Organometallic alkylation of 2-chloro-4,6-dimethoxy-1,3,5-triazine: A study

Article abstract of DOI:10.1016/j.tet.2005.02.085

The reactivity of 2-chloro-4,6-dimethoxy-1,3,5-triazine (1) has been investigated in Pd- or Ni-catalyzed cross-coupling processes with organostannanes, Grignard reagents, organoalanes and organozinc halides. All organometallic reagents considered form new C-C bonds on the heteroaromatic ring and afford the corresponding 2-alkyl-4,6-dimethoxy-1,3,5-triazines in moderate to very good yields. The collected data allows the choice of the alkylating agent as well as the experimental conditions depending on the residue to transfer.

Full text of DOI:10.1016/j.tet.2005.02.085

Tetrahedron 61 (2005) 4475–4483
Organometallic alkylation of
2-chloro-4,6-dimethoxy-1,3,5-triazine: a study
*
Simona Samaritani, Giovanni Signore, Corrado Malanga and Rita Menicagli
`
Dipartimento di Chimica e Chimica Industriale, Universita di Pisa, Via Risorgimento 35, 56126 Pisa, Italy
Received 30 August 2004; revised 4 February 2005; accepted 18 February 2005
Available online 23 March 2005
Abstract—The reactivity of 2-chloro-4,6-dimethoxy-1,3,5-triazine (1) has been investigated in Pd- or Ni-catalyzed cross-coupling processes
with organostannanes, Grignard reagents, organoalanes and organozinc halides. All organometallic reagents considered form new C–C
bonds on the heteroaromatic ring and afford the corresponding 2-alkyl-4,6-dimethoxy-1,3,5-triazines in moderate to very good yields. The
collected data allows the choice of the alkylating agent as well as the experimental conditions depending on the residue to transfer.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
2. Results and discussion
During the last few years the potential of 1,3,5-triazine
derivatives in molecular recognition, agrochemical and
medicinal properties has been subject to investigation.1 Our
studies pointed out that 2-alkyl-4,6-dihetero(N,O)alkyl-
1,3,5-triazines (Fig. 1) show interesting antitumor proper-
ties.1c–e Among the structures studied, 2-(alk-10-ynyl)-4,6-
dimethoxy-1,3,5-triazines were the most promising com-
pounds. In order to gain an insight into the structure–activity
relationship, the synthesis of 2-aryl (alkyl or alk-10-enyl or
benzyl or allyl)-4,6-dimethoxy-1,3,5-triazines was
necessary.
Since the 1990s, transition metal catalyzed cross-coupling
reactions have been described for the preparation of
symmetrical and non-symmetrical 1,3,5-triazine systems,
starting from 2,4,6-trichloro-1,3,5-triazine or its deriva-
tives.2 Recently we used Sonogashira cross-coupling to
prepare 2-(alk-10-ynyl)-4,6-dialkoxy-1,3,5-triazines.3 The
good results obtained in the Sonogashira3 and in the Stille1e
cross-couplings prompted us to extend this last approach to
the transfer of other unsaturated residues onto the hetero-
aromatic ring (Scheme 1). The use of tributylalk-1-
enylstannanes in Pd-catalyzed cross-coupling procedures
is well known,4 and in our case the introduction of prop-1-
enyl residue was successfully achieved, affording (E,Z)-2a
(Scheme 1). The diastereomeric composition (glc) of the
product was the same as the starting organotin derivative. In
turn, when Stille cross-couplings are carried out with allyl
stannanes, a process of isomerization of the double bond is
often observed,4,5 which can sometimes be prevented by
using tri(2-furyl)phosphine as the palladium ligand.5d
Nevertheless, the description of Stille non-isomerized allyl
products under more usual conditions is frequent.4,5b,6
Figure 1.
The use of transition metal-catalyzed cross-coupling reac-
tions, between 2-chloro-4,6-dimethoxy-1,3,5-triazine (1)
and different organometallic reagents, is hereby reported
and critically discussed in order to provide the most
convenient procedures for the synthesis of the desired
compounds.
Keywords: 2-Chloro-4,6-dimethoxy-1,3,5-triazine; Organometallics;
Coupling reactions; Palladium and nickel catalysts.
*
Corresponding author. Tel.: C39 50 2219281; fax: C39 50 2219260;
e-mail: rime@dcci.unipi.it
Scheme 1.
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.02.085

4476
S. Samaritani et al. / Tetrahedron 61 (2005) 4475–4483
Table 1. Kumada cross-coupling between 1 and Grignard reagentsa
Therefore, the synthesis of 2-allyl-4,6-dimethoxy-1,3,5-
triazine was attempted under the same conditions allowing
the preparation of the other derivatives (Scheme 1). It was
found that the structure of the product was strongly affected
by the work-up procedure: as a matter of fact, when the
usual hydrolysis sequence was carried out [Procedure A: (1)
KFaq (60% wt); (2) filtration on Florisilw/silica gel], only
(E)-2-prop-10-enyl-4,6-dimethoxy-1,3,5-triazine [(E)-2a]
was obtained. It has to be underlined that only 2-allyl-4,6-
dimethoxy-1,3,5-triazine had been detected (glc and GC/
ms) in the reaction mixture prior to hydrolysis.
Entry
t (h),
T (8C)
R
Et2O/THF
2 %
Yieldb
1
2
3
4
5
6
7
8
2, 25
1, 25
4, 25
76, 25
48, 60
14, 25
3, 25
Et (d)
i.Bu (e)
i.Pr (f)
Bn (g)
b-Methallyl (c)
Ph (h)
m.F-C6H4 (i)
p.MeO–C6H4 (j)
100/0
100/0
100/0
100/0
80/20
95/5
74
60
68
35
0
75
65
30c
50/50
50/50
28, 25
a Reactions carried out in the presence of NiCl2(dppe)2, 1/RMgX/catZ1/
1.3/0.05.
b Isolated yield.
c 50% conversion (glc).
