Access to 1,4-Dihydrobenzo[e][1,2,4]triazin-4-yl Derivatives

Article abstract of DOI:10.1021/acs.orglett.5b03528

A simple, one-pot method for the preparation of 1-aryl-3-phenyl-1,4-dihydrobenzo[e][1,2,4]triazin-4-yl radicals by addition of aryllithium to the readily available 3-phenylbenzo[e][1,2,4]triazine followed by aerial oxidation is described. The intermediate

Full text of DOI:10.1021/acs.orglett.5b03528

Letter
pubs.acs.org/OrgLett
Access to 1,4-Dihydrobenzo[e][1,2,4]triazin-4-yl Derivatives
Christos P. Constantinides,† Emilia Obijalska,‡ and Piotr Kaszynski*,‡,§
́
†Department of Chemistry, North Carolina State University, Raleigh, North Carolina 27695, United States
‡Faculty of Chemistry, University of Łod
́
z, 91403 Łodz, Poland
́
́
́
§Center of Molecular and Macromolecular Studies, Polish Academy of Sciences, 90363 Łod
́
z, Poland
́
S
* Supporting Information
ABSTRACT: A simple, one-pot method for the preparation of 1-aryl-3-phenyl-1,4-
dihydrobenzo[e][1,2,4]triazin-4-yl radicals by addition of aryllithium to the readily
available 3-phenylbenzo[e][1,2,4]triazine followed by aerial oxidation is described. The
intermediate anion is also trapped as an N-benzyloxycarbonyl derivative and purified
prior to deprotection and oxidation to the radical. The method was demonstrated for
nine (het)arenes, and the regioselectivity of nucleophilic addition to the benzo[e][1,2,4]triazine and trapping of the intermediate
anion with electrophiles was assessed computationally.
he electronic structure and the generally easily accessible
singly occupied molecular orbital (SOMO) make stable π-
delocalized radicals attractive structural elements for advanced
functional materials1−3 such as those for molecular elec-
tronics,4,5 energy storage,6 solar cells,7 controlled polymer-
ization,8,9 and biophysical10,11 applications. The Blatter
radical12 (1a, R = Ar = Ph, Figure 1) and its derivatives,
low reactivity and regioselectivity of N-acylation. For these
reasons, the overall yields are often low and the methods fail for
some substrates. Efficient methods have also been developed
for postcyclization ring substitution,21,22,25−27 functional group
transformations,25 and ring annulation,16,28,29 which signifi-
cantly expand the structural variety of the parent 1,4-
dihydrobenzo[e][1,2,4]trazin-4-yl. While the substituent at
the C(3) position is easily modified by the choice of
appropriate carboxylic acid RCOOH,23 the choice of
substituent at the N(1) is limited to the synthetically available
stable arylhydrazines. Since the N(1) position carries the
positive spin density, the ability to manipulate with the N(1)
substituent provides an important tool for controlling spin
delocalization and, as a consequence, electrochemical proper-
ties and intermolecular spin exchange interactions.
T
Here, we present a one-pot, simple method for preparation
of 1,4-dihydrobenzo[e][1,2,4]triazin-4-yl radicals 1 by adding
organometallic reagents to easily available benzo[e][1,2,4]-
triazine 2 followed by oxidation of the resulting anion 3
(Scheme 1). The method is potentially general, permits
introduction of a substituent at the N(1) position post-
cyclization step, and avoids the use of arylhydrazines.
Initially, we investigated the formation of the Blatter radical
(1a) by addition of PhLi to benzo[e][1,2,4]triazine 2 in THF
solutions (Scheme 1). We established that the complete
consumption of 2 requires a small excess of PhLi (1.1 equiv),
Figure 1. Comparison of two known (A and B) and new (C) methods
for construction of the 1,4-dihydrobenzo[e][1,2,4]triazin-4-yl skeleton.
