Iodine-catalyzed stepwise [4+2] cycloaddition of phenothiazine- and ferrocene-containing Schiff bases with DHP promoted by microwave irradiation

Article abstract of DOI:10.1016/j.tet.2010.10.046

On simultaneous effect of iodine-catalysis and microwave irradiation Schiff bases deactivated by electron-donating C-phenothiazinyl- and ferrocenyl-substituents, respectively, underwent formal inverse electron demand aza-Diels-Alder (DA) cycloaddition wit

Full text of DOI:10.1016/j.tet.2010.10.046

Tetrahedron 66 (2010) 9938e9944
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Iodine-catalyzed stepwise [4þ2] cycloaddition of phenothiazine- and
ferrocene-containing Schiff bases with DHP promoted by microwave irradiation
a
a
a
a
b,
*
ꢀ
ꢀ
ꢀ
ꢀ
Emese Gal , Castelia Cristea , Luminita Silaghi-Dumitrescu , Tamas Lovasz , Antal Csampai
a
ꢀ
Faculty of Chemistry and Chemical Engineering, Babes-Bolyai University, Arany Janos str. 11, 400028 Cluj-Napoca, Romania
Institute of Chemistry, Eotvos Lorand University, P.O. Box. 32, H-1518, Budapest 112, Hungary
b
€
€
ꢀ
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 27 July 2010
Received in revised form 29 September 2010
Accepted 18 October 2010
Available online 17 November 2010
On simultaneous effect of iodine-catalysis and microwave irradiation Schiff bases deactivated by elec-
tron-donating C-phenothiazinyl- and ferrocenyl-substituents, respectively, underwent formal inverse
electron demand aza-DielseAlder (DA) cycloaddition with 3,4-dihydro-2H-pyrane (DHP) employed as
donor component. Depending on the substitution pattern of the N-phenyl group the reactions of phe-
nothiazine-containing imines afforded 2H-pyrano[3,2-c]quinolines or 3-(3-hydroxypropyl)quinolines.
Irrespective of the electronic properties of the N-phenyl substituent the less reactive ferrocene-based
imines were directly converted into quinoline products. The intermediate iodoiminium ions were ana-
lysed by B3LYP/DGZVP calculations suggesting stepwise mode for the cycloaddition process. In one case
the regioselectivity of the second step of cycloaddition was also interpreted by DFT analysis of the
alternative rotamers of the primarily formed DHP adduct.
Keywords:
[4þ2] Cycloaddition
Iodine-catalysis
Microwave-assisted reactions
Frontier molecular orbitals
DFT
Ó 2010 Elsevier Ltd. All rights reserved.
1. Introduction
molecular motifs to obtain novel model compounds for an ongoing
biological assay. Here we present the microwave-assisted synthesis
Phenothiazine and quinoline are two heterocyclic cores re-
sponsible for diverse biological activities as well as physical and
chemicalpropertiesoftheirderivatives. Investigationsrelatedtonew
synthetic methods and properties of such heterocyclic compounds
appear interesting for both fundamental research and industrial
applications. Phenothiazine is present as a major pharmacophore in
many types of drugs, pesticides and compounds with analytical ap-
plications (redox indicators and reagents in spectrophotometric de-
terminations), high temperature antioxidants for lubricants and
dyes.1 Quinoline and tetrahydroquinoline derivatives are often en-
countered in both natural and synthetic products displaying valuable
biological activity.2 On the other hand, during the last decades fer-
rocene-containing heterocycles have also attracted remarkable at-
tention due to their wide range of promising biological activity and
application even in therapy.3 The common feature of both pheno-
thiazine and ferrocene units is their low reduction potential allowing
the generation of reactive radical cations under physiological con-
ditions actually responsible for the observed activity.4,5 In the light of
these aspects we have focused our attention on phenothiazinyl- and
ferrocenyl-substituted quinolines having in mind the synthetic
combinationof thebeneficialpropertiesofthebiologicallypromising
of new phenothiazinyl- and ferrocenyl-Schiff bases incorporating an
imine group of decreased electrophilicity and their microwave-
assisted formal aza-DielseAlder (DA) cycloaddition with 3,4-dihy-
dro-2H-pyrane (DHP) conducted in the presence of catalytic amount
of iodine to obtain a series of novel hexahydro-2H-pyrano[3,2-c]
quinolines. To our best knowledge the combination of microwave
irradiation and iodine catalysis was used for the first time to promote
the envisaged cycloadditions of our substrates with decreased
reactivity, although a variety of conditions have also been reported
for related cyclisations of N-aryl imines: (i) iodine-catalyzed multi-
step reactions of imines and enolizable aldehydes taking place by
aza-Henry reaction followed by ring closure and dehydrogenation
led to the formation of 2-arylquinolines6 and 2-ferrocenylquino-
lines;7 (ii) hexahydro-2H-pyrano[3,2-c]quinoline- and furo[3,2-c]
quinoline-derivatives were prepared by inverse electron demand
aza-DA addition reactions of N-aryl imines and DHP and 2,3-dihy-
drofurane, respectively, catalyzed by Lewis acids (BF3$OEt2, TiCl4,
ZrCl4, AlCl3, InCl3, NbCl5, FeCl3, LiBF4, salen-AlCl, Yb(OTf)3, Sc(OTf)3,
Sm(OTf)3),8 as well as phosphomolybdic acid,9a tungstophosphoric
acid,9b cerium(IV)-ammonium-nitrate,9c proline-triflate9d and io-
dine;10 (iii) hexahydro-2H-pyrano[3,2-c]quinolines were also resul-
ted in short reaction times from TFA-catalyzed aza-DA cycloaddition
of in situ generated imines and DHP conducted under controlled
microwave conditions.11
* Corresponding author. Tel.: þ36 01 209 0555; fax: þ36 01 209 0602; e-mail
ꢀ
address: csampai@chem.elte.hu (A. Csampai).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.10.046

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E. Gal et al. / Tetrahedron 66 (2010) 9938e9944
9939
2. Results and discussion
isolated as they underwent facile dehydrogenation followed by the
fission of the pyrane ring leading to 3-(3-hydroxypropyl)quinolines
3b,f, which finally reacted with the excess of DHP to give acetals 4b,f
(Scheme 1). It is noteworthy that despite of the presence of nitro
group expected to decrease the tendency of dehydrogenation the
reaction of imine 1a afforded quinoline 3a as the only isolable
product. This reactivity can probably be ascribed to the repulsive
interaction of O1 and the adjacent 10-nitro group in 2a promoting
the opening of the pyrane ring presumably followed by facile de-
hydrogenation of the resulted 1,2-dihydroquinoline intermediate. It
is also of interest that neither 8-nitropyranoquinoline 2k nor the
corresponding 7-nitroquinolines of types 3 and 4 could be isolated
from the reaction mixture. Under microwave irradiation the iodine-
mediated transformations of ferrocenyl-Schiff bases 1hej with DHP
conducted in MeCN (Scheme 1) afforded 2-ferrocenyl-3-(3-
2.1. Synthesis of precursor Schiff bases
Phenothiazinyl- and ferrocenyl-Schiff bases 1aej (Scheme 1)
were obtained in excellent yields in 5 h by the microwave-assisted
condensation of the corresponding carbaldehydes and anilines
using MeCN as solvent (see Experimental). Schiff bases 1aef have
also been conventionally prepared by heating several hours under
reflux the solution of 3-formyl-10-methylphenothiazine and the
corresponding aromatic amine.12 Ferrocenyl Schiff bases 1h,i have
previously been prepared under solvent-free conditions.13 The
condensation of formylferrocene was also attempted with 3- and
4-nitroanilines using conventional heating and microwave irradi-
ation but no imine products were obtained by either methods.
