Preparation of 4-substituted 10-ethylphenothiazines

Article abstract of DOI:10.1039/a704120i

Under appropriate reaction conditions 10-ethylphenothiazine 1 undergoes lithiation at C-4 using an excess of sec-butyllithium-N,N,N′,N′-tetramethylethane-1,2-diamine in diethyl ether. Reaction of the lithiated intermediate with a variety of carbon, halogen, sulfur and silicon electrophiles affords several new 4-substituted 10-ethylphenothiazines 3a-i in good yields.

Full text of DOI:10.1039/a704120i

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Preparation of 4-substituted 10-ethylphenothiazines
Søren Ebdrup,*,a Marianne Schou Jensena and Per Vedsøb
a Novo Nordisk A/S, Novo Nordisk Park, D9, DK-2760 Måløv, Denmark
b Department of Medicinal Chemistry, Royal Danish School of Pharmacy, Universitetsparken 2,
DK-2100 Copenhagen, Denmark
Under appropriate reaction conditions 10-ethylphenothiazine 1 undergoes lithiation at C-4 using an excess
of sec-butyllithium–N,N,NЈ,NЈ-tetramethylethane-1,2-diamine in diethyl ether. Reaction of the lithiated
intermediate with a variety of carbon, halogen, sulfur and silicon electrophiles affords several new
4-substituted 10-ethylphenothiazines 3a–i in good yields.
Li
Introduction
5
6
4
1
S
10N
1
S
N
2
6a
4a
N-Alkylated phenothiazine derivatives can be used to enhance
various reactions of different oxidative enzymes such as perox-
idases and laccases,1–4 e.g. for prevention of dye transfer1–3 dur-
ing washing or for glucose detection.4 In order to investigate the
influence of various ring substituents in N-alkylated phenothi-
azines, procedures for selective introduction of ring substituents
were required. Phenothiazines substituted at C-1 can be made
by C-1 lithiation of N-lithiocarbamate protected phenothiazine5
or by 1,10-dilithiation of phenothiazine followed by reaction
with an electrophile.6–10 In addition, phenothiazines substituted
at C-1 or C-3 can be made from the respective ortho- or para-
substituted diphenylamines by cyclization using sulfur in the
presence of iodine.11 The appropriate diphenylamines are syn-
thesized from 2-chlorobenzoic acid and the appropriately substi-
tuted aminobenzene in two steps.12 When meta-substituted
diphenylamines are subjected to cyclization using sulfur and
iodine a mixture of C-2 and C-4 substituted phenothiazines
is formed with the former as the predominant isomer.11,13
A few 4-substituted phenothiazines have been prepared by
lithiation of N-alkyl phenothiazines7,14,15 followed by reaction
with an electrophile, but yields are low. Cauquil et al. have
reported that a mixture of the 1-carboxylic acid and 4-carboxylic
acid is obtained in yields of 13 and 14% respectively by the
n-butyllithium metalation over 30 h of 10-ethylphenothiazine
and subsequent reaction with carbon dioxide.7
7
8
3
2
i
9a
10a
9
ii
El
S
N
3a–i
Compd.
Electrophile
El
Yield (%)
3a
3b
3c
3d
3e
3f
3g
3h
3i
MeI
DMF
Me
72a
69
63
72
62
69
59
69
50
CHO
CO2H
CHOHBut
Cl
CO2
ButCHO
C2Cl6
I2
I
Me3SiCl
Me2S2
DMF/NaBH4
SiMe3
SMe
CH2OH
Obviously there is no good and high yielding synthesis avail-
able for the preparation of 4-substituted phenothiazines. We
now report a new approach to 4-substituted 10-ethylpheno-
thiazines 3a–i from 10-ethylphenothiazine 1† based on lithi-
ation at C-4 and subsequent reaction with electrophiles.
