2-Alkyl-4,6-dialkylamino-1,3,5-triazines via Grignard alkylation of cyanuric chloride: An aged reaction revisited

Article abstract of DOI:10.1016/S0040-4020(00)00925-X

Suitable one-pot reaction conditions are suggested to prepare, in good overall yields, some 2-(alk-1'-ynyl)- and 2-alkyl-4,6-dialkylamino-1,3,5-triazines via reaction of cyanuric chloride with Grignard reagents followed by amination. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4020(00)00925-X

TETRAHEDRON
Pergamon
Tetrahedron 56 (2000) 9705±9711
2-Alkyl-4,6-dialkylamino-1,3,5-triazines via Grignard Alkylation
of Cyanuric Chloride: An Aged Reaction Revisited
*
Rita Menicagli, Simona Samaritani and Valeria Zucchelli
Dipartimento di Chimica e Chimica Industriale and Centro di Studi del CNR per le Macromolecole Stereordinate ed Otticamente Attive,
Via Risorgimento 35, 56126 Pisa, Italy
Received 24 July 2000; revised 8 September 2000; accepted 28 September 2000
AbstractÐSuitable one-pot reaction conditions are suggested to prepare, in good overall yields, some 2-(alk-10-ynyl)- and 2-alkyl-4,6-
dialkylamino-1,3,5-triazines via reaction of cyanuric chloride with Grignard reagents followed by amination. q 2000 Elsevier Science Ltd.
All rights reserved.
In our studies1 concerning the protection of paper against
pathogenic fungi, we found that 2-(alk-10-ynyl)-4,6-
dimethoxy-1,3,5-triazines showed an appreciable biostatic
activity.2 Taking into account that alkylamino derivatives of
1,3,5-triazine are generally better biostatic agents than
alkoxy derivatives,1 preparation of 2-(alk-10-ynyl)-4,6-
dialkylamino-1,3,5-triazines was necessary in order to
compare their antifungal activities with those of 2-(alk-10-
ynyl)-4,6-dimethoxy-1,3,5-triazines. As repeated attempts
to convert the easily available3 2-chloro-4,6-dimorpholino-
1,3,5-triazine into the corresponding 2-(alk-10-ynyl)-deriva-
tives by the Pd(0) mediated cross-coupling with alk-1-ynes4
always resulted in low (15±21%) yields, Grignard alkynyl-
ation of cyanuric chloride (1, CAUTION) followed by amina-
tion (Scheme 1) was attempted, since the alkylation5 as well
as the alkynylation6 of 1 by organomagnesium reagents and,
to a lesser extent, by lithium derivatives,5m,5q±s,7 has been
known, to the best of our knowledge, since 1910.5a
The reaction between a benzene (CAUTION) solution of 1
and a THF solution of alk-10-ynylmagnesium halides has
been reported to afford 2-(alk-10-ynyl)-4,6-dichloro-1,3,5-
triazines in 50±60% yield.6a Since the puri®cation of these
intermediates might have caused an appreciable loss of the
product owing to the well known8 reactivity of the C±Cl
bonds and the treatment of the crude products with nucleo-
philes would have lead to complex mixtures of compounds,
the reaction between 1 and hex-1-ynylmagnesium bromide
was carried out under the experimental conditions recently
described5w for the nearly quantitative conversion of 1 into
2-(20,60-dichlorobenzyl)-4,6-dichloro-1,3,5-triazine
with
the suitable Grignard reagent: hex-1-ynylmagnesium
bromide (0.8 M, Et2O) was slowly added to a cooled
(58C) benzene solution of 1 ([RMgBr]/[1]ˆ1/1 molar
ratio); unfortunately, under these conditions, only a 30%
(glc)9 conversion of 1 into 2-(hex-10-ynyl)-4,6-dichloro-
1,3,5-triazine (2a, glc-mass) was achieved, even after
re¯uxing the mixture for 50 h. Further experiments were
carried out in order to improve the conversion of 1 into
2a: the best results were obtained, independently of the
solvent (THF, Et2O or THF/Et2O mixtures) used for the
Moreover, the same protocol might also be used for the
preparation of 2-alkyl-4,6-diheteroalkyl-1,3,5-triazines,
which was planned in our investigation.
R
R
C l
1
2 R NH
R
MgX
solvent
2
N
N
N
N
N
N
1
1
R
R
Cl
N
Cl
Cl
N
Cl
N
R
N
N
R
1
1
1
2a -e
Scheme 1.
Keywords: 2,4,6-trichloro-1,3,5-triazine; Grignard reagents; alkynylation; alkylation; nucleophilic substitution.