2"
O
6"
R2
OH R2
2
4a
11
O
R2
10
O
N
H
R1
R1
R1
9
R1
i.)
-H2
H
DHP
4
10b
5
H
H
1
8a
5
7
8
from
from
3 b, f
Q
N
N
Q
N
Q
2a, b, f, h−j
Q
H
[ 3 b, f ]
3a: 38%
3h: 43%
3i: 48%
3j : 39%
1a-j
[ 2a, b, f, h−j ]
2c: 30%
4b: 47%
4f: 48%
2e: 51%
2g: 63%
a
b
c
d
e
f
g
h
i
j
1−4
O
H
R1
H
Me NO2 CO2H Cl OMe CO2Me Cl OMe CO2Me
H
H
R2 NO2
H
H
H
H
H
H
H
H
H
N
H
NO2
Phtz
Q
Phtz Phtz Phtz Phtz Phtz Phtz
Phtz
Fc
Fc
Fc
2k
2'
5'a
S
3'
5'
3'
The numbering of atoms is used for the assignment
of NMR data (see: Experimental)
Phtz =
Fc =
Fe
N
Me
9'
1'
i.) DHP, MeCN, I2 (1 mol%), MW, 80°C, 0.5 h for 1a−g and 1 h for 1h−j.
Scheme 1. Microwave-assisted [4þ2] cycloadditions of phenothiazinyl- and ferrocenyl-Schiff bases with DHP catalyzed by iodine.
2.2. Transformations of Schiff bases with DHP under MW
irradiation
hydroxypropyl)-quinolines 3hej as solely isolable products irre-
spective of the electronic nature of the R1-substituent referring to
highly favoured dehydrogenation and subsequent fission of the
pyrane ring in the primarily formed unisolable pyrano-tetrahy-
droquinolines 2hej. According toTLC-monitoring the completion of
theseconversions accompaniedbythe formationof tarrysubstances
required ca. 1 h taking place significantly slower than those of the
corresponding phenothiazinyl-Schiff bases 1eeg.
It must be noted here thatdcontrary to unisolable 3-(3-hydrox-
ypropyl)quinolines 3b,fdthe isolable 3a and 3hej do not react with
DHP under the employed conditions probably due to the decreased
reactivity of the less accessible hydroxypropyl group sterically hin-
deredbytherotatingproximalnitro-orbulky-ferrocenyl substituent,
respectively. On the other hand, since equimolar amounts of the
corresponding Schiff base and DHP were used in the reactions
studied, the isolated yields of 4b,f (47%and48%, respectively)suggest
that the rate-limiting cycloaddition is followed by fast aromatisation
affording 3b,f, which readily add to the unreacted DHP present in the
reaction mixture.
The prepared Schiff bases 1aej containing highly electron-do-
nating phenothiazinyl- or ferrocenyl groups were tested as acceptor
components under the conditions of inverse electron demand aza-
DA cycloaddition reactions. In the presence of catalysts TFA,
BF3$OEt2, AlCl3 and FeCl3, which have been applied successfully to
analogous reactions of N-aryl imines neither microwave irradiation
nor thermal conditions proved to be efficient enough to achieve
cycloaddition of DHP with these imines containing electron-do-
nating C-aryl groups. To our delight, when iodine was used as cat-
alyst, microwave-assisted cyclisation of 1aej followed by
substituent-dependent transformations could be performed in
acetonitrile (Scheme 1). Since these reactions of the employed
sensitive substrates were accompanied by uncontrolled de-
compositions, possibly including e.g., polymerisation, the products
could be isolated in mediocre yields, but no any reaction took place
when carboxylic acid 1d was used as precursor. The other interesting
feature of the observed substrate-dependence is the relative sta-
bility of the primarily formed 5-(10-methylphenothiazin-3-yl)-2H-
pyrano[3,2-c]quinolines 2c,e,g with electron-withdrawing sub-
stituent in the 9-position preventing spontaneous dehydrogenation
finally leading to aromatisation. When the reactions of imines 1b,f
with electron-donating substituents were conducted under the
same conditions the primarily formed adducts 2b,f could not be
2.3. Structure-determination of compounds 2c,e,g, 3a, hej
and 4b,f
The spectroscopic data listed in the Experimental section are
consistent with the structures of the novel quinoline derivatives,
only the following remarks are necessary. In angular tricycles 2c,e,g

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E. Gal et al. / Tetrahedron 66 (2010) 9938e9944
9940
the presence of cis-fused six-membered rings and the pseudoe-
quatorial position of the phenothiazinyl group in the 5-position
follow from the coupling pattern of H5-, H4a- and H10b signals
with small values of vicinal coupling constants (2.1e2.5 Hz) mea-
sured for the proton pair H4a/H10b and large coupling constants
between protons H4a and H5 (10.7e11.0 Hz). Accordingly, irradi-
ating the pseudoaxial H5 proton besides H20- and H40-protons on
the phenothiazinyl group the equatorial H4 and the axial H3 pro-
tons gave NOE responses in keeping with the cis anellation of the
pyrane- and tetra-hydroquinoline rings. In 2c,e,g, 3hej and 4b,f the
position of the R1 group is reflected by the coupling pattern of
the three protons attached to the condensed benzene ring with
a broadening or a minimal split (1.5e2.5 Hz) of H10- or H5-signals.
In the 1He13C-HMBC spectra of 3a,hej and 4b,f the protons of the
CH2 group directly bonded to the aromatic ring give cross peaks
with the C2eC4 atoms supporting the vicinal position of the
Q-substituent and the hydroxypropyl- or pyranyloxypropyl-group.
Due to the presence of the adjacent 5-nitro group in the peri
position the signal of the H4 proton incorporated in a six-mem-
bered chelate-like structure is significantly downfield-shifted
(8.90 ppm) in the 1H NMR spectrum of 3a, while the same signal of
3hej and 4b,f appears in the range of 7.71e7.89 ppm.
As it was found for 1g/A the population analysis of 1len/A
revealed the participation of LUMOþ1 in the primary interaction
with DHP. The highest LUMO concentration can be found on the
iodine centre as spectacularly represented by the visualized orbitals
of 1m,n/A (Fig. 2) suggesting an equilibrium formation of DHP-
epiiodonium ion 5 (Scheme 2), which may decrease the rate of the
cycloaddition process. On the other hand, pointing to the efficiency
of iodine-activation in the actual addition step, the energy differ-
ence between the LUMO of a protonated imine and the LUMOþ1 of
its iodinated analogue is relatively small (0.22 eVe0.28 eV) and the
atomic charge on the imino carbon is slightly more positive in each
investigated iodoiminium ion type 1/A than that in its protonated
counterpart type 1/B, although the relatively low values of chemical
hardness (h) obtained for both types of ions (see: Supplementary
data) show pronounced orbital control17 in their transformations.
The influence of the C-aryl substituent on the reactivity of
iodoiminium ions towards DHP was studied on the simplified
models 1len/A. The electron chemical potential and the energy
level of LUMOþ1 of phenyl-substituted 1l/A are significantly lower
than those of 1m,n/A with electron-donating Q-groups obviously
decreasing the tendency to undergo electrophilic addition to DHP,
the first step of cycloaddition process of type 1/A/6/7 (Scheme
2). In keeping with our proposed mechanism Overman and Wolfe
postulated that in situ generated N-amidinyliminium ions and
polysubstituted styrenes undergo stepwise cycloaddition affording
diastereomeric dihydropyrimidines.18
In 4b,f the 200-alkoxy group is in an axial position on the satu-
rated pyrane ring as evidenced by the coupling constants (J¼4.3
and 2.7 Hz) of the signal from the equatorial H200 proton.
