Preparation of Halogenated Fluorescent Diaminophenazine Building Blocks

Article abstract of DOI:10.1021/acs.joc.5b01339

A short, convenient, and scalable protocol for the one-pot synthesis of a series of fluorescent 7,8-dihalo-2,3-diaminophenazines is introduced. The synthetic route is based on the oxidative condensation of 4,5-dihalo-1,2-diaminobenzenes in aqueous conditions. The resulting diaminophenazines could be attractive intermediates for the preparation of polyfunctional phenazines and extended polyheteroacenes. We find that the undesired hydroxylation byproducts, typically obtained in aqueous conditions, are completely suppressed by addition of a stoichiometric amount of acetone during the oxidation step allowing for selective formation of 7,8-dihalo-2,2-dimethyl-2,3-dihydro-1H-imidazo[4,5-b]phenazine derivatives with good to excellent yields. Under reductive conditions, the imidazolidine ring can be hydrolyzed into the desired 7,8-dihalo-2,3-diaminophenazines. Furthermore, we report a selective route under highly reducing conditions to monohydrodeaminate the 2,3-di(methylamino) phenazine derivatives, which allows for further structural variations of these phenazine building blocks. All of these derivatives are luminescent, with measured fluorescence quantum-yields of up to 80% in ethanol for the more rigid structures, highlighting the potential of such materials to provide new fluorophores.

Full text of DOI:10.1021/acs.joc.5b01339

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Article
Preparation of Halogenated Fluorescent Diaminophenazine Building Blocks
Matthieu Koepf, Shin Hee Lee, Bradley J. Brennan, Dalvin D Méndez-
Hernández, Victor S. Batista, Gary W. Brudvig, and Robert H. Crabtree
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b01339 • Publication Date (Web): 21 Sep 2015
Downloaded from http://pubs.acs.org on September 22, 2015
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Preparation of Halogenated Fluorescent
Diaminophenazine Building Blocks
Matthieu Koepf‡†, Shin Hee Lee‡, Bradley J. Brennan, Dalvin D. MéndezꢀHernández, Victor S. Batista,
Gary W. Brudvig and Robert H. Crabtree*
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Energy Sciences Institute, and Department of Chemistry, Yale University, P.O. Box 208107, New Haven,
Connecticut 06520ꢀ8107, USA; Eꢀmail: robert.crabtree@yale.edu
ABSTRACT: A short, convenient, and scalable protocol for the oneꢀpot synthesis of a series of
fluorescent 7,8ꢀdihaloꢀ2,3ꢀdiaminophenazines is introduced. The synthetic route is based on the
oxidative condensation of 4,5ꢀdihaloꢀ1,2ꢀdiaminobenzenes in aqueous conditions. The resulting
diaminophenazines could be attractive intermediates for the preparation of polyfunctional phenazines
and extended polyheteroacenes. We find that the undesired hydroxylation byproducts, typically obtained
in aqueous conditions, are completely suppressed by addition of a stoichiometric amount of acetone
during the oxidation step allowing for selective formation of 7,8ꢀdihaloꢀ2,2ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀ
imidazo[4,5ꢀb]phenazine derivatives with good to excellent yields. Under reductive conditions, the
imidazolidine ring can be hydrolyzed into the desired 7,8ꢀdihaloꢀ2,3ꢀdiaminophenazines. Furthermore,
we report a selective route under highly reducing conditions to monoꢀhydrodeaminate the 2,3ꢀ
di(methylamino) phenazine derivatives, which allows for further structural variations of these phenazine
building blocks. All of these derivatives are luminescent, with measured fluorescence quantumꢀyields of
up to 80% in ethanol for the more rigid structures, highlighting the potential of such materials to provide
new fluorophores.
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INTRODUCTION
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Phenazines, (i.e. 5,9ꢀdiazaanthracenes) and their derivatives are important and versatile building
blocks for the preparation of industrial dyes,1 fluorescent or electroꢀactive markers in biological
systems,2,3 antibiotics and antiꢀcancer agents,4ꢀ6 electroꢀactive materials for OFETs, OLEDs, and solid
state memories,7,8 as well as photoactive materials for dye sensitized solar cells and for photocatalysis.9ꢀ
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There is, therefore, a great need to develop efficient protocols for synthesis of these important
building blocks. In this paper, we introduce a convenient and very short synthetic route to 7,8ꢀdihaloꢀ
2,3ꢀdiaminophenazines based on oxidative condensation of 4,5ꢀdihaloꢀ1,2ꢀdiaminobenzenes in aqueous
conditions. The products are suitable for further functionalization to adapt them for a variety of potential
applications.
Several wellꢀestablished methods are available for the preparation of functionalized phenazines.5
The most popular route is based on direct condensation of adequately functionalized oꢀquinone or
catechol with oꢀphenylenediamine derivatives.13ꢀ15 This method permits the preparation of a variety of
extended polyazaacene cores in modest to high yields from readily available starting materials. Other
methods feature the intramolecular cyclization of substituted diphenylamines such as 2,2’ꢀ
diaminodiphenylamines and 2ꢀaminodiphenylamines,16,17 2ꢀnitrodiphenylamines,18 or 2ꢀfluoroꢀ2’ꢀ
nitrodiphenylamines;19 the Pdꢀcatalyzed cyclization of 2ꢀaminoꢀ2’ꢀbromodiphenylamines;20 the
chemical21ꢀ23 or electrochemical24ꢀ26 oxidative cyclization of fluorinated aniline derivatives; and the
oxidative condensation of oꢀphenylenediamines.27,28 We investigate the latter strategy and present an
expeditious protocol for the synthesis of 7,8ꢀdihaloꢀ2,3ꢀdiaminophenazines, where the halogen
substituents can be F, Cl , or Br.
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Our work fills a gap in the literature pertaining to strategies for the preparation of 7,8ꢀdihaloꢀ2,3ꢀ
diaminophenazines, which appear to be appealing building blocks for the preparation of larger
heteroacenes and polyfunctional materials.29ꢀ31 This gap is surprising, considering that the synthesis of 7ꢀ
chloroꢀ and 7ꢀbromoꢀ2,3ꢀdiaminophenazines has been previously described from oxidative coupling of
4ꢀchloroꢀ and 4ꢀbromoꢀ1,2ꢀdiaminobenzene in the presence of iron trichloride or hydrogen
peroxide.28,32,33 In these examples, the cyclization systematically led to the elimination of the halide
substituent rather than leading to a reaction involving the two adjacent unsubstituted positions (positions
5 and 6). This selectivity pattern suggested dihalogenated oꢀphenylenediamines as judicious starting
materials for the preparation of the corresponding 7,8ꢀdihaloꢀ2,3ꢀdiaminophenazines.