Scheme 1 Reagents: i, sec-BuLi–TMEDA; ii, addition of different
electrophiles El. a Yield in reaction mixture.
using BusLi–TMEDA–ButOK in THF as solvent (entry 7). By
comparing entries 3 and 8–10 it is evident that 2.5 equiv. of
BusLi–TMEDA is the optimum for maximum formation of 3a
and for almost complete conversion of starting material. Apply-
ing THF as solvent (entry 12) in order to increase solubility and
to perform the reaction at lower temperature resulted in only
25% formation of 3a. Furthermore, decreasing the lithiation
time from 2.5 to 0.5 h did not affect the yield of 3a (entries 3
and 11).
In all cases the formation of by-products was observed.
GC–MS of the crude reaction mixtures indicated the presence
of other regioisomers and some dimethylated 10-ethylpheno-
thiazines. The following standard procedure for the selective
preparation of 4-substituted 10-ethylphenothiazines 3a–i was
adopted based on the data presented in Table 1. Lithiation
experiments were conducted at room temperature in diethyl
ether for 0.5 h using 2.5 equiv. of BusLi–TMEDA, followed
by reaction with the electrophilic reagent at 0 ЊC. In this way a
wide variety of carbon, halogen, sulfur and silicon substituents
were introduced at the 4-position of 10-ethylphenothiazine 1 in
good yields (Scheme 1). Using DMF as the electrophile gave 10-
Results and discussion
The lithiation of 10-ethylphenothiazine 1 followed by reaction
with methyl iodide was investigated under various reaction
conditions. As shown in Table 1, lithiation of 10-ethylpheno-
thiazine 1 using BusLi in the presence of N,N,NЈ,NЈ-
tetramethylethane-1,2-diamine (TMEDA) or ButLi–TMEDA
(entries 3 and 4) was superior to BunLi–TMEDA (entry 2).
The lithiation was greatly improved when it was effected in the
presence of TMEDA (compare entries 1 and 3). Performing the
lithiation using BusLi–TMEDA or ButLi in the presence of
ButOK followed by methylation gave 4-methyl-10-ethylpheno-
thiazine 3a in 0–45% (entries 5–7). The best result was obtained
† An ethyl group was used to block the ring nitrogen since more bulky
substituents would result in low water solubility, making the substrates
unsuitable as enzyme mediators. Use of an N-methyl group was
expected to give more C-1 substituted products.
J. Chem. Soc., Perkin Trans. 1, 1998
351

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Table 1 Optimization of the conditions for the deprotonation of 10-ethylphenothiazine 1 and subsequent reaction with iodomethane
Products (%)
Entry
Base/TMEDA
Equiv.
Solvent
T/ЊC
3a
By-products
1
1
2
3
4
5
6
7
8
9
BusLia
BunLi
BusLi
ButLi
BusLib
ButLia,b
BusLib
BusLi
BusLi
BusLi
BusLi
BusLi
2.5
2.5
2.5
2.5
2.5
2.5
2.5
1.1
1.6
2.0
2.5
2.5
Et2O
Et2O
Et2O
Et2O
Et2O
THF
THF
Et2O
Et2O
Et2O
Et2O
THF
20
20
20
20
20
Ϫ50
Ϫ50
20
20
20
20
Ϫ20
17
47
72
67
0
20
45
49
67
69
72
25
5
51
21
31
6
78
2
7
2
94
73
32
38
13
9
7
14
13
20
22
24
11
10
11c
12
4
64
a TMEDA not added. b 2.5 equiv. ButOK added. c Deprotonation for 0.5 h, all other experiments 2.5 h.
