saracoglu2007

Tetrahedron 63 (2007) 4199–4236
Tetrahedron report number 797
Recent advances and applications in 1,2,4,5-tetrazine
chemistry
Nurullah Saracoglu*
Department of Chemistry, Faculty of Science and Arts, Atat€
urk University, 25240 Erzurum, Turkey
Received 31 January 2007
Available online 16 February 2007
Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4200
2. Synthesis of new 1,2,4,5-tetrazine derivatives and their applications . . . . . . . . . . . . . . . . . . . . . . . 4200
2.1. High-nitrogen materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4200
2.2. Unsymmetrical substituted 1,2,4,5-tetrazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4202
2.3. Symmetrical substituted 1,2,4,5-tetrazines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4208
3. Natural product synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4209
3.1. Total synthesis of ningalin A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4209
3.2. Total synthesis of lamellarin O and lukianol A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4209
3.3. Total synthesis of permethyl storniamide A . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4209
3.4. Total synthesis of ningalin B . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4211
3.5. Total synthesis of ningalin D . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4212
3.6. Total synthesis of Amaryllidaceae alkaloids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4213
3.7. Asymmetric total synthesis of ent-()-roseophilin . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4214
3.8. Structural revision and synthesis of cytotoxic marine alkaloid, zarzissine . . . . . . . . . . . . . . 4214
4. Annulations of pyridazine moiety to natural products, alkaloids or drugs . . . . . . . . . . . . . . . . . . 4215
5. Other applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4220
5.1. Pyridazine-based syntheses and transformations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4220
5.2. Synthesis and studies on systems with the exception of pyridazine . . . . . . . . . . . . . . . . . . . . 4224
6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4232
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4232
References and notes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4232
Biographical sketch . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4236
Abbreviations: Ac, acetyl; Ar, aryl; Bn, benzyl; Boc, tert-butoxycarbonyl; Bu, butyl; Bz, benzoyl; CBz, benzylcarboxy; DABCO, 1,4-diazabicyclo[2.2.2]octane; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; DDQ, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; DMA, N,N-dimethylacetamide; DMAP, 4-(dimethylamino)-pyridine; DMSO, dimethyl sulfoxide; DMPY, 3,5-dimethylpyrazol-1-yl; DOPA, 3,4-dihydroxyphenylalanine; DSC, differential scanning
calorimetry; EDG, electron-deficient group; EGA, evolved gas analysis; EWG, electron-withdrawing group; LG, leaving group; LHMDS, lithium hexamethyldisilazide; LUMO, lowest unoccupied molecular orbital; nAChR, nicotinic acetylcholine receptor; NBS, N-bromosuccinimide; NDHf, normalised heat of formation; m-CPBA, meta-chloroperbenzoic acid; MOM, methoxymethyl; Ra-Ni, Raney-nickel; Red-Al, sodium bis(2-methoxyethoxy)aluminium hydride; PIFA,
bis[(trifluoroacetoxy)iodo]benzene; p-TosOH, para-toluenesulfonic acid; SEM, (trimethylsilyl)ethoxymethyl; TBAF, tetrabutylammonium fluoride; TBS, tertbutyldimethylsilyl; TEA, triethylamine; TGA, thermogravimetric analysis; TG-FTIR, thermogravimetric analyzer-Fourier-transform infrared spectrometer;
TIPS, triisopropysilyl; TMS, trimethylsilyl; TPP, meso-tetraphenylporphyrin.
* Tel.: +90 442 231 4425; fax: +90 442 236 0948; e-mail: [email protected]
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.02.051
4200
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
nitrogen. The termination step of the reaction oxidises dihydropyridazines 8 to pyridazines 9, followed by a 1,3-hydrogen shift from 7 (Scheme 1). Pyridazines can be prepared by
direct cycloaddition of an alkyne as dienophile with 1,2,4,5tetrazines.
1. Introduction
N
N
N
N
N
N
N
N
N
N
1
N
N
2
3
There are three possible tetrazine isomers. To date, the
chemistry of 1,2,3,4-tetrazine (1) has been reviewed,1–4 but
there have been no surveys concerning 1,2,3,5-tetrazine (2)
derivatives, which are the least-known class of tetrazine isomers. Several excellent reviews of the 1,2,4,5-tetrazine (3)
literature have, however, been published in various journals5–11 and in the first and latest editions of Comprehensive
Heterocyclic Chemistry.2,12 Furthermore, reviews on annelated [1,2,3,4]tetrazines and the coordination chemistry of
1,2,4,5-tetrazines have been published by Shawali and
Elsheikh13 and by Kaim,14 respectively. The present review
focuses on the chemistry of 1,2,4,5-tetrazine and its derivatives in the last 10 years from 1996 up to the first half of
2006, because these compounds are still of synthetic and
theoretical interest to organic chemists, due to their high
reactivity as dienes in cycloaddition reactions.
2. Synthesis of new 1,2,4,5-tetrazine derivatives and their
applications
2.1. High-nitrogen materials
Organic compounds with a high-nitrogen content currently
attract significant attention from many researchers, due
to their novel energetic properties.1,16–24 3-Hydrazino1,2,4,5-tetrazine (12) was synthesised by Chavez and Hiskey.25 The synthesis of 12 was realised in three steps starting
from the readily available 3,6-bis(3,5-dimethylpyrazol-1yl)-1,2,4,5-tetrazine (10). The reaction of 12 with diethoxymethyl acetate gave the triazolo[4,3-b][1,2,4,5]tetrazine
bi-heterocyclic ring system 13. Furthermore, Chavez and
Hiskey reported similar reactions of 3-(3,5-dimethylpyrazol-1-yl)-6-hydrazine-1,2,4,5-tetrazine (11) to give 3,6disubstituted derivatives of the triazolo[4,3-b][1,2,4,5]tetrazine ring system (Scheme 2).25 The synthesis of the tetrazine
14 and the bistriazolo compound 15 was not achieved.
1,2,4,5-Tetrazines are mostly able to take part in LUMOdienecontrolled [4+2] inverse-Diels–Alder cycloaddition processes, which efficiently lead to the construction of
substituted dihydropyridazine and pyridazine systems. This
process is known as the Carboni–Lindsey reaction.15 Tetrazines 4 react with dienophiles 5 to give the bicyclic adducts
6. The pronounced localisation of the N]N bond in the
highly strained adduct 6 favours extrusion of molecular
R
N
R
N
N
The thermal decomposition of nitrogen-rich tetrazole and
tetrazine structures was investigated by L€obbecke and coworkers.26 The thermal decomposition behaviour of the
samples was characterised by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and evolved
N
N
R1
N
[4+2]
N
+
N
R1
R
4
R
5
R1
R
-N2
R1
6
N
N
R
R
R1
1,3-H shift
R1
R1
HN
N
R1
N
N
[O]
R1
R1
R
R
R
7
8
9
Scheme 1.
Me
Me
Me
NH2NH2·H2O
N N
N
N
N
N
N N
Me
Me
10
N N
H2NHN
X
N N
(EtO)2CHOAc
N N
Scheme 2.
1. (EtO)2CHOAc
2. NH3
NHNH2
N N
12
N N
14
N N
N
15
NH2
N N
NH2 16
1. MnO2
2. NH2NH2·H2O
NHNH2
N N
2. NH3
N N
N N
N
N
Me
N
N
11
2 NH2NH2·H2O
H2NHN
N
N N
N N
1. BrCN
N
N
N
N N
13
N
N
N
NH2
N N
17
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
N N
N N
N N
Ph
N
N
N N
N N
N N
3
18
19
N N
N N
4201
HN N
N N
N N
N N
N N
N NH
20
N N
N N
N N
N N
N N
N N
21
22
Scheme 3.
gas analysis (EGA). The structures of some of the tetrazines
3, 19–22 used are given in Scheme 3.
Treatment of the DMSO solvate with boiling water gives
pure 27, which was found to be thermally stable up to
252 C, and the heat of formation was determined to be
+862 kJ mol1 by combustion calorimetry. The synthesis,
characterisation, structural analysis and thermal analysis
of 27 were also investigated by Kerth and L€obbecke and
by Hiskey and group.18,28 They showed that the azobis(amino-tetrazine) 27 is a new high-nitrogen material with
remarkable thermal stability and insensitivity against friction and impact and which decomposes at relatively high
temperatures (>250 C), releasing one of the highest heats
of decomposition ever measured by DSC. The decomposition pathway and thermal analysis of the products were,
however, described. Talawar’s group suggested that TGFTIR studies indicate the presence of NH2CN/NH3 and
HCN as major decomposition products during the thermal
studies of 27.29
The thermal decomposition of the tetrazine derivatives resulted in opening of the heterocyclic ring to give the nitriles
and N2, and dicyanogen transforms into N2 and soot, as
shown in Scheme 4. The formation of nitriles was identified
by gas chromatography and EGA. The most interesting thermal behaviour was exhibited by the tetrazolyl-substituted
tetrazine 20. The molar decomposition enthalpy measured
for 20 is remarkably high and resembles that of a high
explosive.
3,3-Azobis(6-amino-1,2,4,5-tetrazine) (27), a novel highnitrogen energetic material, was prepared by Hiskey and
co-workers (Scheme 5).27 The hydrazo compound 25 was
obtained by treatment of the readily available 10 with
0.5 equiv of hydrazine. Oxidation of 25 to give 26 was
achieved with N-bromosuccinimide (NBS), which is used as
both an oxidant and a brominating agent. When 26 was reacted with ammonia in dimethyl sulfoxide (DMSO), a redbrown precipitate, which is the bis-DMSO solvate of 27,
was isolated. The structure of the bis-DMSO solvate of 27,
confirmed by X-ray crystal structure analysis, provides the
first evidence for the synthesis of an azo-1,2,4,5-tetrazine.
Although 3,6-bis(2H-tetrazol-5-yl)-1,2,4,5-tetrazine (20)
was first synthesised by Curtius et al.,30a the reactions of
20 have not yet been reported.30b Tetrazolyl-tetrazine 20
was synthesised via the Curtius protocol by Sauer et al., as
shown in Scheme 6, and these workers showed that 20 is
a versatile bifunctional building block for the synthesis of
linear oligoheterocyles with redox-active heterocycles.30b
N N
R
R
2R C
N
+ N2
N N
4
N N
N N
N N
N N
R1
2 R1
R1
R2
R2
R2
23
N + 2 N2 +2 N
C
C C N
24
N2 + soot
Scheme 4.
Me
N N
N
N
Me
N
N
N2H4
Me
N N
N
N
N N
Me
10
N N
H H
N N
N N
Me
Me
N
Me
N
N N
Me
25
NBS
N N
H2N
N N
N N
N N
N N
27
Scheme 5.
NH3
NH2
DMSO
Me
N N
N
N
N N
N N
N N
Br
Me
N
N N
26
Me
N
Br
Me
4202
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
HN N
N N
HN N
N N
N2H4
CN
71%
N NH
HN N
N NH
CrO3
N N
72%
HN N
N N
29
28
N N
N NH
N N
N N
20
Scheme 6.
In spite of the high-energy content of 20, Sauer et al. stated
that the tetrazine derivative 20 can be used as a highly
reactive diene in inverse-Diels–Alder reactions, as long as
the necessary safety rules are obeyed. The pyridazine
derivatives 30 and 31 were isolated in high yield from the
reaction of 20 with 1-methoxycyclopentene and cyclooctyne (Scheme 7). When 20 was reacted with phenyl
isocyanate as the acylating agent, the bis(oxadiazine)tetrazine 32 was isolated in 75% yield. Unfortunately, their
attempts to perform the synthesis of the analogues with
phenyl isothiocyanate or dicyclohexyl carbodiimide were
unsuccessful. The tetrazine 20 was reacted with 2 equiv
of an aliphatic, aromatic or heteroaromatic acyl chloride
to form the 5-substituted 3,6-bis(1,3,4-oxadiazol-2-yl)1,2,4,5-tetrazines 32–34 (Scheme 7). The cycloaddition
reaction of the bis(oxadiazol-2-yl)-1,2,4,5-tetrazine 35
with norborna-2,5-diene as an angle-strained dienophile
could also be achieved.
tetrazole tautomerisations and irreversible tetrazole transformations for 40 are described by Nuynh et al.35
2.2. Unsymmetrical substituted 1,2,4,5-tetrazines
The unsymmetrical disubstituted 1,2,4,5-tetrazines have
been studied less extensively, because they are synthetically
less accessible. 3,6-Bis(methylthio)-1,2,4,5-tetrazine (41)
has been the most widely utilised to synthesise unsymmetrical 1,2,3,4-tetrazines.36–38 The selective preparation of
3-methoxy-6-methylthio-1,2,4,5-tetrazine (42) and 3,6-dimethoxy-1,2,4,5-tetrazine (43) was reported by Sakya and
co-workers (Scheme 9).39 The preparation of 42 and 43
was accomplished by reacting 41 with a catalytic quantity
of sodium methoxide in methanol. The minor amount of
the dihydrotetrazine 44 formed was deoxidised to 42 upon
treatment with ferric chloride. The unsymmetrical tetrazine
42 underwent a Diels–Alder reaction in a predictable manner with electron-rich (enamines, silyl enol ethers) and neutral dienophiles as well as conjugated and unconjugated
alkynes with the resulting regioselective formation of the
products 45 and 46 (Table 1).
