Metallation reactions. XXXVI. A study on the metallation of (methylthio)- and (methylsulfonyl)thiophenes

Article abstract of DOI:10.1002/jhet.5570440316

Methylthio- and methylsulfonyl thiophenes were polymetallated by n-buthyllithium and superbase (LICKOR) in one-step. 2-(Methylthio)thiophene was bimetallated in 5 and in alpha to the methylthio sulfur atom by superbase. 3-(Methylthio)thiophene was bimetallated in both 2 and 5 positions by the organolithium and trimetallated in these two positions and in alpha to the thioethereal sulfur atom by superbase. 3-(Methylsulfonyl)thiophene was bimetallated in 2 and in alpha to the sulfonyl sulfur atom by the organolithium while the 2-(methylsulfonyl)thiophene underwent degradation in the same conditions.

Full text of DOI:10.1002/jhet.5570440316

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Metallation Reactions. XXXVI. A Study on the Metallation of
(Methylthio)- and (Methylsulfonyl)thiophenes
Claudia Fattuoni,* Michele Usai, Maria G. Cabiddu, Enzo Cadoni, Stefania De
Montis, Francesca Sotgiu, Salvatore Cabiddu
Dipartimento di Scienze Chimiche, Università di Cagliari, Cittadella Universitaria di Monserrato, SS. 554,
Bivio per Sestu. I-09042 Monserrato (CA), Italy
Received June 20, 2006
No reaction
S
S
S
S
S
S
S
S
O2
O2
O2
S
S
S
S
S
S
Methylthio- and methylsulfonyl thiophenes were polymetallated by n-buthyllithium and superbase
(LICKOR) in one-step. 2-(Methylthio)thiophene was bimetallated in 5 and in alpha to the methylthio
sulfur atom by superbase. 3-(Methylthio)thiophene was bimetallated in both 2 and 5 positions by the
organolithium and trimetallated in these two positions and in alpha to the thioethereal sulfur atom by
superbase. 3-(Methylsulfonyl)thiophene was bimetallated in 2 and in alpha to the sulfonyl sulfur atom by
the organolithium while the 2-(methylsulfonyl)thiophene underwent degradation in the same conditions.
J. Heterocyclic Chem., 44, 609 (2007).
INTRODUCTION
[20,21] with the aim of carrying out a one-step
polymetallation in the side chain and in the ring that could
allow their polyfunctionalization after electrophilic
quenching.
Thiophenes and benzothiophenes constitute an
important class of molecules for their application as
organic optical materials or pharmacologically active
products [1-7]. Owing to their various applications it is
important to find new synthetic methods for their
polyfunctionalization with rapid and high yielding
procedures.
This study should be particularly important as these
substrates have been only monolithiated through
hydrogen-metal or halogen-metal exchange [9-11, 22-26].
As a matter of fact in 1959 Gol'dfarb first reported the
lithiation of 1a using n-butyllithium at 0°C in ether
obtaining the 5-carboxylic acid in 86% yield [22].
Barbarella et al. reported analogous results (88% yield)
working in ether at room temperature [23]. A change of
the solvent (dioxane/hexane) and a lowering of the
temperature (-10°C) gave a 30% yield of the 5-monoli-
thiated product as reported by Noack et al. [24].
The reactivity of thiophene towards organolithiums has
been extensively studied and the directing power of a
wide range of substituents on the ring has been examined
[8-11]; nevertheless, the direct polymetallation of
(methylthio)- and (methylsulfonyl)thiophenes on the
chain or on the ring has never been reported.
We have previously studied the directing power of the
methylthio group on the benzene ring in metallation
reactions: the monometallation occurs in the alpha
position while the one-step bimetallation occurs in ortho
and alpha position either with organolithiums or
superbases [12-14]. On the other hand, mono- di- or
polymetallation of linear alkyl aryl sulfones usually leads
to mono- di- or poly-alpha-metallations [15]. The
isopropyl phenyl sulfone was monometallated in alpha
[16], while dimetallation leads to alpha,ortho-disubsti-
tution [17]. Furthermore, the dimetallation of tert-butyl
phenyl sulfone leads to di-ortho,ortho-metallation
[18,19].