Table 2 13C NMR Spectral data of 10-ethylphenothiazine 1 and various synthesized 4-substituted 10-ethylphenothiazines 3a–i (CDCl3)
Carbon atom, δC
Compd C-1
C-2
C-3
C-4
C-4a
C-5a
C-6
C-7
C-8
C-9
C-9a
C-10a
C-11
C-12
1a
115.0
127.1
126.3
126.6
126.0
125.9
127.5
128.0
126.2
126.9
126.7
122.2
123.6
123.5
124.7
122.0
122.5k
132.2
128.4
120.0
121.8
127.3
135.5
132.9
131.5
140.8
131.2
97.0
138.7
136.1
138.1
124.4
124.4
127.3
127.4
127.7
127.4
127.3
127.5
122.2
122.0
122.6
122.5
122.0
127.1
127.1
127.5
127.4
127.1
115.0
114.9
115.2
115.1
114.9
114.9
144.8
145.8
145.5
146.0k
146.0
144.6
145.7
144.9k
144.9
145.3
145.1
145.3
145.9k
144.4
145.3
145.1
145.1k
145.3
13.0
13.1
12.8
13.0
13.0
12.9
13.0
13.2
13.0
13.0
41.7
41.8
42.2
42.2
41.7
42.2
42.2
41.6
41.9
41.8
3aa,d
3ba,e
3ca, f
3da,g
3eb
113.0
119.6
119.7
114.2
113.3
115.1
116.3
112.5
114.9k
124.4k 124.6k
130.3
126.9
125.0
123.4
130.5
131.5
123.9l
124.1l
124.3
124.9
125.4
124.4
124.7
125.4
124.0l
124.2l
122.4k 127.1
115.1
3f b
127.5k 122.6
127.4k 115.0
3gb,c,h
3hb,i
3ia,i
127.3
127.6
122.2
122.3
127.1
127.3
115.0
114.9
127.4m 122.2
127.3m 115.1k 145.5
a Recorded at 75 MHz. Assignments based on those of ref. 5 and 16 and by comparison with the assignment of 3g. b Recorded at 100 MHz.
Assignment based on those of ref. 5 and 16 and by comparison with the assignment of 3g. c Assignment based on HSQC and HMBC (J 6 Hz)
experiments. d δ 19.9 (ArCH3). e δ 189.9 (CHO). f δ 170.7 (CO2H). g δ 25.9 [C(CH3)3], 36.6 [C(CH3)3], 77.0 (CHOH). h δ Ϫ0.4 (SiCH3)3. i δ 16.3 (SCH3).
j δ 63.4 (CH2OH). k These δC assignments may be interchangeable. l These δC assignments may be interchangeable. m These δC assignments may be
interchangeable.
ethyl-4-formylphenothiazine 3b in 69% yield together with 7%
of 10-ethyl-1,6-diformylphenothiazine. In all other cases minor
amounts of by-products were present but not identified. The
site of lithiation was confirmed as being C-4, by comparison of
the melting point of 10-ethylphenothiazine-4-carboxylic acid 3c
(mp 178.5 ЊC, uncorrected) with that reported by Cauquil et al.
(mp 182 ЊC). They unambiguously proved the structure by de-
sulfurisation of 3c to give N-phenyl-N-(3-carboxyphenyl)-
ethylamine.7
All glassware was flame dried prior to use. MgSO4 was used to
dry solutions. Solvents were removed in vacuo by rotary evapor-
ation. Melting points are uncorrected. Microanalyses were
conducted at Novo Nordisk A/S. Bruker DRX 400 and Bruker
300 ie instruments were used to record 1H NMR spectra at 400
and 300 MHz with tetramethylsilane (TMS) as internal stand-
ard, and 13C NMR spectra at 100 and 75.5 MHz respectively
with the solvent peak at 76.9 ppm for CDCl3 and 39.6 ppm for
[2H6]DMSO as internal reference. Coupling constants (J) are
given in Hz. Mass spectra were recorded at Novo Nordisk A/S
using electron impact ionisation on a Carlo-Erba 8000 GC
coupled to a VG autospec Ultima sector MS instrument. The
GC used for the optimization of the deprotonation reaction
was a Varian Star 3400 CX. Thin layer chromatography was
performed on Merck DC-Alufolien, silica gel 60 F254, and com-
ponents were visualised by UV254. Flash chromatography17 was
performed using silica gel Merck 60 size 40–63 µm.
Furthermore 13C NMR data (Table 2) are in agreement with
the site of substitution being at C-4. The assignment of 13C
NMR signals are based on values given in the literature5,16
and by comparison with the assignment of 3g (see below).