2.4. Structure-reactivity relationships observed for the
reactions of the Schiff bases
In contrast to the experimental findings comparison of re-
activity indices
m
and Sc2LUMOþ1 and atomic charges calculated for
1m/A and 1n/A (Table S1) would lead to a conclusion that the
ferrocene-containing iodoiminium ion is more reactive than the
phenothiazinyl-substituted ion. The experimentally observed de-
creased reactivity of ferrocenylimines (reaction time: 1 h) relative
to that of phenothiazinyl analogues (reaction time: 0.5 h) can be
attributed to the unfavourable energetics of the addition step with
DHP as demonstrated on model reactions 1len/A / 6len by
means of B3LYP/DGZVP method (Scheme 2). The order of calculated
energies seems to correlate with the electron-donating ability of
the Q-substituents and the experimental observations pointing to
the significantly decreased reactivity of 1n/A stabilized by the
In order to disclose the characteristic substituent-dependence
experimentally observed for cycloadditions and subsequent aro-
matisation of the quinoline moiety comparative DFT calculations14
were carried out on appropriately selected models at the B3LYP
level of theory15 using a DGZVP basis set.16 We concentrated on the
structure and reactivity of the activated intermediates formed by
iodination of the precursor imines, and compared the characteris-
tics of iodine- and proton-activation by DFT analysis performed on
iodoiminium ion 1g/A, zwitterion 1d/B as well as on simplified
iodoiminium- and protoiminium-ions 1len/A and 1len/B, re-
spectively (Fig. 1, Scheme 2, for calculated data and further details,
see Supplementary data).
highly electron-donating ferrocenyl group (
D
E¼25.53 kcal/mol).
This stabilization is probably associated with the bonding overlap
CO2Me
CO2
S
S
Q
N
I
Q
N
N
N
H
H
I
1g/A
N
Me
N
Me
1l−n/B
1l−n/A
1d/B
S
Fe
1n: Q =
1l: Q =
1m: Q =
N
Me
Fig. 1. Model iodoiminium- and protoiminium-ions analyzed by B3LYP/DGZVP calculations.
O
H
H
O
O
H
+ DHP
DHP
H
H
I
1l-n /A
+
H
H
Q
N
1l-n
N
N
I
Q
Q
5
7l-n
I
6l-n
for 1l−n/A + DHP
ΔE(l) = + 5.58 kcal/mol; ΔE(m) = + 13.30 kcal/mol; ΔE(n) = + 25.53 kcal/mol
6l−n:
Desigantion of l-n by substituent Q: see on Figure 1
Scheme 2. Proposed mechanism of iodine-catalyzed cycloaddition reactions of activated model imines 1len/A and the energetics of the first step calculated by B3LYP/DGZVP
method.

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E. Gal et al. / Tetrahedron 66 (2010) 9938e9944
9941
Fig. 2. Contour plot of frontier MO’s of iodoiminium ions 1m/A and 1n/A.
between the iron centre and the imino carbon atom19 as clearly
discernible on the contour plot of the HOMO shown in Fig. 2. The
DHP-mediated cycloaddition of N-3-nitrophenylimine 1a affording
selectively 3a was interpreted via DFT analysis of the simplified
rotamer models of the primarily formed DHP-adduct (8/I and 8/II:
Fig. 3) carried out at B3LYP/DGZVP level of theory. In agreement
with the experimentally observed regioselectivity 8/I proved to be
more stable by 4.15 kcal/mol than 8/II. This relative stability can at
anellated pyranoquinolines could not be detected by 1H NMR in the
crude reaction mixtures even in traces. On the other hand
(4aR
*
,5S
*
,10bR ) was established as relative configuration for each
*
isolated pyrano[3,2-c]quinoline. These compounds were resulted
from the cyclisation of adducts (e.g., types 6 and 8), which are ste-
rically less crowded than their less stable diastereomers [e.g., 9,
(9e8/I)¼7.55 kcal/mol: Fig. 3], the potential precursors of pyrano
[3,2-c]quinolines with relative configuration (4aR ,5R ,10bR ).
Consequently, it seems that the formation of the tricyclic products
with relative configuration (4aR ,5S ,10bR ) can probably be as-
DE
*
*
*
least partially be due to a much stronger
p-stacking interaction
between the nitrophenyl group and the pyrane-1-ium moiety in 8/I
than in 8/II as suggested by the distances between the interacting
atoms in the optimized structures (d[2e20]¼2.701 Å in 8/I; d
[6e20]¼3.820 Å in 8/II). This view gains spectacular support
from the contour plot of HOMO calculated for 8/I, which clearly
indicates electron delocalization associated with partial bonding
between C2 and C20 atoms, while the HOMO of the less stable 8/II is
concentrated on the C-phenyl group (Fig. 3).
*
*
*
cribed to the slow, thermodynamicallycontrolled diastereoselective
addition of DHP to the iminium ions containing electron rich C-aryl
substituents. It is also worth to point out that a significant
p
-stacking interaction was also detected in 9 as evidenced by the
C2eC20 distance (d[2e20]¼2.430 Å) and the calculated HOMO
showing electron density between these interacting atoms (Fig. 3).
Accordingly, the analogous DHP-mediated transformations of more
Fig. 3. Non-bonding distances of the interacting atoms, relative stability and contour plot of HOMO’s calculated for rotamer models 8/I and 8/II and diastereomeric adduct 9 by
B3LYP/DGZVP method.
The
p
-stacking interaction must also control the stereochemical
reactive imines without highly electron-donating C-aryl sub-
stituents generally afford mixtures of diastereomeric pyrano[3,2-c]
outcome of the cyclisation steps type 6 / 7 (Scheme 2) yielding
products incorporating cis fused pyrane- and quinoline-rings. By
means of further DFT modelling of adduct 8 we could not find any
local minimum representing such a conformation predisposed for
cylisation leading to trans anellated rings. The validity of this ‘neg-
ative result’ can obviously be extended to DHP-adducts with other
aryl substituents in keeping with the fact that the presence of trans
quinolines with relative configurations (4aR
*
,5S
*
,10bR ) and
*
(4aR ,5R ,10bR
*
*
*
), respectively.8e10
A further issue of substituent-dependent reactivity to be discussed
here is thatdcontrary to isolable 5-(10-methylphenothiazin-3-yl)-
2H-pyrano[3,2-c]quinolines 2e,gdtheir unisolable ferrocenyl-ana-
logues 2h,j with the same electron-withdrawing substituents in the

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E. Gal et al. / Tetrahedron 66 (2010) 9938e9944
9942
9-position undergo aromatisation involving dehydrogenation and
subsequent fission of the pyrane ring (Scheme 1). This spectacular
differenceinstabilitycan beattributedtotheenhanced stabilityof the
ferrocenylimine moiety formed in the primary dehydrogenation step.
This view was supported by the energetics of hypothetical oxygen-
mediated transformations of tetrahydroisoquinolines 10len into
11len (Scheme 3) obtained by B3LYP/DGZVP calculations.
