2,6-difunctionalization of N-substituted dithienothiazines via dilithiation

Article abstract of DOI:10.1055/s-0033-1340307

The regioselective lithiation of dithienothiazines followed by electrophilic trapping in a one-pot fashion is an efficient route to 2-mono- and 2,6-difunctionalized dithienothiazines. A pseudo five-component dilithiation-diformylation-double-Wittig olefination sequence gives a dithienothiazine symmetrically functionalized with α,β-unsaturated ester side chains in excellent yield. Georg Thieme Verlag Stuttgart. New York.

Full text of DOI:10.1055/s-0033-1340307

LETTER
▌371
letter
2,6-Difunctionalization of N-Substituted Dithienothiazines via Dilithiation
2,6-Difunctionalized Dithienothiazines
Catherine Dostert, Daniel Czajkowski, Thomas J. J. Müller*
Institut für Organische Chemie und Makromolekulare Chemie der Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1,
40225 Düsseldorf, Germany
Fax +49(211)8114324; E-mail: ThomasJJ.Mueller@uni-duesseldorf.de
Received: 17.10.2013; Accepted after revision: 31.10.2013
(2b) was successfully used as an amine component, albeit
with a lower yield of the corresponding dithienothiazine
3b. Nevertheless, the introduction of a solubilizing hexyl
group is very attractive. Therefore, by combining a hexyl
Abstract: The regioselective lithiation of dithienothiazines fol-
lowed by electrophilic trapping in a one-pot fashion is an efficient
route to 2-mono- and 2,6-difunctionalized dithienothiazines. A
pseudo five-component dilithiation–diformylation–double-Wittig
olefination sequence gives a dithienothiazine symmetrically func- substituent with the higher yield of aniline derivatives, we
tionalized with α,β-unsaturated ester side chains in excellent yield.
successfully introduced a 4-hexylphenyl substituent in the
dithienothiazine 3c.
Key words: addition reactions, heterocycles, lithiation, multicom-
ponent reactions, Wittig reactions
S
S
R
NH2
+
S
In recent years, interest in electroactive organic molecules
has increased enormously because of their important tech-
nological applications, ranging from organic light-emit-
ting diodes1 through organic photovoltaic devices2 to
organic field-effect transistors.3 The main advantages of
using organic materials are their low production costs;
their favorable properties, such as flexibility, transparen-
cy, and light weight; and their good processability.
Br
Br
1
2
Pd(dba)2 (5 mol%)
dppf (10 mol%)
NaOt-Bu (3 equiv)
toluene, 110 °C, 30 h
S
S
S
We recently described dithienothiazines as a new class of
electron-rich heterocycles.4 As a consequence of their
unique electronic properties, which show two reversible
oxidations with Nernstian behavior at low oxidation po-
tentials, dithienothiazines are well suited, in principle, for
use as hole conductors or as donor components in donor–
acceptor compounds. Functionalization of the hetero-
cyclic core of dithienothiazines represents a key step to
achieving potential applications of these compounds, and
is a major challenge. Most interestingly, annelation of
thiophene offers an easy entry to typical thiophene trans-
formations, such as lithiation in the α-position with re-
spect to the sulfur atom;5 furthermore, it is also amenable
to sequential one-pot processing.6 Here, we report a prac-
tical scale-up of the synthesis of three selected N-substi-
N
R
3a: R = Ph (75%)
3b: R = n-hexyl (46%)
3c: R = p-(n-hexyl)phenyl (72%).
3
Scheme 1 Synthesis of selected dithienothiazines 3 by twofold
Buchwald–Hartwig coupling
Next we tested several methods for functionalizing dithi-
enothiazines by exploiting the inherent reactivity of thio-
phenes. However, attempted bromination with bromine
or N-bromosuccinimide as brominating reagent5a to give
2,6-dibromodithienothiazines failed in a range of solvents
and at various reaction temperatures. As a last resort, we
attempted dual α-selective dilithiation, followed by dual
electrophilic trapping (Scheme 2).
tuted
dithienothiazines,
together
with
the
functionalization of this new class of electron-rich hetero-
cycles through dilithiation and electrophilic trapping.
