Functional group transformations in derivatives of 1,4-dihydrobenzo[1,2,4] triazinyl radical

Article abstract of DOI:10.1021/jo500898e

Transformations of functional groups OCOPh, OCH₂Ph, I, NO ₂, and CO₂Me in Blatter's radical derivatives 1-5 were investigated in order to develop synthetic tools for incorporation of the benzo[1,2,4]triazinyl system into c

Full text of DOI:10.1021/jo500898e

Article
pubs.acs.org/joc
Functional Group Transformations in Derivatives of 1,4-
Dihydrobenzo[1,2,4]triazinyl Radical
Agnieszka Bodzioch,†,§ Minyan Zheng,†,∥ Piotr Kaszynski,*,†,‡ and Greta Utecht†,⊥
́
†Organic Materials Research Group Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37235, United States
‡Faculty of Chemistry, University of Łod
́
z, Tamka 12, 91403 Łodz, Poland
́
́
́
S
* Supporting Information
ABSTRACT: Transformations of functional groups OCOPh,
OCH2Ph, I, NO2, and CO2Me in Blatter’s radical derivatives 1−5
were investigated in order to develop synthetic tools for incorporation
of the benzo[1,2,4]triazinyl system into complex molecular
architectures. Thus, basic hydrolysis of OCOPh or Pd-catalyzed
debenzylation of OCH2Ph gave phenol functionality, which was
acylated and alkylated. Pd-catalyzed Suzuki, Negishi, Sonogashira, and
Heck C−C cross-coupling reactions of iodo derivatives 1c, 1d, and 2d
were also successful and efficient. Reduction of NO2 in 1e led to
aniline derivative 1t, which was reductively alkylated with hexanal and
coupled to L-proline. Selected benzo[1,2,4]triazinyl radicals were
characterized by EPR and electronic absorption spectroscopy, and the
results were analyzed in tandem with DFT computational methods. Lastly, the mechanism for formation of the 1,4-
dihydrobenzo[1,2,4]triazine ring was investigated using the B3LYP/6-31G(2d,p) method.
little attention, and only a handful of derivatives have been
reported in the literature. This situation changed several years
ago when Koutentis began systematic development of synthetic
access to this class of radicals. Since then, Koutentis optimized
the classic synthetic routes to the benzo[1,2,4]triazinyl
skeleton,19 demonstrated Pd-catalyzed C−C cross-coupling
reactions of the 7-iodo derivatives,20−23 fused 5-membered
heterocyclic rings at the 6,7 positions,17,24 and applied
benzo[1,2,4]triazinyls toward the synthesis of other hetero-
cycles.25 More recently, he has developed another synthetic
pathway to the benzo[1,2,4]triazinyl, potentially widening the
scope of substitution patterns on the heterocycle.18 While the
structural variety of benzo[1,2,4]triazinyl derivatives has
increased dramatically, there still remains a need for broader
investigation of functionalized derivatives of the radical and
functional group transformations in the presence of the
unpaired electron. Such functionalized derivatives are required
for the development of advanced materials and are of interest in
our research program aimed at investigation of organic
semiconductors.
INTRODUCTION
■
Stable π-delocalized radicals are becoming important structural
elements of materials for solar cells,1 energy storage,2
electronic,3,4 and biological5−8 applications.9,10 Their incorpo-
ration into more complex molecular architectures and tuning of
properties can be accomplished through functional group
transformations. In this context, we recently demonstrated a
number of chemical transformations on derivatives of the 1,3,5-
triphenyl-6-oxoverdazyl radical (I, Figure 1).11 However, the
benzo[1,2,4]triazinyl radical appears even more interesting in
the context of developing new materials.12,13
Figure 1. Structure and numbering scheme for 1,3,5-triphenyl-6-
oxoverdazyl (I) and 1,3-diphenyl-1,4-dihydrobenzo[1,2,4]triazinyl
(Blatter’s radical, II).
Herein, we report the investigation of functionalized
derivatives of Blatter’s radical II containing OCOPh (OBz),
OCH2Ph (OBn), NO2, CO2Me, and I groups substituted on
the phenyl rings (Chart 1). We focused on 7-(trifluoromethyl)-
benzo[1,2,4]triazinyl radicals 1 and also prepared 7-iodo
derivatives 2a and 2d26 and report an attempted synthesis of
7-fluoro analogue 3d. We additionally describe two 7-
1,3-Diphenylbenzo[1,2,4]triazinyl (II), also known as
Blatter’s radical,14 is prototypical of a family of exceptionally
stable organic radicals, which broadly absorb in the visible
range15,16 and exhibit reversible redox potentials with a
relatively narrow electrochemical window.17,18 Due to its
inefficient and cumbersome synthesis, the radical has received
Received: April 22, 2014
Published: July 28, 2014
© 2014 American Chemical Society
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Chart 1
a
Scheme 1. Synthesis of Radicals 1−4
a
Reagents and conditions: (i) (COCl)2, DMF (cat.), CH2Cl2, rt; (ii) 4-ZC6H4NH2, CH2Cl2, Et3N, rt; (iii) SOCl2 (excess), reflux; (iv) 4-
XC6H4NHNH2 (19: a, X = OBz; b, X = OBn; c, X = I; e, X = H), Et3N, CH2Cl2/MeCN, rt; (v) air, DBU, Pd/C, CH2Cl2, rt.
unsubstituted derivatives 4a and 4b and preparation of
functionalized 6-trifluoromethyl derivatives 5f and 5h. We
investigated transformations of these functionalities to esters,
ethers, amides, and alkylamines, and demonstrate Pd-catalyzed
C−C coupling reactions. We also characterize selected radicals
by electrochemical and spectroscopic methods and briefly
investigate the effect of the substituent on the phenyl rings on
electronic absorption and EPR spectra. The experimental data
are augmented with DFT computational results, which also
include mechanistic studies of the formation of the 1,3-
diphenyl-1,4-dihydrobenzo[1,2,4]triazine.
low hydrolytic stability of the ester under the reaction
conditions.
Radicals 1 and 2 were conveniently isolated by column
chromatography on SiO2. In contrast, radicals 4 partially
decomposed under the same conditions, and pure compounds
were obtained using SiO2 passivated with Et3N.
The requisite amidrazones 6−9 were obtained from 4-
substituted benzoic acids 10, which were converted to amides
11−14 and subsequently to imidoyl chlories 15−18 using
SOCl2 (Scheme 1). Reactions of chlorides 15−18 with an
appropriate arylhydrazine 1911 gave the desired amidrazones
6−9, respectively, isolated in 29−85% yield after chromatog-
raphy. In general, reactions with 4-iodophenylhydrazine (19c)
gave higher yields of amidrazones, while the lowest yield of 29%
was obtained for 6a containing the benzoyloxy group.
Reactions of benzoyloxy imidoyl chloride 15a with
hydrazines 19b (X = OBn) and 19g (X = CO2H) gave
complex mixtures of products from which no amidrazones 6f
and 6g could be isolated. Amidrazones 6a, 6b, and 7a were
obtained conveniently by reacting appropriate imidoyl chloride
with hydrazine hydrochloride 19a·HCl (X = OBz) in the
presence of an additional 1 equiv of Et3N.11
RESULTS
■
Synthesis of Radicals 1-5. Benzo[1,2,4]triazinyls 1−4
with a substituent at the C(7) position were prepared following
the classical Neugebauer route,15 which involves oxidative
cyclization of the corresponding amidrazones 6−9 (Scheme 1).
The aerial oxidation of 6, 7, and 9 in the presence of catalytic
amounts of Pd/C and DBU, according to a general method,19
gave the expected radicals 1, 2,26 and 4, respectively, in yields
ranging from 32% to 89%. No 7-fluorobenzo[1,2,4]triazinyl 3d
was obtained from fluoroamidrazone 8d under these
conditions, and only a complex mixture of products was
observed by TLC. The low yields obtained for radicals
containing the benzoyloxy group are presumably due to the
Amidrazones 6−9 had limited stability to purification on
SiO2 and storage, which hampered complete characterization
efforts. For instance, within several hours, amidrazone 6c
underwent partial oxidation in the solid state giving a number
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a
Scheme 2. Synthesis of Radicals 5
a
Reagents and conditions: (i) C6H5CHO, EtOH, reflux, 2h for 19c or C6H5CHO, EtOH, 0 °C → rt, overnight for 19b; (ii) 4-fluoro-3-
nitro(trifluoromethyl)benzene (21), K2CO3, DMSO, rt, 16h; (iii) NH2OH·•HCl, pyridine, 80 °C, 20 h; (iv) ArCOCl from 10d or 10h, Et3N,
CH2Cl2, 0 °C → rt, 20 h; (v) Sn, AcOH, rt 30 min → reflux 10 min; (vi) air, base or NaIO4, rt.
of products including radical 1c, as demonstrated by TLC
analysis. Most amidrazones underwent slow decomposition
during recrystallization; however, no radicals were detected by
TLC.
radical 5h in nearly quantitative yield. Although leuco 25h
appeared stable in air, it undergoes quick aerial oxidation to 5h
upon treatment with 1 equiv of KOH, in analogy to the first
reported synthesis of Blatter’s radical II.14
The preparation of the benzyloxy hydrazide 24f was
problematic. Attempts at acylation of hydrazine 23b with acid
chloride derived from 4-benzyloxybenozic acid (10b) using
several different reaction conditions (CH2Cl2 and Et3N, neat
pyridine cold or warm) resulted in the appearance of a new,
unidentified major product, similar to that observed during the
preparation of 24h. Unfortunately, the expected hydrazide 24f
and the unknown side product could not be separated by
chromatography, and this approach was abandoned. Another
preparation of hydrazide 24f was attempted starting with
bisbenzyloxy hydrazide 26. Unfortunately, arylation18 of 26
with 21 in sec-butanol containing K2CO3 gave a complex
mixture of products from which 24f could not be isolated.
The overall yields for benzo[1,2,4]triazinyls 1, 2, and 4 range
from 12% to 25% based on acid 10. Exceptionally high overall
yields of about 53% were obtained for iodo radicals 1c and 1d.
Benzo[1,2,4]triazinyls 5f and 5h, with the CF3 substituent at
the C(6) position, were obtained according to a new, recently
described procedure18 (Scheme 2). Thus, arylation of
hydrazones 20b and 20c with 1-fluoro-2-nitro-4-
(trifluoromethyl)benzene (21) in DMSO containing K2CO3
gave the corresponding products 22b and 22c in 99% and 60%
yield, respectively. The double activation of the fluorine atom in
21 by the NO2 and CF3 substituents for nucleophilic aromatic
substitution permitted the arylation to be conducted at ambient
temperature rather than at 100 °C.18 Treatment of hydrazones
22 with an excess NH2OH·HCl in hot pyridine,18 removed the
benzal group and hydrazines 23b and 23c was obtained in 64%
and 77% yield, respectively. In both cases, the reaction was
incomplete and unreacted hydrazones 22 could be separated
from the crude product. A subsequent reaction of 23c with acid
chloride derived from monomethyl terephthalate (10h) in
CH2Cl2 containing Et3N at −5 °C gave the desired hydrazide
24h in 71% yield. The reaction was incomplete, as evident from
the remaining unreacted hydrazine, even when using an excess
acid chloride. No reaction occurred with the acid anhydride
derived from 10h. At ambient temperatures and above, the
formation of an unidentified side product was observed by
TLC.
Functional Group Transformations in Benzo[1,2,4]-
triazinyl Derivatives. Deprotection of the phenolic function-
ality and formation of bisphenols 1i and 4i was performed by
basic hydrolysis of bis-benzoates 1a and 4a, respectively,
according to conditions used for the 6-oxoverdazyl analogue.11
Thus, treatment of 1a and 4a with stoichiometric amounts of
KOH in CH2Cl2/MeOH at ambient temperature gave the
desired diphenols 1i and 4i in 97% and 58% yield, respectively
(Schemes 3 and 4). Similarly, monophenol 1j was obtained in
90% yield by hydrolysis of benzoate 1b (Scheme 3). Both
mono- and bisphenol radicals can be stored in the solid form at
ambient temperature; however, they undergo slow decom-
position in solutions, as evidenced by the appearance of a blue
spot on TLC.
Finally, hydrazide 24h was converted to the corresponding
radical 5h by reduction with excess tin powder in hot acetic
acid followed by oxidation. The original method18 was
modified, and during workup the reaction mixture was diluted
with CH2Cl2 and washed with aq NaHCO3. Chromatography
on the resulting product permitted isolation of the leuco 25h in
49% yield, which was oxidized with NaIO4 to the expected
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a
Scheme 3. Transformations of the OH Groups in 1
a
Reagents and conditions: (i) 0.1 N KOH in MeOH, CH2Cl2/MeOH, 1 h, rt; (ii) C10H15-1-COCl, Et3N, CH2Cl2, 1 h, rt; (iii) (S)-(+)-citronellyl
bromide, K2CO3, MeCN, 4 h, reflux.
a
91% yield (Scheme 3). Phenol 1j was alkylated with (S)-
(+)-citronellyl bromide under standard conditions (MeCN,
K2CO3), and the resulting ether 1m was isolated in 55% yield.
Similar alkylation of 4i with 1-iodoheptane gave diether 4n in
56% yield (Scheme 4). Interestingly, in the former alkylation
reaction with citronellyl bromide, TLC analysis showed
evidence of a major polar side product appearing as a blue
spot on TLC. No such side product was observed in the
alkylation of 4i with heptyl iodide.
