(E)-3-(2-Alkyl-10H-phenothiazin-3-yl)-1-arylprop-2-en-1-ones: Preparative, IR, NMR and DFT study on their substituent-dependent reactivity in hydrazinolysis and sonication-assisted oxidation with copper(II)nitrate

Article abstract of DOI:10.1039/b608455a

A series of novel 3(5)-aryl/ferrocenyl-5(3)-phenothiazinylpyrazoles and pyrazolines were obtained by substituent-dependent regioselective condensation of the corresponding (E)-3-(2-alkyl-10H-phenothiazin-3-yl)-1-aryl/ ferrocenylprop-2-en-1-one with hydrazine or methylhydrazine in acetic acid. The different propensity of the primary formed β-hydrazino adducts to undergo competitive retro-Mannich reaction was interpreted in terms of tautomerisation equilibrium constants calculated by DFT using a solvent model. The regioselectivity of the cyclisation reactions with methylhydrazine and the substituent-dependent redox properties of pyrazolines were also rationalized by comparative DFT calculations performed for simplified model molecules. On the effect of ultrasound-promoted oxidation with copper(ii)nitrate phenothiazine-containing pyrazolines, enones and oxo-compounds were selectively transformed into sulfoxides. Only one sulfoxide enone was partially converted into an oxirane derivative. The structure of the novel products was determined by IR and NMR spectroscopy including COSY, HSQC, HMBC and DNOE measurements. The Royal Society of Chemistry 2006.

Full text of DOI:10.1039/b608455a

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PAPER
www.rsc.org/obc | Organic & Biomolecular Chemistry
(E)-3-(2-Alkyl-10H-phenothiazin-3-yl)-1-arylprop-2-en-1-ones: preparative,
IR, NMR and DFT study on their substituent-dependent reactivity in
hydrazinolysis and sonication-assisted oxidation with copper(II)nitrate†
Luiza Ga˘ina˘,a Antal Csa´mpai,*b Gyo¨rgy Tu´ro´s,b Tama´s Lova´sz,a Vira´g Zsoldos-Ma´dy,c Ioan A. Silberga and
Pa´l Soha´r*b,c
Received 14th June 2006, Accepted 18th September 2006
First published as an Advance Article on the web 24th October 2006
DOI: 10.1039/b608455a
A series of novel 3(5)-aryl/ferrocenyl-5(3)-phenothiazinylpyrazoles and pyrazolines were obtained
by substituent-dependent regioselective condensation of the corresponding (E)-3-(2-alkyl-10H-
phenothiazin-3-yl)-1-aryl/ferrocenylprop-2-en-1-one with hydrazine or methylhydrazine in acetic acid.
The different propensity of the primary formed b-hydrazino adducts to undergo competitive retro-
Mannich reaction was interpreted in terms of tautomerisation equilibrium constants calculated by
DFT using a solvent model. The regioselectivity of the cyclisation reactions with methylhydrazine and
the substituent-dependent redox properties of pyrazolines were also rationalized by comparative DFT
calculations performed for simplified model molecules. On the effect of ultrasound-promoted oxidation
with copper(II)nitrate phenothiazine-containing pyrazolines, enones and oxo-compounds were
selectively transformed into sulfoxides. Only one sulfoxide enone was partially converted into an
oxirane derivative. The structure of the novel products was determined by IR and NMR spectroscopy
including COSY, HSQC, HMBC and DNOE measurements.
by the aldol condensation of formyl phenothiazines with aryl-
Introduction
methyl ketones, to obtain novel pyrazole/pyrazoline derivatives
In the course of our study on ferrocenyl heterocycles,1b including
substituted with phenothiazinyl and aryl (including ferrocenyl)
phenothiazine derivatives,2 we synthesized variable new com-
groups (Scheme 1).
pounds of theoretical, chemical, physical and/or potential bio-
logical interest via enones.3 Enones readily react with hydrazines
yielding pyrazolines and pyrazoles,4,5 so it seemed reasonable
Results and discussion
to apply this reaction to our phenothiazinyl enones, formed
1. Synthesis of new phenothiazinyl enones
aDepartment of Organic Chemistry, Babes¸-Bolyai University, str.
The procedure already established for obtaining enone 4a by
the condensation of 10-methyl-phenothiazin-3-carboxaldehyde
2 with m-nitroacetophenone3 was extended to the preparation
of analogues using p-methoxyacetophenone, 2-acetylnaphthalene
and acetylferrocene. The corresponding enones 4b–d and 5d were
thus obtained in 60–97% yield.
Arany Ja´nos 11, RO-40028, Cluj-Napoca, Romania
bInstitute of Chemistry, Eo¨tvo¨s Lora´nd University, P. O. B. 32, H-1518,
Budapest-112, Hungary
cResearch Group for Structural Chemistry and Spectroscopy, Hungarian
Academy of Sciences, Eo¨tvo¨s Lora´nd University, P. O. B. 32, H-1518,
Budapest-112, Hungary
† Study on ferrocenes, part 19. For part 18 see ref. 1a.
Scheme 1
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Table 1 Free energy (G)a and equilibrium of aryl methyl ketones IIIa–d
and the corresponding enols IIa–d (see Scheme 2) and their equilibrium
calculated by B3LYP/6–31G(d,p) in acetic acid (e = 6.15) using IEFPCM
solvent model
2. Reactions of enones with hydrazine hydrate
2.1 Cyclisations. Cyclisations were first attempted in
ethanol, but TLC analysis showed the formation of multi com-
ponent mixtures. Boiling acetic acid proved to be a suitable
solvent in which enones 4a–d and 5d gave 1-acetyl-3-aryl-5-
phenothiazinylpyrazolines 6a–d and 7d (Scheme 1) in good yields
(75–85%). Spontaneous aromatisation was obviously prevented by
the electron-withdrawing N-acetyl group present in the products.
The increased redox potential of 6a–d and 7d is also reflected in
their attempted oxidation reactions discussed later.
G(III) (au)
G(II) (au)
DG(II–III)/kJ mol−1 K(II/III)
a
b
c
−589.317091 −589.298461 48.92
−499.311991 −499.288729 61.11
−538.419438 −538.397319 58.20
−1803.218399 −1803.193065 78.41
3.04 × 10−9
2.29 × 10−11
7.37 × 10−11
2.23 × 10−14
d
a Zero-point energy (ZPE, kJ mol−1): 366.88 for IIIa; 446.42 for IIIb; 482.71
for IIIc; 540.13.88 for IIId; 365.28 for IIa; 444.68 for IIb; 481.15 for IIc;
537.79 for IId.