In order to understand if the formation of (E)-2a was a base-
and/or Pd-mediated process, in a further experience the
reaction mixture was (1) filtered on Florisilw/silica gel, to
remove most of the catalyst and (2) treated with the KF
solution (Procedure B). Under these conditions no traces of
(E)-2a were detected and 2b was obtained in good yield
(69%). Moreover, the quantitative isomerization of 2b into
(E)-2a was achieved when a pure sample of 2b was treated
with both a 60% KF aqueous solution and a catalytic amount
of Pd/C. In turn, 2b was recovered unreacted when it was
treated with the same basic solution in the absence of the Pd
catalyst. The observed base- and Pd-catalyzed isomerization
process conveniently afforded 2 (20,20-dialkylalk-10-enyl)-
4,6-dimethoxy-1,3,5-triazines, whose synthesis would
otherwise need the tedious preparation of the necessary
2-alkyl-1-haloalk-1-enes. In order to verify this possibility,
a cross-coupling reaction was carried out between 1 and
2-methylprop–2-enyltributylstannane (b-methallyltributyl-
tin, Scheme 1), following the work-up Procedure A. The
reaction was much slower and no isomerization was
observed; eventually, 2c was recovered with a moderate
(55%) isolated yield.
smoothly with primary, a-branched primary and secondary
Grignard reagents (Table 1, entries 1–3) and afforded the
corresponding products 2d–f in good isolated yields
(60–74%).
As far as arylmagnesium halides are concerned, the
outcome of the reaction was strongly affected by the nature
of the aromatic Grignard reagent used. In particular, good
results were obtained in the preparation of 2h–i (Table 1,
entries 6 and 7), while repeated experiments carried out in
the presence of p-methoxyphenylmagnesium bromide
always afforded 2j in modest yield, due to the partial
conversion of 1 (Table 1, entry 8).
Moreover, it should be noted that, under the reaction
conditions, minor amounts of by-products (7–10%) arising
from the di- and trialkylation of 1 were observed (GC/ms).
In a further step and with the aim of comparing the use of
organotin and organomagnesium derivatives in the alkenyl-
ation of 1, the possible synthetic pathways to the necessary
unsaturated organometallic reagents were critically con-
sidered (Scheme 3). A common and convenient synthetic
procedure for the preparation of 1-haloalk-1-enes,
precursors of both organometals, is the halolysys of C–B8
or C–Al9 bonds, arising from hydroboration10 or hydro-
alumination11 processes (Scheme 3, sequences A, B). An
alternative, more recent procedure (Scheme 3, Sequence C)
allows the direct transmetallation of the unsaturated residue
from organoalane to organotin.12 Unfortunately, this rather
attractive approach is not general, since the obtained yields
are satisfactory only in the case of non-a-substituted
organoalanes.12 Moreover, the preparation of vinylic
Although tetraalkyltin compounds are sometimes used as
cross-coupling alkylating agents,4 their use for the prep-
aration of 2-alkyl-4,6-dialkoxy-1,3,5-triazines seemed
rather expensive. To overcome this problem, the use of
readily available Grignard reagents under the Kumada
reaction conditions was investigated (Scheme 2). In this
context, arylation and allylation processes, previously
carried out via Stille reaction, were repeated and compared
under the Kumada protocol. A preliminary experiment,
carried out in the presence of PdCl2(PPh3)2, afforded only
by-products arising from decomposition of 1. Although
recently iron-catalyzed cross-couplings between RMgBr
(RZn.C14H29 and Ph) and 1 were described,2e the
availability of NiCl2(dppe) in our laboratory prompted us
to use this catalyst, which is widely employed in Kumada
cross-couplings.7 The main results obtained are collected in
Table 1: while the reaction failed in the cases of Bn- and
b-MethallylMgCl (Table 1, entries 4 and 5), 1 reacted
Scheme 3.
Scheme 2.

S. Samaritani et al. / Tetrahedron 61 (2005) 4475–4483
4477
Grignard reagents has been recently achieved by Mn-
promoted carbomagnesiation of acetylenic linkages.13
that the synthesis of alkenylalanes via hydroalumination is
more convenient than the preparation of alkenylstannanes.
This observation suggested the use of unsaturated alanes in
the synthesis of other triazine derivatives. Thus, in a further
experiment, phenylethyne was used as precursor of the
organoaluminium reagent and afforded the expected 2l in
moderate (51%) yield (Table 2, entry 3). In this case, a
significant (21%) amount of 2-phenylethynyl-4,6-
dimethoxy-1,3,5-triazine3b was observed due to the com-
petitive metallation of phenylethyne. The cases reported in
entries 4–6 of Table 2 were considered to verify if
b-branched unsaturated residues as well as internal alkenyl
chaines could be transferred. The reactions were carried out
in the presence of ZnCl2, to enhance the reactivity of
sterically hindered alkenylalanes.14b In none of the
examples appreciable amounts of the corresponding
2-alkenyl-4,6-dimethoxy-1,3,5-triazines were isolated, but
2e was always present in the reaction mixtures.
Taking into account that (i) alk-1-enyldialkylalanes are
often key intermediates in the preparation of the corre-
sponding halides and that (ii) these organometallic reagents
have been known for years as alkenylating agents in Pd or
Ni catalysed cross-coupling reactions,14 their use for the
alkenylation of 1 was considered.
In order to verify the reactivity of alkenylalanes with 1
under the usual cross-coupling conditions, 1 was reacted
with di-isobutyl(hex-1-enyl)alane in CH2Cl2, using PdCl2-
(PPh3)2 as catalyst. Since only decomposition products were
observed, the reaction was repeated in THF (Table 2,
entry 1). In this case, the analysis of the reacti0on mixture
revealed the formation of the expected 2-(hex-1 -enyl)-4,6-
dimethoxy-1,3,5-triazine (2k). Nevertheless, 2k was
recovered in modest yield (38%) due to 0the competitive
formation of an equimolar amount of 2-(2 -methylpropyl)-
4,6-dimethoxy-1,3,5-triazine (2e). In a further experiment
the lack of selectivity in the chain transfer was solved
(Table 2, entry 2) by replacing PdCl2(PPh3)2 with
Pd(PPh3)4. In the presence of this catalyst the conversion
of 1 into 2k was completely chemoselective and the desired
derivative was recovered in 60% yield (Table 2, entry 2).