Method B: 3-Formyl-10-methyl-10H-phenothiazine/for-mylfer-
rocene (2.0 mmol) and methyl-4-aminobenzoate (0.302 g,
2.0 mmol) were dissolved in MeCN (4 mL) in a 10 mL microwave
reaction vessel. The reaction mixture was subjected to microwave
irradiation using power level of 100 W at 80 ꢀC for 30 min. After
cooling the precipitated product was filtered off. Analytical sample
was recrystallized from ethanol.
Desigantion of l-n by substituent Q:
see on Figure 1
+ H2O2
+ O2
N
H
Q
N
Q
11l−n
10l−n
ΔE(l) = − 47.33 kcal/mol; ΔE(m) = − 48.11 kcal/mol; ΔE(n) = − 51.88 kcal/mol
Scheme 3. Calculated energetics of hypothetical oxygen-mediated dehydrogenation of models 10len.
3. Conclusion
4.2.1. Methyl
4-[(10-methyl-10H-phenothiazin-3-yl)methyl-enea-
mino]benzoate (1g). Yellow powder; yield: 0.696 g, 93% (by method
Our novel method based on simultaneous application of mi-
crowave irradiation and iodine-catalysis to a formal hetero DA
reaction of DHP and imines with decreased electrophilic character
provides an easy access to hexahydro-2H-pyrano[3,2-c]quinolines-
and 3-(3-hydroxypropyl)quinolines with phenothiazinyl- and fer-
rocenyl-substituents of potential biological interest. The results of
high-level DFT analysis carried out on the intermediate iodoimi-
nium ions, highlighting a multistep mechanism and characteristic
substituent-dependence in the cycloaddition process and sub-
sequent aromatisation, allow the prediction of reliable structure
ereactivity relationships, which must be taken into account to set
up procedures for related cycloadditions.
A), 0.674 g, 90% (by method B); mp 190e192 ꢀC; nmax 2977, 2894,
1707 cmꢁ1,1437,1330,1079 cmꢁ1 in L molꢁ1 cmꢁ1) 273 (55,881),
; l(e
386 (897) nm; 1H NMR
d
8.21(1H, s, CH]N), 7.98 (2H, br d, J¼8.3 Hz,
H3,5), 7.62 (1H, d, J¼1.6 Hz, H40), 7.56 (1H, dd, J¼8.3 and 1.6 Hz, H20),
7.13e7.10 (3H, overlapping brd and t, J¼8.3 and 7.8 Hz, H2,6 and H80),
6.89 (1H, t, J¼7.8 Hz, H70), 6.76 and 6.75 (2H, overlapping d’s, J¼8.4
and 8.2 Hz, H10 and H90), 3.84 (3H, s, CO2CH3), 3.34 (3H, s, NCH3); 13C
NMR
d
167.3 (CO2CH3), 160.5, (CH]N), 156.7 (C1), 149.3 (C100a),
145.0 (C90a), 135.0 (C30), 131.3 (C3,5), 130.8 (C4), 129.7 (C20), 128.0
(C40), 127.7 (C80), 127.5 (C60), 124.2 (C40a), 123.6 (C70), 123.2 (C50a),
121.2 (C2,6),114.9 (C90),114.3 (C10), 52.4 (CO2CH3), 36.1 (NCH3). Anal.
Calcd for C22H18N2O2S (374.46) C, 70.57; H, 4.85; N, 7.48; S, 8.56.
Found: C, 70.73; H, 4.90; N, 7.38; S, 8.50%. The analytical and spec-
troscopic data of the samples obtained by the two methods are
identical within experimental error.
4. Experimental
4.1. General
4.2.2. Methyl 4-(ferrocenylmethyleneamino)benzoate (1j). Orange
powder; yield: 0.590 g, 85% (by method A), 0.576 g, 83% (by method
Melting points were obtained with an Electrothermal 1A 9200
digital melting point apparatus. IR spectra were recorded in liquid
film with an FT-IR Bruker Vector 22 spectrometer. The UV spectra
were recorded with an UVevis PerkineElmer Lambda 35 spectro-
photometer. The 1H and 13C NMR spectra were recorded in CDCl3
solution in 5 mm tubes at rt, on a Bruker DRX-500 spectrometer at
500.13 (1H) and 125.76 (13C) MHz, respectively, with the deuterium
signal of the solvent as the lock and TMS as internal standard. The
assignments of 1H- and 13C-signals were based on DEPT, 2D-COSY,
2D-HSQC, 2D-HMBC and DNOE experiments.
All calculations were carried out with the Gaussian 03 suite of
programs.20 On request the optimized structures are available from
the authors.
The reaction mixtures wereirradiated in a CEM Discover LabMate
microwave reactor. Purification of compounds 2e, 3a and 4b,f was
performed by semi preparative HPLC instrument Agilent 1200. The
reactions were monitored byanalytical TLC carried out on precoated
plates (silica gel 60, F254) and visualized by UV light. Phenothiazinyl
Schiff bases 1aef and ferrocenyl Schiff bases 1h,i were prepared
according to described procedures (cf. Refs. 12,13, respectively).
B); mp 146e148 ꢀC; nmax 2990, 2842, 1620, 1435, 2956 cmꢁ1
;
l
(
e
in
L molꢁ1 cmꢁ1) 271 (227,300); 468 (1421) nm; 1H NMR
d 8.21(1H, s,
CH]N), 7.97 (2H, br d, J¼8.3 Hz, H3), 7.10 (2H, br d, J¼8.3 Hz, H2),
4.77 (2H, br s, H20,50), 4.48 (2H, br s, H30,40), 4.20 (5H, s, Cp ring, Fc),
3.85 (3H, s, CO2CH3); 13C NMR
d 167.3 (CO2CH3), 163.6, (CH]N),
156.9 (C1), 131.4 (C3,5), 127.2 (C4), 121.0 (C2,6), 80.1 (C10), 72.5
(C30,40), 70.1 (C20,50), 52.5 (CO2CH3). Anal. Calcd for C19H17FeNO2
(347.19) C, 65.73; H, 4.94; N, 4.03. Found: C, 65.88; H, 4.78; N, 3.98%.
The analytical and spectroscopic data of the samples obtained by
the two methods are identical within experimental error.
4.3. General procedure for iodine-catalyzed cycloadditions
assisted by microwave irradiation
To a solution of the corresponding Schiff base 1aej (2.85 mmol)
and 3,4-dihydro-2H-pyran (0.24 g, 2.85 mmol) in 4 mL of MeCN
was added iodine (7.2 mg, 0.0285 mmol). The resulting mixture was
subjected to irradiation in microwave reactor using power level of
100W at 80 ꢀC (reaction time: 0.5 h for 1aeg; 1 h for 1hej). Water
(15 mL) was added to the reaction mixture then the mixture was
extracted with CH2Cl2 (3ꢂ10 mL). The organic layer was dried on
anhydrous sodium sulfate and then filtered. The solvent was re-
moved in vacuo and the residue was purified by column chroma-
tography on silica using CH2Cl2/MeOH (80/1) as eluent to afford
2c,e,g, 3a,hej and 4b,f. After the reaction of 1d no formation of any
product was detected by TLC. Further purification of 2e, 3a and 4b,f
were performed by HPLC equipped with column LunaÒ C8 (2),
4.2. General procedures for synthesis of Schiff bases 1g and 1j
Method A: 3-Formyl-10-methyl-10H-phenothiazine/for-mylfer-
rocene (2.0 mmol) and methyl-4-aminobenzoate (0.302 g,
2.0 mmol) were refluxed in EtOH (10 mL) under nitrogen (reaction
time: 5 h for 1g and 8 h for 1j). After cooling the reaction mixture
the precipitated product was filtered off. Analytical sample was
recrystallized from ethanol.
