Regioselective mono-bromination of pyrrolo[2,1-f][1,2,4]triazin-4-amine

Article abstract of DOI:10.14233/ajchem.2014.17858

Pyrrolo[2,1-f][1,2,4]triazin-4-amine is regioselectively brominated when treated with 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione in different solvents. The brominated product, 5,7-dibromopyrrolo[2,1-f][1,2,4]triazin-4-amine predominates when the reaction is run in dichloromethane. The subsequent debromination process utilizes lithium-bromine exchange to give the desired product 5-bromo-pyrrolo[2,1- f][1,2,4]triazin-4-amine.

Full text of DOI:10.14233/ajchem.2014.17858

Asian Journal of Chemistry; Vol. 26, No. 20 (2014), 7083-7084
ASIAN JOURNAL OF CHEMISTRY
http://dx.doi.org/10.14233/ajchem.2014.17858
NOTE
Regioselective Mono-bromination of Pyrrolo[2,1-f][1,2,4]triazin-4-amine
1,*
1
1
1
1
2,*
LEI BI , SHENG FANG , RAN ZHANG , XIANZHEN YIN , CHENCHAO FU and LEI YAO
1School of Chemistry and Chemical Engineering, Anhui University of Technology, 59 Hudong Road, Maanshan 243002, Anhui, P.R. China
2School of Pharmacy, Yantai University, 32 Qingquan Road, Yantai 264005, Shandong, P.R. China
*Corresponding authors: E-mail: lei_bi@hotmail.com; yaoleiytu@163.com
Received: 19 April 2014;
Accepted: 16 June 2014;
Published online: 25 September 2014;
AJC-16076
Pyrrolo[2,1-f][1,2,4]triazin-4-amine is regioselectively brominated when treated with 1,3-dibromo-5,5-dimethylimidazolidine-2,4-dione
in different solvents. The brominated product, 5,7-dibromopyrrolo[2,1-f][1,2,4]triazin-4-amine predominates when the reaction is run in
dichloromethane. The subsequent debromination process utilizes lithium-bromine exchange to give the desired product 5-bromo-pyrrolo[2,1-
f][1,2,4]triazin-4-amine.
Keywords: Over-bromination, Lithium-bromine exchange.
Among the most routinely conducted organic transfor-
mations, bromination is undoubtedly irreplaceable in synthetic
chemistry. For alkyl bromides, the brominated position
provides a good site for subsequent nucleophilic substitution.
On the other hand, as versatile intermediates, aromatic bromides
are ideal precursors in transition metal-catalyzed coupling
reactions, namely Suzuki reaction and the like. Mechanis-
tically, a bromination process can proceed via quite different
pathways. For the instance of alkyl benzenes, bromination
occurs either at the benzylic position by free radical or on the
benzene ring through aromatic substitution (SNAr), according
to the brominating agent and the specific reaction condition.
Pyrrolo[2,1-f][1,2,4]triazin-4-amine has a [6,5] fused
heterocyclic ring. Containing multiple nitrogen atoms, it has
caught attention from the pharmaceutical industry1-5. Chemical
structures further derived from it have demonstrated excellent
stage. Instead, it continued to take place at position 7, resulting
in 5,7-dibromopyrrolo[2,1-f][1,2,4]-triazin-4-amine. In order
to generate new leads, monosubstituted bromide at different
positions of the 5-membered ring of the title compound was
desired and over-bromination needed to be avoided.
For the 5-membered ring, positions 5, 6 and 7 are all likely
to be brominated. However, by examining the structure of
pyrrolo[2,1-f][1,2,4]triazin-4-amine, we find the electron
density at position 7 is higher than that at position 5. That is to
say, in electronic bromination reactions, position 7 is more
reactive than position 5. This explains why it is not possible to
get 5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine without a
significant amount of disubstituted bromide. It is the intrinsic
trend that determines when dichloromethane is the solvent,
only 1/3 of the product is exclusively brominated at position 5
while the rest 2/3 is at both position 5 and position 7.
biological activities in therapeutic fields such as cancer1,4,5
,
To overcome this hurdle, an alternative route was taken.
After numerous fruitless attempts to increase the amount of
the 5-brominated product, we decided to convert the 5,7-
dibromide, previously considered as a by-product, to the
desired 5-bromide. We rationalized that the bromine molecule
at position 7 was supposedly more prone to lithium-halogen
exchange, since this position is more reactive in electronic
substitution reactions than position 5. To test our assumption,
we monitored the progress of the exchange by TLC while
treating the isolated 5,7-dibromopyrrolo[2,1-f][1,2,4]triazin-
4-amine with n-butyl lithium. Gratifyingly, not only debromi-
nation took place rapidly but the transformation was also rather
angiogenesis1,2, ocular disorder2, and neuro degenerative
disorder3. These molecules are prepared by regioselective
bromination of the title compound, followed by one of the
coupling reactions, typically Suzuki reaction.
In literature, the positions 5 and 7 of pyrrolo[2,1-f][1,2,4]-
triazin-4-amine could be selectively brominated just by using
different solvents (N,N'-dimethyl formamide vs. dichloro-
methane) with the same brominating agent 1,3-dibromo-5,5-
dimethylimidazolidine-2,4-dione (Fig.1). However, this bromi-
nation step turned out to be troublesome in practice. Bromi-
nation at position 5 would not stop at the single substitution