Compound 1b was first monolithiated with n-
butyllithium at 0°C in ether by Gronowitz in 1958 giving
the 2-carboxylic acid as only product in 70% yield [25].
More recently Taylor and Vogel obtained a 3:1 mixture of
2- and 5–substituted products performing the reaction in
ether/hexane at room temperature [26].
The monolithiation of 1c with n-butyllithium at 0°C in
ether allowed Gronowitz to prepare the (3-thienyl-
sulfonyl)acetic acid derived from the alpha-substitution
[25].
RESULTS AND DISCUSSION
The starting compounds (1a-d) were treated with
different metallating reagents: n-butyllithium (BuLi) and
the superbasic mixture n-butyllithium/potassium tert-
butoxide (LICKOR). All metallated compounds were
quenched with iodomethane and analysed by GC/MS.
In connection with these studies, in this work we
examined the reaction of 2-(methylthio)-(1a), 3-(methyl-
thio)- (1b), 3-(methylsulfonyl)- (1c) and 2-(methylsul-
fonyl)-thiophene (1d) with n-butyllithium and superbases

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C. Fattuoni, M. Usai, M. G. Cabiddu, E. Cadoni, S. De Montis, F. Sotgiu, S. Cabiddu
Vol 44
It was already known that 1a can be monometallated by
using five or six molar equivalents of superbase were
unsuccessful: in fact only 5 was isolated but the amount
of degradation products increased. It is noteworthy that
the superbase always required short reaction times (about
15') because longer times gave resinous products probably
deriving from ring opening [27,28].
Then we examined the compound 1b (Scheme 2, Table
2). It was already known that its reaction with one molar
equivalent of n-butyllithium gives two isomeric 2-
lithiated (6) and 5-lithiated (7) intermediates as proven by
the isolation of 8 and 9 after quenching with iodomethane
[26].
one molar equivalent of n-butyllithium in the thiophene 5-
position to give the monolithiated intermediate 2 [9,22-
24]. All attempts to substitute other hydrogen atoms using
two or more (even six) molar equivalents of n-
butyllithium led to the same result (Scheme 1, Table 1), as
proven by the isolation of 3 as the sole product, after
quenching of 2 with iodomethane.
Scheme 1
S
1a
Table 2
Metallation of 3-(methylthio)thiophene (1b)
Li
S
S
Li
S
S
Li
S
S
RM (equivalents) SM recovered (%) [a] Metallated positions (%) [a]
2
4
2,5,ꢀS
2
5
2,5
BuLi (1)
BuLi (2)
BuLi (3)
BuLi (4)
BuLi (6)
LICKOR (1)
LICKOR (2)
LICKOR (3)
LICKOR (4)
LICKOR (5)
LICKOR (6)
tr
tr
tr
tr
tr
40
tr
tr
tr
tr
tr
69 [b] 30 [b]
26
20
54
>98
>99
>99
5
17
92
45
18
S
S
3
5
40
63
15
20
8
55
82
>99
Table 1
Metallation of 2-(methylthio)thiophene (1a)
RM (equivalents) SM recovered (%) [a] Metallated positions (%) [a]
[a] Ratio in crude product determined by GC/MS. [b] In agreement with
literature data, see ref. [26] reporting the quenching with carbon dioxide.
5,ꢀS
5
68 [b]
>99
>99
>99
>99
97
BuLi (1)
BuLi (2)
BuLi (3)
BuLi (4)
BuLi (6)
LICKOR (1)
LICKOR (2)
LICKOR (3)
LICKOR (4)
LICKOR (5)
LICKOR (6)
32
tr
tr
tr
tr
tr
tr
tr
tr
tr
tr
tr
tr
tr
tr
tr
Two molar equivalents of n-butyllithium gave three
products: 8, 9 and 11, the last one deriving from the 2,5-
dilithiated intermediate 10, in the relative percentage of
26%, 20% and 54%.
