Pyrrolo[2,1-d][1,2,3,5]tetrazines, a new class of azolotetrazines related to the antitumor drug temozolomide

Article abstract of DOI:10.1055/s-1999-3628

A series of derivatives of the new ring system pyrrolo[2,1- d][1,2,3,5]tetrazine, potential antineoplastic agents, were obtained in good yield from the reaction of 2-diazopyrroles with isocyanates at room temperature and in the dark. Atomic charges at C-4

Full text of DOI:10.1055/s-1999-3628

2082
PAPER
Pyrrolo[2,1-d][1,2,3,5]tetrazines, a New Class of Azolotetrazines Related to the
Antitumor Drug Temozolomide
Patrizia Diana, Paola Barraja, Antonino Lauria, Anna Maria Almerico, Gaetano Dattolo, and Girolamo Cirrincione*
Dipartimento Farmacochimico-Tossicologico e Biologico, Università degli Studi, Via Archirafi 32, 90123 Palermo, Italy
Fax +39(091)6169999; E-mail: gcirrinc@mbox.unipa.it
Recieved 27 April 1999; revised 28 July 1999
The very few 2-diazopyrroles that are known were pre-
Abstract: A series of derivatives of the new ring system pyrro-
pared by direct introduction of the diazo group into the
lo[2,1-d][1,2,3,5]tetrazine, potential antineoplastic agents, were ob-
pyrrole ring and were obtained in very low yields (2-6%).7
tained in good yield from the reaction of 2-diazopyrroles with
isocyanates at room temperature and in the dark. Atomic charges at
Our recent studies demonstrated that 2- and 3-aminopyr-
C-4, a good parameter to predict the antineoplastic activity for this
roles behave similarly towards protonation.8 These results
type of compounds, were found to be very close to that of temozo-
allowed us to believe that the failure in the diazotization
lomide (2), the antitumor drug currently used in therapy.
of 2-aminopyrroles might be ascribed to the instability of
Key words: pyrrolotetrazines, azolotetrazines, 2-diazopyrroles,
the reaction products rather than to a lack of reactivity of
temozolomide, antineoplastic agents
the reagents. Under suitable reaction conditions, however,
it was possible to diazotize 2-aminopyrroles 3a-d, which
led to the isolation of the corresponding 2-diazopyrroles
4a-d in preparative yields.9 Compounds 3c and 3d were
synthesized from 2-acetamido-3-cyano-4-methyl-5-phe-
nylpyrrole (7) which was derived from 3a. The diazotiza-
tion of 3d to 4d also led to a small quantity of 5-methyl-
6-phenylpyrrolo[2,3-d][1,2,3]triazine-4-one (6) due to an
intramolecular coupling reaction of the diazo group with
the carboxamide moiety. It was impossible to obtain pure
4d even after flash chromatography since it slowly but
continuously transformed into the pyrrolotriazine com-
pound 6. Thus 4d was used as crude product obtained
from the diazotization. The pyrrolotriazine derivative 6,
instead, was obtained as pure compound (Table).
Since the early 1980s azolotetrazine systems have re-
ceived remarkable attention because of the outstanding
antineoplastic activity, exhibited by the two imidazo-tet-
razinone derivatives: mitozolomide 1 and temozolomide
2.1-3
The preparation of these useful synthons constituted the
synthetic entry to the pyrrolo[2,1-d][1,2,3,5]tetrazine ring
system 5. However, when the 2-diazopyrroles 4a-d ob-
tained from the corresponding 2-aminopyrroles 3a-d were
reacted under the same reaction conditions employed for
the synthesis of the azolotetrazine (equimolecular
amounts of isocyanates in dichloromethane or ethyl ace-
tate at room temperature, in the dark), there was no reac-
tion at all, even after one month. The title compounds
were instead obtained in 45-60% yields using a ten-fold
excess of isocyanate and dimethylformamide as a solvent.
Considering that the negative charge of the 2-diazopyr-
roles is mainly located on the ipso carbon,9 the mechanism
leading to the pyrrolotetrazinones, involving the forma-
tion of a spiro compound, seems likely. Also, more severe
reaction conditions, necessary for the cycloaddition of the
isocyanates to the 2-diazopyrroles are due to the reduced
electrophilicity of the diazo group bounded to the pyrrole
nucleus, the more electron rich azole ring.
