1-Alkyl-3-ethylthio-4-(N-benzoyl-N-phenylamino)-quinolinium salts? Synthesis and transformations

Article abstract of DOI:10.3987/COM-08-11421

The reaction of 1-alkyl-4-(phenylamino)quinolinium 3-thiolates (2) with benzoyl chloride leads to 1-alkyl-3-benzoylthio-4-(phenylamino)quinolinium chloride (6). In the presence of DABCO, compounds (6) split off hydrogen chloride yielding 1-alkyl-3-benzoylthio-1,4-dihydro-4-(phenylimino)quinoline (7). Alkylation of 4-(phenylimino)quinoline (7) with ethyl bromide leads to 1-alkyl-3-ethylthio-4-(N-benzoyl-N-phenylamino)quinolinium bromide (10). The structure of the obtained compounds were analyzed using ¹H NMR (NOE) and ¹⁵N NMR spectral methods. The structure of compound (10a) was confirmed by X-ray analysis. The Japan Institute of Heterocyclic Chemistry.

Full text of DOI:10.3987/COM-08-11421

HETEROCYCLES, Vol. 75, No. 11, 2008
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HETEROCYCLES, Vol. 75, No. 11, 2008, pp. 2649 - 2657. © The Japan Institute of Heterocyclic Chemistry
Received, 28th April, 2008, Accepted, 13th June, 2008, Published online, 16th June, 2008. COM-08-11421
1-ALKYL-3-ETHYLTHIO-4-(N-BENZOYL-N-PHENYLAMINO)-
QUINOLINIUM SALTS ― SYNTHESIS AND TRANSFORMATIONS#
Andrzej Zięba*a and Kinga Suwińskab
aDepartment of Organic Chemistry, Medical University of Silesia, Jagiellońska 4,
41-200 Sosnowiec, Poland
bInstitute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52,
01-224 Warsaw, Poland
E-mail: zieba@sum.edu.pl
Abstract – The reaction of 1-alkyl-4-(phenylamino)quinolinium 3-thiolates (2)
with benzoyl chloride leads to 1-alkyl-3-benzoylthio-4-(phenylamino)quinolinium
chloride (6). In the presence of DABCO, compounds (6) split off hydrogen chloride
yielding 1-alkyl-3-benzoylthio-1,4-dihydro-4-(phenylimino)quinoline (7). Alkyla-
tion of 4-(phenylimino)quinoline (7) with ethyl bromide leads to 1-alkyl-3-
ethylthio-4-(N-benzoyl-N-phenylamino)quinolinium bromide (10). The structure of
1
the obtained compounds were analyzed using H NMR (NOE) and 15N NMR
spectral methods. The structure of compound (10a) was confirmed by X-ray
analysis.
INTRODUCTION
Phenothiazine derivatives exhibit interesting chemical properties and pharmaceutical activities.1 Many
phenothiazine derivatives with the substituent attached to the thiazine nitrogen have been used as
neuroleptic and antihistaminic drugs.2,3 In our earlier reports we described a two-step synthesis of 5-alkyl-
12H-quino[3,4-b][1,4]benzothiazinium chloride4,5 3 from thioquinantrenediinium bis-salts6 1 via 1-alkyl-
4-(phenylamino)quinolinium 3-thiolates 2 (Scheme 1). This reaction is a new method of synthesis of the
1,4-thiazine systems. Adaptation of the described procedure to obtain the 3-thiolates 4 and 12-substituted
quino[3,4-b][1,4]benzothiazine derivatives (5) in the reaction of thioquinantrenediinium bis-salts (1) with
secondary amines was unsuccessful (Scheme 1).