* Corresponding author. Tel.: 139-50-918281; fax: 139-50-918260; e-mail: rime@dcci.unipi.it
0040±4020/00/$ - see front matter q 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4020(00)00925-X

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R. Menicagli et al. / Tetrahedron 56 (2000) 9705±9711
Table 1. Synthesis of 2-(alk-10-ynyl)-4,6-dialkyl(aryl)amino-1,3,5-triazines (3a±e) (In all cases, a solution of the Grignard reagent was added to a solution of 1
in THF at 08C; a [RMgX]/[1]ˆ1/1 molar ratio was used if not otherwise stated (see Experimental))
Entry
1
R
2
a
Solvent
Et2O
R12NH
Et2NH
3 (% yield)a
a (82)
n-Bu
2
3
n-Bu
t-Bu
a
Et2O
b (66)
c (75)
b
THF/Et2Ob
4
5
t-Bu
b
c
THF/Et2Ob
THF/Et2Od
d (60)
e (51)
Phc
a Evaluated on isolated, chemically pure compounds.
b 5.5/1 v/v.
c An excess of phenylethynylmagnesium chloride (1.5 molar equivalents) was used to obtain the maximum conversion (60%) of 1 into 2c.
d 1/2 v/v.
preparation and/or the solubilization of the Grignard
acetylenic reagent, when a THF solution of 1 was used.10
It is noteworthy that, under our experimental conditions,
no appreciable formation of the feared disubstituted
byproducts6a was observed.
obtained (Scheme 2); even worse results were obtained
when the nucleophilic substitution was attempted both in
the presence of t-BuOK13 and under the phase-transfer
conditions,1b,14 which always allowed us to react 1 with
both O- and N-nucleophilic reagents. On the other hand, a
nearly quantitative yield (98%) of 2-(hex-10-ynyl)-4-chloro-
6-(400-methoxyphenoxy)-1,3,5-triazine (4b) was obtained
when 2a was treated with an excess of 4-methoxyphenol
(Scheme 2). The absence, also in this case, of any traces
of disubstitution products, could be rationalized by
The nearly quantitative (glc)11 alkynylation of 1 prompted
us to attempt the in situ treatment of 2a with N-nucleophiles
according to the reaction conditions described for the
conversion of 2-(20,60-dichlorobenzyl)-4,6-dichloro-1,3,5-
triazine into the corresponding 2-(20,60-dichlorobenzyl)-
4,6-diarylamino-1,3,5-triazines.5w The chemoselectivity of
the reaction was not predictable, since it has been reported
that the acetylenic bond, activated by an heterocyclic ring,
easily undergoes conjugate addition.6c,12
assuming that the alk-10-ynyl substituent shows
a
deactivating effect comparable to that shown by an alkoxy
substituent: 2,4,6-trialkoxy-1,3,5-triazines are prepared
from the corresponding dialkoxy precursors only under
suitable reaction conditions.1b,8,13,14a
The direct treatment of 2a with an excess (3 molar
equivalents) of morpholine in the presence of diisopropyl-
ethylamine (DIPEA, 3 molar equivalents)5w afforded
2-(hex-10-ynyl)-4,6-dimorpholino-1,3,5-triazine (3a) in
very good yield (82%, Table 1, entry 1) and no conjugate
addition byproducts were detected. The syntheses of the
other 2-(alk-10-ynyl)-4,6-dialkyl(aryl)amino-1,3,5-triazines
(3b±e) were therefore carried out under the one-pot experi-
mental protocol used for 3a (Table 1, entries 2±5).
The satisfactory results obtained in the synthesis of 3a±e
suggested using a similar one-pot procedure also for the
preparation of 2-alkyl-4,6-dialkylamino-1,3,5-triazines.
As already stated for acetylenic derivatives, several studies
concerning the alkylation of 1 by Grignard reagents5 are
available which, however, do not succeed in exhaustively
describing the reactivity of 1 towards these organometallics.
n
n
B u
Bu
Although the preparation of 2-(alk-10-ynyl)-4,6-dimethoxy-
1,3,5-triazines can be effectively carried out by a Pd(0)
catalyzed cross-coupling,4 the described easy conversion
of 2-(trimethylsilylethynyl)-4,6-dichloro-1,3,5-triazine into
the corresponding 4,6-dimethoxy derivative by reaction
with absolute methanol6b suggested the attempt to convert
2a into the corresponding 2-(hex-10-ynyl)-4,6-dimethoxy-
1,3,5-triazine by the same procedure. In our hands this
approach failed: when a large excess (3 molar equivalents)
of absolute methanol was added to 2a, only a 40% yield of
2-(hex-10-ynyl)-4-chloro-6-methoxy-1,3,5-triazine (4a) was
3 ROH
N
N
N
N
3 DIPEA
R
Cl
N
2a
Cl
O
N
Cl
1,4-dioxane
25º
C
R = Me (
R = 4-MeO-C6H4 4b
)
4a
(
)
Scheme 2.