Although the yield obtained in the synthesis of 2k was lower
than that obtained in the preparation of 2a by the Stille
cross-coupling (70%, see Scheme 1), it has to be underlined
On the basis of these results it seems reasonable to conclude
that alk-1-enyldi-isobutylalanes can be successfully used to
prepare 2-(alk-10-enyl)-4,6-dialkoxy-1,3,5-triazines only
when the unsaturated chain is not hindered.
Although it is well-known that ethereal solvents can
sometimes inhibit the reactivity of organoalanes,15 the
cross-couplings of 1 with unsaturated organoalanes
(Table 2, entries 1–3) were successfully carried out in the
presence of THF. These results suggested the in situ
Table 2. Cross-coupling reactions between 1 and alkenyldiisobutylalanesa
Entry
t (h)
THF/n.Hexane
2 % Yieldb
1c
2f
3h
15 (rt), 5d
13 (rt), 4g
5 (rt), 30d
50/50
60/40
60/40
38e
(k)
(k)
60
51i
(I)
k
4j
5j
6j
48 (rt)
50/50
75/25
45/55
—
m
20 (rt), 4l
4 (rt), 15g
—
m
—
a 1/Organometal/catZ1/1.15/0.03.
b Isolated yield.
c Reaction carried out in the presence of PdCl2(PPh3)2.
d TZ40 8C.
e From the reaction mixture 2-i.butyl-4,6-dimethoxy-1,3,5-triazine (2e) was recovered (45%).
90% conversion (glc).
f
g TZ50 8C.
h 100% conversion (glc).
i
A sample (21%) of 2-(20-phenylethynyl)-4,6-dimethoxy-1,3,5-triazine3b was isolated.
0.5 equiv of ZnCl2 were added.
j
k In the reaction mixture the main product was 2e (30%) along with traces of the desired product (GC/ms).
At reflux.
l
mIn the reaction mixture only 2e was detected (glc).

4478
S. Samaritani et al. / Tetrahedron 61 (2005) 4475–4483
Table 3. Cross-coupling reactions between 1 and in situ prepared organoalanesa
Entry
t (h)
Et2O/THF
R
2 % Yieldb
1
2
3
4
4
2
2
18
100/0
100/0
100/0
100/0
65/35
Et (d)
n.Hex (m)
i.Bu (e)
(S)-(2Me)Bu (n)
i.Pr (f)
81
75
70
70
43d
4
5c
(o)e
6e
6
60/40
62
7
8
9
10
3f
12
200
2f
100/0
70/30
50/50
65/35
Bn (g)
Ph (h)
m.F-C6H4 (i)
p.MeO-C6H4 (j)
74
75
—
88
g
a 1/AlR3/PdCl2(PPh3)2Z1/1.15/0.03; reactions carried out at reflux if not otherwise stated; quantitative conversion was observed if not otherwise stated.
b Isolated yield.
c 82% conversion (glc).
d In the reaction mixture 2-n.propyl-4,6-dimethoxy-1,3,5-triazine was also recovered (21%).17
e When b-methallylMgCl was used 2-(20-methylprop-10-enyl)-4,6-dimethoxy-1,3,5-triazine (2o) was obtained.
Reaction carried out at room temperature.
f
g Repeated experiences never afforded more than 10% conversion (glc) of 1.
preparation of trialkyl (aryl or allyl or benzyl) alanes by a
transmetallation reaction between AlCl3 and the suitable
Grignard reagent15 (Table 3). This approach, which was not
a priori predictable, due to the possible interaction between
Lewis acids and the catalytic system used,16 would simplify
the procedure, avoiding the rather cumbersome isolation of
the organoalanes.
these organometallic reagents are complementary to the
previously studied ones. In fact, they allowed the benzyl-
ation of 1 as well as the synthesis of 2o via the isomerization
of the corresponding methallyl residue. Moreover, while
Grignard reagents had afforded minor amounts of di- and
trialkylated products (Table 1), no appreciable amounts
(glc) of these byproducts were observed when trialkylalanes
were used. Nevertheless, the protocol seemed rather
expensive, because only one out of the three residues
could be transferred from the organoalane to the hetero-
aromatic ring.15 Further efforts were thus made to use mixed
organoalanes (REt2Al) for the one-pot transfer of non-
aliphatic residues. These organometallic reagents can be
readily obtained by reaction between chlorodiethylalane
and a suitable Grignard reagent.15 While the cross-coupling
between 1 and benzyldiethylalane gave unsatisfactory
results in the presence of both Pd(PPh3)4 and PdCl2(PPh3)2
(Table 4, entries 1 and 2), the reaction of 4-methoxyphenyl-
as well as diethylphenylalane afforded 2j and 2h in 71 and
The collected data (Table 3) shows that 1 can be
conveniently alkylated by organoalanes prepared in situ,
and that the presence of magnesium salts does not affect the
activity of the catalytic system.16 In particular: (i) the yield
of 2 was very good (70–81%) when aliphatic primary (Table
3, entries 1 and 2) as well as a-branched primary (Table 3,
entries 3 and 4) alanes were used. (ii) The partial
isomerization of the transferred chain was observed when
tri-isopropylalane was used (Table 3, entry 5) and, in
repeated experiments, carried out under different reaction
conditions (solvent, temperature, catalyst), the formation of
2-n-propyl-4,6-dimethoxy-1,3,5-triazine17 could never be
avoided. Anyway, chemically pure 2f was recovered in 43%
yield. (iii) When b-methallylmagnesium chloride was used
for the preparation of the corresponding alane, the cross-
coupling yielded 2-(20-methylprop-10-enyl)-4,6-dimethoxy-
1,3,5-triazine (2o), isolated in 62% yield. (iv) Tribenzyl-
alane was particularly reactive and afforded the desired 2 g
in 74% yield (Table 3, entry 7). (v) Eventually, triarylalanes
could be employed in the cross-coupling reaction with 1,
although the outcome of the reaction seemed to depend on
the nature of the transferred aryl residue. As a matter of fact,
while triphenylalane and tri(4-methoxyphenyl)alane
afforded 2h and 2j in very good yields (Table 3, entries 08
and 10, respectively), it was not possible to obtain 2-(3 -
fluorophenyl)-4,6-dimethoxy-1,3,5-triazine (2i, Table 3,
entry 9), contrary to what was observed with Grignard
reagents (see Table 1, entries 6–8).