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HETEROCYCLES, Vol. 75, No. 11, 2008
2
H
N
1
H
N
3
4
_
11
8
12
S
10
9
_
5
Cl
N
+
N
+
R
S
7
R
NH2
6
2
3
+
N
R
S
S
N
+
R
R1
H
R1
N
_
N
N
1
2Cl
R1
_
S
_
Cl
R1 = alkyl
N
+
R = alkyl
N
R
S
R
+
4
5
Scheme 1
The present study was aimed at using of 1-alkyl-4-(phenylamino)quinolinium 3-thiolates (2) as a source
of 1-alkyl-4-(N-alkyl-N-phenylamino)quinolinium 3-thiolates (4). Cyclization of the 3-thiolates (4) could
possibly lead to the expected 12-substituted quino[3,4-b][1,4]benzothiazine derivatives (5).
R1
H
N
N
_
_
S
S
N
R
+
N
R
+
2
4
RESULTS AND DISCUSSION
The thiolate function in 1-alkyl-4-aminoquinolinium 3-thiolates can be protected as a thioester, from
which it is regenerated by aminolysis reaction.7 The reactions of 1-alkyl-4-(phenylamino)quinolinium 3-
thiolates (2) with benzoyl chloride (Scheme 2) occur easily as S-acylation and led to 1-methyl-3-
benzoylthio-4-(phenylamino)quinolinium chlorides (6). The structure of compounds 6 was confirmed by
1H and N NMR spectra. In H NMR spectra of compounds (6a-b) in CDCl3 solution, the signal of NH
amine proton occurs in a typical range at δ = 11.80 and 11.97 ppm. The 15N NMR spectrum of the
compound (6a) in DMSO-d6 revealed two resonances at δΝ = − 220.3 and − 254.4. They were assigned
15
1
1
with the help of the H–15N HSQC and HMBC spectra. In the case of the quinoline endocyclic nitrogen
atom (δN = − 220.3), a three-bond correlation with the H8 proton (δH = 8.24-8.29) and a two-bond

HETEROCYCLES, Vol. 75, No. 11, 2008
2651
correlation with the H2 proton (δΗ = 9.12) were observed. A one-bond correlation between the exocyclic
1
nitrogen atom (δN = − 254.4) and the NH proton (δΗ = 11.52, JN-H = 92 Hz) was also detected. These
results provided the evidence for NH group being present at the 4-position in the quinoline ring.8
H
H
N
N
O
C
N
O
C
_
S
S
S
DABCO
HCl
PhCOCl
PhNH2
N
R
N
R
_
N
R
+
+
Cl
2a R =Me
2b R =Et
6a R=Me
6b R=Et
7a R=Me
7b R=Et
EtBr
EtBr
O
O
C
Et
C
N
N
N
O
S
Et
S
+
S
C
Et
_
_
_
Br
N
R
N
N
R
_
+
+
Br
Br
R
9
8
10a R=Me
10b R=Et
PhNH2
PhCOBr
Et
N
N
_
S
Et
S
N
R
N
R
+
11a R=Me
11b R=Et
4
Scheme 2
The reaction of salt 6 with aniline occurs via nucleophilic attack of the amine nitrogen atom on the
carboxylic carbon atom and results in restitution of the thiolate function at the 3-position in the quinoline
ring.

