ortho-lithiation of benzene-1,2-dithiol: A methodology for ortho-functionalization of benzene-1,2-dithiol

Article abstract of DOI:10.1515/znb-2002-1210

The ortho-lithiation of benzene-1,2-dithiol with three equivalents of nBuLi afforded monoas well as di-C-lithiated intermediates. The surprising kinetically controlled formation of di-C-lithiated species offers the opportunity to obtain dimercaptobenzoic and -terephthalic acid derivatives in a onepot synthesis in reasonable yields. Both compounds are versatile building blocks for the synthesis of macrocycles containing arylenedithiol units. Focusing on novel terephthalic acid derivatives, two preparation routes, via amide and via alkyl linkage, respectively, have been elaborated. The reaction sequence (i) sulfur protection using either isopropyl or benzyl groups, (ii) transformation of the carboxylic function into an amide or an alkyl group and (iii) subsequent removal of the protection groups afforded the terephthaldiamidedithiol 6 and the 1,2-bis(2,3-dimercaptophenyl)ethane 11.

Full text of DOI:10.1515/znb-2002-1210

ortho-Lithiation of Benzene-1,2-dithiol: A Methodology for
ortho-Functionalization of Benzene-1,2-dithiol
Han Vinh Huynha, Wolfram W. Seidela, Thomas Lu¨ggera, Roland Fro¨hlichb, Birgit Wibbelingb,
and F. Ekkehardt Hahna
a
Institut fu¨r Anorganische und Analytische Chemie, Westfa¨lische Wilhelms-Universita¨t
Mu¨nster, Wilhelm-Klemm-Straße 8, D-48149 Mu¨nster, Germany
b Organisch-Chemisches Institut, Westfa¨lische Wilhelms-Universita¨t Mu¨nster,
Corrensstraße 40, D-48149 Mu¨nster, Germany
Reprint requests to Prof. Dr. F. E. Hahn. E-mail: fehahn@uni-muenster.de
Dedicated to Professor Albrecht Mewis on the occasion of his 60th birthday
Z. Naturforsch. 57 b, 1401–1408 (2002); received October 7, 2002
ortho-Functionalized Benzene-1,2-dithiols, Bis(benzene-1,2-dithiol), Ligand Synthesis
The ortho-lithiation of benzene-1,2-dithiol with three equivalents of nBuLi afforded mono-
as well as di-C-lithiated intermediates. The surprising kinetically controlled formation of di-
C-lithiated species offers the opportunity to obtain dimercaptobenzoic and -terephthalic acid
derivatives in a onepot synthesis in reasonable yields. Both compounds are versatile building
blocks for the synthesis of macrocycles containing arylenedithiol units. Focusing on novel
terephthalic acid derivatives, two preparation routes, via amide and via alkyl linkage, respec-
tively, have been elaborated. The reaction sequence (i) sulfur protection using either isopropyl
or benzyl groups, (ii) transformation of the carboxylic function into an amide or an alkyl group
and (iii) subsequent removal of the protection groups afforded the terephthaldiamidedithiol 6
and the 1,2-bis(2,3-dimercaptophenyl)ethane 11.
Introduction
the synthesis and molecular structures of several
functionalized benzene-1,2-dithiol derivatives.
The chemistry of benzene-1,2-dithiol is widely
ranged. In organic synthesis it has been used as a
precursor for 1,3-benzodithioles [1], organo-poly-
sulfides [2] with antifungal activity [3], spirans
[4] and macrocyclic sulfides [5]. The coordination
chemistry of benzene-1,2-dithiolate ligands has also
been studied intensively during the last decades [6].