Table 4. Cross-coupling reaction between 1 and benzyl(aryl)diethylalanes
REt2Ala
Entry
t (h)
Et2O/THF
R
2 % Yieldb
1
68
3
25
10
70/30
100/0
0/100
70/30
Bn (g)
Bn (g)
p.MeOC6H4 (j)
Ph (h)
35c
35c
71
2d
3
4
65e
a Reactions carried out in the presence of Pd(PPh3)4 in refluxing solvent,
1/REt2Al/catZ1/1.15/0.03; 100% conversion (glc).
b Chromatographic yield.
c 2-Ethyl-4,6-dimethoxy-1,3,5-triazine (2d) was also detected (glc).
d Reaction carried out in the presence of PdCl2(PPh3)2.
e Isolated yield.
The results concerning trialkyl (or aryl) alanes showed that

S. Samaritani et al. / Tetrahedron 61 (2005) 4475–4483
4479
Table 5. Cross-coupling reaction between 1 and in situ prepared organozinc
halidesa
3. Conclusions
In the search for a0general, simple approach to the synthesis
of 2-alkyl (alk-1 -enyl- or aryl or allyl or benzyl)-4,6-
dialkoxy-1,3,5-triazines, the reactivity of commercially
available 1 has been investigated in Pd- or Ni-catalyzed
cross-coupling processes with organostannanes, Grignard
reagents, symmetrical and non-symmetrical organoalanes
and organozinc halides. It has been found that all the
organometallic reagents studied can be used to form new
C–C bonds on the heteroaromatic ring and that the choice of
the alkylating agent and/or the experimental conditions can
be modulated in dependence on the residue to transfer. In
particular: (i) according to what previously observed in the
case of aryltin derivatives,1e alk-1-enyl- and allylstannanes
afforded good results and, at least in the case of allyl
derivative 2b, suitable work-up conditions have been found
to avoid double bond migration. (ii) Kumada cross-coupling
proved a very simple, convenient and economical process
for the transfer of saturated chains. Unfortunately, the same
methodology was not synthetically useful to transfer benzyl
and b-methallyl residues. In the case of aryl Grignard
reagents, the yield seems to be affected by the nature of the
substituents, although further experiments are necessary to
account for this. (iii) Critical observations concerning the
synthesis of alk-1-enyl organometallic reagents suggested
the use of alk-1-enyldialkylalanes for the preparation of
2-(alk-10-enyl)-4,6-dimethoxy-1,3,5-triazines. Unfortu-
nately the reaction fails, even in the presence of ZnCl2,14b
in the case of a-branched and/or b-hindered residues. On the
other hand, organoalanes (R3Al) were found to be efficient
agents in the alkylation, benzylation and arylation of 1. This
last process can be carried out also by using the
economically more convenient aryldiethylalanes, which, at
least in the case of 2j, afforded the product in even better
yield than using organotin derivatives.1e Moreover, the easy
in situ preparative protocol of these organometallic reagents
has to be underlined. (iv) The cross-coupling reactions
between 1 and organozinc halides were also very interest-
ing, not only for the synthesis of functionalized 2p, but also
in the case of 2c,f, h–j
Entry
t (h)
Et2O/THF
R
2 % Yieldb
1c,d
2
3
2
2
1.5
4
0/100
90/10
65/35
100/0
0/100
p.EtOOCC6H4 (p) 78
p.MeOC6H4 (j)
Ph (h)
i.Pr (f)
80e
91
3
4
64f
42
5d
b-Methallyl (c)
a Reactions carried out at room temperature, in the presence of prereduced
(i.PrMgCl) PdCl2(PPh3)2, 1/RZnX/catZ1/1.15/0.03, 100% conversion if
not otherwise stated.
b Isolated yield.
c The organozinc reagent was commercially available.
d 90% conversion (glc).
e Chromatographic yield.
f
5% of 2-n.propyl-4,6-dimethoxy-1,3,5-triazine was also present.17
65% yields, respectively (Table 4, entries 3 and 4), thus
showing that aryldiethylalanes are at least comparable with
aryltributyltin reagents in this type of cross-coupling
reactions.1e
After investigation of the experimental conditions suitable
for the selective transfer of alkyl, aryl, alkenyl residues, the
synthesis of some functionalized derivatives was con-
sidered. The inspection of the literature would suggest use
of organotin reagents, which tolerate most functional groups
well, nevertheless the long and often expensive procedures
necessary for their preparation prompted us to test the
reactivity of 1 towards organozinc reagents.18–21
Commercial 4-carbethoxyphenylzinc iodide was reacted
with 1 in the presence of PdCl2(PPh3)2, after the reduction
of the catalyst by iso-propylmagnesium chloride (Table 5,
entry 1) and afforded the expected product 2p in very good
(78%) yield. This encouraging result suggested the use of
organozinc reagents as alternative alkylating agents with
respect of Grignard reagents.
Our results provide useful guidelines to choose the suitable
organometallic reagent (Sn, Mg, Al, Zn), as well as the
catalytic system (Pd or Ni) for a direct, time-saving
preparation of 2-alkyl (aryl or alk-10-enyl or allyl)-4,6-
dimethoxy-1,3,5-triazines.
Some organozinc derivatives were thus prepared by
transmetallation,21 starting from the corresponding organo-
magnesium compound and were used under the same
reaction conditions affording 2p.
4. Experimental
The yields in the expected products, after generally short
reaction times, were very good and polyalkylation
byproducts were never observed in the reaction mixtures
(Table 5, entries 2–5).