2.2 Retro-Mannich type reaction and its theoretical
interpretation
unambiguously shows that Id → IId (related to IIId → IId) must be
much less favoured process (at least by three orders of magnitude)
than fragmentations Ia–c → IIa–c. This view can probably be
extended to the corresponding intermediates with X = NNH2;
A common characteristic side reaction, with the exception
of precursors containing ferrocenyl substituent (4d and 5d),
was the formation of N-acetyl-Nꢀ-[(10-methylphenothiazine-3-
yl)methylene]hydrazine (8) as by-product. Klimova et al. reported
similar fragmentation reactions accompanying enone cyclisa-
tions with thiosemicarbazides.6 Fang et al. have demonstrated
that certain isolated b-phenylhydrazino adducts undergo such
fragmentation with a proposed concerted mechanism affording
phenylhydrazones.7 It must be pointed out that, although the
concerted mechanism seems reasonable for this reaction, in the
lack of conclusive evidence stepwise transformation can also be
taken into consideration. In keeping with these precedents our
reactions must involve the formation of a b-adduct [I: X =
=
NNHAc; NN C(Me)Ar moieties.
3. Substituent-dependent cyclisations with methylhydrazine and
their theoretical interpretation
The cyclisations with methylhydrazine under the same conditions
provided in most cases aromatic products, that is, 1-methyl-3-
aryl-5-phenothiazinyl pyrazoles, 10b–d, 11a and 12d (Scheme 3).
Pyrazoline 13d was only formed as a by product. Apparently,
the electron-deficient acetylated nitrogen is mainly responsible for
the increased resistance to oxidation in the above cases. (This
difference in reactivity will be discussed later.) The yields of
pyrazoles were lower, 54–65% than those of N-acetylpyrazolines.
A general problem was raised by the positional isomerism in the
forming pyrazol(in)es as reported for a number of analogous
reactions.4a–e The majority of products (10b–d, 13d) have the
1-Me-5-phenothiazinyl (Ptz) substitution pattern while 1-Me-3-
Ptz substitution was evidenced by NMR (see later) for 11a and
12d. In order to get quantitative information on the relative
reactivity of the electrophilic centres of our precursor enones
in acetic acid solution we carried out again density functional
(DFT) calculations for simplified models IVa–e (Scheme 4) and
their O-protonated forms (IV+a–e) at B3LYP/6–31G(d,p) level
using an IEFPCM solvent model (Table 2). In each case the
geometry optimization was followed by calculation of the energy
and population of the frontier molecular orbitals.10,11 Molecu-
lar reactivity indices such as electronic chemical potential12a–I
=
O; NNH2; NNHAc; NN C(Me)Ar] and its subsequent frag-
mentation affording 8 and an enol or enhydrazine/enhydrazone
intermediate (II) which finally undergoes tautomerisation to III
(Scheme 2). Of course, the methyl ketone (III: X = O) can
react with a hydrazine component present in the reaction mixture
yielding a hydrazone or azine product (III: X = NNH2; NNHAc;
ꢀ
=
NN C(Me)Ar). Accordingly, a significant amount (14%) of N,N -
=
bis[1-(m-nitrophenyl)ethylene]hydrazine (IIIa, X = NN C(Me)-
m-NO2Ph) could also be isolated from the reaction mixture
obtained after the reaction of enone 4a. As in the case of 4d and
5d, such fragmentation was not observed even in trace amounts,
a particular inhibition must be attributed to the ferrocenyl group.
Since fragmentation I → II, taking place either with concerted
mechanism or in a stepwise manner, is eventually associated with
=
the tautomerisation of the ArC( X)CH2 moiety of the b-adduct,
we tried to approach the observed substrate-dependence through
the calculated substrate-dependence of oxo-enol tautomerisation
III ↔ II. The computations were carried out by the Gaussian
program package8 at B3LYP/6–31G(d,p) level of DFT using
IEFPCM solvent model9 adequately representing the applied
reaction conditions (solvent: AcOH, e = 6.15). On the optimized
structures, frequency calculations gave the change in free energy
values (DG), and the series of K(II/III) constants were obtained
as exp(−DG/RT) (Table 1). The comparison of K(II/III) values
[l = (EHOMO + ELUMO )/2], chemical hardness12a–I [g = (ELUMO
−
E
HOMO)/2] and natural charges [q(NBO)]13 are also listed in
Table 2. The local electrophilicity of the carbonyl- and b-carbon
atoms were characterized by their local LUMO electron deficiency
(R c2LUMO ) and the LUMO energy in the neutral and O-protonated
counterparts. The relative proton affinities of IVa–d (DDG) and
equilibrium constants (Ka) for the process IV + AcOH ↔
IV+ + AcO− were obtained from the thermodynamic results of
frequency calculations carried out on the same level of DFT with
the same solvent model. The electron chemical potential values
(l), representing the escaping tendency of molecular electrons,
clearly reflect the relative electrophilicity of the studied models.
According to general expectations, m-nitrophenyl derivative IVa
is characterized by the lowest l value (−5.00 eV) and ferrocenyl
vinyl ketone IVd is the less electrophilic model (l = −3.58 eV).
Scheme 2
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Scheme 3
Fig. 1
finally result in the preferred formation of pyrazoles with the
“unexpected” 1-Me-3-Ptz substitution pattern in all cases. The
observed regioselectivity can be successfully interpreted by the
relative weighting of LUMO in the neutral and protonated model
enones IVa–e and IV+a–e, respectively.