The interest in benzene-1,2-dithiolate complexes
was not only prompted by their remarkable elec-
tronic and magnetic properties in general, but also
by their relevance as models for the active sites
of metal containing enzymes [7]. However, lig-
ands having two or more benzene-1,2-dithiolate
donor sets were unknown until recently, when we
reported the first amide- and alkyl-bridged tris-
and bis(benzenedithiolate) ligands and their coor-
dination chemistry [8]. In our attempt to synthe-
size ortho-functionalized benzenedithiols as build-
ing blocks for poly(benzenedithiolate) ligands we
investigated the mechanism of the ortho-lithiation
of benzene-1,2-dithiol based on the method de-
scribed by Block et al. [9]. Herein, we report on
Results and Discussion
Generation and reactions of lithiated arenedithiols
For the preparation of diamide bridged poly-
(benzenedithiol) ligands we used the 2,3-di(alkyl-
mercapto)benzoic acids 2a/b as suitable precur-
sors. These compounds can be prepared in mod-
erate yields ( 40 %) by direct ortho-lithiation of
benzene-1,2-dithiol with at least three equivalents of
nBuLi followed by treatment with dry CO2 and sub-
sequent alkylation of the thiol functions with alkyl-
bromides as depicted in Scheme 1. In addition, this
reaction sequence also afforded the 1,2-di(alkyl-
mercapto)benzenes 1a/b ( 20 %) and surprisingly
the 2,3-di(alkylmercapto)terephthalic acids 3a/b (
30 %) as byproducts. These products can be isolated
in analytically pure form by column chromatogra-
phy (SiO2, eluent: diethyl ether / petroleum ether
/ acetic acid 1 : 3 : 0.03). The addition of small
amounts of acetic acid to the eluent turned out to
c
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¨
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1402
H. V. Huynh et al. · ortho-Lithiation of Benzene-1,2-dithiol
Scheme 1.
Fig. 2. Molecular structure of 2,3-di(benzylmercapto)-
terephthalic acid 3b (upper plot) and the two-dimen-
sional endless chain (lower plot) of 3b formed by hy-
˚
drogen bonds. Selected bond lengths [A] and angles [ ]:
C1-C11 1.503(3), C11-O11 1.250(3), C11-O12 1.266(3),
C2-S21 1.778(2), S21-C22 1.824(3), C3-S31 1.778(2),
S31-C32 1.830(2), C4-C41 1.504(3), C41-O41 1.254(3),
C41-O42 1.267(3); C6-C1-C11 116.2(2), C2-C1-C11
123.2(2), O11-C11-O12124.5(2), O11-C11-C1 117.6(2),
O12-C11-C1 117.8(2), C1-C2-S21 121.5(2), C3-C2-S21
119.7(2), C4-C3-S31 118.3(2), C2-C3-S31 122.0(2), C5-
C4-C41 118.5(2), C3-C4-C41 120.5(2), O41-C41-O42
124.7(2), O41-C41-C4 118.6(2), O42-C41-C4 116.6(2).
˚
of 2.65 A 2b crystallizes as a dimer and the tereph-
Fig. 1. Molecular structure of 2,3-di(benzylmercapto)-
thalic acid derivative 3b on the other hand forms
a two-dimensional endless chain. As expected the
˚
benzoic acid 2b. Selected bond lengths [A] and angles
[ ]: C1-C31 1.491(5), C5-S1 1.765(3), C6-S2 1.779(3),
S1-C11 1.818(3), S2-C21 1.811(5), C31-O31 1.111(5),
C31-O32 1.171(6); C2-C1-C31 117.5(3), C6-C1-C31
122.8(3), C4-C5-S1 123.0(3), C6-C5-S1 117.3(2), C1-
C6-S2 123.0(2), C5-C6-S2 117.8(2), O31-C31-O32
115.7(4), O31-C31-C1 128.2(4), O32-C31-C1 116.1(4).
2
˚
S-C(sp ) distances are slightly shorter (0.05 A) than
the S-C(sp3) distances. However, the change of the
frontier orbital energies of the aromatic system by
the linkage of an additional carboxylic group does
not affect the S-C(sp2) bond length. In contrast to
2b, the benzyl protecting groups in 3b point to dif-
ferent sides of the aromatic ring formed by C1 - C6.
be essential to reduce the tailing phenomenon often
observed for carboxylic acids on silicagel, which
otherwise makes the separation of 2a/b and 3a/b
very difficult.
The carboxylic acids 2a/b and 3a/b are soluble in
most organicsolventsexceptfor hexane. The molec-
ular structures of 2b and 3b which have been deter-
mined by single crystal X-ray diffraction methods
are depicted in Figures 1 and 2. Due to the hydrogen
bonds between two carboxylic acid groups lead-
We were particularly interested in 3a/b because
terephthalic acid derivatives are versatile building
blocks for the synthesis of poly(benzenedithiol)
macrocycles. In general, two reaction pathways A
and B leading to the formation of the di-C-lithiated
species as an intermediate for the terephthalic acid
derivatives 3 are feasible (Scheme 2).
To shed light onto the mechanism involved, we
ing to an intermolecular oxygen-oxygen-distance carried out lithiation experiments with benzene-
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H. V. Huynh et al. · ortho-Lithiation of Benzene-1,2-dithiol
1403
Fig. 3. Product distribution exam-
ined by EI-MS.