150ꢂ10 mm, 5
mm, 00F-4249-N0, Phenomenex; mobile phase:

ꢀ
E. Gal et al. / Tetrahedron 66 (2010) 9938e9944
9943
water-MeCN (25/75 v/v%); solvent for the samples: MeOH/MeCN
(25/75 v/v%); column temperature: 50 ꢃ 1 ꢀC; ELSD detector
temperature: 50 ꢃ 1 ꢀC; flow rate: 2 mL/min; injected volume:
(C10b), 69.1 (C2), 54.3 (C5), 52.0 (CO2CH3), 38.8 (C4a), 35.8 (NCH3),
24.3 (C4), 22.3 (C3). Anal. Calcd for C27H26N2O3S (458.57) C, 70.72;
H, 5.71; N, 6.11; S, 6.99. Found: C, 70.79; H, 5.62; N, 6.27; S, 7.04%.
100 mL; run time: 30 min. Under these conditions the following
retention times (min) were measured for the appropriate sub-
strates, products and reference compounds: z12 (1a,b,e,f,); z17
(2e and 3a); z23 (4b); z19 (4f); z11 (10-methylphenothiazine);
z8 (10-methyl-3-formylphenothiazine).
4.3.4. 3-[((3-Hydroxypropyl)-5-nitroquinoline-2-yl)-10-methyl-10H-
phenothiazine (3a). Light-brown powder, 0.480 g, 38%; mp
85e88 ꢀC; nmax 3214, 2963, 2876, 1539, 1474, 1331, 1291, 1055 cmꢁ1
;
l(e d 8.90 (1H, s, H4),
in L molꢁ1 cmꢁ1) 269 (174,466) nm; 1H NMR
8.43 (1H, d, J¼7.9 Hz, H8), 8.34 (1H, d, J¼7.9 Hz, H6), 7.73 (1H, t,
J¼7.9 Hz, H7), 7.42 (1H, br d, J¼8.3 Hz, H20), 7.39 (1H, br s, H40), 7.19
(1H, br t, J¼7.9 Hz, H80), 7.15 (1H, d, J¼7.9 Hz, H60), 6.96 (1H, br t,
J¼7.9 Hz, H70), 6.91 (1H, br d, J¼7.9 Hz, H90), 6.85 (1H, d, J¼8.3 Hz,
H10), 3.61 (2H, t, J¼6.8 Hz, H11), 3.43 (3H, s, NCH3), 3.00 (2H, t,
J¼6.8 Hz, H9), 1.94 (1H, br s, OH), 1.84 (2H, qi, J¼6.8 Hz, H10); 13C
4.3.1. (4aR
*
,5S
*
,10bR )-5-(10-Methyl-10H-phenothiazin-3-yl)-9-ni-
*
tro-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline (2c). Dark
yellow powder; yield: 0.381 g, 30%; mp 106e109 ꢀC; nmax 3376,
2932, 1546, 1464, 1331, 1256, 1083 cmꢁ1 in L molꢁ1 cmꢁ1) 258
; l(e
(58,982), 379 (8145) nm; 1H NMR
d
8.17 (1H, d, J¼2.0 Hz, H10), 7.99
(1H, dd, J¼9.0, 2.0 Hz, H8), 7.19 (1H, br t, J¼7.9 Hz, H80), 7.17e7.11
(3H, m, H20, H40, H60), 6.95 (1H, br t, J¼7.9 Hz, H70), 6.84 (1H, br d,
J¼7.9 Hz, H90), 6.80 (1H, d, J¼8.3 Hz, H10), 6.45 (1H, d, J¼9.0 Hz, H7),
4.74 (1H, br s, NH), 4.69 (1H, d, J¼10.9 Hz, H5), 4.41 (1H, d, J¼2.1 Hz,
H10b), 4.10 (1H, br d, J¼11.5 Hz, H2eq), 3.73 (1H, dt, J¼11.2, 2.1 Hz,
H2ax), 3.39 (3H, s, NCH3), 2.02 (1H, m, H4a), 1.82 (1H, qat, J¼11.2,
2.1 Hz, H3ax), 1.70 (1H, tt, J¼11.2, 2.1 Hz, H4ax), 1.55 (1H, br d,
NMR d
161. 0 (C2), 149.0 (C5), 147.5 (C100a), 146.4 (C90a), 145.4 (C8a),
136.4 (C8), 134.3 (C3), 132.4 (C4), 128.6 (C20), 128.0 (C80), 127.7 (C60),
127.3 (C7), 127.0 (C40), 125.8 (C4a), 125.4 (C30), 125.0 (C40a), 124.7
(C6), 124.1 (C50a), 123.3 (C70), 114.7 (C90), 114.3 (C10), 62.2 (C11), 35.9
(NCH3), 33.6 (C10). Anal. Calcd for C25H21N3O3S (443.52) C, 67.70; H,
4.77; N, 9.47; S, 7.23. Found: C, 67.84; H, 4.61; N, 9.57; S, 7.19%.
J¼11.2 Hz, H4eq), 1.40 (1H, br d, J¼11.2 Hz, H3eq); 13C NMR
d
150.2
4.3.5. 6-Chloro-2-ferrocenyl-3-(3-hydroxypropyl)quinoline
(C6a), 146.5 (C100a), 145.9 (C90a), 138.4 (C9), 135.1 (C30), 128.4 (C10),
128.1 (C80), 127.6, 127.3, 126.5 (C20, C40, C60), 126.3 (C8), 124.9 (C40a),
123.3 (C70), 123.2 (C50a), 119.8 (C10a), 114.6 (C90), 114.5 (C10), 113.5
(C7), 74.2 (C10b), 69.2 (C2), 54.4 (C5), 38.5 (C4a), 35.8 (NCH3), 24.1
(C4), 22.1 (C3). Anal. Calcd for C25H23N3O3S (445.53) C, 67.40; H,
5.20; N, 9.43; S, 7.20. Found: C, 67.21; H, 5.28; N, 9.57; S, 7.26%.
(3h). Dark red powder, 0.500 g, 43%; mp 98e100 ꢀC; nmax. 3234,
2954, 2927, 2854, 1285, 1057 cmꢁ1 in L molꢁ1 cmꢁ1) 273
; l(e
(473,989), 380 (3864) nm; 1H NMR
d
7.91 (1H, d, J¼8.0 Hz, H8), 7.71
(1H, s, H4), 7.61 (1H, br s, H5), 7.48 (1H, br d, J¼8.0 Hz, H7), 4.97 (2H,
br s, H20,50), 4.39 (2H, br s, H30,40), 4.05 (5H, s, Cp ring, Fc), 3.71 (2H,
t, J¼6.8 Hz, H11), 3.16 (2H, t, J¼6.8 Hz, H9), 1.94 (1H, br s, OH), 1.89
(2H, qi, J¼6.8 Hz, H10); 13C NMR
d 159.3 (C2),145.3 (C8a),135.7 (C4),
4.3.2. (4aR
*
,5S
*
,10bR
*
)-10-Chloro-5-(10-methyl-10H-phenothiazin-
134.4 (C3), 131.6 (C6), 130.5 (C7), 129.5 (C8), 128.1 (C4a), 85.3 (C10),
70.9 (C30,40), 70.3 (C20,50), 70.3 (Cp ring, Fc), 62.5 (C11), 34.2 (C10),
29.9 (C9). Anal. Calcd for C22H20ClFeNO (405.70) C, 65.13; H, 4.97;
Cl, 8.74; N, 3.45. Found: C, 65.09; H, 5.08; Cl, 8.67; N, 3.55%.