4.1. General procedures and materials
Solvents were purified and dried by standard methods.22
2-Chloro-4,6-dimethoxy-1,3,5-triazine (CDMT, 1) was
prepared according to a reported procedure.23 Benzyl- and
allylmagnesium chlorides (1 and 2 M, respectively in
diethylether) and 4-carbethoxyphenylzinc iodide (0.5 M in
THF) were purchased from Aldrich; the other Grignard
reagents used were prepared from the corresponding alkyl
halides according to reported procedures.24,25 (S)-2-methyl-
butylmagnesium chloride was prepared from (S)-2-methyl-
1-chlorobutane (optical purity 97.5%26). Hydroalumination
It has to be underlined that, when iso-propylzinc chloride
was used, the reaction was not optimized to avoid the
isomerization product (Table 5, entry 4) and that the cross-
coupling with b-methallylzinc chloride afforded 2c in
moderate (42%) yield (Table 5, entry 5). Anyway, the
simplicity of the whole one-pot cross-coupling process
make it undoubtedly interesting in the planning of 2-alkyl-
4,6-dialkoxy-1,3,5-triazines.

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S. Samaritani et al. / Tetrahedron 61 (2005) 4475–4483
of alk-1-ynes was performed according to described
protocols.11a,27 Chlorotributyltin (Aldrich) and chloro-
diethylalane (Schering) were distilled before use (bp
93–95 8C/0.2 mmHg28 and 90 8C/10 mmHg15); aluminium
trichloride was sublimed (194 8C)29 under nitrogen; zinc
dichloride (Aldrich) was dried at 140 8C/0.03 mmHg
(15 h);30 the catalysts Pd(PPh3)4, PdCl2(PPh3)2 and NiCl2-
(dppe) were prepared according to literature.31–33 GLC
analyses were performed on a Perkin–Elmer 8500 instru-
ment [ZB1 capillary column (15 m!0.25 mm), film
0.25 mm] equipped with a flame ionization detector and a
split–splitless injector, with He as carrier gas. The
evaluation (glc) of conversions and yields was carried out
by using suitable hydrocarbons as internal standards. Thin
layer chromatography (TLC) analyses were performed on
silica gel 60 plates (Fluka) and flash chromatography
purifications were carried out on silica gel 60 (Fluka, 230–
400 mesh) using the eluting mixtures (v/v) reported for each
case. Melting points were determined using a Kofler hot-
stage apparatus and are not corrected. Optycal rotatory
power was measured by a Perkin–Elmer 142 polarimeter.
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 taken on a
Perkin–Elmer Q-Mass 910 instrument.
(1 equiv) was slowly added to a cooled (0 8C) diethyl
ether solution of dry ZnCl2 (0.615 g, 4.60 mmol) and the
mixture was stirred at 0 8C for 15 min.
4.6. Reaction of 1 with organotin compounds (Scheme 1)
In a typical procedure, a THF (20 ml) solution of 1 (0.500 g,
2.85 mmol) was treated, under nitrogen, with PdCl2(PPh3)2
(0.03 equiv) and the suitable organotin compound
(1.1 equiv); the mixture was refluxed (12–40 h) until
satisfactory conversion of 1 (TLC and glc) was achieved.
The reaction mixture was cooled and treated according to
one of the following procedures: Procedure A: (1) treatment
with 60% KF aqueous solution; (2) filtration on Florisilw/
silica gel; Procedure B: (1) filtration on Florisilw/silica gel;
(2) treatment with 60% KF aqueous solution. The recovered
organic phase was dried over Na2SO4 and, after removal of
solvents, the crude products were purified by flash
chromatography. Chemically pure 2a–c (for the character-
izations see below) were isolated in 70, 69 and 55% yields,
respectively.
4.7. Reaction of 1 with RMgX (Table 1)
In a typical procedure, the suitable Grignard reagent
(1.15 equiv) was quickly added to a cooled (0 8C) solution
of 1 (0.500 g, 2.85 mmol) and NiCl2(dppe) (0.05 equiv) in
diethyl ether. The mixture was stirred at room temperature
until a satisfactory conversion of 1 (TLC and glc) was
achieved. After hydrolysis with a saturated solution of
NH4Cl, the reaction mixture was extracted in CHCl3,
dried over Na2SO4 and, after removal of the solvent, the
crude products were purified by flash chromatography.
Chemically pure 2d–j (for the characterizations see below)
were isolated in 30–75% yields.
4.2. Synthesis of organotin compounds
Chlorotributyltin (0.8 equiv) in THF was slowly added to a
solution of the suitable Grignard reagent in the same
solvent, and the reaction mixture was refluxed until
complete conversion of the chlorotributyltin (GLC,
GC/ms). The mixture was hydrolysed (NH4Claq) extracted
with diethyl ether and dried; after removal of the
solvent (20 mmHg) the crude product was purified by
distillation. The pure organotin derivatives, obtained with
the reported yield, showed: (E,Z)-prop-1-enyltributyltin
(77%, bp 86–88 8C/1 mmHg, E/ZZ60/40, glc); prop-2-
enyltributyltin (81%, bp 84–87 8C/0.05 mmHg, lit.34
106 8C/0.1 mmHg); 2-methylprop-2-enyltributyltin (77%,
bp 119–120 8C/1 mmHg, lit.35 110 8C/0.3 mmHg).
4.8. Reaction of 1 with alk-1-enyldi-isobutylalanes
(Table 2)
The hexane solution of alkenylalane was diluted with THF
(THF/hexane see Table 2) and treated with 1 (0.500 g,
2.85 mmol) and Pd(PPh3)4 (0.03 equiv); the reaction
mixture was stirred at the temperature and for the time
reported in Table 2 and was monitored by TLC and glc.
After hydrolysis with a saturated aqueous solution of
NH4Cl, the reaction mixture was extracted with CHCl3,
dried over Na2SO4 and, after removal of the solvent, the
crude products were purified by flash chromatography.
