A convenient access to benzo-substituted phthalazines as potential precursors to DNA intercalators

Article abstract of DOI:10.1016/S0040-4039(01)01302-8

2-Nitro-5-methoxybenzaldehyde is converted to amines 2 and 7 via two alternative routes. Upon diazotisation and Sandmeyer reaction, halides 4 and 9 are formed, which, through lithiation and formylation lead to the o-phthalaldehyde. Further cyclisation with hydrazine gives the 5-methoxy-substituted phthalazine.

Full text of DOI:10.1016/S0040-4039(01)01302-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6589–6592
A convenient access to benzo-substituted phthalazines as
potential precursors to DNA intercalators
Petros G. Tsoungas† and Mark Searcey*
Department of Pharmaceutical and Biological Chemistry, University of London School of Pharmacy, 29/39 Brunswick Square,
London WC1N 1AX, UK
Received 21 June 2001; revised 12 July 2001; accepted 19 July 2001
Abstract—2-Nitro-5-methoxybenzaldehyde is converted to amines 2 and 7 via two alternative routes. Upon diazotisation and
Sandmeyer reaction, halides 4 and 9 are formed, which, through lithiation and formylation lead to the o-phthalaldehyde. Further
cyclisation with hydrazine gives the 5-methoxy-substituted phthalazine. © 2001 Elsevier Science Ltd. All rights reserved.
Antitumour antibiotics that bind to DNA by intercala-
tion form a large family of potent agents that have
potential in the clinic.1 These include bis-intercalators
such as echinomycin, sandramycin, triostin A, the
luzopeptins2 and quinaldopeptin,2 as well as monointer-
calating alkylators such as the azinomycins A and B.3
Studies of structure–activity relationships for these
compounds have been fairly limited because of their
structural complexity and, without doubt, this has con-
tributed to their lack of progression into useful thera-
peutic entities. Combinatorial methods and solid-phase
reagents and synthesis offer us an alternative route into
these structurally complex molecules and, as part of an
ongoing research programme to investigate the effects
of structure on the biological activity of both natural4
and synthetic intercalators,5 we required easy synthetic
access to a library of potential chromophore structures.
of 1,2-diacylbenzenes or their aldehyde counterparts
with hydrazine gives 1,4-disubstituted- or the parent,
unsubstituted-phthalazines, respectively.7 Most of the
reported methods for the synthesis of o-phthalalde-
hydes involve the oxidation of a suitably 1,2-disubsti-
tuted benzene.9 Reductive10 or oxidative11 ring-opening
of heterocycles has also been reported. There has also
been a report on the lithiation and formylation of a
simple benzene ring.12 Despite the ingenuity of most of
these methods, there are limitations with regard to: (a)
the nature and pattern of substitution on the benzene
unit that could tolerate the reaction conditions and (b)
the accessibility of suitably substituted benzene
precursors.
A convenient route to 1,4-substituted phthalazines that
could comfortably tolerate substituents on the benzene
ring involves the rearrangement of hydrazones of o-
hydroxyaryl ketones.13 The present report, complemen-
tary to the latter, describes a convenient access to
phthalazines that allows a diverse substitution pattern
on the benzene ring for benzo- and peri-annelation
(Scheme 1). A 5-methoxy-substituent, through its
directing effects for lithiation, serves as an entry for
later stage derivatisation of the benzene ring, ultimately
leading to further functionalisation and/or ‘linear’ or
‘angular’ benzo- and peri-annelation.
The 1,2-disubstitution of aromatic nuclei is an impor-
tant target in synthesis, as it provides an entry to either
functionalisation or ring annelation.6,7 Phthalazines,
like the other members of the isomeric benzodiazine
series, have found wide application as therapeutic
agents.8 Despite their significance, there are only a
limited number of routes for their synthesis, especially
when diverse substitution is required on the benzene
ring to allow their conjugation to more complex struc-
tures.7,8 The most commonly employed approach is
through o-disubstituted benzenes. Thus, condensation
Aldehyde 1 (obtained by methylation of the corre-
sponding commercially available hydroxy compound14)
is reduced by either of the two routes A or B (Scheme
1). Catalytic hydrogenation (route A) gives 2 in 74%
yield. Diazotation of the amine, in the presence of
trimethylsilyl halide (either chloride or bromide—both
* Corresponding author. Tel.: +44-020-7753-5873; fax: +44-020-7753-
5964; e-mail: mark.searcey@ulsop.ac.uk
Permanent address: Ministry of Development, Dept. of Research
†
and Technology, Messogion Ave 14-18, Athens GR-11510, Greece.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01302-8