3,6-Bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (10) has
frequently been used to synthesise novel high-nitrogen
materials, as shown in Scheme 8.31–34 The normalised heat
of formation (NDHf) for the 3,6-diazido-1,2,4,5-tetrazine
(40), experimentally determined using an additive method,
was shown to be the highest positive NDHf, compared to
other organic molecules. Furthermore, unexpected azido-
HN N
N N
N NH
N N
OMe
20 °C, MeC
-N2, -MeOH
95%
N N
30
HN N
N N
Five new unsymmetrical 1,2,4,5-tetrazines, namely 6-[(tertbutyloxycarbonyl)-amino]-3-(methylthio)-1,2,4,5-tetrazine
(47), 6-(acetylamino)-3-(methylthio)-1,2,4,5-tetrazine (48),
N N
N NH
N N
N N
PhHN
N N
O
N N
O
31
Me
NHPh
O
N N
N
N
32
H37C18
N N
N N
N N
O
N N
O
35
N N
N N Me
N
N
33
-2N2
N N
C18H37
Me
N N
N N
N N
O
N N
O
34
CH2Cl2, rt, 3 h,
-N2, 77%
N N
N N
H37C18
O
N N
36
Scheme 7.
N N
MeCOCl
-HCl
O
N N
N N
20
2 PhNCO
-2N2, 75%
N N
N NH
HN N
N N
20 °C, MeCN
-N2, 83%
O
C18H37
Me
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
N N
N N
N N
H
NH
NH
N N
NNO2
N
N
H2N
NH2
Me
(2 eq.)
N
N
N NH
N N
N
N
N
N
N N
38
NH
N N
NH2
N
N
NH
H
N N
37
NH2
O2NN
4203
Me
10
Me
NH
Me
H2N
NH2
(2 eq.)
NH2
HN
NH
N
N
N
N
NH 39
NH
NNO2
H2N
2 N2H4
H2N
N N
H2NHN
NHNH2
N N
14
NaNO2
HCl/H2O
0 °C
N N
N3
N3
N N
40
Scheme 8.
3-methylsulfinyl-6-(methylthio)-1,2,4,5-tetrazine (49), 6(benzyloxycarbonyl)amino-3-(methylthio)-1,2,4,5-tetrazine
(50) and 3-(benzyloxycarbonyl)amino-6-methylsulfinyl1,2,4,5-tetrazine (51), were prepared by Boger et al. at different times,40,41 and the scope of their participation in
regioselective inverse-demand Diels–Alder reactions was
disclosed. The tetrazines 47, 48 and 50 were obtained by
the selective displacement of one methylthio group of 3,6bis(methylthio)-1,2,4,5-tetrazine (41) with the anions of
tert-butyl carbamate, acetamide and benzyl carbamate in
a one-step procedure. The sulfur oxidation of 41 and 50
with the DABCO–Br2 complex and m-CPBA gave the other
tetrazines 49 and 51, respectively (Scheme 10). Some cycloadducts of the five tetrazines are given in Table 2.
SMe
N
N
N
N
OMe
MeOH/NaOMe
N
N
SMe
41
N
N
+
N
N
SMe
42
OMe
N
N
OMe
+
R
N
N
OMe
43
X -N2
-HX
R
Scheme 9.
OMe
R
N
N
SMe
SMe
45
46
OMe
+
HN
HN
N
N
SMe
44
Boger and co-workers also reported the relative reactivity of
tetrazines 41–43, 47 and 48 towards N-vinyl pyrrolidinone.40 The corresponding experiments indicated that the reactivity of tetrazine 48 is greater than that of the other
tetrazines. The experimental findings were consistent with
Austin model 1 (AM1) computational studies of a full
range of substituted 1,2,4,5-tetrazines, where the LUMO
of both 47 and 48 was at a higher energy than that of 3,6dicarbomethoxy-1,2,4,5-tetrazine, but lower than those of
6-methoxy-3-(methylthio)-42 or 3,6-dimethoxy-1,2,4,5-tetrazine (43) (Fig. 1). The regioselectivity of the cycloadditions for 47, 48 and 49 is consistent with the expectation
that the methylthio group controls by stabilising a partial
negative charge at C-3 (Fig. 2).41 The dienophile follows
by the added ability of the acylamino group to stabilise
a partial positive charge on C-6 of the electron-deficient
tetrazine. The observed regioselectivity is supported by
AM1 computational studies. In an analogous manner, the
methylsulfinyl group for 51 would control the reaction orientation by stabilising a partial negative charge at C-3.
These predictions are supported by AM1 and MNDO computational studies. C-3 of both 49 and 50 bears a significant
partial negative charge, while C-6 is more electropositive
(Fig. 2).
Heuschmann and Hartmann investigated the steric effects
on the regioselectivity in the two-step Diels–Alder reaction
of unsymmetrical substituted tetrazines 56b,c with 2-cyclopropylidene-4,5-dihydro-1,3-dimethyl-imidazolidine.42 The
selected 1,2,4,5-tetrazines 56b,c were prepared from diacylhydrazides 52 according to a procedure developed by
Stolle.43 The reaction of the hydrazides 52 with phosphorus
pentachloride afforded the hydrazidedioyl dichlorides 53
4204
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
Table 1. Diels–Alder reactions of 3-methoxy-6-methylthio-1,2,4,5-tetrazine (42)
Dienophile
Product
Dienophile
Product
OMe
N
N
N
OMe
(CH2)3CN
OMe
(CH2)3CN
(CH2)2CN
Ph
TMSO
OMe
SMe
OMe
(CH2)3CN
SMe
O
OMe
N
N
N
SMe
N
N
N
N
SMe
SMe
NHBoc
NH2COO-t-Bu
N
N
NaH, 69%
SMe
47
N
N
NHAc
1. NH3/MeOH
N
N
2. Ac2O, DMAP
80 °C, 71%
NHAc
N
N
N
N
SMe
48
SMe
41
DABCO-2Br2
HOAc-H2O
CH2Cl2
52%
(CH2)3CN
N
N
SMe
N
N
Ph
N
N
Ph
N
N
(CH2)3CN
Ph
OMe
OTBS
OMe
OMe
SMe
Ph
OTBS
SMe
SMe
OMe
N
N
SMe
N
N
SMe
SMe
N
(CH2)2CN
N
N
N
N
HN
N
N
N
OTBS
SMe
N
O
OMe
NH2COOBn
NaH, 61%
N
N
NHBoc
N
N
SMe
N
N
N
N
N
N
OMe
N
N
OMe
N
N
N
N
N
N
SMe
SMe
SMe
SMe
OMe
48
47
41
42
43
reactivity
Figure 1.
SMe
N
N
O
NHCBz
NHCBz
N
N
N
N
N
N
SMe
S
Me
49
m-CPBA
N
N
CH2Cl2
85%
O
50
N
N
S
Me
51
or the 1,3,4-oxadiazoles 54, which were reacted with hydrazine hydrate to yield the dihydrotetrazines. The hydrotetrazines 55 were oxidised to the tetrazines 56 by nitrous gases
(Scheme 11).
Scheme 10.
Table 2. Cycloadducts for unsymmetrical-1,2,4,5-tetrazines 47–51
Dienophile
N
RO
Products of 47
Products of 48
Products of 49
Products of 50
Products of 51
NHBoc
NHAc
SMe
NHCBz
NHCBz
N
N
OR
R=OCH3, OEt
N
N
SMe
SMe
NHBoc
NHAc
N
N
OMe
SMe
O
N
N
N
N
N
OMe
SMe
NHBoc
N
N
S
O
O
Me
N
N
OMe
SMe
SMe
N
N
SMe
SMe
O
Me
S
Me
NHCBz
OEt
N
N
O
NHCBz
N
N
S
O
NHCBz
OEt
N
N
S
N
N
Me
SMe
NHAc
N
N
SMe
N
N
S
Me
NHCBz
N
N
SMe
O
S
Me
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
O
C-6
C-3
4205
O
R
HN
δδ+
N
N
N
N R1 δ+ EDG
δSMe
HN
N
N
R
R1
SMe
SMe
δEDG N
N
N
N
δ+
δO S
SMe
R1
N
N
O
C-3
+
R1 δ
S
C-6
Me
Me
Figure 2.
Ph
N
N
Ph
N
N
O
O
Cl
Cl
Ph
Ar
53
or
PCl5
Ar
52
N
N
Ph
N
N
O
Ph
NH
NH
NOx
N
N
N
N
Ar
Ar
55
56
Ar
54
52-56
a
b
Ar
Ph
2-Me-C6H4
c
2,4,6-Me3-C6H4
Scheme 11.
3,6-Diphenyl-1,2,4,5-tetrazine 56a reacted rapidly at room
temperature with cyclopropylidene-imidazolidine 57 to give
a spiro adduct 62a via [4+2] cycloaddition in accordance
with a general mechanism. Heuschmann and co-workers reported the reaction of the unsymmetrical tetrazine 56b with
57 at low temperature (10 C) (Scheme 12).42 After this
reaction was completed, the reaction mixture was characterised as a mixture of zwitterions 58b and 59b (33:67) by
NMR spectroscopy at 50 C. After the solution of zwitterions (33:67) was allowed to warm to room temperature, only
the spiro adduct 62b could be identified, besides 44% of the
tetrazine 56b. The reaction of 56b with 57 in tetrahydrofuran
was completed at room temperature in a few minutes and
84% of isomer 62b was isolated after recrystallisation.
When the dienophile 57 was added to the other tetrazine
56c at 10 C, only one regioisomeric zwitterion 59c was
formed. With warming of this zwitterion to room temperature, dispiro adducts 62c or 63c could not be identified and
the zwitterion decomposed to the starting materials 56b
and 57. These experimental results showed that the first reversible step of the cycloaddition affording zwitterions
58 and 59 is controlled by steric effects. The overall regioselectivity is, however, determined in the second step of cycloaddition, and a methyl group in the 2- or 6-position of the
aryl ring will completely prevent nucleophilic attack at the
adjacent side from the same side of the tetrazine ring.
Kotschy et al. investigated the reactions of tetrazines 64a–c
bearing a leaving group with various nucleophiles to give the
monosubstitution products 65, 66 and 67 (Scheme 13).44
When methanol and isobutyl mercaptan are used as nucleophile, the disubstitution products (68b,c,e) are also formed.
The reaction of the chlorotetrazines 65a–c with hydrazine
and potassium hydroxide resulted only in decomposition.
When tetrazines 66a–c and 67a–c were reacted with the hydrazine, they showed outstanding reactivity, and both 66b
and 67b gave only ipso-substitution products 66e and 67e,
respectively, which were unexpected. Furthermore, ipsosubstitution products 66d,e and 67d,e and normal substitution products 69a,c,f were obtained from 66a–c and 67a–c.
The influence of the nucleophiles and substituents used on
tetrazines was supported by quantum chemical calculations.
Novak and Kotschy reported the results of the first crosscoupling reactions on tetrazines.45 They reacted a series
of substituted chlorotetrazines 64a, 70a–h with different
terminal alkynes 71a–d under Sonogashira and Negishi
coupling conditions to yield the alkynyl-tetrazines 72
(Scheme 14).
New 1,2,4,5-tetrazines 73 and 74 and the known 1,2,4,5tetrazines 64a, 70g and 43 were synthesised and their electrochemical and fluorescence properties, including the
lifetimes of the excited states in solution and in the solid
Ph
N
N
Me
N
N
+
N
N
Me
Ar
56
Me
57
N
Ph
N
N
Ph
N
N
N
N
Me
N
N
N
Ar
58
Ph
Ar
Me
59
Me
N
N
N
N
N
N
Ph
N
N
N
N
N
Me
Ar
60
Ar N
Me
61
-N2
Me
N
N
N
Ph
N
Me
N
N
Me
N
N
Ar Me
Ar
62
63
56-63 a
Ar
Scheme 12.
Me
N
-N2
Ph
NH
Me
Ph
b
c
2-Me-C6H4
2,4,6-Me3-C6H 4
4206
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
LG
N
N
LG
HNu
N
N
N
N
LG
64a-c
N2H4
N
N
Nu
66a-c
67a-c
N
N
Nu
68b,c,e
Nu'
LG
N
N
or KOH
+N
N
Nu
65a-i
66a-i
67a-i
LG
N
N
Nu
N
N
N
+
N
N
N
NuH
64a, 65: LG: Cl
a: NH3
b: MeOH 64b, 66: LG: 3,5-dimethyl-pyrazol-1-yl
c: i-BuSH 64c, 67: LG: 4-bromo-3,5-dimethyl-pyrazol-1-yl
d: KOH
e: N2H4
f : morpholine
g: BuNH2
h: Et2NH
i : pyrrolidine
N
N
Nu
Nu'
69a,c,f
66d-e, 67d-e
Scheme 13.
N
N
state, were investigated by Audebert et al.,46 who compared
the same features for the already known dichlorotetrazine
64a (Scheme 15).
