A convergent approach to (R)-Tiagabine by a regio- and stereocontrolled hydroiodination of alkynes

Article abstract of DOI:10.1039/c005042c

The occurrence of unsaturated systems in natural products combined with the mildness and the wide range of applicability of CeCl₃ promoted methodologies suggest several potential future synthetic applications within the field of total synthesis of biologically active molecules. On this concept, the use of CeCl₃·7H₂O-NaI system as an efficient heterogeneous promoter has been highlighted in the iodofunctionalization of carbon-carbon triple bonds. The study has shown that this method would be particularly interesting for the stereoselective formation of trisubstituted (Z)- or (E)-iodoalkenes by simply changing the nature of the solvent. The methodology has been successfully applied to the synthesis of (R)-1-[4,4-bis-(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid 1, named (R)-Tiagabine, which is a potent and selective γ-aminobutyric acid (GABA) uptake inhibitor with proven anticonvulsant efficacy in humans. The Royal Society of Chemistry 2010.

Full text of DOI:10.1039/c005042c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
A convergent approach to (R)-Tiagabine by a regio- and stereocontrolled
hydroiodination of alkynes†
Giuseppe Bartoli,a Roberto Cipolletti,b Giustino Di Antonio,b,c Riccardo Giovannini,c Silvia Lanari,b
Mauro Marcolinib and Enrico Marcantoni*b
Received 13th April 2010, Accepted 21st May 2010
First published as an Advance Article on the web 9th June 2010
DOI: 10.1039/c005042c
The occurrence of unsaturated systems in natural products combined with the mildness and the wide
range of applicability of CeCl3 promoted methodologies suggest several potential future synthetic
applications within the field of total synthesis of biologically active molecules. On this concept, the use
of CeCl3·7H2O–NaI system as an efficient heterogeneous promoter has been highlighted in the
iodofunctionalization of carbon–carbon triple bonds. The study has shown that this method would be
particularly interesting for the stereoselective formation of trisubstituted (Z)- or (E)-iodoalkenes by
simply changing the nature of the solvent. The methodology has been successfully applied to the
synthesis of (R)-1-[4,4-bis-(3-methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid 1, named
(R)-Tiagabine, which is a potent and selective g-aminobutyric acid (GABA) uptake inhibitor with
proven anticonvulsant efficacy in humans.
Compound 1, named (R)-Tiagabine (Fig. 1), is a GABA uptake
Introduction
inhibitor marketed for the treatment of epilepsy.8 It is known that
thiophene derivatives show numerous biological activities9 and
are of potential pharmacological significance,10 consequently our
attention was focused on a convergent synthesis of 1. Furthermore,
a series of cyclic amino acids and their derivatives which have
diheteroaryl vinyl functions such as (R)-Tiagabine, have been
found to inhibit key functional components of g-amino butyric
acid (GABA) in the mammalian central nervous system (CNS).11
The observations of using these compounds as the basis for
the design of new centrally-acting drugs have also stimulated
investigations of their synthesis.12 The overall strategy used for the
preparation of the 4,4-diaryl/diheteroaryl butenyl structural class
shows the major limitation in using hard conditions and reagents
that are expensive and sensitive to air.13 In order to further research
on the biological activities of Tiagabine analogues, a new and more
practical synthetic route would be useful.
Trisubstituted alkenes have been and continue to be highly
significant organic compounds with biological activity. A large
number of compounds having biological and pharmaceutical
activity incorporate this moiety, and a plethora of methods for the
synthesis of this valuable fragment is known in organic chemistry.1
Recent years have witnessed the wide development of palladium
catalyzed C(sp2)–carbon bond-forming reactions, in large part due
to typically mild reaction conditions, the ease of preparation of a
wide range of coupling partners, and the tolerance of a wide variety
of sensitive functionalities in this transformation.2 In particular,
the Pd-catalyzed coupling processes of alkenyl halides and related
compounds have become a central tool for the synthesis of
biologically active compounds both in academia and industry.3
Today, the Pd-catalyzed cross-coupling reactions of boronic acids
with organic halides, known as Suzuki–Miyaura couplings,4
may be frequently applied in the industrial manufacture of fine
chemicals and pharmaceuticals.5 One of the most remarkable
applications of the Suzuki reaction in biological active products
synthesis is found in the synthesis of polytoxin by Kishi and
coworkers.6 In continuation of the work of some of us on the
synthesis of molecule targets with biological activity,7 we report
herein a demonstration of the utility of the Suzuki reaction by
a simple and convergent synthetic approach for (R)-1-[4,4-bis-(3-
methyl-2-thienyl)-3-butenyl]-3-piperidinecarboxylic acid (1).
Fig. 1 Structure of (R)-Tiagabine.
aDepartment of Organic Chemistry “A. Mangini”, University of Bologna,
viale Risorgiment 4, I-40136 Bologna, Italy
bSchool of Science and Technology, Chemistry Division, University of
Camerino, via S. Agostino 1, I-62032 Camerino (MC), Italy. E-mail: enrico.
marcantoni@unicam.it; Fax: +39 0737 402297
In the present work, not only a robust linear approach allowing
exclusive formation of the desired (R)-Tiagabine (1) has been
described, but also the ability of CeCl3·7H2O to promote the regio-
and diastereoselective addition to carbon–carbon triple bonds
by selective coordination to p-electrons of alkynes for obtaining
multifunctionalized trisubstituted alkenes.
cChemistry Research Centre, Boehringer-Ingelheim S.p.A., via Lorenzini 8,
I-20139 Milano, Italy
† Dedicated to Prof. Goffredo Rosini, University of Bologna, on the
occasion of his 70th birthday
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internal alkenyl iodides are scarcely obtained and difficulties
in handling vinyl-metal species detract from the utility of this
method.22 Hydroiodination via in situ generation of hydrogen
iodide has also been reported.23 This strategy uses expensive
reagents and harsh conditions, and only gives satisfactory results
when starting from symmetric internal alkynes (R1 = R2 in 9).
Accordingly, these drawbacks have stimulated the search for better
catalysts that could be superior to the existing ones with regard to
selectivity and handling of reagents.
Studies by us and by others have resulted in the development
of methodologies involving the CeCl3·7H2O–NaI system for
providing new means for promoting organic transformations in
a variety of systems.24 The commercially available reagents such
as CeCl3·7H2O and NaI can be used in combination without any
special caution.25 The CeCl3·7H2O–NaI system acts as a Lewis
acid that activates multiple bonds via p-binding and the new bond-
forming reactions proceed through an interaction between Ce(III)
and C–C multiple bond.26 Recently, Silveira and coworkers have
reported the first methodology of hydrochalcogenation of terminal
alkynes promoted by CeCl3.27 In the light of this background that
we have studied a convenient procedure for transforming alkynes
9 into the corresponding alkenyl iodides10 using the CeCl3·7H2O–
NaI system.
