The synthesis of phthalazine derivatives commonly in-
volves multistep procedures concluding with ring closing
reactions, ring enlargement, or aromatization of 1,2-dihy-
Scheme 1. Strategy for a One-Pot Method To Access Phthala-
zines
7
dro- or 1,2,4,5-tetrahydrophthalazines. Also reported are
inverse electron-demand DielsꢀAlder (IEDDA) reactions
8 8d
of 1,2,4,5-tetrazines with arynes and arenes or pyrida-
9
zino[4,5-d]pyridazine with enamines as a method for the
synthesis of phthalazine derivatives. The first synthesis of
1
0
phthalazine in 1893 by Gabriel et al. involved the ring
closing reaction of ortho-carbonylbenzaldehyde or 1,2-bis-
dichloromethylbenzene with hydrazine. This transforma-
tion, the ring closure of ortho-dicarbonyls with hydrazine,
still comprises the standard route for the preparation of
1
1,12
phthalazines.
in the 1,4-position are usually synthesized via halogenation
Phthalazines with halogen substituents
1
3
of 2,3-dihydrophthalazine-1,4-dione. Both methods,
however, are often preceded by many synthetic steps,
depending on the degree of substitution in positions 5 to
8
of the resulting phthalazine. For example, Tsoungas et al.
reported such a procedure of six steps starting from
-methoxy-2-nitrobenzaldehyde via final reaction of the
formed dialdehyde with hydrazine to give 6-methox-
starting material for the bidentate Lewis acid catalyzed
15
IEDDA reaction developed in our lab, we set out to close
this gap in the synthesis portfolio of heterocycles. Herein,
we present a general method by which not only 4- to
5
1
1b
yphthalazine (5i) in a overall yield of less than 20%.
Another ring closing reaction is the cyclization of aromatic
aldazines, which is conducted in liquid AlCl /AlBr , com-
8-substituted phthalazines, but also pyridazino-heteroaro-
matics, are prepared in a one-pot procedure from simple
aromatic aldehydes in good to excellent yields.
3
3
1
4
prising rather harsh conditions.
The key step of this new method is the transformation of
an aromatic aldehyde into a directed ortho-metalation
group (DMG). Directed ortho-lithiation is a very elegant
method to form ortho-substituted aromatics and has been
Despite these efforts no approaches for a direct method
for a wide range of substituted phthalazines in one pot
from simple starting materials are reported to the best
of our knowledge. As 1,2-diazines represent a valuable
16
widely applied. Although an aldehyde is per-se no direct-
ing group they can be reacted with lithium amides to form
(
7) (a) Patel, N. R. In Chemistry of Heterocyclic Compounds: A Series
R-aminoalkoxides 2, which in turn are moderate to good
DMGs. Based on this principle first applied by Comins
1
7
of Monographs; Castle, R. N., Ed.; John Wiley & Sons, Inc.: Hoboken, NJ,
USA; Vol. 27, pp 323ꢀ760. (b) Brown, D. D. J. Cinnolines and Phtha-
lazines: Supplement II, Volume 64; Chemistry of Heterocyclic Com-
pounds: A Series Of Monographs; 2005.
(
Chim. Acta 2009, 92, 298–312. (b) Girardot, M.; Nomak, R.; Snyder,
J. K. J. Org. Chem. 1998, 63, 10063–10068. (c) Baumann, L.; Folkerts,
A.; Imming, P.; Klindert, T.; Massa, W.; Seitz, G.; Wocadlo, S. Liebigs
Ann. 1995, 1995, 661–666. (d) Seitz, G.; Hoferichter, R.; Mohr, R.
Angew. Chem., Int. Ed. Engl. 1987, 26, 332–334.
1
7a,b
et al.,
for this strategy (Scheme 1). Commonly, the auxiliary
we developed a new highly efficient protocol
ꢂ
8) (a) Margeti ꢀc , D.; Murata, Y.; Komatsu, K.; Marini ꢀc , Z. Helv.
