Efficient palladium-catalyzed synthesis of unsymmetrical (het)aryltetrazines

Article abstract of DOI:10.1055/s-2007-967991

Palladium-catalyzed copper(I)-mediated cross-coupling reaction of 3-methylthio-6-(morpholin-4-yl)-1,2,4,5-tetrazine with a wide range of boronic acids and organotin derivatives led to new unsymmetrical aryl- and hetaryl-substituted tetrazines in moderate

Full text of DOI:10.1055/s-2007-967991

204
LETTER
Efficient Palladium-Catalyzed Synthesis of Unsymmetrical (Het)aryl-
tetrazines
Efficient
P
alladium
i
-Cata
l
c
yzedSynth
o
esis of
U
nsy
l
a
y
s
ltetrazines Leconte,a Anne Keromnes-Wuillaume,b Franck Suzenet,*a Gérald Guillaumeta
a
Institut de Chimie Organique et Analytique, UMR 6005, Université d’Orléans, BP 6759, 45067 Orléans, France
b
CEA Le Ripault, BP 16, 37260 Monts, France
Fax +33(2)38417281; E-mail: franck.suzenet@univ-orleans.fr
Received 27 July 2006
During the course of our investigations on carbon–carbon
bond formation between a 1,2,4,5-tetrazine core and aro-
matic or heteroaromatic derivatives, we thought about
well-established Suzuki or Stille cross-coupling reac-
Abstract: Palladium-catalyzed copper(I)-mediated cross-coupling
reaction of 3-methylthio-6-(morpholin-4-yl)-1,2,4,5-tetrazine with
a wide range of boronic acids and organotin derivatives led to new
unsymmetrical aryl- and hetaryl-substituted tetrazines in moderate
to good yields. These results represent the first cross-coupling reac- tions.11 Kotschy’s group has reported an unsuccessful
Suzuki cross-coupling reaction10 suggesting that boronic
tions of readily available 3-methylthiotetrazine under Suzuki-like
and Stille-like conditions and could extend the scope of tetrazine
chemistry.
acids initiate unexpected side reactions under alkaline
conditions. Furthermore, other reactive organometallic
species such as organolithium, Grignard or arylzinc
Key words: 3-methylthio-1,2,4,5-tetrazine, Pd-catalyzed, Cu(I)-
assisted, Suzuki-like reactions, Stille-like reactions
reagents were unsuccessfull along with an attempted
Heck reaction.10
Over the past two decades, the chemistry of tetrazines has
S
N
N
received a growing interest,1 in particular in the fields of
organic synthesis,2 pesticides3 and pyrotechnics.4 Their
specific reactivity properties, due to an extremely
electron-deficient core, make them a partner of choice in
the inverse-electron demand Diels–Alder reaction5 and
open the way to the synthesis of the core of various natural
products5b,e as well as heterocyclic rings such as
pyridazines5c–f,6 or 1,2,4-triazines.7
N
S
N
N
morpholine (1.2 equiv)
N
N
N
N
EtOH, reflux
overnight
S
O
1 (94%)
Scheme 1 Preparation of 3-methylthio-6-(morpholin-4-yl)-1,2,4,5-
tetrazine 1
An overall view of tetrazine chemistry clearly indicates
that the 3,6-bis(methylthio)-1,2,4,5-tetrazine is readily
accessible6c,12 on a large scale. Liebeskind and co-work-
ers,13 as well as we, have recently developed copper(I)-
mediated palladium-catalyzed cross-coupling reactions
between heteroaromatic thioethers and organoborons14
and organostannanes.15 These methods have been extend-
ed to various thioether substrates.16 We decided to apply
this cross-coupling approach to methylthiotetrazines.
The use of these compounds is weakened by the lack of
synthetic methods providing unsymmetrical tetrazines.
Nucleophilic substitution remains the most common
way, generally by using 3,6-dichloro-, 3,6-bis(3,5-di-
methylpyrazol-1-yl)- or 3,6-bis(methylthio)-1,2,4,5-tetra-
zines.8 The use of amines, thiols or alkoxide derivatives as
nucleophiles often leads to the desired substituted prod-
ucts in good yields.8 However, this subtitution pathway
has deficiencies since the carbon–carbon bond formation According to Kotschy et al. (vide infra),10 3-chloro-
is poorly represented in literature and is restricted to few 1,2,4,5-tetrazine bearing a morpholino substituent is one
carbon nucleophiles such as cyanides or malonic acid of the more stable substrates when involved in Sono-
derivatives.5c,e,9
gashira cross-coupling. Therefore, we decided to start our
investigations with the 3-methylthio-6-(morpholin-4-yl)-
1,2,4,5-tetrazine (1). This compound was readily obtained
by nucleophilic displacement of one methylthio group of
3,6-bis(methylthio)-1,2,4,5-tetrazine with morpholine
(Scheme 1).17
Recently, Kotschy’s group10 reported the synthesis of
unsymmetrical tetrazines from cross-coupling reactions
of 6-substituted 3-chloro-1,2,4,5-tetrazines with different
alkynes with encouraging yields. The authors have shown
that the reactivity of chlorotetrazines depends on the
nature of the ring substituent and that electron-deficient The first cross-coupling attempt was performed with the
tetrazines are unstable under the required experimental commercially available 4-methoxyphenylboronic acid
conditions.