98
tr
70 [c]
90 [d]
56 [e]
6 [f]
Scheme 2
S
[a] Ratio in crude product determined by GC/MS. [b] In agreement with
literature data, see ref. [22] reporting the quenching with carbon dioxide.
[c] Unidentified degradation products have been detected in 30% total
amount. [d] Degradation products have been detected in 10% total
amount. [e] Degradation products have been detected in 44% total
amount. [f] Degradation products have been detected in 94% total
amount.
S
1b
Li
S
S
S
S
S
S
Li
Li
Li
Li
S
S
S
Li
Li
S
6
7
10
12
S
S
When the reaction was performed with one or two
molar equivalents of LICKOR only 3 was obtained. On
the other hand, three molar equivalents of LICKOR led to
the bimetallated intermediate 4 deriving from the
substitution of one hydrogen of the methylthio group and
of the 5-hydrogen atom of the ring. This intermediate
gave, after quenching with iodomethane, the product 5 in
70% yield. In this reaction the GC/MS analysis also
revealed the presence of degradation products. Using four
molar equivalents of LICKOR 5 was obtained in 90%
yield. All attempts to substitute other hydrogen atoms
S
S
S
S
8
9
11
13
Three molar equivalents of n-butyllithium gave almost
quantitatively the disubstituted product 11. The same
result was obtained performing the metallation with four,
five or six molar equivalents of the same reagent. The
reaction with one molar equivalent of LICKOR afforded
products 8, 9 and 11 in the relative percentage of 40%,

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Metallation Reactions. XXXVI. A Study on the Metallation
of (Methylthio)- and (Methylsulfonyl)thiophenes
611
15%, 5% beside 40% of the starting material. Using two
molar equivalents of superbase we obtained 8, 9 and 11 in
the percentage of 63%, 20%, 17% and traces of the
starting material. We did not find any monosubstituted
product using three molar equivalents of superbase: in
fact we obtained the disubstituted compound 11 together
with a small amount of 13 deriving from the 2,5,ꢀS-
trimetallated intermediate 12, in the ratio of 92:8. Four
equivalents of LICKOR gave a greater amount of 13: the
ratio 13:11 was 55:45. Performing the reaction with five
molar equivalents of superbase the ratio 13:11 was 82:18.
The compound 13 was isolated as the only product when
six molar equivalents of LICKOR were used.
Scheme 3
O2
S
S
1c
O2
S
O2
Li
Li
S
Li
S
S
14
15
O2
S
O2
S
S
S
16
17
This study has been extended to the sulfonyl derivatives
1c and 1d. It was known that 3-(methylsulfonyl)-
thiophene (1c) can be monolithiated alpha to the methyl-
sulfonyl group [25]. Two molar equivalents of n-
butyllithium (Scheme 3, Table 3) gave two products: 14
derived from an alpha-S lithiation and 15 derived from
bimetallation in alpha-S and in 2, as proven by the
isolation of 16 and 17 in the ratio of 10:90 after quenching
with iodomethane. The use of three or more molar
equivalents of n-butyllithium led only to 17. Attempts to
replace other hydrogen atoms using the superbasic
mixture were unsuccessful. In fact two molar equivalents
of LICKOR gave a mixture of 16 and 17 in the ratio of
12:88, while four equivalents gave the same products in
the ratio of 8:92; six equivalents gave 17 as the only
product. Degradation products were formed in all
reactions lowering the global yield of target compounds.
3-(Methylsulfonyl)thiophene (1d) showed
a great
instability towards the metallating reagent employed (both
n-butyllithium, with or without TMEDA, and LICKOR)
at any temperature and reaction time. In fact, even when
the reaction was performed adding the substrate to a
mixture of the metallating reagent and the electrophile,
only degradation products were obtained.