Scheme 4. Transformations of the OH Groups in 4
Iodine containing benzo[1,2,4]triazinyl derivatives 1c, 1d,
and 2d, were tested as substrates for Pd-catalyzed C−C
coupling reactions. Thus, radical 1c reacted smoothly with 4-
methoxyphenylboronic acid under Suzuki conditions20 (reflux-
ing toluene/water) and the coupling product 1o was isolated in
83% yield (Scheme 5). A similar coupling reaction with
potassium 4-methoxyphenyltrifluoroborate27 under Molander
conditions,28 afforded 1o in 51% yield accompanied by small
amounts of deiodinated product 1p (11% yield). The phenol
functionality in 1o was then deprotected under reductive
conditions (H2, 5% Pd/C) giving phenol 1q in 90% yield
(Scheme 5).
a
Reagents and conditions: (i) H2, 10% Pd/C, THF/EtOH, 12 h, rt;
(ii) 0.1 N KOH in MeOH, CH2Cl2/MeOH, 1 h, rt; (iii) n-C7H15I,
K2CO3, MeCN, 6 h, reflux.
The benzyl group in radical 4b was removed under reductive
conditions (H2 and 10% Pd/C) giving monophenol 4k, which
opens possibilities for differentiation of the two hydroxyl
groups (Scheme 4). The second hydroxy group in 4k was
deprotected under basic hydrolytic conditions giving another
route to bisphenol 4i in 87% yield. All phenols in series 1 and 4
were purified by column chromatography (SiO2).
With access to phenolic derivatives of Blatter’s radical, their
reactivity was investigated under a variety conditions. Thus, a
reaction of bisphenol 1i with adamantane-1-carbonyl chloride
in the presence of Et3N provided corresponding diester 1l in
The synthetic utility of the two iodine atoms in radical 1d
was demonstrated using modified Sonogashira29 and Negishi30
cross-coupling reactions at ambient temperature (Scheme 6).
Thus, a reaction of 1d with phenylacetylene cleanly afforded 1r
in 80% yield. However, the Negishi reaction of 1d with 4-
(methoxyphenyl)zinc reagent was more complicated and
resulted in a mixture of the expected 1s and its leuco form.
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a
Scheme 5. Transformations of I and OH groups in 1c
a
Reagents and conditions: (i) β = 2, Pd(OAc)2, K2CO3, toluene/H2O, 24 h reflux; (ii) β = BF3K, PdCl2(PPh3)2, Cs2CO3, toluene/H2O, 24 h, reflux;
(iii) H2, 10% Pd/C, THF/EtOH, 12 h, rt.
a
Scheme 6. Transformations of 1d
a
Reagents and conditions: (i) phenylacetylene, PdCl2(PPh3)2, CuI, Et3N, DMF, 12 h, rt; (ii) (4-methoxyphenyl)zinc bromide, PEPPSi-IPr, THF, 4
h, rt.
a
Scheme 7. Transformation of 2d
a
Reagents and conditions: (i) methyl acrylate, Et3N, Pd(OAc)2, (o-MeOC6H4)3P, DMF, 5 h, 100 °C.
Radical 1s was isolated in 46% yield after a solution of the
mixture of products was allowed to oxidize in air.
catalytic reduction of 1e with H2 (50 psi) in the presence of
Pd/C was completed in 2 h affording the leuco form, which
after exposure to air gave aniline derivative 1t in 98% yield.
DCC coupling of amine 1t with N-Boc-protected L-proline
afforded the corresponding amide 1u in 93% yield. Amino-
substituted radical 1t was also used for the reductive amination
with hexanal in the presence of NaBH3CN giving 1v. The
reductive amination reaction was incomplete, and no attempt at
optimizing the reaction conditions was made. Radical 1v
undergoes partial reduction during the reaction, as evident by
TLC analysis of the crude reaction mixture, but any leuco forms
A Heck C−C cross-coupling reaction31 was demonstrated on
radical 2d containing three iodine atoms (Scheme 7). Thus, a
reaction of 2d with methyl acrylate in DMF under typical
reaction conditions in the presence of Et3N gave the
corresponding radical 27 in 68% yield after 5 h at 100 °C.
Interestingly, the triester 27 crystallized with two molecules of
water, which can be largely removed when CH2Cl2 solutions
are dried with MgSO4.
Transformations of benzo[1,2,4]triazinyl containing a nitro
group were investigated using radical 1e (Scheme 8). Thus,
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a
Scheme 8. Transformation of 1e
a
Reagents and conditions: (i) H2 (50 psi), Pd/C, THF/EtOH, 2h, rt; (ii) N-Boc-L-proline, DCC, DMAP, CH2Cl2, 12 h, rt; (iii) (1) hexanal,
NaBH3CN, MeOH, 24 h, rt, (2) air.
a
are converted to their corresponding radicals during the
workup procedure.
Scheme 10. Chemical reduction and oxidation of 2a
Finally, deprotection of the carboxy group in 5h was
investigated. Thus, treatment of 5h with 1.5 equiv of KOH in
EtOH/THF at 60 °C resulted in hydrolysis of the ester group,
and acid 5w was isolated in 73% yield (Scheme 9).
a
Scheme 9. Transformation of 5h
a
Reagents and conditions: (i) ascorbic acid, DMSO/H2O (2:1), rt; (ii)
NaIO4, AcOEt/H2O, rt, 15 min.
a
Reagents and conditions: (i) KOH, EtOH/THF (1:1).
Reductive Stability of 1. The chemical stability of
benzo[1,2,4]triazinyl against natural reducing reagents was
qualitatively tested on radical 2a in aqueous media. Thus, a 15
mM solution of 2a in DMSO/H2O (2:1) was reduced with 5
equiv of ascorbic acid after 2 h to the yellow leuco form 28,
which was reoxidized to 2a with NaIO4 (Scheme 10). In
contrast, no reduction of 2a with glucose was observed under
identical conditions even after 24 h.
Mechanistic Studies. For a better understanding of the
formation of the benzo[1,2,4]triazine skeleton, the cyclization
was modeled in a CH2Cl2 dielectric medium using the B3LYP/
6-31G(2d,p) method and PCM solvation model.32 Analysis of
7-unsubstituted azo imino derivative 29a, formed as the
oxidation product of the corresponding amidrazone, revealed
that the C(8a)···N(1) distance in the syn-conformer is 3.354 Å,
which is close to the sum of the van der Waals radii (3.31 Å).33
This distance contracts to 2.155 Å in the transition state 30⧧a,
Figure 2. Proposed mechanism for the formation of 1,3-diphenyl-1,4-
dihydrobenzo[1,2,4]triazine 32.
The process is endothermic by 9.0 kcal/mol (ΔG298 = 11.7
kcal/mol), and stabilization occurs by tautomerization to 32a
with an exotherm of −28.2 kcal/mol (ΔG298 = −27.8 kcal/
mol). In the 4H tautomer, the C(8a)−N(1) distance is 1.417 Å.
The tautomerization may occur by proton transfer from the
which is ΔG⧧ = 38.6 kcal/mol relative to 29a, and then to
298
1.476 Å in the cyclic nonaromatic product 31a (Figures 2−4).
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Figure 3. B3LYP/6-31G(2d,p)-optimized geometries for structures involved in formation of 32a from 29a.
Figure 4. B3LYP/6-31G(2d,p) potential energy surface for two proposed mechanisms for the formation of 32 from 29 in Figure 2: Z = H (black), Z
= OH (red), Z = CN (blue). Full thermodynamic data is provided in the Supporting Information.
reaction medium to the N(4) position to form 31[H+],
followed by deprotonation at the C(8a) position. Since the
reaction is conducted in the presence of an amine, it is
reasonabe to assume for the purpose of the calculations, that an
ammonium cation, such as [HNMe3]+ is the source of the
proton. Such a proton transfer to 31a and formation of
31[H+]a is endothermic by 7.1 kcal/mol, which is followed by a
significant exotherm (ΔH = −35.3 kcal/mol) upon deproto-
nation and the formation of 32a.
skeleton. The overall process is moderately exothermic with
free energy change of 16.0 kcal/mol.
Brief investigations of the substituent effect on the cyclization
energies were conducted using the OH and CN groups at the
C(7) position (Figure 4).34 The results demonstrate that the
substituents have little impact on the cyclization activation
energies for the neutral precursor 29. In contrast, they have a
more pronounced effect on the energetics of the protonation of
29 and its subsequent cyclization. Thus, an electron-donating
substituent, OH, lowers the protonation energy and raises the
cyclization activation barrier by about 4 kcal/mol. In contrast,
the CN substituent increases both the protonation and
cyclization activation free energy by about 5 kcal/mol.
Electronic Absorption Spectroscopy. Blatter’s radicals
are dark brown-red in solutions. UV−vis spectroscopic analysis
of two selected radicals, 1r and 4n, revealed similar spectra with
strong absorption bands around 300 nm (301 and 283 nm,
respectively) and low to medium intensity bands in the visible
range (Figure 5). The obtained spectra are qualitatively similar
to that of Batter’s radical (II).15
Alternatively, the protonation may occur prior to the
cyclization step (Figure 2). Thus, proton transfer from
ammonium [HNMe3]+ to 29a and formation of 29[H+]a is
moderately endothermic (5.7 kcal/mol). Computational
modeling demonstrates that the C(8a) and N(1) atoms are
significantly closer in the syn-conformer (2.923 Å) of the
protonated 29[H+]a than in the neutral form 29a. The
cyclization to 31[H+]a proceeds through a late transition state
30[H+]⧧a (dC···N = 1.807 Å) with a low activation energy of
ΔG⧧ = 16.7 kcal/mol (Figures 3 and 4). The process is
298
endothermic and, due to the relatively low ΔG⧧298, is reversible.
The cyclic cation 31[H+]a undergoes deprotonation-aromatiza-
tion to form 32a. Thus, computational results strongly indicate
the later mechanism, protonation−cyclization−deprotonation,
as the most likely process leading to the benzo[1,2,4]triazine
TD-DFT computational analysis of 1r and a model
dimethoxy derivative 4x in CH2Cl2 dielectric medium revealed
several (5 and 9, respectively) low oscillator strength excitations
in the visible range. In general, all excitations involve multiple
transitions and excitations in 1r have higher oscillator strength
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Figure 7. EPR spectrum of 1t recorded in benzene.
Figure 5. Electronic absorption spectra for 1r and 4n (CH2Cl2).
than those in the dimethoxy 4x. The lowest energy excitation
for the dimethoxy 4x is calculated at 581 nm and involves
mainly the α-HOMO (SOMO) → α-LUMO transition (f =
0.005), while the excitation at 499 nm is largely due to the β-
HOMO → β-LUMO transition (f = 0.04). The SOMO and the
β-LUMO orbitals are localized on the benzo[1,2,4]triazinyl
ring, while the α-LUMO and β-HOMO are delocalized on the
coplanar ring at the C(3) position (Figure 6). For the acetylene
electron density of the phenyl ring attached at the nodal
position C(3). Thus, substitution of the NO2 group for the
NH2 in 1t reduces the aN2 hfcc in 1e by 0.65 G (calculated 0.56
G) and increases the aN4 hfcc by 0.15 G (calculated 0.29 G).
Although the experimental values for aN1 are close and about
6.8 G for the two radicals, DFT calculations show larger hfcc
for this position, by 0.2 G, in nitro 1e than in amine 1t. This
effect is consistent with polarization of electron density in the
triazine ring by the substituents, and greater contribution of the
polar resonance form B in the structure of nitro derivative 1e
than in amino analogue 1t (Figure 8).
DISCUSSION AND CONCLUSIONS
■
Derivatives of Blatter’s radical II with a wide variety of
substituents are available either through classical methods
involving oxidative cyclization of amidrazones (such as 6−9,
Scheme 1, method A) or using a recently elaborated reductive
cyclization of N′,N′-diarylhydrazides (e.g., Scheme 2, method
B). Due to regiochemical aspects of the cyclization, the former
method is suitable for the preparation of 7-substituted
benzo[1,2,4]triazinyls, while the latter method can be used
for regiospecific syntheses of the radical with other substitution
patterns (e.g., 6-CF3 derivatives 5).
Pd-catalyzed oxidation of amidrazones and formation of the
benzo[1,2,4]triazinyl was generally efficient for 1, 2, and 4,
which were formed in yields ranging from 63% (1d) to 89%
(1c). Lower yields of the radicals were obtained from
amidrazones containing the benzoyloxy substituent (about
50%), presumably due to sensitivity of the ester group to the
reaction conditions. Surprisingly, no expected radical was
obtained in the case of Z = F (3, Scheme 1), and it is not clear
whether the decomposition occurs at the amidrazone or at the
radical stage.