3-yl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline
(2e). Yellowish-white powder; yield: 0.632 g, 51%; mp 73e76 ꢀC;
nmax 3360, 2937, 1465, 12,581,074 cmꢁ1 in L molꢁ1 cmꢁ1) 229
; l(e
(28,940), 259 (39,754) nm; 1H NMR
d
7.20e7.12 (5H, m, H10, H20,
H40, H60, H80), 7.02 (1H, dd, J¼8.7, 2.4 Hz, H8), 6.93 (1H, t, J¼7.8 Hz,
H70), 6.82 (1H, d, J¼7.9 Hz, H90), 6.78 (1H, d, J¼8.5 Hz, H10), 6.41 (1H,
d, J¼8.7 Hz, H7), 3.98 (1H, br s, NH), 4.57 (1H, d, J¼11.2 Hz, H5), 4.30
(1H, d, J¼2.7 Hz, H10b), 4.08 (1H, br d, J¼11.1 Hz, H2eq), 3.70 (1H, dt,
J¼11.3, 2.1 Hz, H2ax), 3.38 (3H, s, NCH3), 2.00 (1H, m, H4a), 1.79 (1H,
qat, J¼12.2, 2.6 Hz, H3ax), 1.64 (1H, tt, J¼12.1, 2.2 Hz, H4ax), 1.51 (1H,
br d, J¼12.7 Hz, H4eq), 1.34 (1H, br d, J¼12.2 Hz, H3eq); 13C NMR
4.3.6. 5-Ferrocenyl-3-(3-hydroxypropyl)-6-methoxyquinoline
(3i). Dark red powder, 0.553 g, 48%; mp 137e138 ꢀC; nmax 2989,
2930, 2823, 1272, 1033 cmꢁ1
; l(e in L ) 274
molꢁ1 cmꢁ1
(542,360) nm; 1H NMR
d
7.90 (1H, d, J¼8.2 Hz, H8), 7.72 (1H, s, H4),
7.22 (1H, br d, J¼8.2 Hz, H7), 6.92 (1H, br s, H5), 4.92 (2H, br s,
H20,50), 4.34 (2H, br s, H30,40), 4.06 (5H, s, Cp ring, Fc), 3.85 (3H, s,
OCH3), 3.71 (2H, t, J¼6.8 Hz, H11), 3.14 (2H, t, J¼6.8 Hz, H9), 1.96
d
146.2 (C100a), 145.9 (C90a), 144.2 (C6a), 136.3 (C30), 130.9 (C10),
(1H, br s, OH), 1.90 (2H, qi, J¼6.8 Hz, H10); 13C NMR
d 157.8 (C2),
129.7 (C8), 128.0, 127.6, 127.4, 126.6 (C20, C40, C60, C80), 124.6 (C40a),
124.2 (C9), 123.5 (C50a), 123.0 (C70), 120.7 (C10a), 114.5 (C90), 114.4
(C10), 115.7 (C7), 74.5 (C10b), 69.1 (C2), 54.4 (C5), 39.0 (C4a), 35.8
(NCH3), 24.4 (C4), 22.4 (C3). Anal. Calcd for C25H23ClN2OS (434.98)
C, 69.03; H, 5.33; Cl, 8.15; N, 6.44; S, 7.37. Found: C, 68.91; H, 5.25;
Cl, 8.24; N, 6.31; S, 7.30%.
155.9 (C6), 143.0 (C8a), 134.9 (C3), 134.0 (C4), 130.7 (C4a), 130.2
(C8), 122.0 (C7), 107.3 (C5), 86.0 (C10), 70.6 (C30,40), 69.8 (C20,50),
70.0 (Cp ring, Fc), 62.6 (C11), 56.0 (OCH3), 34.2 (C10), 29.7 (C9).
Anal. Calcd for C23H23FeNO2 (401.28) C, 68.84; H, 5.78; N, 3.49.
Found: C, 68.79; H, 5.68; N, 3.60%.
4.3.7. Methyl-5-ferrocenyl-3-(3-hydroxypropyl)quinoline-6-carbox-
4.3.3. Methyl-(4aR
*
,5S
*
,10bR
*
)-5-(10-methyl-10H-phenothiazin-3-
ylate (3j). Red powder, 0.476 g, 39%; mp 54e57 ꢀC; nmax 3139, 2998,
yl)-3,4,4a,5,6,10b-hexahydro-2H-pyrano[3,2-c]quinoline-9-carboxyl-
2935, 2832, 1721, 1291, 1038 cmꢁ1 in L molꢁ1 cmꢁ1) 273
; l(e
ate (2g). Yellowish-white powder 0.823 g, 63%; mp 95e98 ꢀC; nmax
(489,344) nm; 1H NMR
d
8.40 (1H, br s, H5), 8.12 (1H,br d, J¼7.4 Hz,
3374, 2954, 2857, 1692, 1464, 1437, 1332, 1079 cmꢁ1
;
l(
e
in
H7), 7.97 (1H, d, J¼7.4 Hz, H8), 7.88 (1H, s, H4), 5.01 (2H, br s, H20,50),
4.41 (2H, br s, H30,40), 4.07 (5H, s, Cp ring, Fc), 3.90 (3H, s, CO2CH3),
3.73 (2H, t, J¼6.8 Hz, H11), 3.17 (2H, t, J¼6.8 Hz, H9), 1.92 (2H, qi,
L molꢁ1 cmꢁ1) 275 (175,105) nm; 1H NMR
d
7.96 (1H, d, J¼2.0 Hz,
H10), 7.78 (1H, dd, J¼8.7, 2.0 Hz, H8), 7.20 (1H, t, J¼7.9 Hz, H80),
7.18e7.11 (3H, m, H20, H40, H60), 6.93 (1H, br t, J¼7.9 Hz, H70), 6.84
(1H, br d, J¼7.9 Hz, H90), 6.81 (1H, d, J¼8.5 Hz, H10), 6.48 (1H, d,
J¼8.7 Hz, H7), 4.79 (1H, br s, NH), 4.67 (1H, d, J¼10.9 Hz, H5), 4.40
(1H, d, J¼2.4 Hz, H10b), 4.08 (1H, br d, J¼11.3 Hz, H2eq), 3.85 (3H, s,
CO2CH3), 3.71 (1H, dt, J¼11.3, 2.1 Hz, H2ax), 3.40 (3H, s, NCH3), 1.98
(1H, m, H4a), 1.81 (1H, qat, J¼11.3, 2.4 Hz, H3ax), 1.70 (1H, tt, J¼11.2,
2.4 Hz, H4ax), 1.53 (1H, br d, J¼11.3 Hz, H4eq), 1.39 (1H, br d,
J¼6.8 Hz, H10); 13C NMR
d 167.4 (CO2CH3), 161.6 (C2), 148.8 (C8a),
136.9 (C4), 134.6 (C3), 130.5 (C5), 129.3 (C8), 128.6 (C7), 127.3 (C4a),
126.3 (C6), 85.1 (C10), 71.2 (C30,40), 70.7 (C20,50), 70.3 (Cp ring, Fc),
62.5 (C11), 52.7 (CO2CH3), 34.0 (C10), 29.8 (C9). Anal. Calcd for
C24H23FeNO3 (429.29) C, 67.15; H, 5.40; N, 3.26. Found: C, 67.33; H,
5.61; N, 3.34%.