Most syntheses of azolotetrazinones have involved a slow
reaction of the corresponding diazoazoles with alkyl or
aryl isocyanates at room temperature, in the dark, in an in-
ert organic solvent.4 The mechanism of this type of reac-
tion is not completely clarified. A concerted mechanism4a
formerly proposed seems unlikely since concerted mech-
anisms where heterocumulenes act as dipolarophiles have
generally been discounted.5 A stepwise ionic pathway
might involve either an initial nucleophilic attack at the
isocyanate carbon, to give a dipolar intermediate which
undergoes ring closure or a [3+2] cycloaddition leading to
a spiro compound which by a [1,5] sigmatropic rearrange-
ment affords the bicyclic system.6
Pyrrolotetrazines, compounds that hold the deaza skeleton
of temozolomide, are unknown, probably because of the
unavailability of 2-diazopyrroles. In fact, until recently it
was believed that 2-aminopyrroles would not behave as
aromatic amines, and that their diazotization and subse-
quent neutralization would not lead to the diazo species.
The structures of the pyrrolotetrazinones were confirmed
by spectroscopic data, in particular, the 13C NMR spectra
showed a pattern of the pyrrole carbons compatible with a
1H-pyrrole structure and completely different from that of
the starting 2-diazopyrroles which have a 2H-pyrrole
Synthesis 1999, No. 12, 2082–2086 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Pyrrolo[2,1-d][1,2,3,5]tetrazines
2083
Scheme
2-Aminopyrroles 3a,d
structure.9 The signals of carbonyl carbon of the tetrazine
moiety were found in the range 137-141 ppm, in agree-
ment with the values observed for azolotetrazinones.10 In
the 1H NMR spectrum of the carboxamido derivative 5d,
the amide protons appeared as two distinct signals, δ 5.81,
1H and 8.01, 1H, due to a hydrogen bond with N-1 of the
tetrazine moiety.
Derivatives 3a,b were prepared from 1-acetamido-1-phenylpropan-
2-one12 or 2-acetamido-1-phenylpropan-1-one13 and malononitrile
according to the procedure described in the literature.14
2-Acetamido-3-cyano-4-methyl-5-phenylpyrrole (7)
Compound 3a (3.94 g, 20 mmol) dissolved in Ac2O (30 mL) was
heated for 10 min on a steam bath. The precipitate formed was fil-
tered and dried under vacuum to give 7 (4.78 g, 100%).
Since the key step of the proposed mode of action of te-
mozolomide is the nucleophilic attack at the electron-de-
ficient C-4 position, calculation of atomic charges at this
site of pyrrolotetrazinones and comparison with that of te-
mozolomide can be a good parameter to predict the elec-
trophilic and antineoplastic activity. Thus we calculated
the atomic charge at C-4 for all the pyrrolotetrazinone de-
rivatives and for temozolomide.11 The values were found
in the range 0.438-0.442, very close to that of temozolo-
mide (0.444), and point to the potential biological activity
of this new class of azolotetrazinones.
2-Aminopyrroles 3c,d
To a solution of the acetylamino derivative 7 (10.0 g, 41.8 mmol) in
anhyd EtOH (100 mL), dry HCl was bubbled for 10 h at 0°C to ob-
tain 3d or at 60°C to obtain 3c. The mixture was then refluxed for
10 min. After cooling, the solvent was evaporated under reduced
pressure and the solid residue was taken up with H2O (100 mL) and
neutralized with aq NH3 (14%). The precipitate obtained was fil-
tered off, air-dried and recrystallized from EtOH to give 3c,d (Ta-
ble).
2-Diazopyrroles 4a-d; General Procedure
NaNO2 (207 mg, 3 mmol) dissolved in the minimum volume of H2O
was added dropwise to a solution of the aminopyrroles 3a-d (3
mmol) in HOAc (80%, 6 mL), at 0°C with stirring and under a N2
atm. The mixture was kept at 0°C for 30 min and aq Na2CO3
solution (20%, 25 mL) was added. A gummy residue that soon
solidified was formed. Purification by flash chromatography,
eluting with CH2Cl2 gave 4a-d (Table).