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P. G. Tsoungas, M. Searcey / Tetrahedron Letters 42 (2001) 6589–6592
H3CO
H3CO
H3CO
(iv)
H3CO
OR
OR
OH
CHO
(ii)
OH
NH2
-
N2+Br
Br
72%
2
3
4a R = TMS
5
6
(iii)
(v)
76%
58% 4b from 2
(i)
74%
4b R = H
Route A
CHO
H3CO
H3CO
CHO
CHO
H3CO
(x)
N
N
NO2
82%
1
12
(ix)
81%
(vi)
Route B
CHO
O
H3CO
CHO
H3CO
CHO
H3CO
H3CO
(vii)
O
(viii)
(iv)
-
45%
N2+Br
Br
NH2
X
7
8
9
10 X = Br
69% (Fe/HCl)
48% (FeSO4/NH4OH)
76% (2 steps)
11 X =CHO
Scheme 1. (i) H2, Pd/C (10%), rt, 48 h; (ii) NaNO2, TMSBr(Cl); (iii) TBAF, CH2Cl2, rt; (iv) n-BuLi, −78°C, THF, DMF; (v) PCC,
t
CH2Cl2, rt, 6 h; (vi) Fe, HCl or FeSO4, NH4OH; (vii) BuONO, CuBr, HBr; (viii) (CH2OH)2, TSA, C6H6, D, 24 h; (ix) 3N HCl,
12 h; (x) N2H4/EtOH/0°C–rt.
were equally effective)15 gave a mixture of both the
O-silyl-derivative and the free alcohol 4a and 4b,
respectively.16 The former is easily converted into the
free alcohol, giving a final yield for the conversion of 2
to 4 of 58%. Halogen lithium exchange followed by
formylation leads to 5, which is mildly oxidised to the
o-phthalaldehyde 6.
along with the N-silyl derivative. Diazotation/Sand-
meyer reaction conditions, similar to those for the
conversion of 2 to 4, gave ill-defined products.
An alternative approach to 4 and 5 through bromina-
tion of the commercially available m-anisaldehyde,
although seemingly attractive, suffers from two serious
limitations: (a) a mixture of all o-/p-bromo-isomers is
obtained, thus necessitating chromatographic separa-
tion of the desired isomer on a preparative scale and (b)
as a consequence of (a), the substitution pattern diver-
sity in the benzene ring is limited.
Attempts to protect the aldehyde 1 as the acetal or
dioxolane prior to reduction were unsuccessful, proba-
bly due to steric impedance known in acetal
formation.14
Alternatively, the amine 7 is obtained by the selective
reduction of 1 by either of the two well-known reagents
Fe/HCl17 or FeSO4/NH4OH18 in 69 and 48% yields,
respectively. Diazotation followed by Sandmeyer reac-
tion furnishes the bromide 9.19 1,3-Dioxolane protec-
tion of the aldehyde, followed by lithiation/formylation
gives 1120 in 76% yield. Deprotection of 11 readily leads
to 6. The ortho-phthalaldehyde 6 is converted to the
target phthalazine 12 in excellent (82%) yield.21
An attempt to prepare the mixed halide 1415,22 and
subsequently convert it to either 15 or 9 (and ultimately
to 6) was unsuccessful (Scheme 2). Thus, 2 was treated
with DMSO/TMSCl to obtain the amine 13 in situ
The aldehydes 16 and 17 were isolated in minor yields
(<5%) from the conversion of 10 to 11. Aldehyde 16
can be derived from a nucleophilic displacement of
either 1,3-dioxolane or the bromide by the O-lithiated
18 (Scheme 3) followed by hydrolysis.23 Aldehyde 17 on
the other hand, appears to be the result of a directed
ortho-lithiation by 1,3-dioxolane 10,24 the effect
enhanced by the m-methoxy-group.25 A recent litera-
ture report is in agreement with this rationale.23 Carry-
ing out the lithiation at −100°C and using n-BuLi and
DMF in the minimum possible excess (e.g. 1.2 and 2.0
mol equiv., respectively) suppresses the formation of
both 16 and 17.
H3CO
H3CO
OH
NH2
Cl
NH2
2
13
H3CO
H3CO
or
Cl
Cl
CHO
9
Br
Bromination of 12 (Br2/AcOH 0°C to rt, 6 h) appears
to favour substitution at the 5- rather than the alterna-
tive 7-position. This is in line with the analogous case in
6-hydroxy-substituted quinolines.26
14
15
Scheme 2.