R. Menicagli et al. / Tetrahedron 56 (2000) 9705±9711
9707
A recent patent5w deals with 2,4-dialkylamino-1,3,5-tria-
zines bearing, in the C6 position a further C±C bonded
substituent (R). While the systems characterized by a benzyl
moiety (Rˆ2-chloro, 2,4- and 2,6-dichlorobenzyl) have
been prepared by the reaction of 1 with the suitable
Grignard reagent, other derivatives bearing substituents
(RˆC1±C10 alkyl, C3±C10 alkenyl, C3±C10 alkynyl, C3±C7
cycloalkyl and phenyl) which theoretically might have been
introduced by the same approach have been synthesized via
rather time consuming multistep approaches. On the other
hand, although the procedure reported by Hirt5d is usually
cited for the Grignard alkylation of 1, it has to be said that
Hirt adopted in fact the Barbier15 protocol.16 Moreover, no
clear information is available about the conditions suitable
to selectively convert 1 into its monoalkylderivatives.
coloured and uneluable byproducts, the reaction was
attempted by using a much more diluted (0.13 M) solution
of the Grignard reagent and a more nucleophilic amine for
the conversion of 5b into 6c (Table 2, entry 3). Under these
conditions an almost colourless solution was obtained after
adding the Grignard reagent and the following reaction with
morpholine gave 6c in satisfactory (75%) yield (Table 2,
entry 3). Similar results were obtained, under comparable
reaction conditions, in all the other cases tested (Table 2,
entries 4±6), although the reaction between 1 and (S)-2-
methylbutylmagnesium chloride was rather peculiar.
When 1.2 molar equivalents of the Grignard reagent were
used, the conversion of 1 into 5d was 60% and the following
treatment with morpholine gave 6e in a poor (47%) overall
yield (see Ref. 11). It has to be underlined, however, that no
reduction products were observed. The nearly complete
conversion of 1 into 5d was achieved only when an excess
(2.2 molar equivalents) of the Grignard reagent was used;
under these conditions chemically pure 6e was ®nally
isolated in satisfactory yield (78%, Table 2, entry 5).
In summary, since no general procedure was available, the
experimental conditions to selectively and completely
convert 1 into the corresponding monoalkylation products
by aliphatic (primary, secondary, a-branched primary),
benzyl and phenyl Grignard reagents had to be sought.
An attempt to convert 5a into the corresponding dimethoxy
derivative was also carried out. The reaction of intermedi-
ates 5 with O-nucleophiles is, in principle, more interesting
than that of intermediates 2, since 2-(alk-10-ynyl)-4,6-
dialkoxy-1,3,5-triazines are readily available by the Pd(0)
catalysed cross-coupling.4
On an analytical scale, the reaction of 1 with 2-phenylethyl-
magnesium bromide was attempted under the experimental
conditions recently reported.5w When complete conversion
of 1 (3 h, glc, see Ref. 9) into 5a was achieved, diethylamine
and DIPEA were added,5w and the corresponding 2-(20-
phenylethyl)-4-(N,N-diethylamino)-6-chloro-1,3,5-triazine
(6a) was formed (glc-mass) in nearly quantitative (glc)
yield. On a preparative scale 6a was recovered in good
(78%) overall yield (Table 2, entry 1).
The conversion of 2-alkyl-4,6-dichloro-1,3,5-triazines into
the corresponding dialkoxy derivatives by reaction with
alcohols has been reported too;5k,m when we reacted 5a
with absolute methanol, in the presence of DIPEA, only a
42% yield of 2-(20-phenylethyl)-4-methoxy-6-chloro-1,3,5-
triazine (7) was recovered and attempts to force the nucleo-
philic substitution always resulted in the formation of
complex deep coloured mixtures containing appreciable
Under comparable experimental conditions, the reaction of
benzylmagnesium chloride with 1 was not so satisfactory:
the addition of a 0.78 M Et2O solution of benzylmagnesium
chloride to 1 resulted in the formation of a deep red mixture
from which, after treating with diethylamine, 6b was
recovered in a poor (37%) yield (Table 2, entry 2). In a
further experiment, in order to avoid the formation of the
amounts
of
2-(20-phenylethyl)-4(N,N-isopropylethyl-
amino)-6-chloro-1,3,5-triazine17 but no trace of the desired
compounds.
Table 2. Synthesis of 2-alkyl-1,3,5-triazine derivatives (6a±f) (A benzene solution of 1 was used; in each case the complete conversion of the precursor into
5a±e (glc) was reached; a 1/[RMgX]/[YH]ˆ1/1.2/3 molar ratio was used, if not otherwise stated)
Entry
1
RMgX (Molarity)a
(0.68)
5
a
Y, Z
6 (% yield)b
a (78)
YˆEt2N,c ZˆCl
2
3
(0.78)
(0.13)
b
b
YˆZˆEt2N
YˆZˆ
b (37)
c (75)
4
(0.29)d
c
YˆZˆ
d (79)
5
6
(0.23)e
PhMgBr (0.22)d
d
e
YˆZˆ
YˆZˆ
e (78)
f (73)
a In diethyl ether, if not otherwise stated.
b Isolated yield of recovered, chemically pure compounds.
c 1.1 molar equivalents were used.
d In a 1/1 Et2O/THF mixture.
e The quantitative conversion of 1 into 5d was achieved only when 2.2 molar equivalents of the Grignard reagent were used.

