Synthesis and transformations of pyrrolo[1,2-a][1,3,5]-triazines

Article abstract of DOI:10.1016/j.tetlet.2018.11.002

Pyrrolotriazines and related fused azaheterocycles have high potential for the synthesis of bioactive compounds, especially as a purine base isoster in carbon linked nucleosides. Although many structurally related compounds have already been synthesized and used in medicinal chemistry, pyrrolo[1,3,5]triazines have barely been described. The present work describes the synthesis of such heterocycles via condensation of 2-amino-3-ethoxycarbonylpyrrole with ethoxycarbonyliso(thio)cyanate. In a brief reactivity study of the obtained fused pyrroles, O- and S-alkylation, ester hydrolysis as well as regioselective bromination at the 6-position was demonstrated.

Full text of DOI:10.1016/j.tetlet.2018.11.002

Accepted Manuscript
Synthesis and transformations of pyrrolo[1,2-a][1,3,5]-triazines
Jonas Verhoeven, B. Narendraprasad Reddy, Lieven Meerpoel, Jan Willem
Thuring, Guido Verniest
PII:
S0040-4039(18)31318-2
https://doi.org/10.1016/j.tetlet.2018.11.002
TETL 50387
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
5 October 2018
1 November 2018
2 November 2018
Please cite this article as: Verhoeven, J., Reddy, B.N., Meerpoel, L., Thuring, J.W., Verniest, G., Synthesis and
transformations of pyrrolo[1,2-a][1,3,5]-triazines, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.
2018.11.002
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pyrrolo[1,2-a][1,3,5]-triazines
Jonas Verhoeven, B. Narendraprasad Reddy, Lieven Meerpoel, Jan Willem Thuring, Guido Verniest
OMe
N
aq. NaOH
N
1) 2-chloroacetaldehyde
Et3N, reflux, 20 min.
2) iso(thio)cyanate, rt, 2h
X1Me
X1= S or O
OMe
N
N
dioxane
rt, 3.5h
HOOC
NH2
HCl
O
N
HN
OEt
X2
OMe
N
X1Me
3) KOtBu, rt, 0.5h
4) MeI, K2CO3, reflux, 1h
EtOOC
X1= S or O
N
NBS or NIS
DMF, rt, 4h
N
X1Me
N
EtOOC
X1= S or O
X2= Br or I