The population data (Table 2) suggest that without protonation,
only the nitrophenyl model IVa has increased carbonyl reactivity
in the orbital-controlled14 addition towards the more nucleophilic
methylated nitrogen of methyl-hydrazine (R c2HOMO = 0.488 on
NHMe and 0.155 on NH2 as calculated by the same method),
but enones IVb–e with larger R c2LUMO values on C-b are more
likely to undergo conjugate addition with the reagent, which
is also preferred under thermodynamic control [cf. DG(VII–V)
in Table 3]. Population analysis of LUMOs (Table 2) shows
substantially higher carbonyl reactivity for each O-protonated
model (IV+a–e). Enhanced carbonyl reactivity of IV+a–e is also
Scheme 4
It is worth noting that even protonated ferrocenyl vinyl ketone
(IVd+) is not as electrophilic as the neutral vinyl m-nitrophenyl
ketone IVa. Although IV+ cations are expected to be involved
in charge controlled reactions,14 protonation decreases molecular
hardness (g) values also increasing the efficiency of orbital
interactions. On the other hand, considering the natural charge
=
values on C O/C-b carbon atoms in the electrophilic species
(Table 2) and on NHMe/NH2 nitrogen atoms in methylhydrazine
(q = −0.547/q = −0.767), charge controlled additions would
dominantly give allylalcohol intermediates VII/P/a–e (Fig. 1)
which would finally be converted into the “normal” regioisomeric
pyrazoles (VI, Scheme 4) in all cases. The free energy values (G) of
four types of possible adducts (Va–e, V/a–e, VIIa–e and VII/a–
e, Fig. 1) were also obtained by DFT frequency calculations
performed on the optimized structures at B3LYP/6–31G(d,p)
level of theory using IEFPCM solvent model (Table 3, solvent:
AcOH, e = 6.15). The DG values show that b-adducts are much
more stable than the corresponding allylalcohols [see DG(VII–
V) and DG(VII/P–V/P) in columns 7 and 8]. Regioselectivity
would be less influenced by the relative stability of NHMe- and
NH2 adducts—as reflected from DG(V–V/P) and DG(VII–VII/P)
values (Table 3, columns 3 and 6). Nevertheless, the dominance
of thermodynamic control in the primary addition step would
reflected from the increased positive values of natural charge [cf.
+
=
q(NBO) on C O for IVa–e and IV a–e in Table 2].
On the basis of these results it can be stated that the conjugate
addition of methylhydrazine at C-b finally yielding the expected
pyrazole (IV → V → VI) is preferred over the nucleophilic addition
to the carbonyl group in neutral enones IVb–e, while IVa and each
cation of type IV+ are susceptible to react with the nucleophile at
the carbonyl group to give the corresponding hydrazinoacetal VII
which is then transformed into the regioisomeric pyrazoline VIII.
In accord with the expectations, much lower LUMO energy (i.e.
larger electron affinity) and electronic chemical potential (l) values
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were obtained for IV+a–e than for their neutral counterparts IVa–
e which are less sensitive to nucleophilic attack. The comparison
of these data characterizing the electronic properties of Ar
substituents suggests that addition of IVd → Vd (Ar = ferrocenyl)
is much slower than addition of neutral enones with less electron-
donating aryl substituents (IVb,c,e → Vb,c,e: Scheme 4). On
the other hand, according to the relative proton affinity values
and equilibrium constants obtained for the process IV + AcOH
↔ IV+ + AcO− (Table 2) IVd has far the best chance to be
transformed into the more electrophilic protonated form IV+d
(e.g. IVd is more basic than anisyl derivative IVb by more than one
magnitude). Although IV+d must be present in low concentration
in the reaction mixture, its enhanced reactivity, which is reflected in
electron chemical potential, chemical hardness and LUMO energy
(l = −4.81 eV vs. −3.58 eV for IVd; g = 1.48 eV vs. 1.85 eV for
IVd; ELUMO = −3.33 eV vs.–1.73 eV for IVd), significantly increases
the possibility of the primary addition at the carbonyl group.
The above discussed view about the relative possibilities of alter-
native reaction pathways is in accord with the experimental results
as under the applied conditions 3-nitrobenzoyl enone 4a (modelled
by IVa) yields exclusively pyrazole 11a with unexpected substituent
pattern, while the presence of strongly electron-releasing ferro-
cenyl group in the enone precursor 5d (R = n-Bu) increases
the chance of O-protonation and, consequently the formation of
analogous pyrazole 12d. The reason of the different regioselectivity
observed for the cyclisation of 10-methylphenothiazinylenone
4d (R = Me) is not clear at the moment, but the alternative
reaction pathway can not be ruled out completely considering
the formation of a substantial amount of tarry materials and
the relatively low yields of the “normal” regioisomers 10d and
13d (18 and 27%, respectively). The cyclisations of 4b,c to
10b,c presumably proceed via the generally accepted mechanism7
involving the primary conjugate addition of methylhydrazine on
the unprotonated enones.
Scheme 5
loss of a hydrogen atom or a hydride anion from the saturated
carbon atom adjacent to the substituted nitrogen generating the
corresponding intermediate. The free energy values of the models
were resulted from frequency calculations carried out on the
optimized structures (Table 4). Comparison of the substituent-
dependent changes in free energy associated with the formation of
the possible intermediates (listed in row 3) shows that—in keeping
with general expectations—the N-methyl group renders a higher
degree of stabilization both to radical (XII) and cationic (XIII)
intermediates than does the N-acetyl group (by 9.04 kJ mol−1 and
94.29 kJ mol−1, respectively). The difference is more than ten times
larger for the formation of cationic intermediates than obtained
for the formation of radical intermediates, suggesting that the
ionic mechanism might be better adopted to the experimental
observations. As the cyclisation reactions with methylhydrazine
were conducted under inert conditions, we cannot unambiguously
identify the possible oxidant at the moment. Finally, from ther-
modynamic point of view, aromatisation of N-methylpyrazoline is
also preferred over that of N-acetylpyrazoline by 47.18 kJ mol−1
(Table 4: row 3).