All mps points were taken on a Buchi-Tottoli capillary apparatus
and are uncorrected. IR spectra were determined with a Jasco FT/IR
1
5300 spectrophotometer in CHBr3. H (200 MHz) and 13C (50.3
MHz) NMR spectra were measured in DMSO-d6 solution (TMS as
internal reference) using a Bruker AC series 200 MHz spectrome-
ter. Column chromatography was performed with Merck silica gel
(230-400 mesh) ASTM. Satisfactory microanalyses were obtained
for all new compounds: C ± 0.2, H, ± 0.1, N, ± 0.1.
Compound 4a
Yield = 76%
Mp: 72-73°C (EtOH). [Lit:9 72-73°C]
Synthesis 1999, No. 12, 2082–2086 ISSN 0039-7881 © Thieme Stuttgart · New York

2084
P. Diana et al.
PAPER
Table Spectroscopic Data for Compounds 3-7
Pro-
duct
Yield
%
Mp
IR (CHBr3)
1H NMR (DMSO/TMS) ppm, J (Hz)
13C NMR (DMSO/TMS) ppm
°Ca
ν (cm-1)
3c
80
118-
119b
3474 and
1.26 (t, 3H, J = 6.9 , CH3), 2.27 (s, 3H, CH3), 12.2 (q, CH3), 14.6 (q, CH3), 57.9 (t, CH2),
4.16 (q, 2H, J = 6.9 , CH2), 5.68 (s, 2H, NH2) 93.4 (s, C-3), 113.4 (s, C-4), 120.2 (s, C-5),
7.16 (t, 1H, J = 7.9 , C6H5), 7.25-7.35 (m, 4H, 125.0 (d, C6H5), 126.0 (d, C6H5), 128.4 (d,
3397 (NH2),
3326 (NH),
1647 (CO)
C6H5), 10.35 (br s, 1H, NH)
C6H5), 133.1 (s, C6H5), 148.0 (s, C-2), 165.8
(s, CO)
3d
4b
4c
90
80
77
173-
175
3391 and
2.54 (s, 3H, CH3), 5.66 (br s, 2H, NH2), 6.30 (br 12.4 (q, CH3), 97.3 (s, C-3), 111.4 (s, C-4),
s, 2H, NH2) 7.15 (t, 1H, J = 8.1 , C6H5), 7.30 (d, 119.8 (s, C-5), 124.9 (d, C6H5) 126.3 (d,
2H, J = 8.1 , C6H5), 7.36 (t, 2H, J = 8.1 , C6H5), C6H5), 128.5 (d, C6H5), 133.30 (s, C6H5),
3304 (NH2),
3153 (NH),
1659 (CO)
10.35 (s, 1H, NH)
146.4 (s, C-2), 168.9 (s, CO)
80-82
77-80
2218 (CN),
2096 (N2)
2.35 (s, 3H, CH3), 7.43-7.49 (m, 2H, C6H5),
7.51-7.55 (m, 3H, C6H5)
16.7 (q, CH3), 85.3 (s, C-2), 104.1 (s, C-3),
112.8 (s, CN), 128.4 (d, C6H5), 128.6 (d,
C6H5), 128.9 (d, C6H5), 131.3 (s, C6H5), 132.0
(s, C-3), 136.4 (s, C-4), 151.7 (s, C-5)
2112 (N2),
1713 (CO)
1.34 (t, 3H, J = 7.4 , CH3), 2.55 (s, 3H, CH3), 12.9 (q, CH3), 13. 9 (q, CH3), 60.6 (t, CH2),
4.34 (q, 2H, J = 7.4 , CH2), 7.27-7.47 (m, 4H, 89.0 (s, C-2), 127.9 (d, C-2’ and C-6’), 128.3
C6H5), 7.70-7.74 (m, 1H, C6H5)
(d, C-4’), 128.5 (d, C-3’ and C-5’), 130.5 (s,
C-1’), 135.9 (s, C-4), 153.9 (s, C-3), 155.3 (s,
C-5), 172.0 (s, CO)
5a
5b
45
60
113-
115
2234 (CN),
1736 (CO)