The results obtained, together with those derived from
the literature, allow to selectively prepare mono- or
bimetallated intermediates starting from 1a and 1c, and
mono-, bi- or trimetallated species starting from 1b by
careful choice of the proper conditions. In fact:
i)
In the case of 1a, the best experimental
conditions to substitute the hydrogen atom at 5 required
two molar equivalents of n-butyllithium. To substitute
both the 5-hydrogen and the one alpha to the thioethereal
group, four molar equivalents of superbase should be used
(Table 1 and Scheme 1).
Table 3
Metallation of 3-(methylsulfonyl)thiophene (1c)
ii)
In the case of 1b, the substitution of the
RM (equivalents) SM recovered (%) [a] Metallated positions (%) [a]
ꢀS
88 [b]
10
2,ꢀS
hydrogen atom at 2 is achievable using one molar
equivalent of n-butyllithium while both the annular
hydrogen atoms at 3 and 5 can be substituted simul-
taneously using four molar equivalents of superbase.
Finally, the substitution of three hydrogen atoms 2, 5 and
alpha to the thioethereal group, requires the use of six
molar equivalents of superbase (Table 2 and Scheme 2).
BuLi (1)
BuLi (2)
BuLi (3)
12
tr
tr
tr
tr
tr
tr
90
>98
>99
88
92
>99
BuLi (6)
LICKOR (2) [c]
LICKOR (4) [c]
LICKOR (6) [c]
12
8
[a] Ratio in crude product determined by GC/MS. [b] In agreement with
literature data, see ref. [25] reporting the quenching with CO2. [c] In the
reactions with LICKOR degradation products were always formed
lowering the desired products yields, see Experimental.
iii)
In the case of 1c, the hydrogen atom alpha to the
sulfonyl group can be substituted using one molar
equivalent of n-butyllithium [25]. Three molar equivalents
of n-butyllithium allow substitution of both the 2-
hydrogen atom and the hydrogen atom alpha to the
sulfonyl group (Table 3 and Scheme 3).
The different behaviour of 1c compared with the
analogous (methylsulfonyl)benzene must be evidenced:
the benzene derivative undergoes substitution of the
hydrogen atom alpha to the sulfonyl group [15], whereas
the thiophene derivative is metallated at the 2 annular
position and alpha to the sulfonyl group. In the thiophene
derivative the heterocyclic sulfur clearly plays
fundamental role in stabilizing the neighbouring
carbanion.
EXPERIMENTAL
The ir spectra were recorded with a Perkin-Elmer 1310
grating spectrophotometer. Nmr spectra were recorded on a
Varian VXR-300 spectrometer operating at 300 MHz for 1H nmr
and 75 MHz for 13C nmr spectra. Chemical shifts are reported in
a

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Vol 44
ppm relative to tetramethylsilane and J values in Hz. The mass
spectral data were recorded at 70 eV with a Hewlett-Packard
5989A GC-MS system with HP 5890 GC fitted with a capillary
column (50 mꢀ0.2 mm) packed with DH 50.2 Petrocol (0.50 μm
film thickness). Microanalyses were carried out on a Carlo Erba
1106 element analyzer.
Reagent-grade reagents and solvents were used. All reagents
were purchased from Aldrich Chemical Co. Solutions of n-
butyllithium in hexane were purchased from Aldrich Chemical
Company and were analysed before use [29]. All solvents were
dried and purified using standard techniques. 2-(Methylthio)-
(1a) and 3-(methylthio)thiophene (1b), 3-(methylsulfonyl)- (1c)
and 2-(methylsulfonyl)thiophene (1d) were prepared by
published methods [9, 25, 30].
stirring was continued for 15 min at –78 °C. The mixture was then
treated dropwise with an excess of iodomethane (2.61 g, 18.4
mmol) in dry THF (10 mL). After twenty minutes the cooling bath
was removed, the reaction mixture was treated with 10% aqueous
hydrochloric acid, poured into water, the organic layer separated
and the aqueous layer extracted with diethyl ether. The combined
organic extracts were dried (sodium sulfate), concentrated and
analysed by GC/MS. The analyses (see Table 1) showed the
presence of 3 (97%) and traces of 5. The starting material
remaining was about 3%.