Chemically pure 2k and l (for the characterizations see
below) were isolated in 58 and 51% yields, respectively.
4.3. In situ preparation of symmetrical organoalanes
In a typical procedure, an ethereal solution of freshly
sublimed AlCl3 (0.400 g, 3.00 mmol) was slowly added to
the suitable Grignard reagent (3 equiv) and the mixture was
stirred for 1–12 h at room temperature.
4.9. Reaction of 1 with symmetrical organoalanes
(Table 3)
4.4. In situ preparation of diethylbenzyl (or aryl)
organoalanes
A mixture of solid 1 (0.500 g, 2.85 mmol) and PdCl2(PPh3)2
(0.03 equiv) was added to the white suspension of AlR3 and
the mixture was stirred under the experimental conditions
described in Table 3 until the maximum conversion of 1
(TLC and glc) was achieved. After hydrolysis with a
saturated aqueous solution of NH4Cl, the reaction mixture
was extracted with CHCl3, dried over Na2SO4 and, after
removal of the solvent, the crude products were purified by
flash chromatography. Chemically pure 2d–j,m–o (for the
In a typical procedure, the suitable Grignard reagent
(1 equiv) was added to a cooled (0 8C) ethereal solution of
freshly distilled Et2AlCl (0.2 ml, 1.6 mmol), and the
reaction mixture was stirred at room temperature for 8 h.
4.5. In situ preparation of organozinc halides
In a typical procedure, the suitable Grignard reagent

S. Samaritani et al. / Tetrahedron 61 (2005) 4475–4483
4481
characterizations see below) were isolated in 43–88%
yields.
(dt, JZ6.9 Hz, J0Z1.5 Hz, 2H), 3.61 (s, 6H), 5.03–5.16 (m,
2H), 6.20 (ddt, JZ17.2 Hz, J0Z10.1 Hz, J00Z6.9 Hz, 1H),
13C NMR (C6D6): 43.3, 54.5, 117.4, 133.5, 173.0, 181.2.
Anal. Calcd for C8H11N3O2: C 53.03, H 6.12, N 23.19%;
found: C 53.00, H 6.15, N 23.23%.
4.10. Reaction of 1 with benzyl (or aryl) diethylalanes
(Table 4)
4.12.4. 2-(20-Methyl-20-propenyl)-4,6-dimethoxy-1,3,5-
triazine (2c). Petroleum spirit/ethyl acetate 85/15 v/v,
pale yellow oil; GC/ms (m/z, I%): 195 (MC%, 22), 194
(100), 181 (6), 180 (67), 155 (25), 126 (6), 125 (5), 123 (8),
122 (6), 109 (9), 96 (9), 95 (7), 82 (8), 80 (7), 72 (14), 70
(13), 69 (10), 58 (11); 1H NMR: 1.47 (s, 3H), 3.50 (s, 2H),
4.09 (s, 6H), 4.92 (d, JZ1.5 Hz, 1H), 4.96 (d, JZ1.5 Hz
1H); 13C NMR: 22.8, 47.4, 55.2, 114.4, 140.9, 172.8, 181.4.
Anal. Calcd for C9H13N3O2: C 55.37, H 6.71, N 21.52%;
found: C 55.33, H 6.75, N 21.50%.
Following the same protocol as 4.9, compound 1 (0.500 g,
2.85 mmol), Pd(PPh3)4 (0.03 equiv) and the organoalanes
were reacted under the experimental conditions specified in
Table 4. The reaction mixture was stirred until the complete
conversion of 1 (TLC and glc) was achieved. After
hydrolysis with a saturated solution of NH4Cl, the reaction
mixture was extracted with CHCl3, dried over Na2SO4 and,
after removal of the solvent, the crude products were
purified by flash chromatography. The reaction afforded
2g,h,j in 35, 65 and 71% yields, respectively.
4.11. Reaction of 1 with RZnX (Table 5)
4.12.5. 2-Ethyl-4,6-dimethoxy-1,3,5-triazine (2d).
Petroleum spirit/ethyl acetate 70/30 v/v; white solid mp
67 8C; GC/ms: (m/z, I%): 170 (4), 169 (MC%, 100), 168 (67),
154 (41), 101 (30), 83 (10), 70 (55), 69 (54), 68 (19), 58 (6),
To the suspension of organozinc halide, 1 (0.500 g,
2.85 mmol) and the catalyst, prepared immediately before
use by addition of 2 equiv of i-PrMgCl to PdCl2(PPh3)2,
were added. The reaction mixture was stirred at room
temperature until the complete conversion of 1 (TLC and
glc) was achieved (Table 5). After hydrolysis with a
saturated aqueous solution of NH4Cl, the reaction mixture
was extracted with CHCl3, dried over Na2SO4 and, after
removal of the solvent, the crude products were purified by
flash chromatography. The reaction afforded 2c,f,h,j,p in
42–91% yields (Table 5).
1
56 (14); H NMR: 1.38 (t, JZ7.7 Hz, 3H), 2.83 (q, JZ
7.6 Hz, 2H), 4.10 (s, 6H); 13C NMR: 11.5, 32.1, 55.3, 172.7,
184.5. Anal. Calcd for C7H11N3O2: C 49.70, H 6.55, N
24.84%; found: C 49.73, H 6.57, N 24.80%.
4.12.6. 2-(20-Methylpropyl)-4,6-dimethoxy-1,3,5-triazine
(2e). Hexane/ethyl acetate 70/30 v/v, yellow oil; GC/ms
(m/z, I%): 197 (MC%, 1), 196 (4), 182 (36), 155 (100), 126
(10), 101 (4), 82 (14), 72 (16), 69 (12), 58 (46), 55 (23); 1H
NMR: 0.79 (d, JZ6.6 Hz, 6H), 2.12 (sept, JZ6.8 Hz, 1H),
2.44 (d, JZ7.2 Hz, 2H), 3.87 (s, 6H); 13C NMR: 22.3, 27.4,
47.4, 54.8, 172.2, 182.6. Anal. Calcd for C9H15N3O2: C
54.81, H 7.67, N 21.30%; found: C 54.84, H 7.69, N
21.28%.