Table 1. Relative ratios of 1a and the deuterated species
D1 and D2 under various reaction conditions with consid-
eration of their natural isotope distributions.
Equivalents Reaction
Ratio
1a [%]
Ratio
[%]
Ratio
[%]
of n-BuLi
time [h]
1
2
5
65
65
2
2
28
–
33
65
3
62
10
3.5
64
36
and D1 still contribute to the product mixture with
2 % and 33 %, respectively. These products must be
formed by protonolysis during the relatively long
reaction time. If three equivalents of nBuLi are em-
ployed, as expected, D1 is the main product with
62 %. However, D2 is still found in the mixture. On
the other hand, the contributions of 1a and D2 differ
by 18 %, which does not support the equilibrium
proposed for pathway A. The variation of reaction
time and the use of 3.5 equivalents of nBuLi fi-
nally disclosed, that the lithiation process is already
completed within two hours. The observation that
no di(thioether) 1a could be detected anymore pro-
vided further evidence to reject the equilibrium pro-
posed in pathway A. Obviously, the formation of the
di-C-lithiated species follows pathway B which in-
cludes a fast, kinetically controlled and irreversible
second C-lithiation in the para-position to the first
lithium atom by (local) excess of nBuLi. In addi-
tion, longer reaction times are unfavorable, but drive
the protonolysis of the lithium intermediates. These
results clearly demonstrate that the reaction condi-
tions used in the third procedure are optimal for the
preparation of both mono- as well as di-C-lithiated
species.
Scheme 2.
Scheme 3.
1,2-dithiol applying different amounts of lithiating
reagent and various reaction times. In order to sep-
arate the deprotonation from the carbonylation step
the generated lithium intermediates were trapped
with excess D2O and subsequently isopropylbro-
mide (Scheme 3). The product ratios were exam-
ined by mass spectrometry (Fig. 3). Table 1 sum-
marizes the resulting ratios of the three products
1a, D1 and D2 relative to each other under con-
sideration of their natural isotope distribution. The
Synthesis of amide derivatives
Macrocycles containing two (or more) benzene-
application of a five-fold excess of nBuLi leads af- 1,2-dithiol units are accessible by bridging two (or
ter 65 h reaction time to a product distribution in more) molecules of 3a/b twice. The reaction of
which D2 is the main product with 65 %. However, the acid chlorides of 3a/b with suitable diamines
even for the use of such an excess of nBuLi 1a under dilute conditions is one possible route to
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1404
H. V. Huynh et al. · ortho-Lithiation of Benzene-1,2-dithiol
Scheme 4.
Fig. 5. Molecular structure of the tertiary diamide 5.
Hydrogen atoms have been omitted. Selected bond
˚
lengths [A] and angles [ ]: C1-S1 1.7768(19), S1-
C7 1.830(2), C2-S2 1.776(2), C1-C2 1.402(3), C2-
C3 1.400(3), C13-O1 1.227(3), C13-N1 1.339(3), S1-
C1-C2 122.03(14), C1-C2-S2 122.07(15), C1-C2-C3
119.52(17), N1-C13-O1 123.7(2), C6-C13-O 119.57(19),
C6-C13-N1 116.57(18), C1-S1-C7 101.17(9).
Fig. 4. Molecular structure of the chiral diamide 4. Hy-
drogen atoms have been omitted. Selected bond lengths
˚
[A] and angles [ ]: S1-C2 1.789(7), S1-C12 1.838(8),
thalene in THF. Because of the convenience and the
mild conditions of this reaction sequence, we found
this method superior with respect to the standard
procedure using sodium in liquid ammonia. Subse-
quent acidification with hydrochloric acid (37 %)
lead to the formation of the dithiol 6. However, we
found that the isopropyl groups in 5 could not be
removed using either Na/C10H8/THF nor Na/NH3.