5. Sonication-assisted oxidation reactions with copper(II) nitrate
trihydrate
4. Theoretical interpretation of different redox proporties of
N-acetyl- and N-methylpyrazolines
In order to get pyrazoles without an N-substituent, we envisaged
oxidation of 6a–d and 7d followed by facile deacylation of
the resulting aromatic products. Preliminary experiments using
classical oxidation agents, including attempts with high redox
potential quinones (e.g. DDQ) failed. This is why we resorted
to the sonication-assisted oxidation with copper(II) nitrate, a
procedure successfully applied to aromatisation of pyrazolines.15
Instead of the expected dehydrogenation reaction, on the effect
of the “in situ” generated nitrogen dioxide16 oxidation of sulfur
atom occurred to give sulfoxides 9a–c (Scheme 1). This finding
refers to the preference of primary single electron transfer from
the phenothiazinyl ring16 over the hydrogen-abstraction from
The spectacular difference in the propensity of N-acetyl- and
N-methylpyrazolines to undergo spontaneous dehydrogenation
under the conditions of cyclisation reactions discussed above
was also studied by DFT calculations, which were performed
for simplified models XIa,b–XIVa,b (Scheme 5) at B3LYP/6–
31G(d,p) level of theory using IEFPCM solvent model (solvent:
AcOH, e = 6,15). Two possible mechanisms involving radical and
cationic intermediates XIIa,b and XIIIa,b, respectively, were taken
into account. Concluding from the highly significant substrate
dependence we assume that the rate-determining step is the
Table 4 Free energy valuesa of model pyrazolines XIa,b, radicals XIIa,b, cations XIIIa,b and pyirazoles XIVa,b, (see Scheme 5) calculated by B3LYP/6–
31G(d,p) in acetic acid (e = 6.15) using IEFPCM solvent model
G(XI) (au)
G(XII) (au)
G(XIII) (au)
G(XIV) (au)
DG(XII–XI)b/kJ mol−1 DG(XIII–XI)b/kJ mol−1 DG(XIV–XI)b/kJ mol−1
a
−266.623705 −265.987472 265.866276
−379.979412 −379.339739 379.186074
265.461863
378.799602
1670.54
1679.58
−9.04
1988.77
2083.06
−94.29
3050.63
3097.81
−47.18
b
a–b
a ZPE [kJ mol−1]: 318.02 for XIa; 343.01 for XIb; 276.14 for XIIa; 303.88 for XIIb; 286.44 for XIIIa; 307.91 for XIIIb; 258.65 for XIVa; 282.99 for XIVb.
b In the third row for columns 5–7: DDG(a–b).
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Scheme 6
the pyrazolyl moiety.15 Unfortunately the ferrocenyl-substituted
6. Structure
substrates underwent decomposition under the applied conditions.
However, the relatively short reaction time, the high yields of
sulfoxides 9a–c (sometimes reaching 95%) and the simplicity of
the reaction conditions made us to subject phenothiazinyl enones
to this procedure of S-oxidation, not mentioned so far in the
literature. By means of this method, 4a–c were smoothly converted
into their sulfoxide derivatives (14a–c Scheme 6), without sulfone
contaminations. Besides S-oxidation, enone 4b partially under-
went subsequent epoxidation on the double bond, yielding oxirane
15b (Scheme 6). The primary oxidation of the sulfur atom probably
decreases the electron-donating ability of the phenothiazine unit,
indirectly decreasing the chance of electrophilic epoxidation on
the attached double bond. This deactivation must be partially
compensated by the electron-donating anisyl group in sulfoxide
14b, the precursor of 15b. In a separate experiment, 14b was
subjected to prolonged oxidative procedure (10 h) affording
oxirane 15b in good yield (85%).
The spectral data (Tables 5–8) of our new compounds are self-
explanatory concerning the supposed structures and only a few
additional remarks are necessary.
The position of the NAc group in 6a–d and 7d is proved by
HMBC experiments (for 6a–c and 7d) which demonstrate 3J(C,H)
coupling between the H of pyrazoline-CH and the carbonyl carbon
of the acetyl group and between the CH2-hydrogens and C-1 of
the aryl or ferrocenyl moiety (Ar, Scheme 1), respectively.
The chemical non-equivalence of C/H-2,5 and C/H-3,4 atom
pairs in 6d, 7d and 13d is due to molecular asymmetry (the presence
of a chirality center). Of course, in the spectra of 10d and 12d,
which do not contain chiral atoms, the aforementioned H and C
atom pairs give identical signals.
Besides the IR, 1H- and 13C-NMR characteristics of the
azomethine, acetyl and NH groups the structure of compound 8 is
confirmed by the significant downfield shift of H-3 and H-5 signals
(by ca. 0.4–0.5 ppm compared to 6a–d and 7d) as a consequence
We also tested this protocol on simpler 10-alkylphenothiazines
1–3 and found that S-oxidation took place selectively resulting in
sulfoxides 16–18 irrespective of the ring substituents (Scheme 7).
It is also worth pointing out that the formyl group in 2 proved to
be resistant to oxidation under the employed conditions which is
capable of oxidizing even the highly deactivated diacetyl derivative
3 (Scheme 7). To the best of our knowledge this is the first example
for the sulfoxidation of a 3,7-diacylphenothiazine. Due to its
simplicity and potential to produce sulfoxides with high yields
and chemoselectivity, this method represents an advantageous
alternative to the classical S-oxidation reactions applied so far
in phenothiazine chemistry.17
=
of summarized –I– and anisotropic effects of the vicinal C N
double bond.
In case of 9a–c, the pyrazolyl methine carbon and the S atom
of the sulfinyl group, the two chirality centres, make possible
the presence of two diastereomers. In the 1H- and 13C-NMR
spectra of 9a–c all resonances appear as doubled signals of equal
intensity proving the formation of a 1 : 1 mixture of diastereomers
containing the pyrazolyl methine proton and sulfinyl oxygen in
syn and anti arrangements. This observation is an indirect proof
of the presence of an SO group (besides of the mSO IR band, cf.
Table 8).
Similarly the ab ovo, more probable, chemically-expected po-
sition of the NMe group in 10b–d and 13d is proved by HMBC
measurements. For 10b, the supposed regioisomeric structure is
also supported by NOE experiments. Intensity enhancements were
observed on the H-3 and H-5 signals of phenothiazine ring when
the Hs of the NMe group were irradiated.
HMBC results confirmed the unexpected regioisomeric struc-
tures for 11a and 12d. Accordingly, we detected NOE between
the Hs of NMe group and H-2,5 of the substituted Cp ring of
ferrocene for compound 12d.
1
In the H- and 13C-NMR spectra of 15b the signals of two
Scheme 7
saturated methine groups appear in the interval characteristic
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Table 7 13C NMR chemical shiftsa of phenothiazine carbons in compounds 6a–d, 7d, 8, 9a–c, 10b–d, 11a, 12d, 13d, 14a–c, 15b and 16–18b
Compd.
