Solid-phase synthesis of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine derivatives

Article abstract of DOI:10.1016/j.tetlet.2005.02.154

A general method is reported for the solid-phase synthesis of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine derivatives based on the cyclization of resin-bound chlorophthalazines 4 with various hydrazides or sodium azide. The resin-bound chlorophthalazines 4, produced by nucleophilic aromatic substitution reaction of dichlorophthalazine with the secondary amine resins 2, served as the key intermediate for subsequent triazolophthalazine resins 6 and tetrazolophthalazine resins 8, which provided the desired products 7 and 9 in good yields and purities.

Full text of DOI:10.1016/j.tetlet.2005.02.154

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 3107–3110
Solid-phase synthesis of [1,2,4]triazolo[3,4-a]phthalazine and
tetrazolo[5,1-a]phthalazine derivatives
Jong Yeon Hwang, Hyung-Sub Choi and Young-Dae Gong*
Medicinal Science Division, Korea Research Institute of Chemical Technology, The Center for High Throughput Chemistry,
PO Box 107, 100 Jang-dong, Yuseong-gu, Daejon 305-600/305343, Republic of Korea
Received 20 January 2005; revised 24 February 2005; accepted 28 February 2005
Available online 19 March 2005
Abstract—A general method is reported for the solid-phase synthesis of [1,2,4]triazolo[3,4-a]phthalazine and tetrazolo[5,1-a]phthal-
azine derivatives based on the cyclization of resin-bound chlorophthalazines 4 with various hydrazides or sodium azide. The resin-
bound chlorophthalazines 4, produced by nucleophilic aromatic substitution reaction of dichlorophthalazine with the secondary
amine resins 2, served as the key intermediate for subsequent triazolophthalazine resins 6 and tetrazolophthalazine resins 8, which
provided the desired products 7 and 9 in good yields and purities.
ꢀ
2005 Elsevier Ltd. All rights reserved.
Solid-phase synthesis has emerged as a powerful tech-
nique in generating combinatorial libraries of small
organic molecules useful for drug discovery. Hetero-
cyclic skeletons provide scaffolds on which pharmaco-
solid-phase to find novel hit compounds toward multiple
biological targets.
1
Herein, we would like to report our finding about
an efficient procedure for the synthesis of [1,2,4]triaz-
olo[3,4-a]phthalazine and tetrazolo[5,1-a]phthalazine
derivatives on solid-phase. The reaction sequence is
illustrated in Scheme 1. We selected resin-bound chloro-
phthalazines 4 as the key intermediate for synthesis
of these derivatives on solid-phase, since it can afford
various heterocyclic fused phthalazine compounds and
easily release final products from the solid support
under 5% trifluoroacetic acid (TFA) condition.
2
phore can arrange to yield potent and selective drugs.
In this respect, phthalazine scaffold have shown its
potential as a privileged structure for the generation of
3
drug-like libraries in drug-discovery process. Moreover,
heterocyclic fused phthalazines have been found effec-
4
tive for the inhibitor of p38 MAP kinase, selective bind-
5
6
ing of GABA receptor, antianxiety drug, antitumor
7
agent, high-affinity ligands to the a d-1 subunit of cal-
2
8
cium channel. Therefore, many reports have been de-
scribed in the solution-phase synthesis of heterocyclic
4
–9
fused phthalazine derivatives.
However, the solid-
As the first step, the resin-bound secondary amines 2
were prepared from acid sensitive methoxybenzaldehyde
(AMEBA) resin and various primary amines by reduc-
tive amination in the presence of NaBH(OAc)3 in
DMF. Formation of the resin 2 was confirmed by the
disappearance of the aldehyde carbonyl band at
phase synthesis of heterocyclic fused phthalazines has
been scarcely reported in the research field of drug-like
library construction, as compared with their simple aro-
matic phthalazine derivatives. As a part of our research
on drug discovery program, we needed to develop a
facile and rapid solid-phase parallel approach for the
construction of drug-like small organic molecules using
À1
1670 cm by attenuated total reflection (ATR) FTIR
on single beads. Resins 2 were then treated with 1,4-
dichlorophthalazine 3 and triethylamine (TEA) in
dimethylsulfoxide (DMSO) at 80 ꢁC to give the
resin-bound chlorophthalazines 4. With the chloro-
phthalazine resin 4 in hand, we first examined the
incorporation of resins 4 with substituted hydrazides 5
and TEA in xylene at 110 ꢁC for the formation of
1
0
various heterocycles. Especially, we were interested in
constructing heterocyclic fused phthalazine libraries on
Keywords: Solid-phase synthesis; Triazolophthalazine; Tetrazolo-
phthalazine.
[
1,2,4]triazolo[3,4-a]phthalazine resins 6. And subse-
*
Corresponding author. Tel.: +82 42 860 7149; fax: +82 42 861
291; e-mail: ydgong@krict.re.kr
quent treatment of the heterocyclic fused resins 6 with
5% TFA in DCM at rt for 3 h gave the desired
1
0
040-4039/$ - see front matter ꢀ 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2005.02.154