(2a) under standard conditions using copper(I) methyl-
salicylate (CuMeSal) and tetrakis(triphenylphos-
phine)palladium [Pd(PPh3)4, (5 mol%)] in refluxing
tetrahydrofuran (Scheme 2). After 48 hours, the coupled
product 3a was isolated with a promising 46% yield. No
degradation of the starting material was observed, which
was recovered (42%; Table 1, entry 1).
SYNLETT 2007, No. 2, pp 0204–0210
Advanced online publication: 24.01.2007
DOI: 10.1055/s-2007-967991; Art ID: D22306ST
© Georg Thieme Verlag Stuttgart · New York
0
1.
0
2.
2
0
0
7

LETTER
Efficient Palladium-Catalyzed Synthesis of Unsymmetrical (Het)aryltetrazines
205
OMe
OMe
N
N
S
CuMeSal (2.2 equiv)
Pd(PPh3)4 (5 mol%)
N
N
N
N
+
N
N
THF, reflux
N
N
O
48 h
B(OH)2
O
1
2a (2.2 equiv)
3a (46%)
Scheme 2 Pd-catalyzed cross-coupling reaction between tetrazine 1 and boronic acid 2a
CuTC (2.2 equiv)
Pd(PPh3)4 (5 mol%)
N
N
N
N
N
N
N
O
N
+
(HO)2B
2b–i
R
O
N
R
S
DME, 200 °C, 2 h
microwaves
N
1
3b–i
Scheme 3 Extension of the reaction to various boronic acid derivatives
In a second set of experiments (Table 1), the nature of the Different boronic acids were evaluated under the previous
copper cofactor was investigated. Among the copper(I) conditions (Scheme 3). Results are summarized in
carboxylates examined, copper(I) thiophene-2-carboxy- Table 2. Methylthiotetrazine 1 proved to react readily
late (CuTC) gave the best results (Table 1, entry 2). As to with electron-rich arylboronic acids in good yields
the solvent, no significant difference was observed be- (Table 2, entries 1 and 2). On using electron-poor aryl-
tween tetrahydrofuran and 1,2-dimethoxyethane (DME; boronic acids 2d, 2e and 2f, the corresponding products
Table 1, entry 3). However, the yield dramatically de- were isolated in 56%, 54% and 28% yields respectively
creased when a non-polar aprotic solvent like toluene was (Table 2, entries 3–5). Nevertheless, the reaction with
used (Table 1, entry 4).
boronic acids 2g–i gave the resulting products 3g–i which
were first isolated as mixtures with the starting material 1.
A treatment with m-chloroperoxybenzoic acid (MCPBA)
in dichloromethane converted tetrazine 1 into the more
polar 3-methylsulfinyl-6-(morpholin-4-yl)-1,2,4,5-tetra-
zine and 3-methylsulfonyl-6-(morpholin-4-yl)-1,2,4,5-
tetrazine (Table 2, entries 6–8),5f,19 which were easily
removed after purification. However, this oxidation step
probably initiated side reactions responsible for low
yields.
Increasing the charge of the palladium catalyst brought no
improvement (Table 1, entry 5), no more and no less than
a progressive addition of the boronic acid 2a and CuTC
(Table 1, entry 6). We then decided to take advantage of
microwave activation on this copper-promoted reac-
tion.16b After few attempts of optimizing the temperature
(Table 1, entries 7 and 8), the reaction time (Table 1, en-
tries 8 and 9) or the amount of Pd catalyst (Table 1, entries
8 and 10), the best reaction conditions were achieved in
DME at 200 °C (microwave irradiation) over two hours
(Table 1, entry 9).18
Table 1 Optimization of the Pd-Catalyzed Cross-Coupling Conditions between Tetrazine 1 and Boronic Acid 2a
Entry
Pd(PPh3)4
5 mol%
5 mol%
5 mol%
5 mol%
15 mol%
5 mol%
5 mol%
5 mol%
5 mol%
10 mol%
‘Cu’
Solvent
THF
Heating, Time
Yield (%)a
Recovered tetrazine 1 (%)
1
2
CuMeSal
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
CuTC
Reflux, 48 h
46
68
66
14
61
46
62
71
67
71
42
20
14
75
16
31
23
20
20
21
THF
Reflux, 48 h
3
DME
Toluene
DME
DME
DME
DME
DME
DME
Reflux, 48 h
4
Reflux, 48 h
5
Reflux, 48 h
6b
7
Reflux, 48 h
Microwaves,c 180 °C, 2 h
Microwaves,c 200 °C, 2 h
Microwaves,c 200 °C, 4 h
Microwaves,c 200 °C, 2 h
8
9
10
a Isolated yield of the pure product.
b Run performed with progressive addition of boronic acid and CuTC quantities.
c Run performed with a Biotage Initiator microwave apparatus (control by means of temperature).
Synlett 2007, No. 2, 204–210 © Thieme Stuttgart · New York

206
N. Leconte et al.
LETTER
Table 2 Copper(I)-Promoted Palladium-Catalyzed Cross-Coupling of Boronic Acids 2b–i with 3-Methylthio-6-(morpholin-4-yl)-1,2,4,5-
tetrazine 1
Entry
RB(OH)2
Product
Yield (%)a
Recovered 1 (%)
B(OH)2
N
N
OMe
1
67
21
MeO
N
N
2b
2c
N
O
3b
B(OH)2
N
N
2
3
58
56
21
23
N
N
N
O
3c
B(OH)2
N
N
N
N
O
O
O
N
2d
2e
O
3d
O
B(OH)2
N
N
4
54
27
N
N
N
O
3e
B(OH)2
N
CN
CF3
Br
N
5
28
31
42
49
NC
F3C
Br
N
2f
N
N
O
3f
B(OH)2
N
N
6b
n.d.
n.d.