0
N,N,N -trimethylethylenediamine (TMDA) A1 is used as
lithium amide LiA1 for the formation of R-aminoalkoxides 2.
Herein, we report for the first time the application of
bis(2-methoxyethyl)amine (BMEA) A2 for this purpose
constituting a much cheaper solution than A1. The
bis(2-methoxyethyl)amino group itself is a chelating
ligand intensively studied in the lithiation of N,N-bis(2-
(
9) (a) Haider, N.; Loll, C. J. Heterocycl. Chem. 1994, 31, 357–360.
b) Haider, N. Tetrahedron 1991, 47, 3959–3968.
10) (a) Gabriel, S.; Neumann, A. Ber. Dtsch. Chem. Ges. 1893, 26,
(
(
5
2
21–527. (b) Gabriel, S.; Pinkus, G. Ber. Dtsch. Chem. Ges. 1893, 26,
1
8
210–2216.
(
methoxyethyl)-2-methylprop-2-en-1-amine. After the in
11) For 1,4-unsubstituted phthalazines, see: (a) Meresse, P.;
Bertounesque, E.; Imbert, T.; Monneret, C. Tetrahedron 1999, 55,
12805–12818. (b) Tsoungas, P. G.; Searcey, M. Tetrahedron Lett.
2
001, 42, 6589–6592.
(15) (a) Kessler, S. N.; Neuburger, M.; Wegner, H. A. Eur. J. Org.
Chem. 2011, 3238–3245. (b) Kessler, S. N.; Wegner, H. A. Org. Lett.
2010, 12, 4062–4065. (c) Wegner, H.; Kessler, S. Synlett 2012, 699–705.
For selected pioneering examples of noncatalyzed IEDDA reactions of
1,2-diazines, see: (d) Gruseck, U.; Heuschmann, M. Tetrahedron Lett.
1987, 28, 6027–6030. (e) Boger, D. L.; Coleman, R. S. J. Org. Chem.
1984, 49, 2240–2245. (f) Boger, D. L.; Sakya, S. M. J. Org. Chem. 1988,
53, 1415–1423. (g) Oishi, E.; Taido, N.; Iwamoto, K.; Miyashita, A.;
Higashino, T. Chem. Pharm. Bull. 1990, 38, 3268–3272.
(
12) For 1,4-substituted phthalazines, see: (a) Wharton, C. J.; Wrig-
glesworth, R. J. Chem. Soc., Perkin Trans. 1 1985, 809–813. (b) A. Joule,
J.; Karim Karim, A.; Armengol, M. Heterocycles 2001, 55, 2139. (c)
Kotali, A.; Lafazanis, I.; Harris, P. Synthesis 2009, 2009, 836–840.
(
1
d) Chan, C.-W.; Zhou, Z.; Chan, A. S. C.; Yu, W.-Y. Org. Lett. 2010,
2, 3926–3929. (e) G. Tsoungas, P.; Cordopatis, P.; Gardikis, Y.;
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(
Davis, W. D.; Hartung, J.; Jeong, K. S.; Ogino, Y.; Shibata, T.;
Sharpless, K. B. J. Org. Chem. 1993, 58, 844–849. (b) Becker, H.; King,
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(16) (a) Mongin, F. Tetrahedron 2001, 57, 4059–4090. (b) Snieckus,
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(17) (a) Comins, D. L.; Brown, J. D. Tetrahedron Lett. 1981, 22,
4213–4216. (b) Comins, D. L.; Brown, J. D. J. Org. Chem. 1984, 49,
1078–1083. (c) Comins, D. L.; Killpack, M. O. J. Org. Chem. 1987, 52,
104–109. (d) Comins, D. L.; Killpack, M. O. J. Org. Chem. 1990, 55, 69–
73. (e) Comins, D. L. Synlett 1992, 615–625.
(18) (a) Fraenkel, G.; Qiu, F. J. Am. Chem. Soc. 1997, 119, 3571–
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(14) Robev, S. K. Tetrahedron Lett. 1981, 22, 345–348.
B
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