3108
J. Y. Hwang et al. / Tetrahedron Letters 46 (2005) 3107–3110
Cl
O
N
N
R2
NH
2
N
H
R1
R1
Cl
N
5
N
i
3
ii
R1
N
N
iii
N
N
H
O
N
H
R2
Cl
N N
1
2
4
6
v
iv
R1
R1
R1
HN
HN
N
N
N
iv
N
N
N
N
R2
N
N
N N
N N
N N
9
8
7
1
Scheme 1. Reagents and conditions: (i) R NH
2
, NaBH(OAc)
3
, AcOH, DMF, rt, 24 h; (ii) TEA, DMSO, 80 ꢁC, 12 h; (iii) TEA, xylene, 110 ꢁC, 24 h;
(
iv) TFA/DCM (5:95), rt, 3 h; (v) NaN , NMP, 120 ꢁC, 24 h.
3
[
1,2,4]triazolo[3,4-a]phthalazines 7. As shown in Table 1,
Table 2.
Product
1
a
Yield (%)
b
Purity (%)
by using the sequence of reactions, we could obtain var-
ious [1,2,4]triazolo[3,4-a]phthalazines analogues in good
four-step overall yields with high purities. In addition,
Figure 1 shows the purity and LC/MS spectrum of rep-
R
N
9a
9b
90
98
1
1
Bn
65
58
49
78
82
100
89
resentative product 7a.
9
9
9
9
c
d
e
f
4-Cl–Bn
2-Cl–Bn
2-Me–Bn
n-Pr
83
93
For further investigation of potential of the resins 4, we
also examined the formation of tetrazolo[5,1-a]phthal-
azine derivatives 9 from the resin-bound chloro-
phthalazines 4 treated with NaN3 in 1-methyl-2-
pyrrolidinone (NMP) at 120 ꢁC. The desired tetraz-
olo[5,1-a]phthalazines 9 were cleaved from the resins
92
9
g
64
59
N
9h
N
73
77
8
with 5% TFA in DCM at rt for 3 h in good yields
and purities as shown in Table 2. Figure 2 shows the
purity and LC/MS spectrum of representative product
a
Four-step overall yields from AMEBA resin 1 (loading capacity of
the resin 1 is 1.2 mmol/g).
All of the crude products were checked by LC/MS.
12
b
9
a.
Table 1.
Product
1
R
2
R
a
Yield (%)
b
Purity (%)
N
N
7
a
4-tert-Bu–Ph
73
49
97
97
7
b
3-MeO–Ph
N
N
N
7
7
7
c
d
e
3-F–Ph
57
41
42
95
90
96
3
4-CF –Ph
4-Cl–Ph
Ph
7
7
7
7
7
f
Bn
Bn
62
59
40
61
62
82
88
74
92
85
g
h
i
2
CH Ph
4-Cl–Bn
n-Pr
n-Pr
2-Cl–Ph
4-tert-Bu–Ph
2-Cl–Ph
j
a
Four-step overall yields from AMEBA resin 1 (loading capacity of the resin 1 is 1.2 mmol/g).
All of the crude products were checked by LC/MS.
b