C-1a
C-2
C-3
C-4
C-5
C-5a
C-6a
C-7
C-8
C-9
C-10
C-10a
6a
6b
6c
6d
7d
8
146.0
146.1
146.0
146.0
145.5
147.8
114.6
114.5
114.6
114.6
115.8
114.3
125.5
125.6
125.6
125.2
124.9
127.57
130.3
132.4
130.2
132.3
130.2
132.3
127.6c
128.3
128.2
127.86
124.7
126.9
133.4d
133.0
133.0
133.1
133.2
133.1
133.2c,e
136.1
136.8
136.7
136.9
136.7
128.6
135.4
135.6
136.1
136.2
136.0
136.1
124.4c
125.2
123.3e
127.9
128.4
135.0
128.6
129.4
129.3
133.5
122.3
130.5
132.0
124.4
124.6
124.7
124.5
124.7
125.4
132.0
133.4e
127.4
129.5
127.5
129.6
128.3c
127.6
127.6
124.6
124.8
126.5
132.3
131.43
131.54c
131.36
131.5
134.8
133.7c,e
124.8
124.46c
124.6
124.6
126.0
124.5
125.13c
125.5c
125.01c
125.6
125.07c
125.62c
125.4c
124.5
125.4
124.2
125.5
124.3
124.7
125.6
125.6
124.6
125.2
125.5
124.4
123.3
123.5
123.5
123.4
127.5
127.5
127.5d
127.5
127.6
127.64
127.3
129.3
131.3
131.4
128.3e
123.0
122.9
122.9
122.9
122.7
123.4
122.47
122.50
122.35
122.39
122.37
122.42
123.2
123.3
123.3e
122.9
122.7
122.9
123.3
123.0
123.1
122.1
122.3
123.88
132.0
128.0
127.9
127.9
127.9
127.8
128.0
133.3
133.4e
133.3e
114.5
114.4
114.4
114.5
115.7
114.8
116.4c
116.8c
115.9c,e
145.9
145.7
145.8
145.7
145.2
123.2
124.7c
124.8c
124.99c
124.95c
124.92c
124.97c
123.3
123.2
124.4
123.6
125.1
123.6
124.3
125.3
125.2
125.0
125.2
125.2
124.4
145.4
9a
139.85c,e 115.9c,e
140.05c
140.09c
139.7c,e
9b
9c
140.16c
140.20c
139.8c,e
116.1c
116.7c
115.9c,e
133.3e
116.2c
116.7 c
114.7
114.7
114.3
114.48c
115.7c
114.48c
116.5
116.2
116.2
115.8
115.9
116.7c
116.4
140.15c
140.18c
145.7
145.7
145.7
145.9c
145.6
145.8
139.6
139.8
139.7
140.1
140.3
139.3
140.9
10b
10c
10d
11a
12d
13d
14a
14b
14c
15b
16
146.4
146.5
146.4
146.0c
144.9
146.1
141.7
141.2
141.3
139.0
140.3
144.1
140.9
114.38
114.4
114.7
114.54e
115.8c
114.52c
116.8
116.5
116.5
116.0
11.9
127.7
127.7
127.7
127.6
127.6c
127.6
131.4
131.48
131.58c
131.28
131.5
131.5
133.7c,e
128.1
128.1
128.1
127.9
127.8e
127.9
133.8
133.5
133.3
132.0
133.2
133.7
133.2c,e
17
18
116.6c
116.4
a In ppm (dTMS = 0 ppm) at 125.7 MHz. Solvent: CDCl3. b Assignments were supported by DEPT, HMQC (except for 9a and 18) and HMBC (except for
6d, 9a, 16 and 18). c Interchangeable assignments (See Table 2a for compound 6b and 9b). d Overlapping lines (See Table 2a). e Two coalesced lines.
Table 8 Characteristic IR frequencies [cm−1] of compounds 6a–d, 7d, 8, 9a–c, 10b–d, 11a, 12d, 13d, 14a–c, 15b and 16–18a,b
Bands of the
phenothiazine moiety
=
=
Compound
mC O band
mC C band
mSO band
c CArH band
masCp–Fe–Cp band
6a
1661
1646
1662
1646
1658
1695
1667
1653
1661
—
—
—
—
—
1608
1607
1602
1601
1601
1601
1591
1606
1589
1611
1601
1606
1606
1606
1603
1586
1466
1465
1465
1465
1464
1466
1464
1463
1464
1465
1460
1462
1466
1454
1464
1466
1463
1465
1464
1457
1462
1479
1257
1258
1256
1253
1248
1254
1261
1250
1260
1248
1260
1259
1260
1285
1251
1218
1259
1261
1256
1261
1260
1249
—
—
—
—
—
—
817, 752
—
—
—
487
491
—
—
—
—
—
—
489
—
505, 488
495
—
—
—
6b
840, 808, 743
836, 805, 752
856, 755
818, 747
808, 744
811, 757, 739
815, 755
819, 753
834, 821, 783, 764
802, 705
818, 750
798, 752, 737
823, 758
815, 747
813, 754
834, 805
810, 747
813, 753
765
764, 751
6c
6d
7d
8
9a
1049, 1027
1046, 1022
1049, 1027
—
—
—
—
—
—
1021
1020
1020
1057
1020
1046, 1025
1024
9b
9c
10b
10c
10d
11a
12d
13d
14a
14b
14c
15b
16
—
1656
1654
1654
1654
—
1682
1674
1602, 1585
1586
1601, 1588
1584
1605, 1086
1589
—
—
—
—
17
18
826
a In KBr discs. b Further bands: mNH: 3200–2800 diffuse band (8); masNO2 and msNO2: 1498 and 1332 (6a), 1530 and 1350 (9a and 11a), 1526 and 1354
(14a); mC–O (oxirane ring): 876 and 839 (15b).
for oxiranes18a instead of the signals of olefinic CH CH moiety
arising from the parent enone sulfoxide 14b. The absence of the
=
respectively, in the ranges expected for compounds containing
benzophenone- and acetophenone-type –C(sp2)–CO–C(sp2) and
C(sp3)–CO–C(sp2) moieties.18b
The signals of the oxirane-Hs of 15b appear doubled with similar
intensities while neither the other 1H-NMR signals nor the carbon
lines without exception are doubled. From the AB-type spectrum
of the oxirane-Hs, the coupling constants of the two components
=
C C double bond in 15b is also reflected in the significant upfield
shifts of the signal of ortho-Hs of the aryl group and H-3 and H-5
signals of the phenothiazinyl group.