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HETEROCYCLES, Vol. 75, No. 11, 2008
Table 1. Preparation of 1-alkyl-4-(phenylamino)quinolinium 3-thiolates (2) from 1-alkyl-3-benzoylthio-4-
(phenylamino)quinolinium chloride (6).
Substrate
Product
2a
Yield[%]
6a
6b
74
62
2b
In the presence of a base (DABCO), the compounds (6) were dehydrochlorinated to 1-alkyl-3-
benzoylthio-1,4-dihydro-4-(phenylimino)quinoline (7) with quantitative yield. On the other hand, the
reaction of 4-(phenylimino)quinolines (7) with hydrogen chloride led with quantitative yield to 4-
(phenylamino)quinoline derivatives (6). The course of these reactions confirms the imine structure of
compounds (7).
In our earlier report, we described reactions of 1-alkyl-3-alkylthio-1,4-dihydro-4-(phenylimino)-
quinolines with alkylating agents, which occurred as N-alkylation at the imine nitrogen atom and led to 1-
alkyl-3-alkylthio-4-(N-alkyl-N-phenylamino)quinoline salts.4 We expected that 1-alkyl-3-benzoylthio-4-
(N-ethyl-N-phenylamino)quinolinium bromide (8) can be obtained in the same way. A cleavage of the
thioester group in the presence of aniline could possibly lead to the expected 3-thiolates (4).
Contrary to expectation the reactions of the 4-iminochinolines (7) with ethyl bromide led to 1-alkyl-3-
ethylthio-4-(N-benzoyl-N-phenylamino)quinolinium bromides (10). The reaction of compounds (10) with
aniline led to 1-alkyl-3-ethylthio-1,4-dihydro-4-(phenylimino)quinolines (11) (Scheme 2).
A two-step reaction mechanism is proposed in order to explain the formation of compounds (10)
following alkylation of compounds (7) with ethyl bromide. In the first step the compound (7) undergoes
S-alkylation to give intermediate of the sulfonium salt structure (9). Then the sulfonium salt (9)
undergoes intramolecular rearrangement to give compounds (10) by acylation at imine nitrogen atom.
This hypothesis is supported by reaction 4-(phenylimino)quinolines (11) with benzoyl bromide. The
structure of compounds (10) was studied using NOE 1H-1H homonuclear experiment (Scheme 3) as well
as X-ray analysis (Figure 1).
O
CH2Me
C
N
N
N
O
S
CH2Me
1.8 %
S
C
N
H
H
+
+
_
_
Me
Me
Br
Br
8
10a
Scheme 3

HETEROCYCLES, Vol. 75, No. 11, 2008
2653
Irradiation of methylene protons (δ = 3.34 - 3.40) in MeCH2 group of the compound (10a) increased the
intensity of quinoline H2 signal (δ = 8.52, 1.8 %) (Scheme 3). This rules out the expected compound (8)
to be the product of the reaction considered as its ethyl group is linked to the exocyclic nitrogen atom in
the 4-position of quinoline.
X-Ray analysis of the derivative (10a) demonstrated definitely that the examined compound has the
structure of 1-methyl-3-ethylthio-4-(N-benzoyl-N-phenylamino)quinolinium bromide (Figure 1).
The quinoline moiety is planar, maximum deviation from planarity is 0.024(4) Å for atom C3 and the
methyl group at the endocyclic nitrogen atom is in the quinoline plane. The valence angle C8A-N1-C2 is
equal to 121.8(3)° which is a value typical of azine salts. The bond length between the carbonyl carbon
atom and exocyclic nitrogen atom N2 is equal to 1.383(5) Å.
C21
C22
C20
C23
C24
C17
C15
C19
C18
C12
C16
C5
C13
O1
N2
C4
C14
C4a
S1
C3
C6
C10
C7
C11
C8a
C2
O1W
C8
N1
C9
Br1
Figure 1. View of 1-methyl-3-ethylthio-4-(N-benzoyl-N-phenylamino)quinolinium bromide 10a.
EXPERIMENTAL
1
Melting points are uncorrected. H NMR spectra (at 300 MHz) were recorded using a Varian VXR 300
spectrometer at 303 K. Proton chemical shifts are reported relative to TMS (δ = 0.0) as internal standards.
15N NMR spectra were recorded in the DMSO solution using a Bruker AM 500 spectrometer at 50.698
1
MHz. NOE H-1H homonuclear experinent was carried out for (10a) in the CDCl3 solution at 500 MHz.
EI MS spectra were recorded using an LKB GC MS 20091 spectrometer at 75 eV.
X-Ray data were collected on a Bruker KappaApexII diffractometer with graphite monochromated
MoKα radiation ( λ = 0.71073 Å). Diffractometer control program Collect,9 unit cell parameters and data
reduction with Denzo and Scalepak.10 The structure was solved by direct methods SHELXS-9711 and
refined by full-matrix least-squares minimization based on all unique F2 (SHELXL-9712).