Molecular fragments derived from arylhydrazine (red) and from
carboxylic acid (blue) are color coded.
although exceptionally stable with favorable electrochemical
properties,13 were relatively little explored in this context
largely due to insufficient accessibility. Only relatively
recently,14 Koutentis undertook the systematic investigation
of synthetic methods, which have opened up a broader access
to such derivatives. As a consequence, a number of magneto-
chemical and spectroscopic investigations have already
appeared in the literature.15−20
Scheme 1. Preparation of Radical 1 from
Benzo[e][1,2,4]triazine 2
During the past decade, the group of Koutentis has
developed and optimized two practical strategies to the 1,4-
dihydrobenzo[e][1,2,4]triazin-4-yl skeleton, all using carboxylic
acids RCOOH and hydrazines ArNHN2 as the key starting
materials (Figure 1). The synthesis is a multistep process
involving either amidrazones (oxidative 6-π electrocyclization,
method A)14,21−24 or hydrazides (reductive cyclocondensation,
method B)23,25,26 as intermediates and frequently suffers from
Received: December 17, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03528
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Letter
and the addition of PhLi either at −78 or at −5 °C (ice−salt
bath) gives essentially the same result (Table 1). The resulting
50%, Table 1). In the second modification, we generated PhLi
in situ from PhBr and t-BuLi at −78 °C.30 In this case, the yield
of the Blatter radical 1a was only 30%.
The new method of synthesizing 1,4-dihydrobenzo[e]-
[1,2,4]triazin-4-yl radicals was extended to other aryllithium
derivatives using air as the oxidant for the intermediate anion 3,
and the results are shown in Table 1. To ensure complete
consumption of 2, the aryllithium derivatives were generated
using 1.5 equiv of the appropriate bromoarene. Thus, reactions
of 2-naphthyllithium and 1-naphthyllithium with 2 gave the
corresponding radicals 1b and 1c in 54% and 63% isolated
yields, respectively. Larger aryllithium derivatives, 9-anthrace-
nyllithium and 1-pyrenyllithium, with 2 gave the corresponding
radicals 1d and 1e in lower yields, 26% and 32%, respectively,
which may be related to the sterically congested positions. The
“in situ” method was less effective in generation of radical 1b,
and in the case of 9-bromoanthracene no radical 1d was
isolated. Two examples of substituted phenyllithium derivative
were investigated. Thus, aryllithium reagents, generated from 1-
bromo-3-trifluoromethybenzene and 2-bromoanisole, gave the
expected radicals 1f and 1g, respectively, in good yields. The
methoxyphenyl derivative 1g showed low stability during
chromatographic separation and was isolated by direct
crystallization from the reaction mixture.
Table 1. Preparation of 1-Aryl-3-phenyl-1,4-
dihydrobenzo[e][1,2,4]triazin-4-yls 1 from
a
Benzo[e][1,2,4]triazine 2
Finally two pyridine derivatives, 1h and 1i, were prepared
from benzo[e][1,2,4]triazine 2. The former radical was
obtained in about 60% yield using the pre-prepared 2-
pyridyllithium or 35% yield following the “in situ” method.
This compares to about 45% of 1h obtained in three steps from
benzoic acid, 2-pyridylhydrazine, and 2-fluoronitrobenzene
according to method B (Figure 1).23 The synthesis of the 3-
pyridyl isomer 1i could not be accomplished using the
preprepared 3-pyridyllithium due to its low yield and low
stability.31 Derivative 1i was, however, prepared in 32−36%
yield using the “in situ” method.
The low stability of the 1-(2-methoxyphenyl) derivative 1g
observed during its isolation is presumably due to the low
oxidation potential of the 1,4-dihydrobenzo[e][1,2,4]triazin-1-
yl ring resulting from the presence of an electron-donating
substituent. In fact, the electron-donating ability of the N(1)
substituent, 2-MeOC6H4 > C6H5 > 2-NC5H4, correlates with
the observed stability of the radicals: 1h can be purified on SiO2
and alumina, 1a is unstable on SiO2 but alumina works well,
and 1g is unstable on either solid support.32 A comparison of
redox potentials for the three derivatives with electronically
different substituents shows that replacement of the Ph
a
According to Scheme 1. Typical procedures: (1) ArLi prepared from
0.65 mmol of the appropriate ArBr and 1.2 mmol of t-BuLi in THF (5
mL) was added to 0.5 mmol of 2 in THF (2 mL) at −5 °C; (2) t-BuLi
(1.43 mmol) was added to a solution of ArBr (0.65 mmol) and 2 (0.5
mmol) in THF (2 mL) at −78 °C. Yield after chromatography.