Results and discussion
A very broadly applicable strategy for the preparation of trisub-
stituted alkenes in a stereoselective manner involves alkynes as a
valuable functional group.14 The stereoselective transformations
of alkynes for the preparation of functionalized alkenes have
emerged as powerful synthetic tools,15 thus, we have thought to
the functionalization of carbon–carbon triple bonds for installing
the dithienylvinyl moiety in the molecule target 1.
Retrosynthetic analysis reveals a route based on a convergent
approach as outlined in Scheme 1. We have devised that the alkenyl
thiophene derivative 3, the key compound for the Suzuki coupling,
could be introduced by hydrofunctionalization of alkyne 4. The
alkenyl triflates (X = OTf in compound 3) have been found to
be superior to alkenyl halides,16 but they are rather expensive and
their uses especially for the large-scale synthetic operation may
not be economical. Thus, in the cases of vinyl moieties, iodides,
and a lesser extension bromides, are commonly employed in the
Suzuki reaction. Alkenyl chlorides are known to be less reactive
than iodides or bromides, due to their slow oxidative addition
to palladium.17 Given that alkenyl iodides are generally more
desirable that their bromo or chloro analogs,18 there are a large
number of methods developed for hydroiodination of alkynes and
chemists continue to find ways to improve it.
The treatment of phenylacetylene (9a) with 1.0 molar equiv of
the CeCl3·7H2O–NaI system in acetonitrile was inefficient at room
temperature and moderate conversion into alkenyl iodide 10a was
obtained at reflux temperature. The results are summarized in
Table 1. By screening the various conditions we have observed
that the amounts optimized of CeCl3·7H2O and NaI used in the
reaction request a molar ratio of alkyne 9a, CeCl3·7H2O, and NaI
equal to 1 : 1.5 : 3. The use of a large excess of the CeCl3·7H2O–
NaI system afforded the alkenyl iodide adduct in significantly
lower yield. Analogously, with a reduction of the amount of
CeCl3·7H2O–NaI the process becomes slower and the hydroiodi-
nation is not complete even after prolonged reaction times. A va-
riety of solvents29 were investigated and the efficiency based on the
reaction conversion of 9a and yields of 10a is CH3CN > toluene ꢀ
CH2Cl2 > THF > EtOH > DMF. In the case of AcOEt as a more
inexpensive and environmental benign solvent than CH3CN, our
procedure gave, contrary to the resulted reported in literature,30
a
Scheme 1 Retrosynthesis of (R)-Tiagabine (1).
very low yield of adduct, and many side products were formed. The
procedure in acetonitrile is not accompanied by small amounts of
the hydrolysis product,31 and with almost exclusive regiocontrol
nucleophilic attack on the more substituted carbon atom. The
presence of CeCl3·7H2O has been found to be essential for the
reaction, because when the same reaction was carried out in the
absence of CeCl3·7H2O no hydroiodination took place.
In general, the direct conversion of substituted alkynes into
the desired alkenyl iodides by hydroiodination (Scheme 2) with
hydrogen iodide appears to be the most convenient method, but
often leads to low yields, and side reactions due to uncontrollable
iodine liberation.19 More convenient is the sequential reaction
of hydrometalation of various metal hydrides such as Schwartz’s
reagent to alkynes followed by demetalation with iodine.20 Mild-
ness of the reaction conditions makes it useful to prepare 1-iodo-1-
alkenes (R1 = H in 10) in an anti-Markovnikov fashion.21 However,
Having established what appeared to be the promoting pathway
of the solid CeCl3·7H2O, we switched our attention to the water of
crystallization in the cerium(III) salt. The selection of hydrated
Ce(III) salt plays a crucial role in the ability of the system to
promote region- and stereoselective hydroiodination of alkynes,
and it seemed appropriate to investigate the source of the vinyl
hydrogen in our reaction. In fact, the reaction of 9a works only
32
in the presence of hydrated CeCl3, while with dry CeCl3 in dry
acetonitrile no hydroiodination product 10a was detected. When
the reaction was repeated with <1 equiv of water,33 decreased
activity was observed and the alkenyl iodide 10a was obtained
in a yield less than 60%. In addition, with 4 equiv of water,
Scheme 2 Hydroiodination reaction of alkynes.
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Table 1 Hydroiodination of alkynes 9a–l by CeCl3·7H2O (1.5 eq) and NaI (3.0 eq) in CH3CN under reflux conditions
Entrya
R1
R2
Alkyne
Time/h
Yield (%)b
Alkenyl Iodidec
Z/Ed)
1
2
3
4
C6H5
H
H
H
H
H
H
CH3
CH3
CH(CH3)2
CH(CH3)2
COOCH3
COCH3
COCH3
CH2OH
CH2OCOPh
CH2OCOPh
9a
9b
9c
9d
9e
9f
9g
9g
9h
9h
9i
24
20
14
30
45
24
24
24
24
24
14
16
16
24
24
24
90
95
95
82
75
90
90
55
82
79
93
84
10a
10b
10c
10d
10e
10f
10g
10g
10h
10h
10i
—
—
—
—
—
—
11g
11g
11h
11h
—
2-CH3C6H4
2-CH3OC6H4
4-BrC6H4
4-CF3C6H4
C6H5CH2CH2
C6H5
C6H5
C6H5
C6H5
H
C6H5
C6H5
CH3
CH3
5
6
7e
95 : 05
20 : 80
92 : 08
16 : 84
99 : 01
96 : 04
11 : 89
8f
9
10f
11
12
13 f
14
15e
16f
9j
10j
11j
11j
9j
82
10j
9k
9l
mixture of products28
79
57
10l
10l
11l
11l
99 : 01
99 : 01
CH3
9l
a All reactions were carried out by stirring mixtures of alkyne 9 and CeCl3·7H2O–NaI system in acetonitrile (10 mL mmol-1 of alkyne) for the selected
reaction times. b Yields of products isolated by flash chromatography. c All products were identified by their IR, NMR, and GC-MS spectra. d Calculated
Z/E ratio on the mixture of diastereomers isolated by column chromatography. e Regiosomer ratio by NMR: 10g : 11g (90 : 10 in acetonitrile and 97 : 03
in toluene); 10l : 11l (92 : 08 in acetonitrile and 85 : 15 in toluene). f The reaction was carried out in the same conditions but using toluene as solvent.