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HETEROCYCLES, Vol. 75, No. 11, 2008
Crystal data: C25H23N2OS+·Br¯·H2O, M = 497.44, light-yellow block, 0.50 × 0.30 × 0.30 mm,
orthorhombic, space group Pbca, a = 13.26(3), b = 9.4976(5), c = 36.548(1) Å, V = 4605.8(3) Å3, Z = 8,
Dc = 1.435 g/cm3, F(000) = 2048, μ = 1.900 mm-1, T = 100(2)K, 2θmax = 55.0º. 23818 reflections
collected, 5041 unique (Rint = 0.044). Final GooF = 1.08, R = 0.059, wR = 0.102, R indices based on 3975
reflections with I >2σ(I) for 288 parameters and 0 restraints.
The crystallographic data for the structure (10a) have been deposited at the Cambridge Crystallographic
Data Center (depository number CCDC-689038).
1-Alkyl-3-benzoylthio-4-(phenylamino)quinolinium chloride (6):
A. From 1-alkyl-4-(phenylamino)quinolinium 3-thiolates (2)
The mixture of 1-alkyl-4-(phenylamino)quinolinium 3-thiolates (2) (1 mmol) and benzoyl chloride (702
mg, 5 mmol) was mixed at rt for 2 h. The obtained chloride (6) was filtered off and washed with Et2O.
The raw product was purified through recrystallization from EtOH.
B. From 1-alkyl-3-benzoylthio-1,4-dihydro-4-(phenylimino)quinoline (7)
Hydrogen chloride was passed through the solution of 4-(phenylimino)quinoline (7) (1 mmol) in dry
benzene (15 mL) at rt over 5 min. The solid product was filtered off and washed with dry benzene. The
raw product was purified through recrystallization from EtOH.
1
1-Methyl-3-benzoylthio-4-(phenylamino)quinolinium chloride (6a): yield: (A) 92 %, (B) 89 %. H NMR
(CDCl3) δ: 4.27(s, 3H, NMe), 7.02-7.16(m, 3H, Harom), 7.18-7.26(m, 2H, Harom), 7.29-7.42(m, 3H, Harom),
7.49-7.58(m, 3H, Harom), 7.82-7.93(m, 2H, Harom), 8.61(s, 1H, H2quinolinyl), 9.37-9.48(m, 1H, H5quinolinyl),
11.80(s, 1H, NH). Anal. Calcd for C23H19ClN2OS: C 67.89, H 4.71, Cl 8.71, N 6.88, S 7.88. Found: C
67.81, H 4.64, Cl 8.62, N 6.81, S 7.95.
1-Ethyl-3-benzoylthio-4-(phenylamino)quinolinium chloride (6b): yield: (A) 90%, (B) 86%. 1H NMR
(CDCl3) δ: 1.62-1.81(t, J=7.5 Hz, 3H, NCH2Me), 4.14-4.26(q, J=7.5 Hz, 2H, NCH2Me), 7.05-7.23(m. 3H,
Harom), 7.25-7.48(m, 5H, Harom), 7.52-7.64(m, 3H, Harom), 7.85-8.07(m, 2H, Harom), 8.75(s, 1H, H2quinolinyl),
9.41-9.51(m, 1H, H5quinolinyl), 11.97(s, 1H, NH). Anal. Calcd for C24H21ClN2OS: C 68.48, H 5.03, Cl 8.42,
N 6.65, S 7.62. Found: C 68.43, H 5.12, Cl 8.29, N 6.57, S 7.69.
1-Alkyl-4-(phenylamino)quinolinium-3-thiolate (2) from chloride (6):
Aniline (280 mg, 3 mmol) was added to the mixture of chloride (6) (1 mmol) in dry pyridine (10 mL)
and the whole was mixed at 70 oC for 2 h. The solid product was filtered off and washed with dry Et2O.
The raw product was purified through recrystallization from EtOH.