Apparently the presence of two tertiary amides in-
stead of secondary amides prevents the S-CH(CH3 )2
bond cleavage. If tertiary terephthalamides are em-
ployed, the S-protecting group cannot be isopropyl
but must be benzyl instead. The S-CH2Ph bonds in
the benzyl S-protected analogue of 5 are cleaved
easily leading to the corresponding dithiol [8b]. In
quest for an explanation of the difference in the re-
activity between 4 and 5 we performed single crystal
X-ray structure determinations of both. The molec-
ular structures and the numbering schemes are de-
picted in Figures 4 and 5. Structural parameters for
both compounds are unexceptional and no essen-
tial differences could be detected. In contrast to the
trans position of the isopropyl groups in 5, the iso-
propyl groups in 4 are found on the same side of
the aromatic ring formed by the carbon atoms C1-
C6 revealing a reduced steric crowding. However,
the amide substituents of both 4 and 5 point in op-
posite directions and are strongly twisted out of
the aromatic plane, which is expected for the ter-
tiary amide 5 but rather unusual for the secondary
S2-C3 1.799(7), S2-C9 1.836(7), N1-C7 1.348(8), N2-
C8 1.318(8), O1-C7 1.233(8), O2-C8 1.219(8), C1-
C2 1.363(9), C1-C6 1.405(10), C1-C7 1.509(9), C2-
C3 1.400(9), C3-C4 1.354(10), C4-C5 1.407(10), C4-C8
1.525(9), C5-C6 1.364(10); C2-S1-C12 105.3(3), C3-S2-
C9 103.2(3), C1-C2-S1 122.6(5), C3-C2- S1 118.0(5),
C4-C3-S2 117.4(5), C2-C3-S2 121.3(5), C3-C4-C8
123.3(6), C5-C4-C8 116.9(6), O1-C7-N1 123.1(6),
O1-C7-C1 120.9(5), N1-C7-C1 116.0(5), O2-C8-N2
124.3(6), O2-C8-C4 120.7(6), N2-C8-C4 115.0(6).
such diamide-bridged compounds. To investigate
the chemical properties of such amides in gen-
eral and to seek for the best thiol protection group
we synthesized the secondary and chiral diamide
4 as well as the tertiary diamide 5. Both com-
pounds can be obtained in good yields by reac-
tion of the acid chloride, generated by chlorination
of 3a with SOCl2, with two equivalents of (S)-1-
phenylethylamine or diethylamine, respectively, in
the presence of triethylamine as a base (Scheme 4).
Both compounds are soluble in halocarbon solvents,
THF, methanol, and DMF and insoluble in hexane,
pentane or water. In contrast to 4, the tertiary di-
amide 5 is even soluble in diethyl ether. The de-
crease in solubility going from tertiary to secondary
diamide is obviously due to the ability of the latter
to form hydrogen bonds.
The subsequent reductive cleavage of the sulfur
protecting isopropyl groups in 4 can be accom-
plished by treatment with metallic sodium / naph-
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H. V. Huynh et al. · ortho-Lithiation of Benzene-1,2-dithiol
1405
Fig. 6. Molecular structure of 1,2-bis[2,3-di(isopropyl-
mercapto)phenyl]ethane 10. Hydrogen atoms have been
˚
omitted. Selected bond lengths [A] and angles [ ]: C1-
Scheme 5.
S1 1.776(2), C2-C13 1.497(4), C6-S2 1.771(3), C7-S2
1.817(3), C10-S1 1.836(3); C6-C1-S1 119.2(2), C2-C1-
S1 120.0(2), C3-C2-C13 119.9(3), C1-C2-C13 122.5(3),
C5-C6-S2 123.4(2), C1-C6-S2 117.2(2), C1-S1-C10
102.1(2), C6-S2-C7 106.2(1).
amide 4. Steric rather than electronic effects must
be made responsible for this observation [10].
The more striking difference in the solubility of
these compounds demonstrates the strong influence
of hydrogen bonds formed by amide protons. The
dithiol 6 with secondary amide groups is solely sol-
uble in dimethylformamide or dimethylacetamide.
The decrease in solubility of 6 compared to its pre-
cursor 4 is caused by additional NH S hydrogen
bonds also indicated by a downfield shift of the
than undergo a Wurtz-type coupling reaction giv-
ing the sulfur protected bis(benzenedithiol) deriva-
tive 10 (yield 87 %). The reductive cleavage of the
isopropyl groups analogous to 4 yielded 11 in ac-
ceptable purity after several washing steps. Further
purification of 11 by recrystallization turned out to
be difficult. Therefore we verified at least the iden-
tity of the sulfur protected compound 10 which can
be crystallized from dichloromethane / hexane solu-
tion by single crystal X-ray structure determination.
The molecular structure depicted in Fig. 6 unequiv-
ocally proves that two aryldithiol units are linked
by a C2 backbone.