R
R
N
N
Cl
70a-h,64a
5% (PPh3)2PdCl2, 5% CuI
R1
+
N
N
2 eq. TEA, DMA
N
N
71a-d
Audebert and co-workers described the properties of
several new substituted tetrazines, which display fully reversible electrochemical behaviour and an intense fluorescence, both in solution and in the solid state. The results
showed that the fluorescence lifetimes are long and the
emission can be efficiently quenched by electron donors
such as aromatic compounds, which highlights the ability
of these new compounds to be used in sensor devices.
The new tetrazines 73 and 74 were synthesised from the
nucleophilic substitution reaction of 3,5-dichloro-1,2,4,5tetrazine (64a) with 1-naphthol and butane-1,4-diol.
Audebert et al. reported the synthesis and electrochemical
properties of new tetrazines 75–78 using a similar approach
(Scheme 16).47
R1
72
70a R = morpholin, 70b R = pyrrolidinyl, 70c R=NEt2, 70d R = NHBu,
70e R = NH2, 70f R = dimethylpyrazolyl, 70g R = OMe, 64a R = Cl,
71a R1 = C(Me)2OH, 71b R1 = Ph, 71c R1 = Bu, 71d R1 = TMS
Scheme 14.
Cl
N
N
OMe
Cl
N
N
N
N
Cl
64a
N N
N N
OMe
70g
N
N Cl
N N
O
O
N
N
N
N
N
N
O
N N
OMe
43
Rao and Hu reported the synthesis, X-ray crystallographic
analysis and antitumour activity of 1-acyl-3,6-disubstituted
phenyl-1,4-dihydro-1,2,4,5-tetrazines 80a–k or 81a–k as
shown in Scheme 17.48 The title compounds were prepared
Cl
Cl
73
N
N
74
Scheme 15.
N
N
O
O
N
N
N
N
74
HO
N
N
Cl
Cl
HS
(excess)
N
N
(1 eq.)
N
N
O
O
N
N
N
N
S
N
N
S
Cl
OH
1. MeOH
2. HO(CH2)4OH
N
N
Cl
64a
(excess)
64a
(1 eq.)
N
N
O
O
N
N
N
N
S
OH
N
N
N
N
O
OH
78
N N
SH
HS
75
Scheme 16.
S
S
N N
76
N
N
OH
O
N
N
S
N
N
OH
77
HO
SH
OH
O
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
R
R
R
O
N
N
NH
NH
(R'CO)2O/pyridine
N
HN
or ClCOR'/pyridine
R'
79
4207
C
N
N
a: R = H, R' = Me; b: R = H, R' = Et;
c: R = H, R' = i-Pr; d: R = CF3, R' = Me;
e: R = CF3, R' = Et; f: R = CF3, R' = i-Pr;
g: R = Cl, R' = Me; h: R = Cl, R' = Et;
i: R = Cl, R' = i-Pr; j: R = H, R' = ClCH2;
k: R = CF3, R' = ClCH2
O
R'
or
R'
80
N
N
N
NH
C
R'
R'
81
Scheme 17.
from the dihydro-1,2,4,5-tetrazines 79a–k, anhydrides or
acyl chlorides. This reaction yields 1,4-dihydro derivatives
possessing an obvious boat conformation rather than 1,2-dihydro derivatives. Their antitumour activities were evaluated
in vitro by the SRB method for A-549 cells and by the MTT
method for P-388 cells. The findings obtained show that
these acyl derivatives may have potential antitumour
O
R
N
N
N
N
B
O
solvent
+
140 °C
82 R = CO2Me
10 R = DMPY
3 R=H
R1
N
N
R1
R
83 R1 = Me
84 R1 = nBu
85 R1 = Ph
86 R1 = TMS
87 R1 = H
N
N
N
88-96
N
O
B
Arylboronic acids and esters represent one of the most
commonly used classes of synthetic intermediates.50–53
Harrity et al. reported the synthesis of highly functionalised
pyridazine boronic esters 88–104 using the cycloaddition
reactions of some substituted alkynylboronic esters 83–87
with symmetrical tetrazines 3, 10 and 82 and the synthesis
and cycloadditions of unsymmetrical tetrazines 97, 99 and
100 using 10, which was employed as a common intermediate for the preparation of the unsymmetrical tetrazines
(Scheme 18).54
R = CO2Me R1 = Me
R = CO2Me R1 = n-Bu
R = CO2Me R1 = Ph
R = CO2Me R1 = TMS
R = DMPY R1 = Me
R = DMPY R1 = Ph
R = DMPY R1 = TMS
R = H R1 = Ph
R = H R1 = H
The nucleophilic substitution of the dimethylpyrazolyl
moiety in 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (10) with aliphatic, cycloaliphatic, and aromatic amines,
and also with NH-heterocycles, was applied by Rusinov and
co-workers to synthesise both unsymmetrical tetrazines
105a–f and 106a–f (Scheme 19 and Table 3) and symmetrical tetrazines, which are shown in Section 2.3 (see Scheme
22 and Table 5).55
O
N
1. NH3 (excess)
toluene
N
N
Me
O
B
O
R
Me
Me
88
89
90
91
92
93
94
95
96
R
activities, and compound 80j is especially effective against
A-549, with 80c and 80j highly effective against P-388.
Recently, Rao and Hu have reported further work49 in this
area and prepared 14 compounds of both 3,6-disubstituted1,4-dihydro-1,2,4,5-tetrazine and 1,2,4,5-tetrazine derivatives, with their antitumour activities being evaluated.
Me
N
10
N(Boc)2
N
2. Boc2O, DMAP N
Ph
N
N
N
PhNO2
140 °C, 16 h
Me
N
Me
97
N
N
Me
N(Boc)2
Ph
N
N
98
B
O
O
Me
At the same time, Rusinov and co-workers reported heteroaryl displacements in 3,6-disubstituted 1,2,4,5-tetrazines 10,
107–111 with 1-methyl- and 1,6-dimethylquinaldinium
iodides 112a,b in the presence of triethylamine in acetonitrile.56 These displacements gave the C-nucleophilic substitution products 113–118a,e in excellent yield (50–98%)
(Scheme 20). When the substitution reaction of 10 with
1,6-dimethylquinaldinium iodide 112b was carried out in
less polar solvents such as toluene, the addition products
119 and 120 were formed instead of the substitution product
113b, as depicted in Scheme 20.
a) 1. NH3,(excess), 2. Boc2O, DMAP (99: 70%)
b) 1. H2N(CH2)2OH, 2. triphosgene (100: 73%)
O
O
N
N
Me
O
R
N
N
N
N
N
Me
99 R = H
100 R = Bn
O
PhNO2
140 °C, 16 h
O
B
101 R = H R1 = Ph
102 R = H R1 = Bu
103 R = Bn R1 = Ph
104 R = Bn R1 = Bu
R1
N
N
Me
O
R
N
N
N
B
O
O
Me
101-104
R1
There are only two previous papers on the synthesis of 3,6dibenzoyltetrazines, and their reactivity as azadienes was
Scheme 18.
Me
N N
N
N
N
N
Me
HNu1
Me
N N
N
N N
Me
Scheme 19.
10
Me
Nu1
N
Me
HNu2
N N
Nu2
Nu1
N N
N N
105
106
4208
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
Table 3. Unsymmetrical substituted 1,2,4,5-tetrazines
Me
Me
Nu2
Nu1
N
Me
N N
N N
N
N N
105
106
N N
N
N
Me
HN
N
N N
N N
N N
N
HN
N N
Me
NH
105a
N N
N
105b
Br
Me
N N
106b
106c
106d
N N
HN
NH2
R1 = H
R1 = Me
R1 = OMe
R1 = F
R1 = Cl
R1 = Br
NH
N N
N N
105c
R1
Me
HO
HO
N N
N
HN
N N
105d
N
HN
NH
NH
N N
N N
105e
F
Me
Me
N
NH
106g R1 = R2 = H
R1 = Me R2 = H
R1 = H R2 = Me
R1 = R2 = Me
R2
R1 = OMe R2 = H
R1 = Cl R2 = H
R1
R1 = Br R2 = H
R1 = Me R2 = H
N N
N N
NH
N
HN
O
N N
106f
N N
N N
Me
N
N N
106e
Me
N
N N
N N
N3
N
Me
NH
N N
HO
N
N
HN
S
N
N N
Me
106a R1 = R2 = H
R1 = Me R2 = H
R1 = H R2 = Me
R1 = R2 = Me
R2
R1 = OMe R2 = H
R1 = F R2 = H
R1
R1 = Cl R2 = H
R1 = Br R2 = H
N N
N
N N
Me
Nu1
N N
N N
105f
not investigated.57,58 Snyder and co-workers reported the direct conversion of heteroaromatic esters into methyl ketones
with trimethylaluminum.59 While tetrazine 82 did not react
cleanly with Me3Al, the 1,4-dihydro-1,2,4,5-tetrazine 121,
which is the synthetic precursor of 82, reacted with Me3Al
to produce the monoketone 122. Both the synthesis and
cycloadditions of the unsymmetrical tetrazines 123 and
125 were, however, also reported (Scheme 21 and Table 4).
2.3. Symmetrical substituted 1,2,4,5-tetrazines
The synthesis of symmetrical tetrazines 126a–l via the
nucleophilic substitution of the dimethylpyrazolyl moiety
in 3,6-bis(3,5-dimethylpyrazol-1-yl)-1,2,4,5-tetrazine (10)
was performed by Rusinov et al. (Scheme 22 and Table 5).55
Katritzky et al. prepared the 3,6-bis-(4-halophenyl)-1,2,4,5tetrazines 130 and 131 by modifying the general Pinner
method.60 Aminobenzonitrile (127) was cyclised by heating
HN
N
O
N N
106h
with anhydrous hydrazine into the previously unreported
3,6-bis-(4-aminophenyl)-1,2-dihydro-1,2,4,5-tetrazine(128)
in 51% yield. After the isolation and oxidation of dihydrotetrazine 128 to 129, diamine 129 was converted by a
Sandmeyer reaction into the iodophenyl 130 and bromophenyl 131 derivatives (Scheme 23).
The synthesis of 3,6-diacyl-1,2,4,5-tetrazines and their participation in the Diels–Alder reaction are limited. Snyder
et al. also achieved the synthesis and cycloadditions (134
and 135) of diketone 133 obtained from the reaction of the
1,2-dihydro-1,2,4,5-tetrazine 121 with Me3Al depending
upon the reaction conditions (Scheme 24).59
Tetrazine 141 was synthesised by Boger et al. in five steps
and in 28% overall yield from the commercially available
3,4-dimethoxybenzaldehyde (136), as depicted in Scheme
25.61 The first systematic study of the [4+2] cycloaddition
reactions of 3,6-diacyl-1,2,4,5-tetrazines was reported.
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
R
N
N
R
Me
I- N+
N
N
+
NEt3
R
10,107-111
MeCN
R1
112a: R1= H
112b: R1= Me
N
N
N
N
10, 113:
107, 114:
108, 115:
109, 116:
110, 117:
111, 118:
Me
N
113-118
4209
R: 3,5-dimethyl-pyrazol-1-yl
R: 4-bromo-3,5-dimethyl-pyrazol-1-yl
R: 4-chloro-3,5-dimethyl-pyrazol-1-yl
R: benzotriazol-1-yl
R: imidazol-1-yl
R: 4-methylimidazol-1-yl
R1
Me
Me
Me
N
N
N
N
Me
N
N
N
N
N
112b, NEt3, toluene
N
N
N
N
N
Me
Me
-N2
Me
Me
N
113b
Me
Me
Me
10
Me
N
N
N
N
N
Me
Me
N+
N
N
N
Me
NHMe
+
N
N
Me
N
Me
Me
N
119
Me
N
N
NHMe
N
N
N
Me
N
Me
120
Scheme 20.
COMe
CO2Me
N
HN
NH AlMe3 (3 eq.), -20 °C
N
N
HN
NH
N
COMe
[NOx]
CO2Me
122
CO2Me
121
N
N
N
N
CO2Me
123
NaBH4
OH
N
HN
NH
N
OH
[NOx]
CO2Me
124
N
N
N
N
CO2Me
125
include the tunichromes. Boger et al. reported the concise
and efficient total synthesis of ningalin A (145) based on
a heterocyclic azadiene Diels–Alder strategy (1,2,4,5-tetrazine/1,2-diazine/pyrrole).63 The Diels–Alder reaction
of the 1,2,4,5-tetrazine 82 with the acetylene 142 to give
the diazine 143 was the first step in the synthesis. Subsequent
reductive ring contraction of 1,2-diazine 143 from the treatment with zinc in AcOH afforded the desired pyrrole 144.
After deprotection of the MOM group and the first lactonisation, more forcing conditions (DBU) were required for the
formation of the second lactone. Demethylation with BBr3
completed the first total synthesis of the ningalin A (145)
(Scheme 26).
3.2. Total synthesis of lamellarin O and lukianol A
Scheme 21.
Diels–Alder cycloadditions of 141 were also observed towards both electron-rich and neutral alkenes and alkynyl
dienophiles (Table 6), as demonstrated by the formation of
1,2-diazines. Typically, the alkyne dienophiles were not as
reactive as the corresponding alkenes (Fig. 3).