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RESULTS AND DISCUSSION
As previously observed in the case of monoꢀhalogenated and halogen free 1,2ꢀ
diaminobenzenes,28,34,35 the direct treatment of 4,5ꢀdihaloꢀ1,2ꢀdiaminobenzene with aqueous iron
trichloride, under acidic conditions, leads to the formation of a mixture of products that include
monohydroxylated 7,8ꢀdihaloꢀphenazine derivatives (Scheme 1 and Supporting Information). We find
that the presence of an equimolar amount of acetone allows for the oxidation of 4,5ꢀdihaloꢀ1,2ꢀ
diaminobenzene derivatives selectively, yielding the corresponding 7,8ꢀdihaloꢀ2,2ꢀdimethylꢀ2,3ꢀ
dihydroꢀ1Hꢀimidazo[4,5ꢀb]phenazine, with good to excellent yields (Scheme 1). Moreover, formation of
both 2,3ꢀdiaminophenazines and hydroxylated derivatives can be completely suppressed under
optimized conditions.36 In the case of the halogenꢀfree oꢀphenylenediamine starting material, however,
hydroxylation of the phenazine could not be entirely suppressed, even upon addition of a large excess of
acetone (see SI).
The selective formation of the imidazolidine derivatives 3a─c from the halogenated oꢀ
phenylenediamines is remarkable. In test reactions, the direct condensation of acetone with 7,8ꢀdichloroꢀ
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1,2ꢀdiaminophenazine was not observed under simple acid catalysis. It is, therefore, likely that cyclic
acetone adducts of the 4,5ꢀdihaloꢀ1,2ꢀdiaminobenzene starting material are formed prior to condensation
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of the phenazine backbone. Plausible intermediates that could lead to the imidazolidine derivatives are
the corresponding 5,6ꢀdihaloꢀ2,2ꢀdimethylꢀ2Hꢀbenzo[d]imidazoles.
Scheme 1. Chemicallyꢀdriven oxidative condensation of 4,5ꢀdihaloꢀ1,2ꢀdiaminobenzene derivatives in
aqueous conditions, in absence (right) or presence (bottom left) of acetone.
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b
Based on the isolated mixture of products. Ratio estimated using liquid chromatography mass
spectrometry (LCMS) analysis.
This idea is consistent with previous studies showing that 2Hꢀbenzo[d]imidazoles can readily undergo
nucleophilic attack on the 5 and 6 positions, due to their oꢀbenzoquinone diimine character.37,38
Furthermore, highly efficient ipso substitution of chloro groups was reported upon treatment of 5,6ꢀ
dichloroꢀ2Hꢀbenzo[d]imidazole with N, O, or S nucleophiles.39 In the latter study, the authors identified
a phenazine derivative as the major byproduct of the reaction. The formation of the phenazine derivative
was explained by the reaction of 5,6ꢀdichloroꢀ2Hꢀbenzo[d]imidazole with traces of 4,5ꢀdichloroꢀ1,2ꢀ
diaminobenzene that were present after the in situ hydrolysis of the former.39
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The condensation of acetone on oꢀphenylenediamine to form 2,2ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀ
benzo[d]imidazole is known to have very fast kinetics under mild acid catalysis.40 Therefore, it is likely
that under the strongly acidic conditions used in the present work, the starting 4,5ꢀdihaloꢀ1,2ꢀ
diaminobenzenes equilibrate with the corresponding 5,6ꢀdihaloꢀ2,2ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀ
benzo[d]imidazole derivatives. In the latter derivatives, the inclusion of the two amino groups in a five
membered ring increases their conjugation with the adjacent phenyl ring. This may explain the selective
oxidation of the 5,6ꢀdihaloꢀ2,2ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀbenzo[d]imidazole derivatives by iron
trichloride over the nonꢀcyclized 4,5ꢀdihaloꢀ1,2ꢀdiaminobenzenes and, thus, the formation of the 5,6ꢀ
dihaloꢀ2,2ꢀdimethylꢀ2Hꢀbenzo[d]imidazole intermediates.
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In the proposed reaction scheme (cf. to SI), the formation of the phenazines 3a─c results from the
ipso substitution of the halogen groups in the 5,6ꢀdihaloꢀ2,2ꢀdimethylꢀ2Hꢀbenzo[d]imidazoles by the
remaining oꢀphenylenediamines, followed by the tautomerization into the final imidazolidine products.
Due to the complex sequence of reactions required for formation of the latter compounds in a oneꢀpot
approach, a strict control of the stoichiometry of the reagents is crucial to achieve high yields.
Importantly, this strategy is readily scalable to gramꢀscale synthesis as shown for compound 3b (see
experimental section).
The assignment of 3a─c as having a fully oxidized phenazine core fused to a dihydroꢀimidazole
(imidazolidine) ring is supported by extensive NMR characterization (see SI). In particular, the
observation of throughꢀspace spin polarization transfer (NOE), between the protons of the methyl groups
and those of the amine groups, unambiguously permitted the assignment of the secondary amine groups
to the five membered rings rather than to the pyrazine cycle.
Next, we investigated ways to obtain the desired 7,8ꢀdihaloꢀ2,3ꢀdiaminophenazine cores by opening
the imidazolidine ring. First, we examined the acidꢀcatalyzed hydrolysis of the Me2C protecting group
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using 3b as a model compound. Negligible hydrolysis to 1b occurred under any of the following
conditions: concentrated HCl; TFA or sulfuric acid in the presence of 5–10% of water between room
temperature and 60°C. Upon treatment of 3b with 5ꢀ10% water in concentrated sulfuric acid (or TFA), at
temperatures higher than 70°C, slow hydrolysis of the Me2C protecting group occurred over the course
of several days, yielding the desired phenazine 1b concurrently with the formation of the undesired
monohydroxylated derivative 2b. Unfortunately, the latter process could not be avoided and it hampered
the use of acid hydrolysis as a direct way to obtain the targeted diaminophenazine derivatives.
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Noting that the electron withdrawing character of the phenazine core may impede deprotection by
greatly increasing the acidity of the amino substituents, we thought that its reduction to the
corresponding N,Nꢀdihydrophenazine might allow hydrolysis of the Me2C protecting group under mild
conditions. Indeed, we find that the treatment of 3b with an aqueous solution of sodium dithionite at
room temperature, under an inert atmosphere, directly leads to the very clean deprotection of the amines.
After completion of the hydrolysis, simple exposure to air led to the spontaneous oxidation of the N,Nꢀ
dihydrophenazine intermediate to give 1b in excellent yields (Scheme 2). This approach was very
efficient for all three imidazolidine derivatives 3a─c, with no noticeable side reactions.
Scheme 2. Hydrolysis of the Me2C protecting group under reductive conditions.