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R. Menicagli et al. / Tetrahedron 56 (2000) 9705±9711
In summary, in order to prepare 2-(alk-10-ynyl)- and
2-alkyl-4,6-dialkylamino-1,3,5-triazines (3a±e and 6a±f,
respectively) in good, overall yields, by the one-pot protocol
described (see Experimental), the following points should
be considered: (1) the almost quantitative alkynylation of 1
by acetylenic Grignard reagents can be carried out only if a
THF solution of 1 is used; (2) similarly good results can be
achieved in the alkylation of 1 only if a benzene solution of
the precursor is used; (3) in the concentration range we used
for Grignard reagents, no trace of dialk-10-ynyl- or dialkyl
derivatives arises; (4) when N-nucleophiles are used in the
second step of the process no problems subsist; (5) only
monosubstitution products are obtained, at least under the
conditions reported, when dichloro intermediates are
reacted with O-nucleophiles.
Perkin±Elmer±Sciex API III mass spectrometer (Sciex
Co., Thornhill, Ontario, Canada).
General procedure for the preparation of 2-(alk-10-ynyl)-
4,6-dichloro-1,3,5-triazine intermediates (2a±c)
A 0.1 M solution (diethyl ether or diethyl ether/THF) of the
suitable acetylenic Grignard reagent was slowly added to a
cooled (58C), mechanically stirred THF solution (0.1 M) of
1 (1/Grignard reagentˆ1/1 molar ratio if not otherwise
stated); the mixture was cooled to 08C and, after 2 h, the
temperature was raised to 258C and stirring was continued
until the maximum conversion of the substrate (glc) was
reached. For each case the Grignard acetylenic reagent
used and the solvent used for the addition, the conversion
(time, h) and the glc-mass characterization of the inter-
mediate are reported:
2-(Hex-10-ynyl)-4,6-dichloro-1,3,5-triazine (2a). Hex-1-
ynylmagnesium bromide, diethyl ether, 100% (3); m/z
(I%): 229 (M1z, 1.1), 228 (11.5), 214 (68.7), 200 (30.1),
187 (74.4), 163 (7.5), 139 (11.4), 126 (9.0), 106 (24.2), 92
(23.8), 87 (100), 77 (19.4), 64 (43.7), 51 (14.0), 43 (19.3), 39
(10.7).
Experimental
Materials and instruments
Diethyl ether, benzene (CAUTION), tetrahydrofuran (THF)
and 1,4-dioxane were puri®ed by standard methods18 and
distilled from Na before use. N,N-Diethylamine (bp 568C),
morpholine (bp 1288C) and N,N-diisopropylethylamine
(DIPEA, bp 1278C) were distilled from KOH under nitrogen
before use. Methanol was dried according to a reported
procedure.18 4-Methoxyphenol (mp 558C) and 4-methoxy-
aniline (mp 588C) were recrystallized from light petroleum
ether19 and a 1/1 mixture of diethyl ether/hexane, respec-
tively. 2,4,6-Trichloro-1,3,5-triazine (1, CAUTION) was
recrystallized from anhydrous CCl4 and stored under
2-t-Butylethynyl-4,6-dichloro-1,3,5-triazine (2b). t-Butyl-
ethynylmagnesium bromide, THF/diethyl ether 5.5/1 v/v,
100% (15); m/z (I%): 229 (M1z, 1.6), 228 (15.0), 214
(36.0), 106 (25.9), 92 (100), 87 (35.6), 62 (18.7).
2-Phenylethynyl-4,6-dichloro-1,3,5-triazine (2c). Phenyl-
ethynylmagnesium chloride, THF/diethyl ether 1/2 v/v,
85% (110);22 m/z (I%): 249 (M1z, 100), 153 (27.9), 127
(25.89), 100 (11.4), 75 (5.7), 87 (37.9), 61 (11.3), 52 (3.7).
