Cobalt-catalyzed arylation or benzylation of 2-chloro-4,6-dimethoxy-1,3,5- triazine

Article abstract of DOI:10.1055/s-0029-1218307

A variety of functionalized aryl bromides or benzyl chlorides were coupled with 2-chloro-4,6-dimethoxy-1,3,5-trazine in good yields by a one-step procedure via cobalt catalysis. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218307

3192
LETTER
Cobalt-Catalyzed Arylation or Benzylation of 2-Chloro-4,6-dimethoxy-1,3,5-
triazine
Arylation
e
or Benzylat
a
ion of 2-Ch
n
loro-4,6-dim
n
ethoxy-1,3,5
e
-triazine Marie Bégouin,a Stéphanie Claudel,a Corinne Gosmini*b
a
Institut de Chimie et des Matériaux Paris Est, ICMPE, CNRS-Université de Paris, 12 Val de Marne, UMR7182,
2-8 rue Henri Dunant, 94320 Thiais, France
b
Laboratoire Hétéroéléments et Coordination, Ecole Polytechnique, CNRS, 91128 Palaiseau Cedex, France
Fax +33(1)69334440; E-mail: corinne.gosmini@polytechnique.edu
Received 11 September 2009
cross-coupling reaction devoted to the direct synthesis of
2-aryldiazines such as 2-arylpyrimidines or 2-arylpyra-
zines.12 The key step of this procedure is the formation of
aromatic organozinc reagents and their coupling with
2-chlorodiazines using the same cobalt catalyst. However,
this last protocol cannot be applied to 2-chloropyridines as
coupling partners.13
Abstract: A variety of functionalized aryl bromides or benzyl chlo-
rides were coupled with 2-chloro-4,6-dimethoxy-1,3,5-trazine in
good yields by a one-step procedure via cobalt catalysis.
Key words: cobalt, catalysis, cross-coupling, arylation, azo com-
pounds
In the course of our work on the cobalt-catalyzed cross-
coupling of nitrogen heteroaromatic compounds, the cur-
rent paper deals with a method of coupling of organozinc
compounds with a halotriazine. It seems interesting to de-
velop a convenient method for the one-step synthesis of
various 2-aryl (or benzyl)-4,6-dimethoxy-1,3,5-triazines.
To the best of our knowledge, this is the first cobalt-cata-
lyzed reductive coupling of aryl or benzyl halides with 2-
chloro-4,6-dimethoxy-1,3,5-trazine. Stemming from our
previous results concerning the reactivity of aryl zinc spe-
cies obtained under cobalt catalysis,14 we were convinced
that 2-chloro-4,6-dimethoxy-1,3,5-trazine could be cross-
coupled in the same way with these arylzinc species.
Therefore, we first investigated a two-step coupling in-
volving formation of 4-(ethoxycarbonyl)phenyl zinc bro-
mide from ethyl 4-bromobenzoate using cobalt catalysis
and subsequent coupling with 2-chloro-4,6-dimethoxy-
1,3,5-triazine without further addition of cobalt catalyst
(Scheme 1).
1,3,5-Triazines have emerged as versatile heterocycles
finding applications either as ligand in the palladium-cat-
alyzed Suzuki–Miyaura cross-coupling1 or in material2 as
well as in medicinal chemistry. In the latter field, 1,3,5-tri-
azines constitute the pharmacophore of therapeutic agents
used to treat cancer,3 diabetes,4 dyslipidaemia,5 microbial
and bacterial infections6 or inflammatory diseases.7 More
specifically, recent studies have shown promising acti-
vities for 2,4,6-tris(N,N-dialkylamino)-1,3,5-triazines
against cancer which stressed the need for developing ef-
ficient access to other 2-aryl- (or benzyl)-substituted
1,3,5-triazines. Then, classical cross-coupling processes
such as the Kumada, Corriu, Negishi, Stille, or Suzuki
reactions are of utmost importance to create C–C bonds
for modern organic synthesis and are heavily dominated
by the use of palladium or nickel complexes, presenting
an excellent compatibility with many functional groups.8
In this manner, Menicagli et al.9 have worked on the
cross-coupling of various organometallic reagents with
chlorotriazines using Pd or Ni catalysis. However, these
catalysts have some disadvantages resulting from the high
price of palladium precursors, the toxicity of nickel salts
and the need for ancillary ligands to stabilize and activate
these catalytic species. Fortunately, inexpensive, stable
and toxicologically benign iron or cobalt salts as catalyst
under ‘ligand-free’ conditions are commercially avail-
able. The elegant iron methodology is essentially limited
to cross-coupling of Grignard, organomanganese or re-
cently organozinc reagents with various compounds.10 In
these cross-coupling protocols, the major difficulty lies in
the preparation of functionalized organometallics. More-
over, sometimes cobalt catalysts can present a higher re-
activity for various C–C bond-forming reactions that has
been demonstrated by different groups and ours.11 Recent-
ly, we have reported a very efficient Co(II)-mediated
The coupling product was detected in 79% GC yield.
Then, we tried to develop a simple Barbier-type procedure
and applied this method to various aromatic bromides
(Scheme 2).
As shown in Table 1, this reaction was successful with