1
amide proton resonances in the H NMR spectra
from 7.55 ppm in 4 to 9.04 ppm in 6. The corre-
sponding dithiol derived from 5 with tertiary amide
groups on the other hand dissolves even in diethyl
ether [8b] showing no significant difference in sol-
ubility to its sulfur protected analogue 5. Therefore
the reactivity difference can probably be attributed
to the importance of an amide proton in the cleav-
age reaction of 4 rather than to steric or electronic
effects in the aromatic system.
Conclusion
Dimercaptoterephthalic acid derivatives found
first as surprising byproducts in the synthesis of
dimercaptobenzoic acid can be obtained in reason-
able yields by certain control measures in the ortho-
Synthesis of carbon linked derivatives
Recently we reported the use of the benzoic acid lithiation of dilithium-benz-1,2-dithiolate. Efforts
derivative 2a as a precursor for diamide bridged to develop an alternative and more exclusive syn-
bis(aryldithiol) compounds [8d]. However, the ben- thesis for dimercaptoterephthalic acid were unsuc-
zoic acid 2a can also be applied as starting mate- cessful so far. The appropriateness of certain thiol
rial for an alkyl linkage. For that purpose, 2a has protection groups in the synthesis of amide linked
to be converted into the isopropyl ester 7 (yield poly(aryldithiol) macrocycles is restricted to the
86 %) by reaction of the corresponding acid chlo- particular type of the amide function. In addition,
ride with isopropanol (Scheme 5). The reduction dimercaptobenzoic acid derivatives are useful in
of 7 with LiAlH4 and subsequent acidification af- the synthesis of solely alkyl-linked poly(aryldithiol)
forded the benzyl alcohol 8 (yield 80 %), which compounds. All the dithiols descibed here are new
can quantitatively be brominated to the correspond- and promising ligands for coordination chemistry
ing benzyl bromide 9 with PBr3. Compound 9 can experiments.
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1406
H. V. Huynh et al. · ortho-Lithiation of Benzene-1,2-dithiol
Experimental Section
in 20 ml of nhexane was added 4 ml of 2.5 M nBuLi in
hexane (10 mmol) at -78 C. The suspension was stirred
at ambient temperature for 2 h and carefully quenched by
adding 250 l of D2O. After stirring for another 1 h the
solvent was removed in vacuo. The residue was dissolved
in 40 ml of methanol and 806 l (8.6 mmol) of isopropyl
bromide was added to the solution. The resulting mix-
ture was refluxed for 24 h and the solvent was evaporated
in vacuo again. The residue was dissolved in 20 ml of
If not noted otherwise, all manipulations were per-
formed in an atmosphere of dry argon by using stan-
dard Schlenk techniques. Solvents were dried by stan-
dard methods and freshly distilled prior to use. N,N,N',N'-
tetramethylethylenediamine (TMEDA) was purified by
vacuum distillation from Na / benzophenone. 1H and
13C NMR spectra were recorded on a Bruker AC 200
NMR spectrometer. Elemental analyses were performed
at the Westfa¨lische Wilhelms-Universita¨t Mu¨nster on
Vario EL III CHNS and Foss Heraeus CHN-O-Rapid
elemental analyzers. Mass spectra were obtained using
Varian MAT 212 (EI), and DANI 8521/Finnigan MAT
IDT 800 (GCMS) spectrometers, respectively. IR spectra
were recorded on a Bruker Vektor 22 with KBr wafers,
thoseof liquidsneatbetween KBr windows. Benzene-1,2-
dithiol was prepared following a literature method [11].
The benzoic acid derivatives 2a and 3a were prepared as
published [8a]. Compound 1a was isolated as a byproduct
during the preparation of 2a. The terephthalic acid deriva-
tive 3b was isolated as a byproduct during the preparation
of 2b [8b]. The preparation of diamide 5 [8b], bromide
9, bis(dithiol) 11 and its precursor 10 has recently been
reported [8d].
diethyl ether and washed with water (2
20 ml). The
organic phase was dried over MgSO4. After removal of
the solvent in vacuo a product mixture was obtained as a
slightly yellow oil. MS (EI): m/z (%) = 228 (76.39) [D2]+,
227 (100.00) [D1]+.
Preparation of diamide 4: Two drops of N,N-dimethyl-
formamide and thionyl chloride (1 ml) were added to a
solution of 3a (1.04 g, 3.31 mmol) in chloroform (10 ml).
The reaction mixture was heated under reflux conditions
for 3 h and allowed to cool to ambient temperature.