N
2g
N
N
O
3g
B(OH)2
N
N
7b
N
2h
2i
N
N
O
3h
B(OH)2
N
N
N
8b
60
n.d.
N
N
O
3i
a Isolated yield of the pure product.
b An oxidative treatment with MCPBA was required after completion of the cross-coupling reaction.
Synlett 2007, No. 2, 204–210 © Thieme Stuttgart · New York

LETTER
Efficient Palladium-Catalyzed Synthesis of Unsymmetrical (Het)aryltetrazines
207
CuTC (2.2 equiv)
N
N
N
N
N
N
N
Pd(PPh3)4 (5 mol%)
Bu3Sn R
+
O
N
O
N
R
S
DME, 200 °C, 2 h
microwaves
N
4a–d
3j–l
1
Scheme 4 Extension of the reaction to organostannanes derivatives
Table 3 Copper(I)-Promoted Palladium-Catalyzed Cross-Coupling of Stannanes 4a–d with 3-Methylthio-6-(morpholin-4-yl)-1,2,4,5-tetra-
zine 1 under Microwave Irradiation
Entry
RSnBu3
Product
Yield (%)a
Recovered 1 (%)
OMe
N
MeO
SnBu3
N
1
49
28
N
N
4a
N
O
3a
SnBu3
N
2b
34
n.d.
4b
N
N
N
N
O
3j
S
N
N
S
N
35
31
SnBu3
3
4
N
52c
29c
N
4c
O
3k
N
N
SnBu3
N
N
N
8
38
4d
N
30c
28c
N
O
3l
a Isolated yield of the pure product.
b An oxidative treatment with MCPBA was required after completion of the cross-coupling reaction.
c Reactions carried out in refluxing DME for 48 h.
The cross-coupling method was then extended to organo- Once 1 reacted with styryl derivative 4b,22 the crude mix-
tin derivatives (Scheme 4). Different organostannanes ture underwent an oxidative treatment with MCPBA,19
were evaluated using Pd(PPh3)4 and CuTC in DME under which affected the isolated yield of the product 3j
microwave irradiation for two hours (Table 3).20
(Table 3, entry 2). The high sensitivity of the organotin
derivatives towards the cross-coupling reaction condi-
tions was also demonstrated through two additional
experiments (Table 3, entries 3 and 4). Reactions of 1 with
organostannanes 4c and 4d23 were performed in DME
under microwave irradiation and in refluxing DME. It is
noteworthy that desired tetrazines 3k and 3l were isolated
in higher yields in refluxing DME.24
The reaction of methylthiotetrazine 1 with organostan-
nane 4a21 was performed (Table 3, entry 1) and compared
to the cross-coupling between 1 and organoboron 2a
(Scheme 2). A lower yield of the desired product 3a and
degradation products were observed in the former reaction.
Synlett 2007, No. 2, 204–210 © Thieme Stuttgart · New York

208
N. Leconte et al.
LETTER
Tetrahedron 1998, 54, 4297. (h) Girardot, M.; Nomak, R.;
Snyder, J. K. J. Org. Chem. 1998, 63, 10063. (i) Wan, Z.-
K.; Woo, G. H. C.; Snyder, J. K. Tetrahedron 2001, 57,
5497. (j) Hamasaki, A.; Zimpleman, J. M.; Hwang, I.;
Boger, D. L. J. Am. Chem. Soc. 2005, 127, 10767; and
references cited therein.
Lastly, when the electron-deficient 3-methylthio-6-meth-
oxy-1,2,4,5-tetrazine (5)6c was reacted with 2a at 200 °C
under microwave irradiation, the coupled product 6 was
isolated in 12% yield among degradation products
(Scheme 5).25 Under the same experimental conditions,
the 3-chloro-6-methylthio-1,2,4,5-tetrazine, unfortunate-
ly, degraded completely.
(7) Seitz, G.; Yang, X.-G. Arch. Pharm. (Weinheim) 1991, 324,
803.
(8) (a) Sakya, S. M.; Groskopf, K. K.; Boger, D. L. Tetrahedron
Lett. 1997, 38, 3805. (b) Novak, Z.; Bostai, B.; Csekei, M.;
Lorincz, K.; Kotschy, A. Heterocycles 2003, 60, 2653.
(c) Huynh, M. H. V.; Hiskey, M. A.; Chavez, D. E.; Naud,
D. L.; Gilardi, R. D. J. Am. Chem. Soc. 2005, 127, 12537;
and references cited therein.
O
S
O
CuTC (2.2 equiv)
Pd(PPh3)4 (5 mol%)
N
N
N
N
+
N
DME, 200 °C, 2 h
microwaves
(9) Mangia, A.; Bartesi, F.; Amendola, U. J. Heterocycl. Chem.
1977, 14, 587.
N
O
N
O
B(OH)2
2a
N
(10) Novak, Z.; Kotschy, A. Org. Lett. 2003, 5, 3495.