Table 2 Hydroiodination of 9a promoted by various hydrated Lewis
essentially identical results were obtained as with the cerium salt
heptahydrate. Thus, in our hydroiodination reaction which gave
(Z)-alkenyl iodides, the iodine and the vinyl hydrogen add to the
alkyne in a trans-fashion and the vinyl hydrogen comes from the
hydroxyl group of water. To obtain further evidence to confirm
the source of the vinyl hydrogen in our reaction, we have carried
out the reaction by using dry CeCl3 and adding D2O instead
of H2O.34 By NMR and MS techniques after quenching of the
reaction mixture we observed deuterium incorporation at vinyl-
position (Scheme 3). This deuteration experiment would strongly
support the effective participation by the water as the source of
the vinyl hydrogen.
acidsa
Lewis acid
Yield (%)b
Lewis acid
Yield (%)b
CeCl3·7H2O
90
60
64
47
25
InBr3
33
40
45
CeBr3
Yb(OTf)3
LaCl3·7H2O
La(NO3)3·6H2O
TiCl4
c
CeI3
Ce(OTf)3
InCl3
38
Traced
a Conditions: Lewis acid, substrate 9a, and NaI were mixed in acetonitrile
(10 mL mmol-1 of alkyne 9a), and stirred at reflux for 24 h. b Yields of
products isolated. c CeI3 is not able to promote hydroiodination in the
absence of NaI. d Starting material was recovered after reaction.
of the thermodynamically more stable isomer (Z)-10. The stere-
ochemistry was confirmed by NOESY-1D experiments,40 which
revealed key correlations between vinyl protons and protons in
vinyl substituents as shown in Fig. 2. The selective formation
of the (Z)-10 isomer would require that the species [H]+ and
[I]- are donated by different molecules in a stepwise process. A
possible reaction mechanism, depicted in Scheme 4, may involve
the following steps: (i) coordination of the alkynyl moiety of 9 to
the Ce(III) salt gives the complex A; (ii) the complex A may form
an organocerium intermediate B or C by the nucleophilic attack of
iodide anion; (iii) rapid protodemetalation,41 by coordinated water
molecules on the surface, which serve as hydrogen donors, affords
products 10 with high diastereoselectivity. In a non polar solvent
such as toluene (Table 1, entries 8, 10, and 13) transfer of iodide
anion to the complex A, in competition with diffusion, occurs
rapidly through path a and affords predominantly the syn addition
products (E-configuration). In contrast, in polar solvents such as
CH3CN the solvation free energy stabilizes the separate ions and
the change in mechanism may be due to a slower addition of iodide
anion and subsequent formation of the thermodynamically more
stable (Z)-isomers (path b).42 As confirmation of this, noteworthy
are the results 15 and 16 in Table 1 indicating the presence of an
intramolecular coordination in the mixture of the two possible
Scheme 3 Deuteration experiment with 9a.
It should be to noted that the mixture might at the end just form
HI in situ, but in the presence of a strongly hindered base such as
2,6-di-tert-butyl-4-methylpyridine, which only binds to HI without
deactivating the CeCl3·7H2O–NaI system,35 the methodology has
afforded alkenyl iodides 10 in high yield and with absolutely purity.
This investigation aimed at confirming the exception of a Brønsted
acid pathway in our procedure. Thus, not only does our Lewis
acid system perform best in the presence of water,36 but also its
promoting activity is amplified by the water. This effect is taken as a
proof-of-principle that substrate interaction cerium(III) Lewis acid
species and water are not mutually exclusive.37 Finally, different
Lewis acids proved to be less effective affording the corresponding
alkenyl iodide product in lower yield (Table 2).38
The methodology tolerates alkyl-, aryl- and heteroaryl-
substituents on the alkyne moiety, and in the case of internal
alkynes (R1 and R2 π H) the hydroiodination proceeds in a
highly strereoselective manner,39 with the preferential formation
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Scheme 4 Proposed reaction mechanism.
reaction with terminal acetylene 6. This intermediate was easily
prepared by conversion of 3-methyl-2-thiophenecarboxaldehyde
commercially available by the procedure of Corey and Fuchs45
followed by treatment with n-butyllithium.46 Unfortunately, it was
found that in classical Sonogashira reaction conditions terminal
acetylene 6 undergoes a homo-coupling reaction in the presence
of a copper(I) halide catalyst, known as the Glaser reaction.47
The homo-coupling product was the major product instead of
the desired disubstituted product 4 even using ultrapure nitrogen
as the protection gas. The use of hydrogen gas as a reducing
reagent48 or under copper-free Sonogashira reaction conditions49
provide the desired product 4 in more than 15% yield as part
of a complicated mixture. After numerous unsuccessful attempts,
it sounds clear that this procedure would not be effective for
alkyne 4. Thus, we have thought to change synthetic strategy
from C(sp)–C(sp3) Sonogashira coupling reaction to C(sp2)–C(sp)
bond-forming reaction to avoid the homo-coupled byproduct.
Treatment of 8 (Scheme 5) with 3-butyn-1-ol in the presence
of catalytic 10% Pd/C and CuI and ethanolamine in water at
80 ◦C afforded the 2-thienylbutynyl alcohol derivative 12 in good
yield (Scheme 4). Subsequent bromination of the alcohol 12 with
CBr4 and PPh3 furnished bromide 13 in 88% yield. Finally, The
heteroaryl substituted compound 13, after purification, reacted
Fig. 2 Stereochemistry assigned by nOe studies.
regioisomers, and the corresponding vinyl iodide (Z)-10l was
isolated in high selectivity, irrespective of the solvent (acetonitrile
or toluene) chosen. Unfortunately, no anti-iodoceration species
could be discerned from the 1H NMR and 13C NMR, due,
very probably, to the presence of paramagnetic Ce(III) species.43
However, preliminary study by employment of an online ESI-
MS technique44 in the positive ion mode, allowed us to suggest
species that contain a cerium–carbon bond. A complete study on
the mechanistic aspects of the activation of carbon–carbon triple
bonds by Ce(III) salts that will provide experimental evidence for
the formation of organocerium species, will be reported in due
course.
With an efficient procedure in hand for obtaining alkenyl iodide
3, we decided to explore the synthetic application of alkyne 4.
The facility to obtain the bromide 5 by alkylation of the (R)-
enantiomer of ethyl nipecotate under mildly basic conditions using
2-bromoethanol,12c suggested to us the Sonogashira coupling
Scheme 5 Convergent synthesis of (R)-Tiagabine.