While cyclization of amidrazones and hydrazides and
formation of the corresponding radicals works well, both
methods suffer from inconsistent and rather modest availability
of the required intermediates. For instance, amidrazones are
typically obtained using two general methods: from imidoyl
chlorides or hydrazonoyl chlorides. The yields of amidrazones
in the former method appear to depend on the substituent. For
example, a moderately electron-attracting substituent in the
para position of the hydrazine, PhNHNH2, promotes the
formation of the amidrazone. Thus, 4-iodophenylhydrazine (σp
= +0.18)38 gave the highest yields of amidrazones (58−85%),
4-(benzoyloxy)phenylhydrazine (σp = +0.13)38 gave moderate
yields of 30−40%, and poor yields of amidrazones were
obtained with parent PhNHNH2 (σp = 0.0). On the other hand,
phenylhydrazines containing CO2− (σp = 0.0)38 and OBn (σp ≈
Figure 6. B3LYP/6-31G(2d,p)-derived contours and energies of
frontier molecular orbitals relevant to low energy excitations for 4x in
CH2Cl2 dielectric medium.
derivative 1r analogous excitations have lower energies, at 638
and 552 nm, respectively. Higher energy excitations, at 479 nm
(f = 0.04) and 474 nm (f = 0.47), in 1r involve HOMO−1 and
LUMO+1 orbitals localized on the tolane substituents.34
EPR Spectroscopy. EPR spectra of several derivatives 1
exhibit 12 principal bands35 due to coupling to three 19F and
quadrupolar 14N nuclei broadened by minor coupling to 1H’s of
the benzene rings as shown for 1t in Figure 7. Simulation of the
experimental spectra aided with DFT calculations demonstrates
that the highest hfcc values, about 6.5 G, are associated with the
N(1) atoms and smaller, of about 4 G with N(2), and N(4) and
F atoms (Table 1). The benzo[1,2,4]trizine ring H atoms have
smaller hfcc with the largest of about 1.8 G for the H(5) atom.
This assignment of the largest hfcc to the N(1) atom is
consistent with results of ENDOR and isotope labeling studies
of the Blatter and related radicals.15,36,37 Interestingly, the
distribution of spin density in the triazinyl ring is affected by
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a
Table 1. Hyperfine Coupling Constants (G) for Selected Radicals
compd
aN(1)
aN(2)
aN(4)
aH(5)
aH(6)
aH(8)
aF
aHo/m
aHo/m
aHo/m
aHo/m
g
1c X = I Y = OBn
1e X = H, Y = NO2
1t X = H, Y = NH2
6.20
6.78
6.83
4.89
3.89
4.54
3.75
4.36
4.21
1.75
1.44
1.53
0.23
0.88
1.15
0.94
0.94
1.30
4.19
4.32
3.53
0.78
0.75
0.89
0.68
0.76
0.81
0.65
0.23
0.60
0.37
0.16
0.14
2.0040
2.0042
2.0050
a
Assigned on the basis of B3LYP/EPR-II//B3LYP/6-31G(2d,p) results.
reductive amination in the presence of NaBH3CN. We also
observed that the benzo[1,2,4]triazinyl is reduced with ascorbic
acid in aqueous media.
The stability and scope of functional group transformations
observed for Blatter’s radical (II) is in sharp contrast to those
previously found for the analogous 6-oxoverdazyl (I)
derivatives.11 For instance, while all attempted Pd-catalyzed
C−C cross-coupling reactions involving II gave the expected
products, none of these reactions were successful with 6-
oxoverdazyl (I) derivatives. Also, the carboxylic acid derivative
of I could not be isolated, while acid 5w appears stable. Another
significant difference was observed in phenol derivatives. While
N(1) phenol groups of both I and II can be acylated, only N(1)
phenol derivatives of the latter (compounds 1j and 4i) undergo
efficient alkylation under basic conditions. In contrast, the N(1)
phenol of 6-oxoverdazyl does not give the expected O-
alkylation product and undergoes rapid decomposition in air
in the presence of a base.11 This high reactivity of the verdazyl
phenolate anion was ascribed to an extensive spin delocalization
onto the oxygen atom with the calculated spin density of 0.21.
On the other hand, oxygen atom in the phenoxide anion of II
has a lower spin concentration (0.17) presumably due to less
efficient π−π overlap of the N(1) phenyl ring and the triazinyl
ring due to a high dihedral angle of about 60° observed in the
solid state.22−24,39,40
Figure 8. Two resonance forms of radical 1.
−0.2) gave no product that could be isolated. In all cases, the
preparation of amidrazones is accompanied by formation of
several side products, and their purification is complicated by
their tendency to oxidize in air. The formation of N,N-
diarylhydrazines and their hydrazide intermediates (e.g., 23 and
24 in Scheme 2), in method B, is even more challenging and
substituent dependent, as our results confirmed the recent
findings.18
Using methods A and B, we prepared 11 derivatives of
Blatter’s radical containing five functional groups, OBn, OBz,
CO2Me, NO2, and I, substituted on the phenyl rings. Their
subsequent transformations, which involved basic hydrolysis
and catalytic hydrogenation, provided access to phenol, aniline,
and carboxylic acid derivatives, which were acylated and
alkylated in good to excellent yields.
Investigation of iodo derivatives 1c, 1d, and 2d demonstrated
a broad scope of Pd-catalyzed C−C cross coupling reactions
that include Suzuki, Heck, Negishi, and Sonogashira methods
permitting arylation, vinylation, and ethynylation of Blatter’s
radical in good to excellent yields. The reported reactions
complement and expand the previously reported Suzuki and
Stille arylation at the C(7) position20,23 and that of the triiodo
derivative 2d.26
Transformations presented here demonstrate robustness of
Blatter’s radical and excellent stability of the heterocycle under
variety of reactions conditions that include: basic medium,
catalytic hydrogenation, organometallic reagents, and pro-
longed heating at 100 °C. The stability of the radical to these
conditions appears to be the same whether or not the shielding
CF3 group is present at the high spin position C(7). The radical
is also stable in the presence of the CC bond in citronellyl
derivative 1m.
Mechanistic investigation of the benzo[1,2,4]triazine ring
formation revealed a low activation energy pathway to
cyclization of the protonated imino azo intermediate, such as
29[H+]a (ΔG⧧ = 16.7 kcal/mol), which is consistent with
298
the original report of cyclization of 29a41 in isopropanol in the
presence of HBr at ambient temperature.14 In contrast,
electrocyclization of unprotonated 29a requires significantly
higher activation energy (ΔG⧧
= 38.6 kcal/mol) in
298
agreement with reports of such cyclizations in hot DMSO
(150 °C) in the absence of acid.15,16 Mercury oxide appears to
promote cyclization of 29a in warm ethanol,15 presumably by
coordinating to the N(4) atom in 29 and forming a complex,
such as 33. Low-temperature formation of the benzo[1,2,4]-
triazine ring was also reported in reactions of a nitrile imine 34
with iminophosphorane42 35a (Z = OMe, Figure 9) or with
sulfimide 35b (Z = H).43 Betaines 36a and 36b, respectively,
were postulated as intermediates undergoing cyclization,
although our brief investigation failed to locate the structure
36b as a minimum on the potential energy surface.
Alternatively, the betaines may undergo fragmentation with
loss of neutral Ph3P or Me2S molecule leading to azoimine 29,
In some reactions the benzo[1,2,4]triazinyl undergoes 1
electron reduction to the leuco form, which can be quickly
reoxidized with air or chemically to the radical. Thus, formation
of the leuco form is typically observed in catalytic hydrogenation
(H2/Pd and H2/Pt), the Negishi coupling reactions, and
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substitution of an amino group into nitro derivative 1e
increases the aN1 hfcc value by 0.21 G in 1y according to
DFT calculations. Spin delocalization from C(5) and C(8) is
hampered by steric congestion at these positions and poor
orbital overlap between the aromatic and ring and the
heterocycle.
SUMMARY
■
Benzo[1,2,4]triazinyl is an exceptionally robust radical stable
under a number of typical reaction conditions that include ester
hydrolysis, O- and N-alkylation, O- and N-acylation, catalytic
reduction, and Pd-catalyzed C−C cross-coupling reactions. In
some reactions, the radical is reduced to the leuco form, which
can be easily oxidized to the radical. These reactions permit
incorporation of Blatter’s radical into complex molecular
architectures and expansion of the spin delocalization by
placing π substituents at high spin density positions through
Heck, Sonogashira, or Suzuki reactions of appropriate iodo
derivatives.
Figure 9. Proposed alternative mechanism for the formation of 29
from 36.
which upon proton transfer from R3N·HCl, present in the
reaction medium, electrocyclizes to benzo[1,2,4]triazine 32 as
shown in Figure 2.
Thus, it appears that protonation of the N(4) atom or
coordination with a Lewis acid dramatically accelerates
cyclization of the azo imines by lowering the activation energy
by about 20 kcal/mol, and such a process occurs at low
temperatures. This finding is consistent with recently described
examples of Lewis acid catalyzed 6-π electrocyclization of
substituted 1,3,5-hexatriene, although coordination of the
adjacent carbonyl group lowered the activation energy for
cyclization only by about 2 kcal/mol.44
Overall, transformations presented here permit incorporation
of Blatter’s radical into complex molecular architectures using
several types of functional groups. For instance, an efficient
formation of proline amide derivative 1u suggests the possibility
of incorporation of II into biomolecules. Substitution of
Blatter’s radical II also allows for more extensive spin
delocalization by placing π-conjugated groups in the C(7)
position of the heterocyclic ring and para position of the phenyl
ring at the N(1) position. Indeed, DFT modeling demonstrates
significant spin delocalization in the tolane (1r) and acrylic
ester (27) derivatives (Figure 10). Experimental and theoretical
results indicate that spin density delocalization onto N(1)
position and its substituent can be enhanced by using electron-
attracting substituents at the C(3) position and electron-
releasing substituents at the N(1) position. For instance,
Mechanistic analysis indicates that the formation of the
benzo[1,2,4]triazine ring of the Blatter’s radical proceeds
through a 6π electrocyclization process of a protonated (or
Lewis acid coordinated) azo imine with the activation energy of
ΔG⧧ = 16.7 kcal/mol.
298
COMPUTATIONAL DETAILS
■
Quantum-mechanical calculations were carried out at the B3LYP/6-
31G(2d,p) level of theory using the Gaussian 09 suite of programs.45
Geometry optimizations were undertaken using tight convergence
limits and without symmetry constraints. No conformational search
was attempted. Electronic excitation energies for 1r and 4x in CH2Cl2
dielectric medium were obtained at the UB3LYP/6-31G(2d,p) level
using the time-dependent DFT method46 and PCM solvation model32
supplied in the Gaussian package.
EXPERIMENTAL SECTION
■
Reagents and solvents were obtained commercially. Reactions were
carried out under argon, and subsequent manipulations were
conducted in air. NMR spectra were obtained at 400 MHz (1H)
and 100 MHz (13C) in CDCl3 or DMSO-d6 and referenced to the
solvent, unless otherwise specified. UV−vis spectra were recorded in
Figure 10. Total spin density map for 1r and 27 (B3LYP/6-31G(2d,p)).
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spectroscopic grade CH2Cl2 at concentrations of (1−10) × 10−5 M.
Extinction coefficient were obtained by fitting the maximum
absorbance at about 350 nm against concentration in agreement
with Beer’s law.
X-band EPR spectra were taken using modulation amplitude 0.10 G
and spectral width of 100 G. Solutions in distilled benzene were
degassed by three freeze/pump/thaw cycles. The g value for radicals
was obtained from experimental parameters using WinEPR Sinfonia
1.26 program. Simulation of the EPR spectra was done with PEST
program (EPR-winSim.2002 version 0.98 for Windows using results of
B3LYP/EPR-II/B3LYP/6-31G(2d,p) for initial input. The resulting
hfcc values were perturbed until the global minimum for the fit was
achieved. Spectra used for simulation were generated by reflection of
the left half of each spectrum.
General Procedures for Synthesis of Radicals 1, 2, and 4.
Following a general procedure,19 a solution of DBU (0.1 mmol) and
amidrazone 6, 7, or 9 (1.0 mmol) in dry CH2Cl2 (2 mL) containing
10% Pd/C (1.6 mol %) was stirred overnight at rt. After evaporation of
the solvent, the crude product was purified by flash chromatography
(hexane/CH2Cl2, 1:1). Analytically pure radicals 1, 2, or 4,
respectively, were obtained by recrystallization from either hexane or
AcOEt.
7-(Trifluoromethyl)-1,3-bis(4-(benzoyloxy)phenyl)-1,4-dihydro-
benzo[1,2,4]triazin-4-yl (1a). Radical 1a (0.308 g, 52% yield) was
obtained from 0.590 g of 6a: Rf = 0.80 (CH2Cl2); mp 195−196 °C; IR
(KBr) 1737 (CO), 1266, 1200, 1062, 709 cm−1; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C34H22F3N3O4 593.1557, found 593.1530.
Anal. Calcd for C34H21F3N3O4: C, 68.92; H, 3.57; N, 7.09. Found: C,
68.73; H, 3.69; N, 6.93.
7-(Trifluoromethyl)-1-(4-(benzoyloxy)phenyl)-3-(4-(benzyloxy)-
phenyl)-1,4-dihydrobenzo[1,2,4]triazin-4-yl (1b). Radical 1b (0.283
g, 49% yield) was obtained from 0.580 g of 6b: Rf = 0.90 (CH2Cl2);
mp 186−187 °C; IR (KBr) 1735 (CO), 1319, 1264, 1203, 1064,
707 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C34H24F3N3O3
579.1764, found 579.1751. Anal. Calcd for C34H23F3N3O3: C, 70.58;
H, 4.01; N, 7.26. Found: C, 70.55; H, 3.95; N, 7.11.
