Synthesis of pyridazines functionalized with amino acid side chains

Article abstract of DOI:10.1016/j.tetlet.2007.11.149

A simple route for the preparation of 3,4,6-substituted pyridazines is described by using Tebbe olefination of esters then Diels-Alder reaction of the resulting enol ethers with tetrazine.

Full text of DOI:10.1016/j.tetlet.2007.11.149

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Tetrahedron Letters 49 (2008) 903–905
Synthesis of pyridazines functionalized with amino acid side chains
Enrique Mann, Lionel Moisan, Jun-Li Hou, Julius Rebek, Jr. *
The Skaggs Institute for Chemical Biology, The Scripps Research Institute, Mail MB-26, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
Received 25 October 2007; revised 20 November 2007; accepted 26 November 2007
Abstract
A simple route for the preparation of 3,4,6-substituted pyridazines is described by using Tebbe olefination of esters then Diels–Alder
reaction of the resulting enol ethers with tetrazine.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Pyridazine; Tetrazine; Tebbe reagent; Inverse electron demand Diels–Alder reaction
The pyridazine ring is often encountered as a structural
component of compounds possessing biological activity:
analgesic,1 antibacterial,2 antiinflammatory,3 antihyperten-
sive4 or antihistaminic5 activities have all been reported.
This heterocycle is also useful for the preparation of
other heterocycles,6 p-conjugated organic materials with
desirable electronic properties7 and self-assembled supra-
molecular architectures.8 These pharmacological and
technological properties of pyridazines encourage the
development of methods for their synthesis and functional-
ization.9 The inverse electron demand Diels–Alder reaction
(IEDDAR) between 1,2,4,5-tetrazine diester 1 (Fig. 1) and
electron-rich dienophiles has proven to be an effective syn-
thetic route toward substituted pyridazines,10 and we apply
it here.
In connection with our studies on the synthesis of
heterocyclic a-helix mimetics,11 the preparation of 3,4,6-tri-
substituted pyridazine 2a, bearing an indole side chain was
required (Fig. 1). This structure is inspired by Hamilton’s
terephthalamide scaffold 3 known to disrupt protein–pro-
tein interactions12 when R1–3 are typically side chains of
hydrophobic amino acids. The pyridazine scaffold offers
remote hydrophilic sites, regioselective functionalization11
O
R1
NH
O
O
CO2CH3
CO2CH3
N
N
N
N
N
N
O
R2
N
Boc
CO2CH3
CO2CH3
R3
O
N
1
2a
R3
3
Fig. 1. Structures of tetrazine 1, pyridazine 2a and Hamilton’s tereph-
thalamide scaffold 3.
and a variety of amino acid side chains for small library
synthesis.
As a first approach to compound 2a, the diester 113 was
reacted with the commercially available 2-methoxy-3,4-
dihydro-2H-pyrane to give pyridazine 4 in good yield.
Subsequent treatment under standard Fischer indole syn-
thesis14 conditions led predominantly to the decomposition
of the starting material and the formation of the desired
compound 5 in a disappointing 13% yield11c (Scheme 1).
A shorter, higher yielding route was found in the IED-
DAR employing a dienophile with the indole ring already
present in its structure. Different electron-rich dienophiles
such as enamines,15 ketene acetals,16 or enol ethers17,18
have been employed in this type of [4+2] cycloaddition
reaction. Since the conversion of esters into enol ethers
*
Corresponding author. Tel.: +1 858 784 2250; fax: +1 858 784 2876.
E-mail address: jrebek@scripps.edu (J. Rebek, Jr.).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.149