1
Tetrahedron Letters
Synthesis and transformations of pyrrolo[1,2-a][1,3,5]-triazines
Jonas Verhoevena, B. Narendraprasad Reddya, Lieven Meerpoelb, Jan Willem Thuringb, Guido Verniesta,b
a Research Group of Organic Chemistry, Department of Chemistry and Department of Bioengineering Sciences, Faculty of Sciences and Bioengineering Sciences
Vrije Universiteit Brussel, Pleinlaan 2, 1050 Brussels, Belgium
b Janssen Research & Development, Turnhoutseweg 30, B-2340 Beerse, Belgium
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Pyrrolotriazines and related fused azaheterocycles have high potential for the synthesis of
bioactive compounds, especially as a purine base isoster in carbon linked nucleosides. Although
many structurally related compounds have already been synthesized and used in medicinal
chemistry, pyrrolo[1,3,5]triazines have barely been described. The present work describes the
synthesis of such heterocycles via condensation of 2-amino-3-ethoxycarbonylpyrrole with
ethoxycarbonyliso(thio)cyanate. In a brief reactivity study of the obtained fused pyrroles, O- and
S-alkylation, ester hydrolysis as well as regioselective bromination at the 6-position was
demonstrated.
Available online
Keywords:
Pyrrolotriazines
Bromination
Cyclocondensation
Aminopyrrole
2009 Elsevier Ltd. All rights reserved.
Nucleoside analogues
1. Introduction
described despite its potential as novel building block in
medicinal chemistry.
Pyrrolotriazine templates are commonly used in medicinal
chemistry to synthesize various biologically active molecules.1-3
As examples in the field of antiviral carbon linked nucleoside
analogues (C-nucleosides), the well described
NH2
N
H
N
O
O
Me
NH2
N
O
P
HO
HN
H
N
O
N
O
N
O
N
Ph
pyrrolo[1,2,4]triazine heterocyclic moiety has been used as
nucleobase replacement in the development of the anti-HCV
compound 14, whereas the pyrrolo[2,3]pyrimidine scaffold is the
nucleobase analogue in the broad spectrum antiviral compound
BCX4430 25 (Scheme 1). Also in biologically active small
molecules with kinase activity, various pyrrolotriazine building
blocks are frequently implemented, for example in the potent
pan-Aurora kinase inhibitor 3.6 The pyrrolo[1,3,5]triazine
scaffold (Scheme 1, type 4) however, is far less described in the
literature. Few examples are reported in which
Me
OH
HO
OH
HO
2
1
H
HCV/Ebola virus
inhibitor
N
HCV inhibitor
N
R1
NH
R1
O
N
N
N
N
NH
H
R2
N
N
N
N
R2
N
X
S
N
R3
H
EtO2C
O
OH
3
4a: R1=H, R2=Ph (X=S)
described
4b: R1=R2 = H: (X=S or O)
4c: R1=R2=S or O
R3= COOR
O
Aurora kinase inhibitor
not described
pyrrolo[1,3,5]triazines (type 4) are synthesized from the
condensation of 2-aminopyrroles with iso(thio)cyanates followed
by intramolecular cyclization.7-9 Alternatively, their synthesis has
been described via photolytic transformations of pyridazino[l,2-
b]phthalazine-6,11-dione10 or 1,2,4-triazolo[1,2-a]pyridazine-l,3-
dione.11 Also, treatment of 2,5-diaryl-3,3,4,4-
not described
F
Scheme 1. Examples of biological relevant scaffolds containing a
pyrrolotriazine motif and previously described pyrrolo[1,3,5]triazine 4a.
tetracyanopyrrolidines with diazomethane12 and [3+2]-
cycloaddition chemistry using 1,3,5-triazines and 3,3-
2. Results and discussion
dimethoxycyclopropene13 has yielded heterocyclic structures of
type 4. A large variety of phenyl substituted pyrrolotriazines
(type 4a) has been disclosed in a patent published in 2000.14 In
all prepared examples, a phenyl group (R2=Ph) is attached to the
pyrrole ring, decreasing its usefulness as a versatile, low
molecular weight building block. The synthesis of the
In a first attempt to provide entry to pyrrolotriazines 4b-c, 2-
nitropyrrole 5 was treated with isothiocyanate 6 in the presence
of triethylamine, affording the condensation product 7 (Scheme
2). In a following step, a cyclization was planned by reduction of
the nitro group and in situ attack of the formed N-atom to the
carbamate carbonyl group.15 Unfortunately, various attempts to
reduce the nitro group in 7 to obtain 2-aminopyrrole 8 using
SnCl2/HCl, Fe or Zn/HOAc, or hydrogenation over Pd/C were
corresponding pyrrolotriazine in which R2=H (4b) has not been