Yield after crystallization.
b)
c)
substituent at the N(1) position in 1a with 2-pyridyl in 1h
dark solution of anion 3 was exposed to air for several hours,
and the generated radical 1a was isolated by chromatography
(neutral or basic Al2O3) in 70−78% overall yield. Oxidation of
anion 3 took place within 30 min and with essentially the same
yield of 1a, when pure oxygen was used instead of air.
Alternatively, addition of aqueous solution of NaIO4 (2 equiv)
to the reaction mixture gives radical 1a in 68% yield after 30
min and small amounts of overoxidation product, presumably a
derivative of the benzo[e][1,2,4]triazin-7-one.14 Overall, the
new protocol (method C in Figure 1) gives the Blatter radical
1a in three steps from commercial materials and about 40%
yield, which compares to about 25−30% (method A)14 or 55%
(method B) of 1a obtained in three to four steps from the
appropriate acid, amine, and hydrazine.23
0/+1
increases the E1/2
by 0.06 V (or 0.14 V in ref 23), while
replacement with the 2-methoxyphenyl in 1g lowers the
oxidation potential by 0.04 V (Figure 2).33 The reduction
−1/0
potentials E1/2
also follow the same order (Figure 2) and
the lowest is measured for the 2-methoxyphenyl derivative 1g
−1/0
(E1/2
(E1/2
= −1.01 V), while the highest for the 2-pyridyl 1h
= −0.76 V).
−1/0
To avoid purification of oxidatively fragile radicals, such as
1g, we focused on an alternative route in which isolation from
the reaction mixture of the desired nucleophilic adduct to 2
takes place before the radical generation. Thus, treatment of
anion 3a with BnBr gave the known34 4-benzyl derivative 4a-4
as the sole product isolated by chromatography in 43% yield
(Scheme 2). Unfortunately, 4a-4 showed limited stability on
solid support, and attempts at reductive removal of the benzyl
group using standard conditions (H2 up to 55 psi, 10% Pd/C,
Two modifications of the new method were briefly
investigated. Thus, replacement of PhLi with PhMgCl in
THF and using air as the oxidant gave 1a in lower yields (ca.
B
DOI: 10.1021/acs.orglett.5b03528
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Letter
treatment of 5a-2 with 3 equiv of MeLi in THF and exposure of
the solution to air. Radical 1a was formed as the sole product
(by TLC) and isolated in 51% yield after recrystallization.
The developed two-step protocol was subsequently applied
for the preparation of 1g. Thus, the CBz-protected derivatives
5g-2 and 5g-4 were obtained in 7% and 42% yields,35
respectively, by column chromatography. Subsequent catalytic
deprotection of one of the isomers, 5g-2, and controlled aerial
oxidation gave 1g in 82% yield after recrystallization.
From a mechanistic point of view, the reaction involves the
addition of the aryl anion to the LUMO of the benzo[e]-
[1,2,4]triazine 2 and the formation of a delocalized amidinyl-
type anion 3. Computational results suggest similar LUMO
density on the nitrogen atoms (Figure 3), although condensed
Figure 2. Cyclic voltammograms for 1-phenyl (1a, black), 1-(2-
methoxyphenyl) (1g, red), and 1-(2-pyridyl) (1h, blue) 1,4-
dihydrobenzo[e][1,2,4]triazin-4-yls (0.5 mM) in CH2Cl2 [n-Bu4N]+
[PF6]− (50 mM), ca. 20 °C, 50 mV s−1, glassy carbon electrode.