J¼11.3 Hz, H3eq); 13C NMR
d
167. 6 (CO2CH3), 149.0 (C6a), 146.1
4.3.8. 3-{6-Methyl-3-[3-(tetrahydro-2H-pyran2yloxy)-propyl]quino-
(C100a), 146.0 (C90a), 136.1 (C30), 133.9 (C10), 131.8 (C8), 128.1 (C80),
127.6, 127.4, 126.5 (C20, C40, C60), 124.6 (C40a), 123.4 (C50a), 123.1
(C70), 119.1 (C9), 118.9 (C10a), 114.6 (C90), 114.5 (C10), 113.7 (C7), 74.7
lin-2-yl}-10-methyl-10H-phenothiazine (4b). Yellow oil, 0.665 g,
47%; nmax 2955, 2983, 1463, 1392, 1331, 1256, 1175 cmꢁ1
;
l(e
in
L molꢁ1 cmꢁ1) 270 (229,712) nm; 1H NMR
d
7.95 (1H, d, J¼8.5 Hz,

ꢀ
E. Gal et al. / Tetrahedron 66 (2010) 9938e9944
9944
3. (a) Weber, B.; Serafin, A.; Michie, J.; Van Rensburg, C.; Swarts, C. J.; Bohm, L.
Anticancer Res. 2004, 24, 763 (2B); (b) Jaouen, G.; Top, S.; Vessieres, A.; Leclercq,
H8), 7.72 (1H, s, H4), 7.32e7.29 (2H, overlapping br d and br s, J¼8.4,
H20 and H40), 7.46 (1H, br s, H5), 7.42 (1H, br d, J¼8.5 Hz, H7), 7.10
(1H, br t, J¼7.7 Hz, H80), 7.07 (1H, br d, J¼7.7, Hz, H60), 6.86 (1H, br t,
J¼7.7 Hz, H70), 6.81 (1H, d, J¼8.7 Hz, H10), 6.76 (1H, br d, J¼8.4 Hz,
H10), 4.39 (1H, dd, J¼4.4, 2.7 Hz, H200), 3.69 (1H, m, H600ax), 3.61 (1H,
ꢀ
G.; McGlinchey, M. J. Curr. Med. Chem. 2004, 11, 2505; (c) Zsoldos-Mady, V.;
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Csampai, A.; Szabo, R.; Meszaros-Alapi, E.; Pasztor, J.; Hudecz, F.; Sohar, P.
ChemMedChem 2006, 1, 1119; (d) Klimova, T.; Klimova, E. I.; Martinez Garcia, M.;
ꢀ
ꢀ
ꢀ
ꢀ
Vazquez Lopez, E. A.; Alvarez Toledano, C.; Toscano, A. R.; Ruõz Ramõrez, L.
J. Organomet. Chem. 2001, 628, 107; (e) Hillard, E.; Vessieres, A.; Thouin, L.;
m, H11A), 3.34 (3H, s, NCH3), 3.33e3.26 (2H, m, H600 and H11B),
eq
ꢀ
Jaouen, G.; Amatore, C. Angew. Chem., Int. Ed. 2006, 45, 285; (f) Damljanovic, I.;
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Vukicevic, M.; Radulovic, N.; Palic, R.; Ellmerer, E.; Ratkovic, Z.; Joksovic, M. D.;
2.89e2.75 (2H, m, H9), 2.46 (3H, s, CH3),1.78 (2H, qi, J¼7.4 Hz, H10),
1.65 (1H, m, H400ax), 1.55e1.36 (5H, H300ax, H300eq, H400eq, H500
Vukicevic, R. D. Bioorg. Med. Chem. Lett. 2009, 19, 1093; (g) Joksovic, M. D.;
ax
ꢀ
ꢀ
ꢀ
ꢀ
Markovic, V.; Juranic, Z. D.; Stanojkovic, T.; Jovanovic, L. S.; Damljanovic, I. S.;
H500eq); 13C NMR
d
158.9 (C2), 146.2 (C100a), 145.9 (C90a), 145.4
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
Meszaros Szecsenyi, K.; Todorovic, N.; Trifunovic, S.; Vukicevic, R. D. J. Orga-
nomet. Chem. 2009, 694, 3935; (h) Biot, C.; Glorian, G.; Maciejewski, L. A.;
Brocard, J. S. J. Med. Chem. 1997, 40, 3715.
(C8a), 136.7 (C6), 135.4 (C30), 136.0 (C4), 133.7 (C3), 129.1 (C8), 128.1
(C4a), 128.6 (C20), 128.1 (C40), 127.9 (C80), 127.6 (C60), 123.9 (C40a),
123.7 (C50a), 123.0 (C70), 131.7 (C7), 114.5 (C90), 114.1 (C10), 126.1
(C5), 99.1 (C200), 66.9 (C11), 62.7 (C600), 35.8 (NCH3), 31.2 (C300), 31.0
(C10), 30.0 (C9), 25.9 (C500), 22.0 (CH3), 19.9 (C400). Anal. Calcd for
C31H32N2O2S (496.66) C, 74.97; H, 6.49; N, 5.64; S, 6.46. Found: C,
75.08; H, 6.41; N, 5.59; S, 6.55%.
4. Representative references reporting on the activity of phenothiazine radicals:
(a) Holt Sackett, P.; McCreery, R. L. J. Med. Chem. 1979, 22, 1447; (b) Kawai, K.;
Takada, T.; Tojo, S.; Majima, T. Tetrahedron Lett. 2001, 43, 89; (c) Muraoka, S.;
Miura, T. Pharmacol. Toxicol. 2003, 92, 100; (d) Gutierrez-Correa, J.; Krauth-
Siegel, R. L.; Stoppani, A. O. M. Free Radical Res. 2003, 37, 281; (e) Striplin, D. R.;
Reece, S. Y.; McCafferty, D. G.; Wall, C. G.; Friesen, D. A.; Erickson, B. W.;
Meyer, T. J. J. Am. Chem. Soc. 2004, 126, 5282.
5. Representative references reporting on the activity of ferricenium radicals: (a)
Koepf-Maier, P.; Koepf, H.; Neuse, E. W. J. Cancer Res. Clin. Oncol. 1984, 108, 336;
(b) Neuse, E. W.; Kanzawa, F. Appl. Organomet. Chem. 1990, 4, 19; (c) Tamura, H.;
Miwa, M. Org. Lett. 1997, 11, 1177; (d) Caldwell, G.; Meirim, M. G.; Neuse, E. W.;
Van Rensburg, C. E. J. Appl. Organomet. Chem. 1998, 12, 793; (e) Kuchler, B.;
Abdel-Ghany, A. G.; Bross, P.; Nandy, A.; Rasched, I.; Ghisla, S. Biochem. J. 1999,
337, 225; (f) Neuse, E. W. Macromol. Symp. 2001, 172, 127.