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with (R)-ethyl nipecotate to afford the ester 4. In the key step,
alkenyl iodide 14 was formed in 94% yield with 99% Z-selectivity
by applying our procedure to alkynyl compound 4. With the
core unit in hand, the palladium-catalyzed Suzuki coupling with
3-methyl-2-thienylboronic acid gave the N-alkylated amino acid
ester derivative 15. Hydrolysis under basic conditions provided
the free acid which was isolated as its crystalline hydrocholoride
salt 16, more stable than free-amine (with high optical and LC
chromatography purity).
All air-sensitive reactions are carried out in flame dried
glassware under an atmosphere of dry nitrogen. Solvents were
distilled under nitrogen, tetrahydrofuran (THF) from sodium
benzophenone ketyl and dichloromethane (CH2Cl2) from calcium
hydride. Solutions were evaporated under reduced pressure with
a rotary evaporator and the residue was chromatographed on a
Baker silica gel (230–400 mesh) column using ethyl acetate in
hexane as the eluent. Analytical thin layer chromatography was
performed using pre-coated glass-backed plates (Merck Kieselgel
60 F254) and visualized by UV light (254 nm) and/or by dipping
the plates into Von’s reagent (1.0 g of ceric sulfate and 24.0 g of
ammonium molybdate in 31 mL of sulfuric acid and 470 mL of
water).
Conclusion
Following the convergent strategy as described in this work, it has
been possible to synthesize diheteroalkenyl compounds, and in
particular the strategy was efficiently applied for the preparation
of (R)-Tiagabine (1). The strategy introduced herein has three key
points which make it considerably more useful in comparison to
the procedure reported so far: (i) the synthetic route is brief and
conveniently produces the target compound from easily accessible
starting materials, (ii) the desired biologically active trisubstituted
alkenes were prepared by palladium-catalyzed coupling reactions
without homo-coupled byproducts, and (iii) our procedure will
be able to have the possibility of being used in the synthesis of
diaryl vinyl functions with different aryl groups and to obtain
molecules with an improved potency and pharmacological profile
than (R)-Tiagabine.
With regard to the effectiveness of the CeCl3·7H2O–NaI system
in promoting organic transformations, the results obtained in
this study support the important role that this Lewis acid plays
in the synthesis of biologically active molecules. Our procedure
of hydroiodination of substituted alkynes would be particularly
interesting for the reason that it would allow the stereoselective
formation of trisubstituted (Z)- or (E)-iodoalkenes by simply
changing the polarity of the solvent. Further utilization of this
flexible methodology in the synthesis of other biologically active
compounds will be reported in due course.
General experimental procedure for alkenyl iodide synthesis
To a stirred suspension of alkyne 9a–l (1 mmol) and sodium
iodide (0.45 g, 3.0 mmol) in 15 mL of the appropriate solvent
(Table 1) was added cerium(III) chloride heptahydrate (0.56 g,
1.5 mmol), and the resulting mixture was stirred at reflux until the
disappearance of the starting alkyne. The reaction progress was
monitored by withdrawing aliquots, which were analyzed by GC
or TLC analysis, and the products were identified by GC-MS. The
reaction mixture was diluted with ether and treated with 0.5 N HCl
(15 mL). The organic layer was separated, and the aqueous layer
was extracted with ether (4 ¥ 25 mL). The combined organic layers
were washed with 10% NaHCO3 solution (2 ¥ 15 mL), with 10%
Na2S2O3 solution (1 ¥ 10 mL) and brine and dried over anhydrous
Na2SO4. Solvent was removed by rotary evaporation and the crude
product was purified by silica gel chromatography using hexane as
eluent to give the corresponding alkenyl iodide 10a–l.
1-(1-Iodoethenyl)benzene (10a)50. Colorless oil (yield 90%): IR
(neat) n 3057, 1559, 1487, 896, 767, 697 cm-1; 1H NMR (400 MHz)
d = 7.34-7.28 (m, 3H, Arom.), 7.53-7.48 (m, 2H, Arom.), 6.47 (d,
1H, J = 1.7 Hz), 6.10 (d, 1H, J = 1.7 Hz); 13C NMR (100 MHz)
d = 140.3, 127.0, 126.5, 125.9, 120.9, 102.3; EI-MS m/z = 230
[M+], 127, 103 (100) [M+ - I], 77, 51, 39.
1-(1-Iodoethenyl)-2-methylbenzene (10b). Colorless oil (yield
95%): IR (neat) n 3062, 1618, 1455, 905, 763, 627 cm-1; 1H NMR
(200 MHz) d = 7.30-7.23 (m, 4H, Arom.), 6.23 (d, 1H, J = 1.4 Hz),
6.18 (d, 1H, J = 1.4 Hz), 2.44 (s, 3H); 13C NMR (50 MHz) d =
140.9, 132.9, 128.1, 127.2, 125.9, 124.8, 122.6, 104.2, 21.3; EI-MS
m/z = 244 [M+], 127, 117 (100) [M+ - I], 115, 91, 65, 51, 39. Anal.
C9H9I requires: C, 44.29; H, 3.72%; found: C, 44.25; H, 3.58%.
Experimental
1H NMR spectra were recorded in CDCl3 on Varian Gemini 200
or Varian 400 spectrometers and are reported as follows: chemical
shift, d (ppm) [number of protons, multiplicity, and coupling
constant J (Hz)]. Residual protic solvent CHCl3 (dH = 7.26 ppm)
was used as the internal reference. 13C NMR spectra were recorded
in CDCl3 at 50 MHz or 100 MHz on Varian Gemini 200 or Varian
400 spectrometers, using the central resonance of CDCl3 (dC = 77.0
ppm) as the internal reference. The 13C NMR peaks were assigned
by standard methods using HMQC and DEPT experiments.
Z/E Assignments were based on nOe studies. Mass spectra were
recorded on a gas chromatography with a mass-selective detector,
utilizing electron ionization (EI) at an ionizing energy of 70 eV
or on a LC-MS utilizing an electrospray ionization (ESI) source.
Microanalyses were performed with a EA1108 CHNS-D Fisons
Instrument. Optical rotations were recorded on a polarimeter with
a path length of 1 dm and are given in units of 10-1 deg cm2 g-1.
Concentrations are quoted in g/100 mL. Melting points were
determined in open capillary tubes on a Bu¨chi 535 melting point
apparatus and are uncorrected.