7-(Trifluoromethyl)-3-(4-(benzyloxy)phenyl)-1-(4-iodophenyl)-
1,4-dihydrobenzo[1,2,4]triazin-4-yl (1c). Radical 1c (0.583 g, 89%
yield) was obtained from 0.519 g of 6c: Rf = 0.95 (CH2Cl2); mp 209−
210 °C; IR (KBr) 1604, 1481, 1402, 1362, 1319, 1262, 1169, 1106,
823 cm−1; HRMS (ESI-TOF) m/z [M]+ calcd for C27H18F3IN3O
584.0441, found 584.0440. Anal. Calcd for C27H18F3IN3O: C, 55.50;
H, 3.10; N, 7.19. Found: C, 54.92; H, 2.97; N, 6.94.
7-(Trifluoromethyl)-1,3-bis(4-iodophenyl)-1,4-dihydrobenzo-
[1,2,4]triazin-4-yl (1d). Radical 1d (1.121 g, 74% yield) was obtained
from 1.502 g of 6d: Rf = 0.96 (CH2Cl2); mp 247−248 °C dec (DSC);
IR (KBr) 1582, 1484, 1319, 1261, 1111, 1066, 823 cm−1; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C20H12F3I2N3 604.9067, found
604.9104. Anal. Calcd for C20H11F3I2N3: C, 39.76; H, 1.84; N, 6.96.
Found: C, 39.55; H, 1.69; N, 6.84.
7-(Trifluoromethyl)-3-(4-nitrophenyl)-1-phenyl-1,4-dihydro-
benzo[1,2,4]triazin-4-yl (1e). Radical 1e (0.732 g, 74% yield) was
obtained from 1.003 g of 6e: Rf = 0.85 (CH2Cl2); mp 109−111 °C; IR
(KBr) 1534, 1354, 1311, 1264, 1126, 700 cm−1; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C20H13F3N4O2 398.0985, found 398.0996.
7-Iodo-1,3-bis(4-(benzoyloxy)phenyl)-1,4-dihydrobenzo[1,2,4]-
triazin-4-yl (2a). Radical 2a (0.637 g, 32% yield) was obtained from
2.013 g of 7a: Rf = 0.73 (CH2Cl2); mp 185−187 °C; IR (KBr) 1739
(CO), 1502, 1395, 1264, 1204, 1058, 704 cm−1; HRMS (ESI-TOF)
m/z [M]+ calcd for C33H21IN3O4 650.0571, found 650.0577. Anal.
Calcd for C33H21IN3O4: C, 60.94; H, 3.25; N, 6.46. Found: C, 61.00;
H, 3.53; N, 6.43.
calcd for C33H23N3O4 525.1683, found 525.1684. Anal. Calcd for
C33H22N3O4: C, 75.56; H, 4.23; N, 8.01. Found: C, 75.54; H, 4.19; N,
7.98.
1-(4-(Benzoyloxy)phenyl)-3-(4-(benzyloxy)phenyl)-1,4-
dihydrobenzo[1,2,4]triazin-4-yl (4b). Radical 4b (0.504 g, 36% yield)
was obtained from 1.405 g of 9b: Rf = 0.76 (CH2Cl2); mp 118−120
°C; IR (KBr) 1736 (CO), 1605, 1503, 1395, 1250, 1200, 707 cm−1;
HRMS (ESI-TOF) m/z [M]+ calcd for C33H24N3O3 510.1812, found
510.1833. Anal. Calcd for C33H24N3O3: C, 77.63; H, 4.74; N, 8.23.
Found: C, 77.39; H, 4.99; N, 7.93.
6-(Trifluoromethyl)-1-(4-iodophenyl)-3-(4-(methoxycarbon-
yl)phenyl)-1,4-dihydrobenzo[1,2,4]triazin-4-yl (5h). Tin powder
(153 mg, 1.28 mmol) was added to a vigorously stirred solution of
hydrazide 24h (188 mg, 0.321 mmol) in glacial acetic acid (5 mL).
The resulting mixture was stirred at rt for 30 min and then heated at
ca. 118 °C for 10 min. After cooling, the mixture was diluted with
CH2Cl2, and the organic phase was washed with water (2 × 20 mL),
saturated NaHCO3 (20 mL), and water (20 mL) and dried (Na2SO4).
After evaporation of the solvent, the crude product was purified by
flash chromatography (CH2Cl2; Rf = 0.87) giving 85 mg (49% yield)
of leuco 25h as a red solid: mp 180−182 °C; 1H NMR (DMSO-d6, 400
MHz) δ 3.87 (s, 3H), 6.52 (d, J = 8.4 Hz, 1H), 6.97 (bs, 1H), 7.02 (d,
J = 9.0 Hz, 1H), 7.30 (d, J = 8.6 Hz, 2H), 7.74 (d, J = 8.7 Hz, 2H),
7.95 (d, J = 8.4 Hz, 2H), 8.05 (d, J = 8.5 Hz, 2H), 9.17 (s, 1H); IR
(KBr) 3376 (NH), 1708 (CO), 1487, 1335, 1288, 1114 cm−1;
HRMS (ESI-TOF) m/z [M]+ calcd for C22H15F3IN3O2 537.0156,
found 537.0150.
A solution of NaIO4 (0.123 mmol, 26 mg) in H2O (0.5 mL) was
added to a solution of crude leuco 25h (30 mg, 0.056 mmol) in
CH2Cl2/MeOH (1:1, 1 mL). The resulting mixture was stirred for 30
min at rt, diluted with CH2Cl2, and washed with H2O, and the organic
solution was dried (Na2SO4). Evaporation of the solvent gave 29 mg
(99% yield) of radical 5h as a black green solid, which was purified
further by recrystallization from hexane: mp 220−222 °C; IR (KBr)
1718 (CO), 1277, 1116, 712 cm−1; HRMS (ESI-TOF) m/z [M]+
calcd for C22H14F3IN3O2 536.0077, found 536.0108. Anal. Calcd for
C22H14F3IN3O2: C, 49.27; H, 2.63; N, 7.84. Found: C, 49.34; H, 2.70;
N, 7.79.
1,4-Dihydrobenzo[1,2,4]triazinyls through Functional
Group Transformations. General Procedure for Deprotection of
the Phenolic Functionality. Method A. Hydrolysis of Benzoate
Esters. A solution of benzoate ester (0.5 mmol) in CH2Cl2/MeOH
(3:1, 4 mL) was treated with 0.1 M solution of KOH in MeOH (1
equiv). The resulting mixture was stirred at rt for 0.5 h until TLC
(CH2Cl2) showed the absence of starting material. The reaction
mixture was diluted with CH2Cl2 (10 mL) and washed with H2O (3 ×
5 mL). The organic layer was dried (Na2SO4), and solvents were
evaporated. The crude product was purified by flash chromatography
(CH2Cl2).
Method B. Hydrogenation of Benzyl Ethers. A solution of
benzyloxy derivative (0.15 mmol) in THF/EtOH (1:1, 5 mL)
containing 10% Pd/C (5 mol %) was stirred at rt under positive
pressure of H2 until the starting material was completely consumed
(by TLC analysis). The reaction mixture was filtered through Celite,
solvents were evaporated, and crude product was purified by flash
chromatography.
7-(Trifluoromethyl)-1,3-bis(4-(adamantane-1-carbonyloxy)-
phenyl)-1,4-dihydrobenzo[1,2,4]triazin-4-yl (1l, through Esterifica-
tion). Bisphenol 1i (0.096 g, 97% yield) was obtained from 0.153 g of
1a according to method A (Rf = 0.05 (CH2Cl2): mp 222−224 °C; IR
(KBr) 3415 (OH), 1610, 1507, 1338, 1270, 1169, 1134, 832 cm−1;
HRMS (ESI-TOF) m/z [M]+ calcd for C20H13F3N3O2 384.0954,
found 384.0960). A solution of radical 1i (70 mg, 0.18 mmol),
adamantane-1-carbonyl chloride (72 mg, 0.36 mmol), and Et3N (0.05
mL, 0.36 mmol) in dry CH2Cl2 (5 mL) was stirred at rt until all
starting bisphenol 1i was consumed (TLC, CH2Cl2, ∼1 h). The
reaction mixture was diluted with CH2Cl2 (5 mL) and washed with
H2O (2 × 5 mL). The organic layer was dried (Na2SO4), and solvents
were evaporated. The resulting crude product was purified by
recrystallization (MeCN) giving 117 mg (91% yield) of diester 1l as
7-Iodo-1,3-bis(4-iodophenyl)-1,4-dihydrobenzo[1,2,4]triazin-4-yl
(2d). Radical 2d (0.825 g, 55% yield) was obtained from 1.514 g of 7d:
Rf = 0.93 (CH2Cl2); mp 175−178 °C; IR (KBr) 1473, 1394 cm−1.
Anal. Calcd for C19H11I3N3: C, 34.47; H, 1.67; N, 6.35. Found: C,
34.63; H, 1.63; N, 6.27.
1,3-Bis(4-(benzoyloxy)phenyl)-1,4-dihydrobenzo[1,2,4]triazin-4-yl
(4a). Radical 4a (0.486 g, 34% yield) was obtained from 1.211 g of 9a:
Rf = 0.59 (CH2Cl2); mp 171−173 °C; IR (KBr) 1733 (CO), 1501,
1398, 1266, 1207, 1061, 710 cm−1; HRMS (ESI-TOF) m/z [M + H]+
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a black brown solid: mp >260 °C; HRMS (ESI-TOF) m/z [M + H]+
calcd for C42H42F3N3O4 709.3122, found 709.3121. Anal. Calcd for
C42H41F3N3O4: C, 71.17; H, 5.83; N, 5.93. Anal. Calcd for
C42H41F3N3O4·H2O: C, 69.41; H, 5.96; N, 5.78. Found: C, 69.49;
H, 5.81; N, 5.73.
C36H21F3N3: C, 78.25; H, 3.83; N, 7.60. Anal. Calcd for C36H21F3N3·
H2O: C, 75.78; H, 4.06; N, 7.36. Found: C, 76.01; H, 4.08; N, 7.07.
7-(Trifluoromethyl)-1,3-bis[4-(4-methoxyphenyl)phenyl]-1,4-di-
hydro-benzo[1,2,4]triazin-4-yl (1s, through Negishi Cross-Coupling
Reaction). A suspension of dry ZnCl2 (412 mg, 3.03 mmol) in dry
THF (3 mL) at 0 °C was treated with a solution of (4-
methoxyphenyl)magnesium bromide (533 mg, 2.53 mmol) in THF
(4 mL). The reaction mixture was stirred at 0 °C for 15 min and then
at rt for 20 min. PEPPSI-Ipr (9 mg, 10 mol %) was added, and the
reaction mixture was stirred for 10 min, followed by addition of radical
1d (76 mg, 0.126 mmol). The reaction mixture was then stirred for 4 h
and quenched with NH4Cl, and products were extracted into AcOEt.
The organic extracts were washed with H2O and brine and dried
(Na2SO4). The solvent was evaporated, and the crude product was
purified on silica gel (CH2Cl2, Rf = 0.95) giving 33 mg (46% yield) of
radical 1s as a dark brown solid: mp 159−161 °C; IR (KBr) 2924,
1606, 1496, 1398, 1315, 1248, 1108, 826 cm−1; HRMS (ESI-TOF) m/
z [M]+ calcd for C34H25F3N3O2 564.1893, found 564.1906. Anal.
Calcd for C34H25F3N3O2: C, 72.33; H, 4.46, N, 7.44. Found: C, 71.79;
H. 4.81; N, 7.04.
7-(Trifluoromethyl)-3-(4-aminophenyl)-1-phenyl-1,4-dihydro-
benzo[1,2,4]triazin-4-yl (1t, through Reduction of the NO2 Group).
A solution of radical 1e (160 mg, 0.4 mmol) in THF/EtOH (1:1, 10
mL) containing 10% Pd/C (42 mg, 10 mol %) was hydrogenated at 50
psi until starting material was no longer detectable (TLC). The green
reaction mixture was stirred in air (ca. 30 min), and the resulting dark
brown solution was passed through Celite. Solvents were evaporated,
and the resulting crude product was purified by flash column
chromatography (SiO2, CH2Cl2, Rf = 0.30) giving 140 mg (98%
yield) of 1t as a dark brown solid: mp 178−180 °C; IR (KBr) 3470
and 3323 (NH), 1618, 1397, 1316, 1113 cm−1; HRMS (ESI-TOF) m/
z [M + H]+ calcd for C20H15F3N4 368.1249, found 368.1284. Anal.
Calcd for C20H14F3N4: C, 65.39; H, 3.84; N, 15.25. Found: C, 65.16;
H, 3.98; N, 15.02.
7-(Trifluoromethyl)-3-(4-(N-BOC-pyrrolidine-2-carboxamido)-
phenyl)-1-phenyl-1,4-dihydrobenzo[1,2,4]triazin-4-yl (1u, through
Amidation Reaction). DCC (96 mg, 0.465 mmol) and catalytic
amounts of DMAP were added to a solution of N-BOC-L-proline (73
mg, 0.342 mmol) in CH2Cl2 (5 mL). The resulting mixture was stirred
at rt for 30 min. Amine 1t (114 mg, 0.311 mmol) in CH2Cl2 (2 mL)
was added, and the mixture was stirred for 24 h. The reaction mixture
was diluted with CH2Cl2, washed with H2O, and dried (Na2SO4).