3. Natural product synthesis
3.1. Total synthesis of ningalin A
First isolated in 1997 by Fenical and Kang, the ningalins
constitute a family of structurally interesting and biologically active natural marine products.62 Ningalin A (145)
and the related ningalins B–D are the newest members of
the family of DOPA-derived o-catechol metabolites that
Lamellarin O (150) is a prototypical member of a rapidly
growing class of natural marine products.64 Lukianol A
(151) was shown to exhibit cytotoxic activity against a cell
line derived from human epidermatoid carcinoma.65,66
Boger et al. prepared the 1,2-diazine 147 by intramolecular
cycloaddition using acetylene 146 and 1,2,4,5-tetrazine
82. After Zn-reductive ring contraction followed by N-alkylation of the pyrrole, the symmetric diester 148 was
selectively hydrolysed with LiOH to provide the mono
acid. Decarboxylation of the resulting acid afforded the
trisubstituted pyrrole 149. This key compound was converted into lamellarin O (150) and lukianol A (151)
(Scheme 27).63
3.3. Total synthesis of permethyl storniamide A
Storniamide A is a secondary metabolite.67 The same synthesis methodology for ningalin A (145), lamellarin O (150) and
4210
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
Table 4. Cycloadditions of unsymmetrical tetrazines 123 and 125
Tetrazine
Dienophile
Product
Tetrazine
Dienophile
Product
COMe
COMe
N
N
COMe
N
N
N
N
N
N
N
CO2Me
CO2Me
COMe
COMe
CO2Me
123
N
N
N
H
OH
N
N
N
H
CO2Me
OH
COMe
N
N
N
N
CO2Me
123
OH
OEt
CO2Me
OEt
COMe
N
N
N
N
OEt
N
N
OEt
CO2Me
125
N
N
CO2Me
OEt
CO2Me
CO2Me
(4:96)
Me
N N
N
N
Me
N
N
HNu3
Me
10
(1:1)
lukianol A (151) was also applied in the synthesis of permethyl storniamide (155).63 The cycloaddition of 152 with the
tetrazine 82 followed by zinc reductive ring contraction provided the pyrrole compound 154. After N-alkylation and diamidation, thioether oxidation with subsequent thermal
sulfoxide elimination gave the separable dienamide 155
(Scheme 28).
N N
Nu3
Nu3
N N
N N
Me
OEt
N
N
126
Scheme 22.
Table 5. Symmetrical substituted 1,2,4,5-tetrazines
N N
Nu3
Nu3
N N
126
O
N N
NH
HN
N N
N N
N N
N N
HN
NH
NH
N N
O
126g
N N
126d
126a
NH
N
N
N
N
N N
126j
HO
N N
N N
HN
N
NH
N
N N
126e
N N
OH
126b
N N
O
N
N
N N
O
N N
N N
N
N
N N
N N
126h
126k
Br
N N
N N
HN
NH
NH
N
N N
N N
126c
N N
N N
NH
NH
N
126i
126f
NH
N N
N N
126l
Br
CN
H2N
127
NH2NH2
HN NH
H2N
NH2
N N
4% H2O2
H2N
N N
128
HCl, NaNO2
KI
N N
I
HBr, NaNO2
CuBr
N N
I
N N
130
Scheme 23.
NH2
N N
129
Br
Br
N N
131
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
CO2Me
N
HN
NH
N
COMe
AlMe3 (6 eq.), rt
N
HN
CO2Me
121
4211
COMe
COMe
[NOx]
NH
N
N
N
COMe
132
N
N
N
N
-N2
COMe
134
COMe
133
N
H
COMe
N
N
N
H
COMe
135
Scheme 24.
OTMS
O
MeO
TMSCN, ZnI2
100%
MeO
MeO
OH
HCl-EtOH
CN
76%
MeO
MeO
NH2+Cl-
MeO
138
137
136
OEt
NH2NH2
OMe
OMe
OMe
MeO
MeO
MeO
O
N
N
OH
OH
Dess-Martin
N
N
90%
N
N
FeCl3
N
N
N
HN
OH
O
OH
MeO
MeO
MeO
OMe
140
OMe
141
NH
N
OMe
139
Scheme 25.
3.4. Total synthesis of ningalin B
Ningalin B (161) is a natural product possessing a 3,4-diarylsubstituted pyrrole nucleus.62 Boger et al. described a concise and efficient approach to the total synthesis of ningalin
B.68 The Diels–Alder reaction of the acetylene 156 with the
1,2,4,5-tetrazine 82 afforded the 1,2-diazine 157 in excellent
yield. The transformation of the 1,2-diazine 157 to the pyrrole 158 was performed with Zn in AcOH. After N-alkylation, lactonisation and decarboxylation, demethylation
Table 6. Diels–Alder reactions of 3,6-bis(3,4-dimethoxybenzoyl)-1,2,4,5-tetrazine (141) with alkenes and alkynes
Dienophile
Product
Dienophile
Product
O
N
N
or
O
O
Ar
N N
Ar
OMe
Ar
OEt
O
Ar
EtO
OEt
N N
O
O
N N
Ar
OEt or
OAc
Ar
N N
Ph
Ar
N N
O
O
NEt2
Ar
Ar
OH
N N
O
Ar
O
N N
Ar
R
O
O
Ar
NEt2
O
Me
OTMS
Ar
O
O
Ph
O
O
R
R=OEt, Ph, CO2CH3
Ar
O
N N
Ar
R=OEt, Ph, CO2Me
Ar
Ph
Ph
No reaction
4212
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
NR2
EtO
OEt
with BBr3 completed the total synthesis of ningalin B (161)
(Scheme 29).
OAc
OEt
3.5. Total synthesis of ningalin D
NR2
OEt
Ph
CO2Me
Boger et al. also achieved the total synthesis of ningalin D
(165) using a nine-step reaction.69 The first step of the
Figure 3. Relative dienophile reactivity towards 141.
MeO2C
OMe
OMOM
OMe
MeO
NN
NN
82
CO2Me
-N2
MOMO
MeO2C
MOMO
142
MeO
MeO MeO OMe OMe
OMOM
CO2Me
N N
143
Zn, AcOH
OH
HO
HO
O
O
1. HCl-EtOAc
2. DBU
3. BBr3
OH
MOMO
O
N
H
MeO MeO OMe OMe
MeO2C
O
145 (ningalin A)
OMOM
CO2Me
N
H
144
Scheme 26.
MeO2C
OBn
BnO
NN
NN
82
BnO
-N2
146
OBn
CO2Me
MeO2C
CO2Me
N N
147
Zn, AcOH
HO
OH
N
BnO
CO2Me
N
O
OBn
BnO
CO2Me
MeO2C
O
149
OMe
OMe
150 (lamellarin O)
HO
OH
O
N
O
OH
151 (lukianol A)
Scheme 27.
OBn
CO2Me
N
H
148
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
OMe
MeO
152
MeO
CO2Me
NN
82
OMe
MeO
MeO MeO OMe OMe
NN
MeO2C
4213
-N2
MeO
OMe
MeO2C
OMe
CO2Me
N N
153
Zn, AcOH
MeO MeO OMe OMe
MeO
MeO MeO OMe OMe
OMe
H
N
MeO
H
N
N
O
OMe
MeO2C
O
CO2Me
N
H
154
OMe
155 (permethyl storniamide A)
Scheme 28.
synthesis is the preparation of the diazine 163 from the symmetrical alkyne 162 and tetrazine 82. The transformation of
163 into the pyrrole is the second step. N-Alkylation, a double Dieckmann condensation and Suzuki coupling afforded
the ningalin D skeleton. The final step was deprotection
with BBr3 to give ningalin D (165) (Scheme 30).
serves as an intermediate for the synthesis of 173 and 174.
Boger and Wolkenberg reported the fascinating synthesis
of 172, 173 and 174 from Amaryllidaceae alkaloids.74 Their
strategy is based on the intramolecular inverse-Diels–Alder
reaction of the unsymmetrical tetrazine 167, which was
prepared by the reaction of 3,6-bis(methylthio)-1,2,4,5-tetrazine (41) with 1-amino-3-butyne 166. The first intramolecular [4+2] cycloaddition was achieved at room temperature
during N-acylation of 167 with Boc2O/DMAP. After the
1,2-diazine 168 was N-Boc deprotected, the resulting compound 169 was submitted to the N-acylation reaction to
yield 170. The second intramolecular [4+2] cycloaddition
at high temperature and the aromatisation via elimination
of methanol provided the anhydrolcorinone precursor 171.
3.6. Total synthesis of Amaryllidaceae alkaloids
Lycorine alkaloids isolated from Amaryllidaceous plants
have potent biological activity. Hippadine70 (173) inhibits
fertility in male mice, while anhydrolycorinium chloride71
(174) exhibits cytotoxic activity against a number of tumour
cells. The natural product, anhydrolcorinone72,73 (172),
MeO2C
OMe
OMe
MeO
NN
NN
82
MeO MeO OMe OMe
CO2Me
-N2
MeO
OMOM
CO2Me
MeO2C
MOMO
156
N N
157
Zn, AcOH
OH HO
HO
OH
MeO MeO OMe OMe
MeO MeO OMe OMe
K2CO3
OMOM
O
MeO2C
N
O
MeO2C
N
Br
CO2Me
160
OMe
159
OH
161 (ningalin B)
Scheme 29.
OMe
OMOM
MeO2C
CO2Me
N
H
158
4214
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
MeO2C
OMe
MeO
OMe
MeO
MeO2C
NN
NN
82
MeO MeO OMe OMe
CO2Me
MeO2C
MeO2C
-N2
CO2Me
CO2Me
N N
163
CO2Me
162
OH
HO
HO
MeO
OH
O
BBr3
O
MeO
OMe
OMe
O
O
N
N
HO
MeO
OH
HO
OMe
MeO
OH
OMe
OMe
OH
OH
OMe
165 (ningalin D)
164
Scheme 30.
Reductive desulfurisation of 171 with Ra-Ni yielded
anhydrolycorinone (172), which was transformed into
hippadine (173) and anhydrolycorinium chloride (174)
(Scheme 31).
sequence provided the tricyclic core 178 in 19 steps
(Scheme 32). Condensation of 178 with 179 followed by
final deprotection afforded (22S,23S)-181.
3.7. Asymmetric total synthesis of ent-(L)-roseophilin
3.8. Structural revision and synthesis of cytotoxic
marine alkaloid, zarzissine
Roseophilin75 (181) is a novel antitumour antibiotic possessing a pentacyclic skeleton. A Diels–Alder reaction of
dimethyl-1,2,4,5-tetrazine-3,6-dicarboxylate (82) with optically active enol ether 175 bearing the C23 chiral centre provided the optically active 1,2-diazine 176.76 Reductive ring
contraction of 176 gave the pyrrole 177 in good yield. This
The cytotoxic natural marine product, zarzissine,77 deduced
to be 2-amino-1H-imidazo[4,5-d]pyridazine (182), was
reported to have a broad range of activities, being active
against Staphylococcus aureus, and the fungi Candida albicans and C. tropicais, as well as against several tumour cell
lines (Fig. 4). Snyder et al. reported that 2-substituted
Boc
SMe
N
N
N
N
HN
NEt3/MeOH
+
51%
HCl.H2N
N
N
166
SMe
41
N
BOC2O
DMAP
N
N
96%
HCl.HN
HCl/EtOH
N
N
N
N
SMe
SMe
SMe
167
168
169
N-acylation
O
O
N
Red-Al, O2, HCl
O
N
Scheme 31.
O
ClN+
O
173
-N2
-MeOH
171
172
O
265 °C
O
DDQ
174
O
O
N
Ra-Ni
O
O
O
O
O
SMe
N
MeO
N
N
170
SMe
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
CO2Me
MeO2C
25 °C, 60 h
N MeO
+
N
N
N
(R) OBn
175
CO2Me
82
OBn
N
N
4215
MeO2C
OBn
Zn/TFA
HN
MeO2C
MeO2C
176
177
OMe
O
TIPSN
Bu4NF
aq. HCl
23
N
.HCl
OMe
OH
OMe
N
SEM
Cl
179
n-BuLi
CeCl3, -55 °C
N
SEM O
O
O
HN
178
TIPSN
Cl
ent-181.HCl
Cl
180
Scheme 32.
N
H2N
N
H
N
N
N
N
N
H
N
carbazole alkaloids.79,80 Snyder and co-workers reported
that reductive ring contraction of dimethyl 5H-pyridazino[4,5-b]indole-1,4-dicarboxylate 189d (and 189a–c)
formed from the reaction of indole 188d (and 188a–c) and
tetrazine 82 produced dimethyl 2,4-dihydropyrrole[3,4-b]indole-1,3-dicarboxylate 190d.81 Benzo[b]carbazole derivative 191 was obtained by the reaction of pyrroleindole
190d with benzyne (Scheme 34).
H2N
183
alternative structure for zarzissine
182
structure reported for zarzissine
Figure 4. Possible structures for zarzissine.
imidazoles have proved to be good dienophiles with 1,2,4,5tetrazine to produce imidazo[4,5-d]pyridazines in excellent
yields.78 This group synthesised the structure reported for
the marine cytotoxic agent, zarzissine, 2-amino-1H-imidazo[4,5-d]pyridazine (182), from the cycloaddition of
2-amino-1H-imidazole 184 and dimethyl 1,2,4,5-tetrazine3,5-dicarboxylate 82 and it proved to have spectroscopic
data quite different from those reported for zarzissine
(Scheme 33). They thought that the most reasonable
structure for zarzissine is the 2-amino-1H-imidazo[4,5-b]pyridazine (183) and this compound was also synthesised,
but the true identity of zarzissine remains unconfirmed
(Scheme 33).