HETEROCYCLES, Vol. 75, No. 11, 2008
2655
1-Alkyl-3-benzoylthio-1,4-dihydro-4-(phenylimino)quinoline (7):
The solution of DABCO (135 mg, 1.2 mmol) in MeOH (5 mL) was added to the mixture of chloride (6)
(1 mmol) in MeOH (10 mL) and the whole was mixed at rt for 1 h. The product was filtered off and
washed with MeOH. The raw product was purified through recrystallization from EtOH.
1-Methyl-3-benzoylthio-1,4-dihydro-4-(phenylimino)quinoline (7a): yield 84%. oil. EI MS, (m/z):
1
370(M+, 60%), 265(M+-105, 65%). H NMR (CDCl3) δ: 4,17(s, 3H, NMe), 7.05-7.32(m, 7H, Harom),
7.43-7.60(m, 3H, Harom), 7.62-7.80(m, 3H, Harom), 7.86-7.95(m, 1H, H5quinolinyl), 9.12(s, 1H, H2quinolinyl).
Anal. Calcd for C23H18N2OS: C 74.57, H 4.90, N 7.56, S 8.65. Found: C 74.55, H 4.97, N 7.48, S 8.72.
1-Ethyl-3-benzoylthio-1,4-dihydro-4-(phenylimino)quinoline (7b): yield 75%. oil EI MS, (m/z): 384(M+,
72%), 279(M+-105, 68%). 1H NMR (CDCl3) δ: 1.73-1.88(t, J=7.1 Hz, 3H, NCH2Me), 4.11-4.25(q, J= 7.1
Hz, 2H, NCH2Me), 7.05-7,45(m, 7H, Harom), 7.48-7.59(m, 3H, Harom), 7.60-7.79(m, 3H, Harom), 8.12-
8.20(m, 1H, H5quinolinyl), 9.17(s, 1H, H2quinolinyl) (Anal. Calcd for C24H20N2OS: C 74.97, H 5.24, N 7.29, S
8.34. Found: C 74.94, H 5.18, N 7.22, S 8.32.
1-Alkyl-3-ethylthio-4-(N-benzoyl-N-phenylamino)quinolinium bromide (10):
A. From 1-alkyl-3-benzoylthio-1,4-dihydro-4-(phenylimino)quinoline (7)
The mixture of 1-alkyl-3-benzoylthio-1,4-dihydro-4-(phenylimino)quinoline (7) (1 mmol) and ethyl
o
bromide (545 mg, 5 mmol) was mixed at 50 C for 2 h. The mixture was cooled down to rt, the product
was filtered off and washed with Et2O. The raw product was purified through recrystallization from EtOH.
B. From 1-alkyl-3-ethylthio-1,4-dihydro-4-(phenylimino)quinolines (11)
The mixture of compound (11) (1 mmol) and benzoyl bromide (555 mg, 3 mmol) was mixed at 70 oC for
4 h. The obtained bromide (10) was filtered off and washed with Et2O. The raw product was purified
through recrystallization from EtOH.
1-Methyl-3-ethylthio-4-(N-benzoyl-N-phenylamino)quinolinium bromide (10a: yield: (A) 87%, (B) 91%.
1H NMR (DMSO-d6) δ: 1.18-35(t, J=7.0 Hz, 3H, SCH2Me), 3.34-3.40(q, J=7.0 Hz, 2H, SCH2Me),
4.72(s, 3H, NMe), 7.06-7.66(m, 10H, Harom), 7.93-8.10(m, 1H, Harom), 8.12-8.19(m, 1H, Harom), 8.28-
8.36(m, 1H, Harom), 8.52(s, 1H, H2quinolinyl), 9.78-9.90(m, 1H, H5quinolinyl). Anal. Calcd for C25H23BrN2OS:
C 62.63, H 4.84, N 5.84, S 6.62. Found: C 62.57, H 4.93, N 5.79, S 6.67.
1-Ethyl-3-ethylthio-4-(N-benzoyl-N-phenylamino)quinolinium bromide (10b): yield: (A) 91%, (B) 94 %.