nitrogen.18 Alk-1-ynes were stored over 4 A molecular
Ê
sieves and distilled immediately before use. Benzylmagne-
sium chloride (1.5 M in diethyl ether) was purchased from
Aldrich, while ethylmagnesium, 2-phenylethylmagnesium
and phenylmagnesium bromides, as well as (S)-2-methyl-
butylmagnesium and isopropylmagnesium chlorides were
prepared from the corresponding alkyl halides according
to reported procedures.20 Acetylenic Grignard reagents
were prepared from the corresponding alk-1-ynes and the
suitable alkylmagnesium halide according to reported
procedures.20 Glc analyses were performed on a Perkin±
Elmer 8500 instrument (a DB1, 15 m£0.32 mm capillary
column was used) equipped with a ¯ame ionization detector
and a split±splitless injector, with He carrier gas. TLC
analyses were performed on silica gel 60 plates (Fluka)
and ¯ash chromatography21 puri®cations were carried out
on silica gel 60 (Fluka, 230±400 mesh) using the solvent
eluting mixtures reported for each case. Melting points were
determined using a Kof¯er hot-stage apparatus and are not
corrected. Optical rotatory powers were measured by a
Perkin±Elmer 142 polarimeter equipped with a temperature
control device (^0.18C). 1H and 13C NMR (200 and
50 MHz, respectively) spectra were recorded on a Varian
Gemini 200 spectrometer; all NMR data were obtained
using CDCl3 solutions if not otherwise stated. Chemical
shifts (d ppm) are referred to tetramethylsilane (TMS) (1H
NMR) or CDCl3 (13C NMR) as internal standard. Mass
spectra (m/z, I%) were recorded on a Perkin±Elmer
Q-Mass 910 instrument; IS mass spectra, acquired in
MCA mode by summing 10 scans, were acquired on a
General procedure for the preparation of 2-(alk-10-ynyl)-
4,6-diheteroalkyl-1,3,5-triazines (3a±e)
A 1,4-dioxane solution of the suitable nucleophile and
DIPEA was slowly added to the stirred solution of the
1,3,5-triazine intermediate (2a±c) at room temperature
(nucleophile/DIPEA/2a±cˆ3/3/1 molar ratio); stirring was
continued until the complete conversion of intermediates
was achieved (glc, TLC), solvents were removed at reduced
pressure and the residue was triturated and hydrolyzed with
0.6 M HCl; organic products, extracted with CHCl3, were
washed with water and dried over anhydrous Na2SO4. The
removal of the solvent at reduced pressure and the puri®ca-
tion by ¯ash chromatography afforded the chemically pure
compounds. For each case the starting intermediate, the
nucleophile used, the time necessary to achieve the
complete conversion of the intermediate, the mixture of
solvents (v/v) used for the ¯ash chromatography, the
yield, the chemical±physycal and the spectroscopic
characterization are reported:
2-(Hex-10-ynyl)-4,6-dimorpholino-1,3,5-triazine (3a). 2a;
Morpholine; 15 h; hexane/ethyl acetate 60/40; 82%; white
solid, mp 92±938C; m/z (I%): 331 (M1z, 12.6), 301 (18.4),
286 (25.5), 274 (30.6), 113 (4.4), 81 (5.0), 55 (100); IS
mass: [M11]1ˆ332, [M123]1ˆ354; 1H NMR: 3.90±
3.60 (m, 16H), 2.42 (t, Jˆ7.16 Hz, 2H, CuC±CH2CH2),
1.69±1.40 (m, 4H, CH2CH2CH3), 0.93 (t, Jˆ7.16 Hz, 3H,

R. Menicagli et al. / Tetrahedron 56 (2000) 9705±9711
9709
CH2CH3); 13C NMR: 164.2, 159.4, 89.5, 79.8, 66.7, 43.5,
30.0, 22.1, 19.0, 13.5. Found: C, 61.4; H, 7.4; N, 21.2.
C17H25N5O2 requires C, 61.6; H, 7.6; N, 21.1%.
ether 70/30 v/v; 98%; pale yellow solid, mp 49±508C; m/z
(I%): 317 (M1z, 47.6), 282 (5.8), 260 (16.8), 214 (100), 171
(7.3), 147 (6.2), 123 (4.0), 107 (3.1), 87 (11.5), 77 (6.6), 63
(13.1), 52 (63.5); IS mass: [M11]1ˆ318, [M123]1ˆ340;
1H NMR: 7.12±7.07 (m, 2H, Harom), 6.94±6.90 (m, 2H,
Harom), 3.80 (s, 3H, O±CH3), 2.46 (t, Jˆ6.98 Hz, 2H,
CuC±CH2CH2), 1.69±1.35 (m, 4H, CH2CH2CH3),
0.92 (t, Jˆ7.20 Hz, 3H, CH2CH2CH3); 13C NMR: 172.3,
171.0, 162.7, 157.5, 144.7, 121.8, 114.5, 98.4, 78.2, 55.4,
29.4, 21.8, 19.0, 13.3. Found: C, 60.9; H, 5.0; N, 13.5; Cl,
11.0. C16H16ClN3O2 requires C, 60.5; H, 5.1; N, 13.2; Cl,
11.2%.
2-(Hex-10-ynyl)-4,6-di(N,N-diethylamino)-1,3,5-triazine
(3b). 2a; diethylamine; 40 h; hexane/ethyl acetate 90/10;
66%; viscous liquid; m/z (I%): 303 (M1z, 72.6), 288
(16.2), 274 (100), 260 (19.78), 232 (4.1), 99 (5.2); IS
1
mass: [M11]1ˆ304, [M123]1ˆ326; H NMR (DMSO-
d6, 608C): 3.50 (q, Jˆ7.15 Hz, 8H, N±CH2CH3), 2.45 (t,
Jˆ7.06 Hz, 2H, CuC±CH2CH2), 1.61±1.32 (m, 4H,
CH2CH2±CH3), 1.09 (t, Jˆ7.16 Hz, 12H, N±CH2CH3),
0.93 (t, Jˆ7.16 Hz, 3H, CH2CH2CH3); 13C NMR: 163.2,
158.3, 87.0, 80.6, 40.3, 40.0, 29.5, 21.2, 17.7, 12.9.