1-(1-Iodoethenyl)-2-methoxybenzene (10c)51. Colorless oil
(yield 95%): IR (neat) n 3038, 1600, 1459, 1251, 1041, 902,
1
750 cm-1; H NMR (400 MHz) d = 7.33-7.25 (m, 2H, Arom.),
6.95-6.87 (m, 2H, Arom.), 6.30 (d, 1H, J = 1.0 Hz), 6.18 (d, 1H,
J = 1.0 Hz), 3.90 (s, 3H); 13C NMR (100 MHz) d = 190.1, 128.3,
125.9, 122.5, 121.0, 120.5, 112.3, 104.8, 61.5; EI-MS m/z = 260
[M+], 133 (100) [M+ - I], 127, 118, 105, 89, 77, 51, 39. Anal.
C9H9IO requires: C, 41.56; H, 3.49%; found: C, 41.53; H, 3.44%.
1-(1-Iodoethenyl)-4-bromobenzene (10d)52. Pale yellow oil
(yield 80%): IR (neat) n 3086, 1583, 1485, 1077, 892, 793 cm-1;
1H NMR (200 MHz) d = 7.48-7.27 (m, 5H, Arom.), 6.47 (d, 1H,
J = 1.9 Hz), 6.10 (d, 1H, J = 1.9 Hz); 13C NMR (50 MHz) d =
140.2, 129.9, 129.1, 127.6, 122.5, 105.2; EI-MS m/z = 310 and
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308 [M+], 183 and 185 (100) [M+ - I], 127, 102, 75, 63, 51. Anal.
C8H6BrI requires: C, 31.10; H, 1.96%; found: C, 31.07; H, 1.93%.
[M+ - I], 129, 127, 102, 76, 51, 43 (100). Anal. C10H9IO requires: C,
44.14; H, 3.33%; found: C, 44.10; H, 3.28%. The major isomer in
acetonitrile was identified as iodide (Z)-10j: 1H NMR (400 MHz)
d = 7.53-7.50 (m, 2H, Arom.), 7.37-7.35 (m, 3H, Arom.), 6.99 (s,
1H), 2.36 (s, 3H); 13C NMR (100 MHz) d = 200.8, 143.0, 135.8,
128.7, 127.4, 126.4, 105.1, 44.3. The major isomer in toluene was
1-(1-Iodoethenyl)-4-(trifluoromethyl)benzene (10e)52. Pale yel-
low oil (yield 75%): IR (neat) n 3077, 1594, 1409, 1055, 849,
1
790 cm-1; H NMR (400 MHz) d = 7.60 (d, 2H, J = 1.1 Hz,
Arom.), 6.42 (d, 1H, J = 1.9 Hz), 6.07 (d, 1H, J = 1.9 Hz); 13C
NMR (100 MHz) d = 159.7, 135.2, 130.3, 128.6, 128.0, 127.6,
126.8, 121.7, 120.3, 117.3, 114.0, 11.7, 104.6, 60.1; EI-MS m/z =
286 [M+], 159 (100) [M+ - I], 140, 127, 75, 65, 51, 39. Anal. C9H6F3I
requires: C, 34.85; H, 5.85%; found: C, 32.20; H, 6.12%.
1
identified as iodide (E)-10j: H NMR (400 MHz) d = 7.68-7.65
(m, 2H, Arom.), 7.44-7.42 (m, 3H, Arom.), 7.04 (s, 1H), 2.45 (s,
3H); 13C NMR (100 MHz) d = 200.2, 137.2, 133.5, 128.6, 128.0,
126.9, 101.5, 44.5.
(Z)-3-Iodo- and (Z)-2-iodo-2-butenylbenzoate (10l and 11l)58.
Colorless oil (yield 79%), which was determined by H NMR
1-(3-Iodo-3-butenyl)benzene (10f)53. Pale red oil (yield 90%):
IR (neat) n 3039, 3016, 1595, 1422, 1027, 985, 722 cm-1; 1H
NMR (400 MHz) d = 7.37-7.31 (m, 2H, Arom.), 7.28-7.19 (m,
3H, Arom.), 5.97 (d, 1H, J = 1.9 Hz), 5.70 (d, 1H, J = 1.9 Hz),
2.85 (t, 2H, J = 6.9 Hz), 2.68 (t, 2H, J = 7.0 Hz); 13C NMR
(100 MHz) d = 135.3, 128.6, 126.9, 126.0, 119.7, 105.1, 45.7, 39.3;
EI-MS m/z = 258 [M+], 131 (100) [M+ - I], 127, 91, 77, 65, 51,
39. Anal. C10H11I requires: C, 46.54; H, 4.30%; found: C, 46.57;
H, 4.29%.
1
analysis to be an 92 : 08 mixture of 3-iodo-2l and 2-iodo-2l: IR
(neat) n 3049, 1731, 1596, 1214, 1129, 772, 618 cm-1; EI-MS m/z =
175 [M+ - I], 127, 105 (100), 77, 51, 39. The major isomer was
1
identified as (Z)-3-iodo-10l: H NMR (400 MHz) d = 8.06-8.04
(m, 2H, Arom.), 7.58-7.46 (m, 1H, Arom.), 7.45-7.42 (m, 2H,
Arom.), 5.90-5.87 (m, 1H), 4.85 (d, 1H, J = 1.3 Hz), 4.83 (d, 1H,
J = 1.3 Hz), 2.58 (d, 3H, J = 1.3 Hz); 13C NMR (100 MHz)
d = 166.5, 133.4, 133.2, 129.9, 129.7, 128.5, 104.7, 69.3, 34.0.
The minor isomer was identified as (Z)-2-iodo-11l: 1H NMR
(400 MHz) d = 8.06-8.04 (m, 2H, Arom.), 7.58-7.46 (m, 1H,
Arom.), 7.45-7.42 (m, 2H, Arom.), 6.13-6.08 (m, 1H), 5.01 (d,
2H, J = 1.3 Hz), 1.83 (d, 3H, J = 6.4 Hz); 13C NMR (100 MHz)
d = 166.3, 135.2, 130.1, 128.6, 128.5, 102.1, 72.4, 21.8.