Similar result was obtained performing the reaction with two
molar equivalents of the superbasic mixture.
When three molar equivalents of LICKOR were used the
GC/MS analyses (see Table 1) exhibited the presence of 5
(70%), various unidentified products (30%) and traces of
starting material.
Authentic samples
When four molar equivalents of LICKOR were used the
GC/MS analyses (see Table 1) exhibited the presence of 5
(90%), various unidentified products (10%) and traces of
starting material.
Analogous results were obtained performing the reaction with
five molar equivalents of LICKOR (see Table 1) but the yield of 5
lowered to 56% and the yield of unidentified products became 44%.
When the reaction was performed with six molar equivalents
of LICKOR the GC/MS analyses showed 5 in 6% yield. Various
unidentified products were also formed in 94% yield.
3-(Ethylsulfonyl)thiophene (16). To a vigorously stirred 1.6
M solution of n-butyllithium in hexane (5.5 mL, 8.5 mmol) 1c (1
g, 7.7 mmol) in dry THF (20 mL) was added dropwise at 0 °C
under argon. After 1 hour, a solution of iodomethane (1.21 g, 8.5
mmol) in dry THF (10 mL) was added dropwise and the reaction
was completed by stirring for 20 minutes at the same
temperature. The cooling bath was removed, the reaction
mixture was hydrolysed with water and the pH adjusted to 4-5
by addition of 10% aqueous hydrochloric acid. The organic
layer was separated, the aqueous layer extracted with diethyl
ether and the organic solutions combined, dried (sodium sulfate)
and evaporated. The crude product was flash-chromatographed
on silica gel using 1:1 light petroleum/diethyl ether as eluent to
give a brown oil, 0.89 g (71%); ir (neat): 2970, 2940, 1490,
1450, 1400, 1300, 1260, 1220, 1200, 1130, 1100, 1045, 900,
860, 820, 780, 720 cm-1; 1H nmr (deuterochloroform): ꢁ 1.27 (t,
J = 7.5 Hz, 3H, CH2CH3), 3.11 (q, J = 7.5 Hz, 2H, CH2CH3),
7.35 (dd, J = 1.2 Hz and J = 5.1 Hz, 1H, H-4), 7.45 (dd, J = 3.0
Hz and J = 5.1 Hz, 1H, H-5), 8.05 (dd, J = 1.2 Hz and J = 3.3
Hz, 1H, H-2); 13C nmr (deuterochloroform): ꢁ 7.36 (CH3), 50.76
(CH2), 125.93 (CH-4), 128.26 (CH-5), 132.61 (CH-2), 138.93
In this manner, the following compounds were isolated and
characterised:
5-Methyl-2-(methylthio)thiophene (3). This compound was
obtained from 1a and two molar equivalents of n-butyllithium.
The crude product was flash-chromatographed on silica gel
using light petroleum as eluent to give a pale yellow oil, 0.90 g
(81%), bp 82-83° (10 mm) [lit. [31], bp 90-92° (20 mm)]; ir
(neat) 2960, 2920, 1460, 1380, 1310, 1260, 1220, 800, 730 cm-1;
1H nmr (deuterochloroform): ꢁ 2.47 (s, 3H, CH3), 2.48 (s, 3H,
SCH3), 6.63 (d, J = 3.6 Hz, 1H, H-4 or H-3), 6.64 (d, J = 3.6 Hz,
1H, H-3 or H-4); 13C nmr (deuterochloroform): ꢁ 15.41 (CH3),
22.45 (SCH3), 125.37 (CH-3), 131.81 (CH-4), 133.80 (C-2),
+
(C-3); ms: m/z 176 (M+, 47), 147 (C4H3O2S2 , 40), 131
+
+
(C4H3OS2 , 26), 100 (C4H4OS+, 35), 84 (C4H4S+, 54), 57 (C2HS+,
142.83 C-5); ms: m/z 144 (M+, 100), 129 (C5H5S2 , 97), 85
+
25), 45 (CHS+, 58), 39 (C3H3 , 100). Anal. Calcd. for C6H8O2S2:
(C4H5S+, 45), 45 (CHS+, 38). This product was also identified by
comparison with an authentic sample prepared by literature
methods [31].