Carbapenems are a class of beta-lactam antibiotics, and
tricyclic carbapenem GG-326 has received considerable attention due to its broad spectrum of antibacterial activity
and resistance to hydrolysis by beta-lactamases.82–85 The
synthesis of novel tricyclic diazocarbapenem precursor
195 and the protected carbapenems 196 and 197 was described by Sakya et al. (Scheme 35).86 The tricyclic carbapenem skeleton was accomplished by an intramolecular
nucleophilic substitution of diazine sulfone 194, which
was obtained from the inverse-Diels–Alder reaction of alkyne 192 with tetrazine 41.
Psoralens, natural products known as furocoumarins, are
commonly used in the photochemotherapy of several skin
diseases, including psoriasis, vitiligo, and T-cell lymphoma,
and a number of autoimmune disorders.87 Uriarte et al.
reported the results of Diels–Alder reactions between
methoxypsoralenes and 1,2,4,5-tetrazines.88 The reaction
of 8-methoxypsoralen (198c) and 3,6-bistrifluoromethyl-
4. Annulations of pyridazine moiety to natural products,
alkaloids or drugs
Indole-2,3-quinodimethanes and their related stable equivalents have been exploited for years for the synthesis of
CO2Me
CO2Me
N
BzHN
+
N
H
N
N
N
N
N
cycloaddition
BnHN
then oxidation
by tetrazine
N
H
CO2Me
82
184
N
N
N
N
N3
N
H
N
186
Scheme 33.
N
N
MOM
187
N
N
1. HOAc/HCl
2. aq KOH
N
N
H
CO2Me
185
1. H2, Pd-C
2. 1% KOH
N
N
H2N
182
N
N
H2N
N
H
N
183
4216
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
MeO2C
CO2Me
+
N
R
N
N
(70-96%)
CO2Me
N
R
MeO2C
MeO2C
NH
N
a: R = H
b: R = Ac
c: R = Bn
d: R = Bz
189a-d
82
N
N
Bz
189d
N
CO2Me
188a-d
MeO2C
N
-N2
N
N
1.
Zn/AcOH
CO2Me
N
Bz
190d
CO2Me 2. K2CO3/MeOH
CO2Me
N
H
191
Scheme 34.
1,2,4,5-tetrazine (199) was accomplished by the release
of diatomic nitrogen and opening of the furan ring to
leave a 6-pyridazinocoumarin 201. When 3,6-bis(methoxycarbonyl)-1,2,4,5-tetrazine (82) was used as diene, cycloaddition occurred by conversion of the furan ring into a pyrone
ring 202a–c (Scheme 36).
yield. Linear pyridazine furocoumarin 207 was obtained
by a two-step reaction using 205 (Scheme 37). The same
group also synthesised new pyridazinofurocoumarins and
their carboxamide derivatives at C4 or C1 and C4 by a similar
strategy (Scheme 38).90,91 Furthermore, this approach was
used to prepare the 4-carboxamide derivatives of pyridazino[4,5-b]benzo[b]furan 225 and pyridazino[4,5-b]indole
226 (Scheme 39).92
In order to prevent the opening of the furan ring in the
furocoumarin during the cycloadditions of 3,6-bistrifluoromethyl-1,2,4,5-tetrazine (199), Uriarte and co-workers
developed a new strategy to synthesise linear and angular
pyridazine furocoumarins.89 This group used didhydrofuro[2,3-h]coumarin-9-one, which is accompanied by an
enol form, as a dienophile in the cycloadditions for the fusing of the pyridazine ring. From the one-step reaction of 203
and tetrazine with concomitant loss of N2 and water, angular
pyridazine furocoumarin 204 was synthesised in a good
Gonzales–Gomez and Uriarte prepared 2-chloro-pyridazino[4,3-h]psoralen 229 from the Diels–Alder reaction of
3,6-dichloro-1,2,4,5-tetrazine (64a) and 8-methoxy-psoralen (198c) in a one-pot procedure.93 The transformation
of this intermediate 229 into the 2-triflate derivative 230
allowed a Pd-catalysed reduction, methoxycarbonylation
and Sonogashira cross-coupling reactions at C2
(Scheme 40).
SMe
TBSO
H H
+
N
N
N
N
SMe
xylene
TBSO
N
N
H H
140 °C, 3 d
1. LHMDS,
benzyl bromoacetate
SO2Me
TBSO
N
N
H H
2. m-CPBA
NH
O
SMe
41
192
NH
O
SMe
O
193
N
GG-326
SO2Me
O
194
OBn
1. LHMDS
2. TBAF
OH
H H
O
N
OMe
CO2H
OH
H H
MeO2S
OH
H H
N
N
MeO2S
OH
H H
N
N
N
N
+
O
N
197
O
O
ONa
N
O
ONa
196 O
N
195 O
ONa
Scheme 35.
N
N
O
O
R
OH
OMe
200 R=H
201 R=CF3
Scheme 36.
CO2Me
R
R
N N 3
R=H
N N
199 R=CF3
R
-N2
CO2Me
N N
N N 82
R1
N
N
R1
CO2Me
O
O
O
R2
-N2
-MeOH
198a R1=OMe R2=H
198b R1=H R2=OH
198c R1=H R2=OMe
O
O
O
R2
202a-c
O
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
O
O O
203 O
O
O
F3C
N N
204
CF3
O
O
EtO2C
CF3
F3C
O
MeO
N
N
dioxane, reflux
-N2
-H2O
N
N
205
N
N
EtO2C
dioxane, reflux
-N2
-H2O
CF3
199
4217
CF3
O
MeO
206
BBr3, CH2Cl2, reflu
F3C
N
N
O
CF3
O
O
207
Scheme 37.
Me
O
O
ROC
210-214 N N
O
O
Me
O
MeO2C
N N
209
208
Me
Me
O
O
O
O
O
O
O
O
COR'
Me
Me
O
210 R = OMe R' = N(CH2)4,
211 R = R' = N(CH2)4
212 R = OMe R' = NH(CH2)2NMe2
213 R = R' = NH(CH2)2NMe2
214 R = NH(CH2)2NMe2 R' = N(CH2)4
O
MeO2C
O
O
CO2Me
N N
215
Me
N
N
N
O
CO2Me
O
O
Me
N
O
216
Me
Me
218
219 R=OMe R'=N(CH2)4,
220 R=R'=N(CH2)4
221 R=OMe R'=NH(CH2)2NMe2
222 R=R'=NH(CH2)2NMe2
223 R=NH(CH2)2NMe2 R'=N(CH2)4
ROC
N
N
O
O
O
O
O
Me
217
COR'
219-223
Scheme 38.
CO2Me
Gonzales-Gomez and co-workers achieved a convenient
preparation of the parent benzodifuran 234 from resorcinol
followed by DDQ oxidation.94 The cycloaddition of the
benzodifuran 234 and 235 with the tetrazine 82 afforded
novel pyridazino-psoralen derivatives (236–239) upon the
expected furan ring expansion (Scheme 41).
The Aspidosperma family, particularly the complex pentacyclic ABCDE framework, represents one of the largest groups
of indole alkaloids, with more than 250 compounds isolated
from various biological sources.95–98 Snyder and co-workers
reported tryptamine-tethered tetrazines as 241, which were
prepared by the displacement of methylthiolate from both
3,6-bis-(methylthio)-1,2,4,5-tetrazine (41) with tryptamine
O
O
N
N
CO2Me
MeO2C
N
N
N
N
N
82
CO2Me
N
73%
X
224
82
CO2Me
CO2Me
95%
225 X=O
226 X=NH
MeO2C
N
N
X
227
CONRR'
N
X
228
N
H
188a
amine
(CH2)4NH
Me2N(CH2)2NH2
amine
R'RNOC
N
Scheme 39.
N
N
CONRR'
4218
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
240 via ethylamine.99 Their attempts to convert the tethered
diazine 243 into the pentacyclic core 244 of aspidosperma
alkaloids were unsuccessful (Scheme 42).
the respective N-protected epibatidine analogues 249a–d in
good yields after inverse cycloaddition, release of nitrogen
and elimination of methanol, respectively. Removal of the
protecting groups from 249a and 249b afforded the pyridazine analogues 250 and 251 of epibatidine. The deprotection of 249c into 252 furnished complex mixtures, while
that of 249d resulted in the formation of an unexpected
cyclohexene derivative 254 in addition to small amounts of
the epibatidine analogue 255 (Scheme 43). The pyridazine
analogue 253 of ()-epibatidine and its N-methyl derivative
255 was found to be the most active, retaining much of the
potency of natural epibatidine.
Epibatidine (245), a pyridylazabicyclo[2.2.1]heptane, is an
alkaloid isolated from the skin of a South American
frog.100 It is one of the most potent analgesics known, some
10-fold more potent than morphine. Seitz and co-workers
presented a new strategy for the synthesis of novel epibatidine analogues, in which the 2-chloropridinyl moiety of epibatidine is replaced by differently substituted pyridazine
rings.101 As outlined in Scheme 43, the commercially available 3-tropanone 246 could be converted in seven steps into
the electron-rich dienophilic enol ether 247. The enol ether
247 reacted with the tetrazines 199, 248, 64a and 3 to yield
(+)-Anatoxin-a (256) is a potent neurotoxic alkaloid isolated
from blue-green algae.102,103 It is one of the most potent
+
O
O
O
N
N
Cl
OTf
N
N
N
N
2
Cl
N
N
CH2Cl2, 140 °C, 30 h
then i-Pr2NEt
O
O
O
O
O
O
OMe
Cl
OMe
OMe
198c
64a
229
230
OH
CO2Me
N
N
O
N
N
O
O
O
O
O
OMe
231
N
N
O
O
O
OMe
232
OMe
233
Scheme 40.
CO2Me
N
N
CO2Me
O
O
+
N
N
-N2
N
N
-MeOH
CO2Me
CO2Me
N
N
N
N
+
O
O
O
O
O
O
O
R
CO2Me
R
R
234 R=H
235 R=CHO
82
236 R=H (65%)
238 R=CHO (70%)
237 R=H (15%)
239 R=CHO (5%)
Scheme 41.
O
N
Bn
240
N
N
N
N
SMe
41
N D
E
C
B
A
N
H
aspidosperma
alkaloid core
Scheme 42.
N
NH
SMe
NH2
+
N
N
N
Bn
N
N
241
N
N
Ac 2O
-N2
SMe
SMe
N
Bn
242
O
O
N
N
N
N
X
N
Bn
244
CN
N
Bn
243
CN
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
4219
R
H N
OMe N
N
EtO2C
N
seven-step
199 R = CF3
N 248 R = Py(2)
N 64a R = Cl
3
R=H
R
R
EtO2C
N
R
249a-d
O
247
246
H
Cl
N
H
N
H
N
N
N
H
N
N
N
N
N
N
Cl
251
250
H
N
N
N
Py(2)
CF3
245
epibatidine
Cl
Py(2)
CF3
a: R = CF3
N b: R = Py(2)
N c: R = Cl
d: R = H
252
Me
253
N
N
N
N
N
NH2
254
255
Scheme 43.
agonists at the nicotinic acetylcholine receptor (nAChR)
discovered to date.104,105 Both (+)-anatoxin-a (256) and
()-norferuginin (258) are derivatives of tropane alkaloids.106–108 Racemic ()-pyrido[3,4-b]homotropane109,110
(257) is the first bioisosteric and conformationally
constrained variation, while the enantiomerically pure pyrido[3,4-b]tropane111 (259) is the conformationally restricted
bioisosteric variant of ()-norferuginin (258). Because of
their unusual biological properties, these alkaloids provide
an attractive lead for the design of novel structural analogues.
Seitz et al. developed a strategy for the synthesis of novel
pyridazine and pyrimidine analogues of 257 and 259.112
The versatile chiral building block, (+)-2-tropinone 260, is
transformed into the ring-expanded silyl enol ether 261 and
into the enamine 263. The inverse-Diels–Alder reactions of
H
EtO2C
O
N
H
N
N
257
(±)-pyrido[3,4-b]homotropane
OTMS
EtO2C
N
TMSCHN2
AlMe 3
94%
261
1.
N
N
Seitz and co-workers synthesised anabasine analogues with
potential nicotinic acetylcholine receptor agonist activity.113
()-Anabasine (266) is one of several minor tobacco alkaloids.114–118 These workers described a novel multistep synthesis of anabasine analogues containing a pyridazine
moiety instead of a pyridine nucleus in the 2-position of
the piperidine ring of the alkaloid. The new racemic or enantiopure 2-(2-methoxyethenyl)-piperidines 267 were synthesised as electron-rich dienophiles. The inverse cycloaddition
process of these dienophiles with 1,2,4,5-tetrazines (3, 82
and 199) gave the racemic and enantiopure 4-(piperidine2-yl)-pyridazines 268, 269 and 271 (Scheme 45).