(Z)- and (E)-1-(1-Iodo-1-propenyl)benzene (10g)54. Pink liquid
(yield 90%), which was determined by 1H NMR analysis to be an
95 : 05 mixture of iodides (Z)- and (E)-10g: IR (neat) n 3056, 1681,
1487, 1441, 851, 753, 693, 627 cm-1; EI-MS m/z = 244 [M+], 127,
117 (100) [M+ - I], 102, 91, 76, 63, 51, 39. Anal. C9H9I requires: C,
44.29; H, 3.72%; found: C, 44.25; H, 3.70%. The major isomer in
acetonitrile was identified as iodide (Z)-10g: 1H NMR (200 MHz)
d = 7.58-7.53 (m, 2H, Arom.), 7.45-7.33 (m, 3H, Arom.), 6.06 (q,
1H, J = 6.6 Hz), 2.05 (d, 3H, J = 6.6 Hz); 13C NMR (50 MHz) d =
137.9, 131.4 128.3, 126.2, 125.8, 105.2, 20.2. The major isomer in
toluene was identified as iodide (E)-10g: 1H NMR (200 MHz) d =
7.44-7.31 (m, 5H, Arom.), 6.67 (q, 1H, J = 7.2 Hz), 1.72 (d, 3H,
J = 7.2 Hz); 13C NMR (50 MHz) d = 139.0, 129.7, 128.2, 126.5,
126.2, 103.1, 15.8.
Convergent synthesis of (R)-Tiagabine
2-Iodo-3-methylthiophene (8)
To a solution of commercially available of 3-methylthiophene (3 g,
30.61 mmol) in benzene (10 mL) were added in small portions
merc◦uric oxide (6.12 g, 28.30 mmol) and iodine (7.95 g, 31.4 mmol)
at 0 C. The mixture was stirred at room temperature for 0.5 h,
and the precipitate was filtered and washed with ether. The filtrate
and washings were washed with aqueous Na2S2O3 and dried over
Na2SO4. The solvent was removed by rotary evaporation, and the
crude product was purified by column chromatography of silica gel
and hexane as eluent to provide 5 g (yield 73%) of the title product
8 as a pale-red liquid: IR (neat) n 3029, 1374, 1211, 1093, 961,
825, 737 cm-1; 1H NMR (400 MHz) d = 7.35 (d, 1H, J = 5.6 Hz),
6.76 (d, 1H, J = 5.5 Hz), 2.23 (s, 3H); 13C NMR (50 MHz) d =
142.8, 130.3, 129.1, 74.6, 18.2; EI-MS m/z = 224 [M+], 127, 97
(100) [M+ - I], 69, 53, 45. Anal. C5H5IS requires: C, 26.80; H, 2.25;
S, 14.31%; found: C, 26.77; H, 2.19; S, 14.29%.
(Z)- and (E)-1-(1-Iodo-3-methyl-1-butenyl)benzene (10h)55.
1
Colorless oil (yield 82%), which was determined by H NMR
analysis to be an 92 : 08 mixture of iodides (Z)- and (E)-10h: IR
(neat) n 3056, 1625, 1442, 755, 616 cm-1; EI-MS m/z = 272 [M+],
145 (100) [M+ - I], 129, 127, 117, 91, 77, 51, 39. Anal. C11H13I
requires: C, 48.55; H, 4.82%; found: C, 48.51; H, 4.79%. The
1
major isomer in acetonitrile was identified as iodide (Z)-10h: H
NMR (200 MHz) d = 7.51-7.29 (m, 5H, Arom.), 5.72 (d, 1H, J =
8.4 Hz), 2.80-2.70 (m, 1H), 1.15 (d, 6H, J = 6.6 Hz); 13C NMR
(50 MHz) d = 142.7, 139.1, 128.6, 127.3, 125.9, 100.1, 29.5, 20.3.
The major isomer in toluene was identified as iodide (E)-10h: 1H
NMR (200 MHz) d = 7.51-7.29 (m, 5H, Arom.), 6.35 (d, 1H, J =
10.2 Hz), 2.38-2.30 (m, 1H), 1.00 (d, 6H, J = 6.6 Hz); 13C NMR
(50 MHz) d = 148.3, 143.0, 128.4, 126.9, 125.7, 99.0, 23.7, 20.5.
4-(3-Methyl-2-thienyl)-3-butyn-1-ol (12). A mixture of 2-
iodo-3-methylthiophene (8) (1.5 g, 6.69 mmol), 10% Pd/C
(0.174 mmol), PPh3 (0.35 g, 1.34 mmol), CuI (0.064 g, 0.335 mmol)
and ethanolamine (1.22 g, 20.07 mmol) in water (40 mL) was
stirred at 25 ◦C for 30 min under nitrogen. The 3-butyn-1-ol
(0.70 g, 10.03 mmol) was added, and the mixture was initially
Methyl (Z)-3-iodo-2-propenoate (10i)56. Pale yellow oil (yield
1
93%): IR (neat) n 3025, 1728, 1597, 1205, 1166 cm-1; H NMR
(200 MHz) d = 7.39 (d, 1H, J = 8.8 Hz), 6.81 (d, 1H, J = 8.8 Hz),
3.66 (s, 3H); 13C NMR (50 MHz) d = 164.2, 129.5, 95.0, 52.3;
EI-MS m/z = 212 (100) [M+], 181, 153, 127, 85, 59, 53, 29.
(Z)- and (E)-4-Iodo-phenyl-3-buten-2-one (10j)57. Pink liquid
(yield 84%), which was determined by 1H NMR analysis to be an
96 : 04 mixture of iodides (Z)- and (E)-10j: IR (neat) n 3056, 1694,
1567, 1488, 1170, 975, 757, 693 cm-1; EI-MS m/z = 272 [M+], 145
◦
stirred at room temperature for 1 h and then at 80 C for 18 h.
After completion of the reaction, the mixture was cooled to
room temperature, diluted with ethyl acetate (50 mL), and filtered
through Celite. The organic layer was separated and the aqueous
layer was extracted with additional ethyl acetate (5 ¥ 25 mL), and
the combined organic phases were washed with water (2 ¥ 15 mL)
and brine (2 ¥ 15 mL), and dried over anhydrous Na2SO4. The
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solvent was removed and the crude residue was purified by column
chromatography on silica gel, using hexane–ethyl acetate (70 : 30)
to afford the desired 4-(3-methyl-2-thienyl)-3-butyn-1-ol (12) as
mass by filtration chromatography over a short plug of neutral
alumina using diethyl ether as solvent. The filtrate was washed
with aqueous 10% NaHCO3 solution, with aqueous 10% Na2S2O3,
and with saturated NaCl solution, and dried over Na2SO4. After
removal of the solvent in vacuo, the crude residue was further
purified by column chromatography over silica gel (90 : 10 hexane–
THF) to give 0.3 g (yield 94%) of the 99 : 01 mixture (Z)-14 and
(E)-14 as a pale red liquid: IR (neat) n 3028, 3021, 1731, 1600,
1200, 781, 624 cm-1; 1H NMR (400 MHz) d = 6.75-6.71 (m, 2H),
6.54 (t, 0.1 ¥ 1H, J = 10.4 Hz, (E)-isomer), 5.74 (t, 0.9 ¥ 1H,
J = 6.4 Hz, (Z)-isomer), 4.11-4.05 (m, 2H), 2.98-2.14 (m, 8H),
2.12 (s, 0.9 ¥ 3H), 2.02 (s, 0.9 ¥ 3H), 2.00-1.39 (m, 5H), 1.21 (t,
0.9 ¥ 3H, J = 6.8 Hz), 1.20 (t, 0.1 ¥ 3H, J = 6.8 Hz); 13C NMR
(100 MHz, Z/E mixture) d = 174.4, 146.4, 141.1, 141.0, 135.6,
134.8, 130.7, 130.4, 129.9, 124.9, 124.4, 123.9, 93.6, 85.6, 60.5,
57.3, 56.8, 55.6, 55.4, 53.7, 42.1, 42.0, 35.3, 30.3, 27.1, 24.8, 24.7,
15.2, 14.8, 14.4; EI-MS m/z = 306, 296, 170 (100), 142, 127, 99, 42.