(11) (a) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett.
1979, 20, 3437. (b) Stille, J. K. Angew. Chem. Int. Ed. 1986,
25, 508. For recent reviews on Pd-catalyzed cross-coupling
reactions, see: (c) Littke, A. F.; Fu, G. C. Angew. Chem. Int.
Ed. 2002, 41, 4176. (d) Nicolaou, K. C.; Bulger, P. G.;
Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442. (e) For a
recent review on the applications of the Suzuki–Miyaura
cross-coupling reactions, see: Kotha, S.; Lahiri, K.;
Kashinath, D. Tetrahedron 2002, 58, 9633. (f) For a recent
review on the mechanisms of the Stille cross-coupling
reactions, see: Espinet, P.; Echavarren, A. M. Angew. Chem.
Int. Ed. 2004, 43, 4704.
(12) Sandström, J. Acta Chem. Scand. 1961, 15, 1575.
(13) (a) Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122,
11260. (b) Savarin, C.; Srogl, J.; Liebeskind, L. S. Org. Lett.
2001, 3, 91. (c) Savarin, C.; Liebeskind, L. S. Org. Lett.
2001, 3, 2149. (d) Kusturin, C. L.; Liebeskind, L. S.;
Neumann, W. L. Org. Lett. 2002, 4, 983.
5
6 (12%)
Scheme 5 Pd-catalyzed cross-coupling reaction of 3-methylthio-6-
methoxy-1,2,4,5-tetrazine (5) and boronic acid 2a
In conclusion, we have demonstrated the cross-coupling
of a 3-methylthio-1,2,4,5-tetrazine with boronic acids
and organostannane derivatives. Microwave irradiation
allows shorter reaction times. This reaction constitutes a
very efficient way for the synthesis of unsymmetrical
tetrazines with vinyl, aryl and heteroaryl substituents.
Work is in progress to increase the diversity of both
substituents on tetrazines.
Acknowledgment
We thank the Commissariat à l’Energie Atomique and the Conseil
Régional de la Région Centre for financial support.
(14) (a) Liebeskind, L. S.; Srogl, J. Org. Lett. 2002, 4, 979.
(b) Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.;
Guillaumet, G. Synlett 2002, 447.
(15) (a) Egi, M.; Liebeskind, L. S. Org. Lett. 2003, 5, 801.
(b) Alphonse, F.-A.; Suzenet, F.; Keromnes, A.; Lebret, B.;
Guillaumet, G. Org. Lett. 2003, 5, 803.
References and Notes
(1) Sauer, J. Comprehensive Heterocyclic Chemistry II, Vol. 6;
Pergamon: London, 1996, 901–965.
(2) Boger, D. L.; Weinreb, S. M. Hetero Diels–Alder
Methodology in Organic Synthesis; Academic Press: San
Diego, CA, 1987.
(3) Schirmer, U.; Wierzer, B.; Meyer, N.; Neugebauer, F. A.;
Fischer, H. Ger. Patent, 3508214, 1986; Chem. Abstr. 1987,
106, 45718.
(4) (a) Chavez, D. E.; Hiskey, M. A. J. Energ. Mat. 1999, 174,
357. (b) Chavez, D. E.; Hiskey, M. A.; Naud, D. L.
Propellants, Explos., Pyrotech. 2004, 29, 209.
(5) (a) Boger, D. L. Tetrahedron 1983, 39, 2869. (b) Boger, D.
L. Chem. Rev. 1986, 86, 781. (c) Yang, X.-G.; Seitz, G.
Arch. Pharm. (Weinheim) 1992, 325, 559. (d) Boger, D. L.;
Schaum, R. P.; Garbaccio, R. M. J. Org. Chem. 1998, 63,
6329. (e) Benson, S. C.; Lee, L.; Yang, L.; Snyder, J. K.
Tetrahedron 2000, 56, 1165. (f) Hamasaki, A.; Ducray, R.;
Boger, D. L. J. Org. Chem. 2006, 71, 185.
(6) (a) Boger, D. L.; Coleman, R. S.; Panek, J. S.; Yohannes, D.
J. Org. Chem. 1984, 49, 4405. (b) Boger, D. L.; Panek, J. S.;
Duff, S. R. J. Am. Chem. Soc. 1985, 107, 5745. (c) Boger,
D. L.; Sakya, S. M. J. Org. Chem. 1988, 53, 1415.
(d) Yang, X.-G.; Seitz, G. Chem.-Ztg. 1991, 115, 367.
(e) Boger, D. L.; Zhang, M. J. Am. Chem. Soc. 1991, 113,
4230. (f) Benson, S. C.; Lee, L.; Snyder, J. K. Tetrahedron
Lett. 1996, 37, 5061. (g) Sauer, J.; Heldmann, D. K.
(16) (a) Kusturin, C.; Liebeskind, L. S.; Rahman, H.; Sample, K.;
Schweitzer, B.; Srogl, J.; Neumann, W. L. Org. Lett. 2003,
5, 4349. (b) Oumouch, S.; Bourotte, M.; Schmitt, M.;
Bourguignon, J.-J. Synthesis 2005, 25. (c) Richardson, C.;
Rewcastle, G. W.; Hoyer, D.; Denny, W. A. J. Org. Chem.