S
S
BuLi
S
S
S
S
Li
Li
N
R
α-selective
N
R
We examined the scale-up of the intermolecular/intramo-
lecular Buchwald–Hartwig synthesis of 4-phenyl-4H-
dithieno[2,3-b:3′,2′-e][1,4]thiazine (3a) from bis(3-bro-
mo-2-thienyl) sulfide (1) and aniline (2a). Linear scale-up
from 0.5 to 3 mmol was uneventful (Scheme 1). Further-
more, we were able to reduce the catalyst loading to
5 mol% and the ligand loading to 10 mol% without any
decrease in yield. Besides aniline (2a), hexan-1-amine
dilithiation
S
electrophile E
S
S
E
E
electrophilic
trapping
N
R
Scheme 2 General concept for functionalizing dithienothiazines by
sequential dilithiation and electrophilic trapping in a one-pot reaction
SYNLETT 2014, 25, 0371–0374
Advanced online publication: 13.11.2013
DOI: 10.1055/s-0033-1340307; Art ID: ST-2013-B0975-L
© Georg Thieme Verlag Stuttgart · New York
On the basis of our previous findings on sequential de-
symmetrization by electrophilic trapping of various dili-
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

372
C. Dostert et al.
LETTER
thiothiophenes, readily available by halogen–metal
exchange,6 we reasoned that dilithiation of dithienothi-
azines with butyllithium as a base might lead to a perfect
entry to one-pot electrophilic trapping reactions.
Table 1 Synthesis of 2,6-Disubstituted Dithienothiazines 5
Entry Electrophile
Product
Yield
(%)
Dithienothiazines 3 were deprotonated by inverse addi-
tion to two equivalents of butyllithium in dry tetrahydro-
furan containing N,N,N′,N′-tetramethylethylenediamine
at –78 °C under nitrogen to give the corresponding puta-
tive dilithio species, which were treated with two equiva-
lents of a suitable electrophile 4 to give 2,6-disubstituted
dithienothiazines 5 in moderate to good yields (Scheme 3
and Table 1). The structures of all the new compounds
were unambiguously assigned by NMR, IR, and mass
spectroscopy and by elemental analysis.
S
S
S
D
D
N
nhexyl
1
2
D2O (4a)
63
66
5a
S
N
O
O
S
S
DMF (4b)
n-BuLi–TMEDA
1:1 (2.2 equiv)
THF, –78 °C, 2 h
5b
S
N
S
N
S
S
S
S
S
E
E
HO
OH
S
S
then:
electrophile 4
–78 °C, 1.5 h
N
R
R
3
5 (26–88%)
3
acetone (4c)
26
Scheme 3 Symmetrical functionalization of dithienothiazines 3 by
sequential α-dilithiation and electrophilic trapping to give 2,6-disub-
stituted dithienothiazines 5
5c
S
N
O
O
S
S
Similarly, monolithiation was achieved by treating dithi-
enothiazine 3c with one equivalent of butyllithium and
N,N,N′,N′-tetramethylethylenediamine, with subsequent
trapping by N,N-dimethylformamide. After aqueous
workup, the monoaldehyde 6 was isolated in a good yield
(Scheme 4).
4
DMF (4b)
88
nhexyl
5d
S
N
S
N
O
S
S
S
S
S
N
S
S
I
I
n-BuLi–TMEDA
1:1 (1 equiv)
THF, –78 °C, 2 h
then:
DMF, –78 °C, 1.5 h
then:
5
I2 (4d)
73
nhexyl
nhexyl
H2O, –78 °C to r.t.
nhexyl
3c
6 (68%)
5e
Scheme 4 Synthesis of 2-formyldithienothiazine 6
trapping with N,N-dimethylformamide, treatment with
water, and subsequent addition of the phosphonium salt 7
to give the double-olefination product 8 in 79% yield
(Scheme 6). Most interestingly, no addition of base in the
terminal olefination step was necessary, and the overall
yield of the one-pot sequence was considerably higher
than that of the stepwise process with intermediate isola-
tion of the dialdehyde 5d.