H
256
(+)-anatoxin-a
N
both compounds with 1,2,4,5-tetrazines provided the enantiopure target compounds 262, 264 and 265 (Scheme 44).
N
O
258
(-)-norferuginin
H
259
pyrido[3,4-b]tropane
EtO2C
O
N
N
O
N
morpholine
260
p-TosOH
91%
263
N
1.
N
N
, toluene, 60 h, reflux
N
3
N
N
262
Scheme 44.
H
N
R
N 199 R = CF3
N 82 R = CO2Me
R
2. p-TosOH/benzene, reflux
3. conc. HCl, dioxane
4. conc. NH3 pH = 9
2. TMSI/CHCl3, 3.5 h, 80 °C
3. MeOH
H
N
R
N
N
N
R
264 R = CF3
265 R = H
4220
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
R
N
O
+
OEt OMe
(±)-267
N
N
R
N
N
1. no solvent
N (±)-268 R = H
N (±)-269 R = CF3
N
H
12 h, 80 °C
2. TMSI, CHCl3
R
3
R=H
199 R = CF3
R
R
N
H
266
N
O
OEt OMe
R
(S)-267
CO2Me
N
N
N
H
(S)-268 R = H
(S)-269 R = CF3
N
N
N
H
N
H
-MeOH
N
CO2Me
O
CO2Me
(S)-270
N N
(S)-271
Scheme 45.
1,2,4,5-tetrazine 82 to yield azinylvinylpyridazines.127
They also observed that all the reactions of the three diphenylazinyl-substituted 1-trans-3-trans dienes 277a–c with
tetrazine gave the expected trans-azinylvinylpyridazines
282a–c, while, interestingly, the three 1-cis-3-trans azinyldienes 276a–c furnished different products. The cis product
281a was obtained from 276a, whereas the other two cis
molecules 276b,c afforded the same trans products 282b,c,
which were also produced from the fully trans isomer
(Scheme 47). This group suggested that such isomerisation
may be due to the tautomeric equilibrium of the intermediate. The semiempirical calculations also supported the
importance of the influence of the hetaryl group in such
isomerisations.
C-Nucleosides bearing five-membered nitrogen heterocycles are known to possess varied biological activities.119–123 The pyrrole C-nucleosides also exhibit
anticancer activity, while simple substituted pyrroles are
known to exhibit antineoplastic and antileukemic activities.124,125 Dubreuil et al. prepared126a the pyridazine
C-nucleosides 274a,b by using 272 with the procedure
described by Seitz and Richter (Scheme 46).126b The last
step was conversion of these pyridazine C-nucleosides
274a,b on extrusion of a nitrogen atom into the corresponding pyrrole derivatives 275a,b by electrochemical or chemical methods.
5. Other applications
Smith and co-workers described the synthesis of a new azobridged ring system using an intramolecular tandem cyclisation process as the key step.128 The cycloaddition reaction of
dienamine 283 with diester tetrazine 82 afforded the intermediate product, 1,2-dihydropyridazine 284. Finally,
5.1. Pyridazine-based syntheses and transformations
Hajos and co-workers reported that the azinyldienamines
276a–c and 277a–c underwent a Diels–Alder reaction with
CO2Me
O
O
OH
HO
N
R N
BnO
HO
OH
272
BnO
OBn
273a R = Ph
273b R = nBu
N
N
82
CO2Me
toluene, reflux
MeO2C
N
N
O
CO2Me
BnO
BnO
R
OBn
274a R = Ph (56%)
274b R = nBu (65%)
1. Zn/HOAc or electrolysis
2. H2/Pd-C, EtOAc, rt
MeO2C
NH
O
BnO
BnO
Scheme 46.
R
OBn
275a R = Ph
275b R = nBu
CO2Me
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
Y
N
N
4221
Ph
X
N
N
Ph
276a-c
N
N
CO2Me
N
N 82
Y
N
MeO2C
N
N
N
N
X
Ph
E
HN
N
Ph
NH
MeO2C
N
N
N
Y
Ph
X
Ph
H
N
N
Ph
CO2Me
N
N 82
CO2Me
MeO2C
N
N
N
279
N
X
CO2Me
278
MeO2C
Ph
277a-c
CO2Me
E
Y
Y
Ph
X
Ph
Y
Ph
X
Ph
Y
Ph
X
Ph
280
E=CO2Me
a: X = Y = CH
b: X = N Y = CH
c: X = Y = N
N
N
CO2Me
MeO2C
N
CO2Me
281a
282a-c
Scheme 47.
a tandem cyclisation reaction of the intermediate 284 provided the azo-bridged tricyclic ring system 285. In contrast
to 2-methy-1-morpholin-1,3-pentadiene (283), 286 reacted
with 2 mol of tetrazine to give the dipyridazine structure
287 (Scheme 48). Kotschy et al. also investigated the
thermal decomposition at 110–150 C of the azo-bridged
tricyclic ring system 285a,b to give dimethyl 4-methylpyridazine-3,6-dicarboxylate 291 in excellent yield.129 When
samples of 285a,b were heated at 200, 250 and 300 C,
however, the increasing pyrolysis temperature caused an
increase in the proportion of side products. They proposed
a mechanism for the decomposition and this mechanism
was supported by quantum chemical calculations and experimental evidence. According to the proposed mechanism,
the initial step of the thermal decomposition of 285a,b is
a retro-Diels–Alder reaction that leads either to 288a,b or
289a,b, which is in tautomeric equilibrium with 290a,b
(Scheme 49).
Appropriately substituted azolyldienamines 298a–c underwent double inverse-Diels–Alder reactions with tetrazine
derivatives to give azolylpyridazines 301 and dihydropyridazines 302, as depicted in Scheme 50.130 Smith et al.
accomplished the reaction of dienamines with dimethyl
ester tetrazine 82 to yield the m- and p-phenylenebridged bis-azolylvinyl-pyridazines 306a,b and 307a,b
(Scheme 51).131
Further intensive studies of the parent compound 3 have
been hindered, due to the fact that the preparation of 3
is often accompanied by various synthetic obstacles.
This compound has become readily available, however,
N
CO2Me
Me
N
Me
X+
N
N
N
N
Me
-N2
N
X
N
82 (2 eq.)
O
-2 N2
Me
MeO2C
N
X
N
HN
N
CO2Me
Me
N
N
N
CO2Me
287
O
Scheme 48.
CO2Me
Me
284
MeO2C
286
N
CO2Me
MeO2C
Me
N
N
Me
CO2Me
82
283
CO2Me
N
CO2Me
Me
Me
MeO2C
N
X
285a X = O
285b X = NMe
4222
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
N
MeO2C
N
Me
N
N
Me
CO2Me
Me
MeO2C
N
MeO2C
X
288a,b
MeO2C
285a X = O
285b X = NMe
110-150 °C
N
N
Me
+
N
X
296a,b
N
294
MeO2C
291
H
Me
CHO
295
MeO2C
292a,b
+
X
290a,b
X
Me
N
N
MeO2C
MeO2C
291 + 292a,b +
HN
MeO2C
Me
N
HN
N
289a,b
pyrol.
vacuum or
solution
X
H
Me
N
X
MeO2C
N
N
N
Me
MeO2C
Me
X
297a,b
293
Scheme 49.
R
R
N N 82
N N 199
R 248
Me
NR2
Het
R
N N
N
Het
R
R2N
R
Me
N 89
N 199
248
R
-N2
N
N
R
300
NR2:
morphonyl 298a,302a
pyrrolidinyl 298b,c,302b,c,e
Ph
N
N
NH
N
R
Het
H
R
299
Het:
N
Me
HN
N
-N2
298a-c
N
NR2 N
N
R
R
R:
82: 301a,b;302a,b
-CO2Me
199: 301c;302b
-CF3
-2-pryidyl 248: 301d,a;302e,303
Me
N
N
NR2
R
302a-c,e
R
301a-e
Cl
298a,b
301a,c,d
R
Me
+ N
HN
Het
N
N
R
303
Cl
298c
301b,e
Scheme 50.
Ph
MeO2C
Ph
N N
N
N N
N
N
N
N
82 (2 eq.)
CO2Me
CO2Me
-2N2
-pyrrolidine
N
N N
Ph
N
N
N
N N
Ph
N
304a,b
MeO2C
306a,b
MeO2C
N N
N
Ph
N
N
N
N
N
N
N
N
82 (2 eq.)
-2N2
-pyrrolidine
305a,b
N
CO2Me
MeO2C
(CH2)n
308
n=1-4
- N2
- HX
N
N
N
N
3
R1
- N2
R2
N
N
R1
310
Scheme 52.
N
307a,b
Scheme 51.
(CH2)n
309
N
N
Ph
N
R2
X
CO2Me
Ph
N
N
Ph
through a method developed by Sichert132a and a similar
procedure published by van der Plas.132b Sauer et al. optimised the synthesis procedure for 1,2,4,5-tetrazine (3) and
investigated its reaction kinetics and reactivity to yield
simple 4- and 4,5-substituted pyridazines 310 using electron-rich alkenes and alkynes as dienophiles (Scheme
52).133,134 They also synthesised both metalated (metal¼Si, Ge and Sn) and unmetalated substituted pyridazines
(Table 7).
N N
The use of analogues of 3,6-dichloro-1,2,4,5-tetrazine (64a)
as herbicides has been reported.135 Sparey and Harrison described the rapid access to a range of highly functionalised
pyridazines (Table 8) by using the 3,6-dichlorotetrazine
64a as an efficient azadiene in inverse electron-demand
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
Table 7. Cycloadducts of 1,2,4,5-tetrazine (3)
Cl
Product (309)
Dienophile (X: NMe2,
OMe, OSiMe3)
Product (310)
Cl
N
N
N
N
R1
N
N
4223
SnBu3
Cl
X
R2
R1
R2
H
H
H
H
H
H
H
H
H
H
H
MeS
MeS
Me3C
Me3Sn
Bu3Sn
Me3Ge
Me3Si
H
CMe3
Ph
C6H4-pOMe
C6H4-pONO2
NMe2
OMe
SMe
SnBu3
GeBu3
SiMe3
NMe2
SMe
CMe3
SnMe3
SnBu3
GeMe3
SiMe3
X
Scheme 53.
The pyridazine nucleus is of considerable interest because of
its synthetic applications and important pharmacological activities. Balci and co-workers reported the first synthesis of
unusual bicyclic endoperoxides containing both pyridazine
and peroxide units and their chemical transformations.
Inverse-Diels–Alder cycloaddition of dimethyl 1,2,4,5-tetrazine-3,6-dicarboxylate (82) with unsaturated bicyclic
endoperoxides (323, 327, 332, 335 and 343) gave the products 324, 328, 333, 334, 336, 337, 344 and 345 containing
bicyclic endoperoxide-pyridazine rings.141,142 Balci et al.
also investigated various transformations of these endoperoxides, yielding new pyridazine derivatives 325–348
(Schemes 55–59).
N
N
X
Cl
311
64a
N
N
SnBu3
N
N
toluene, reflux
N
N
X
N
N
cycloadditions with alkenes and alkynes, as depicted in
Scheme 53 for the synthesis of 311.136
1,8-Bis(dimethylamino)naphthalene (312) is both a ‘proton
sponge’ and unusually highly reactive in electrophilic
substitution reactions.137–139 In spite of the large steric
strains in this molecule, the peri-dimethylamino groups
retain their strong electron-donating effect towards the
aromatic p-system. In order to form new possible ‘proton
sponges’, Ozeryanskii and co-workers performed [4+2]
cycloadditions of 5,6-bis(dimethylamino)acenaphthalene
(313), dimethylamino-acenaphthalene 314, acenaphthalene
315 and 1,8-bis(dimethylamino)-4-vinylnaphthalene (316)
with tetrazines 56a and 82 to yield new pyridazine derivatives 318–322 (Scheme 54).140 They showed that these compounds can change the site of protonation, depending on the
solvent, and obtained quantitative data on the reactivities of
the ‘proton sponge’. The obtained data were also compared
with the corresponding data for a series of close analogues.
The aza substitution in the larger polycyclic aromatic hydrocarbons can either enhance or diminish the biological activity.143 Therefore, Balci et al. also aimed to synthesise the
phthalazine-type dihydrodiols and diol epoxides.144 The reaction of dimethyl ester tetrazine 82 with benzene cis-diol
349 as dienophile in CH2Cl2 to form the main core 351
gave the dihydrodiol 350 containing the 1,4-dihydropyridazine ring. Attempts to oxidise the dihydropyridazine 350
to the pyridazine 351 resulted in the formation of the 5and 5,6-dihydroxy-phthalazine derivatives 352 and 353.
We have investigated the Diels–Alder reaction of tetrazine
with cyclohexadiene acetonide 354 and epoxy-ketal cyclohexene 356.144 These reactions led to the possible carcinogenic phthalazine type of dihydrodiol 355 and diol
epoxide 357, where the hydroxyl groups are protected
(Scheme 60).