Interestingly, no additional acid catalyst was required to promote the reaction; after the reduction of
the phenazine core, the weakly acidic solution resulting from the decomposition of sodium dithionite
was sufficient to fully hydrolyze the Me2C protecting group.41 This simple protocol thus provides a very
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convenient way to deprotect the 7,8ꢀdihaloꢀ2,2ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀb]phenazine
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series, and permits the preparation of a variety of 7,8ꢀdihaloꢀ1,2ꢀdiaminophenazines in high yields.
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The imidazolidine series was expanded via alkylation of 3a─c with MeI to obtain the very soluble
derivatives 4a─c (Scheme 3). The latter failed to undergo hydrolysis of the Me2C protecting group under
the conditions used for the parent 3a─c derivatives. After treatment with sodium dithionite and reꢀ
oxidation in air, most of the starting material was recovered; no traces of the desired 7,8ꢀdihaloꢀ2,3ꢀ
di(methylamino)phenazines could be detected. Neither the addition of catalytic amounts of strong acid
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(trifluoroacetic acid, hydrochloric acid, or p-toluenesulfonic acid) after full reduction of the starting
material nor the direct treatment of 4b with SnCl2 in hydrochloric acid provided the desired products.
Treatment with zinc powder in aqueous conditions in the presence of acetic acid, however, permitted the
isolation of the desired 7,8ꢀdihaloꢀ2,3ꢀdi(methylamino)phenazines 5a─c in good yields (Scheme 3).
Scheme 3. Nꢀmethylation of compounds 3a─c, hydrolysis of the Me2C protecting group under reductive
conditions, and hydrodeamination.
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Portionꢀwise addition of the reagents; addition of 7.5 – 15 equivalents of zinc. Direct addition of a
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large excess of the reagents; addition of 25ꢀ50 equivalents of zinc. See SI for detailed procedures.
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Monoꢀhydrodeamination of the desired phenazines to give 6a─c was identified as a major side
reaction. The product distribution was found to be highly sensitive to the rate of addition and amount of
zinc powder and acetic acid. In the case of fast addition of a large excess of the latter reagents, 7,8ꢀ
dichloroꢀ2ꢀmethylaminophenazine 6b could be obtained as the main product in good yield (Scheme 3).
Under the conditions tested, the hydrodeamination reaction is selective for Nꢀmethylated derivatives;
treatment of the parent imidazolidine derivative 3b under the same conditions led to the isolation of the
7,8ꢀdichloroꢀ2,3ꢀdiaminophenazine 1b as the major product of the reaction, with no noticeable
hydrodeamination observed. This provides an alternative route for the hydrolysis of the Me2C protecting
group of 3a─c derivatives. The rationalization of the selective monoꢀhydrodeamination of the
bis(methylamino)phenazine derivatives is beyond the scope of this letter and will be the topic of further
investigations.
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Having access to a variety of hitherto unknown phenazine building blocks, we next investigated the
fundamental physicochemical properties of a few representative analogues (Table 1). Overall, the
photophysical properties of the newly synthesized aminophenazines are comparable with data reported
previously for related compounds.42,43 In brief, the absorption spectra of the dichloroꢀphenazine
derivatives 1b, 3b─6b are depicted in Figure 1a. As can be observed, the imidazolidine derivatives 3b
and 4b exhibit slightly redꢀ shifted visible absorption bands compared to those of the corresponding
uncyclized diamines 1b and 5b. Furthermore, the vibronic fine structure of the absorption band is better
resolved in the case of the imidazolidine derivatives, and the latter generally possess higher extinction
coefficients. Methylation of the amino substituents does not induce any marked shift of the absorption
bands; however, it does lead to slight variations in the extinction coefficients. Finally, the monoꢀamino
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derivative 6b exhibits a very distinct spectrum with a large redꢀshift and significant broadening of the
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main visible bands, as was reported for the unhalogenated bisꢀ and monoꢀaminophenazines.43
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Table 1. Comparison of experimental and theoretical properties of phenazines derivatives.
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a
a
b
c,d
e
Phenazine
λmax, abs
ɛmax, abs
λmax, emission
E0ꢀ0 c E0ꢀ0
Фfluor
E1/2 (0/ꢀ1) f
calc
M-1 cm-1
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20.8
18.8
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27.0
30.0
27.0
29.3
13.3
20.8
25.2
11.4
×
103
nm
nm
eV
eV
V vs. NHE
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442
442
440
471
473
457
471
473
434
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443
490
537
549
550
496
506
508
488
497
500
529
541
542
599
2.52
2.48
2.47
2.62
2.56
2.56
2.61
2.56
2.56
2.58
2.51
2.53
2.25
2.57
2.46
2.50
2.93
2.86
2.85
2.83
2.77
2.77
2.58
2.48
2.48
2.11
n.d.
0.10
n.d.
n.d.
0.42
n.d.
0.80
0.70
0.11
n.d.
0.14
n.d.
0.06
n.d.
n.d.
1a
1b
1c
3a
3b
3c
4a
4b
4c
5a
5b
5c
n.d.
n.d.
n.d.
n.d.
-1.34
-1.27
irreversible
n.d.
irreversible
n.d.
-0.98
6b
a
Reported for the wavelength with the highest extinction coefficient in the visible range; spectra
b
recorded in absolute ethanol at room temperature. Excitation at 300 nm, for samples with an optical
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density (OD) below 0.06; recorded in absolute ethanol at room temperature. Estimated from the
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d
crossing point of the normalized experimental absorption and emission spectra.
Calculations
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e
performed at the CAMꢀB3LYP42/6ꢀ31G(d,p) level of theory using Gaussian09. Excitation at 300 nm,
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under aerobic conditions; sample OD was adjusted to 0.049 using rhodamineꢀ6G as the reference (Фfluor
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Rhodamineꢀ6G ~ 0.95); spectra collected in absolute ethanol at room temperature. Measured in
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dichloromethane using 0.1 M tetraꢀnꢀbutylammonium hexafluorophosphate as supporting electrolyte,
using platinum as working and counter electrodes and ferrocene (Fc) as the internal reference, with E1/2
(Fc+/Fc) = 0.72 V vs. NHE. n.d. = not determined.
Similar trends apply to the fluorinated and brominated series (see SI for the full spectra). A more
substantial variation of the extinction coefficients is observed after the methylation of the amine
substituents in the latter series. Across the phenazine spectra, a systematic blue shift is noticeable on
going from the fluorinated derivatives to the chlorinated and brominated analogues (Table 1). This is
consistent with the slightly greater πꢀdonating character of the fluorine substituents, as compared to the
Cl or Br substituents. The inductive effects of the three halogens are comparable, which are indicated by
the SwainꢀLupton parameters: F: F = +0.45, R = ꢀ0.39; Cl: F = +0.42, R = ꢀ0.19; Br: F = +0.45, R = ꢀ
0.22 (where F is the field effect parameter, and R is the resonance parameter).44
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Figure 1. Absorption (a) and normalized emission (b) spectra of the dichloroꢀphenazine derivatives 1b,
3b─6b, collected in absolute ethanol at room temperature. The emission spectra were recorded with
excitation at 300 nm.