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1H NMR (DMSO-d6) δ: 1.25-1.34(t, J=7.2 Hz, 3H, SCH2Me), 1.54-1.79(t, J=7.5 Hz, 3H, NCH2Me),
3.35-3.47(q, J=7.2 Hz, 2H, SCH2Me), 5.05-5.24(q, J=7.5 Hz, 2H, NCH2Me), 7.05-7.82(m, 10H, Harom),
7.82-7.98(m, 1H, Harom), 8.11-8.23(m, 1H, Harom), 8.32-8.41(m, 1H, Harom), 8.61(s, 1H, H2quinolinyl), 9.69-
9.86(m, 1H, H5quinolinyl). Anal. Calcd for C26H25BrN2OS: C 63.28, H 5.11, N 5.68, S 6.50. Found: C 63.23,
H 5.07, N 5.59, S 6.55.
1-Alkyl-3-ethylthio-1,4-dihydro-4-(phenylimino)quinoline (11):
Aniline (140 mg, 1.2 mmol) was added to the mixture of bromide (10) (1 mmol) in dry pyridine (10 mL)
and the whole was mixed at 70 °C for 4 h. After cooling down to rt the mixture was poured into water
(50 mL). The resulting solid was filtered off and washed with water. The product was dehydrated in a
vacuum exsiccator over calcium chloride. The raw product was recrystallized from EtOH.
o
1-Methyl-3-ethylthio-1,4-dihydro-4-(phenylimino)quinoline (11a): yield 76%. mp 106-108 C. EI MS,
1
(m/z): 294(M+, 82%). H NMR (CDCl3) δ: 0.99-1.04(t, J=7.4 Hz, 3H, SCH2Me), 2.49-2.55(q, J=7.4 Hz,
2H, SCH2Me), 3.66(s, 1H, NMe), 6.64-6.72(m, 2H, Harom ), 6.81-6.85(m, 1H, Harom ), 7.05-7.10(m, 1H,
H6quinolinyl), 7.14-7.19(m, 2H, Harom ), 7.40-7.43(m, 1H, H8quinolinyl), 7.49-7.54(m, 1H, H7quinolinyl), 7.64(s,
1H, H2quinolinyl), 7.93-7.99(m, 1H, H5quinolinyl). Anal. Calcd for C18H18N2S: C 73.43, H 6.16, N 9.51, S
10.89. Found: C 73.40, H 6.19, N 9.42, S 10.96.
1-Ethyl-3-ethylthio-1,4-dihydro-4-(phenylimino)quinoline (11b): yield 84%. oil. EI MS, (m/z): 308(M+,
1
87%). H NMR (CDCl3) δ: 1.05-1.15(t, J=7.4 Hz, 3H, SCH2Me), 1.40-1.49(t, J=7.5 Hz, 3H, NCH2Me),
2.52-2.67(q, J=7.4 Hz, 2H, SCH2Me), 4.01-4.12(q, J=7.5 Hz, 2H, NCH2Me), 6.84-6.90(m, 2H, Harom),
6.92-6.99(m, 1H, Harom), 7.02-7.11(m, 1H, Harom), 7.19-7.31(m, 3H, Harom), 7.42-7.48(m, 1H, Harom),
7.52(s, 1H, H2quinolinyl), 8.02-8.19(m, 1H, H5quinolinyl). Anal. Calcd for C19H20N2S: C 73.99, H 6.54, N
9.08, S 10.39. Found: C 73.94, H 6.49, N 9.01, S 10.34.
REFERENCES
#
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