Unambiguous assignment of the protonated carbons in 3g was
obtained via a 2D heterocorrelation experiment (HSQC). Long-
range correlations were determined by a long-range HMBC
experiment optimized for 6 Hz. The following long-range cor-
relations were observed (long-range correlations to protonated
carbons are omitted): C-10a with N-CH2 and H-2; C-9a with
N-CH2 and H-8; C-4 with H-2 and H-3; C-4a with H-1 and
H-3; C-5a with H-7 and H-9.
Materials
All solvents and reagents were obtained from Merck and
Aldrich and used without further purification. The solvents
used were: tetrahydrofuran (THF) dried (LabScan 4103/3),
N,N-dimethylformamide (DMF) (Aldrich 22,705–6), 1,4-
dioxane dried (Merck 3110) and diethyl ether (ether) dried
(Aldrich 29,608–2). Phenothiazine was from Hoechst (99%).
10-Ethylphenothiazine 1 was prepared with slight modification
of the procedure described by Gilman et al.14 A mixture of
phenothiazine (18 g, 90 mmol), absolute ethanol (8 cm3) and
ethyl iodide (8 cm3, 99 mmol) was heated in a glass screw cap
vessel18 for 18 h at 105 ЊC to give 1 (32.6 g, 79%), mp 101.5–
102.5 ЊC (from ethyl acetate–ethanol) (lit.,14 101–103 ЊC).
In conclusion the experiments above demonstrate that 4-
substituted 10-ethylphenothiazines 3a–i are now accessible
through lithiation of 10-ethylphenothiazine 1 and subsequent
reaction with an electrophile.
Experimental
General methods
All reactions involving air-sensitive reagents were performed
under nitrogen or argon using syringe–septum cap techniques.
352
J. Chem. Soc., Perkin Trans. 1, 1998

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n-Butyllithium, sec-butylithium and tert-butyllithium were
7.36 (t, 1H, J 8.0, 8-H), 7.36 (dd, 1H, J 7.5 and 1.5, 7-H), 7.55
titrated prior to use.19
(dd, 1H, J 7.5 and 1.5, 2-H), 7.65 (dd, 1H, J 7.5 and 1.5, 4-H),
10.19 (s, CHO), 10.23 (s, CHO); δC(100 MHz; CDCl3) 14.7
(CH3), 53.8 (CH2), 123.9 (C-9), 126.9 (C-7), 126.9 (C-3), 128.2
(C-4), 128.3 (C-1), 129.6 (C-8), 132.0 (C-2), 132.3 (C-4a), 133.0
(C-5a), 134.2 (C-6), 145.1 (C-9a), 147.3 (C-10a), 189.6 (CHO),
190.2 (CHO).
Procedure for the optimization of the deprotonation reaction of
10-ethylphenothiazine 1
10-Ethylphenothiazine 1 (1.03 g, 4.5 mmol) was dissolved in
a dry solvent (ether 30 cm3, THF 18 cm3 or dioxane 10 cm3)
followed by addition of TMEDA and a base (n-, sec- or tert-
butyllithium for some experiments together with sodium tert-
butoxide). After stirring for 0.5 or 2.5 h, respectively, at room
temperature, iodomethane (0.84 cm3, 14 mmol) was added at
0 ЊC and stirring was continued at room temperature for 1 h.
The reaction mixture was quenched with saturated aqueous
NH4Cl (15 cm3) and water (5 cm3) and the aqueous phase
extracted with dichloromethane (3 × 15 cm3). The combined
organic phases were dried and evaporated to give the crude
product. The composition of the crude products was analysed
by GC (results are shown in Table 1).
10-Ethylphenothiazine-4-carboxylic acid 3c. The general
procedure was used with carbon dioxide as the electrophile.