2005, 70, 7436. (d) Leconte, N.; Pellegatti, L.; Xavier, N.;
Tatibouët, A.; Suzenet, F.; Rollin, P.; Guillaumet, G.
Synthesis, accepted.
(17) (17) 3-Methylthio-6-(morpholin-4-yl)-1,2,4,5-tetrazine
(1): To a suspension of 3,6-bis(methylthio)-1,2,4,5-tetrazine
(1.08 g, 6.2 mmol) in EtOH (20 mL) at 25 °C, morpholine
(660 mL, 7.5 mmol) was added. After the mixture was
refluxed for 15 h, it was allowed to cool to r.t. and the solvent
was removed under reduced pressure. The residue was
purified by chromatography on silica gel (cyclohexane–
EtOAc = 95:5 to 8:2). 3-Methylthiotetrazine 1 (1.24 g, 94%)
was obtained as a red solid; mp 131–132 °C. MS
(Ionspray®): m/z = 214 [M + H]+. 1H NMR (250 MHz,
CDCl3): d = 3.94 (dt, J = 1.0, 4.8 Hz, 4 H), 3.84 (dt, J = 1.0,
4.8 Hz, 4 H), 2.67 (s, 3 H). 13C NMR (62.5 MHz, CDCl3):
d = 166.6 (C), 160.5 (C), 66.5 (CH2), 43.9 (CH2), 13.7 (CH3).
IR: 2965, 2908, 1524, 1441, 1267, 1113, 920, 847, 791
cm–1. HRMS: m/z [M+·] calcd for C7H11N5OS: 213.0684;
found: 213.0687.
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Efficient Palladium-Catalyzed Synthesis of Unsymmetrical (Het)aryltetrazines
209
(18) Palladium-Catalyzed Cross-Coupling Reaction of
Compound 1 with Boronic Acids 2a–i; General
3-(Morpholin-4-yl)-6-(4-acetylphenyl)-1,2,4,5-tetrazine
(3e): 4-Acetylphenylboronic acid(2e) was used as the
boronic acid derivative; yield: 54%; red solid; mp 194–197
°C. MS (Ionspray®): m/z = 286 [M + H]+. 1H NMR (250
MHz, CDCl3): d = 8.49 (d, J = 8.8 Hz, 2 H), 8.11 (d, J = 8.8
Hz, 2 H), 4.09 (t, J = 4.6 Hz, 4 H), 3.89 (t, J = 4.6 Hz, 4 H),
2.41 (s, 3 H). 13C NMR (62.5 MHz, CDCl3): d = 197.7 (C),
160.2 (C), 158.7 (C), 138.6 (C), 136.9 (C), 129.1 (CH),
126.4 (CH), 66.6 (CH2), 43.9 (CH2), 26.9 (CH3). IR: 2975,
2874, 2324, 1676, 1536, 1269, 1114, 943, 849 cm–1. HRMS:
m/z [M+·] calcd for C14H15N5O2: 285.1226; found: 285.1216.
3-(Morpholin-4-yl)-6-(3-cyanophenyl)-1,2,4,5-tetrazine
(3f): 3-Cyanophenylboronic acid (2f) was used as the
boronic acid derivative; yield: 28%; red solid; mp 197–198
°C. MS (Ionspray®): m/z = 269 [M + H]+. 1H NMR (250
MHz, CDCl3): d = 8.71 (dt, J = 0.5, 1.5 Hz, 1 H), 8.63 (dt,
J = 1.5, 8.0 Hz, 1 H), 7.79 (dt, J = 1.5, 8.0 Hz, 1 H), 7.65 (dt,
J = 0.5, 8.0 Hz, 1 H), 4.09 (t, J = 4.7 Hz, 4 H), 3.89 (t, J = 4.7
Hz, 4 H). 13C NMR (62.5 MHz, CDCl3): d = 160.4 (C), 157.8
(C), 134.1 (C), 133.8 (CH), 130.1 (CH), 130.0 (CH), 129.8
(CH), 118.5 (C), 113.5 (C), 66.5 (CH2), 43.9 (CH2). IR:
2872, 2235, 1536, 1446, 1255, 1117, 1034, 966 cm–1.
HRMS: m/z [M+·] calcd for C13H12N6O: 268.1073; found:
268.1079.
Procedure: 3-Methylthio-6-(morpholin-4-yl)-1,2,4,5-
tetrazine (1; 100 mg, 0.5 mmol), boronic acid (1.1 mmol)
and CuTC (197 mg, 1.1 mmol) were dissolved in anhyd
DME (5 mL) in a sealed reaction vessel under argon. After
the mixture was degassed, Pd(PPh3)4 (27 mg, 0.025 mmol)
was added and the reaction mixture was stirred under
microwave irradiation at 200 °C (14–16 bars) for 2 h. The
reaction mixture was then allowed to cool to r.t., poured into
sat. aq Na2CO3 and extracted with CH2Cl2. The organic
phases were collected, dried over MgSO4 and the solvent
was removed under reduced pressure. Desired compounds
were purified by chromatography on silica gel (PE–EtOAc =
95:5 to 7:3).