Anal. C17H24INO2S requires: C, 47.12; H, 5.58; N, 3.23; S, 7.40%;
found: C, 47.09; H, 5.53; N, 3.20; S, 7.37%.
◦
white solid (1.0 g, yield 90%): m.p. 50–53 C; IR (nujol) n 3350,
1422, 1043, 831, 712 cm-1; 1H NMR (400 MHz) d = 7.06 (d, 1H,
J = 5.1 Hz), 6.78 (d, 1H, J = 5.1 Hz), 3.80 (t, 2H, J = 6.4 Hz), 2.72
(d, 2H, J = 6.0 Hz), 2.27 (s, 3H); 13C NMR (100 MHz) d = 142.1,
129.1, 125.1, 118.7, 92.7, 75.3, 61.1, 24.3, 15.0; EI-MS m/z = 166
[M+], 135 (100), 91, 77, 65, 51, 39. Anal. C9H10OS requires: C,
65.02; H, 6.06; S, 19.29%; found: C, 64.97; H, 6.03; S, 19.29%.
2-(4-Bromo-1-butynyl)-3-methylthiophene (13). To a solution
of 12 (0.65 g, 3.91 mmol) in dry CH2Cl2 (15 mL) was added CBr4
(1.55 g, 4.69 mmol) at -30 ◦C in one portion. The mixture was
stirred vigorously for 10 min, and a solution of PPh3 (1.24 g,
4.57 mmol) in dry CH2Cl2 (10 mL) was added. The solution
was stirred for 2 h at -30 ◦C, warmed up to 0 ◦C, and then
stirred another hour. The crude reaction mixture was filtered
through a thin layer of silica gel, concentrated in vacuo, and
after purification by column chromatography on silica gel, using
hexane–ethyl acetate (90 : 10) as eluent, 0.79 g of 2-(4-bromo-1-
butynyl)-3-methylthiophene (13) was obtained (yield 88%): IR
Ethyl (3R)-1-[4,4-bis(3-methyl-2-thienyl)-3-butenyl]hexahydro-
3-pyridinecarboxylate (15). A 25 mL two-neck round bot-
tom flask containing a magnetic stir bar was charged with
1
(neat) n 3027, 1400, 1210, 954, 713 cm-1; H NMR (200 MHz)
alkenyl iodide 14 (0.15 g, 0.35 mmol), under
a nitro-
d = 7.10 (d, 1H, J = 5.1 Hz), 6.81 (d, 1H, J = 5.1 Hz), 3.53 (t,
2H, J = 7.3 Hz), 3.03 (d, 2H, J = 7.3 Hz), 2.31 (s, 3H); 13C NMR
(50 MHz) d = 142.6, 129.3, 125.4, 118.5, 92.8, 75.6, 29.7, 24.4,
15.1; EI-MS m/z = 230 [M+ + 2], 228 [M+], 147, 135 (100), 115,
91, 77, 63. Anal. C9H9BrS requires: C, 47.18; H, 3.96; S, 13.99%;
found: C, 47.14; H, 3.92; S, 13.95%.
gen atmosphere. To the flask was added solution of
a
tetrakis(triphenylphopshine)palladium(0) (9 mg, 0.008 mmol) in
dimethoxyethane (1.5 mL) and aqueous Na2CO3 solution (2M,
0.35 mL, 0.7 mmol). The resultant solution was stirred at
room temperature for 15 min, then a solution of 3-methyl-2-
thienylboronic acid (62 mg, 0.437 mmol) in ethanol (1.5 mL) was
added dropwise by syringe. The reaction mixture was heated to
90 ◦C and stirred for 2 h. The solution was cooled to room temper-
ature and filtered through a pad of Celite using dichloromethane,
and dried over MgSO4. The solvent was evaporated and the crude
chromatographed on silica gel column (EtOAc–hexane 20 : 80) to
afford the title compound 15 (0.1 g, yield 76%) as a colorless oil:
IR (neat) n 3037, 3021, 1731, 1614, 1179, 711, 631 cm-1; 1H NMR
(400 MHz) d = 7.30 (d, 1H, J = 5.1 Hz), 7.04 (d, 1H, J = 5.1 Hz),
6.83 (d, 1H, J = 5.1 Hz), 6.76 (d, 1H, J = 5.1 Hz), 6.04 (t, 1H, J =
7.7 Hz), 4.11 (q, 2H, J = 7.3 Hz), 2.97 (d, 1H, J = 9.4 Hz), 2.74
(d, 1H, J = 11.1 Hz), 2.57-2.47 (m, 3H), 2.36-2.31 (m, 2H), 2.14
(t, 1H, J = 10.3 Hz), 2.04 (s, 3H), 2.02 (s, 3H), 1.94 (qd, 2H, J =
10.7 and 2.6 Hz), 1.69 (dt, 1H, J = 13.2 and 3.4 Hz), 1.56 (qt, 1H,
J = 11.5 and 3.4 Hz), 1.42 (qd, 1H, J = 11.5 and 3.8 Hz), 1.24 (t,
3H, J = 6.8 Hz); 13C NMR (100 MHz) d = 174.3, 139.8, 135.5,
135.4, 133.7, 133.5, 131.3, 129.7, 128.3, 124.4, 122.8, 58.3, 55.4,
53.6, 42.0, 27.6, 27.1, 24.7, 15.0, 14.5, 14.3; EI-MS m/z = 403
[M+], 358, 170 (100), 142, 111, 99. Anal. C22H29NO2S2 requires: C,
65.47; H, 7.24; N, 3.47; S, 15.89%; found: C, 65.46; H, 7.20; N,
3.60; S, 15.87%.