Scheme 2. Preparation of Radical 1 from
Benzo[e][1,2,4]triazine 2 via the Protection/Deprotection
Route
Figure 3. M062x/6-31+G(2d,p)-derived LUMO contour for 3-
phenylbenzo[e][1,2,4]triazine (2, E = −1.85 eV, left) and HOMO
for anion 3 (E = −4.59 eV, right) in THF dielectric medium.
electronic Fukui functions36,37 clearly indicate the highest
+
electrophilicity (either total f+ or pi fπ ) of the N(1) position in
the triazinyl ring (Table 3).33 This electronic preference for the
rt) failed. Therefore, we focused on N-acyl derivatives,
expecting better behavior. Thus, treatment of the anion 3a
with BnOCOCl (CBzCl) gave two isomers 5a-2 and 5a-4 in
about 30% yield each (Table 2),35 which were separated by
Table 3. Fukui Electrophilicity Indices for Selected Atoms in
3-Phenylbenzo[e][1,2,4]triazine (2) and Nucleophilicity
Indices for Selected Atoms in Anion 3
2
3
Table 2. Preparation of 1-Aryl-3-phenyl-1,4-
dihydrobenzo[e][1,2,4]triazin-4-yls 1 through the
Benzyloxycarbonyl (CBz) Protection/Deprotection Route
+
−
atom
f+
fπ
f−
fπ
a
N(1)
N(2)
C(3)
N(4)
0.22
0.11
0.04
0.17
0.24
0.11
0.05
0.18
0.14
0.19
0.153
0.145
regioselectivity of the nucleophilic attack is also favored
thermodynamically. DFT calculations in THF dielectric
medium show that the addition of the Ph− to the N(1)
position is preferred by ΔH = 8.9 kcal mol−1 over addition to
the N(4) position or ΔH = 11.3 kcal mol−1 over the attack on
the N(2) atom. Similar analysis for anion 3a using the more
a
According to Scheme 2. Typical procedures: (1) 2.2 mmol of ArLi
was added to 2 mmol of 2 in THF (6 mL) at −5 °C followed by
CBzCl. (2) CBz-protected derivative was hydrogenated (10% Pd/C, 5
mol %) in an EtOH/THF solution and oxidized with air. (3) 3 equiv
of MeLi was added to 5-2 in THF at −5 °C, stirred, and oxidized with
−
appropriate Fukui π functions (fπ in Table 3) shows a rather
weak preference of the electrophilic attack on the N(2) atom,
which is reflected in the formation of a mixture of the two
isomers (Table 2).
b
c
air. From the N(2) isomer. From the N(4) isomer.
In summary, the presented method permits the introduction
of a (het)aryl substituent at the N(1) position at the post
cyclization step and avoids using arylhydrazines; it shifts the
dependence of the synthesis from the availability of the
hydrazines to the accessibility of [1,2,4]triazines38 and the
efficiency of the generation of aryllithium reagents. The new
method appears to be general, although the regioselectivity of
anion addition may depend on the structure of the [1,2,4]-
triazine; this, in turn, could be assessed computationally using
the Fukui functions. Overall, the new procedure for making 1,4-
SiO2 chromatography from small amounts of radical 1a (14%
yield). Removal of the CBz protecting group was accomplished
quantitatively under standard conditions (H2 1 atm, 10% Pd/C
in EtOH/THF; Table 2); interestingly, the reaction was faster
for the 2-isomer (5a-2).
After the catalyst was filtered, the resulting solution was
exposed to air, and the resulting radical 1a, formed as the only
product by TLC, was isolated quantitatively by evaporation of
the solution. The CBz protective group was also removed by
C
DOI: 10.1021/acs.orglett.5b03528
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Letter
(15) Constantinides, C. P.; Berezin, A. A.; Manoli, M.; Leitus, G. M.;
Bendikov, M.; Rawson, J. M.; Koutentis, P. A. New J. Chem. 2014, 38,
949−954.
(16) Constantinides, C. P.; Berezin, A. A.; Manoli, M.; Leitus, G. M.;
Zissimou, G.; Bendikov, M.; Rawson, J. M.; Koutentis, P. A. Chem. -
Eur. J. 2014, 20, 5388−5396.