Volatiles were removed in vacuo and the residue redis-
solved in THF. The yellowish solution was then added
dropwise to a solution of (S)-1-phenylethylamine (900 l,
6.98 mmol) and triethylamine (1 ml, 7.17 mmol) in THF
(40 ml). The mixture was filtered after stirring for 12 h
and the solvent was evaporated in vacuo. The residue was
1a: 1H NMR (200.13 MHz, CDCl3): = 7.33 (dd, 2 H,
Ar-H), 7.14 (dd, 2 H, Ar-H), 3.48 (m, 3J = 6.4 Hz, 2 H,
washed with diethyl ether (2
20 ml), redissolved in
SCH), 1.33 (d, 3J = 6.4 Hz, 12 H, CH3). – 13
C
1H NMR
dichloromethane and washed with saturated brine. The
organic phase was dried over MgSO4. Removal of the
solvent in vacuo gave 4 (1.435 g, 2.76 mmol, 83 %) as an
off-white powder. IR (KBr): ˜ = 3287 (st, N-H), 3060 (s,
Ar-H), 2972, 2927, 2865 (m, SC-H), 1642 (st, C=O), 1531
(st, C=O), 700 (s, Ar-H) cm 1. – 1H NMR (200.13 MHz,
CDCl3): = 7.55 (s, 2 H, Ar-H), 7.49 - 7.21 (m, 10 H,
(50.32 MHz, CDCl3): = 137.5, 130.6, 126.3 (Ar-C), 36.8
(SCH), 22.8 (CH3). – MS (EI): m/z (%) = 226 (60) [M]+,
184 (25) [M-C3H6]+, 142 (100) [M-2C3H7]+, 108 (10)
[M-2C3H7-H2S]+, 97 (16) [C5H5S]+, 78 (46) [C6H6]+,
41 (81) [C3H5]+. – C12H18S2 (226.39): calcd. C 63.66,
H 8.01, S 28.32; found C 63.92, H 7.91, S 28.26. 2b: 1H
NMR (200.13 MHz, CDCl3): = 11.30 (s, br, 1 H, CO2H),
7.52 - 6.93 (m, 13 H, Ar-H), 4.07 (s, 2 H, SCH2), 4.03 (s,
3
Ar-H), 7.15 (d, J = 8.0 Hz, 2 H, CONH), 5.32 (m, 2
3
H, NCH), 3.38 (sept, 2 H, SCH), 1.60 (d, J = 6.8 Hz,
6 H, CH(CH3)), 1.12 (d, 3J = 6.8 Hz, 6 H, SCH(CH3)2),
2 H, SCH2). – 13
C
1H NMR (50.32 MHz, CDCl3):
=
1.04 (d, 3J = 6.4 Hz, 6 H, SCH(CH3)2). – 13
C
1H NMR
171.2 (CO2H), 146.9, 137.6, 136.4, 135.8, 129.4, 129.2,
128.9, 128.7, 128.4, 128.3, 127.5, 127.4, 126.4 (Ar-C),
40.8 (SCH2), 37.4 (SCH2). – MS (EI): m/z (%) = 366 (6)
[M]+, 275 (3) [M-CH2Ph]+, 244 (10) [M-SCH2Ph]+, 91
(100) [CH2Ph]+. – C21H18O2S2 (366.49): calcd. C 68.82,
H 4.95; found C 68.79, H 5.54.
(50.32 MHz, CDCl3): = 166.7 (CONH), 143.4, 142.6,
137.9, 129.0, 128.6, 127.4, 126.4 (Ar-C), 49.5 (NCH),
41.2 (SCH), 22.7 (CH3), 21.5 (CH3). – MS (EI): m/z
(%) = 520 (100) [M]+, 373 (21), 105 (28) [C7H5O]+. –
C30H36N2O2S2 (520.74): calcd. C 69.19, H 6.97, N 5.38,
S 12.31; found C 68.84, H 6.99, N 5.28, S 12.51.
Preparation of dithiol 6: A sample of 4 (1.35 g,
2.6 mmol) and naphthalene (1 g, 7.8 mmol) were dis-
solved in THF (50 ml) and pieces of sodium (300 mg,
13 mmol) were added. The reaction mixture was stirred
for 12 h at ambient temperature and methanol (5 ml) was
added dropwise. The stirring was continued for 30 min.
and the solvent was evaporated in vacuo. The residue was
3b: 1H NMR (200.13 MHz, CDCl3): = 9.21 (s, br, 1
H, CO2H), 7.10 - 7.30 (m, 10 H, CH2-Ar-H), 7.74 (s, 2 H,
Ar-H), 4.13 (s, 4 H, SCH2). 13
C
1H NMR (50.32 MHz,
CDCl3): = 170.0 (CO2H), 140.6, 139.8, 136.0 (Ar-C),
130.0, 129.2, 128.6, 127.7 (CH2-Ar-C), 42.8 (SCH2). –
MS (EI):m/z (%) = 410 (4) [M]+, 320 (2) [M-CH2Ph]+, 91
(100) [CH2Ph]+. – C22H18O4S2 (410.50): calcd. C 64.37,
H 4.42; found C 64.06, H 4.86.