Further transformations of 2,6-diformyldithienothiazines
are exemplified by a double-Wittig carbonyl olefination
(Scheme 5). Wittig reaction of dialdehyde 5d with (2-eth-
oxy-2-oxoethyl)(triphenyl)phosphonium chloride (7) in
the presence of cesium carbonate as a base in tetrahydro-
furan at 50 °C for 70 minutes gave the bis(α,β-unsaturated
ester) 8 exclusively as the E,E-isomer in a yield of 66%.
Inspired by the successful conversion of dialdehyde 5d by
a double-Wittig olefination and by Schlosser’s sequential
N,N-dimethylformamide trapping of aryllithium deriva-
tives and their subsequent olefination in a one-pot fashion,7
we envisioned a novel pseudo five-component process
starting from dithienothiazine 3c. The one-pot reaction
began with the dilithiation of 3c, which was followed by
In conclusion, we have developed a straightforward and
efficient one-pot route to 2-monofunctionalized and 2,6-
difunctionalized dithienothiazines by site-selective lithia-
tion of dithienothiazines followed by trapping with an
electrophile. Synthetically valuable diiodides and dialde-
hydes might be obtained in moderate to very good yields
by this method. Furthermore, the potential of one-pot
Synlett 2014, 25, 371–374
© Georg Thieme Verlag Stuttgart · New York

LETTER
2,6-Difunctionalized Dithienothiazines
373
cessively added. The mixture was stirred in an oil bath at 100 °C for
40 h and then allowed to cool to r.t. When conversion was complete
(TLC), H2O (50 mL) was added, and the mixture was extracted with
CH2Cl2 (3 × 50 mL). The organic layers were combined, dried
(MgSO4), filtered, and concentrated in vacuo. The residue was ad-
sorbed on Celite and purified by chromatography (silica gel, 2.5%
Et3N–hexane) to give yellow crystals; yield: 673 mg (78%); mp
93 °C, Rf = 0.26. IR (ATR): 513 (m), 521 (w), 533 (w), 606 (m),
629 (m), 683 (s), 687 (s), 722 (m), 795 (m), 835 (m), 853 (m), 916
(w), 993 (s), 1007 (w), 1072 (w), 1098 (m), 1221 (m), 1275 (m),
1375 (m), 1398 (m), 1444 (w), 1487 (s), 1512 (m), 1555 (m), 2852
(w), 2924 (w), 3119 (w) cm–1. 1H NMR (500 MHz, acetone-d6): δ =
6.19 (d, J = 5.5 Hz, 2 H), 7.23 (d, J = 5.5 Hz, 2 H), 7.38–7.43 (m,
3 H), 7.53–7.57 (m, 2 H). 13C NMR (125 MHz, acetone-d6): δ =
104.9 (Cquat), 121.0 (CH), 125.0 (CH), 128.3 (CH), 128.7 (CH),
131.2 (CH), 144.9 (2 Cquat). MS (EI+, 70 eV), m/z (%) = 287 (6)