Solvents were evaporated, and the resulting crude product was purified
by flash column chromatography (SiO2, hexane/AcOEt, 2:1) giving
163 mg (93% yield) of radical 1u as a dark brown solid: mp 177−179
°C; IR (KBr) 3327 (NH), 1701 (CO), 1604, 1546, 1394, 1317,
1162, 1121 cm−1; HRMS (ESI-TOF) m/z [M]+ calcd for
C30H29F3N5O3 564.2217, found 564.2234. Anal. Calcd for
C30H29F3N5O3: C, 63.82; H, 5.18; N, 12.40. Calcd for
C30H29F3N5O3·1/2H2O: C, 62.32; H, 5.27; N, 12.21. Found: C,
62.87; H, 5.37; N, 11.84.
7-(Trifluoromethyl)-3-(4-(hexylamino)phenyl)-1-phenyl-1,4-dihy-
drobenzo[1,2,4]triazin-4-yl (1v, through Reductive Amination).
Freshly distilled hexanal (58 mg, 0.583 mmol) and amine 1t (214
mg, 0.53 mmol) in a solution of MeOH (5 mL) was stirred at rt for 15
min. The reaction mixture was then treated with a solution of
NaBH3CN (55 mg, 0.874 mmol) in MeOH (0.5 mL), and stirring was
continued for 24 h. Saturated aqueous NaHCO3 was added, the
organic products were extracted with AcOEt, and the extracts were
dried (Na2SO4), while kept open to the air. Solvents were removed,
and the residue was separated by flash column chromatography (SiO2,
CH2Cl2, Rf = 0.90) giving 62 mg (24% yield) of radical 1v as the first
fraction: mp 91−92 °C; IR (KBr) 3408 (NH), 2924, 1609, 1397,
1316, 1113 cm−1; HRMS (ESI-TOF) m/z [M]+ calcd for C26H26F3N4
451.2104, found 451.2108. Anal. Calcd for C26H26F3N4: C, 69.16; H,
5.80; N, 12.41. Found: C, 69.31; H, 5.87; N, 12.23.
7-(Trifluoromethyl)-3-(4-benzyloxyphenyl)-1-((S)-4-citronellyloxy-
phenyl)-1,4-dihydrobenzo[1,2,4]triazin-4-yl (1m, through O-Alkyla-
tion). Phenol 1j (0.085 g, 90% yield) was obtained from 0.117 g of
benzoate 1b according to method A in 90% yield (Rf = 0.23 (CH2Cl2):
mp 110−112 °C; IR (KBr) 3343 (OH), 1605, 1506, 1324, 1256, 1119,
834 cm−1; HRMS (ESI-TOF) m/z [M]+ calcd for C27H19F3N3O2
474.1424, found 474.1433.) A solution of phenol 1j (45 mg, 0.095
mmol) and (S)-(+)-citronellyl bromide (22 mg, 0.02 mL, 0.1 mmol)
in dry MeCN (3 mL) containing K2CO3 (14 mg, 0.1 mmol) was
refluxed for 4 h. Saturated aqueous NaHCO3 was added, and the
mixture was extracted with AcOEt. The extract was washed with water
and dried (Na2SO4). Solvents were evaporated, and the residue was
purified by flash chromatography (SiO2, hexanes/CH2Cl2, 1:1; Rf =
0.65, CH2Cl2) giving 32 mg (55% yield) of 1m as a dark brown solid:
mp 101−104 °C; IR (KBr) 2926, 1605, 1508, 1324, 1252, 1119, 837
cm−1; HRMS (ESI-TOF) m/z [M]+ calcd for C37H37F3N3O2
612.2832, found 612.2815.
7-(Trifluoromethyl)-3-(4-(benzyloxy)phenyl)-1-[4-(4-methoxy-
phenyl)phenyl]-1,4-dihydrobenzo[1,2,4]triazin-4-yl (1o, through
Suzuki Cross-Coupling Reaction). Method A. A solution of radical
1c (200 mg, 0.342 mmol) in degassed toluene (6 mL) and water (0.5
mL) were added via a syringe to a mixture of Pd(OAc)2 (4 mg, 5 mol
%), p-methoxyphenylboronic acid (157 mg, 1.03 mmol), and K2CO3
(142 mg, 1.03 mmol). The resulting mixture was refluxed for 12 h,
cooled, and concentrated in vacuo. The crude product was purified by
flash chromatography (hexanes/CH2Cl2, 2:1, Rf = 0.90; CH2Cl2)
giving 160 mg (83% yield) of 1o as a dark brown solid: mp 154−155
°C; IR (KBr) 1607, 1495, 1397, 1251, 1125 cm−1; HRMS (ESI-TOF)
m/z [M + H]+ calcd for C34H26F3N3O2 565.1972, found 565.1983.
Anal. Calcd for C34H25F3N3O2: C, 72.33; H, 4.46; N, 7.44. Found: C,
72.03; H, 4.43; N, 7.31.
Method B. A solution of radical 1c (58 mg, 0.1 mmol) in degassed
toluene (3 mL) and water (0.75 mL) was added via syringe to a
mixture of PdCl2(PPh3)2 (4 mg, 5 mol %), potassium p-
methoxyphenyltrifluoroborate (22 mg, 0.105 mmol), and Cs2CO3
(98 mg, 0.3 mmol). The resulting mixture was refluxed for 24 h. After
cooling, the solution was filtered through Celite, diluted with H2O,
and extracted into AcOEt. The combined organic layers were dried
(Na2SO4) and concentrated in vacuo. The residue was purified by flash
chromatography (SiO2, hexanes/CH2Cl2, 2:1) giving 28 mg (51%
yield) of 1o as the second fraction. The first fraction (5 mg, 11% yield)
was identified as deiodinatined product 1p: mp 181−182 °C; IR (KBr)
1606, 1495, 1398, 1250, 1124, 826 cm−1; HRMS (ESI-TOF) m/z
[M]+ calcd for C27H19F3N3O 458.1475, found 458.1461.
7-(Trifluoromethyl)-3-(4-hydroxyphenyl)-1-[4-(4-methoxyphen-
yl)phenyl]-1,4-dihydrobenzo[1,2,4]triazin-4-yl (1q, through Cata-
lytic Debenzylation). Phenol 1q (0.063g, 90% yield) was obtained
from 0.083 g of 1o according to method B as a black solid: mp 232−
235 °C; IR (KBr) 1609, 1496, 1397, 1274, 1261, 1174, 1107, 823
cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C27H20F3N3O2
475.1502, found 475.1507.
7-(Trifluoromethyl)-1,3-bis[4-(phenylethynyl)phenyl]-1,4-dihy-
drobenzo[1,2,4]triazin-4-yl (1r, through Sonogashira Cross-Cou-
pling Reaction). A solution of 1d (100 mg, 0.166 mmol) in degassed
DMF (2 mL) was treated with phenylacetylene (34 mg, 0.332 mmol),
PdCl2(PPh3)2 (9 mg, 4 mol %), CuI (2.5 mg, 4 mol %), and Et3N
(0.07 mL, 0.50 mmol). The resulting mixture was stirred at rt for 24 h
under an Ar atmosphere. The solution was filtered through Celite,
diluted with H2O, and extracted into AcOEt. The combined organic
layers were dried (Na2SO4) and concentrated in vacuo. The crude
product was purified by flash chromatography (SiO2, CH2Cl2, Rf =
0.99) giving 73 mg (80% yield) of 1r as a black brown solid: mp 220−
222 °C dec (DSC); IR (KBr) 2209 (CC), 1605, 1510, 1393, 1317,
1262, 1116, 1064, 846, 756, 690 cm−1; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C36H22F3N3 553.1760, found 553.1779. Anal. Calcd for
The unreacted amine 1t was isolated as the second fraction (125
mg).
1,3-Bis(4-heptyloxyphenyl)-1,4-dihydrobenzo[1,2,4]triazin-4-yl
(4n, O-Alkylation). The phenol functionality in 4b (0.206 g) was
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deprotected according to method B giving 0.107 g (63% yield) of 4k:
mp 188−190 °C; IR (KBr) 3423 (OH), 1735 (CO), 1608, 1492,
1396, 1262, 1204, 1172, 1062, 706 cm−1; HRMS (ESI-TOF) m/z
[M]+ calcd for C26H18N3O3 420.1343, found 420.1364. Subsequent
hydrolysis of the benzoate group according to method A gave
dihydroxy derivative 4i in 87% yield: mp 176−179 °C; HRMS (ESI-
TOF) m/z [M]+ calcd for C19H14N3O2 316.1081, found 316.1091.
A suspension of phenol 4i (93 mg, 0.294 mmol), K2CO3 (89 mg,
0.647 mmol), and n-iodoheptane (0.1 mL, 0.647 mmol) in dry MeCN
(6 mL) was refluxed for 6 h. Saturated aqueous NaHCO3 was added,
and the mixture was extracted with AcOEt. The organic extract was
washed with H2O and dried (Na2SO4). Solvents were removed, and
the resulting crude product was purified by flash chromatography
(SiO2, hexanes/CH2Cl2, 1:1) giving 85 mg (56% yield) of 4n as a
brown solid: mp 65−66 °C. Anal. Calcd for C33H42N3O2: C, 77.31; H,
8.26; N, 8.20. Found: C, 77.39; H, 8.27; N, 8.07.
6-(Trifluoromethyl)-1-(4-iodophenyl)-3-(4-(hydroxycarbonyl)-
phenyl)-1,4-dihydrobenzo[1,2,4]triazin-4-yl (5w, through Methyl
Ester Hydrolysis). A solution of radical 5h (57 mg, 0.106 mmol) in
THF/H2O (9:1, 1.1 mL) was treated with 0.1 N KOH in EtOH (1.59
mL, 0.159 mmol). The reaction mixture was stirred for 48 h at 60 °C
and poured into 10% HCl (2 mL). The resulting mixture was extracted
with AcOEt, and the organic layer was washed with H2O and dried
(Na2SO4). The solvents were removed, and the resulting crude
product was purified by flash chromatography (SiO2, AcOEt) giving 40
mg (73% yield) of 5w as a brown solid: mp >260 °C; IR (KBr) 1687
(CO), 1392, 1338, 1270, 1127, 712 cm−1; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C21H13F3IN3O2 523.0004, found 522.9985. Anal.
Calcd for C21H12F3IN3O2: C, 48.30; H, 2.32; N, 8.05. Found: C,
48.13; H, 2.40; N, 7.93.
7-(2-(Methoxycarbonyl)ethenyl)-1,3-bis(4-(2-(methoxycarbonyl)-
ethenyl)phenyl)-1,4-dihydrobenzo[1,2,4]triazin-4-yl (27, through
Heck Coupling). Methyl acrylate (77 mg, 0.9 mmol) was added to
mixture of triiodo derivative 2d (100 mg, 0.15 mmol), Et3N (91 mg,
0.9 mmol), Pd(OAc)2 (5 mg, 0.0225 mmol), and tris(o-
methoxyphenyl)phosphine (10 mol %, 16 mg, 0.045 mmol) in DMF
(5 mL). The resulting mixture was heated for 5 h at 100 °C and
cooled, H2O was added, and the products were extracted into AcOEt.
The solvents were removed, and the crude product was purified by
flash chromatography (SiO2, AcOEt/hexane, 3:1; Rf = 0.68, CH2Cl2)
giving 55 mg (68% yield) of radical 27 as a brown solid: mp 163−165
°C; IR (KBr) 3061, 3033, 1717 (CO), 1633, 1598, 1507, 1324,
1278, 1205, 1171 cm−1; HRMS (ESI-TOF) m/z [M]+ calcd for
C31H26N3O6 536.1816, found 536.1832. Anal. Calcd for C31H26N3O6:
C, 69.39; H, 4.88; N, 7.83. Calcd for C31H26N3O6·1/2H2O: C, 68.25;
H, 4.99; N, 7.70. Found: C, 68.66; H, 5.37; N, 7.49.
Intermediates to 1,4-Dihydrobenzo[1,2,4]triazinyls. General
Procedures for Synthesis of Amidrazones 6−9. Method A. A
solution of benzimidoyl chloride 15, 16, 17, or 18 (1.0 mmol) in dry
CH2Cl2 (3 mL) and Et3N (1.0 mmol) was added to hydrazine 19 (1
mmol) in a solution of dry CH2Cl2 (3 mL). The mixture was stirred
overnight at rt under Ar. A 1% solution of HCl was added, and the
organic products were extracted (CH2Cl2). The combined extracts
were dried (Na2SO4) and solvents evaporated. The crude products 6,
7, 8, or 9, respectively, were partially purified by flash chromatography
(SiO2, hexane/CH2Cl2, 3:1) and due to limited stability quickly used
in subsequent reactions.
142.3, 144.2, 151.4, 165.0, 165.7; HRMS (ESI-TOF) m/z [M + H]+
calcd for C34H25F3N3O4 596.1792, found 596.1806.