3-(Morpholin-4-yl)-6-(4-methoxyphenyl)-1,2,4,5-
tetrazine (3a): 4-Methoxyphenylboronic acid (2a; yield:
71%) and 1-methoxy-4-tributylstannylbenzene (4a; yield:
49%) were used as the boronic acid and the organostannane
derivatives, respectively; red solid; mp 176–178 °C. MS
(Ionspray®): m/z = 274 [M + H]+. 1H NMR (250 MHz,
CDCl3): d = 8.34 (d, J = 9.0 Hz, 2 H), 7.05 (d, J = 9.0 Hz, 2
H), 4.04 (t, J = 4.5 Hz, 4 H), 3.89 (s, 3 H), 3.87 (t, J = 4.5 Hz,
4 H). 13C NMR (62.5 MHz, CDCl3): d = 162.0 (C), 160.6
(C), 159.5 (C), 128.0 (CH), 125.3 (C), 114.6 (CH), 66.6
(CH2), 55.6 (CH3), 43.9 (CH2). IR: 2917, 1607, 1512, 1438,
1244, 1116, 1034, 936, 837 cm–1. Anal. Calcd for
3-(Morpholin-4-yl)-6-(3-trifluoromethylphenyl)-1,2,4,5-
tetrazine (3g): 3-Trifluoromethylphenylboronic acid (2g)
was used as the boronic acid derivative; yield: 31%; red
solid; mp 144 °C. MS (Ionspray®): m/z = 311.5 [M + H]+. 1H
NMR (250 MHz, CDCl3): d = 8.69 (s, 1 H), 8.58 (d, J = 7.8
Hz, 1 H), 7.76 (d, J = 7.8 Hz, 1 H), 7.66 (t, J = 7.8 Hz, 1 H),
4.08 (t, J = 4.5 Hz, 4 H), 3.89 (t, J = 4.5 Hz, 4 H). 13C NMR
(62.5 MHz, CDCl3): d = 160.5 (C), 158.4 (C), 133.6 (C),
131.6 (2JC–F = 33 Hz, C), 129.7 (CH), 129.3 (CH), 127.3
C13H15N6O2 (273): C, 57.13; H, 5.53; N, 25.63. Found: C,
57.34; H, 5.52; N, 24.48.
3-(Morpholin-4-yl)-6-(3-methoxyphenyl)-1,2,4,5-
tetrazine (3b): 3-Methoxyphenylboronic acid (2b) was used
as the boronic acid derivative; yield: 67%; red solid; mp
140–142 °C. MS (Ionspray®): m/z = 274 [M + H]+. 1H NMR
(250 MHz, CDCl3): d = 7.99 (dt, J = 1.0, 8.0 Hz, 1 H), 7.93
(dd, J = 1.0, 2.6 Hz, 1 H), 7.43 (t, J = 8.0 Hz, 1 H), 7.05 (ddd,
J = 1.0, 2.6, 8.0 Hz, 1 H), 4.05 (t, J = 4.5 Hz, 4 H), 3.89 (s, 3
H), 3.87 (t, J = 4.5 Hz, 4 H). 13C NMR (62.5 MHz, CDCl3):
d = 160.5 (C), 160.2 (C), 159.3 (C), 134.0 (C), 130.1 (CH),
118.8 (CH), 117.4 (CH), 110.7 (CH), 66.5 (CH2), 55.5
(CH3), 43.8 (CH2). IR: 2927, 2857, 1598, 1522, 1448, 1262,
1229, 1119, 963, 786 cm–1. HRMS: m/z [M+·] calcd for
C13H15N5O2: 273.1226; found: 273.1220.
(3JC–F = 4 Hz, CH), 124.1 (1JC–F = 271 Hz, C), 123.2 (3JC–F
4 Hz, CH), 66.5 (CH2), 43.9 (CH2). IR: 2917, 2850, 1530,
1446, 1302, 1268, 1166, 1120, 1066, 1034, 963, 945, 695
=
cm–1. HRMS: m/z [M+·] calcd for C13H12N5OF3: 311.0994;
found: 311.0991.
3-(Morpholin-4-yl)-6-(3-bromophenyl)-1,2,4,5-tetrazine
(3h): 3-Bromophenylboronic acid (2h) was used as the
boronic acid derivative; yield: 42%; red solid; mp 141–142
°C. 1H NMR (250 MHz, CDCl3): d = 8.56 (t, J = 1.5 Hz, 1
H), 8.33 (ddd, J = 1.0, 1.5, 8.0 Hz, 1 H), 7.64 (ddd, J = 1.0,
1.5, 8.0 Hz, 1 H), 7.40 (t, J = 8.0 Hz, 1 H), 4.07 (t, J = 4.4
Hz, 4 H), 3.88 (t, J = 4.4 Hz, 4 H). 13C NMR (62.5 MHz,
CDCl3): d = 160.5 (C), 158.4 (C), 134.8 (C), 133.7 (CH),
130.6 (CH), 129.4 (CH), 124.8 (CH), 123.4 (C), 66.6 (CH2),
43.9 (CH2). IR: 2361, 2337, 1530, 1447, 1254, 1123, 1031,
944, 780, 733 cm–1. HRMS: m/z [M+·] calcd for
3-(Morpholin-4-yl)-6-(3-methylphenyl)-1,2,4,5-tetrazine
(3c): 3-Methylphenylboronic acid (2c) was used as the
boronic acid derivative; yield 58%; red solid; mp 127–129
°C. MS (Ionspray®): m/z = 258.5 [M + H]+. 1H NMR (250
MHz, CDCl3): d = 8.22 (s, 1 H), 8.20 (d, J = 7.8 Hz, 1 H),
7.42 (t, J = 7.8 Hz, 1 H), 7.33 (d, J = 7.8 Hz, 1 H), 4.06 (t,
J = 4.7 Hz, 4 H), 3.88 (t, J = 4.7 Hz, 4 H), 2.46 (s, 3 H). 13
C
NMR (62.5 MHz, CDCl3): d = 160.6 (C), 159.7 (C), 139.9
(C), 132.6 (C), 131.6 (CH), 129.1 (CH), 127.1 (CH), 123.6
(CH), 66.6 (CH2), 43.9 (CH2), 21.7 (CH3). IR: 2965, 2860,
2362, 2338, 1521, 1451, 1252, 1116, 941, 784 cm–1. HRMS:
m/z [M+·] calcd for C13H15N5O: 257.1277; found: 257.1288.