The reaction mixture was poured into dry ice (30 g) in ether
(40 cm3). When the carbon dioxide had evaporated, aqueous
NaOH (8% w/v; 100 cm3) was added and the two phases separ-
ated. The aqueous phase was washed with ether (4 × 150 cm3),
acidified with aqueous HCl (37% w/v; 45 cm3) and the precipi-
tated crude product dissolved in dichloromethane (200 cm3).
The organic phase was washed with water (200 cm3), dried and
evaporated to give a yellow oil (2.4 g). The crude product was
subjected to flash chromatography (glacial acetic acid–ethyl
acetate–heptane, 1:35:64) to provide 3c as yellow crystals (1.5
g, 63%), mp 178.5 ЊC (from toluene) (lit.,7 182 ЊC), Rf (glacial
acetic acid–ethyl acetate–heptane, 1:35:64) 0.24 (Found: C,
66.3; H, 4.9; N, 5.0; S, 11.8. Calc. for C15H13NO2S: C, 66.4; H,
4.8; N, 5.2; S, 11.8%); δH(400 MHz; [2H6]DMSO) 1.27 (t, 3H,
J 7, CH3), 3.88 (q, 2H, J 7, CH2), 6.91 (dt, 1H, J 1.0 and 7.5,
H-7), 6.97 (dd, 1H, J 8 and 1, H-9), 7.13 (dd, 1H, J 8.0 and 1.5,
6-H), 7.15 (dd, 1H, J 8.0 and 1.0, 1-H), 7.20 (dt, 1H, J 1.5 and
7.5, 8-H), 7.24 (t, 1H, J 7.5, 2-H), 7.43 (dd, 1H, J 7.5 and 1.0,
3-H).
10-Ethyl-4-(2,2-dimethyl-1-hydroxypropyl)phenothiazine 3d.
The general procedure was used with trimethylacetaldehyde
(3.00 cm3, 27.3 mmol) as the electrophile. The mixture was
stirred for 40 min at room temp. before HCl (5% w/v; 50 cm3)
was added followed by stirring for 1 h. The ether phase was
separated and washed with water (40 cm3). The aqueous phases
were combined and extracted with dichloromethane (3 × 80
cm3). The combined organic phases were dried and evaporated
to give a light yellow oil (4.28 g) which was subjected to flash
chromatography (ethyl acetate–heptane, 1:10 → 1:8) to pro-
vide 3d as a light yellow oil (1.98 g, 72%) which crystallized
upon standing, mp 94–95 ЊC (from ethanol–water, 4:1); Rf
(ethyl acetate–heptane, 1:2) 0.54 (Found: C, 72.8; H, 7.6; N,
4.3; S, 10.2. Calc. for C19H23NOS: C, 72.8; H, 7.4; N, 4.5; S,
10.2%); δH(400 MHz; CDCl3) 1.01 [s, 9H, C(CH3)3], 1.40 (t, 3H,
J 7.0, CH2CH3), 1.84 (br s, 1H, COH), 3.94 (q, 2H, J 7.0, CH2),
5.04 (s, 1H, ArCH), 6.84 (dd, 1H, J 10 and 4, 1-H), 6.88 (dd,
1H, J 7.5 and 1.5, 9-H), 6.91 (dt, 1H, J 1.0 and 7.5, 7-H), 7.15–
7.20 (m, 4H, 2-H, 3-H, 6-H and 8-H).
General procedure for preparation of 4-substituted
10-ethylphenothiazines 3
10-Ethylphenothiazine 1 (2 g, 8.8 mmol) was dissolved in dry
ether (50 cm3) under an atmosphere of argon. After 10 min,
TMEDA (3.32 cm3, 22 mmol) was added followed by sec-
butyllithium (15.9 cm3 of a 1.38  solution in hexane, 22 mmol).
The mixture was kept at room temperature for 0.5 h before the
electrophile was added at 0 ЊC.