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All of the derivatives are luminescent in ethanol. Their main emission peaks are reported in Table 1
(see Figure 1b and SI for full emission spectra). Likely due to their increased rigidity, the imidazolidine
derivatives show a smaller Stokes shift as compared to the acyclic derivatives, with typical values of 40
nm for the former as compared to 100 nm for the latter. Furthermore, methylation of the amines resulted
in a minor decrease in the Stokes shift (<10 nm). The fluorescence quantum yields (Фfluor, Table 1) for
1b, 3bꢀ6b, 4a and 4c were measured at room temperature in airꢀsaturated ethanol. As shown by the
chlorinated aminophenazines 1b and 3b─6b, two main factors appear to modulate the quantum yield of
fluorescence of the derivatives. The alkylation of the amino substituents, as well as inclusion of the
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latter substituents in the imidazolidine rings leads to a remarkable increase of fluorescence with Фfluor
~
0.10, 0.14, 0.42 and 0.70 for 1b, 5b, 3b and 4b, respectively. The latter trend can be rationalized by the
progressive suppression of the major nonꢀradiative deꢀexcitation pathways associated with vibrational
and rotational degrees of freedom of the amino groups. Finally, the change in the fluorescence quantum
yields for the methylated imidazolidine series 4a─c follows the expected trend with Фfluor ~ 0.80, 0.70
and 0.11 for 4a, 4b, and 4c. The decrease in fluorescence from the fluorinated to the brominated
derivatives is likely due to the increasing heavy atom effect of the halogen substituents.
The main trends in the absorption and emission properties of the phenazine derivatives were
captured by DFT and TDDFT calculations, performed at the CAMꢀB3LYP45/6ꢀ31G(d,p) level of theory,
using the SMD continuum solvation model.46,47 As shown in Table 1, the experimental and theoretical
E0ꢀ0 energies are in good agreement, consistent with previous studies.48 Deviations, when comparing the
E0ꢀ0 energies of the cyclized systems, might be due to the lack of specific solventꢀsolute interactions,
including hydrogen bonds in ethanol. An extended computational analysis of the photophysical
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properties of phenazine derivatives, including more detailed solvents effects, will be the topic of a
forthcoming report.
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Finally, the electrochemical properties of 4aꢀc, 5b, and 6b were investigated in dichloromethane
with 0.1 M tetraꢀn-butylammonium hexafluorophosphate. All of the compounds featured irreversible
oxidation waves, above 1.15 V vs. NHE, as expected for the oxidation of alkylamino substituents.49 In
addition, 4a, 4b and 6b exhibited a reversible oneꢀelectron redox couple at ꢀ1.34 V, ꢀ1.27 V and ꢀ0.98 V
vs. NHE, respectively. The latter can be assigned to the reduction of the phenazine to its radical anion.
Compounds 4c, and 5b, in contrast, featured irreversible cathodic waves. The presence of bromine
substituents may explain this behavior in the case of 4c; however, the irreversible cathodic current
associated with 5b was not expected. It could be related to the selective hydrodeamination reaction
observed for the di(methylamino)phenazines derivatives under reductive conditions (see above).
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CONCLUSION
Our straightforward and scalable synthetic strategy allows for the preparation of a variety of
potentially useful aminophenazine motifs, featuring halogenꢀsubstituents as synthetic handles for further
modification. We have shown that the in situ protection of the halogenated oꢀphenylenediamine starting
material by direct condensation with acetone is critical to suppress the monoꢀhydroxylation of the
phenazine products, otherwise occurring under oxidative treatment in aqueous conditions. The resulting
imidazolidine derivatives were particularly robust toward hydrolysis and upon methylation exhibited a
strong fluorescence in protic media, making these derivatives promising candidates for further
development as fluorophores. The reduction of the phenazine core was required to permit the hydrolysis
of the imidazolidine ring and isolation of the targeted 7,8ꢀdihaloꢀ2,3ꢀdiaminophenazines. Interestingly,
we found that the use of zinc/acetic acid not only permits the deprotection of both the methylated and
parent imidazolidine derivatives, but under specific reaction conditions can also lead to the selective
monoꢀhydrodeamination of the di(methylamine)phenazine derivatives. Our results taken together
suggest multiple ways to increase the structural variety of the synthetically accessible halogenated
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aminophenazines, and allow the preparation of versatile building blocks that appear suitable for
obtaining extended and highly functionalized heteroacene materials. In that sense, we note several
recent examples that demonstrate the potential of chloro,50 fluoro42 and amino substituents35,51ꢀ53 in
phenazine derivatives to lead to further modification of 7,8ꢀdihaloꢀ2,3ꢀdiaminophenazines.
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EXPERIMENTAL SECTION
Materials. All chemicals and solvents were commercially available and used as obtained, without
further purification.
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Instrumentation and Characterization. H spectra were recorded at 400 MHz, F NMR at 376
MHz, and proton decoupled 13C NMR (13C{1H} NMR) at 101 MHz. Chemical shifts are reported as
ppm from the internal reference tetramethylsilane (1H) or residual solvent peak (13C). Highꢀresolution
mass spectrometry (HRMS) was performed on a QꢀTOF LC/MS with API by direct injection of a
methanolic solution at ~ 0.5 mg/mL concentration. Analytical LC/MS analysis was performed on a
system equipped with a C18 column (1.8 ꢁm, 4.6 x 50 mm).
General procedure 1 (GP1) for the synthesis of compounds 3a─c. The 4,5ꢀdihaloꢀ1,2ꢀdiamino
benzene (1 mmol, 1 eq.) was dispersed in 1.33 M HCl (9 mL). Acetone (74 ꢁL, 58.5 mg, 1mmol, 1 eq.)
was added and the mixture was stirred at room temperature for 5 minutes. A solution of iron trichloride
hexahydrate (561 mg, 2.05 mmol, 2 eq.) in 2 mL of water was added and the mixture was stirred at
room temperature in the dark. After 8 hours the mixture was poured into brine (150 mL) and neutralized
by the slow addition of sodium bicarbonate (~2 g). A solution of ethylenediamine tetraacetate (0.5 M, 25
mL), prepared in 1 M aqueous sodium hydroxide, was added and the aqueous phase was extracted with
ethyl acetate containing 10 volume% of 2ꢀpropanol (3 x 125 mL). The combined organic layer was
washed with brine (1 x 150 mL) and water (1 x 40 mL), dried over Na2SO4, filtered and the solvent was
evaporated. In the case of dichloro and dibromo derivatives 3b and 3c, the solid was suspended in
dichloromethane (15 mL), sonicated (1ꢀ2 minutes) and filtered. It was washed with dichloromethane
until the filtrate appeared pale yellow (25ꢀ50 mL dichloromethane). The solid was dried and used
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without further purification. In the case of the difluoro derivatives 3a, due to the high solubility of the
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material, it was purified by a short plug filtration (SiO2, EtOAc/hexanes = 3/2; dry loading).