Procedure 3 is described as an example for the mech- dissolved in degassed water (50 ml) and washed with di-
anistic studies: To a mixture of 405 mg (2.85 mmol) of ethyl ether (3 20 ml). The aqueous phase was then acid-
benzene-1,2-dithiol and 430 l (2.87 mmol) of TMEDA ified with hydrochloric acid (37 %) to pH = 2 upon which
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H. V. Huynh et al. · ortho-Lithiation of Benzene-1,2-dithiol
1407
Table 2. Selected crystal and data collection details for 2b, 3b, 4, 5 and 10.
2b
3b CHCl3
4
5
10
Formula
fw [amu]
C21H18O2S2
366.47
40.7590(10)
12.7660(10)
7.6430(10)
90
C23H19Cl3O4S
529.85
C30H36N2O2S2
520.73
10.1020(10)
8.5394(9)
32.535(3)
90
93.329
90
2801.9(5)
0.71073
D8 APEX
153(2)
1.234
C22H36N2OsS2
424.65
10.434(2)
17.614(2)
13.648(2)
90
103.33(2)
90
2440.7(7)
0.71073
CAD 4
293(2)
1.156
C26H38S4
478.80
9.0676(6)
10.3173(7)
15.3445(11)
90
106.891(2)
90
1373.6(2)
0.71073
D8 APEX
233(2)
1.158
˚
a [A]
9.5770(10)
11.3410(10)
11.5650(10)
05.560(10)
99.280(10)
1.130(10)
1191.6(2)
1.54178
˚
b [A]
˚
c [A]
[deg]
[deg]
92.040(10)
90
[deg]
3
˚
V [A ]
3974.4(6)
0.71073
Kappa CCD
198(2)
˚
[A]
Instrument
Temp [K]
dcalc [g cm
Kappa CCD
223(2)
1
]
1.225
1.477
¯
Space group
C2/c
P1
P21
P21/n
P21/c
Z
8
2
4
4
2
1
[mm
]
0.278
5.364
SORTAV
4860
4521
0.219
0.237
0.357
Abs. correct.
Unique data
Obs. data [I > 2(I)] 3180
SORTAV
4531
SADABS
7256
none
SADABS
1790
3170
6663
2609
1524
R1 (obs.) [%]
R2 (all) [%]
GOF
7.92, wR1 = 25.70 4.74, wR1 = 13.06 7.24, wR1 = 18.94 3.76, wR1 = 9.37 3.79, wR1 = 9.69
10.75, wR2 = 28.67 5.07, wR2 = 13.28 7.76, wR2 = 19.34 5.11, wR2 = 10.10 4.46, wR2 = 10.27
1.043
1.041
1.077
1.061
1.032
No. of variables
227
292
0.759 / –0.946
658
1.110 / –0.341
262
0.194 / –0.203
136
0.247 / –0.167
Res. elec.