In accordance with the above stated structural difference, the
carbonyl lines of 14b and 15b appear at 188.7 and 197.2 ppm,
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are 6.6 and 7.1 Hz, respectively, characteristic of cis isomers.18c It
means that the relative configurations of the carbons in the oxirane
ring do not differ in the two components. Thus the existence of the
latter requires the presence of a third chiral centrum provided by
the sulfoxide structure. Accordingly, in the IR spectrum of 15b, a
very intense mSO band (1027 cm−1) appears and the mass spectrum
proved the molecular formulae (C23H19NO4S) in keeping with the
sulfoxide structure.
(E)-10-Methyl-3[1-(2-naphthyl)-1-oxo-2-propen-3-yl]-10H-
phenothiazine (4c). Yellow powder; (0.382 g, 97%); mp 162–
163 ◦C (from EtOH); (found C 79.4, H 4.9, N 3.5, S
8.25, C26H19NOS requires C 79.4, H 4.9, N 3.6, S 8.15%);
mmax(KBr)/cm−1 1652, 1597, 1586, 1455, 1261, 813 and 762; dH
(400 MHz; CDCl3): 3,41 (3 H, s), 6.82 (1 H d, J = 8.8), 6.84 (1 H,
d, J = 8.4), 6.97 (1 H, t, J = 8.4), 7.15 (1 H, d, J = 7.7), 7.19 (1 H,
d, J = 8.4), 7.45 (1 H, d, J = 8.4), 7.49 (1 H d, J = 1.6), 7.56 (1 H,
d, J = 15.4), 7.58–7.62 (2 H, m), 7.70 (1 H, d, J = 15.4), 7.90 (1 H
dd, J = 7.2 and 1.6), 7.93 (1 H, dd, J = 8.8 and 1.6), 8.01 (1 H, dd,
J = 8.1 and 1.6), 8.09 (1 H, dd, J = 8.4 and 1.6) and 8.53 (1 H, dd,
J = 8.1 and 1.6). dC (100 MHz; CDCl3): 35.6, 114.1, 114.4, 119.9,
122.6, 123.1, 124.0, 124.5, 126.3, 126.7, 127.3, 127.7, 127.8, 128.3,
128.5, 129.4 (two overlapping lines), 129.8, 132.6 (two overlapping
lines), 135.4, 135.8, 143.7, 144.8, 147.9 and 190.1.
Experimental
Melting points (uncorrected) were obtained with an Electro-
thermal IA 9200 digital melting point apparatus. Elemental
analyses were performed by a VARIO EL III instrument. IR
spectra were recorded in KBr pellets with a BRUKER IFS 55 FT-
spectrometer. 1H- and 13C-NMR spectra were recorded in CDCl3
solution in 5 mm tubes at RT, on a Bruker DRX 400-(only for 4b,c)
and 500 spectrometers at 400/500 (1H) and 100/125 (13C) MHz,
using TMS as internal reference with the deuterium signal of the
solvent as the lock. J Values are given in Hz. The spectral data
of 4b,c are listed in the experimental part. The standard Bruker
micro program NOEMULT.AU to generate NOE was used with a
selective pre-irradiation time. DEPT spectra were run in a standard
manner, using only the H = 135◦ pulse to separate CH/CH3 and
CH2 lines phased “up” and “down”, respectively. 2D-HMQC and
2D-HMBC spectra were obtained by using the standard Bruker
pulse programs INV4GS and INV4GSLPLRND, respectively.
General procedure for the preparation of compounds 6a–d, 7d, 8,
10b–d, 11a, 12d, 13d. Hydrazine hydrate (0.145 g, 30 mmol) for
compounds 6a–d and 8 or methyl hydrazine (0.136 g, 30 mmol) for
compounds 7d, 10b–d, 11a, 12d and 13d was added to chalcones
4a–d and 5d (1.5 mmol) suspended in acetic acid (50 cm3). The
reaction mixture was heated under reflux for 5–8 h then solvent was
evaporated in vacuo. The solid residue was washed with water and
filtered off. Purification was made by column chromatography on
silica using toluene as eluent and the products were re-crystallised
from EtOH–n-hexane (2 : 1) if otherwise not stated.
3-[1-Acetyl-3-(nitrophenyl)-4,5-dihydropyrazol-5-yl]-10-methyl-
10H-phenothiazine (6a). Yellow powder, (0.527 g, 79%); mp 155–
156 ◦C; (found C 64. 9, H 4.6, N 12.6, S 7.2; C24H20N4O3S requires
C 64.85, H 4.5, N 12.6, S 7.2%).
=
The mass spectra of IIIa (X = NN C(Me)-m-NO2Ph), 14a,b
and 16 were obtained by a Bruker Esquine 3000+ ion trap mass
spectrometer equipped with electrospray ionisation source.
Phenothiazine derivatives 1–3, 4a,d and 5d were pre-
pared according to described procedures.2,3,19,20 Acetylferrocene,
methylhydrazine, hydrazine hydrate, 2-acetylnaphthalene, m-
nitroacetophenone, p-methoxyacetophenone and phenothiazine
were purchased from Sigma-Aldrich.
3-[1-Acetyl-3-(4-methoxyphenyl)-4,5-dihydropyrazol-5-yl]-10-
methyl-10H-phenothiazine
(0.535 g 83%); mp 137–138 C; (found C 69.95, H 5.4, N 9.8, S
7.65; C25H23N3O2S requires C 69.9, H 5.4, N 9.8, S 7.5%).
(6b). Yellowish-white
powder,
◦
3-[1-Acetyl-3-(2-naphthyl)-4,5-dihydropyrazol-5-yl]-10-methyl-
10H-phenothiazine (6c). Reddish-white powder; (0.573 g, 85%);
mp 170–171 ◦C; (found C 74.8, H 5.2, N 9.4, S 7.0; C28H23N3OS
requires C 74.8, H 5.2, N 9.35, S 7.1%).
General procedure for the preparation of enones 4b,c
To the stirred solution of the appropriate 10-alkyl-3-formyl-
phenothiazine (1 mmol) and p-methoxyacetophenone (0.150 g,
1 mmol) or 2-acetylnaphthalene (0.146 g, 1 mmol) in ethanol
(20 cm3) 10% methanolic solution of NaOH (1 cm3) was added
dropwise over 3 min at 25 ◦C. The mixture was stirred for 8 h
at 40–50 ◦C. The product precipitated on cooling was filtered
and washed with cold ethanol (3 cm3) then purified by column
chromatography on silica using dichloromethane as eluent.