10-Ethyl-4-methylphenothiazine 3a. The general procedure
was used with MeI (1.7 cm3, 27.2 mmol) as the electrophile,
stirring for 1 h before quenching with saturated aqueous NH4Cl
(30 cm3). The ether phase was separated and washed with water
(30 cm3) and the combined water phases were extracted with
dichloromethane (3 × 25 cm3). The combined organic phases
were dried and evaporated to give the crude product as a light
yellow oil (2.71 g); GC yields: 72%, 3a; 5%, 1 and 21% of six
different mono- and di-substituted by-products in concentra-
tions above 1%. The crude product was recrystallized twice
from ethanol–water (7:1) to give white crystals (1.12 g); GC
yields: 85%, 3a and 14% of five by-products, mp 52–54 ЊC. A
third recrystallization did not increase the purity; δH(400 MHz;
CDCl3) 1.39 (t, 3H, J 7, CH2CH3), 2.34 (s, 3H, ArCH3), 3.90 (q,
2 H, J 7.0, CH2), 6.72 (br d, 1H, J 8, 1-H), 6.81 (br d, 1H, J 7.5,
9-H), 6.84 (br d, 1H, J 8.0, 3-H), 6.88 (dt, 1H, J 1.5 and 7.5, 7-
H), 7.04 (t, 1H, J 7.5, 2-H), 7.13 (dt, 1H, J 1.5 and 7.5, 8-H),
7.15 (dd, 1H, J 8.0 and 1.5, 6-H) (Found: Mϩ, 241.092 743.
C15H15NS requires Mϩ, 241.092 521).
10-Ethyl-4-formylphenothiazine 3b. The general procedure
was used with dry DMF (2.11 cm3, 27.3 mmol) as the electro-
phile, stirring for 20 min. The reaction mixture was poured into
aqueous HCl (4.5% w/v; 180 cm3) at 0 ЊC, stirring for 30 min.
The ether phase was separated and the water phase was
extracted with chloroform (4 × 100 cm3). The combined
organic phases were dried and evaporated to give an orange oil
(2.8 g). The crude product was subjected to flash chroma-
tography (ethyl acetate–heptane, 1:8) to provide 3b as yellow
crystals (1.56 g, 69%) and 10-ethyl-1,6-diformylphenothiazine
as yellow crystals (0.167 g, 7%). Data for 3b, mp 46–48 ЊC (from
ethyl acetate–heptane, 1:10); Rf (ethyl acetate–heptane, 1:2)
0.52 (Found: C, 70.9; H, 5.3; N, 5.3; S, 12.5. Calc. for
C15H13NOS: C, 70.6; H, 5.1; N, 5.5; S, 12.6%); δH(400 MHz;
CDCl3) 1.41 (t, 3H, J 7, CH3), 3.92 (q, 2H, J 7, CH2), 6.86 (dd,
1H, J 8 and 1, 9-H), 6.93 (dt, 1H, J 1.0 and 7.5, 7-H), 7.01 (dd,
1H, J 8.0 and 1.5, 1-H), 7.15 (dd, 1H, J 7.5 and 1.5, 6-H), 7.18
(dt, 1H, J 1.5 and 8.0, 8-H), 7.24 (t, 1H, J 7.5, 2-H), 7.43 (dd,
J 8.0 and 1.5, 3-H), 10.26 (s, CHO). Data for 10-ethyl-1,6-
diformylphenothiazine, mp 132 ЊC (from ethyl acetate–heptane,
1:10); Rf (ethyl acetate–heptane, 1:2) 0.45 (Found: C, 68.0; H,
4.65; N, 4.8. Calc. for C16H13NO2S: C, 67.8; H, 4.6; N, 4.9%);
δH(400 MHz; CDCl3) 1.21 (t, 3H, J 7, CH3), 3.87 (q, 2H, J 7,
CH2), 7.12 (t, 1H, J 8, 3-H), 7.30 (dd, 1H, J 8.0 and 1.5, 9-H),
4-Chloro-10-ethylphenothiazine 3e. The general procedure
was used with hexachloroethane (6.46 g, 27 mmol) as the elec-
trophile, stirring for 1 h. Work-up as described for 3a afforded
an oil (4.14 g). The crude product was subjected to flash chro-
matography (ethyl acetate–heptane, 0:1 → 1:8) to provide 3e
as light yellow crystals (1.43 g, 62%), mp 44–44.5 ЊC (from
ethanol); Rf (ethyl acetate–heptane, 1:6) 0.49 (Found: C, 63.9;
H, 4.5; N, 5.2; S, 12.0. Calc. for C14H12ClNS: C, 64.2; H, 4.6; N,
5.35; S, 12.25%); δH(400 MHz; CDCl3) 1.28 (t, 3H, J 7, CH3),
3.77 (q, 2H, J 7, CH2), 6.60 (dd, 1H, J 8.0 and 1.0, 1-H), 6.72
(dd, 1H, J 8.5 and 1.5, 9-H), 6.80 (dt, 1H, J 1.5 and 7.5, 7-H),
6.85 (dd, 1H, J 8.0 and 1.0, 3-H), 6.93 (t, 1H, J 8.0, 2-H), 7.03
(dt, 1H, J 1.5 and 8.5, 8-H), 7.04 (dd, 1H, J 7.5 and 1.5, 6-H).