2
Tetrahedron
not successful. As we suspected that the thiocarbonyl
recovery at different reaction scales mainly due to poor solubility
of 15a,b in organic solvents such as Et2O, EtOAc, etc. Attempted
crystallization of 15a and 15b was unsuccessful and
consequently, isolated yields were calculated after further
modification (protection) of the pyrrolotriazine scaffold structure
15a and 15b.
functionality could interfere with the reduction reaction, the S-
methylated precursor 9 was deemed to be a better substrate.
However, the synthesis of 9 proved to be unsuccessful as the
presence of base resulted in the deprotonation of the nitrogen
followed by expulsion of the nitropyrrole, which was
subsequently methylated (10) by the present MeI (Scheme 2).
Pyrrolotriazines 15a and 15b could be efficiently bis-
methylated using standard protection conditions with MeI and
K2CO3 to afford the less polar products 16a and 16b, which were
easily purified via normal phase silica gel chromatography, or via
recrystallization from diethyl ether (Scheme 4). Overall isolated
yields showed to be reproducible on 5-30 g reaction scales
ranging from 19-23% (4 steps) for the synthesis of 16a. Selective
sulphur or oxygen monomethylation could not be achieved by
using stoichiometric amounts of methyl iodide. However, when
equimolar amounts of benzyl bromide were used, a 3:1 ratio of
17 and 18 was obtained, respectively (Scheme 4). The resulting
monobenzylated building block 17 can potentially be used for
orthogonal modifications at the triazine ring.
COOEt
NH
S
nitro
reduction
N
NH2
COOEt
NH
EtOOCN=C=S 6
H
N
S
8
Et3N
NO2
N
NO2
methylation
COOEt
N
CH3CN, rt, 3h, 68%
5
MeS
7
+ base
18%
N
NO2
Me
N
9
NO2
10
Scheme 2. Condensation of 2-nitropyrrole 5 with isothiocyanate 6 and
unsuccessful attempts to reduce and methylate pyrrole 7.
O
OMe
N
MeI (7 eq)
K2CO3 (3.5 eq)
N
N
NH
Because of the observed difficulties in this strategy, and
because of the known instability of 2-aminopyrroles when the
pyrrole is devoid of aromatic or electron withdrawing
N
H
N
X
XMe
acetone, reflux, 1h
EtO2C
EtO2C
15a, X=S
15b, X=O
16a, X=S (19% from 11)
16b, X=O (59%)
substituents, attempts were shifted towards the use of a pyrrolo
carboxylate 13 as substrate. This 2-amino-3-
X=S
BnBr (1 eq)
OH
OBn
ethoxycarbonylpyrrole 13 was synthesized via a Hantzsch type
synthesis by base catalysed condensation of amidine ester 11 and
freshly distilled chloro acetaldehyde 12 (Scheme 3).16-17 The
desired aminopyrrole 13 was obtained smoothly after a short
reaction time and could be stored for two weeks at -20°C without
significant degradation. Substrate 13 was subsequently used
without purification in a condensation reaction with
K2CO3 (3.5 eq)
N
N
N
N
+
N
N
SBn
SBn
acetone, rt, 3d, 36%
EtO2C
EtO2C
17
18
Scheme 4. Bismethylation and monobenzylation of pyrrolo[1,3,5]triazine 15a
and 15b.
isothiocyanate 6 (X=S) or isocyanate 14 (X=O) which readily
proceeds at room temperature resulting in full conversion of the
starting material after two hours. A slow degradation of the
condensation products from step 2 (Scheme 3) was observed
upon prolonged storage (0.5- 2 weeks) at 4°C which resulted in a
reduced reaction quality of the subsequent step. Therefore, the
intermediates were directly treated with KOtBu to promote
intramolecular cyclization, affording desired pyrrolo triazines
15a and 15b after acidic work-up. The use of DBU to promote
cyclization was also successful, however compound 15a was
obtained as a DBU-salt in low yield and an additional acid-base
extraction was required to obtain the neutral compound 15a.
Treatment of intermediates 16a and 16b with aqueous NaOH
in dioxane afforded the corresponding carboxylic acids (19a and
19b), which could be isolated in moderate to good yield when the
pH was carefully controlled to neutral conditions during work up.
Bismethylated pyrrolotriazine 16a was reacted with N-
iodosuccinimide and N-bromosuccinimide affording 20a and
20b, respectively, both as single products (Scheme 5). Whereas a
clean NMR conversion was obtained, compound 20a was
isolated in rather low yield after silica gel chromatography. This
is believed to be a result of the instability of 20a during the
purification and therefore, the halogenated pyrrolotriazines 20a
and 20b are used preferably as such. The halogen atoms in
compounds 20a and 20b can be regarded as handles for a
potential further derivatization of the pyrrole ring.
O
H
Cl
NH2
HCl
O
H
N
NH2
12
HN
OEt
OMe
Et3N, EtOAc, rt-reflux, 20min.
11
COOEt
13
NaOH (1M)
dioxane/H2O (1:2)
N
N
O
1) X=C=NCOOEt
2) 6, X=S; 14, X=O
CH3CN, rt, 2h
N
XMe
OMe
N
N
NH
HOOC
X
rt, 3.5h
19a, X=S (73%)
19b, X=O (64%)
N
N
X
H
EtO2C
2) KOtBu, THF, rt, 30 min.
N
XMe
15a, X=S (82%)
15b, X=O (72%)
X=S
OMe
EtO2C
NIS or NBS (2 eq)
16a (X=S)
16b (X=O)
N
N
DMF, rt, 4h
SMe
N
Scheme 3. Synthesis of pyrrolo[1,3,5]triazine scaffolds 15a and 15b from
amidine ester 11.
EtO2C
20a, X=I (11%)
20b, X=Br (80%)
Purification via either normal phase silica gel- or reversed
phase chromatography of all intermediates as well as the cyclized
products 15a and 15b showed to be inefficient resulting in poor
Scheme 5. Saponification and halogenation of pyrrolo[1,3,5]triazine 16a and
16b.