N′-(4-(Benzoyloxy)phenyl)-N-[4-(trifluoromethyl)phenyl]-4-ben-
zyloxybenzenecarbohydrazonamide (6b). Amidrazone 6b (2.56 g,
43% yield) was obtained from 4.05 g of 15b: mp 78−80 °C; 1H NMR
(CDCl3, 400 MHz) δ 5.09 (s, 2H), 5.86 (br s, 1H), 6.75 (d, J = 8.4 Hz,
2H), 6.97 (d, J = 8.8 Hz, 2H), 7.10 (d, J = 8.8 Hz, 2H), 7.15 (d, J = 9.1
Hz, 2H), 7.43−7.33 (m, 5H), 7.52−7.46 (m, 5H), 7.60−7.69 (m, 3H),
8.19 (d, J = 8.5 Hz, 2H); 13C NMR (CDCl3, 100 MHz) major signals
δ 70.2, 114.0, 115.2, 115.8, 119.8, 122.4, 126.9 (q, J = 4 Hz), 127.6,
128.1, 128.2, 128.7, 128.8, 128.9, 129.2, 129.8, 130.3, 133.6, 136.7;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C34H27F3N3O3 582.1999,
found 582.1991.
N′-(4-Iodophenyl)-N-[4-(trifluoromethyl)phenyl]-4-benzyloxyben-
zenecarbohydrazonamide (6c). Amidrazone 6c (1.81 g, 60% yield)
1
was obtained from 2.12 g of 15c: mp 57−59 °C; H NMR (CDCl3,
400 MHz) δ 5.09 (s, 2H), 5.71 (br s, 1H), 6.73 (d, J = 8.4 Hz, 2H),
6.88 (d, J = 8.8 Hz, 2H), 6.96 (d, J = 8.9 Hz, 2H), 7.33−7.50 (m, 8H),
7.52 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.9 Hz, 2H); 13C NMR (CDCl3,
100 MHz) major signals δ 70.0, 81.6, 115.0, 115.4, 115.5, 126.8 (q, J =
4 Hz), 127.4, 127.9, 128.1, 128.6, 136.4, 137.8, 144.1, 144.4, 159.9.
N′-(4-Iodophenyl)-N-[4-(trifluoromethyl)phenyl]-4-iodobenzene-
carbohydrazonamide (6d). Amidrazone 6d (3.78 g, 85% yield) was
obtained from 3.04 g of 15d: mp 182−183 °C; 1H NMR (CDCl3, 400
MHz) δ 5.63 (br s, 1H), 6.72 (d, J = 8.3 Hz, 2H), 6.90 (d, J = 8.8 Hz,
2H), 7.42 (d, J = 8.6 Hz, 2H), 7.49 (d, J = 8.5 Hz, 2H), 7.55 (d, J = 8.8
Hz, 2H), 7.66 (s, 1H), 7.70 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3,
100 MHz) δ 82.3, 95.2, 115.0, 115.4, 127.0 (q, J = 4 Hz), 127.7, 133.5,
135.0, 137.8, 137.9, 143.8, 144.1; HRMS (ESI-TOF) m/z [M + H]+
calcd for C20H15F3I2N3 607.9302, found 607.9280. Anal. Calcd for
C20H14F3I2N3: C, 39.56; H, 2.32; N, 6.92. Found: C, 39.50; H, 2.22; N,
6.86.
N′-Phenyl-N-[4-(trifluoromethyl)phenyl]-4-nitrobenzenecarbohy-
drazonamide (6e). Amidrazone 6e (1.16 g, 19% yield) was obtained
from 5.02 g of 15e: mp 163−165 °C; 1H NMR (CDCl3, 400 MHz) δ
5.72 (br s, 1H), 6.74 (d, J = 8.2 Hz, 2H), 6.97 (t, J = 7.2 Hz, 1H), 7.17
(d, J = 7.8 Hz, 2H), 7.32 (t, J = 7.7 Hz, 2H), 7.49 (d, J = 8.2 Hz, 2H),
7.85 (d, J = 8.7 Hz, 2H), 8.10 (br s, 1H), 8.19 (d, J = 8.7 Hz, 2H); 13C
NMR (CDCl3, 100 MHz) δ 113.8, 114.8, 121.8, 123.1 (q, J = 33 Hz),
124.1, 126.3, 127.3 (q, J = 4 Hz), 127.9 (q, J = 271 Hz), 129.6, 132.2,
140.8, 143.5, 144.5, 147.5; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C20H16F3N4O2 401.1220, found 401.1218.
N′-(4-(Benzoyloxy)phenyl)-N-(4-iodophenyl)-4-(benzoyloxy)-
benzenecarbohydrazonamide (7a). Amidrazone 7a (2.47 g, 58%
1
yield) was obtained from 3.11 g of 16a: mp 87−90 °C; H NMR
(CDCl3, 400 MHz) δ 5.71 (br s, 1H), 6.49 (d, J = 8.8 Hz, 2H), 7.11
(d, J = 9.1 Hz, 2H), 7.15 (d, J = 9.1 Hz, 2H), 7.21 (d, J = 8.8 Hz, 2H),
7.49−7.54 (m, 6H), 7.61−7.67 (m, 3H), 7.75 (d, J = 8.8 Hz, 2H), 8.20
(d, J = 8.5 Hz, 4H); HRMS (ESI-TOF) m/z [M + H]+ calcd for
C33H25IN3O4 654.0884, found 654.0870.
N,N′-Bis(4-iodophenyl)-4-iodobenzenecarbohydrazonamide
(7d). Amidrazone 7d (3.71 g, 58% yield) was obtained from 4.52 g of
16d; mp 189−190 °C; 1H NMR (CDCl3, 400 MHz) δ 5.49 (br s, 1H),
6.46 (d, J = 8.8 Hz, 2H), 6.89 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.6 Hz,
2H), 7.52 (d, J = 8.8 Hz, 2H), 7.54 (d, J = 8.7 Hz, 2H), 7.58 (br s,
1H), 7.69 (d, J = 8.6 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 82.0,
83.0, 95.1, 115.4, 117.9, 127.9, 133.7, 135.9, 137.7, 137.9, 138.3, 140.8,
144.1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C19H15I3N3
665.8395, found 665.8400. Anal. Calcd for C19H14I3N3, C, 34.31; H,
2.21; N, 6.32. Found: C, 34.53; H, 2.14; N, 6.27.
N′-(4-Fluorophenyl)-N-(4-iodophenyl)-4-iodobenzenecarbohy-
drazonamide (8d). Amidrazone 8d (1.49 g, 32% yield) was obtained
from 3.03 g of 17d: mp 199−201 °C; 1H NMR (CDCl3, 400 MHz) δ
5.52 (br s, 1H), 6.62−6.65 (m, 2H), 6.87 (d, J = 8.8 Hz, 2H), 6.93 (t, J
= 8.6 Hz, 2H), 7.40 (d, J = 8.6 Hz, 2H), 7.47 (s, 1H), 7.52 (d, J = 8.8
Hz, 2H), 7.67 (d, J = 8.6 Hz, 2H). HRMS (ESI-TOF) m/z [M + H]+
calcd for C19H15FI2N3 557.9334, found 557.9345.
Method B. In preparation of amidrazones 6a, 6b, 7a, 9a, and 9b,
hydrazine 19a was generated in situ from hydrochloride 19a·HCl by
using an additional equivalent of Et3N.
N′-(4-(Benzoyloxy)phenyl)-N-[4-(trifluoromethyl)phenyl]-4-(benz-
oyloxy)benzenecarbohydrazonamide (6a). Amidrazone 6a (2.34 g,
1
29% yield) was obtained from 5.52 g of 15a: mp 101−103 °C; H
NMR (CDCl3, 400 MHz) δ 5.81 (br s, 1H), 6.76 (d, J = 8.4 Hz, 2H),
7.12 (d, J = 9.0 Hz, 2H), 7.17 (d, J = 9.0 Hz, 2H), 7.23 (d, J = 8.8 Hz,
2H), 7.46−7.54 (m, 5H), 7.62−7.68 (m, 4H), 7.78 (d, J = 8.8 Hz,
2H), 8.20 (d, J = 8.4 Hz, 4H); 13C NMR (CDCl3, 100 MHz) major
signals δ 113.8, 115.3, 121.8, 122.2, 122.6, 126.7, 126.7 (q, J = 4 Hz),
127.4, 128.4, 128.5, 129.1, 129.4, 130.0, 130.1, 131.5, 133.4, 133.6,
N′-(4-(Benzoyloxy)phenyl)-N-phenyl-4-(benzoyloxy)benzene-
carbohydrazonamide (9a). Amidrazone 9a (1.45 g, 37% yield) was
1
obtained from 2.52 g of 18a: mp 87−90 °C; H NMR (CDCl3, 400
MHz) δ 5.70 (br s, 1H), 6.73 (d, J = 7.8 Hz, 2H), 6.94 (t, J = 7.4 Hz,
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1H), 7.11 (d, J = 9.0 Hz, 2H), 7.15 (d, J = 9.1 Hz, 2H), 7.22 (d, J = 8.7
Hz, 2H), 7.26 (t, J = 8.0 Hz, 1H), 7.49−7.53 (m, 4H), 7.61−7.66 (m,
3H), 7.79 (d, J = 8.7 Hz, 2H), 8.20 (d, J = 8.5 Hz, 4H); 13C NMR
(CDCl3, 100 MHz) δ 113.8, 116.0, 121.0, 121.8, 122.2, 127.6, 128.4,
128.5, 129.3, 129.5, 129.7, 130.06, 130.14, 132.5, 133.4, 133.6, 141.1,
142.8, 144.2, 151.4, 164.9, 165.6; HRMS (ESI-TOF) m/z [M + H]+
calcd for C33H26N3O4 528.1918, found 528.1930.
N′-(4-(Benzoyloxy)phenyl)-N-phenyl-4-(benzyloxy)benzene-
carbohydrazonamide (9b). Amidrazone 9b (1.66 g, 26% yield) was
obtained from 4.03 g of 18b; mp 179−182 °C; 1H NMR (CDCl3, 400
MHz) δ 5.08 (s, 2H), 5.71 (br s, 1H), 6.72 (d, J = 7.7 Hz, 2H), 6.92 (t,
J = 8.2 Hz, 1H), 6.95 (d, J = 8.9 Hz, 2H), 7.09 (d, J = 9.0 Hz, 2H),
7.13 (d, J = 9.2 Hz, 2H), 7.22−7.26 (m, 1H), 7.33−7.52 (m, 8H),
7.61−7.63 (m, 1H), 7.65 (d, J = 8.8 Hz, 2H), 8.20 (d, J = 8.4 Hz, 2H);
13C NMR (CDCl3, 100 MHz) δ 70.0, 113.7, 114.8, 116.4, 120.9, 122.1,
127.4, 128.0, 128.1, 128.4, 128.6, 129.4, 129.8, 130.1, 133.3, 136.6,
138.4, 141.2, 143.2, 143.9, 159.6, 165.7; HRMS (ESI-TOF) m/z [M +
H]+ calcd for C33H28N3O3 514.2125, found 514.2151.
General Procedure for Synthesis of Amides 11−14. A solution of
4-trifluoromethylaniline, 4-iodoaniline, 4-fluoroaniline or aniline (10
mmol) in CH2Cl2 (20 mL), and dry Et3N (10 mmol) was treated with
acid chloride (prepared from appropriate acid 10 and oxalyl chloride,
10 mmol) in CH2Cl2 (20 mL). The mixture was stirred for 2 h at rt,
the resulting white precipitate was filtered, and recrystallized from
AcOEt or EtOH.
C14H9F3N2O3: C, 54.20; H, 2.92; N, 9.03. Found: C, 54.47; H,
2.88; N, 9.03.
4-(Benzoyloxy)-N-(4-iodophenyl)benzamide (12a). Amide 12a
(6.89 g, 94% yield) was obtained from 4.31 g of chloride derived
1
from acid 10a: mp >260 °C; H NMR (DMSO-d6, 400 MHz) δ 7.47
(d, J = 8.2 Hz, 2H), 7.62−7.71 (m, 6H), 7.76 (t, J = 7.0 Hz, 1H), 8.06
(d, J = 8.2 Hz, 2H), 8.16 (d, J = 7.5 Hz, 2H), 10.40 (s, 1H); 13C NMR
(DMSO-d6, 100 MHz) major signals δ 122.4, 122.9, 129.4, 129.7,
130.3, 137.7; IR (KBr) 3348 (NH), 1729 (CO), 1649 (CO),
1502, 1281, 815, 706 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C20H15INO3 444.0091, found 444.0084. Anal. Calcd for
C20H14INO3: C, 54.20; H, 3.18; N, 3.16. Found: C, 53.95; H, 3.20;
N, 3.06.
4-Iodo-N-(4-iodophenyl)benzamide (12d). Amide 12d (7.43 g,
88% yield) was obtained from 5.02 g of chloride derived from acid
10d: mp >260 °C; 1H NMR (DMSO-d6, 400 MHz) δ 7.62 (d, J = 8.8
Hz, 2H), 7.68 (d, J = 8.8 Hz, 2H), 7.73 (d, J = 8.6 Hz, 2H), 7.90 (d, J
= 8.6 Hz, 2H), 10.39 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 87.9,
99.9, 122.9, 130.0, 134.4, 137.7 (2C), 139.3, 165.3; IR (KBr) 3327
(NH), 1649 (CO), 1589, 1519, 818 cm−1; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C13H10I2NO 449.8846, found 449.8838. Anal.
Calcd for C13H9I2NO: C, 34.77; H, 2.02; N, 3.12. Found: C, 34.95; H,
1.99; N, 3.14.