10-Ethyl-4-iodophenothiazine 3f. The general procedure was
used with iodine (6.92 g, 27.3 mmol) as the electrophile, stirring
for 1 h. Quenching with aqueous Na2S2O3 (25% w/v; 60 cm3)
was followed by stirring for 0.5 h. The ether phase was separ-
ated and washed with water (30 cm3). The combined water
phases were extracted with dichloromethane (3 × 30 cm3) and
the combined organic phases were dried and evaporated to give
an oil (3.0 g). The crude product was subjected to flash chroma-
tography (ethyl acetate–heptane, 0:1 → 1:10) to provide 3f
(2.07 g, 69%), mp 116–117 ЊC (from ethyl acetate); Rf (ethyl
J. Chem. Soc., Perkin Trans. 1, 1998
353

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acetate–heptane, 1:6) 0.56 (Found: C, 47.9; H, 3.4; N, 3.9; S,
9.1. Calc. for: C14H12INS: C, 47.6; H, 3.4; N, 4.0; S, 9.1%);
δH(400 MHz; CDCl3) 1.42 (t, 3H, J 7, CH3), 3.89 (q, 2H, J 7,
CH2), 6.82–6.86 (m, 2H, 2-H and 1-H or 9-H), 6.86 (dd, 1H, J
8.0 and 1.5, 9-H or 1-H), 6.95 (dt, 1H, J 1.5 and 7.5, 7-H), 7.17
(dt, 1H, J 1.5 and 7.5, 8-H), 7.19 (dd, 1H, J 7.5 and 1.5, 6-H),
7.43 (dd, 1H, J 6.0 and 3, 3-H).
C15H15NOS: C, 70.0; H, 5.8; N, 5.4; S, 12.5%) δH(400 MHz;
CDCl3) 1.41 (t, 3H, J 7, CH3), 1.91 (br s, 1H, OH), 3.64 (q, 2H,
J 7, CH2CH3), 4.74 (s, 2H, ArCH2), 6.85 (dd, 1H, J 8 and 1.5,
1-H), 6.87 (dd, 1H, J 8.0 and 1.0, 9-H), 6.91 (dt, 1H, J 1.0 and
7.5, 7-H), 7.03 (dd, 1H, J 7.5 and 1, 3-H), 7.16 (dt, 1H, J 1.0 and
7.5, 8-H), 7.16 (t, 1H, J 7.5 and 7.5, 2-H), 7.17 (dd, J 7.5 and
1.0, 6-H).