The unexpected cycloaddition of ketones and aldehydes to
dipyridinyl-1,2,4,5-tetrazine 248 under microwave conditions was described by Schubert et al. as an alternative route
for the synthesis of substituted pyridazines.145 The reaction
Table 8. Cycloadducts of 3,6-dichloro-1,2,4,5-tetrazine (64a)
Dienophile
Product
Dienophile
Product
Cl
Cl
SnBu3
N
N
TBSO
SnBu3
OTMS
OTBS
N
N
Cl
Cl
Cl
Cl
N
N
N
TMS
Cl
Cl
OTMS
N
N
Cl
EtO
EtO
Cl
TMS
N
N
Cl
N
N
OEt
Cl
OEt
4224
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
Me2N
NMe2
Me2N
312
NMe2
313
N N
Ph
NMe2
Me2N
benzene
56a
80 °C
-N2
NH N
N N
56a
NMe2
316
314: R=NMe2
315: R=H
Me2N
313 + Ph
Me2N
R
- Ph
Ph
N NH
Ph
Ph
Ph
Ph
N N
317
Me2N
NMe2
N N
318
NMe2
R
Me2N
NMe2
Ph
MeO2C
CO2Me
Ph
N N
319
Ph
N N
Ph
320:
321:
R=NMe2
R=H
N
322
N
Scheme 54.
mechanism they suggested included the enol tautomer of the
ketone participating in the cycloaddition instead of the keto
tautomer and the rapid elimination of water occurring, resulting in the respective pyridazine derivative 359–365
(Scheme 61 and Table 9). This result showed a shift in the
keto-enol equilibrium to the enol tautomer under microwave
conditions. Reaction of 3-methyl-2-butanone possessing
two enol tautomers with tetrazine 248 gave the pyridazine
derivatives 366 and 367. Moreover, heating of 248 with
water for 20 min to 150 C under microwave irradiation
resulted in the quantitative formation of pyridine-2-carboxylic acid (pyridin-2-ylmethylene)-hydrazide (368).
5.2. Synthesis and studies on systems with the exception
of pyridazine
Warrener and co-workers demonstrated the preparation of
new building block structures (371, 373–376) containing
rigidly linked pyrimidines suitable for uracil and cytosine
elaboration, as shown in Scheme 62.146
CO2Me
N
N
O
O
N
N
82
CO2Me
10 °C, CCl4
-N2
MeO2C
CO2Me
1. thiourea, MeOH
O
O
HN
N
2. pyridine/Ac2O
3. PIFA
OAc
OAc
326
325
324
CO2Me
OAc
N
+
N
MeO2C
CO2Me
323
OAc
N
N
N
N
CO2Me
82
Scheme 55.
MeO2C
O
1. 82/CHCl3/rt
O
MeO2C
N
N
2. PIFA/CHCl3
O
thiourea
O
MeO2C
327
CoTPP or NEt3
MeO2C
O
N
N
MeO2C
Scheme 56.
MeO2C
+
OH
331
OH
N
N
MeO2C
OH
329
MnO2
N
N
MeO2C
328
MeO2C
OH
OH
329
O
N
N
MeO2C
O
330
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
O
O
82
-N2
HN
N
332
PIFA
O
O
MeO2C
Nyitrai and co-workers investigated the light-reductive ring
contractions of some six-membered cyclic iminium ions.148
A consecutive reaction of 1,2(4)-dihydrotetrazine 379 to
give 3,5-diphenyl-1H-triazole (382) has been known for a
long time via a pathway A.149,150 This group determined
that the photoconversion of 379, on raising the concentration
of HCl in 2-propanol, was markedly accelerated and furnished the triazole 382 as a single product in a yield of
50% (pathway B in Scheme 64).
MeO2C
MeO2C
N
N
H
O
O
MeO2C
333
334
Scheme 57.
Extensive kinetic studies of sulfur- and selenium-carbon hetero double bonds as dienophiles towards various cyclic and
acyclic dienes in [4+2] cycloadditions were reported by
Sauer et al.147 The reactions of substituted thiobenzophenones 377a–e with tetrazine 199 were performed in toluene
at 100 C to furnish the products 378a–e, possessing a
6H-[1,3,4]thiadiazine skeleton (Scheme 63).
O
Klug and co-workers determined that, according to quantum
mechanical calculations, 1,4-N,N cycloaddition of alkenes or
alkynes to 1,2,4,5-tetrazines is possible as an alternative to
1,4-C,C cycloaddition (Carboni–Lindsey reaction).151 The
reaction of 56a with 1,4-dimethylpyridinium iodide in the
O
O
HN
N
MeO2C
O
82
O
H
MeO2C
OH
338
OR'
339a: R'=H
339b: R'=Ac
thiourea
-30 °C -MeOH
thiourea
-30 °C -MeOH
MeO2C
MeO2C
O
MeO2C
335
O
N
N
HN
N
-N2
4225
PIFA
O
H
N
N
O
MeO2C
O
337
336
CoTPP or thermolysis
MeO2C
MeO2C
N
N
N
N
O
OR''
MeO2C
H
MeO2C
MeO2C
341a: R'=H
341b: R'=Me
OH
N
N
-MeOH
O
H
O
340
O
O
342
Scheme 58.
MeO2C
MeO2C
O
O
82
-N2
HN
N
MeO2C
O
H
O
PIFA
N
N
thiourea
-30 °C
O
MeO2C
344
343
O
345
CoTPP or thermolysis
-MeOH
MeO2C
MeO2C
N
N
HN
N
N
N
MeO2C
MeO2C
O
O
346
Scheme 59.
O
O
347
MeO2C
O
348
OH
4226
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
MeO2C
CO2Me
+
OH
OH
349
PIFA or O2
HN
N
CHCl3/rt
N
N
N
N
MeO2C
1
-N2
MeO2C
CO2Me
82
H
N
N
OH
OH
OH
MeO2C
OH
351
350
-H2O
MeO2C
MeO2C
N
N
MeO2C
OH
353
MeO2C
N
N
N
N
O
MeO2C
Me
MeO2C
MeO2C
O
O
Me
354
O
Me
355
N
N
OH
OH
352
O
O
O
O
O
Me
357
MeO2C
Me
O
Me
356
Me
Me
Scheme 60.
N
O
HN
N
O
H2O
N
µW, 150 °C N
N
N
N
N
N
R1
OH
R2
R1
-N2
R2
N
N
OH
R1
-H2O
R1
N
N
R2
R2
N
N
N
368
248
358
O
O
N
359-365
O
OH
N
N
+
N N
366
N
N N
367
N
Scheme 61.
Table 9. Cycloadducts of microwave-assisted inverse-Diels–Alder reactions between 248 and various ketones and aldehydes
Reagent
Product
R1
R2
Reagent
Product
R1
R2
Acetone
2-Butanone
3-Pentanone
Acetaldehyde
359
360, 361
362
363
Me
Et, Me
Et
H
H
H, Me
Me
H
Butanal
Hexanal
Octanal
360
364
365
Et
n-Butyl
n-Hexyl
H
H
H
presence of triethylamine in DMF for 24 h gave the pyrazole
derivative 388, which formally corresponds to C,C-[4+2]
cycloaddition, N2 elimination, rearrangement and oxidation
steps (pathway A in Scheme 65). Klug et al., however, isolated only 392 as a major product from the refluxing of a mixture of 1,4-dimethylpyridinium iodide and triethylamine in
ethanol for 24 h. They explained that the formation of 392
can be rationalised by N,N-[4+2] cycloaddition, benzonitrile
elimination, rearrangement and oxidation steps (pathway B
in Scheme 65).
Sauer and co-workers described in detail the synthesis of 3,4diazanorcaradienes 395, 396, 399 and 400 together with the
tetracyclic aliphatic azo compounds 397 and 398, which
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
R
N
N
4227
R
N
+
N
R
N
N
248 R =2-Py
N
N
NEt3
N
R
N
Cl 24 h, CH2Cl2
reflux
14 kbar
Cl
R
N
369 Cl
370
Cl
R
N
N
N
371
Cl
Cl
NaOH
N
N
OMe
R
N
N
MeO
R
N
N
R
N
N
R
OMe
Cl
R
MeO
373
374
O
R
N
N
372
Cl
N
MeO
N
MeO
N
R
N
HN
NH
O
OMe
N
MeO
N
OMe
R
N
R
MeO
MeO
375
N
R
OMe
376
Scheme 62.
S
CF3
CF3
R2
+
R1
R3
N
N
N
N
CF3
199
377a-e
N
N
toluene
100 °C
-N2
S
CF3
Ar
Ar
a: R1 = R2 = R3 = H, b: R1 = OMe, R2 = OMe, R3 = H
c: R1 = Me, R2 = Me, R3 = H, d: R1 = R2 = H, R3 = F
e: R1 = R2 = Cl, R3 = H
378a-e
Scheme 63.
are versatile starting materials in thermolysis and photolysis
reactions (Scheme 66).152 3,4-Diazanorcaradienes were
obtained from the reaction of 1,2,4,5-tetrazines 393 (R1¼
CO2Me, CO2H, CN, CF3, phenyl, aryl and heteroaryl) and
cyclopropenes 394a,b (a: R2¼H and b: R2¼Me) in two steps
including addition and loss of nitrogen. The reaction of diazanorcaradienes 395 and 396 with cyclopropenes gave the
bisadducts 397 and 398 (R1¼CO2Me, CO2H, CN, CF3, aryl
and heteroaryl; R2¼H and Me). Furthermore, detailed kinetic
studies of diazanorcaradienes were undertaken by Sauer et al.
The kinetic data showed that norcaradienes 395 and 396 were
much less reactive dienes than 1,2,4,5-tetrazines by a factor
Ph
HN
N
Ph
N
NH
N
N
Ph
379a
Ph
NH
NH
pathway A
hν, THF
Ph
379b
pathway B
hν,
i-PrOH, HCl
Ph
HN
N
Ph NH
2
NH
NH
N
N
N
Ph
381
Ph
380
+2H+
-NH3
Ph
Ph NH
2
NH+ +2e-/+2H+
NH
Ph
383
Scheme 64.
N
N
HN
N
NH
Ph
384
-NH4+
N
N
NH
Ph
382
of 103–104 for the rate constant. The coupling constants for
the ABX2 spin system and the chemical shift difference
between 7-Hsyn and 7-Hanti in 395 are in accordance with
the diazanorcaradiene structure. The addition reactions of
3,4-diazanorcardienes 399 (R1¼R2¼SMe; R1¼SMe, R2¼
OMe; R1¼R2¼OMe; R1¼Ph, R2¼SMe; R1¼Ph, R2¼OMe)
and 400 (R1¼R2¼SMe; R1¼R2¼OMe) to form bisadducts
of the type 397 and 398 were unsuccessful. This unreactivity
showed that the resonance energy of one or two imino ester
units in 399 and 400 has to be sacrificed.
Sauer et al. also reported that 1,2,4,5-tetrazines 393 (R¼Me,
CO2Me, CO2H, CN, CF3, phenyl, aryl and heteroaryl) and
3,3-bicyclopropenyl 401 readily react to afford the semibulvalenes 404 in a one-pot method, as depicted in Scheme
67.153 The reaction progresses upon the cycloaddition–loss
of nitrogen–intramolecular cycloaddition–valence isomerisation steps. The observed kinetic results for the two-model
system are in agreement with the proposed reaction
mechanism.
Benzo[c]furan (isobenzofuran) is a reactive diene that readily undergoes a Diels–Alder reaction with dienophiles to
restore their aromaticity.154–158 Wong et al. attempted to prepare an isolable versatile building block for linear polycyclic
aromatic compounds.159 For the preparation of silylated
polycyclic aromatic hydrocarbons (PAH), 5,6-bis(trimethylsilyl)benzo[c]furan (406) was chosen as their target molecule. The generation of 406 was achieved by treating 405
4228
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
Ph
C
N
N
Ph
Me
N
pathway A
C
Ph
N
N
Ph
56a
386
Ph
pathway B
N
+
N
N Me
385
-N2
Ph
Me
N
N
N
Ph
N
N
Ph 389
-PhCN
N
N
N
Me
Ph
Ph
N
N
N
N
N
N
N
Me
N
Me
390
Ph 387
[O]
391
[O]
Ph
N
N
N N
Ph
N
Ph
N
Me
388
N
Me
392
Scheme 65.
with 3,6-di(pyridin-2-yl)-1,2,4,5-tetrazine (248) using the
Warrener approach160 as the key step. In the presence of various dienophiles, benzo[c]furan 406 provided the desired Diels–Alder trapping adducts 408–411 (Scheme 68).159,161
Dehydration of 408 to the naphthalenenitrile 412 was accomplished by the reaction of lithium iodide and 1,8-diazabicyclo[5.4.0]undec-1-ene (DBU) in refluxing THF. The
dehydrations in refluxing 90% acetic acid of three quinone
adducts of benzo[c]furan 406 provided the aromatic compounds 413–415.
In the absence of methyl groups, dihydropyrene 419 is thermally stable, whereas the steric interaction between the
heterocycle-methyl hydrogens in 418 destabilises the dihydropyrene more than [22]metacyclophanedienes with a furan
416 or pyrrole 417 on the bridge.162 Mitchell and co-workers
synthesised163 [22]metacyclophanedienes 420, 421 and
R1
R1
R
N
N
H
N
N
394a-b
N
N
R
393
R
-N2
a: R1 = H
b: R1 = Me
R1
R1
R1
R1
394
R
R1
R1
H
R
395 R1 = H
396 R1 = Me
R
R1
7
R1 R
R1
H
6
N
394a
N
N
-N2
R
399
Scheme 66.