4-Iodo-N-(4-fluorophenyl)benzamide (13d). Amide 13d (4.02 g,
90% yield) was obtained from 3.52 g of chloride derived from acid
10d: mp 218−219 °C; 1H NMR (DMSO-d6, 400 MHz) δ 7.18 (t, J =
8.9 Hz, 2H), 7.73 (d, J = 8.4 Hz, 2H), 7.75 (dd, J = 9.1 Hz, J = 5.1 Hz,
2H), 7.91 (d, J = 8.4 Hz, 2H), 10.33 (s, 1H); 13C NMR (DMSO-d6,
100 MHz) δ 99.7, 115.6 (d, J = 22 Hz), 122.6 (d, J = 8 Hz), 130.0,
134.5, 135.7 (d, J = 3 Hz), 137.7, 158.7 (d, J = 240 Hz), 165.1; IR
(KBr) 3328 (NH), 1649 (CO), 1530, 1513, 832 cm−1. Anal. Calcd
for C13H9FINO: C, 45.77; H, 2.66; N, 4.11. Found: C, 45.87; H, 2.75;
N 4.10.
4-Benzoyloxy-N-(4-(trifluoromethyl)phenyl)benzamide (11a).
Amide 11a (8.91 g, 93% yield) was obtained from 5.06 g of chloride
1
derived from acid 10a: mp 285−286 °C DSC; H NMR (DMSO-d6,
400 MHz) δ 7.49 (d, J = 8.6 Hz, 2H), 7.63 (t, J = 7.7 Hz, 2H), 7.72−
7.77 (m, 3H), 8.02 (d, J = 8.6 Hz, 2H), 8.08 (d, J = 8.6 Hz, 2H), 8.16
(d, J = 7.2 Hz, 2H), 10.64 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ
120.5, 122.5, 124.0 (q, J = 32 Hz), 124.9 (q, J = 272 Hz), 126.3 (q, J =
4 Hz), 129.0, 129.4, 129.9, 130.3, 132.6, 134.6, 143.2, 153.7, 164.7,
165.7; IR (KBr) 3350 (NH), 1734 (CO), 1654 (CO), 1116, 705
cm−1. Anal. Calcd for C21H14F3NO3: C, 65.46; H, 3.66; N, 3.63.
Found: C, 65.55; H, 3.76; N, 3.61.
4-Benzoyloxybenzanilide (14a). Amide 14a (3.94 g, 77% yield)
was obtained from 4.24 g of chloride derived from acid 10a: mp 215−
1
217 °C; H NMR (DMSO-d6, 400 MHz) δ 7.11 (t, J = 7.4 Hz, 1H),
7.35 (t, J = 7.9 Hz, 2H), 7.45 (d, J = 8.6 Hz, 2H), 7.62 (t, J = 7.8 Hz,
2H), 7.74−7.78 (m, 3H), 8.05 (d, J = 8.7 Hz, 2H), 8.15 (d, J = 7.2 Hz,
2H), 10.31 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 120.8, 122.4,
124.2, 129.02, 129.04, 129.4, 129.7, 130.3, 133.1, 134.6, 139.4, 153.4,
164.8, 165.2; IR (KBr) 3352 (NH), 1733 (CO), 1649 (CO),
1599, 1530, 1504, 1440, 1279, 705 cm−1. Anal. Calcd for C20H15NO3:
C, 75.70; H, 4.76; N, 4.41. Calcd for C20H15NO3·1/2H2O: C, 73.61; H,
4.94; N, 4.29. Found: C, 73.43; H, 4.95; N, 4.21.
4-Benzyloxybenzanilide (14b). Amide 14b (5.29 g, 86% yield) was
obtained from 5.07 g of chloride derived from acid 10b: mp 210−211
°C (DSC); 1H NMR (DMSO-d6, 400 MHz) δ 5.19 (s, 2H), 7.07 (t, J
= 7.4 Hz, 1H), 7.12 (d, J = 8.9 Hz, 2H), 7.30−7.35 (m, 3H), 7.39 (t, J
= 7.8 Hz, 2H), 7.46 (d, J = 8.6 Hz, 2H), 7.76 (d, J = 9.4 Hz, 2H), 7.95
(d, J = 8.9 Hz, 2H), 10.12 (s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ
69.8, 114.8, 120.7, 123.8, 127.5, 128.2, 128.4, 128.88, 128.93, 130.0,
137.0, 139.7, 161.3, 165.3. Anal. Calcd for C20H17NO2: C, 79.19; H,
5.65; N, 4.62. Found: C, 79.21; H, 5.47; N 4.56.
General Procedure for Synthesis of Benzimidoyl Chlorides (15−
18). Amide 11−14 (1 mmol) was dissolved in excess SOCl2, and the
mixture was refluxed overnight. Excess SOCl2 was evaporated to give
crude imidoyl chloride as a pale yellow solid, which was used for the
next step without additional purification.
4-Benzoyloxy-N-(4-(trifluoromethyl)phenyl)benzimidoyl Chloride
(15a). Chloride 15a (6.29 g, 98% yield) was obtained from 6.05 g of
11a: mp 175−177 °C; 1H NMR (CDCl3, 400 MHz) δ 7.09 (d, J = 8.3
Hz, 2H), 7.37 (d, J = 8.8 Hz, 2H), 7.54 (t, J = 7.7 Hz, 2H), 7.66−7.71
(m, 3H), 8.23 (d, J = 8.0 Hz, 2H), 8.26 (d, J = 8.8 Hz, 2H); 13C NMR
(CDCl3, 100 MHz) δ 120.5; 121.9, 126.2 (q, J = 3 Hz), 127.0 (q, J =
32 Hz), 128.6, 129.0, 130.2, 130.9, 132.4, 133.9, 150.5, 154.3, 164.6
(the CF3 signal was not located); HRMS (ESI-TOF) m/z [M + H]+
calcd for C21H14ClF3NO2 404.0665, found 404.0659.
4-Benzyloxy-N-(4-(trifluoromethyl)phenyl)benzamide (11b).
Amide 11b (7.04 g, 98% yield) was obtained from 4.75 g of chloride
derived from acid 10b: mp 219−220 °C; H NMR (DMSO-d6, 400
1
MHz) δ 5.20 (s, 2H), 7.14 (d, J = 8.9 Hz, 2H,), 7.33 (t, J = 7.2 Hz,
1H), 7.40 (t, J = 7.3 Hz, 2H), 7.46 (d, J = 7.1 Hz, 2H), 7.69 (d, J = 8.7
Hz, 2H), 7.97 (d, J = 8.6 Hz, 2H), 8.01 (d, J = 8.6 Hz, 2H), 10.45 (s,
1H); 13C NMR (DMSO-d6, 100 MHz) δ 69.8, 114.9, 120.4, 123.6 (q, J
= 32 Hz), 124.8 (q, J = 274 Hz), 126.2 (q, J = 4 Hz), 127.0, 128.2,
128.4, 128.9, 130.2, 137.0, 143.4, 161.6, 165.7; IR (KBr) 3226 (NH),
1645 (CO), 1605, 1246, 1173, 754 cm−1. Anal. Calcd for
C21H16F3NO2: C, 67.92; H, 4.34; N, 3.77. Found: C, 67.69; H,
4.20; N, 3.75.
4-Iodo-N-(4-(trifluoromethyl)phenyl)benzamide (11d). Amide
11d (6.96 g, 95% yield) was obtained from 5.03 g of chloride derived
1
from acid 10d: mp 228−230 °C DSC; H NMR (DMSO-d6, 400
MHz) δ 7.72 (d, J = 8.6 Hz, 2H), 7.75 (d, J = 8.4 Hz, 2H), 7.93 (d, J =
8.3 Hz, 2H), 7.99 (d, J = 8.5 Hz, 2H), 10.61 (s, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ 100.1, 120.6, 124.1 (q, J = 32 Hz), 124.7 (q, J
= 271 Hz), 126.2 (q, J = 4 Hz), 130.1, 134.2, 137.7, 143.0, 165.7; IR
(KBr) 3330 (NH), 1657 (CO), 1529, 1331, 1127, 833 cm−1;
HRMS (ESI-TOF) m/z [M + H]+ calcd for C14H10F3INO 391.9754,
found 391.9754. Anal. Calcd for C14H9F3INO: C, 42.99; H, 2.32; N,
3.58. Found: C, 42.89; H, 2.34; N 3.53.
4-Nitro-N-(4-(trifluoromethyl)phenyl)benzamide (11e).47 Amide
11e (5.07 g, 99% yield) was obtained from 3.12 g of chloride derived
from acid 10e: mp 213−214 °C DSC (lit.47 mp 194−196 °C); H
1
NMR (DMSO-d6, 400 MHz) δ 7.73 (d, J = 8.6 Hz, 2H,), 8.00 (d, J =
8.5 Hz, 2H), 8.19 (d, J = 8.9 Hz, 2H), 8.37 (d, J = 8.9 Hz, 2H), 10.86
(s, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 120.5, 123.9, 124.5 (q, J =
32 Hz), 124.7 (q, J = 271 Hz), 126.3 (q, J = 4 Hz), 129.9, 140.3, 142.8,
149.7, 164.8; IR (KBr) 3414 (NH), 1680 (CO), 1603, 1535, 1516,
1347, 1323, 1120, 1065 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd
for C14H10F3N2O3 311.0638, found 311.0638. Anal. Calcd for
4-(Benzyloxy)-N-(4-(trifluoromethyl)phenyl)benzimidoyl Chloride
(15b). Chloride 15b (7.33 g, 99% yield) was obtained from 7.04 g of
1
11b: mp 129−130 °C; H NMR (CDCl3, 400 MHz) δ 5.16 (s, 2H),
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7.04−7.06 (m, 4H), 7.40−7.43 (m, 5H), 7.64 (d, J = 8.4 Hz, 2H), 8.10
(d, J = 9.0 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 70.2, 114.7,
120.7, 124.2 (q, J = 272 Hz), 126.1 (q, J = 4 Hz), 126.7 (q, J = 33 Hz),
127.4, 127.5, 128.2, 128.7, 131.4, 136.1, 144.2, 150.8, 162.2; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C21H16ClF3NO 390.0872, found
390.0866.
giving crude product 22 as an orange oil, which was purified by flash
chromatography (SiO2, CH2Cl2). Recrystallization from hexane gave
analytically pure hydrazone 22 as yellow crystals.
2-Benzylidene-1-(4-(benzyloxy)phenyl)-1-(2-nitro-4-(trifluoro-
methyl)phenyl)hydrazine (22b). Hydrazone 22b (0.601 g, 60% yield)
1
was obtained from 0.620 g of hydrazone 20b: mp 132−134 °C; H
NMR (CDCl3, 400 MHz) δ 5.16 (s, 2H), 6.85 (d, J = 8.8 Hz, 1H),
7.20 (d, J = 9.0 Hz, 2H), 7.25 (d, J = 9.0 Hz, 2H), 7.30−7.50 (m,
4-Iodo-N-(4-(trifluoromethyl)phenyl)benzimidoyl Chloride (15d).
Chloride 15d (6.19 g, 91% yield) was obtained from 6.51 g of 11d: mp
1
1
12H), 7.87 (d, J = 1.3 Hz, 1H); H NMR (DMSO-d6, 400 MHz) δ
101−103 °C; H NMR (CD3CN, 400 MHz) δ 7.14 (d, J = 8.2 Hz,
2H), 7.74 (d, J = 8.3 Hz, 2H), 7.88 (d, J = 8.8 Hz, 2H), 7.93 (d, J = 8.8
Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 100.1, 120.5, 124.2 (q, J =
272), 126.2 (q, J = 4 Hz), 127.2 (q, J = 33 Hz), 130.8, 134.4, 137.8,
144.2, 150.3; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C14H9ClIF3N 409.9420, found 409.9416.
4-Nitro-N-(4-(trifluoromethyl)phenyl)benzimidoyl Chloride (15e).
Chloride 15e (5.24 g, 99% yield) was obtained from 5.03 g of 11e: mp
132−134 °C; 1H NMR (CDCl3, 400 MHz) δ 7.11 (d, J = 8.2 Hz, 2H),
7.72 (d, J = 8.4 Hz, 2H), 8.35 (s, 4H); 13C NMR (CDCl3, 100 MHz) δ
120.2, 123.4, 123.8 (q, J = 272 Hz), 126.0 (q, J = 4 Hz), 127.2 (q, J =
33 Hz), 130.3, 140.0, 142.0, 149.7 (C-NO2 not observed); HRMS
(ESI-TOF) m/z [M + H]+ calcd for C14H9ClF3N2O2 329.0304, found
329.0316.
5.19 (s, 2H), 7.01 (d, J = 9.0 Hz, 2H), 7.24 (d, J = 9.0 Hz, 2H), 7.32−
7.41 (m, 4H), 7.43 (t, J = 7.3 Hz, 2H), 7.48−7.53 (m, 4H), 7.75 (dd, J
= 9.0 Hz, J = 2.0 Hz, 1H), 8.18 (d, J = 1.6 Hz, 1H); 13C NMR
(DMSO-d6, 100 MHz) major signals δ 70.1, 117.6, 120.6, 127.1, 128.4,
128.5, 129.0, 129.2, 129.9, 130.9, 134.5, 136.9, 140.3, 140.6, 151.4,
159.4; IR (KBr) 1622, 1532, 1502, 1324, 1280, 1130 cm−1; HRMS
(ESI-TOF) m/z [M + H]+ calcd for C27H21F3N3O3 492.1530, found
492.1518. Anal. Calcd for C27H20F3N3O3: C, 65.98; H, 4.10; N, 8.55.
Found: C, 65.68; H, 4.06; N, 8.38.