Found: C, 67.5; H, 9.5; N, 23.0. C17H29N5 requires C,
67.3; H, 9.6; N, 23.1%.
General procedure for the preparation of 2-alkyl-4,6-
dichloro-1,3,5-triazine intermediates (5a±e)
A solution (diethyl ether or diethyl ether/THF) of the suit-
able Grignard reagent was slowly added to a cooled
(0±58C), mechanically stirred benzene solution of 1
(1/Grignard reagentˆ1/1.2 molar ratio if not otherwise
stated); the mixture was stirred at 08C for 3±5 h, the
temperature was raised at 258C and stirring was continued
until the complete conversion of the substrate (glc) was
obtained. For each case the Grignard reagent, its molarity,
the solvent used for the addition, the time necessary to
achieve the complete conversion and the glc-mass charac-
terization are reported:
2-t-Butylethynyl-4,6-dimorpholino-1,3,5-triazine (3c). 2b;
Morpholine: 8 h; diethyl ether/hexane 80/20; 75%; white
solid, mp 226±2278C; m/z (I%): 331 (M1z, 11.9), 301
(16.0), 286 (26.8), 274 (23.1), 179 (4.2), 113 (14.8), 92
(12.1), 81 (20.1), 69 (13.7), 55 (100); IS mass:
1
[M11]1ˆ332, [M123]1ˆ354; H NMR: 3.85±3.68 (m,
16H), 1.34 (s, 9H, CH3); 13C NMR: 164.3, 159.5, 96.6,
78.5, 66.7, 43.5, 30.4, 27.7. Found: C, 61.8; H, 7.6; N,
20.9. C17H25N5O2 requires C, 61.6; H, 7.6; N, 21.1%.
2-t-Butylethynyl-4,6-di(40-methoxyanilino)-1,3,5-triazine
(3d). 2b; 4-Methoxyaniline; 45 h; benzene/chloroform/
ethyl acetate 47.5/43/9.5; 60%; white solid, mp 204±
2058C; m/z (I%): 403 (M1z, 100), 388 (32.4), 380 (5.5),
280 (4.6), 207 (6.3), 197 (4.8), 133 (20.1), 89 (4.4), 52
2-(20-Phenylethyl)-4,6-dichloro-1,3,5-triazine (5a). 2-
Phenylethylmagnesium bromide; 0.68; diethyl ether; 3 h;
m/z (I%): 253 (M1z, 16.1), 218 (3.2), 176 (4.2), 157 (3.2),
130 (7.4), 103 (6.5), 91 (100), 87 (7.3), 78 (13.8), 65 (10.9),
62 (9.4).
1
(10.0); IS mass: [M11]1ˆ404, [M123]1ˆ426; H NMR:
8.10 (bs, 2H, NH), 7.47 (d, Jˆ8.95 Hz, 4H, Harom), 6.85 (d,
Jˆ8.95 Hz, 4H, Harom), 3.80 (s, 6H, O±CH3), 1.19 [s, 9H,
C(CH3)3]; 13C NMR: 163.7, 156.3, 130.9, 122.9, 113.9,
113.0 (2C), 99.0, 55.5, 30.1, 27.7. Found: C, 68.2; H, 6.4;
N, 17.6. C23H25N5O2 requires C, 68.5; H, 6.2; N, 17.4%.
2-Benzyl-4,6-dichloro-1,3,5-triazine (5b). Benzylmagne-
sium chloride; 0.78; diethyl ether; 4 h; m/z (I%): 239
(M1z, 26.8), 238 (36.9), 204 (53.3), 143 (18.7), 117 (100),
91 (55.2), 89 (40.5), 87 (23.3), 77 (10.7), 65 (19.7), 62
(26.0).
2-Phenylethynyl-4,6-dimorpholino-1,3,5-triazine (3e). 2c;
Morpholine; 36 h; hexane/ethyl acetate 50/50; 51%; white
solid, mp 193±1958C; m/z (I%): 351 (M1z, 73.3), 321 (85.4),
306 (100), 294 (96.1), 236 (5.4), 208 (11.4), 204 (8.0), 179
2-Isopropyl-4,6-dichloro-1,3,5-triazine (5c). Isopropyl-
magnesium chloride; 0.29; diethyl ether/THF 1/1 v/v; 3 h;
m/z (I%): 191 (M1z, 3.6), 190 (6.2), 176 (100), 165 (1.2),
163 (2.6), 87 (21.1), 68 (3.6), 62 (16.1), 54 (10.6).
1
(7.5), 153 (16.7), 81 (14.6), 69 (3.6), 55 (11.9); H NMR:
7.64±7.59 (m, 2H, Harom); 7.39±7.33 (m, 3H, Harom); 3.90±
3.60 (m, 16H); 13C NMR: 164.2, 159.4, 132.6, 129.5, 128.2,
121.3, 87.9, 86.5, 66.7, 43.6. Found: C, 65.2; H, 6.1; N, 19.7.