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7,8ꢀdifluoroꢀ2,2ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀb]phenazine 3a. GP1 was carried out
using the following quantities of solvents and reagents: 4,5ꢀdifluoroꢀ1,2ꢀdiaminobenzene (145 mg, 1
mmol, 1 eq.) and acetone (74 ꢁL, 58.5 mg, 1mmol, 1 eq.) in 1.33 M aqueous HCl (9 mL), and iron
trichloride hexahydrate (565 mg, 2.1 mmol, 2.05 eq.) in water (2 mL). After filtration over a short plug
of silica (SiO2, EtOAc/hexanes = 3/2, dry loading) the desired compound was obtained as a yellow
powder. Yield: 77 mg, 0.27 mmol, 53 %. 1H NMR (400 MHz, DMSOꢀd6, 25 °C): δ 8.22 (s, 2H), 7.74 (t,
J = 10.3 Hz, 2H), 6.35 (s, 2H), 1.50 (s, 6H). 19F NMR (376 MHz, DMSOꢀd6): δ ꢀ137.7 (t, J = 10.4 Hz).
13C{1H} NMR (101 MHz, DMSOꢀd6): δ 149.4 (dd, J1 = 250 Hz, J2 = 18 Hz), 147.8, 145.2, 136.9 (dd;
J1 = 7 Hz, J2 = 6 Hz), 113.0(dd; J1 = 11 Hz, J2 = 7 Hz), 93.2, 80.0, 30.4. UVꢀVis in ethanol λmax(nm)
[ε(L.molꢀ1.cmꢀ1) x 103]: 258 [71.7], 440 [29.1], 459 [25.8]. HRMS (m/z 100%) calc for C15H12F2N4+H+:
287.1103; found 287.1105.
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7,8ꢀdichloroꢀ2,2ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀb]phenazines 3b. GP1 was carried out
using the following quantities of reagents and solvents: 4,5ꢀdichloroꢀ1,2ꢀdiaminobenzene (178 mg, 1
mmol, 1 eq.) and acetone (74 ꢁL, 58.5 mg, 1 mmol, 1 eq.) in 1.33 M aqueous HCl (9 mL), and iron
trichloride hexahydrate (565 mg, 2.1 mmol, 2.05 eq.) in water (2 mL). The desired compound was
obtained as a yellowꢀbrown powder. Yield: 153 mg, 0.48 mmol, 96 %. 1H NMR (400 MHz, DMSOꢀd6):
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δ 8.50 (s, 2H), 8.00 (s, 2H), 6.34 (s, 2H), 1.51 (s, 6H). C{1H} NMR (101 MHz, DMSOꢀd6): δ 148.1,
146.0, 139.1, 128.2, 128.1, 93.1, 80.3, 30.3. UVꢀVis in ethanol λmax(nm) [ε(L.molꢀ1.cmꢀ1) x 103]: 269
[67.9], 299 [19.3], 447 [25.9] 471 [26.7]. HRMS (m/z 100%) calc for C15H12Cl2N4+H+: 319.0512; found
319.0512.
7,8ꢀdibromoꢀ2,2ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀb]phenazine 3c. GP1 was carried out
using the following quantities of reagents and solvents: 4,5ꢀdibromoꢀ1,2ꢀdiaminobenzene (267 mg, 1
mmol, 1 eq.) and acetone (76 ꢁL, 60.1 mg, 1.03 mmol, 1.03 eq.) in 1.33 M aqueous HCl (9 mL), and
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iron trichloride hexahydrate (562 mg, 2 mmol, 2 eq.) in water (2 mL). The desired compound was
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obtained as a yellowꢀbrown powder. Yield: 144 mg, 0.35 mmol, 71 %. 1H NMR (400 MHz, DMSOꢀd6):
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δ 8.45 (s, 2H), 8.14 (s, 2H), 6.34 (s, 2H), 1.51 (s, 6H). C{1H} NMR (101 MHz, DMSOꢀd6): δ 148.2,
146.0, 139.7, 131.5, 120.4, 93.1, 80.3, 30.3. UVꢀVis in ethanol λmax(nm) [ε(L.molꢀ1.cmꢀ1) x 103]: 271
[72.4], 301 [22.4], 448 [30.4] 473 [27.0]. HRMS (m/z 100%) calc for C15H12Br2N4+H+: 408.9481; found
408.9484.
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Scale up synthesis of 7,8ꢀdichloroꢀ2,2ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀb]phenazines 3b.
4,5ꢀdichloroꢀ1,2ꢀdiamino benzene (1.068 g, 6 mmol, 1 eq.) was sonicated for 2 minutes in 1.33 M HCl
(60 mL). Acetone (444 ꢁL, 351 mg, 6 mmol, 1 eq.) was added and the mixture was stirred at room
temperature for 10 minutes. A solution of iron trichloride hexahydrate (3.32 g, 12.3 mmol, 2.05 eq.) in 8
mL of water was added and the mixture was stirred at room temperature in the dark for 8 hours. The
mixture was then treated as described in GP1, with the appropriate quantity of solvents and reagents
(scaled up six time). Yield: 0.68 g, 2.13 mmol, 71 %.
General procedure 2 (GP2) for the synthesis of compounds 1a─c. 7,8ꢀhaloꢀ2,2ꢀdimethylꢀ2,3ꢀ
dihydroꢀ1Hꢀimidazo[4,5ꢀb]phenazine 3 (0.1 mmol) was suspended in methanol (15 mL) and the
suspension was purged with nitrogen for 10 minutes. A solution of sodium dithionite (0.4 mmol, 4 eq.)
dissolved in nitrogenꢀpurged water (purging time: 10 minutes; 15 mL) was added slowly to the
suspension, and the mixture was stirred under nitrogen at room temperature in the dark. The reaction
was followed by TLC analysis (SiO2, EtOAc). When all the starting material was converted, the mixture
was poured into brine (100 mL) and aqueous sodium bicarbonate (5%, 10 mL) was added. The aqueous
phase was extracted with EtOAc (2 x 50 mL). The combined organic layers were dried over sodium
sulfate, filtered and the solvent was evaporated. The crude material was filtered over a silica short plug
(SiO2, 5% MeOH in EtOAc). Precipitation from CH2Cl2ꢀ10% MeOH / Hexanes yield the desired
product as a light yellow solid.54
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7,8ꢀdifluoroꢀ1,2ꢀdiaminophenazine 1a. GP2 was carried out using the following quantities of
reagents and solvents: 7,8ꢀdifluoroꢀ2,2ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀb]phenazine 3a (29 mg,
0.1 mmol), Na2S2O4 (70 mg, 0.4 mmol), MeOH (15 mL), and water (15 mL). Full conversion was
observed after 2 hours. The desired compound was obtained as a light yellow powder. Yield: 16 mg, 65
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ꢁmol, 65%. 1H NMR (400 MHz, DMSOꢀd6): δ 7.85 (t, J = 10.3 Hz, 2H), 6.88 (s, 2H), 6.36 (s, 4H). F
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NMR (376 MHz, DMSOꢀd6): δ ꢀ136.5 (t, J = 10.5 Hz). C{1H} NMR (101 MHz, DMSOꢀd6): 149.9
(dd, J1 = 252 Hz, J2 = 18 Hz), 144.9, 142.4, 137.5 (m), 113.3 (dd, J1 = 11 Hz, J2 = 7 Hz), 102.2. UVꢀVis
in ethanol λmax(nm) [ε(L.molꢀ1.cmꢀ1) x 103]: 276 [49.1], 433 [17.5]. HRMS (m/z 100%) calc for
C12H8F2N4+H+: 247.0790; found 247.0791.