3-[1-Acetyl-3-(ferrocen-1-yl)-4,5-dihydropyrazol-5-yl]-10-
methyl-10H-phenothiazine (6d). Brown powder; (0.571 g, 75%);
mp 180–182 ◦C; (found C 66.2, H 5.0, N 8.3, S 6.45; C28H25FeN3OS
requires C 66.3, H 5.0, N 8.3, S 6.3%).
3-[1-Acetyl-3-(ferrocen-1-yl)-4,5-dihydropyrazol-5-yl]-10-(n-
butyl)-10H-phenothiazine (7d). Brown plates; (0.659 g, 80%); mp
93–95 ◦C; (found C 67.8, H 5.7, N 7.7, S 5.7; C31H31FeN3OS
requires C 67.75, H 5.7, N 7.6, S 5.8%).
(E)-3[1-(4-Methoxyphenyl)-1-oxo-2-propen-3-yl]-10-methyl-
10H-phenothiazine (4b). Orange powder (0.355 g, 95%); mp
197–200 ◦C (from EtOH); (found: C, 74.0; H, 5.2; N, 3.8, S
8.55, C23H19NO2S requires C, 74.0; H, 5.1; N, 3.75, S 8.6%);
mmax(KBr)/cm−1 1668, 1600, 1588, 1498, 1454, 1332, 1259, 810,
757 and 738; dH (400 MHz; CDCl3): 3.40 (3 H, s), 3.88 (3 H, s),
6.79 (1 H, d, J = 8.4), 7.40 (1 H, d, J = 8.4), 7.43 (1 H, s), 7.14 (1
H, d, J = 7.6), 6.96 (1 H, t, J = 8.0), 7.18 (1 H, t, J = 8.0), 6.82
(1 H, d, J = 8.0), 7.69, (1 H d, J = 15.6), 7.41 (1 H d, J = 15.6),
8.03, (2 H, d, J = 8.8 Hz) and 6.97 (2 H d, J = 8.8). dC (100 MHz;
CDCl3): 35.5, 55.5, 113.8, 114.1, 114.4, 119.7, 122.6, 123.0, 123.9,
126.2, 127.2, 127.7, 129.0, 129.5, 130.7, 131.3, 142.9, 144.8, 147.6,
163.3 and 188.5.
(E)-Nꢀ -[(10-Methyl-10H-phenothiazine-3-yl)methylene]aceto-
hydrazide (8). This compound was separated from 6a–c as
yellowish-white powder; (0.044 g, 10%, from 4◦a and 4b, respec-
tively, and 0.066 g, 15% from 4c) mp 226–227 C (from EtOH);
(found C 64.65, H 5.1, N 14.15, S 10.95; C16H15N3OS requires C
64.6, H 5.1, N 14.1, S 10.8%).
ꢀ
=
N,N -Bis[1-(m-nitrophenyl)ethylene]hydrazine (IIIa, X = NN
C(Me)-m-NO2Ph)21. The mixture obtained from the reaction of
4a was cooled in ice-water to obtain this compound as precipitated
pale yellow crystals; (0.034 g, 14%); mp 198–200 ◦C (from EtOH);
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(found C 59.1, H 4.4, N 17.0; C16H14N4O4 requires C 58.9, H 4.3,
N 17.2%); mmax (KBr)/cm−1 3093, 1610, 1526, 1432, 1345, 737, 678
and 669; dH (500 MHz, CDCl3) 2.41 (3 H, s), 7.64 (1 H, t, J = 7.9),
8.28 (1 H, dd, J = 7.9 and 1.9), 8.30 (1 H, dd, J = 7.9 and 1.9) and
8.75 (1 H, t, J = 1.9); dC (125 MHz, CDCl3) 15.1, 124.4, 129.5,
132.4, 139.6, 149.0 and 156.8. MS (electrospray) 325.1 (ESI−),
327.1 (ESI+).
95%); 214–217 ◦C; (found C 67.4, H 5.2, N 9.5, S 7.2; C25H23N3O3S
requires C 67.4, H 5.2, N 9.4, S 7.2%).
3-[1-Acetyl-3-(2-naphthyl)-4,5-dihydropyrazol-5-yl]-10-methyl-
10H-phenothiazine-5-oxide (9c). White powder; (0.428 g, 92%);
156–158 ◦C; (found C 72.3, H 4.9, N 9.05, S 6.8; C28H23N3O2S
requires C 72.2, H 5.0, N 9.0, S 6.9%).
(E)-10-Methyl-3-[1-(3-nitrophenyl)-1-oxo-2-propen-3-yl]-10H-
phenothiazine-5-oxide (14a). Yellow powder; (0.348 g, 86%); 201–
204 ◦C; (found C 65.2, H 4.1, N 6.8, S 7.9; C22H16N2O4S requires
C 65.3, H 4.0, N 6.9, S 7.9). MS (electrospray) 405.1 (ESI+).
10-Methyl-3-[3-(4-methoxyphenyl)-1-methyl-1H-pyrazol-5-yl]-
10H-phenothiazine (10b). Yellow powder; (0.360 g, 60%); mp
152–153 ◦C, (found C 72.2, H 5.3, N 10.5, S 8.2; C24H21N3OS
requires C 72.15, H 5.3, N 10.5, S 8.0%).
(E)-10-Methyl-3-[1-(4-methoxyphenyl)-1-oxo-2-propen-3-yl]-
10H-phenothiazine-5-oxide (14b). Yellow powder; (0.272 g,
70%); 237–241 ◦C; (found C 80.05, H 4.8, N 3.8, S 8.1; C23H19NO3S
requires C 70.9, H 4.9, N 3.6, S 8.2). MS (electrospray) 390.2
(ESI+).
10-Methyl-3-[1-methyl-3-(naphthalen-2-yl)-1H-pyrazol-5-yl]-
10H-phenothiazine (10c). White powder; (0.409 g, 65%), mp 240–
241 ◦C; (found C 77.3, H 5.1, N 10.05, S 7.7; C27H21N3S requires
C 77.3, H 5.05, N 10.0, S 7.6%).