C19H21N5O2 requires C, 64.9; H, 6.0; N, 19.9%.
2-[(S)-20-Methylbutyl]-4,6-dichloro-1,3,5-triazine (5d).
(S)-2-Methylbutylmagnesium chloride;23 0.23; diethyl
ether; 2 h; m/z (I%): 204 (M1z2CH3, 7.5), 192 (19.9), 190
(35.1), 165 (62.8), 163 (100), 87 (14.2), 82 (4.2), 68 (8.3), 62
(18.9).
2-(Hex-10-ynyl)-4-methoxy-6-chloro-1,3,5-triazine (4a).
2a; Dry methanol; 84 h; hexane/ethyl acetate 90/10; 32%;
waxy solid; m/z (I%): 225 (M1z, 3.2), 210 (13.6), 196 (13.4),
183 (23.7), 106 (5.9), 87 (3.4), 76 (11.1), 64 (11.7), 58 (100),
51 (53.5); IS mass: [M11]1ˆ226, [M123]1ˆ248; 1H
NMR: 4.10 (s, 3H, O±CH3), 2.50 (t, Jˆ7.02 Hz, 2H,
CuC±CH2CH2), 1.39±1.72 (m, 4H, CH2CH2±CH3), 0.94
(t, Jˆ7.16 Hz, 3H, CH2CH2CH3); 13C NMR: 172.1, 171.2,
162.4, 97.8, 78.3, 56.1, 29.6, 22.0, 19.1, 13.4. Found: C,
53.4; H, 5.6; N, 18.3; Cl, 15.9. C10H12ClN3O requires C,
53.2; H, 5.4; N, 18.6; Cl, 15.7%.
2-Phenyl-4,6-dichloro-1,3,5-triazine (5e). Phenylmagne-
sium bromide; 0.22; diethyl ether/THF 1/1 v/v; 3 h; m/z
(I%): 225 (M1z, 100), 129 (44.6), 122 (8.76), 103 (32.1),
87 (27.0), 77 (4.2), 76 (8.0), 62 (1.7).
General procedure for the preparation of 2-alkyl-4,6-
diheteroalkyl-1,3,5-triazines (6a±f)
A 1,4-dioxane solution of the suitable nucleophile and
DIPEA was slowly added to the stirred solution of 1,3,5-
triazine intermediate (5a±e) at room temperature (nucleo-
phile/DIPEA/5a±eˆ3/3/1 molar ratio if not otherwise
2-(Hex-10-ynyl)-4-(400-methoxyphenoxy)-6-chloro-1,3,5-
triazine (4b). 2a; 4-Methoxyphenol; 44 h; hexane/diethyl

9710
R. Menicagli et al. / Tetrahedron 56 (2000) 9705±9711
stated); stirring was continued until complete conversion of
the intermediate was achieved (glc, TLC), solvents were
removed at reduced pressure and the residue was worked
up according to the procedure described for the preparation
of 3a±e. For each case the starting intermediate, the nucleo-
phile used, the time necessary to achieve the complete
conversion of the intermediate, the mixture of eluents (v/
v) used for the ¯ash chromatography, the yield, the chemi-
cal±physical and the spectroscopic characterization are
reported:
(5.1), 265 (100), 234 (9.9), 220 (12.8), 208 (7.3), 179 (4.1),
113 (3.3), 94 (3.2), 69 (2.8), 56 (3.5); H NMR: 3.83±3.68
1
(m, 16H), 2.52 (dd, Jˆ13.74 Hz, J0ˆ6.20 Hz, 1H, Triazine±
CHHCH), 2.29 (dd, Jˆ13.74 Hz, J0ˆ7.98 Hz, 1H,
Triazine±CHHCH), 2.10±1.93 (m, 1H, CH), 1.48±1.11
(m, 2H, CH2CH3), 0.91 (d, Jˆ6.63 Hz, 3H, CHCH3), 0.90
(t, Jˆ7.32 Hz, 3H, CH2CH3); 13C NMR: 177.8, 164.2, 66.8,
45.9, 43.5, 33.3, 29.4, 19.2, 11.3. Found: C, 60.0; H, 8.2; N,
21.9. C16H27N5O2 requires C, 59.8; H, 8.5; N, 21.8%.
2-Phenyl-4,6-dimorpholino-1,3,5-triazine (6f). 5e, Mor-
pholine; 15 h; hexane/ethyl acetate 50/50; 73%; white
solid, mp 190±1918C; m/z (I%): 327 (M1z, 84.2), 297
(98.8), 296 (87.0), 282 (75.1), 270 (100), 252 (21.9), 240
(20.3), 225 (9.7), 212 (17.0), 207 (23.1), 193 (7.4), 184
(18.3), 179 (10.1), 149 (12.1), 129 (10.9), 104 (18.6), 94
(3.2), 82 (2.5), 56 (4.9); 1H NMR: 8.40±8.36 (m, 2H,
Harom), 7.48±7.40 (m, 3H, Harom), 4.05±3.70 (m, 16H); 13C
NMR: 170.4, 165.2, 137.3, 131.2, 128.2, 128.0, 66.3, 43.6.