7,8ꢀdichloroꢀ1,2ꢀdiaminophenazine 1b. GP2 was carried out using the following quantities of
reagents and solvents: 7,8ꢀdichloroꢀ2,2ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀb]phenazine 3b (32 mg,
0.1 mmol), Na2S2O4 (70 mg, 0.4 mmol), MeOH (15 mL), and water (15 mL). Full conversion of the
starting material was observed after 4 hours. The desired compound was obtained as a light yellow
powder. Yield: 27 mg, 97 ꢁmol, 97%. 1H NMR (400 MHz, DMSOꢀd6): δ 8.13 (s, 2H), 6.87 (s, 2H), 6.53
(s, 4H). C{1H} NMR (101 MHz, DMSOꢀd6): δ 145.6, 143.2, 139.4, 128.8, 128.7, 102.0. UVꢀVis in
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ethanol λmax(nm) [ε(L.molꢀ1.cmꢀ1) x 103]: 272 [54.3], 442 [20.8]. HRMS (m/z 100%) calc for
C12H8Cl2N4+H+: 279.0199; found 279.0195.
7,8ꢀdibromoꢀ1,2ꢀdiaminophenazine 1c. GP2 was carried out using the following quantities of
reagents and solvents: 7,8ꢀdibromoꢀ2,2ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀb]phenazine 3c (41 mg,
0.1 mmol), Na2S2O4 (70 mg, 0.4 mmol), MeOH (15 mL), and water (15 mL). Full conversion of the
starting material was observed after 8 hours. The desired compound was obtained as a light yellow
powder. Yield: 33 mg, 90 ꢁmol, 90%. 1H NMR (400 MHz, DMSOꢀd6): δ 8.27 (s, 2H), 6.87 (s, 2H), 6.55
(s, 4H). C{1H} NMR (101 MHz, DMSOꢀd6): δ 145.7, 143.2, 140.0, 132.0, 121.0, 102.0. UVꢀVis in
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ethanol λmax(nm) [ε(L.molꢀ1.cmꢀ1) x 103]: 276 [50.7], 442 [18.8]. HRMS (m/z 100%) calc for
C12H8Br2N4+H+: 368.9168; found 368.9166.
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General procedure 3 (GP3) for the synthesis of compounds 4a─c. 7,8ꢀdihaloꢀ2,2ꢀdimethylꢀ2,3ꢀ
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dihydroꢀ1Hꢀimidazo[4,5ꢀb]phenazine 3 (0.16 mmol) was dissolved in anhydrous DMF (10 mL). The
solution was purged with nitrogen (vacuum/nitrogen cycles, 3x) and cooled down to 0 °C under
nitrogen. Sodium hydride (60%ꢀw/w dispersion in mineral oil, 13.6 mg, 0.35 mmol, 2.2 eq.) was added
and the mixture was stirred under nitrogen at 0 °C for 15 minutes. Methyl iodide (21 ꢁL, 48 mg, 0.33
mmol, 2.1 eq.) was added and the mixture was further stirred at 0 °C for 30 minutes under nitrogen, then
was allowed to warm up to room temperature. After 30 minutes, a saturated aqueous ammonium
chloride solution (1 mL) was added and the mixture was poured into brine (50 mL). The aqueous phase
was extracted with ethyl acetate (3 x 25 mL) and the combined organic layers were further washed with
brine (1 x 50 mL) and water (2 x 50 mL). The organic layer was dried with sodium sulfate, filtered, and
the solvent was evaporated. Column chromatography (SiO2, EtOAc/Hexanes = 1/1) followed by
recrystallization from CH2Cl2/hexanes yielded the desired compounds as light brown needles.55
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7,8ꢀdifluoroꢀ1,2,2,3ꢀtetramethylꢀ2,3ꢀdihydro. ꢀ1Hꢀimidazo[4,5ꢀb]phenazine 4a. GP3 was carried
out using the following quantities of reagents and solvent: 7,8ꢀdifluoroꢀ2,2ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀ
imidazo[4,5ꢀb]phenazine 3a (44.3 mg, 0.16 mmol), sodium hydride (60%ꢀw/w dispersion in mineral oil,
13.6 mg, 0.35 mmol), methyl iodide (21 ꢁL, 48 mg, 0.33 mmol), and DMF (10 mL). The desired
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compound was obtained as a light yellow powder. Yield: 17.1 mg, 55 ꢁmol, 35%. H NMR (400 MHz,
Chloroformꢀd): δ 7.63 (t, J = 9.9 Hz, 2H), 6.36 (s, 2H), 3.00 (s, 6H), 1.52 (s, 6H). 19F NMR (376 MHz,
DMSOꢀd6): δ ꢀ137.6 (t, J = 10.3 Hz). 13C{1H} NMR (101 MHz, Chloroformꢀd): δ 150.4 (dd, J1 = 252.5
Hz, J2= 18.3 Hz), 146.3, 145.1, 137.1 (t, J = 5.7 Hz), 112.81 (dd, J1 = 12.1 Hz, J1 = 6.5 Hz), 92.7, 85.7,
27.8, 23.4. UVꢀVis in ethanol λmax(nm) [ε(L.molꢀ1.cmꢀ1) x 103]: 443 [29.5], 457 [30.0]. HRMS (m/z
100%) calc for C17H16F2N4+H+: 315.1416; found 315.1417.