(17) Constantinides, C. P.; Koutentis, P. A.; Rawson, J. M. Chem. -
Eur. J. 2012, 18, 7109−7116.
dihydrobenzo[e][1,2,4]triazin-4-yl complements the existing
methods and significantly increases the design flexibility and
structural variety of the 1,4-dihydro[1,2,4]triazin-4-yl radicals in
general, making them available for further transformations and
incorporation into more complex architectures.
ASSOCIATED CONTENT
■
(18) Morgan, I. S.; Mansikkamaeki, A.; Zissimou, G. A.; Koutentis, P.
A.; Rouzieres, M.; Clerac, R.; Tuononen, H. M. Chem. - Eur. J. 2015,
21, 15843−15853.
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b03528.
(19) Zheng, Y.; Miao, M.-s.; Kemei, M. C.; Seshadri, R.; Wudl, F. Isr.
J. Chem. 2014, 54, 774−778.
(20) Zheng, Y.; Miao, M.-s.; Dantelle, G.; Eisenmenger, N. D.; Wu,
G.; Yavuz, I.; Chabinyc, M. L.; Houk, K. N.; Wudl, F. Adv. Mater.
2015, 27, 1718−1723.
Preparative and analytical details, EPR and NMR spectra,
electrochemical data, and computational results (PDF)
(21) Constantinides, C. P.; Koutentis, P. A.; Loizou, G. Org. Biomol.
Chem. 2011, 9, 3122−3125.
AUTHOR INFORMATION
■
(22) Constantinides, C. P.; Koutentis, P. A.; Rawson, J. M. Chem. -
Eur. J. 2012, 18, 15433−15438.
Corresponding Author
(23) Berezin, A. A.; Zissimou, G.; Constantinides, C. P.; Beldjoudi,
Y.; Rawson, J. M.; Koutentis, P. A. J. Org. Chem. 2014, 79, 314−327.
(24) Miura, Y.; Yoshioka, N. Chem. Phys. Lett. 2015, 626, 11−14.
*E-mail: piotrk@cbmm.lodz.pl.
Notes
The authors declare no competing financial interest.
́
(25) Bodzioch, A.; Zheng, M.; Kaszynski, P.; Utecht, G. J. Org. Chem.
2014, 79, 7294−7310.
(26) Takahashi, Y.; Miura, Y.; Yoshioka, N. Chem. Lett. 2014, 43,
1236−1238.
ACKNOWLEDGMENTS
■
This work was supported by the National Science Foundation
(CHE-1214104) and the National Science Center (2014/13/
B/ST5/04525) grants. We are grateful to Prof. David A. Shultz
and Prof. Alex Smirnov for their hospitality and Prof. Panayiotis
Koutentis for helpful discussions.
(27) Constantinides, C. P.; Carter, E.; Murphy, D. M.; Manoli, M.;
Leitus, G. M.; Bendikov, M.; Rawson, J. M.; Koutentis, P. A. Chem.
Commun. 2013, 49, 8662−8664.
(28) Berezin, A. A.; Constantinides, C. P.; Drouza, C.; Manoli, M.;
Koutentis, P. A. Org. Lett. 2012, 14, 5586−5589.
(29) Berezin, A. A.; Constantinides, C. P.; Mirallai, S. I.; Manoli, M.;
Cao, L. L.; Rawson, J. M.; Koutentis, P. A. Org. Biomol. Chem. 2013,
11, 6780−6795.
DEDICATION
■
Dedicated to Professor Grzegorz Mloston
his 65th birthday.
́
on the occasion of
(30) The use of t-BuLi instead of n-BuLi avoids the formation of n-
BuBr, which would N-butylate the intermediate anion.
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water increases the stability of benzo[e][1,2,4]triazinyls.
(33) For details, see the Supporting Information.
(34) Neugebauer, F. A.; Umminger, I. Chem. Ber. 1980, 113, 1205−
1225.
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