10-Methyl-3-[1-methyl-3-(ferrocen-1-yl]-1H-pyrazol-5-yl)-10H-
phenothiazine (10d). This compound was separated from 13d as
yellow powder; (0.129 g, 18%); mp 147–148 ◦C; (found C 68.0,
H 4.9, N 8.8 S 6.7; C27H23FeN3S requires C 67.9, H 4.9, N 8.8, S
6.7%).
(E)-10-Methyl-3[1-(2-naphthyl)-1-oxo-2-propen-3-yl]-10H-pheno-
thiazine-5-oxide (14c). White powder; (0.327 g, 80%); 225–
226 ◦C; (found C 76.45, H 4.65, N 3.3, S 7.8; C26H19NO2S requires
C 76.3, H 4.7, N 3.4, S 7.8%).
10-Methyl-3[1-(4-metoxyphenyl)-1-oxo-oxiran-2-yl]-10H-pheno-
thiazine-5-oxide (15b). White powder, (0.032 g, 8% obtained by
treatment of 4b for 1 h; 0.345 g, 85% obtained by treatment of
14b for 10 h), 198–201 C; found C 68.3, H 4. 6, N 3.35, S 8.05;
C23H19NO4S requires C 68.1, H 4.7, N 3.45, S 7.9%).
10-Methyl-3-[1-methyl-3-(3-nitrophenyl)-1H-pyrazol-5-yl]-10H-
phenothiazine (11a). Ochre powder; (0.336 g, 54%); mp 176–
177 ◦C; (found C 66.7, H 4.4, N 13.6, S 7.9; C23H18N4O2S requires
C 66.65, H 4.4, N 13.5, S 7.7%).
◦
10-(n-Butyl)-3-[1-methyl-3-(ferrocenyl)-1H-pyrazol-5-yl]-10H-
phenothiazine (12d). Red plates; (0.545 g, 70%), mp 77–79 ◦C
(from n-hexane); (found C 69.4, H 5.6, N 8.1, S 6.3; C30H29FeN3S
requires C 69.4, H 5.6, N 8.1, S 6.2%).
10-Methyl-10H-phenothiazine-5-oxide (16). White powder;
(0.217 g, 95%), mp 187–189 ◦C [lit.: 185–187 ◦C, ref. 15b]; (found
C 67.9, H 5.95, N 6.1, S 14.1; C13H11NOS requires C 68.1, H 4.8,
N 6.1, S 14.0%).
10-Methyl-3-[1-methyl-3-(ferrocen-1-yl)-4,5-dihydropyrazol-5-
yl]-10H-phenothiazine (13d). This compound was isolated as
major product from the reaction of 4d with methylhydrazine.
Purification made by repeated chromatography on silica with
hexane–ethylacetate 4 : 1 as eluent afforded orange powder;
yield 27%, mp 162–165 ◦C; (found C 67.7, H 5.3, N 8.8, S 6.7;
C27H25FeN3S requires C 67.6, H 5.3, N 8.8, S 6.7%).
3-Formyl-10-methyl-10H-phenothiazine-5-oxide (17). Yellow
powder; (0.232 g, 90%); mp 205–207 ◦C; [lit.: 207–208 ◦C, ref.
15f ] (found C 65.5, H 4.2, N 5.35, S 12.6; C14H11NO2S requires C
65.35, H 4.3, N 5.4, S 12.5%).
3,7-Diacetyl-10-ethyl-10H-phenothiazine-5-oxide, (18). Yellow
powder; (0.278 g, 85%); mp 259–262 ◦C; (found C 65.8, H 4.2,
N 4.5, S 9.95; C18H17NO3S requires C 66.0, H 4.3, N 4.3, S 9.8%).
General procedure for the preparation of oxidation products 9a–c,
14b,c, 15b and 16–18
Conclusions
The corresponding precursor (1–3, 4b,c, 6a–c, or 14b, 1 mmol)
and Cu(NO3)2·3H2O (0.726 g, 3 mmol) were dissolved in DCM
(20 cm3). The reaction mixture was sonicated for 1 h (for 1–3,
4b,c, 6a–c) or 10 h (for 14b) at room temperature. The reaction
was monitored by TLC. After completion the reaction medium
was filtered and the solid was washed with DCM (2 × 20 cm3).
After evaporation the residue obtained was purified (or after the
reaction of 4b or 14b the mixture of 14b and 15b was separated)
by column chromatography on silica using DCM–MeOH (15 : 1)
as eluent and re-crystallised from EtOH.
Besides affording a series of novel heterocyclic derivatives includ-
ing sulfoxides with potential pharmacophoric units the simple
reactions described and theoretically modelled in this paper
may contribute to a better understanding of general substituent-
dependent reactivity of enones and pyrazolines in cyclisations and
redox reactions. The energetic data and reactivity indices obtained
by high-level DFT calculations using adequate solvent model,
can be taken into account to set up procedures for analogous
transformations of aromatic enones. Finally, the new compounds
described in this contribution deserve a multilateral investigation,
both as biologically active substances, and as potential scintillators
in radiation-detecting devices.
3-[1-Acetyl-3-(3-nitrophenyl)-4,5-dihydropyrazol-5-yl]-10-methyl-
10H-phenothiazine-5-oxide (9a). Yellow powder; (0.414 g 90%);
159–165 ◦C; (found C 62.6, H 4.4, N 12.2, S 7.1; C24H20N4O4S
requires C 62.6, H 4.4, N 12.2, S 7.0%).
Acknowledgements
3-[1-Acetyl-3-(4-methoxyphenyl)-4,5-dihydropyrazol-5-yl]-10-
methyl-10H-phenothiazine-5-oxide (9b). White powder; (0.423 g,
The authors express their thanks to the Hungarian–Romanian
Intergovernmental S & T Cooperation Programme (Hu-04/2002
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and Ro-17/2002, respectively), to the Hungarian Research Foun-
dation (OTKA, grants T-043634 and TS-044742) and to the Ro-
manian Research and Education Ministry (MEC, grants CNCSIS
196/2003 and 612/2003) for financial support.
10 K. Fukui, T. Yonezawa and H. Shingu, J. Chem. Phys., 1952, 20, 722–
725.
11 K. Fukui, T. Yonezawa and C. Nagata, J. Chem. Phys., 1957, 26, 831–
842.
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