J. Y. Hwang et al. / Tetrahedron Letters 46 (2005) 3107–3110
3109
Figure 1. LC/MS spectrum of representative product 7a.
Figure 2. LC/MS spectrum of representative product 9a.
In conclusion, we have demonstrated an efficient syn-the-
sis of [1,2,4]triazolo[3,4-a]phthalazines 7 and tetra-
zolo[5,1-a]phthalazines 9 using chlorophthalazine resins
2. (a) Krch nˇ a´ k, V.; Holladay, M. W. Chem. Rev. 2002, 102,
6
1; (b) Thompson, L. A.; Ellman, J. A. Chem. Rev. 1996,
6, 555; (c) Terrett, N. K.; Gardner, M.; Gordon, D. W.;
9
Kobylecki, R. J.; Steele, J. Tetrahedron 1995, 51, 8135.
. (a) Pal, M.; Batchu, V. R.; Parasuraman, K.; Yeleswa-
rapu, K. R. J. Org. Chem. 2003, 68, 6806; (b) Watanabe,
N.; Kabasawa, Y.; Takase, Y.; Matsukura, M.; Miyazaki,
K.; Ishihara, H.; Kodama, K.; Adachi, H. J. Med. Chem.
4
ate for the subsequent cyclization with various
hydrazides or NaN to provide the desired [1,2,4]triaz-
3
. The chlorophthalazines 4 served as the key intermedi-
3
olo[3,4-a]phthalazines 7 or tetrazolo[5,1-a]phthalazines
9
derivatives in good four-step overall yields and purities.
1
998, 41, 3367; (c) Napoletano, M.; Norcini, G.; Pellacini,
F.; Marchini, F.; Morazzoni, G.; Fattori, F.; Ferlenga, P.;
Pradella, L. Bioorg. Med. Chem. Lett. 2002, 12, 5; (d) Van
der Mey, M.; Hatzelmann, A.; Van der Laan, I. J.; Sterk,
G. J.; Thibaut, U.; Timmerman, H. J. Med. Chem. 2001,
44, 2511.
References and notes
1
. (a) Gordon, E. M.; Barrett, R. W.; Dower, W. J.; Foder,
S. P. A.; Gallop, M. A. J. Med. Chem. 1994, 37, 1385; (b)
Dolle, R. E. J. Comb. Chem. 2003, 5, 693.
4. Mavel, S.; Thery, I.; Gueiffier, A. Arch. Pharm. Pharm.
Med. Chem. 2002, 335, 7.

