ-H)], 7.53–7.61 [br. m,

16 H, 4 ϫ (2-, 2Ј-, 6-, 6Ј-H, p-nph)], 8.03–8.22 [br. m, 16 H,

4 ϫ (3-, 3Ј-, 5-, 5Ј-H, p-nph)] ppm. ¹H NMR (400 MHz, [D₆]

DMSO, 80 °C): δ = 2.29 [s, 24 H, 4ϫN(CH₃)₂], 2.94 (s, 4 H, 4ϫ5Ј-

H-e), 3.43 (s, 8 H, piperazine), 4.02 (br. s, 4 H, 4ϫ6-H-a), 4.08 (d,

³J_H,H= 11.2 Hz, 4 H, 4ϫ6Ј-H-a), 4.24 (br. s, 4 H, 4ϫ6-H-e), 4.48

3

(br. d, J_H,H= 9.2 Hz, 4 H, 4ϫ5-H-e), 4.54 (d, J_H,H= 11.2 Hz, 4

H, 4ϫ6Ј-H-e), 5.05 (s, 4 H, 4ϫ2Ј-H-a), 5.07 (s, 4 H, 4ϫ2-H-a),

azolidines or 3,7-dioxa-1-azabicyclo[3.3.0]octanes^[1e,1f,2]

.

3

5.31 (d, J_H,H= 2 Hz, 4 H, 4ϫ4Ј-H-a), 5.35 (s, 4 H, 4ϫ4-H-a),

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5.52 [br. s, 4 H, 2ϫ(N-, NЈ-H)], 7.60 [br. s, 8 H, 4ϫ(2-, 6-H, p-

nph)], 7.67 [d, ³J_H,H= 8.6 Hz, 8 H, 4ϫ(2Ј-, 6Ј-H, p-nph)], 8.07 [br.

3

s, 8 H, 4 ϫ(3-, 5-H, p-nph)], 8.20 [d, J_H,H= 8.6 Hz. 8 H, 4ϫ(3Ј-,

Eur. J. Org. Chem. 2008, 2473–2494

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M. Darabantu et al.

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Received: September 10, 2007

Published Online: April 2, 2008

2494

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Eur. J. Org. Chem. 2008, 2473–2494

Article Doi

Serinolic amino-s-triazines: Iterative synthesis of N-substituted amino-1,3-dioxane derivatives from l-(p-nitrophenyl)serinols and rotational stereochemistry phenomena

DOI: 10.1002/ejoc.200700847

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Full text of DOI:10.1002/ejoc.200700847

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