4.12. Characterization of products 2a–p
For each of the prepared products the flash chromatography
conditions, as well as the chemical-physical and spectro-
scopic characterization are reported.
4.12.1. (E/Z) 2-(10-Propenyl)-4,6-dimethoxy-1,3,5-tria-
zine ((E/Z)-2a). Hexane/acetone 75/25 v/v, pale yellow
oil; diastereoisomeric ratio E/Z (glc): 60/40; GC/ms (m/z,
I%) for Z isomer: 181 (MC%, 12), 166 (100), 151 (36), 109
4.12.7. 2-isoPropyl-4,6-dimethoxy-1,3,5-triazine (2f).
Hexane/ethyl acetate 80/20 v/v, yellow oil; GC/ms (m/z,
I%): 183 (MC%, 13), 182 (10), 169 (10), 168 (100), 72 (10),
1
70 (14), 69 (13), 68 (24), 58 (13); H NMR: 1.19 (d, JZ
13.2 Hz, 6H), 2.86 (sept, JZ13.3 Hz, 1H), 3.92 (s, 6H); 13C
NMR: 20.5, 36.8, 54.8, 172.3, 187.4. Anal. Calcd for
C8H13N3O2: C 52.45, H 7.15, N 22.94%; found: C 52.48, H
7.11, N 22.90%.
1
(52), 82 (9), 66 (18), 58 (49); for E isomer see 4.12.2; H
NMR: 1.98, 2.35 (2dd, JZ7.0 Hz, J0Z1.2 Hz, JZ7.0 Hz,
J0Z1.7 Hz, 3H), 4.05 (s, 6H), 6.27–6.53, 7.43 (m and dq,
JZ16.0 Hz, J0Z7.0 Hz, 2H); 13C NMR: 26.7, 27.7, 54.0,
54.9, 127.3, 129.2, 142.3, 172.4, 174.5, 175.3. Anal. Calcd
for C8H11N3O2: C 53.03, H 6.12, N 23.19%; found: C 53.09,
H 6.14, N 23.15%.
4.12.8. 2-Benzyl-4,6-dimethoxy-1,3,5-triazine (2g).
Hexane/acetone 80/20 v/v, dark yellow oil; GC/ms: (m/z,
I%): 231 (MC%, 38), 230 (100), 216 (14), 201 (6), 159 (9),
1
4.12.2. (E)-2-(10-Propenyl)-4,6-dimethoxy-1,3,5-triazine
((E)-2a). Hexane/ethyl acetate 70/30 v/v, pale yellow oil;
GC/ms (m/z, I%): 181 (MC%, 100), 166 (43), 151 (34), 136
(47), 126 (14), 109 (26), 93 (21), 82 (18), 69 (41), 58 (60);
1H NMR: 1.98 (dd, JZ7.0 Hz, J0Z1.6 Hz, 3H), 4.04 (s,
6H), 6.37 (dq, JZ16.0 Hz, J0Z1.6 Hz, 1H), 7.43 (dq, JZ
15.0 Hz, J0Z7.0 Hz, 1H); 13C NMR: 29.6, 54.8, 129.2,
142.5, 172.4, 174.5. Anal. Calcd for C8H11N3O2: C 53.03, H
6.12, N 23.19%; found: C 53.09, H 6.14, N 23.15%.
158 (9), 132 (23), 117 (12), 116 (12), 91 (18), 69 (4); H
NMR: 4.06 (s, 6H), 4.08 (s, 2H), 7.20–7.50 (m, 5H); 13C
NMR: 45.0, 54.8, 126.6, 128.3, 129.2, 136.3, 172.4, 181.3.
Anal. Calcd for C12H13N3O2: C 62.33, H 5.67, N 18.17%;
found: C 62.35, H 5.70, N 18.13%.
4.12.9. 2-Phenyl-4,6-dimethoxy-1,3,5-triazine (2h).
Petroleum spirit/ethyl acetate 85/15 v/v, white solid mp
66 8C; GC/ms: 218 (MCC1, 13), 217 (MC%, 100), 216 (33),
187 (45), 186 (27), 172 (49), 104 (49), 103 (19), 77 (17), 69
(28); 1H NMR: 4.21 (s, 6H), 7.52–7.66 (m, 3H), 8.56–8.60
(m, 2H); 13C NMR: 55.4, 128.7, 129.3, 133.0, 135.3, 173.2,
175.2. Anal. Calcd for C11H11N3O2: C 60.82, H 5.10, N
19.34%; found: C 60.84, H 5.07, N 19.36%.
4.12.3. 2-(20-Propenyl)-4,6-dimethoxy-1,3,5-triazine
(2b). Hexane/ethyl acetate 70/30 v/v, pale yellow oil;
GC/ms (m/z, I%): 181 (MC%, 15), 180 (99), 155 (7), 108
(4), 82 (6), 69 (4), 41 (73), 39 (100); 1H NMR (C6D6): 3.44

4482
S. Samaritani et al. / Tetrahedron 61 (2005) 4475–4483
4.12.10. 2-(30-Fluorophenyl)-4,6-dimethoxy-1,3,5-tria-
zine (2i). Chemical–physical and spectroscopic properties
were in agreement with the previously reported
characterization.1e
1H NMR: 1.98 (m, 3H), 2.34 (m, 3H), 3.99 (s, 6H), 6.18 (m,
1H); 13C NMR: 21.5, 28.8, 55.2, 123.5, 155.0, 172.6, 175.6.
Anal. Calcd for C9H13N3O2: C 55.37, H 6.71, N 21.52%;
found: C 55.39, H 6.74, N 21.49%.