3110
J. Y. Hwang et al. / Tetrahedron Letters 46 (2005) 3107–3110
5
. (a) Carling, R. W.; Moore, K. W.; Street, L. J.; Wild, D.; 12 mmol, loading 1.2 mmol/g, 100–200 mesh, 1% DVB,
Isted, C.; Leeson, P. D.; Thomas, S.; OÕConnor, D.;
McKernan, R. M.; Quirk, K.; Cook, S. M.; Atack, J. R.;
Wafford, K. A.; Thompson, S. A.; Dawson, G. R.; Ferris,
P.; Castro, J. L. J. Med. Chem. 2004, 47, 1807; (b) Street,
L. J.; Sternfeld, F.; Jelley, R. A.; Reeve, A. J.; Carling, R.
W.; Moore, K. W.; McKernan, R. M.; Sohal, B.; Cook, S.;
Pike, A.; Dawson, G. R.; Bromidge, F. A.; Wafford, K.
A.; Seabrook, G. R.; Thompson, S. A.; Marshall, G.;
Pillai, G. V.; Castro, J. L.; Atack, J. R.; MacLeod, A. M.
J. Med. Chem. 2004, 47, 3642.
. Imamura, Y.; Noda, A.; Imamura, T.; Ono, Y.; Okawara,
T.; Noda, H. Life Sci. 2003, 74, 29.
. Kim, J. S.; Lee, H.-J.; Suh, M.-E.; Park Choo, H.-Y.; Lee,
S. K.; Park, H. J.; Kim, C.; Park, S. W.; Lee, C.-O. Bioorg.
Med. Chem. 2004, 14, 3683.
Novabiochem) in DMF containing 1% AcOH were added
successively 2-(aminomethyl)pyridine (3.7 mL, 36 mmol)
and NaBH(OAc) (7.6 g, 36 mmol). The reaction mixture
3
was shaken at room temperature for 24 h, followed by
washes with DMF (· 2), DCM (· 2), MeOH (· 2). The
resulting resin 2a was treated with 1,4-dichlorophthal-
azine (4.8 g, 24 mmol) and TEA (3.3 mL, 24 mmol) in
DMSO at 80 ꢁC for 12 h, followed by washes with DMF
(· 2), DCM (· 2), MeOH (· 2). Chlorophthalazine resin
4a (100 mg, 0.12 mmol) was cyclized with 4-tert-buty-
lphenylhydrazide (69 mg, 0.36 mmol) in xylene in the
presence of TEA (0.050 mL, 0.36 mmol) at 110 ꢁC for
24 h to give [1,2,4]triazolo[3,4-a]phthalazine resin 5a.
Resin 5a was cleaved with 5% TFA/DCM cocktail
solution to give the corresponding desired product 7a.
6
7
8
. Lebsack, A. D.; Gunzner, J.; Wang, B.; Pracitto, R.;
Schaffhauser, H.; Santini, A.; Aiyar, J.; Bezverkov, R.;
Munoz, B.; Liu, W.; Venkatraman, S. Bioorg. Med. Chem.
Lett. 2004, 14, 2463.
3-(tert-Butylphenyl)-6-(pyridin-2-ylmethylamino)[1,2,4]-
1
triazolo[3,4-a]phthalazine (7a):
CD
7.84–7.80 (m, 3H), 7.74–7.73 (m, 1H), 7.66 (m, 1H), 7.40
H NMR (500 MHz,
3
OD): d 8.40 (br, 1H), 8.37 (m, 1H), 8.16 (m, 1H),
9
. Potts, K. T.; Lovelette, C. J. Org. Chem. 1969, 34, 3221.
(m, 1H) 7.34–7.33 (m, 2H), 7.20 (m, 1H), 4.70 (s, 2H),
1
3
1
0. (a) Yoo, S.-e.; Seo, J.-s.; Yi, K. Y.; Gong, Y.-D. Tetrahe-
dron Lett. 1997, 38, 1203; (b) Yoo, S.-e.; Gong, Y.-D.; Seo,
J.-s.; Sung, M.-M.; Lee, S.; Kim, Y. J. Comb. Chem. 1999,
1.27 (s, 9H); C NMR (125 MHz, CD OD): d 158.3,
3
153.0, 151.8, 148.2, 147.9, 142.7, 137.4, 132.8, 130.9,
127.1, 125.1, 123.6, 123.1, 123.0, 122.9, 122.3, 121.1,
+
118.7; LC/MS (ESI) m/z 409 (M+H) .
12. 6-(Pyridin-2-ylmethylamino)tetrazolo[5,1-a]phthalazine
1, 177; (c) Gong, Y.-D.; Yoo, S.-e. Bull. Korean Chem. Soc.
2001, 21, 941; (d) Gong, Y.-D.; Seo, J.-s.; Chon, Y.-S.;
1
(9a): H NMR (500 MHz, DMSO-d
Hwang, J.-Y.; Park, J.-Y.; Yoo, S.-e. J. Comb. Chem. 2003,
, 577; (e) Lee, I. Y.; Kim, S. Y.; Lee, J. Y.; Yu, C.-M.; Lee,
6
): d 9.09 (m, 1H),
8.75–8.73 (m, 1H), 8.58–8.51 (m, 2H), 8.18 (m, 1H), 8.11–
5
D. H.; Gong, Y.-D. Tetrahedron Lett. 2004, 45, 9319; (f)
Hwang, J. Y.; Choi, H.-S.; Lee, D.-H.; Yoo, S.-e.; Gong,
Y.-D. J. Comb. Chem. 2005, 7, 136.
8.07 (m, 2H), 7.84 (m, 1H), 7.66 (m, 1H), 5.80 (br, 1H),
4.99 (d, 2H, J = 5.6 Hz); C NMR (125 MHz, DMSO-d ):
6
1
3
d 156.8, 154.0, 146.1, 142.5, 140.6, 134.6, 133.0, 125.4,
124.9, 124.7, 124.1, 122.3, 120.5, 44.8; LC/MS (ESI) m/z
278 (M+H) .
1
1. General procedure for the synthesis of [1,2,4]triazolo[3,4-
a]phthalazines: To a suspension of AMEBA resin 1 (10 g,
+