2-Benzylidene-1-(4-iodophenyl)-1-(2-nitro-4-(trifluoromethyl)-
phenyl)hydrazine (22c). Hydrazone 22c (1.052 g, 80% yield) was
1
obtained from 0.823 g of hydrazone 20c: mp 117−119 °C; H NMR
(CDCl3, 400 MHz) δ 6.97 (d, J = 8.7 Hz, 1H), 7.05 (d, J = 8.6 Hz,
2H), 7.29 (s, 1H), 7.32−7.38 (m, 3H), 7.48 (dd, J = 8.0 Hz, J = 1.9
Hz, 2H), 7.59 (dd, J = 8.8 Hz, J = 1.8 Hz, 1H), 7.91 (d, J = 8.6 Hz,
2H), 7.98 (d, J = 1.5 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 93.8,
122.3, 123.0 (q, J = 272 Hz), 123.2 (q, J = 4 Hz), 124.4 (q, J = 34 Hz),
126.9, 128.6 (q, J = 4 Hz), 128.7, 129.3, 129.7, 133.9, 138.7, 140.0,
141.1, 141.6, 141.9; IR (KBr) 1623 (CN), 1537, 1324, 1281, 1124
cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for C20H14F3IN3O2
512.0077, found 512.0094. Anal. Calcd for C20H13F3IN3O2: C, 46.99;
H, 2.56; N, 8.22. Found: C, 47.29; H, 2.77; N, 8.20.
4-(Benzoyloxy)-N-(4-iodophenyl)benzimidoyl Chloride (16a).
Chloride 16a (3.64 g, 99% yield) was obtained from 3.51 g of 12a:
mp 156−158 °C; 1H NMR (CDCl3, 400 MHz) δ 6.79 (d, J = 8.6 Hz,
2H), 7.35 (d, J = 8.8 Hz, 2H), 7.54 (t, J = 7.7 Hz, 2H), 7.67 (t, J = 9.1
Hz, 1H), 7.72 (d, J = 8.6 Hz, 2H), 8.21−8.25 (m, 4H); 13C NMR
(CDCl3, 100 MHz) δ 89.2, 121.8, 122.6, 128.6, 129.0, 130.2, 130.9,
132.7, 133.9, 137.9, 143.0, 147.1, 154.1, 164.6; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C20H14ClINO2 461.9758, found 461.9766.
4-Iodo-N-(4-iodophenyl)benzimidoyl Chloride (16d). Chloride
16d (6.55 g, 90% yield) was obtained from 7.04 g of 12d: mp 104−
107 °C; 1H NMR (CDCl3, 400 MHz) δ 6.78 (d, J = 8.6 Hz, 2H), 7.72
(d, J = 8.6 Hz, 2H), 7.83 (d, J = 8.9 Hz, 2H), 7.86 (d, J = 8.9 Hz, 2H);
13C NMR (CDCl3, 100 MHz) δ 100.1, 120.4, 126.17, 126.20, 130.8,
134.4, 137.8, 144.2, 150.3. 13C NMR (CDCl3, 100 MHz) δ 89.4, 99.8,
122.5, 130.7, 134.7, 137.7, 137.9, 143.2, 146.8; HRMS (ESI-TOF) m/z
[M + H]+ calcd for C13H9ClI2N 467.8513, found 467.8528.
4-Iodo-N-(4-fluorophenyl)benzimidoyl Chloride (17d). Chloride
17d (3.64 g, 99% yield) was obtained from 3.53 g of 13d: mp 209−
General Procedure for Synthesis of Hydrazine 23. Following a
general procedure,18 a mixture of hydrazone 22 (1 mmol) and
H2NOH·HCl (10 mmol) in pyridine (7 mL) was heated at ca. 80 °C
for 20 h. Pyridine was removed in vacuo, the residue was treated with
CH2Cl2, and the resulting suspension was filtered to remove excess
H2NOH·HCl. The filtrate was diluted with additional portion of
CH2Cl2 (20 mL) and washed with 2 M KOH (20 mL), 10% HCl (20
mL), and H2O (20 mL). The organic phase was separated and dried
(Na2SO4), and after evaporation of the solvent, the crude product was
purified by flash chromatography (SiO2, hexane/CH2Cl2, 3:1).
Analytically pure hydrazine 23 was obtained by recrystallization from
hexane.
1
212 °C; H NMR (CDCl3, 400 MHz) δ 7.02 (dd, J = 9.0 Hz, J = 4.9
Hz, 2H), 7.10 (t, J = 8.7 Hz, 2H), 7.82 (d, J = 8.8 Hz, 2H), 7.87 (d, J =
8.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 99.5, 115.6 (d, J = 23
Hz), 122.2 (d, J = 8 Hz), 128.5, 130.7, 134.9, 137.7, 138.0, 160.4 (d, J
= 245 Hz); HRMS (ESI-TOF) m/z [M + H]+ calcd for C13H9ClIFN
359.9452, found 359.9460.
1-(4-(Benzyloxy)phenyl)-1-(2-nitro-4-(trifluoromethyl)phenyl)-
hydrazine (23b). Hydrazine 23b (0.298 g, 64% yield) was obtained
from 0.551 g of 22b: 1H NMR (DMSO-d6, 400 MHz) δ 5.09 (s, 2H),
5.40 (s, 2H), 7.01 (d, J = 9.0 Hz, 2H), 7.24 (d, J = 9.0 Hz, 2H), 7.32−
7.46 (m, 6H), 7.67 (dd, J = 9.0 Hz, J = 2.2 Hz, 1H), 7.95 (d, J = 1.7
Hz, 1H); 13C NMR (DMSO-d6, 100 MHz) δ 69.8, 115.9, 118.7 (q, J =
34 Hz), 120.8, 123.50 (q, J = 4 Hz), 123.7, 124.0 (q, J = 271 Hz),
128.1, 128.2, 128.8, 129.2 (q, J = 3 Hz), 137.4, 139.1, 140.3, 146.1,
4-Benzoyloxy-N-phenylbenzimidoyl Chloride (18a). Chloride 18a
(3.66 g, 99% yield) was obtained from 3.51 g of 14a: mp 119−120 °C;
1H NMR (CDCl3, 400 MHz) δ 7.03 (d, J = 7.3 Hz, 2H), 7.22 (t, J =
8.0 Hz, 1H), 7.36 (d, J = 8.9 Hz, 2H), 7.42 (t, J = 7.9 Hz, 2H), 7.54 (t,
J = 7.7 Hz, 2H), 7.67 (t, J = 7.4 Hz, 1H), 8.23 (d, J = 9.6 Hz, 2H), 8.26
(d, J = 8.8 Hz, 2H); 13C NMR (CDCl3, 100 MHz) δ 120.4, 122.7,
125.1, 128.6, 128.8, 129.1, 130.0, 130.8, 133.0, 133.8, 142.2, 147.5,
153.9, 164.6; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C20H15ClNO2 336.0791, found 336.0783.
4-Benzyloxy-N-phenylbenzimidoyl Chloride (18b). Chloride 18b
(5.24 g, 99% yield) was obtained from 5.02 g of 14b: mp 98−100 °C;
1H NMR (CDCl3, 400 MHz) δ 5.17 (s, 2H), 7.04−7.07 (m, 4H), 7.24
(t, J = 9.3 Hz, 1H), 7.37−7.47 (m, 6H), 8.17 (d, J = 8.9 Hz, 2H); 13C
NMR (CDCl3, 100 MHz) δ 70.1, 114.5, 120.5, 124.7, 127.4, 128.1,
128.2, 128.6, 128.7, 131.2, 136.2, 142.8, 147.7, 161.8; HRMS (ESI-
TOF) m/z [M + H]+ calcd for C20H17ClNO 322.0999, found
322.0986.
General Procedure for Synthesis of Hydrazones 22. A mixture of
benzaldehyde hydrazone 20 (1 mmol), 4-fluoro-3-nitro-
(trifluoromethyl)benzene (21, 1.1 mmol), and K2CO3 (1.1 mmol)
in DMSO (1 mL) and H2O (0.01 mL) was stirred overnight at rt. The
mixture was diluted with AcOEt (20 mL) and washed with H2O (20
mL), 10% HCl (20 mL), 10% NaOH (20 mL), and brine. The organic
phase was separated and dried (Na2SO4), and the solvent was removed
156.0. HRMS (ESI-TOF) m/z [M
C20H16F3N3O3•Na 426.1036, found 426.1036.
+
Na]+ calcd for
1-(4-Iodophenyl)-1-(2-nitro-4-(trifluoromethyl)phenyl)hydrazine
(23c). Hydrazine 23c (0.383 g, 77% yield) was obtained from 0.603 g
of 22c: mp 86−88 °C; 1H NMR (CDCl3, 400 MHz) δ 4.36 (bs, 2H),
6.90 (d, J = 8.9 Hz, 2H), 7.50 (d, J = 8.7 Hz, 1H), 7.61 (d, J = 9.0 Hz,
2H), 7.65 (dd, J = 8.4 Hz, J = 1.8 Hz, 1H), 8.06 (d, J = 1.5 Hz, 1H);
1H NMR (DMSO-d6, 400 MHz) δ 5.50 (s, 2H), 7.03 (d, J = 8.9 Hz,
2H), 7.61 (d, J = 8.9 Hz, 2H), 7.65 (d, J = 8.8 Hz, 1H), 7.81 (dd, J =
8.9 Hz, J = 2.1 Hz, 1H), 8.08 (d, J = 1.6 Hz, 1H); 13C NMR (CDCl3,
100 MHz) major signals δ 86.4, 120.0, 123.8 (q, J = 4 Hz), 124.6,
129.3 (q, J = 3 Hz), 138.4, 142.0, 144.4, 146.6; 13C NMR (DMSO-d6,
100 MHz) δ 86.5, 121.15, 121.17 (q, J = 34 Hz), 123.2 (q, J = 4 Hz),
123.4 (q, J = 272 Hz), 123.6, 129.4 (q, J = 3 Hz), 137.6, 140.7, 144.5,
146.7. Anal. Calcd for C13H9F3IN3O2: C, 36.90; H, 2.14; N, 9.93.
Found, C, 36.99; H, 2.26; N, 9.85.
Methyl 4-(2-(4-(benzyloxy)phenyl)-2-(2-nitro-4-(trifluoromethyl)-
phenyl)hydrazinecarbonyl)benzoate (24h). A solution of hydrazine
23c (358 mg, 0.846 mmol) and Et3N (0.26 mL, 1.86 mmol) in dry
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CH2Cl2 (6 mL) at −5 °C was treated with a solution of acid chloride,
derived from acid 10h (368 mg, 1.86 mmol), in CH2Cl2 (4 mL). The
resulting mixture was slowly warmed to rt and stirred overnight. The
reaction mixture was diluted with CH2Cl2, washed with H2O (2 × 20
mL), dried (Na2SO4), and concentrated in vacuo. The resulting
mixture of products was fractionated by flash chromatography (SiO2,
hexane/CH2Cl2, gradient) giving 65 mg of recovered hydrazine 23c as
the first fraction and 353 mg (71% yield) of hydrazide 24h as the more
ACKNOWLEDGMENTS
■
We thank Dr. Aleksandra Jankowiak for assistance with
spectroscopic analysis and Prof. Panayiotis A. Koutentis for
helpful discussions. This work was supported by the NSF
(Grant No. CHE-1214104). M.Z. thanks for financial support
provided by The National Natural Science Foundation of
China (No. 21102121).
1
polar yellow compound: mp 207−209 °C; H NMR (CDCl3, 400
MHz) δ 3.96 (s, 3H), 6.80 (d, J = 8.2 Hz, 2H), 7.60 (d, J = 7.9 Hz,
2H), 7.84 (s, 4H), 8.14 (d, J = 7.7 Hz, 2H), 8.25 (s, 1H), 8.60 (s, 1H);
1H NMR (DMSO-d6, 400 MHz) δ 3.88 (s, 3H), 6.94 (d, J = 8.9 Hz,
2H), 7.63 (d, J = 6.4 Hz, 1H), 7.64 (d, J = 8.8 Hz, 2H), 7.94−7.99 (m,
3H), 8.07−8.12 (m, 3H), 8.23 (d, J = 1.4 Hz, 1H); 13C NMR
(DMSO-d6, 100 MHz) δ 52.9, 88.6, 121.9, 123.6 (q, J = 271 Hz),
123.8 (q, J = 4 Hz), 124.1, 128.5, 129.8, 130.2 (q, J = 32 Hz), 130.8 (q,
J = 3.3 Hz), 133.2, 135.8, 138.4, 140.8, 141.5, 144.4, 165.4, 165.9; IR
(KBr) 3169 (NH), 1716 (CO), 1673 (CO), 1531, 1327, 1291,
1120 cm−1; HRMS (ESI-TOF) m/z [M + H]+ calcd for
C22H16F3IN3O5 586.0087, found 586.0058. Anal. Calcd for
C22H15F3IN3O5: C, 45.15; H, 2.58; N, 7.18. Found: C, 45.27; H,
2.71; N, 6.89.
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The authors declare no competing financial interest.
§On leave from the Center of Molecular and Macromolecular
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∥Visiting professor from the School of Chemistry and Chemical
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⊥Visiting undergraduate student from the group of Prof.
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