7084 Bi et al.
Asian J. Chem.
O
O
NH2
N
Br
Br
A, 7-bromo
DMF
N
N
NH2
N
Br
Br
5
O
6
N
NH2
N
NH2
NH2
N
N
7
Br
Br
Br
Br
Br
N
n-BuLi
THF
O
+
DCM
N
N
N
N
N
N
C, 5,7-dibromo
Fig. 1. Regioselective bromination of pyrrolo[2,1-f][1,2,4]triazin-4-amine
B, 5-bromo
clean. After aqueous workup, the resulting solution from this
n-butyl lithium titration contained almost exclusively the
desired 5-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine. (Fig. 1)
Synthesis of 7-bromopyrrolo[2,1-f][1,2,4]triazin-4-
amine: A stirred solution containing pyrrolo[2,1-f][1,2,4]-
triazin-4-amine (10 g, 75 mmol) in anhydrous N,N-dimethyl-
formamide (100 mL) was cooled to -20 °C and 1,3-dibromo-
5,5-dimethylhydantoin (10.7 g, 37.4 mmol) was added
portionwise over 45 min. The reaction was stirred for another
45 min and monitored by TLC. After completion, the reaction
mixture was washed with saturated aqueous solution of sodium
sulfite (150 mL) and water. It was then partitioned between
ethyl acetate (0.5 L) and 5 % aqueous solution of sodium
carbonate (500 mL). The organic layer was washed with
aqueous solution of sodium carbonate, dried and concentrated
to afford 13.3 g crude product. It was purified by silica gel
column chromatography (CH2Cl2:MeOH = 100:1) to give the
7-bromo compound as a white crystal (12.3 g, 77 %).
n-butyl lithium dropwise at -60 °C and the progress was
monitored by TLC and LC/MS to determine the end point.
The reaction mixture was quenched with water and extracted
with ethyl acetate. The combined organic phase was washed
with brine, dried and concentrated. The residue was purified
by silica gel column chromatography (petroleum ether/ethyl
acetate = 3:1) to give the 5-bromo compound as a white solid
(4 g).
ACKNOWLEDGEMENTS
This project is supported by Natural Science Research
Program for Higher Education, Key Program, Educational
Commission ofAnhui Province, China (Grant No. KJ2013A062)
and Training Programs of Innovation and Entrepreneurship
for College Students of Anhui Province, China (Grant No.
AH201410360170).
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