Cationic triazinium heterocycles by intramolecular NN bond formation

Article abstract of DOI:10.1016/j.tetlet.2014.03.009

Tricyclic heterocycles with a cationic triazinium core were prepared by an intramolecular NN bond forming reaction of an azine oxime precursor. The azine oxime substrates were prepared by S_NAr N-arylation of 2-formylpyrroles followed by oxime formation of the formyl moiety. The synthesis was demonstrated with five different azines and several functional groups.

Full text of DOI:10.1016/j.tetlet.2014.03.009

Tetrahedron Letters 55 (2014) 2492–2494
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Cationic triazinium heterocycles by intramolecular NAN bond
formation
⇑
Jonathan T. Reeves , Zhengxu S. Han, Navneet Goyal , Heewon Lee, Carl A. Busacca, Chris H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals, Inc., 900 Ridgebury Road, PO Box 368, Ridgefield, CT 06877-0368, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Tricyclic heterocycles with a cationic triazinium core were prepared by an intramolecular NAN bond
forming reaction of an azine oxime precursor. The azine oxime substrates were prepared by SNAr N-ary-
lation of 2-formylpyrroles followed by oxime formation of the formyl moiety. The synthesis was demon-
strated with five different azines and several functional groups.
Received 20 February 2014
Revised 27 February 2014
Accepted 3 March 2014
Available online 11 March 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Heterocycles
Cationic
Triazinium
Intramolecular
Heterocycles are a cornerstone of the pharmaceutical industry.
Approximately 80% of currently marketed drugs contain at least
one heterocyclic ring.1 The development of structurally diverse
new heterocycles can facilitate fine-tuning of structure–activity
relationships. Furthermore, compounds with high water solubility
can be advantageous for increasing bioavailability.2 We describe
herein a simple synthesis of new cationic tricyclic heterocycles
based on an intramolecular NAN bond forming reaction of an azine
oxime substrate.
The concept for the NAN bond forming reaction was based on a
few important precedents (Scheme 1). In 1965, Woodward and
Kemp synthesized benzisoxazole via OAN bond formation by cycli-
zation of a 2-hydroxy benzaldoxime O-sulfate.3 In 1984, Suwinski
and Walczak demonstrated the synthesis of pyrazolo[1,5a]pyri-
reaction in the presence of K2CO3 to afford the adduct 3 in 63%
yield.6 Subsequent treatment with hydroxylamine hydrochloride
gave oxime 4 in 82% yield. Treating a CH2Cl2 solution of 4 and
Et3N (1.2 equiv) with TsCl (1.05 equiv) resulted in consumption
Woodward's benzisoxazole synthesis (1965):
H
H
OSO3
H3N-OSO3
N
O
NaHCO3
N
O
OH
OH
Suwinski's pyrazolo[1,5a]pyridine synthesis (1984):
R
OSO3
R'
R
N
N
N
N
NaHCO3
R'
dines by NAN bond formation from
a-2-pyridyl ketoxime O-sul-
fate substrates.4 Recently, Stambuli and co-workers reported the
synthesis of indazoles via NAN bond formation from 2-amino ary-
loximes via O-mesylation.5 We were interested to see if a similar
displacement would occur in a 1-(pyridin-2-yl)-1H-pyrrole-2-
carbaldehyde derived oxime. In this case, the pyridyl nitrogen
would serve as the nucleophile, and the resultant product would
be a cationic heterocycle.
Stambuli's indazole synthesis (2008):
R'
R'
OH
N
MsCl, Et3N
N
N
NHR
R
Triazinium salt formation (this work):
N
N
N
RSO2X
base
The requisite substrate 4 was prepared in 2 steps from commer-
cially available materials (Scheme 2). Thus, N-arylation of
2-formylpyrrole 1 with 2-fluoropyridine 2 was effected by an SNAr
N
N
N
OH
OSO2R
N
N
N
X
• new heterocyclic systems
• azine may be pyridine, pyridazine, pyrazine, pyrimidine, triazine
• high water solubility
⇑
Corresponding author. Tel.: +1 203 778 7703.
E-mail address: jonathan.reeves@boehringer-ingelheim.com (J.T. Reeves).
Present address: Department of Chemistry, Xavier University of Louisiana,
Drexel Drive, Box 22, New Orleans, LA 70125, USA.
1
Scheme 1. Previous OAN and NAN bond forming heterocycle syntheses and the
present triazinium formation.
http://dx.doi.org/10.1016/j.tetlet.2014.03.009
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