various aryl bromides and the resulting products were iso-
lated in good to excellent yields. As described for the oth-
er Barbier-type procedures using cobalt catalysis, the
major by-product was the reduction one, whereas the ho-
mocoupling product was detected in small amounts. Con-
trary to the coupling with 2-chlorodiazines, coupling in
the ortho, meta or para position led to good yields at room
temperature. Under these standard conditions described
for aromatic bromides, the reaction with 3-thienyl bro-
mide was particularly longer due to its lower reactivity
and its coordination to the cobalt catalyst as previously re-
ported.15
SYNLETT 2009, No. 19, pp 3192–3194
x
x
.x
x
.2
0
0
9
We have extended this cross-coupling of 2-chloro-4,6-
dimethoxy-1,3,5-triazine with various functionalized ben-
Advanced online publication: 23.10.2009
DOI: 10.1055/s-0029-1218307; Art ID: G32109ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Arylation or Benzylation of 2-Chloro-4,6-dimethoxy-1,3,5-triazine
3193
MeO
N
OMe
Cl
N
OMe
N
N
N
N
ZnBr
1) AllylCl (0.3 equiv)
MeCN, CF3CO2H
r.t.
OMe
CoBr2
(0.1 equiv)
+
Zn
Br
2)
(2.5 equiv)
COOEt
79% GC
COOEt
EtOOC
Scheme 1 Two-step procedure for the reductive cross-coupling of 4-EtO2CC6H4Br with 2-chloro-4,6-dimethoxy-1,3,5-triazine
Table 2 Cross-Coupling between 2-Chloro-4,6-dimethoxy-1,3,5-
triazine and Various Benzyl Halides
CoBr2
(0.1 equiv)
1) AllylCl (0.3 equiv)
MeCN, CF3CO2H, r.t.
FG
N
N
OMe
+
Br
Cl
N
Entry
FG-C6H4CH2X
C6H5CH2Cl
Product
12
Yield (%)
2)
OMe
Zn
N
+
(2.5 equiv)
FG
N
N
1
2
3
4
5
6
7
8
80
50
67
67
85
65
77
54
OMe
OMe
C6H5CH2Br
12
Scheme 2 CoBr2-catalyzed synthesis of 2-aryl-4,6-dimethoxy-
1,3,5-triazines
4-ClC6H4CH2Cl
3-MeC6H4CH2Cl
4-FC6H4CH2Cl
4-F3CC6H4CH2Cl
4-MeO2CC6H4CH2Cl
4-NCC6H4CH2Cl
13
14
Table 1 Cross-Coupling between 2-Chloro-4,6-dimethoxy-1,3,5-
triazine and Various Aryl Bromides
15
16
Entry
FG
Time
3 h
Product
Yield (%)
17
1
2
3-F
1
2
84
68
80
51
70
92
73
67
89
88
73
18
4-F
1 h
the other hand, this Barbier-type procedure applied to
benzyl bromide led to a lower yield (Table 2, entry 2).
3
4-EtO2C
2-EtO2C
4-NC
1 h
3
4
1 h
4
In order to examine the role of cobalt catalyst in this reac-
tion, we decided to use a benzylzinc species synthesized
without cobalt. In fact, these last compounds can be ob-
tained without cobalt catalyst in acetonitrile unlike aryl-
zinc bromides. Thus, we synthesized the benzylzinc
bromide in acetonitrile by using zinc dust activated by tri-
fluoroacetic acid and the 2-chloro-4,6-dimethoxy-1,3,5-
trazine was added in the solution. The resulting mixture
was stirred for one hour at ambient temperature and no
cross-coupling occurred. On the other hand, when we add-
ed a catalytic amount of CoBr2 (10 mol%) in the second
step, cross-coupling product was immediately formed. By
this experience, we have demonstrated that cobalt catalyst
plays an important role in the subsequent reaction with
2-chloro-4,6-dimethoxy-1,3,5-triazine (Scheme 4).
5
1 h
5
6
4-F3C
30 min
4 min
1.5 h
30 min
30 min
5 h
6
7
4-Cl
7
8
4-MeO
2-MeO
3-MeO
3-Br-thiophene
8
9
9
10
11
10
11
FG
CoBr2
(0.1 equiv)
1) AllylCl (0.3 equiv)
MeCN, CF3CO2H, r.t.
N
OMe
However, the yield was lower (30% GC yield) than that in
the Barbier protocol described previously in Scheme 3
with benzylzinc bromide (Table 2, entry 2). In fact, more
homocoupling and reduction products from benzylzinc
bromides were obtained decreasing the cross-coupling
yield.
+
2)
Cl
+
N
OMe
N
N
Zn
(3 equiv)
FG
N
N
OMe
OMe
X
Scheme 3 CoBr2-catalyzed synthesis of 2-benzyl-4,6-dimethoxy-
In conclusion, we have devised an expedient route to var-
ious functionalized 2-aryl (or benzyl)-4,6-dimethoxy-
1,3,5-triazines in a Barbier-fashion for more convenience,
using mild reaction conditions.16 The tolerance of our pro-
tocol toward a variety of functional groups enables the
synthesis of a broad spectrum of valuable compounds
from commercially available aryl bromides or benzyl
1,3,5-triazines
zyl halides via the Barbier procedure described earlier
(Scheme 3).
The results are reported in Table 2. Good to excellent
yields were obtained with various benzyl chlorides. On
Synlett 2009, No. 19, 3192–3194 © Thieme Stuttgart · New York

3194
J. M. Bégouin et al.
LETTER
Cl
1)
N
OMe
N
N
N
OMe
Br
CF3CO2H
OMe
2) CoBr2
ZnBr
+ Zn
N
N
OMe
Scheme 4 Role of the cobalt catalyst in the cross-coupling
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2002, 127, 13856.
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sive and environmentally friendly cobalt halide salt with-
out ligand. Finally, this procedure compares favorably
and makes an excellent complement to palladium- or
nickel-catalyzed methods.
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Synthesis of 2-Aryl-4,6-dimethoxy-1,3,5-triazines and
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Synlett 2009, No. 19, 3192–3194 © Thieme Stuttgart · New York