P. G. Tsoungas, M. Searcey / Tetrahedron Letters 42 (2001) 6589–6592
6591
O
OH
H3CO
H3CO
n-BuLi
18
O
N
N CHO
OLi
18
Br
CHO
10
16
O
O
Li
CHO OH
O
H3CO
H3CO
H3CO
O
Li
Br
CHO
10
17
Scheme 3.
The aldehyde 1 has also recently been used as the
starting material in a synthesis of cinnolines27 and
quinazolines28 and can be considered a common start-
ing point for the synthesis of these benzodiazines, a
feature of synthetic significance.
8. Gilchrist, T. L. Heterocyclic Chemistry, 3rd ed.; Long-
mans: Oxford, 1997.
9. (a) Green, G.; Griffith, W. P.; Hollingshead, D. A.; Ley,
S. V.; Schroder, M. J. Chem. Soc., Perkin Trans. 1 1984,
681; (b) Fohlisch, B. Synthesis 1972, 564; (c) Cope, C.;
Fenton, S. W. J. Am. Chem. Soc. 1951, 73, 1668; (d)
Thiele, J.; Gunther, O. Justus. Liebigs Ann. Chem. 1906,
347, 106; (e) Bill, J. C.; Tarbell, D. S. Org. Synth. 1954,
34, 82; (f) Reid, W.; Bodem, H. Chem. Ber. 1956, 89, 708;
(g) Weygand, F.; Kinkel, K. G.; Tietjen, D. Chem. Ber.
1950, 83, 394; (h) Hauptman, S. Chem. Ber. 1960, 93,
2604; (i) Hirano, M.; Yakabe, S.; Chikamori, I.; Clark, J.
H.; Morimoto, T. J. Chem. Res. (S) 1998, 770.
10. (a) Weygand, F.; Tietjen, D. Chem. Ber. 1951, 84, 625;
(b) Birkofer, L.; Frankus, E. Chem. Ber. 1961, 94, 216; (c)
Misiti, D.; DeMarchi, F.; Rosnati, V. Gazz. Chim. Ital.
1963, 93, 52; (d) Reid, W.; Neidhardt, G. Justus. Liebigs
Ann. Chem. 1963, 666, 148; (e) Hana, G. W.; Buchbauer,
G.; Koch, H. Monatsch Chem. 1976, 107, 945; (f) Axen-
rod, T.; Loew, L.; Pregesin, P. S. J. Org. Chem. 1968, 33,
1274; (g) Weygand, F.; Tietjen, D. Angew. Chem. 1952,
64, 458; (h) Weygand, F.; Tietjen, D. Angew. Chem. 1953,
65, 525; (i) Schlessinger, R. H.; Ponticello, I. S. J. Chem.
Soc., Chem. Commun. 1969, 1013.
11. (a) Wenkert, E.; Khatuya, H. Synth. Commun. 1999, 29,
2413; (b) Eikawa, M.; Sakaguchi, S.; Ishii, Y. J. Org.
Chem. 1999, 64, 4676.
12. Einhorn, J.; Lucke, J. L. Tetrahedron Lett. 1986, 27,
1793.
13. (a) Kotali, A.; Tsoungas, P. G. Tetrahedron Lett. 1987,
28, 4321; (b) Kotali, A.; Paulidou, G.; Glaveri, U.;
Tsoungas, P. G. Synthesis 1990, 1172.
14. Greene, T. W.; Wuts, P. G. M. Protective Groups in
Organic Synthesis, 3rd Ed.; Wiley Interscience: New
York, 1999.
In conclusion, a simple and convergent access to phtha-
lazines is described, which allows a diverse substitution
pattern on the benzene ring. Coupled with the arylhy-
drazone rearrangement reaction,13 this may serve as an
efficient and recommended general route for the synthe-
sis of phthalazines.
Acknowledgements
We gratefully acknowledge funding for a EU Marie
Curie Senior Research Fellowship and The Ministry of
Development, Dept. of Research and Technology,
Greece for a sabbatical leave (P.G.T.).
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