10-Ethyl-4-trimethylsilylphenothiazine 3g. The general pro-
cedure was used with chlorotrimethylsilane (4.04 cm3, 32 mmol)
as the electrophile, stirring for 1 h. Work-up as described for 3a
afforded a yellow oil (2.89 g). The crude product was subjected
to flash chromatography (ethyl acetate–heptane, 0:1 → 1:8)
to provide 3g as a yellow oil (1.55 g, 59%), mp 50–50.5 ЊC (from
ethanol–water, 8:1); Rf (ethyl acetate–heptane, 1:3) 0.75
(Found: C, 68.2; H, 7.15; N, 4.7; S, 10.45. Calc. for C17H21NSSi:
C, 68.2; H, 7.1; N, 4.7; S, 10.7%); δH(400 MHz; CDCl3) 0.40 [s,
9H, Si(CH3)3], 1.40 (t, 3H, J 7, CH3) 3.92 (q, 2H, J 7, CH2), 6.87
(dd, 1H, J 8 and 1, 9-H), 6.91 (dd, 1H, J 8.0 and 1.5, 1-H), 6.91
(dt, 1H, J 1.5 and 7.5, 7-H), 7.09 (dd, 1H, J 7.5 and 1.5, 3-H),
7.14 (t, 1H, J 7.6, 2-H), 7.15 (dt, 1H, J 1.5 and 7.5, 8-H), 7.19
(dd, 1H, J 7.6 and 1.5, 6-H).
10-Ethyl-4-(methylthio)phenothiazine 3h. The general pro-
cedure was used with dimethyl disulfide (2.42 cm3, 27 mmol) as
the electrophile, stirring for 1 h. Work-up as described for 3a
afforded a yellow oil (2.69 g). The crude product was subjected
to flash chromatography (ethyl acetate–heptane, 1:10) to pro-
vide 3h as a light yellow oil (1.66 g, 69%); Rf (ethyl acetate–
heptane, 1:6) 0.48 (Found: C, 65.7; H, 5.7; N, 4.8; S, 24.0. Calc.
for C15H15NS2: C, 65.9; H, 5.5; N, 5.1; S, 23.5%); δH(400 MHz;
CDCl3) 1.39 (t, 3H, J 7, CH3), 2.47 (s, 3H, SCH3), 3.88 (q, 2H,
J 7, CH2), 6.68 (dd, 1H, J 8.0 and 1.0, 1-H), 6.83 (dd, 1H,
J 8.0 and 1.0, 9-H or 3-H), 6.84 (dd, 1H, J 8.0 and 1.0, 3-H
or 9-H), 6.89 (dt, 1H, J 1.5 and 7.5, 7-H), 7.10 (t, 1H, J 8.0,
2-H), 7.12 (dd, 1H, J 8.0 and 1.5, 6-H), 7.18 (dt, J 1.5 and 7.5,
8-H) (Found: Mϩ, 273.065 407. C15H15NS2 requires Mϩ,
273.063 593).
10-Ethyl-4-(hydroxymethyl)phenothiazine 3i. 10-Ethyl-4-
formylphenothiazine 3b (1.46 g, 5.7 mmol) was dissolved in
methanol (75 cm3), and NaBH4 (1.41 g, 37 mmol) predissolved
in cold methanol (50 cm3) was added. The reaction mixture was
stirred for 18 h at 0 ЊC, quenched with HCl (3.5% w/v; 30 cm3)
and stirred for an additional 0.5 h before evaporation. Water
(75 cm3) and dichloromethane (75 cm3) were added and the
aqueous phase extracted with dichloromethane (3 × 80 cm3).
The combined organic phases were dried and evaporated to
give a light brown oil (1.42 g). The crude product was recrystal-
lized from ethyl acetate to give crystalline 3i (1.16 g, 80%), mp
98–99 ЊC (from ethyl acetate); Rf (ethyl acetate–heptane, 1:2)
0.39 (Found: C, 69.7; H, 6.0; N, 5.25; S, 12.3. Calc. for
Acknowledgements
Dr Jens Breinholt, Novo Nordisk A/S, is gratefully acknow-
ledged for NMR assistance. Dr Ebbe Kelstrup, The Technical
University of Denmark, is gratefully acknowledged for fruitful
discussions and comments.
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Paper 7/04120I
Received 12th June 1997
Accepted 1st September 1997
354
J. Chem. Soc., Perkin Trans. 1, 1998