N
N
N
N
R
393
Me Me
N
N
N
N
R
393
401
-N2
Me
7a
R
Me
5
7 8
R
Me
6
4N
H
3N
1 H
R
anti-402
8a
N
N
2
Me
1
H
6 H
R
syn-402
R1
H
R
Similar protocols were applied for the synthesis of 1,2-dicyano-4,5,6,7-tetrafluoronaphthalene (428), which transformed fluorine-containing metal naphthalocyanines, and
their nonlinear transmissions were studied by Hanack
et al.164 The generation of N-methyl-4,5,6,7-tetrafluoroisoindole (426), which is a moderately stable compound, is
the key step. The monomer 429 was obtained by reacting
426 with dicyanoacetylene, followed by m-CPBA oxidation
to remove the methylamino group in a one-pot reaction. The
isoindole 426 was used for the synthesis of soluble p-stacking tetracene derivatives 432a–d. Swager and co-workers
also discussed the crystal packing, electrochemical behaviour and UV–vis absorbance spectroscopy of these materials
(Scheme 70).165
R
R1
N
R1
R
R
R
R1
R1
H
R
397 R1 = H
398 R1 = Me
1
N
N
H
N N
422a,b with furan bridges using the Warrener approach.160
The key synthetic step to generate the furans (420–422)
was a Diels–Alder reaction of an aryne-oxonorbornadiene
with dipyridyltetrazine 248 as described in Scheme 69.
The degradation of the bis adduct 424 gave the desired furan
421.
Me
Me
394b
-N2
R
Me
Me
Me
Me
N
N
7
3
R
R
404
400
Scheme 67.
Me
Me
R
R
-N2
R
N
N
403
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
N
N
Me3Si
+
O
Me3Si
405
N
N
4229
Me3Si
CHCl3
N
N
O +
-N2
Me3Si
406
N
N
N
N
fumaronitrile
248
Me3Si
407
CN
O
Me3Si
CN
LiI, DBU
THF, reflux
Me3Si
CN
Me3Si
CN
408
Me3Si
CO2Me
Me3Si
CO2Me
Me3Si
O
Me3Si
412
CO2Me
Me3Si
CO2Me
Me3Si
H O
O
409
410
411
O
O
Me3Si
Me3Si
SiMe3
Me3Si
SiMe3
Me3Si
N Ph
O
H O
O
Me3Si
Me3Si
O
O
413
O
415
414
Scheme 68.
systems.166,167 The synthesis of four novel bridge-fluorinated [2.2]paracyclophanes 433–436 containing naphthalene and anthracene condensed polycyclic subunits was
The rigid skeleton and high strain energy of the [2.2]paracyclophane system leads to unique transannular interactions
that affect both the chemistry and the spectroscopy of these
H
X
H
418
416 X= O
417 X=N-hexyl
O O
420
O
X
419
O
O
421
422a
422b
N
248 (2 eq.)
O
O
THF, rt, 12 h
O
N
N
N
O
N
N
O
hν, rt
O
O
- 407
-2 N2
N
423
Scheme 69.
N
424
421
4230
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
N
F
F
F
N
+
N
NMe
F
R
CN
NMe
CN
F
F
F
a: R=H, R'=OC6H13 PhLi, THF, 0 °C
R R2
b: R=OC6H13, R'=H
Br
c: R=H, R'=C8H17
430a-d
d: R=C8H17, R'=H
Br
R R2
F
R'
R
NaOH (50%, aq.) F
F
CHCl3, rt
F
F
CHCl3, 0 °C
F
F
426
248
F
F
N
425
CN
427
NMe
rt
-N2
F
NC
F
CH2Cl2
N
N
R'
428
m-CPBA
F
F
CN
F
CN
F 429
NMe
F
F
R
R'
432a-d
R
431a-d
R'
Scheme 70.
F2C
F2C
CF2
F2C
F2C
CF2
434
+
F2C
CF2
N
N
F2C
437
F2C
F2C
CF2
438
248
N
N
N
+
F2C
N
CF2
CF2
N
N
-N2
CF2
436
N
CF2
N pentyl ether
N reflux, 187 °C
N
F2C
CF2
435
N
CF2
F2C
CF2
F2C
CF2
433
F2C
F2C
CF2
CF2
433
N
407
Scheme 71.
achieved by Dolbier and co-workers using the Warrener approach,160 as depicted in Scheme 71,168 and details of their
NMR and UV spectra were provided.
Paquette et al. devised a route to the doubly unsaturated
bridgehead sultam 439.169 The irradiation of 439 at 350 nm
resulted in the formation of the structurally novel spiro heterocycle 440 via a two-photon process. These workers suggested the probable mechanism of the generation of 440.
The strained nature of the double bond in 440 was also established by a Diels–Alder cycloaddition with 1,2,4,5-tetrazine
82. The reaction gave dihydro-diazocine 441 via the loss of
nitrogen, followed by cleavage of the cyclobutane ring
(Scheme 72).
CO2Me
hν, 350 nm
OS N
acetone
MeCN
O
439
Scheme 72.
NH
H
O
N
N
H
N
N 82
CO2Me
CH2Cl2, rt
S
O
440
-N2
NH
H
O
H
S
O
MeO2C
CO2Me
N
N
441
A novel one-step, non-obvious route to fully substituted pyrazol-4-ols was reported by Kurth and co-workers.170 The reaction of thietanone 443 with tetrazine 428 in 5% methanolic
KOH resulted in the formation of an unexpected product
447, instead of 444 or 453–454, as shown in Scheme 73.
They isolated the sulfur-extruded products 447–452 from
the reaction of 443 with aryl-substituted tetrazines 56a,
442 and 248 in methanol, ethanol or ethylene glycol.
Kurth et al. designed the synthesis of diazocinones and investigated their conformational analysis.171a The condensation
of aryl-substituted 1,2,4,5-tetrazines 456 with isoxazolylcycobutanones 455 in methanolic KOH provided a general
route to novel isoxazole-substituted dihydrodiazocinones
457 (Scheme 74). The conformational methods of these
eight-membered diaza heterocycles by spectral, crystallographic, kinetic and computational methods showed that
the major contributor was provided by the twist-boat-chair
conformation of cis,cis-1,3-cyclooctadiene, as described by
Anet and Yavari.171b
In their continuing work on the Diels–Alder reactions of
unsaturated bicyclic endoperoxides with tetrazine, Balci
and co-workers reported the trapping of highly reactive
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
-
N
N
O
Ph
S
N
N
RO
Ar
O
N
N
KOH/ROH
Ph
+
Ph
THF
S
443
Ar
442 Ar=p-BrPh
4231
N
NH
Ph
H OR
S
Ph
444
O-K+
Ph
O
RO
Ph
445
Ph
S
-S
O
Ph
Ar
HO
Ar
S
N
N
RO
N
N
Ph
446
Ar
453
Ar
-S
RO
H
O
Ar
O
447: Ar = Ph,
R = Me
H
N
448: Ar = Ph,
R = Et
RO
N
449: Ar = p-BrPh, R = Me
450: Ar = p-BrPh, R = CH2CH2OH
Ph
Ar
451: Ar = 2-pyridyl, R = Me
452: Ar = 2-pyridyl, R = CH2CH2OH
447-452
Ar
Ph
N
N
Ar
454
Scheme 73.
fulvene endoperoxides 458a–e with dimethyl 1,2,4,5-tetrazine carboxylate 82. Treatment of the trapping products
459 with cobalt(II) meso-tetraphenylporphyrin (CoTPP)
gave alkylidene- and arylidenemalonaldehydes 460a–e via
Warrener160 cleavage.172 The reaction of the trapping products 459 with water, followed by bis[(trifluoroacetoxy)iodo]benzene (PIFA) oxidation, provided acrylic acid
O-K+
O
N
N
-N2
THF
O
N
O
N
N
N
Ar2
N O
Ar2
Troschurtz and M€uller tested the reactivity of ketene N,Nacetal (EWG¼CO2Et) 463 with tetrazine 82 at various
temperatures in different solvents.174 This reaction gave no
products that could be characterised. Therefore, they turned
their attention to the cycloaddition reaction of EWGsubstituted ketene N,O-acetals 464a–f with tetrazine 82. A
series of N,O-acetals 464a–f were reacted with the tetrazine
82 to give the tetrafunctionalised pyridazines 465a–f.
Reductive ring contraction of the pyridazines gave the 4aminopyrrole derivatives 466a–f. The cycloaddition of
the ketene acetal 464f and the tetrazine 82 gave the mixture
of the pyridazine 465f and the imide 467, the formation of
which can be explained by an intramolecular imidation.
Furthermore, the synthesis of the 5-amino-1,2,4-triazine derivative 469, which was rearranged to 4-aminoimidazole2,5-dicarboxylic acid dimethyl ester 471, was achieved by
Ar1
O
Ar1 456
KOH/MeOH
Ar2
455
Ar1
N
N
derivatives 462a–e and dimethyl pyridazine-3,6-dicarboxylate (294) via unusual fragmentation (Scheme 75).173
Ar1
457a-h
a: Ar1 =Ph, Ar2 = Ph b: Ar1 = 4-ClC6H4, Ar2 = Ph c: Ar1 = 4-BrC6H4, Ar2 = Ph
d: Ar1 = 4-MeC6H4, Ar2 = Ph, e: Ar1 = Ph, Ar2 = 4-MeOC6H4
f: Ar1 = 4-ClC6H4, Ar2 = 4-MeOC6H4 g: Ar1 = 4-BrC6H4, Ar2 = 4-MeOC6H4
h: Ar1 = 4-MeC6H4, Ar2 = 4-MeOC6H4
Scheme 74.
MeO2C
CO2Me
R1
O
O
+
R2
458a-e
N
N
N
N
CO2Me
82
CHCl3
-50 °C
-N2
H
R1
N
N
O
O
MeO2C
R2
H
459
MeO2C OHH
H2O, CHCl3
HN
O
O
N
-40 °C
H
MeO2C
461
CO2Me
CO2Me
Scheme 75.
R1
CHO
R2
CHO
+
R1
N
N
COOH
+
R2
294
N
N
CO2Me
CO2Me
460a-e
R2
PIFA, CDCl3,
-40 °C
CoTPP
a: R1 = R2 = Me
b: R1 = R2 = Ph
c: R1 = Me, R2 = Ph
d: R1 = H, R2 = Ph
e: R1 = R2 = -(CH2)5-
R1
462a-e
294
4232
N. Saracoglu / Tetrahedron 63 (2007) 4199–4236
O
CO2Me
N
N
EWG
N
N
EtO
EWG
H2N
NH2
-NH3
EWG=CO2Et
465a
463
-N2
+
CO2Me
82
NH2
CO2Me
EWG EWG=CONH2
-MeOH
N
N
74%
NH2
CO2Me
465a-f
-EtOH
464a-f
a: EWG = CO2Et
b: EWG = CO2Me
c: EWG = COMe
d: EWG = COPh
e: EWG = COCF3
f: EWG = CONH2
N
N
NH
O
NH2
CO2Me
467
Zn/AcOH
MeO2C
EWG
HN
NH2
MeO2C
466a-f
CO2Me
N
N
N
N
CO2Me
NH
+
MeO
NH2
CO2Me
82
12%
-N2
-MeOH
N
N
468
N
NH2
CO2Me
469
CO2Me
93%
N
+
-N2
NH2
470
N
N
N
N
CO2Me
82
Zn/AcOH
MeO2C
HN
N
NHR
MeO2C
471 R = H
472 R = Ac
Scheme 76.
the cycloaddition of the tetrazine 82 with O-methylisourea
(468) or cyanamide (470) (Scheme 76).
6. Conclusions
We have described in this review the advances and applications in 1,2,4,5-tetrazine chemistry over the last 10 years.
1,2,4,5-Tetrazine is a highly reactive diene for LUMOdienecontrolled [4+2] inverse-Diels–Alder cycloaddition processes and an excellent precursor to attain the pyridazine
ring, which can also be transformed by reductive ring
contraction to the respective pyrrole ring. Therefore, there
is increased interest among synthetic chemists in both the
synthesis and the applications of new asymmetric and
symmetric 1,2,4,5-tetrazine motifs. 1,2,4,5-Tetrazines have,
however, been very widely utilised for the highly effective
synthesis of natural products, bioactive compounds, ligands,
highly energetic materials, building blocks, diazocinones,
imidazoles, alkylidene-/arylidenemalonaldehydes, acrylic
acid derivatives, pyrazoles and polycyclic aromatic compounds. Such applications of 1,2,4,5-tetrazines continue to
increase rapidly in number.
Acknowledgements
The author would like to thank Professor Arif Dastan and
Associate Professor Murat Celik for their encouragement
and help.
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Biographical sketch
Nurullah Saracoglu was born in Erzurum, Turkey in 1967. He received his B.Sc. in
the Department of Chemistry at Atat€urk University in 1988. He carried out his PhD
under the supervision of Professor Metin Balci at Atat€urk University in 1996. In
February 2006, he was appointed as Professor at Atat€urk University. His research
interests encompass strained organic molecules, heterocyclic compounds and
natural products. Recently, he has focused especially on the chemistry of indole.