[C14H9NS3], 198 (30), 197 (16), 196 (100), 153 (13), 152 (23), 151
(10), 120 (14). UV/Vis (CH2Cl2): λmax (ε) = 248 (19400), 319 nm
(5650). Anal. Calcd for C14H9NS3 (287.4): C, 58.50; H, 3.16; N,
4.87. Found: C, 58.55; H, 3.33; N, 4.59.
S
N
O
O
S
S
nhexyl
5d
Ph3P+CH2CO2Et Cl– (7) (2.15 equiv)
Cs2CO3 (2.15 equiv)
THF, 50 °C, 70 min
S
N
EtO2C
CO2Et
S
S
nhexyl
4-(4-Hexylphenyl)-4H-dithieno[2,3-b:3′,2′-e][1,4]thiazine-2,6-
dicarbaldehyde (5d); Typical Procedure
In a flame-dried Schlenk flask, TMEDA (0.17 mL, 1.20 mmol) was
dissolved in anhydrous THF (5 mL) under N2. The solution was
then cooled to –78 °C and BuLi (1.6 M in hexane; 0.72 mL, 1.2
mmol) was added. Dithienothiazine 3c (186 mg, 0.50 mmol) was
then added in portions and the solution was stirred at –78 °C for 2
h. DMF AcroSeal (0.1 mL, 1.3 mmol) was then added and stirring
was continued for another 1.5 h. At –78 °C, the reaction was
quenched with H2O (25 mL) and the mixture was allowed to warm
to r.t. The resulting mixture was extracted with CH2Cl2 (3 × 20 mL)
and the organic layers were combined, dried (MgSO4), and concen-
trated under reduced pressure. The residue was adsorbed on Celite
and purified by chromatography [silica gel, hexane–EtOAc (20:1) +
2% Et3N)] to give a dark-red viscous oil; yield: 188 mg (88%);
Rf = 0.14. IR (ATR): 621 (w), 667 (m), 733 (w), 770 (w), 789 (w),
835 (m), 1007 (m), 1059 (m), 1115 (w), 1169 (s), 1198 (w), 1236
(m), 1275 (m), 1358 (s), 1389 (m), 1423 (w), 1508 (m), 1562 (m),
8 (66%)
Scheme 5 Synthesis of the bis(α,β-unsaturated ester) 8
S
S
S
n-BuLi–TMEDA 1:1 (2.2 equiv)
N
THF, –78 °C, 2 h
then: DMF (4b) (6 equiv), –78 °C, 0.5 h
then: 0.5 mL H2O, –78 °C to r.t.
then: Ph3P+CH2CO2Et Cl– (7) (2.15 equiv)
50 °C, 1 h
nhexyl
3c
1
1655 (s), 2770 (w), 2816 (w), 2924 (w), 2953 (w) cm–1. H NMR
S
N
EtO2C
CO2Et
S
S
(500 MHz, acetone-d6): δ = 0.90 (t, J = 7.0 Hz, 3 H), 1.29–1.45 (m,
6 H), 1.63–1.74 (m, 2 H), 2.69–2.78 (m, 2 H), 6.81 (s, 2 H), 7.37–
7.58 (m, 4 H), 9.62 (s, 2 H). 13C NMR (125 MHz, acetone-d6): δ =
14.4 (CH3), 23.3 (CH2), 29.9 (CH2), 32.3 (CH2), 32.5 (CH2), 36.3
(CH2), 114.9 (Cquat), 126.8 (CH), 129.7 (CH), 131.9 (CH), 140.6
(Cquat), 141.8 (Cquat), 144.9 (Cquat), 145.0 (Cquat), 182.6 (CH). MS
(EI+, 70 eV): m/z (%) = 429 (17), 428 (27), 427 (100) [M+], 356 (20)
[C17H10NO2S3], 266 (16) [C10H4NO2S3]. UV/Vis (CH2Cl2): λmax (ε)
291 (40550), 448 (5050), 502 nm (5500). Anal. Calcd for
C22H21NO2S3 (427.6): C, 61.79; H, 4.95; N, 3.28. Found: C, 61.90;
H, 5.11; N, 3.51.
nhexyl
8 (79%)
Scheme 6 Pseudo five-component synthesis of the bis(α,β-unsatu-
rated ester) 8 in a one-pot fashion
Pseudo Five-Component Synthesis of Diethyl (2E,2′E)-3,3′-[4-
(4-Hexylphenyl)-4H-dithieno[2,3-b:3′,2′-e][1,4]thiazine-2,6-di-
yl]bisacrylate (8); Typical Procedure
transformations through dilithiodithienothiazines was il-
lustrated by an efficient pseudo five-component synthesis
of a diacrylate derivative. Further studies directed towards
dithienothiazines as substrates in cross-coupling reactions
and investigations of the electronic properties of the deriv-
atives are currently underway.