904
E. Mann et al. / Tetrahedron Letters 49 (2008) 903–905
O
OMe
CO2CH3
CO2CH3
CHO
PhNHNH2
N
N
N
N
1
NH
Dioxane
5m in, rt.
71%
MeOH/AcOH
13%
CO2CH3
4
CO2CH3
5
Scheme 1. Fischer indole synthesis approach to pyridazine 2a.
CO2CH3
CO2CH3
Tebbe reagent
OMe
Boc
1
N
N
N
Boc
N
THF, -40 ºC
N
dioxane, rt.
Boc
CO2CH3
6
7
2a
43% from 6
Scheme 2. Synthesis of pyridazine 2a.
Table 1
Table 1 (continued)
Synthesis of 4-substituted pyridazines 2a–i
Entry Ester
Product
Yield (%)
CO2CH3
1) Tebbe reagent
THF, -40 ºC to rt
3
CO2CH3
R
N
N
4
5
R CO2CH3
NHBoc
N
N
CO2CH3
2) Tetrazine 1
6
7
8
9
39
6
BocHN
BocHN
dioxane, rt
CO2CH3
2f
CO2CH3
CO2CH3
2
Entry Ester
Product
CO2CH3
Yield (%)
43
CO2CH3
N
N
NHBoc
31a
CO2CH3
N
N
1
2g
N
Boc
N
CO2CH3
CO2CH3
2a
2b
Boc
CO2CH3
CO2CH3
S
N
N
CO2CH3
CO2CH3
41
S
N
N
2h
2
3
65
54
58
CO2CH3
CO2CH3
CO2CH3
CO2CH3
SC(Ph)3
N
N
35a
(Ph)3C
CO2CH3
S
2i
N
N
CO2CH3
CO2CH3
2c
a
CO2CH3
CO2CH3
Yields determined from tetrazine 1.
by reaction with the Tebbe reagent is a well established
procedure,19 the N-Boc protected derivative 6 of the com-
mercially available methyl-2-(1H-indol-3-yl) acetate was
selected as the precursor of the electron-rich dienophile 7
(Scheme 2). Treatment of compound 6 with the Tebbe
reagent in tetrahydrofuran at low temperature afforded
the desired enol ether 7, and reaction with tetrazine 1 at
room temperature to afford pyridazine 2a in 43% overall
yield from compound 6.20
CO2CH3
N
N
4
BnO
OBn
2d
CO2CH3
CO2CH3
CO2CH3
t
CO2 Bu
N
N
CH3O2C
t
5
41
The scope of this method was expanded with several
commercially available esters which were subjected to the
sequence (Table 1). The Tebbe reaction is compatible with
CO2 Bu
2e

E. Mann et al. / Tetrahedron Letters 49 (2008) 903–905
905
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the presence of a variety of functional groups such as car-
bamates (2f–g), ethers (2d), thioethers (2h–i) or sterically
challenged esters (2e), allowing the preparation of pyrida-
zines containing substituents that are conveniently pro-
tected side chains of functional amino acids. Various
compounds containing either aromatic or aliphatic substit-
uents in position 4 of the pyridazine core were prepared.
The best yields were obtained with esters with aromatic
rings in their structures (entries 1–4). For example, the syn-
thesis of compound 2e, which features a tert-butyl ester of
a glutamic acid residue, began with the commercially avail-
able tert-butyl methyl glutarate (entry 5). The Tebbe
reagent showed exclusive regioselectivity, giving the enol
ether of the less hindered methyl ester.
In summary, we have developed a method for the prep-
aration of functionalized 4-substituted pyridazines from
esters via Tebbe olefination, and IEDDAR reaction of
the resulting enol ethers. This procedure yielded, among
other examples, several pyridazines with protected side
chains of common amino acids. In addition, aldehyde 4
provides a function that can be elaborated into uncommon
side chains.
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Acknowledgments
17. For previous use of cyclic or acyclic enol ethers as dienophiles for the
IEDDAR with tetrazines see: (a) Gnichtel, H.; Gumprecht, C. Liebigs
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19. Hartley, R. C.; McKiernan, G. J. J. Chem. Soc., Perkin Trans. 1 2002,
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We are grateful to the Skaggs Institute for Research and
to Novartis for support. The Spanish Ministerio de Educa-
cion y Ciencia (Secretaria de Estado de Universidades e
Investigacion) provided a Postdoctoral Fellowship to
E.M. We thank Professor D. L. Boger for advice and help-
ful discussions.
References and notes
20. Tebbe reagent: l-Chlorobis(cyclopentadienyl)-(dimethylaluminium)-
l-methylenetitanium, Tebbe, F. N.; Parshall, G. W.; Reddy, G. S. J.
Am. Chem. Soc. 1978, 100, 3611–3613. Representative general
procedure: To a solution of the corresponding ester (1.04 mmol) in
THF (12 ml) cooled at À40 °C is added Tebbe reagent (2.7 ml,
1.3 equiv, 0.5 M in toluene). After 30 min the temperature is raised to
ambient over a period of 2 h. The mixture is then cooled to À10 °C
and the reaction is quenched by the dropwise addition of NaOH
(700 ll, 2 M solution). Reaction mixture is then allowed to warm to
room temperature. The solution is then diluted with excess of ether
and filtered through a pad of Celite. Solvent is removed under reduced
pressure and the crude residue is directly diluted in dioxane (10 ml)
and added to a solution of tetrazine 1 (203 mg, 1.0 mmol) in dioxane
(10 ml). After 18 h at room temperature, volatiles are removed and
the crude residue is purified on silica gel (hexane/AcOEt mixtures) to
afford the desired products.
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