2.30 (s, 3H, CH3), 3.92 (s, 3H, CH3), 7.32-7.39 10.7 (q, CH3), 37.0 (q, CH3), 94.8 (s, C-8),
(m, 2H, C6H5), 7.44-7.51 (m, 3H, C6H5)
112.1 (s, CN), 127.8 (d, C6H5), 128.1 (s, C-7),
128.4 (s, C-6), 129.1 (s, C6H5), 129.4 (d,
C6H5), 130.8 (d, C6H5), 138.9 (s, C-8a), 140.2
(s, C-4)
152-
154
2230 (CN),
1736 (CO)
2.85 (s, 3H, CH3), 7.45-7.61 (m, 10H, 2 x C6H5) 13.2 (q, CH3), 93.9 (s, C-8), 112.2 (s, CN),
126.1 (d, C6H5), 127.3 (s, C-6), 129.0 (d,
C6H5), 129.1 (d, C6H5), 129.3 (d, C6H5), 129.4
(d, C6H5), 129.5 (d, C6H5), 129.7 (s, C-7),
131.9 (s, C6H5), 137.0 (s, C6H5), 138.5 (s, C-
8a), 141.2 (s, C-4)
5c
49
123-
125
1732 (CO),
1708 (CO)
1.43 (t, 3H, J = 7.1 , CH3) 2.34 (s, 3H, CH3),
4.47 (q, 2H, J = 7.1 , CH2) 7.47-7.69 (m, 10H, CH2),112.0 (s, C-8), 122.0 (s, C-7), 127.0 (d,
11.3 (q, CH3), 14.5 (q, CH3), 60.7 (t,
2 x C6H5)
C6H5), 127.1 (s, C-6), 127.4 (d, C6H5), 128.5
(d, C6H5), 129.1 (d, C6H5), 129.2 (d, C6H5),
129.8 (s, C6H5), 131.3 (d, C6H5), 136.1 (s,
C6H5), 138.0 (s, C-8a), 140.5 (s, C-4), 162.7 (s,
COOEt)
5d
5e
5f
51
55
53
152-
154
3490 and
2.47 (s, 3H, CH3), 5.81 (br s, 1H, NH), 7.42-
7.54 (m, 10H, 2 x C6H5), 8.01 (br s, 1H, NH)
11.5 (q, CH3), 114.5 (s, C-8), 126.3 (d, C6H5),
127.6 (d, C6H5), 129.0 (d, C6H5), 129.1 (d,
C6H5), 129.2 (s, C-7), 129.3 (d, C6H5), 129.7
(s, C-6), 130.6 (s, C6H5), 131.1 (d, C6H5),
134.5 (s, C-8a), 137.3 (s, C6H5), 140.4 (s, C-4),
164.0 (s, CONH2)
3411 (NH2),
1757 (CO),
1735 (CO)
148-
149
2233 (CN),
1753 (CO)
2.33 (s, 3H, CH3), 7.37-7.55 (m, 10H, 2 x C6H5) 10.8 (q, CH3), 95.7 (s, C-8), 112.1 (s, CN),
126.2 (d, C6H5), 127.9 (d, C6H5), 128.4 (s, C-
7), 129.1 (d, C6H5), 129.2 (s, C6H5), 129.3 (d,
C6H5),129.4 (d, C6H5), 129.5 (s, C-6), 130.8
(d, C6H5), 137.0 (s, C6H5), 138.1 (s, C-8a),
139.9 (s, C-4)
158
2236 (CN),
1746 (CO)
2.27 (s, 3H, CH3), 3.81 (s, 3H, OCH3), 7.09 (d, 10.4 (q, CH3), 55.4.(q, OCH3), 92.2 (s, C-8),
2H, J = 8.8, C-3’ and C-5’), 7.30-7.45 (m, 5H, 112.8 (s, CN), 114.0 (d, C6H4), 127.3 (d,
C6H5), 7.50 (d, 2H, J = 8.8 , C-2’ and C-6’
C6H5), 127.5 (s, C6H4), 127.7 (s, C-7), 128.1
(d, C6H5), 128.5 (s, C-6), 128.6 (d, C6H5),
130.3 (s, C6H5), 130.9 (d, C6H4), 139.2 (s, C-
8a), 139.9 (s, C-4), 159.6 (s, C6H4)
Synthesis 1999, No. 12, 2082–2086 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Pyrrolo[2,1-d][1,2,3,5]tetrazines
2085