J. T. Reeves et al. / Tetrahedron Letters 55 (2014) 2492–2494
2493
Table 1
Scope of triazinium heterocycle formationa
CHO
N
N
F
NH2OH•HCl
N
2
Oximeb
Product
Yieldc (%)
CHO
Entry
N
H
1
N
K2CO3, DMF
100 °C
NaHCO3, MeOH
N
OH
N
3
4
82%
N
63%
N
N
N
1
64
OH
N
N
OTs
OTs
5
• product crystallizes out as mixture
of Cl and OTs salts
4
Et3N, TsCl
CH2Cl2
N
N
4
N
N
N
X
N
N
N
N
• Et3N•HCl and Et3N•TsOH also crystallize out
5
2
3
4
61
51
42
N
N
OH
N
N
N
N
N
N
6
7
Bu3N, Ts2O
CH2Cl2
• with Ts2O, only tosylate counterion possible
• product crystallizes out in high purity
• Bu3N•TsOH remains in solution
4
N
N
N
OTs
OH
OH
N
N
64%
OTs
OTs
5
8
9
Scheme 2. Substrate preparation and optimization of NAN bond formation.
N
N
N
N
of starting material within 1 h and concomitant formation of a
crystalline precipitate. Filtration of this precipitate and 1H NMR
and LC–MS analysis showed it to be the desired product heterocy-
cle 5, but as a mixture of both chloride and tosylate salts. In addi-
tion, the solid was contaminated with the Et3N salts of HCl and
TsOH. While the desired NAN bond formation was achieved, the
complication of two possible counteranions and co-crystallization
of Et3N salts prompted investigation of alternative reaction condi-
tions. To eliminate the formation of product with different count-
eranions, TsCl was replaced with Ts2O. To avoid co-crystallization
of Et3N salts with the product, Et3N was replaced with Bu3N. In this
case, the Bu3NÁTsOH formed in the reaction remained in solution.
Consequently, the product 5 crystallized out as its tosylate salt in
high purity and 64% isolated yield.
The generality of the reaction was explored with respect to var-
iation of the azine moiety and inclusion of functional groups
(Table 1).7 The cyclization occurred with not only 2-pyridyl
substrates (entries 1, 6–8), but also with 2-pyrimidyl (entry 2),
2-pyridazyl (entries 3 and 9), 3-pyrazinyl (entry 4), and 4,6-dime-
thoxy-2-triazinyl (entry 5) substrates. Functionalization of the
azine moiety was also possible with cyano (entry 6), trifluoro-
methyl (entry 7), iodo (entry 8), and methyl ester (entry 9) func-
tional groups. In all cases, the product crystallized directly out of
the reaction mixture, and simple filtration provided material of
high purity.
N
N
N
N
10
11
N
N
N
N
N
N
5
54
OH
N
N
N
OTs
MeO
NC
N
OMe
MeO
NC
OMe
13
12
N
N
N
N
6
7
64
58
OH
OH
N
N
OTs
14
15
N
N
N
N
N
N
OTs
F3C
N
16
F3C
N
17
N
N
OH
8
9
48
71
N
N
OTs
18
19
I
I
N
N
N
N
OH
N
N
The major byproduct in the cyclization reactions was the nitrile
23 derived from competitive oxime dehydration. Running the reac-
tion at lower temperatures did not suppress the formation of the
nitrile. This neutral impurity was soluble in the reaction solution,
however, and therefore was removed from the product in this
way (Scheme 3).
OTs
21
N
N
20
CO2Me
CO2Me
a
Reaction conditions: oxime (1.0 equiv), Ts2O (1.05 equiv), Bu3N (1.2 equiv),
CH2Cl2, 23 °C.
Oxime substrates were prepared by SNAr reaction of 1 with the appropriate
heteroaryl fluoride or chloride, followed by oxime formation as in Scheme 2. See
Supporting Information for procedures and characterization data.
b
The triazinium salts were readily soluble in water. The 1H and
13C NMR spectra of all triazinium salts shown in Table 1 were re-
corded in D2O.
c
Isolated yield.
In summary, a series of new cationic triazinium heterocycles
has been prepared. The key reaction was an intramolecular NAN
bond formation from an azine oxime substrate. By proper choice
of base and sulfonating reagent, the products directly crystallized
out of the reaction mixture in high purity. The reaction was dem-
onstrated on azime oxime substrates derived from pyridine, pyrid-
azine, pyrazine, pyrimidine, and triazine. Several different
functional groups were tolerated.
H
N
N
Bu3N
N
N
OTs
N
N
R
R
22
23
Scheme 3. Nitrile impurity.
Supplementary data
Supplementary data (experimental procedures and character-
ization data (1H and 13C NMR and HRMS)) associated with this arti-
cle can be found, in the online version, at http://dx.doi.org/
10.1016/j.tetlet.2014.03.009.

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J. T. Reeves et al. / Tetrahedron Letters 55 (2014) 2492–2494
6. Ikegami, H.; Jachmann, M.; Nokura, Y.; Iwata, C. WO 2007043677, 2007.
References and notes
7. General procedure for triazinium salt formation: A flask was charged with oxime 4
(1.00 g, 5.34 mmol), CH2Cl2 (10 mL), and Bu3N (1.53 mL, 6.41 mmol). To the
resultant solution at 23 °C was added in portions Ts2O (1.83 g, 5.61 mmol). The
mixture was stirred at 23 °C for 2 h, during which time a solid crystallized out.
The solid was filtered and washed with CH2Cl2 and hexanes, and then dried
under vacuum at 23 °C to give the product 5 (1.17 g, 64%) as a yellow solid. See
the Supporting Information for NMR and HRMS data for all compounds.
1. Bioactive Heterocyclic Compound Classes: Pharmaceuticals; Lamberth, C., Dinges,
J., Eds.; Wiley-Interscience: Weinheim, Germany, 2012.
2. Handbook of Solubility Data for Pharmaceuticals; Jouyban, A., Ed.; CRC Press: Boca
Raton, 2010.
3. Kemp, D. S.; Woodward, R. B. Tetrahedron 1965, 21, 3019–3035.
4. Suwinski, J.; Walczak, K. Polish J. Chem. 1984, 58, 1077–1083.
5. Counceller, C. M.; Eichman, C. C.; Wray, B. C.; Stambuli, J. P. Org. Lett. 2008, 10,
1021–1023.