7,8ꢀdichloroꢀ1,2,2,3ꢀtetramethylꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀb]phenazine 4b. GP3 was carried
out using the following quantities of reagents and solvent: 7,8ꢀdichloroꢀ2,2ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀ
imidazo[4,5ꢀb]phenazine 3b (49.8 mg, 0.16 mmol), sodium hydride (60%ꢀw/w dispersion in mineral oil,
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13.6 mg, 0.35 mmol), methyl iodide (21 ꢁL, 48 mg, 0.33 mmol), and DMF (10 mL). The desired
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compound was obtained as light brown needles. Yield: 18.8 mg, 54 ꢁmol, 35%. H NMR (400 MHz,
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CDCl3): δ 8.00 (s, 2H), 6.34 (s, 2H), 3.01 (s, 6H), 1.54 (s, 6H). C{1H} NMR (101 MHz, CDCl3): δ
146.6, 145.8, 139.1, 130.1, 128.1, 92.7, 85.8, 27.8, 23.5. UVꢀVis in ethanol λmax(nm) [ε(L.molꢀ1.cmꢀ1) x
103]: 270 [65.8], 300 [19.9], 449 [26.4], 471 [27.0]. HRMS (m/z 100%) calc for C17H16Cl2N4+H+:
347.0825; found 347.0827.
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7,8ꢀdibromoꢀ1,2,2,3ꢀtetramethylꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀb]phenazine 4c. GP3 was carried
out using the following quantities of reagents and solvent: 7,8ꢀdibromoꢀ2,2ꢀdimethylꢀ2,3ꢀdihydroꢀ1Hꢀ
imidazo[4,5ꢀb]phenazine 3c (63.2 mg, 0.16 mmol), sodium hydride (60%ꢀw/w dispersion in mineral oil,
13.6 mg, 0.35 mmol), methyl iodide (21 ꢁL, 48 mg, 0.33 mmol), and DMF (10 mL). The desired
1
compound was obtained as brown needles. Yield: 45.6 mg, 105 ꢁmol, 67%. H NMR (400 MHz,
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CDCl3): δ 8.00 (s, 2H), 6.35 (s, 2H), 3.04 (s, 6H), 1.52 (s, 6H). C{1H} NMR (101 MHz, CDCl3): δ
147.4, 146.3, 139.2, 128.3, 128.2, 91.9, 28.1, 23.5. UVꢀVis in ethanol λmax(nm) [ε(L.molꢀ1.cmꢀ1) x 103]:
273 [71.1], 301 [20.1], 451[27.5], 473 [29.3]. HRMS (m/z 100%) calc for C17H16Br2N4+H+: 436.9794;
found 436.9794.
General procedure 4 (GP4) for the synthesis of compounds 5a─c. 7,8ꢀdihaloꢀ1,2,2,3ꢀtetramethylꢀ
2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀb]phenazine 4 (0.1 mmol) was dissolved in a tetrahydrofuranꢀwater 1ꢀ1
mixture (10 mL). The solution was purged with nitrogen (vacuum/nitrogen cycles, 3x) and zinc powder
(16.2 mg, 0.25 mmol, 2.5 eq.) was added. Glacial acetic acid (14.3 ꢁL, 15 mg, 0.25 mmol, 2.5 eq.) was
added and the mixture stirred under nitrogen at 40 °C. After stirring for 30 minutes, TLC analysis (SiO2,
CH2Cl2/acetone = 8/2) indicated the presence of residual starting material. Zinc powder (< 140 ꢁm
particles size) (16.2 mg, 0.25 mmol, 2.5 eq.) was added, the mixture purged with nitrogen
(vacuum/nitrogen cycles 3x), and glacial acetic acid (14.3 ꢁL, 15 mg, 0.25 mmol) was added. The
mixture was further stirred at 40 °C under nitrogen for 30 minutes and the reaction progression was
determined by TLC analysis (SiO2, CH2Cl2/acetone = 8/2). Zinc portions and glacial acetic aliquots
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were added as previously described, until most of the staring material was converted. After the last
zinc/glacial acetic acid addition, the mixture was stirred for 30 minutes, the residual zinc was filtered
out and then the mixture was poured into aqueous sodium bicarbonate (5%, 50 mL). The aqueous phase
was extracted with ethyl acetate (2 x 25 mL) and the combined organic layer was dried over sodium
sulfate, filtered and the solvent was evaporated. Column chromatography (SiO2, CH2Cl2/acetone = 8/2)
followed by precipitation from CH2Cl2/hexanes yield the desired compound as an orange powder.56
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7,8ꢀdifluoroꢀ1,2ꢀdi(methylamino)phenazine 5a. GP4 was carried out using the following
quantities of reagents and solvents: 7,8ꢀdifluoroꢀ1,2,2,3ꢀtetramethylꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀ
b]phenazine 4a (10 mg, 32 ꢁmol), zinc powder (5.2 mg, 80 ꢁmol), glacial acetic acid (4.5 ꢁL, 4.8 mg,
80 ꢁmol), and tetrahydrofuran/water 1/1 (10 mL). Additional zinc (3 x 5.2 mg) and glacial acetic acid (3
x 4.5 ꢁL) were introduced, with an interval of 30 minutes between each addition. The desired compound
was obtained as a yellow powder. Yield: 4.5 mg, 16 ꢁmol, 50%. 1H NMR (400 MHz, CDCl3): δ 7.87 (t,
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J = 10.3 Hz, 2H), 6.64 (s, 2H), 6.52 (q, J = 4.4 Hz, 2H), 2.96 (d, J = 4.4 Hz, 6H). C{1H} NMR (101
MHz, DMSOꢀd6): 144.9, 142.7, 137.5, 113.3 (dd; J1 = 11 Hz, J2 = 7 Hz), 98.3, 30.4. UVꢀVis in ethanol
λmax(nm) [ε(L.molꢀ1.cmꢀ1) x 103]: 261 [33.9], 434 [13.3]. HRMS (m/z 100%) calc for C14H12F2N4+H+:
275.1103; found 275.1101.
7,8ꢀdichloroꢀ1,2ꢀdi(methylamino)phenazine 5b. GP4 was carried out using the following
quantities of reagents and solvents: 7,8ꢀdichloroꢀ1,2,2,3ꢀtetramethylꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀ
b]phenazine 4b (32 mg, 0.92 mmol), zinc powder (15 mg, 0.23 mmol), glacial acetic acid (13 ꢁL, 13.7
mg, 0.23 mmol), and tetrahydrofuran/water 1/1 (10 mL). Additional zinc (3 x 15 mg) and glacial acetic
acid (3 x 13 ꢁL) were introduced, with an interval of 30 minutes between each addition. The desired
1
compound was obtained as an orange powder. Yield: 20 mg, 65 ꢁmol, 71%. H NMR (400 MHz,
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DMSOꢀd6): δ 8.13 (s, 2H), 6.66 (q, J = 4.6 Hz, 1H), 6.63 (s, 1H), 2.96 (d, J = 4.5 Hz, 4H). C{1H}
NMR (101 MHz, DMSOꢀd6): δ 145.4, 143.5, 139.4, 128.9, 128.6, 98.2, 30.4. UVꢀVis in ethanol
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λmax(nm) [ε(L.molꢀ1.cmꢀ1) x 103]: 273 [57.1], 442 [20.8]. HRMS (m/z 100%) calc for C14H12Cl2N4+H+:
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307.0512; found 307.0512.