Table Continued
Pro-
duct
Yield
%
Mp
IR (CHBr3)
1H NMR (DMSO/TMS) ppm, J (Hz)
13C NMR (DMSO/TMS) ppm
°Ca
ν (cm-1)
5g
5h
60
50
109-
110
2240 (CN),
1741 (CO)
2.25 (s, 3H, CH3), 7.43-7.50 (m, 5H, C6H5),
7.64 (s, 4H, C6H4)
10.4 (q, CH3), 92.8 (s, C-8), 112.7 (s, CN),
127.4 (d, C6H4), 127.6 (s, C6H4), 128.1 (s, C-
7), 128.4 (s, C6H5), 128.5 (d, C6H5), 128.6 (s,
C-6), 128.7 (d, C6H5), 129.0 (d, C6H5), 130.9
(d, C6H4), 133.7 (s, C6H4), 136.4 (s, C-8a),
139.7 (s, C-4)
137
2237 (CN),
1738 (CO)
2.28 (s, 3H, CH3), 7.38-7.43 (m, 5H, C6H5),
10.5 (q, CH3), 93.0 (s, C-8), 112.7 (s, CN),
7.54-7.57 (m, 3H, C6H4), 7.66 (br s, 1H, C6H4) 125.6 (d, C6H4), 126.7 (d, C6H4), 127.4 (d,
C6H5), 127.7 (s, C6H5), 128.2 (s, C-7), 128.4
(s, C-6), 128.8 (d, C6H5), 129.3 (d, C6H4),
130.7 (d, C6H4), 130.9 (d, C6H5), 132.9 (s,
C6H4), 138.7 (s, C6H4), 139.0 (s, C-8a), 139.7
(s, C-4)
5i
5j
55
50
163
160
2230 (CN),
1743 (CO)
2.75 (s, 3H, CH3), 7.53-7.61 (m, 5H, C6H5),
7.68 (br s, 4H, C6H4)
12.8 (q, CH3), 90.8 (s, C-8), 112.9 (s, CN),
126.5 (s, C-6), 128.6 (d, C6H4), 128.9 (d,
C6H5), 129.1 (d, C6H5), 129.2 (d, C6H5), 129.3
(d, C6H4), 129.7 (s, C-7), 129.8 (s, C6H5),
133.9 (s, C6H4), 136.3 (s, C6H4), 139.4 (s, C-
8a), 141.1 (s, C-4)
2232 (CN),
1740 (CO)
2.75 (s, 3H, CH3), 7.53-7.61 (m, 5H, C6H5),
7.65 (br s, 3H, C6H4), 7.76 (br s, 1H, C6H4)
12.8 (q, CH3), 91.4 (s, C-8), 112.8 (s, CN),
125.7 (d, C6H4), 126.6 (s, C-6), 126.8 (d,
C6H4), 128.9 (d, C6H4), 129.1 (d, C6H5), 129.2
(d, C6H5), 129.4 (d, C6H4), 129.7 (s, C-7),
129.8 (s, C6H5), 130.8 (d, C6H5), 133.0 (s,
C6H4), 138.5 (s, C6H4), 139.2 (s, C-8a), 141.0
(s, C-4)
6
7
5
235
(dec)
3169-2856
(br, NH),
1666 (CO)
2.51 (s, 3H, CH3), 7.43 (dt, 1H, J = 7.9, 1.2 , H- 10.8 (q, CH3), 109.6 (s, C-4a), 110.9 (s, C-5),
4’), 7.54 (dt, 2H, J = 7.9, 1.2 , H-3’ and H-5’), 127.9 (d, C6H5), 128.1 (d, C6H5), 128.7 (d,
7.69 (dd, 2H, J = 7.9, 1.2 , H-2’ and H-6’),
13.03 (br s, 1H, NH), 14.41 (br s, 1H, NH)
C6H5), 130.6 (s, C-6), 134.4 (s, C6H5), 144.2
(s, C-7a), 156.2 (s, C-4)
219
3358 (NH),
δ = 2.09 (s, 3H, CH3), 2.22 (s, 3H, CH3), 7.28 δ = 11.0 (q, CH3), 22.8 (q, CH3), 86.1 (s, C-
(EtOH) 3212 (NH),
2214 (CN),
1682 (CO)
3), 115.8 (s, CN), 115.9 (s, C-4), 124.5 (s, C-
5), 126.6 (d, C6H5), 128.7 (d, C6H5), 128.8 (d,
C6H5),131.5 (s, C6H5), 133.7 (s, C-2), 169.3
(s, CO).