3-(Morpholin-4-yl)-6-(3-acetylphenyl)-1,2,4,5-tetrazine
(3d): 3-Acetylphenylboronic acid (2d) was used as the
boronic acid derivative; yield: 56%; red solid; mp 174–176
°C. MS (Ionspray®): m/z = 286 [M + H]+. 1H NMR (250
MHz, CDCl3): d = 8.98 (s, 1 H), 8.60 (d, J = 7.9 Hz, 1 H),
8.12 (d, J = 7.9 Hz, 1 H), 7.65 (t, J = 7.9 Hz, 1 H), 4.09 (t,
C12H12N5O79Br: 321.0225; found: 321.0211.
3-(Morpholin-4-yl)-6-(naphtalen-2-yl)-1,2,4,5-tetrazine
(3i): Naphthalen-2-ylboronic acid (2i) was used as boronic
acid derivative; yield: 60%; red solid; mp 172–173 °C. MS
(Ionspray®): m/z = 294 [M + H]+. 1H NMR (250 MHz,
CDCl3): d = 8.93 (s, 1 H), 8.48 (dd, J = 1.8, 8.5 Hz, 1 H), 7.99
(d, J = 8.5 Hz, 2 H), 7.89 (t, J = 5.0 Hz, 1 H), 7.54 (m, 2 H),
4.08 (t, J = 4.5 Hz, 4 H), 3.89 (t, J = 4.5 Hz, 4 H). 13C NMR
(62.5 MHz, CDCl3): d = 160.5 (C), 159.7 (C), 134.7 (C),
133.5 (C), 130.0 (C), 129.2 (CH), 129.0 (CH), 128.0 (CH),
127.4 (CH), 126.8 (CH), 126.5 (CH), 123.3 (CH), 66.6
(CH2), 43.9 (CH2). IR: 2960, 2869, 2359, 1522, 1451, 1336,
1262, 1119, 953 cm–1. Anal. Calcd for C16H15N5O(293): C,
65.52; H, 5.15; N, 23.88. Found: C, 65.64; H, 5.07; N, 23.26.
(19) Cross-Coupling Reaction Followed by an Oxidative
Treatment (Compounds 3g–j): Same procedure as in ref.
18 was used with an extra oxidative step, described as
follows. The crude product was dissolved in CH2Cl2. After
J = 4.4 Hz, 4 H), 3.89 (t, J = 4.4 Hz, 4 H), 2.70 (s, 3 H). 13
C
NMR (62.5 MHz, CDCl3): d = 197.7 (C), 160.5 (C), 158.7
(C), 137.9 (C), 133.2 (C), 130.5 (CH), 130.1 (CH), 129.5
(CH), 126.4 (CH), 66.5 (CH2), 43.8 (CH2), 26.9 (CH3). IR:
2981, 2906, 2359, 2340, 1692, 1536, 1262, 1111, 967, 946
cm–1. HRMS: m/z [M+·] calcd for C14H15N5O2: 285.1226;
found: 285.1213.
Synlett 2007, No. 2, 204–210 © Thieme Stuttgart · New York

210
N. Leconte et al.
LETTER
the temperature was adjusted to 5 °C with an ice bath,
MCPBA (81 mg, 0.47 mmol) was added and the mixture was
stirred for 30 min at 5 °C. The reaction was then hydrolyzed
with sat. aq NaHCO3 and extracted with CH2Cl2. The
organic phases were collected, dried over MgSO4 and the
solvent was removed under reduced pressure. Desired
compounds were purified by chromatography on silica gel
(PE–EtOAc: 95:5 to 7:3).
(250 MHz, CDCl3): d = 8.81 (br s, 2 H), 8.26 (d, J = 4.1 Hz,
2 H), 4.11 (t, J = 4.7 Hz, 4 H), 3.89 (t, J = 4.7 Hz, 4 H). 13
C
NMR (62.5 MHz, CDCl3): d = 160.4 (C), 157.9 (C), 150.9
(C), 140.1 (CH), 66.6 (CH2), 43.9 (CH2); C9 was not
observed. IR: 2989, 2902, 1593, 1520, 1443, 1340, 1250,
1117, 1037, 966, 942, 846 cm–1. Anal. Calcd for
C11H12N6O(244): C, 54.09; H, 4.95; N, 34.41. Found: C,
54.41; H, 4.93; N, 34.55.
(20) Palladium-Catalyzed Cross-Coupling Reaction of
Compound 1 with Organostannanes 4a–d; General
Procedure: Same procedure as in ref. 18 was used except
that the reaction was carried out with organotin derivatives.