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7,8ꢀdibromoꢀ1,2ꢀdi(methylamino)phenazine 5c. GP4 was carried out using the following
quantities of reagents and solvents: 7,8ꢀdibromoꢀ1,2,2,3ꢀtetramethylꢀ2,3ꢀdihydroꢀ1Hꢀimidazo[4,5ꢀ
b]phenazine 4c (36 mg, 0.83 mmol), zinc powder (15 mg, 0.23 mmol), glacial acetic acid (13 ꢁL, 13.7
mg, 0.23 mmol), and tetrahydrofuran/water 1/1 (10 mL). Additional zinc (3 x 15 mg) and glacial acetic
acid (3 x 13 ꢁL) were added, with an interval of 30 minutes between each addition. The desired
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compound was obtained as an orange powder. Yield: 18.4 mg, 47 ꢁmol, 57%. H NMR (400 MHz,
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DMSOꢀd6): δ 8.27 (s, 2H), 6.68 (q, J = 4.5 Hz, 2H), 6.63 (s, 2H), 2.96 (d, J = 4.5 Hz, 6H). C{1H}
NMR (101 MHz, DMSOꢀd6): δ 145.5, 143.5, 140.0, 131.8, 121.2, 98.2, 30.4. UVꢀVis in ethanol
λmax(nm) [ε(L.molꢀ1.cmꢀ1) x 103]: 276 [64.7], 443 [25.2]. HRMS (m/z 100%) calc for C14H12Br2N4+H+:
396.9481; found 396.9470.
Synthesis of 7,8ꢀdichloroꢀ1ꢀmethylaminophenazine 6b. 7,8ꢀdichloroꢀ1,2,2,3ꢀtetramethylꢀ2,3ꢀ
dihydroꢀ1Hꢀimidazo[4,5ꢀb]phenazine 4b (7.2 mg, 22.4 ꢁmol) was dissolved in a tetrahydrofuranꢀwater
1ꢀ1 mixture (4 mL). The solution was purged with nitrogen (vacuum/nitrogen cycles, 3x) and zinc
powder (30 mg, 0.5 mmol, 23 eq.) was added. Water/acetic acid 2/1 mixture (1 mL) was added and then
the mixture was stirred under nitrogen at 40 °C. After stirring for 1 hour the residual zinc was filtered
out and the mixture was poured into aqueous sodium bicarbonate (5%, 50 mL). The aqueous phase was
extracted with ethyl acetate (2 x 25 mL) and the combined organic layer was dried over sodium sulfate,
filtered and the solvent was evaporated. Column chromatography (SiO2, CH2Cl2/acetone = 8/2)
followed by precipitation from CH2Cl2/hexanes yield the desired compound as a red powder. Yield: 4
1
mg, 14 ꢁmol, 63%. H NMR (400 MHz, DMSOꢀd6): δ 8.34 (s, 1H), 8.24 (s, 1H), 7.87 (d, J = 9.4 Hz,
1H), 7.50 (dd, J1 = 9.5 Hz, J2 = 2.5 Hz, 1H), 7.37 (q, J = 5.1 Hz, 1H), 6.65 (d, J = 2.4 Hz, 1H), 2.90 (d, J
= 4.9 Hz, 3H). 13C{1H} NMR (101 MHz, DMSOꢀd6): δ 152.3, 147.1, 142.3, 141.1, 138.6, 133.1, 130.2,
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130.2, 129.5, 128.8, 128.6, 97.1, 29.9. UVꢀVis in ethanol λmax(nm) [ε(L.molꢀ1.cmꢀ1) x 103]: 294 [52.6],
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490 [11.4]. HRMS (m/z 100%) calc for C13H9Cl2N3+H+: 278.0246; found 278.0246.
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ASSOCIATED CONTENT
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SUPPORTING INFORMATION.
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Additional details of the synthetic procedures, 1H, 13C and 19F NMR spectra, LCMS analysis, absorption
and emission spectra, details of quantum yield measurements, and details of computational analysis of
the different phenazine derivatives. This material is available free of charge via the internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
Eꢀmail: robert.crabtree@yale.edu
Present Addresses
†Laboratoire de Chimie et Biologie des Métaux ꢀ CEA Grenoble; 17, rue des Martyrs, Bâtiment K'
38054 Grenoble Cedex 9, France.
‡These authors contributed equally.
ACKNOWLEDGMENTS
We would like to thank the Yale West Campus Analytical Core staff for the help with instrumentation.
This work was funded by U.S. Department of Energy Grant DEꢀFG02ꢀ07ER15909 and a generous gift
from the TomKat Charitable Trust. V.S.B. acknowledges NERSC and support as part of the Argonneꢀ
Northwestern Solar Energy Research (ANSER) Center, an Energy Frontier Research Center funded by
the U.S. Department of Energy, Office of Science, Office of Basic Energy Sciences under award no.
DEꢀSC0001059.
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(36) In the case of the 4,5ꢀbisfluoroꢀ1,2ꢀdiaminobenzene starting material, 7,8ꢀdifluoroꢀ1,2ꢀ
diaminophenazine was present as a minor impurity in the commercially available compound. The latter
diaminophenazine was recovered after the treatment with iron chloride and acetone, however we found
no indications for the competitive formation of this product during the reaction (no hydroxylated
derivative was observed in LCMS analysis). We therefore assume that the 7,8ꢀdifluoroꢀ1,2ꢀ
diaminophenazine collected after the purification was already present in the starting material.
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reaction.
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(51) Engelhart, J. U.; Lindner, B. D.; Tverskoy, O.; Rominger, F.; Bunz, U. H. F. J. Org. Chem. 2013,
78, 10832.
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(52) Li, G.; Wu, Y.; Gao, J.; Wang, C.; Li, J.; Zhang, H.; Zhao, Y.; Zhao, Y.; Zhang, Q. J. Am. Chem
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(53) Gajiwala, H. M.; Zand, R. Polymer 2000, 41, 2009.
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(54) In the case of the difluoro derivatives, the starting material was highly soluble and the reaction
mixture was fully homogeneous. Dichloro and especially dibromo derivatives were much less soluble in
the reaction conditions and the reaction proceeded under heterogeneous conditions.
(55) Due to the high solubility of the difluoro derivatives, the product obtained after column
chromatography was only washed with a minimum volume of hexanes.
(56) A total of 3 to 4 additions of zinc/acetic acid was usually necessary to convert most of the
starting material into the desired product. Sequential addition of the zinc and acetic acid is required to
minimize the hydrodeamination side reaction that is observed during the synthesis. Addition of a large
excess of zinc directly followed by a large excess of acetic acid leads to the rapid conversion of the
starting material into the corresponding 1ꢀmethylaminophenazine derivative.
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