Found: C, 62.6; H, 6.5; N, 21.5. C17H21N5O2 requires C,
62.4; H, 6.5; N, 21.4%.
2-(20-Phenylethyl)-4-(N,N-diethylamino)-6-chloro-1,3,5-
triazine (6a). 5a, Diethylamine (1.1 molar equivalents);
15 h; 78%, viscous liquid; m/z (I%): 290 (M1z, 100), 275
(16.1), 261 (13.0), 255 (3.4), 213 (9.4), 199 (7.0), 186 (6.1),
171 (5.4), 157 (4.4), 132 (8.5), 99 (18.7), 91 (67.5), 77 (5.6),
1
72 (5.4), 69 (10.2), 62 (3.5), 55 (9.5); H NMR: 7.35±7.10
(m, 5H, Harom), 3.59 (q, Jˆ7.10 Hz, 2H, N±CH2CH3), 3.50
(q, Jˆ7.06 Hz, 2H, N±CH2CH3), 3.15±3.04 (m, 2H,
CH2CH2Ph), 3.00±2.91 (m, 2H, CH2Ph), 1.18 (t, Jˆ
7.06 Hz, 3H, CH2CH3), 1.14 (t, Jˆ7.10 Hz, 3H, CH2CH3);
13C NMR: 178.8, 169.8, 164.0, 140.9, 128.2, 125.7, 41.9,
41.7, 39.7, 32.9, 12.6. Found: C, 61.8; H, 6.4; N, 19.6; Cl,
12.2. C15H19ClN4 requires C, 62.0; H, 6.6; N, 19.3; Cl,
12.1%.
2-(20-Phenylethyl)-4-methoxy-6-chloro-1,3,5-triazine (7).
5a, Methanol; 64 h; hexane/ethyl acetate 80/20 v/v; 42%;
viscous liquid; m/z (I%): 249 (M1z, 59.7), 234 (62.0), 172
(29.8), 130 (57.0), 105 (29.9), 91 (100), 78 (16.9), 65 (20.2),
58 (10.6); IS mass: [M11]1ˆ250, [M123]1ˆ272; 1H
NMR: 7.34±7.12 (m, 5H, Harom), 4.06 (s, 3H, CH3), 3.12
(buried m, 4H, CH2CH2); 13C NMR: 182.6, 171.9, 171.2,
140.1, 128.4, 128.2, 126.2, 55.8, 39.9, 32.8. Found: C, 57.9;
H, 4.7; N, 16.6; Cl, 14.3. C12H12ClN3O requires C, 57.7; H,
4.8; N, 16.8; Cl, 14.2%.
2-Benzyl-4,6-di(N,N-diethylamino)-1,3,5-triazine (6b).
5b, Diethylamine; 50 h; hexane/diethyl ether 85/15; 37%;
viscous liquid; m/z (I%): 313 (M1z, 33.9), 298 (7.6), 294
(100), 270 (27.0), 254 (3.2), 242 (4.1), 207 (3.5), 91 (6.4),
69 (3.0); IS mass: [M11]1ˆ314, [M123]1ˆ336; 1H NMR:
7.45±7.40 (m, 2H, Harom), 7.30±7.19 (m, 3H, Harom), 3.78
(s, 2H, CH2Ph), 3.48 (q, Jˆ7.02 Hz, 8H, N±CH2CH3), 1.12
(t, Jˆ7.02 Hz, 12H, CH2CH3); 13C NMR: 175.5, 164.4,
138.9, 129.5, 127.9, 125.9, 45.8, 41.2, 13.3. Found: C,
69.2; H, 8.6; N, 22.2. C18H27N5 requires C, 69.0; H, 8.7;
N, 22.3%.
Acknowledgements
This work was supported, in part, by the Ministero della
Ricerca Scienti®ca e Tecnologica (MURST, Rome) and
by C.N.R. (Comitato Nazionale Scienza e Tecnologia
Beni Culturali).
2-Benzyl-4,6-dimorpholino-1,3,5-triazine (6c). 5b, Mor-
pholine; 15 h; hexane/ethyl acetate 60/40; 75%; glassy
solid; m/z (I%): 341 (M1z, 39.1), 311 (64.0), 296 (53.7),
284 (80.7), 207 (28.5), 179 (17.5), 138 (18.9), 118 (28.1),
113 (47.8), 91 (100), 69 (33.7); 1H NMR: 7.39±7.18 (m, 5H,
Ph), 3.80±3.65 (m, 18H, Ph±CH2, N±CH2±CH2±O); 13C
NMR: 176.4, 164.9, 138.0, 129.3, 128.0, 126.2, 66.7, 45.6,
43.4. Found: C, 63.0; H, 6.6; N, 20.8. C18H23N5O2 requires
C, 63.3; H, 6.8; N, 20.5%.
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Â
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