3-(Morpholin-4-yl)-6-[(E)-styryl]-1,2,4,5-tetrazine (3j):
3-[(E)-2-Phenylethenyl]tributyltin (4b) was used as the
organostannane derivative; yield: 34%; red solid; mp 126
°C. MS (Ionspray®): m/z = 270 [M + H]+. 1H NMR (250
MHz, CDCl3): d = 7.96 (d, J = 16.3 Hz, 1 H), 7.62 (dd, J =
1.5, 8.3 Hz, 2 H), 7.41 (m, 3 H), 7.35 (d, J = 16.3 Hz, 1 H),
4.03 (t, J = 4.5 Hz, 4 H), 3.86 (t, J = 4.5 Hz, 4 H). 13C NMR
(62.5 MHz, CDCl3): d = 160.1 (C), 160.0 (C), 136.0 (C),
135.7 (CH), 129.3 (CH), 129.0 (CH), 127.6 (CH), 121.1
(CH), 66.6 (CH2), 43.8 (CH2). IR: 2956, 2863, 1637, 1521,
1450, 1341, 1254, 1119, 1056, 949, 848, 751, 693 cm–1.
HRMS: m/z [M+·] calcd for C14H15N5O: 269.1277; found:
269.1274.
(21) For preparation of compound 4a, see: Morita, Y.;
Kashiwagi, A.; Nakasuji, K. J. Org. Chem. 1997, 62, 7464.
(22) For preparation of compound 4b, see ref. 15b.
(23) For preparation of compound 4d, see: Peters, D.; Hörnfeldt,
A.-B.; Gronowitz, S. J. Heterocycl. Chem. 1990, 27, 2165.
(24) The same experimental procedure as described in ref. 18 was
used, except that the reaction was carried out in a 10 mL
round-bottomed flask and stirred in refluxing DME for 48 h.
(25) In refluxing DME after 48 hours, only traces of the cross-
coupling product 6 were observed.
3-Methoxy-6-(4-methoxyphenyl)-1,2,4,5-tetrazine (6):
3-Methylthio-6-methoxy-1,2,4,5-tetrazine (5; 129 mg, 0.8
mmol), 4-methoxyphenylboronic acid (2a; 277 mg, 1.8
mmol) and CuTC (342 mg, 1.8 mmol) were dissolved in
anhyd DME (6 mL) in a sealed reaction vessel under argon.
After the mixture was degassed, Pd(PPh3)4 (47 mg, 0.04
mmol) was added and the reaction mixture was stirred under
microwave irradiation at 200 °C for 2 h. The reaction
mixture was then allowed to cool to r.t., poured into sat.
Na2CO3 and extracted with CH2Cl2. The organic phases
were collected, dried over MgSO4 and the solvent was
removed under reduced pressure. Purification by
chromatography on silica gel (PE–EtOAc: 1:0 to 9:1)
afforded compound 7 (22 mg, 12%) as a red solid; mp 119–
120 °C. MS (Ionspray®): m/z = 219 [M + H]+. 1H NMR (250
MHz, CDCl3): d = 8.46 (d, J = 9.0 Hz, 2 H), 7.07 (d, J = 9.0
Hz, 2 H), 4.34 (s, 3 H), 3.91 (s, 3 H). 13C NMR (62.5 MHz,
CDCl3): d = 166.8 (C), 163.1 (C), 162.9 (C), 129.3 (CH),
124.3 (C), 114.8 (CH), 56.6 (CH3), 55.6 (CH3). IR: 2923,
2854, 1602, 1488, 1453, 1376, 1249, 1179, 1117, 1041, 940,
848 cm–1. HRMS: m/z [M+·] calcd for C10H10N4O2:
218.0804; found: 218.0797.
3-(Morpholin-4-yl)-6-(thien-2-yl)-1,2,4,5-tetrazine (3k):
2-Tributylstannylthiophene (4c) was used as the
organostannane derivative; yield: 42%; red solid; mp 187–
191 °C. MS (Ionspray®): m/z = 250 [M + H]+. 1H NMR (250
MHz, CDCl3): d = 8.00 (dd, J = 1.0, 3.8 Hz, 1 H), 7.50 (dd,
J = 1.0, 5.0 Hz, 1 H), 7.19 (dd, J = 3.8, 5.0 Hz, 1 H), 4.03 (t,
J = 4.4 Hz, 4 H), 3.87 (t, J = 4.4 Hz, 4 H). 13C NMR (62.5
MHz, CDCl3): d = 160.4 (C), 157.8 (C), 136.7 (C), 129.2
(CH), 128.5 (CH), 127.6 (CH), 66.6 (CH2), 43.9 (CH2). IR:
2965, 2907, 2866, 2362, 2341, 1529, 1433, 1259, 1112, 941,
718 cm–1. HRMS: m/z [M+·] calcd for C10H11N5OS:
249.0684; found: 249.0693.
3-(Morpholin-4-yl)-6-(pyridin-4-yl)-1,2,4,5-tetrazine
(3l): 4-Tributylstannylpyridine (4d) was used as the
organostannane derivative; yield: 30%; red solid; mp 198–
199 °C. MS (Ionspray®): m/z = 245.5 [M + H]+. 1H NMR
Synlett 2007, No. 2, 204–210 © Thieme Stuttgart · New York

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