(dt, ,1H, J = 7.5, 1.0 Hz, H-4’), 7.42 (dt, 2H,
J = 7.5, 1.0 Hz,, H-3’ and H-5’), 7.46 (dd, 2H
J = 7.5, 1.0 Hz, H-2’ and H-6’), 10.58 (br s,
1H, NH), 11.70 (br s, 1H, NH).
cm-1.
aRecrystallization solvent: EtOH.
bLit.15 135-136°C
References
Pyrrolo[2,1-d][1,2,3,5]tetrazines 5a-j; General Procedure
To a solution of 4a-d (2 mmol) in anhyd DMF (10 mL), the suitable
isocyanate (20 mmol) in anhyd DMF (10 mL) was added dropwise
at r.t., in the dark. The mixture was stirred until the diazo band at
2110 cm-1 disappeared (24-48 h), then poured onto crushed ice (100
g). The precipitate was filtered off, air-dried and purified by flash
chromatography with CH2Cl2 as eluant to give 5a-j (Table).
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Synthesis 1999, No. 12, 2082–2086 ISSN 0039-7881 © Thieme Stuttgart · New York

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P. Diana et al.
PAPER
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M. F. G. J. Chem. Soc. Perkin Trans. I 1995, 249.
(11) PIMMS, Oxford Molecular Ltd., Oxford U.K., according to
Abraham, R. J.; Smith, P. E. J. Comput.-Aided Mol. Design
1989, 3, 175.
(12) a) This N-acetyl-a-amino ketone was prepared according to
the procedure described by Dakin H. D.; West, R. J. Biol.
Chem. 1928, 78, 91; taking care of removing the solvent by
steam distillation to avoid the formation of the N,N-diacetyl-
a-amino ketone;
(4) a) Ege, G.; Gilbert, K. Tetrahedron Lett. 1979, 4253.
b) Lunt, E.; Newton, C. G.; Smith, C.; Stevens, G. P.; Stevens,
M. F. G.; Straw, C. G.; Walsh, R. J. A.; Warren, P. J.; Fizames,
C.; Lavelle, F.; Langdon, S. P.; Vickers, L. M. J. Med. Chem.
1987, 30, 357.
b) Wiley R. H.; Borum, O. H. J. Am. Chem. Soc. 1948, 70,
2005.
c) Ege, G.; Gilbert, K.; Maurer, K. Chem. Ber. 1987, 120,
1375.
(13) This N-acetyl-a-amino ketone was prepared by reduction of
the corresponding oxime with zinc in HOAc and Ac2O taking
care of removing the solvent by steam distillation to avoid the
formation of the N,N-diacetyl-a-amino ketone;
(14) Johnson, R. W.; Mattson, R. J.; Sowell, J. W. Sr. J.
Heterocycl. Chem. 1977, 14, 383.
(5) Gilchrist, T. L.; Storr, R. C. In Organic Reactions and Orbital
Symmetry, 2nd ed., Cambridge University Press, 1979, p 201.
(6) Stevens, M. F. G.; Hickman, J. A.; Stone, R.; Gibson, N. W.;
Baig, G. U.; Lunt, E.; Newton, C. G. J. Med. Chem. 1984, 27,
196.
(7) a) Fischer, H.; Guggemos, H.; Schafer, A. Justus Liebigs Ann.
Chem. 1939, 540, 30.
(15) Toja, E.; De Paoli, A.; Tuan, G.; Kettenring, J. Synthesis 1987,
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b) Tedder, J. M.; Webster, B. J. Chem. Soc. 1962, 1638.
c) Wie, C. T.; Sunder S.; De Witt Blanton C. Jr. Tetrahedron
Lett. 1968, 4605.
Article Identifier:
1437-210X,E;1999,0,12,2082,2086,ftx,en;H02599SS.pdf
Synthesis 1999, No. 12, 2082–2086 ISSN 0039-7881 © Thieme Stuttgart · New York