TMEDA (0.17 mL, 1.20 mmol) was dissolved in anhydrous THF (5
mL) in a flame-dried Schlenk flask under N2.The solution was then
cooled to –78 °C and BuLi (1.6 M in hexane; 0.72 mL, 1.2 mmol
was added, followed by portionwise addition of dithienothiazine 3c
(186 mg, 0.50 mmol). The solution was stirred at –78 °C for 2 h,
DMF AcroSeal (0.1 mL, 1.3 mmol) was added, and stirring was
continued at –78 °C for another 0.5 h. H2O (0.5 mL) was then added
and the mixture was allowed to warm to r.t. Phosphonium chloride
7 (231 mg, 0.6 mmol) was added at –78 °C and the temperature was
raised to 50 °C for 1 h. The mixture was then cooled to r.t. and sub-
jected to aqueous workup with brine and CH2Cl2. The combined or-
ganic layers were dried (MgSO4) and concentrated under reduced
pressure, and the residue was adsorbed on Celite and purified by
flash chromatography [silica gel, hexane–EtOAc (30:1 + 2% Et3N)
to give a dark-red viscous oil; yield: 225 mg (79%); Rf = 0.17. IR
4-Phenyl-4H-dithieno[2,3-b:3′,2′-e][1,4]thiazine (3a); Typical
Procedure
A screw-cap Schlenk vessel was charged with anhydrous toluene
(15 mL) under N2 then sulfide 1 (1.07 g, 3.00 mmol), PhNH2 (2a;
321 mg, 3.45 mmol), bis(dibenzylideneacetone)palladium (5
mol%, 86 mg, 0.15 mmol), 1,1′-bis(diphenylphosphino)ferrocene
(166 mg, 0.30 mmol), and t-BuONa (865 mg, 9.00 mmol) were suc-
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 371–374

374
C. Dostert et al.
LETTER
(ATR): 619 (w), 640 (w), 669 (w), 721 (w), 758 (w), 820 (m), 851
(w), 962 (m), 1003 (w), 1034 (m), 1094 (m), 1152 (s), 1209 (w),
1260 (s), 1300 (m), 1364 (m), 1379 (w), 1427 (m), 1508 (m), 1524
(m), 1557 (w), 1614 (s), 1703 (m), 2855 (w), 2062 (w), 2955 (w),
2978 (w) cm–1. 1H NMR (600 MHz, acetone-d6): δ = 0.90 (t, J = 7.0
Hz, 3 H), 1.23 (t, J = 7.1 Hz, 6 H), 1.32–1.42 (m, 6 H), 1.65–1.71
(m, 2 H), 2.69–2.73 (m, 2 H), 4.14 (q, J = 7.1 Hz, 4 H), 6.02 (d,
J = 15.6 Hz, 2 H), 6.43 (s, 2 H), 7.34–7.37 (m, 2 H), 7.41–7.44 (m,
2 H), 7.51 (d, J = 15.6 Hz, 2 H). 13C NMR (150 MHz, acetone-d6):
δ = 14.4 (CH3), 14.6 (CH3), 23.3 (CH2), 29.8 (CH2), 32.2 (CH2),
32.5 (CH2), 36.3 (CH2), 60.9 (CH2), 106.9 (Cquat), 117.0 (CH), 123.2
(CH), 129.4 (2 CH), 131.5 (CH), 136.7 (2 Cquat), 137.9 (Cquat), 144.9
(Cquat), 166.6 (Cquat). MS (MALDI-TOF): m/z = 567.1 [M+]. UV/Vis
(CH2Cl2): λmax (ε) 312 (38000), 492 nm (5450). Anal. Calcd for
C30H33NO4S3 (567.8): C, 63.46; H, 5.86; N, 2.47; S 16.94. Found:
C, 63.28; H, 6.14; N, 2.45; S, 16.83.
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Acknowledgment
The authors cordially thank the Fonds der Chemischen Industrie for
support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
r
t
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Synlett 2014, 25, 371–374
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