3
8. Haddach, M.; Dyck, B. P.; Huang, C. Q.; Nelson, J.; Guo, Z.;
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Koho. 2000, 2000319279.
Further evaluation of the reactivity of the pyrrole ring revealed
that when 16a was treated with aldehydes 21a-d in the presence
of gold(I)chloride, dimeric structures were obtained (Scheme 6).
This addition was found to proceed smoothly with a three-fold
excess of various aromatic and aliphatic aldehydes at room
temperature in dichloromethane or acetonitrile, affording 22a-d
in high isolated yields after normal phase silica gel
15. (a) Charton, J.; Girault-Mizzi, S.; Debreu-Fontaine, M.; Foufelle,
F.; Hainault, I.; Bizot-Espiard, J.; Caignard, D.; Sergheraert, D.
Bioorg. Med. Chem. 2006, 14, 4490. (b) Pogorelic, I.; Filipan-
Litvic, M.; Merkas, S.; Ljubic, G.; Cepanec, I.; Litvic, M. J. Mol.
Catal. A-Chem. 2007, 274, 202. (c) Fu, L.; Gribble, G. W.
Tetrahedron Lett. 2007, 48, 9155. (d) Gamble, A. B.; Garner, J.
A.; Gordon, C.; O’Conner, S. M. J.; Keller, P. A. Synth. Comm.
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16. Toja, E.; Tarzia, G.; Ferrari, P.; Tuan, G. J. Heterocycl. Chem.
1986, 23, 1555.
17. Gangjee, A. Kurup, S.; Ihnat, M. A.; Thorpe, J. E.; Shenoy, S. S.
Bioorg. Med. Chem. 2010, 18, 3575.
chromatography. Indium(I)chloride also showed to effectively
afford the dimeric product 22b, however in lower (10%) yield in
comparison to the use of gold(I)chloride as Lewis acid.
O
MeO
R
N
SMe
OMe
N
R
H
21
N
N
N
AuCl (20 mol%)
EtO2C
N
OMe
CO2Et
SMe
N
CH2Cl2, rt
EtO2C
N
N
R = -CH2CH3(21a), phenyl (21b)
2,4-dichlorophenyl (21c)
3-methylphenyl (21d)
16a
SMe
22a (85%), 22b (81%)
22c (87%), 22d (88%)
Supplementary Material
Scheme 6. Gold(I)chloride catalyzed coupling of pyrrolo[1,3,5]triazine 16a.
Supplementary data associated with this article can be found,
in the online version, at https://doi.org/………..
3. Conclusion
In summary, a scalable and reproducible protocol for the
synthesis of pyrrolotriazines 15a and 15b has been described
starting from ethyl 3-amino-3-iminopropanoate 11. The novel
protected pyrrolotriazines 16a and 16b carry different anchor
points for orthogonal functionalization of the central scaffold
structure. An unexpected gold(I)chloride mediated double
addition to aldehydes was found to efficiently yield dimeric
pyrrolotriazine structures 22a-d.
Acknowledgments
The authors acknowledge the Vrije Universiteit Brussel (ZAP-
starting grant) for financial support.
References and notes
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4
Tetrahedron
Highlights
* Pyrrolotriazines are isosteres of nucleobases used
to synthesize C-nucleosides
* Pyrrolo[1,3,5]triazines are not well described
* A scalable synthesis of 6-carboxylated
[1,3,5]pyrrolotriazines was developed
* A regioselective halogenation of pyrrolotriazines
was demonstrated