0.961 / –0.927
3
˚
dens. [e/A ]
the off-white product precipitated. The precipitate was fil- matography (SiO2, eluent: diethyl ether / petroleum ether
tered off, washed with water and diethyl ether and dried in 2:1) yielded 7 (910 mg, 3.2 mmol, 86 %) as a yellowish
1
vacuo to give an off-white powder (1.03 g, 2.36 mmol, 91 oil. H NMR (200.13 MHz, CDCl3): = 7.31 (m, 2 H,
%). IR (KBr): ˜ = 3297 (st, N-H), 3031 (w, Ar-H), 2978, Ar-H), 7.20 (dd, 1 H, Ar-H), 5.30 (m, 1 H, OCH), 3.52
2932 (m, C-H), 2510 (m, S-H), 1618 (st, C=O), 1531 (m, 2 H, SCH), 1.39 (d, 12 H, SCH(CH3)2), 1.22 (d, 6
(st, C=O), 700 (s, Ar-H) cm 1. 1H- NMR (200.13 MHz, H, OCH(CH3)2). – 13
C
1H NMR (50.32 MHz, CDCl3):
3
DMF-D7): = 9.04 (d, J = 7.8 Hz, 2 H, CONH), 7.54
= 168.1 (CO), 145.7, 141.7, 129.7, 128.6, 127.8, 123.6
- 7.23 (m, 12 H, Ar-H), 5.26 (m, 2 H, NCH), 1.56 (d, (Ar-C), 69.1 (OCH), 39.4 (SCH), 35.9 (SCH), 23.0, 22.6,
3J = 7.6 Hz, 6 H, CH3). – 13C 1H NMR (50.32 MHz, 21.8 (CH3). – MS (EI): m/z (%) = 312 (100) [M]+, 269
DMF-D7): = 168.7 (CONH), 145.2, 136.8, 133.3, 129.0, (12) [M-C3H7]+, 253 (17) [M-OC3H7]+, 209 (42), 195
127.4, 126.8, 125.0 (Ar-C), 49.8 (NCH), 22.6 (CH3). – (64), 41 (37). – C16H24O2S2 (312.48): calcd. C 61.50, H
MS (EI): m/z (%) = 436 (10) [M]+, 335 (14), 106 (100). – 7.74, S 20.52; found C 61.79, H 7.70 S 20.23.
C24H24N2O2S2 (436.58): calcd. C 66.03, H 5.54, N 6.42,
S 14.69; found C 66.29, H 5.21, N 6.35, S 14.82.
Preparation of alcohol 8: A sample of 7 (500 mg,
1.76 mmol) was dissolved in diethyl ether (20 ml) and
Preparation of ester 7: Two drops of N,N-dimethyl- added dropwise to a suspension of LiAlH4 (67 mg,
formamide and thionyl chloride (0.5 ml) were added to a 1.76 mmol) in diethyl ether (10 ml). The reaction mixture
solution of 2a (1.0 g, 3.7 mmol) in chloroform (5 ml). The was stirred at ambient temperature for 12 h. Hydroly-
reaction mixture was heated under reflux conditions for sis with water and sulfuric acid resulted in the forma-
3 h and allowed to cool to ambient temperature. Volatiles tion of two phases. The organic phase was separated,
were removed in vacuo. The reaction product was re- washed with aqueous NaHCO3 solution (20 ml) and wa-
dissolved in pyridine (5 ml) and isopropanol (10 ml) ter (20 ml), and dried over MgSO4. Removal of the sol-
was added. After being stirred for 12 h, the mixture vent and column chromatography (SiO2, eluant: diethyl
was poured into water (50 ml) and extracted with di- ether / petrol ether 1 : 3) afforded 8 as a colorless oil
ethyl ether (3
20 ml). The organic phase was dried (360 mg, 1.40 mmol, 80 %). The analytical data were
over MgSO4. Removal of the solvent and column chro- identical to those of the product prepared by reaction
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1408
H. V. Huynh et al. · ortho-Lithiation of Benzene-1,2-dithiol
of lithium 2,3-bis(isopropylmercapto)benzene and para- SHELXL [15]. Hydrogen atoms were added to the struc-
formaldehyd [8d].
ture models in calculated positions and were allowed
to refine as riding atoms. ORTEP [16] was used for
all drawings. The correct enantiomer of 4 was deter-
mined based on a Flack parameter of –0.08(14). Addi-
tional data collection and refinement details are listed
in Table 2. Crystallographic data (excluding structure
factors) for the structures reported in this paper have
been deposited with the Cambridge Crystallographic Data
Centre as supplementary publication no. CCDC 194105
- 194109. Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cam-
bridge, CB2 1EZ, UK (Fax: (+44) 1223-336033; e-mail:
deposit@ccdc.ac.uk).
X-ray crystallography: Data were collected on an
Enraf-Nonius KappaCCD, on a Bruker AXS APEX or
on an Enraf-Nonius CAD4 diffractometer. Both area de-
tector systems are equipped with rotating anodes, the
CAD4 system with a sealed tube. All data sets except
for 3b, where Cu-K radiation was applied, were mea-
sured with Mo-K radiation. Empirical absorption cor-
rections were applied on the basis of multiple intensity
measurements utilizing the programs SORTAV [12] and
SADABS [13]. All structures were solved by direct meth-
ods with SHELXS [14] and were refined with anisotropic
thermal parameters for non-hydrogen atoms using
R. Jones, I. K. Dhawan, J. H. Enemark, M. L. Kirk,
Inorg. Chem. 38, 1401 (1999).
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