4.3.9. 3-{6-Methoxy-3-[3-(tetrahydro-2H-pyran2yloxy)-propyl]qui-
nolin-2-yl}-10-methyl-10H-phenothiazine (4f). Light-yellow pow-
der, 0.702 g, 48%; mp 48e52 ꢀC; nmax 2960, 2870, 1468, 1383, 1258,
1226, 1166 cmꢁ1
; l(e
in L molꢁ1 cmꢁ1) 229 (36,656); 261 (46,009);
333 (9064) nm; 1H NMR
d
7.92 (1H, d, J¼9.0 Hz, H8), 7.87 (1H, s, H4),
6. Lin, X.-F.; Cui, S.-L.; Wang, Y.-G. Tetrahedron Lett. 2006, 47, 3127.
7.30 (1H, dd, J¼9.0, 1.7 Hz, H20), 7.26 (1H, br s, H40), 7.22 (1H, dd,
J¼9.0, 2.9 Hz, H7), 7.11 (1H, td, J¼7.7, 1.8 Hz, H80), 7.07 (1H, dd, J¼7.7,
1.8 Hz, H60), 6.97 (1H, d, J¼2.9 Hz, H5), 6.87 (1H, br t, J¼7.7 Hz, H70),
6.81 (1H, d, J¼8.7 Hz, H10), 6.77 (1H, br d, J¼7.7 Hz, H10), 4.39 (1H,
dd, J¼4.4, 2.7 Hz, H200), 3.86 (3H, s, OCH3), 3.69 (1H, m, H600ax), 3.61
€
7. Zora, M.; Velioglu, O J. Organomet. Chem. 2008, 693, 2159.
8. (a) Yadav, J. S.; Reddy, B. V. S.; Madhuri, C. R.; Sabitha, G. Synthesis 2001, 7, 1065;
(b) Babu, G.; Perumal, P. T. Tetrahedron Lett. 1998, 39, 3225; (c) Crousse, B.;
Begue, J. P.; Delpon, D. B. Tetrahedron Lett. 1998, 39, 5765; (d) Ma, Y.; Qian, C.;
Xie, M.; Sun, J. J. Org. Chem. 1999, 64, 6462; (e) Magesh, C. T.; Makesh, S. V.;
Perumal, P. T. Bioorg. Med. Chem. Lett. 2004, 2035; (f) Hadden, M.; Stevenson, P.
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hedron Lett. 1988, 29, 3538; (j) Makesh, M.; Reddy, C. V.; Reddy, K.; Srinavasa, R.
P.; Reddy, V. V. N. Synth. Commun. 2004, 34, 4089; (k) da Silva-Filho, L. C.;
Lacerda, V., Jr.; Constantino, M. G.; Jose da Silva, G. V. Synthesis 2008, 16, 2527;
(l) Narsaiah, A. V. R.; Reddy, A. R.; Reddy, BV. S.; Yadav, J. S. Synth. Commun.
2010, 40, 1750.
9. (a) Nagaiah, K.; Sreemu, D.; Rao, R.; Srininasa, V. G.; Yadav, J. S. Tetrahedron Lett.
2006, 47, 4409; (b) Das, B.; Balasubramanyam, P.; Krishnaiah, M.; Veer-
anjaneyulu, B. Synth. Commun. 2009, 39, 3825; (c) Sindharan, V.; Avendano, C.;
Menendez, J. C. Synthesis 2008, 7, 1039; (d) Li, J.; Li, J.; Su, W. J. Chem. Res. 2009,
8, 499.
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Zhao, J.; Han, J.; Zhu, S.; Zhang, J. Tetrahedron 2010, 66, 913; (c) Xia, M.; Lu, Y.-D.
Synlett 2005, 15, 2357.
(1H, m, H11A), 3.36 (3H, s, NCH3), 3.32e3.27 (2H, m, H600 and
eq
H11B), 2.89e2.75 (2H, m, H9), 1.77 (2H, qi, J¼7.4 Hz, H10), 1.65 (1H,
m, H400ax), 1.53e1.36 (5H, H300ax, H300eq, H400eq, H500 H500eq); 13C
ax
NMR
d
158.2 (C6), 157.6 (C2), 146.0 (two coalesced lines, C90a and
C100a), 143.1 (C8a), 135.7 (C30), 135.2 (C4), 134.0 (C3), 131.2 (C8),
128.9 (C4a), 128.6 (C20), 128.2 (C40), 127.7 (C80), 127.5 (C60), 123.9
(C40a), 123.7 (C50a), 122.9 (C70), 122.0 (C7), 114.5 (C90), 114.1 (C10),
104.8 (C5), 99.1 (C200), 67.0 (C11), 62.8 (C600), 55.9 (OCH3), 35.8
(NCH3), 31.2 (C300), 31.0 (C10), 30.1 (C9), 25.9 (C500), 19.9 (C400). Anal.
Calcd for C31H32N2O3S (512.66) C, 72.63; H, 6.29; N, 5.46; S, 6.25.
Found: C, 72.78; H, 6.34; N, 5.54; S, 6.22%.
11. Xing, X.; Wu, J.; Dai, W. M. Tetrahedron 2006, 62, 11200.
12. Gal, E.; Gaina, L.; Lovasz, T.; Cristea, C.; Silaghi-Dumitrescu, L. Stud. Univ. Babes-
Acknowledgements
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Bolyai, Chem. 2009, 4, 17.
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This work was carried out in the frame of TET Romanian-Hun-
garian bilateral cooperation (OMFB-00735/2008, RO-19/2007) fi-
nancially supported by Romanian Ministry of Education Research,
Youth and Sports (PN-II-ID-564), the Hungarian Scientific Research
Fund (OTKA K-68887) and the European Union and the European
ꢀ
Social Fund (grant agreement no. TAMOP 4.2.1./B-09/KMR-2010-
19. (a) Braunschweig, H.; Radacki, K.; Rais, D.; Seeler, F. Organometallics 2004, 23,
5545; (b) Scheibitz, M.; Bolte, M.; Bats, J. W.; Lerner, H.-W.; Nowik, I.; Herber, R.
H.; Krapp, A.; Lein, M.; Holthausen, M. C.; Wagner, M. Chem.dEur. J. 2004, 11,
584.
0003).
Supplementary data
20. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.; Robb, M. A.;
Cheeseman, J. R.; Montgomery, J. A.; Vreven, T., Jr.; Kudin, K. N.; Burant, J. C.;
Millam, J. M.; Iyengar, S. S.; Tomasi, J.; Barone, V.; Mennucci, B.; Cossi, M.;
Scalmani, G.; Rega, N.; Petersson, G. A.; Nakatsuji, H.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.;
Nakai, H.; Klene, M.; Li, X.; Knox, J. E.; Hratchian, H. P.; Cross, J. B.; Adamo, C.;
Jaramillo, J.; Gomperts, R.; Stratmann, R. E.; Yazyev, O.; Austin, A. J.; Cammi, R.;
Pomelli, C.; Ochterski, J. W.; Ayala, P. Y.; Morokuma, K.; Voth, G. A.; Salvador, P.;
Dannenberg, J. J.; Zakrzewski, V. G.; Dapprich, S.; Daniels, A. D.; Strain, M. C.;
Farkas, O.; Malick, D. K.; Rabuck, A. D.; Raghavachari, K.; Foresman, J. B.;
Ortiz, J. V.; Cui, Q.; Baboul, A. G.; Clifford, S.; Cioslowski, J.; Stefanov, B. B.; Liu, G.;
Liashenko, A.; Piskorz, P.; Komaromi, I.; Martin, R. L.; Fox, D. J.; Keith, T.;
Al-Laham, M. A.; Peng, C. Y.; Nanayakkara, A.; Challacombe, M.; Gill, P. M. W.;
Johnson, B.; Chen, W.; Wong, M. W.; Gonzales, C.; Pople, J. A. GAUSSIAN 03,
Revision A. 1; Gaussian: Pittsburgh, PA, 2003.
Supplementary data associated with this article can be found in
online version, at doi:10.1016/j.tet.2010.10.046.
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