C, 40.89; H, 4.57; S, 36.39. Found: C, 40.97; H, 4.63; S, 36.27.
Metallation of 1a. Method A. To a vigorously stirred 1.6 M
solution of n-butyllithium in hexane (6.5 mL, 10.2 mmol) 1a (1 g,
7.7 mmol) in dry THF (20 mL) was added dropwise at –78 °C
under argon. After fifteen minutes, a solution of iodomethane
(1.77 g, 12.5 mmol) in dry THF (10 mL) was added dropwise and
the reaction was completed by stirring for twenty minutes at the
same temperature. The cooling bath was removed, the reaction
mixture was hydrolysed with water and the pH adjusted to 4-5 by
addition of 10% aqueous hydrochloric acid. The organic layer was
separated, the aqueous layer extracted with diethyl ether and the
organic solutions, combined and dried (sodium sulfate) were
analysed by GC/MS showing the product 3 (68%) (see Table 1)
while the remaining starting material was 32%.
2-(Ethylthio)-5-methylthiophene (5). This compound was
obtained from 1a and four molar equivalents of LICKOR. The
crude product was flash-chromatographed on silica gel using
light petroleum as eluent to give a pale yellow oil, 0.91 g (75%),
bp 64-65° (2 mm) [lit. [32] bp 61-62° (2 mm)]; ir (neat) 2960,
2920, 1460, 1380, 1310, 1260, 1220, 1160, 970, 950, 800 cm-1;
1H nmr (deuterochloroform): ꢁ 1.31 (t, J = 7.5 Hz, 3H,
CH2CH3), 2.48 (s, 3H, CH3), 2.79 (q, J = 7.5 Hz, 2H, CH2CH3),
6.66 (d, J = 3.6 Hz, 1H, H-4), 6.96 (d, J = 3.6 Hz, 1H, H-3); 13
C
nmr (deuterochloroform): ꢁ 14.03 (CH3), 14.70 (CH3), 22.68
(CH2), 125.50 (CH-3), 131.31 (CH-4), 134.16 (C-2), 143.87 (C-
+
+
5); ms: m/z 158 (M+, 77), 143 (C6H7S2 , 9), 129 (C5H5S2 , 100),
+
114 (C4H2S2 , 11), 85 (C4H5S+, 76), 45 (CHS+, 73). This product
When two or three or four or six molar equivalents of n-
butyllithium were used the GC/MS analyses exhibited only 3
with traces of 5 and starting material.
was also identified by comparison with an authentic sample
prepared by literature methods [32].
Metallation of 1a. Method B. To a vigorously stirred solution
of potassium tert-butoxide (1.14 g, 10.2 mmol) and dry THF (20
mL) a 1.4 M solution of n-butyllithium in hexane (6.5 mL, 10.2
mmol) was added under argon at –78 °C. After fifteen minutes a
solution of 1a (1 g, 7.7 mmol) in dry THF (10 mL) was added and
Metallation of 1b. Method A. To a vigorously stirred 1.6 M
solution of n-butyllithium in hexane (6.5 mL, 10.2 mmol) 1b (1
g, 7.7 mmol) in dry THF (20 mL) was added dropwise at –78 °C
under argon. After two hours a solution of iodomethane (1.77 g,
12.5 mmol) in dry THF (10 mL) was added dropwise. After one