4.12.11. 2-(40-Methoxyphenyl)-4,6-dimethoxy-1,3,5-tria-
zine (2j). Hexane/ethyl acetate 80/20 v/v; white solid mp
93–95 8C; GC/ms (m/z, I%): 247 (MC%, 100), 217 (20), 202
4.12.17. 2-(40-Ethoxycarbonylphenyl)-4,6-dimethoxy-
1,3,5-triazine (2p). Hexane/ethyl acetate 70/30 v/v; white
solid, mp 89–91 8C; GC/ms (m/z, I%): 289 (MC%, 75), 261
(11), 259 (26), 245 (16), 244 (100), 231 (11), 216 (18), 186
(44), 176 (27), 159 (33), 148 (16), 144 (27), 132 (10), 130
(28), 116 (12), 107 (12), 104 (10), 103 (20), 102 (44), 100
(26), 99 (15), 90 (10), 84 (12), 76 (27), 75 (25), 72 (48), 70
1
(35), 176 (18), 159 (10), 134 (54), 90 (12), 69 (13); H
NMR: 3.88 (s, 3H), 4.11 (s, 6H), 6,97 (d, JZ9.1 Hz, 2H),
8,46 (d, JZ9.1 Hz, 2H), 13C NMR: 55.0, 55.4, 113.8, 127.5,
130.9, 163.6, 172.7, 174.4. Anal. Calcd for C12H13N3O3: C
58.29, H 5.30, N 16.99%; found: C 58.32, H 5.27, N
16.96%.
1
(14), 69 (66); H NMR: 1.40 (t, JZ7.1 Hz, 3H), 4.11 (s,
6H), 4.39 (q, JZ7.1 Hz, 2H), 8.12 (d, JZ8.7 Hz, 2H), 8.53
(d, JZ8.7 Hz, 2H); 13C NMR: 14.3, 55.3, 61.5, 128.9,
129.6, 134.1, 138.9, 166.1, 173.0, 174.1. Anal. Calcd for
C14H15N3O4: C 58.13, H 5.23, N 14.53%; found: C 58.15, H
5.20, N 14.57%.
4.12.12. 2-(Hex-10-enyl)-4,6-dimethoxy-1,3,5-triazine
(2k). Hexane/acetone 85/15 v/v; yellow oil; GC/ms (m/z,
I%): 223 (MC%, 29), 208 (55), 194 (100), 180 (66), 166 (37),
155 (31), 151 (7), 122 (11), 108 (9), 94 (14), 80 (28), 69
1
(21), 58 (73); H NMR: 0.86 (t, JZ7.0 Hz, 3H), 1.17–1.50
(m, 4H), 2.25 (qd, JZ7.3 Hz, J0Z1.5 Hz, 2H), 3.99 (s, 6H),
6.28 (dt, JZ15.2 Hz, J0Z1.8 Hz, 1H), 7.23 (dt, JZ15.6 Hz,
J0Z7.0 Hz, 1H); 13C NMR: 14.0, 22.5, 30.5, 32.6, 55.1,
128.0, 147.9, 172.7, 175.0. Anal. Calcd for C11H17N3O2: C
59.17, H 7.67, N 18.82%; found: C 59.20, H 7.68, N
18.80%.
Acknowledgements
Financial support by University of Pisa is gratefully
acknowledged. Authors thank Prof. Anna Maria Caporusso
for providing a sample of 3-methylpentyne.
4.12.13. 2-(20-Phenylethenyl)-4,6-dimethoxy-1,3,5-tria-
zine (2l). Petroleum spirit/ethyl acetate 70/30 v/v; white
solid mp 82–84 8C; GC/ms (m/z, I%): 243 (MC%, 32), 242
(100), 228 (19), 185 (25), 171 (10), 170 (32), 128 (32), 77
References and notes
1
(12), 69 (9); H NMR: 4.15 (s, 6H), 7.08 (d, JZ15.7 Hz,
1H), 7.46 (m, 3H), 7.68 (m, 2H), 8.24 (d, JZ15.7 Hz, 1H);
13C NMR: 55.2, 125.5, 128.4, 129.1, 130.2, 135.5, 142.8,
172.8, 175.1. Anal. Calcd for C13H13N3O2: C 64.19, H 5.39,
N 17.27%; found: C 64.21, H 5.42, N 17.24%.
1. (a) Kukla, M. J.; Ludovici, D. W.; Janssen, P. A. J.; Heeres, J.;
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4.12.14. 2-n-Hexyl-4,6-dimethoxy-1,3,5-triazine (2m).
Hexane/ethyl acetate 80/20 v/v; yellow oil; GC/ms (m/z,
I%): 224 (MC%K1, 1), 210 (5), 182 (30), 168 (39), 155
1
(100), 87 (7), 72 (9), 69 (6); H NMR0: 0.68 (t, JZ6.9 Hz,
3H), 1.06–1.20 (m, 6H), 1.59 (tt, JZJ Z7.6 Hz, 2H), 2.53
(t, JZ7.6 Hz, 2H) 3.84 (s, 6H); 13C NMR: 13.8, 22.3, 27.1,
28.7, 31.3, 38.4, 54.7, 172.2, 183.4. Anal. Calcd for
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26
589
0.3), 210 (0.8), 196 (17.5), 182 (20), 155 (100), 72 (11), 69
(6), 58 (34), 41 (45); H NMR: 0.72–0.77 (d and t, JdZ
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1
6.6 Hz, JtZ7.3 Hz, 6H), 1.11 (m, 1H), 1.25 (m, 1H), 1,92
(m, 1H), 2.35 (dd, JZ13.5 Hz, J0Z8.1 Hz, 1H), 2.58 (dd,
JZ13.5 Hz, J0Z6.3 Hz, 1H), 3.9 (s, 6H); 13C NMR: 11.1,
18.9, 29.2, 33.6, 45.4, 54.8, 172.2, 182.9. Anal. Calcd for
C10H17N3O2: C 56.85, H 8.11, N 19.89%; found: C 56.84, H
8.09, N 19.92%.
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GC/ms (m/z, I%): 182 (MK1, 3), 168 (43), 155 (100), 72 (10),
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3H), 1.70 (tq, JZJ0Z7.5 Hz, 2H), 2.60 (t, JZ7.5 Hz, 2H),
3.92 (s, 6H); 13C NMR: 13.5, 20.5, 40.3, 54.8, 172.2, 183.1.
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