Ethyl
(3R)-1-[4-(3-methyl-2-thienyl)-3-butynyl]hexahydro-3-
pyridinecarboxylate (4). The heteroaryl substituted compound
13 (0.40 g, 1.74 mmol) was dissolved in acetone (10 mL) and
to it were added ethyl (R)-3-piperidinecarboxylate tartrate salt
(0.54 g, 1.74 mmol), potassium iodide (0.028 g, 0.174 mmol) and
potassium carbonate (0.48 g, 3.48 mmol). The mixture was kept
stirring for 3 days. The reaction mixture was then filtered and the
solvent was evaporated to give an oil residue which was purified
by column chromatography on silica gel (hexane–ethyl acetate
50 : 50) to give 4 (0.41 g, yield 78%) as a yellow oil: IR (neat) n
3032, 1731, 1446, 1179, 1032, 711 cm-1; 1H NMR (400 MHz) d =
7.04 (d, 1H, J = 5.1 Hz), 6.78 (d, 1H, J = 5.1 Hz), 4.12 (q, 2H,
J = 4.3 Hz), 3.03 (dd, 1H, J = 11.1 and 2.9 Hz), 2.81 (d, 1H, J =
11.1 Hz), 2.72-2.61 (m, 4H), 2.58-2.52 (m, 1H), 2.29 (t, 1H, J =
8.5 Hz), 2.27 (s, 3H), 2.12 (dt, 1H, J = 10.7 and 2.9 Hz), 1.94 (dd,
1H, J = 12.8 and 3.8 Hz), 1.73 (dt, 1H, J = 13.3 and 3.8 Hz), 1.45
(qt, 1H, J = 15.5 and 3.8 Hz), 1.41 (dd, 1H, J = 11.5 and 2.6 Hz),
1.24 (t, 3H, J = 6.8 Hz); 13C NMR (100 MHz) d = 174.4, 141.8,
125.2, 124.8, 123.2, 94.7, 74.3, 60.6, 57.7, 55.3, 53.2, 42.1, 27.1,
24.8, 18.3, 15.0, 14.5; EI-MS m/z = 305 [M+], 170 (100), 142, 95.
Anal. C17H23NO2S requires: C, 66.85; H, 7.59; N, 4.59; S, 10.50%;
found: C, 66.86; H, 7.63; N, 4.57; S, 10.27%.
(3R)-1-[4,4-Bis(3-methyl-2-thienyl)-3-butenyl]hexahydro-3-
piperidinecarboxylic acid hydrochloride (16). To a solution of
Tiagabine ethyl ester 14 (75 mg, 0.18 mmol) in EtOH abs. (5 mL)
was added at room temperature 12 M aqueous NaOH (0.5 mL).
The reaction mixture was stirred for 4 h at room temperature and
then cooled to 5 ◦C. The pH was adjusted to ca. 1 with 4 N aqueous
HCl, CH2Cl2 (30 mL) was added, and the phases were separated.
The organic phase was washed with water (5 mL), with saturated
NaCl solution (5 mL), and dried over Na2SO4. The solvent was
Ethyl (3R)-1-[(Z)- and (E)-4-iodo-4-(3-methyl-2-thienyl)-3-
butenyl]hexahydro-3-pyridinecarboxylate (14). To
a
stirred
suspension of ethyl (3R)-1-[4-(3-methyl-2-thienyl-3-butynyl]-
hexahydro-3-pyridinecarboxylate (4) (0.23 g, 0.75 mmol) and NaI
(0.34 g, 2.26 mmol) in acetonitrile (15 mL) was added CeCl3·7H2O
(0.42 g, 1.12 mmol), and the resulting mixture was stirred at reflux
for 24 h. The hydroiodination adduct was extracted from the solid
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removed in vacuo and the crude product was crystallized from
2-propanol (15 mL) ◦to provide 16 (55 mg, yield 81%) as a white
14 B. M. Trost, N. Maulide and R. C. Livingston, J. Am. Chem. Soc., 2008,
130, 16502(a) B. M. Trost, F. D. Toste and A. B. Pinkerton, Chem. Rev.,
2001, 101, 2067.
1
solid: m.p. 184–185 C; [a]2D5 = -9.98 (c = 1.0, H2O); H NMR
15 B. M. Trost and Z. T. Ball, J. Am. Chem. Soc., 2001, 123, 12726.
16 H. Kilimann, R. Herbst-Irmer, D. Stalke and F. T. Eldmann, Angew.
Chem., Int. Ed. Engl., 1994, 33, 1618.
(400 MHz) d = 9.85 (bs, 1H), 7.22 (d, 1H, J = 5.1 Hz), 7.05 (d,
1H, J = 5.1 Hz), 6.85 (d, 1H, J = 5.1 Hz), 6.74 (d, 1H, J = 5.1 Hz),
5.95 (t, 1H, J = 6.8 Hz), 3.45-2.40 (m, 9H), 2.00 (s, 3H), 1.95 (s,
3H), 1.87-1.22 (m, 4H); 13C NMR (100 MHz, D2O) d = 175.3,
136.7, 134.1, 131.8, 128.5, 130.3, 128.9, 128.5, 125.6, 124.3, 56.3,
53.5, 52.6, 39.7, 24.8, 24.4, 23.4, 22.2, 14.1, 13.7; ESI-MS m/z =
398 [M - HCl + Na], 376 [M - HCl + H]. Anal. C20H26ClNO2S2
requires: C, 58.30; H, 6.36; N, 3.40; S, 15.57%; found: C, 58.28; H,
6.32; N, 3.43; S, 15.59%.
17 H. Doucet, Eur. J. Org. Chem., 2008, 2013.
18 (a) Y. Wu and J. Gao, Org. Lett., 2008, 10, 1535 and references cited
therein; (b) Effective electrophilic coupling partners in the construction
of C–C bonds, see: E. Neghishi and L. Anastasia, Chem. Rev., 2003,
103, 1979; (c) S. Ma, A. Zhang, Y. Yu and W. Xia, J. Org. Chem., 2001,
65, 2287.
19 E. Piers, T. Wong, P. D. Coish and C. Rogers, Can. J. Chem., 1994, 72,
1816–1819.
20 (a) Q. Xie, R. W. Denton and K. A. Parker, Org. Lett., 2008, 10, 5345;
(b) A. Fu¨rstner, E. Kattnig and O. Lepage, J. Am. Chem. Soc., 2006,
128, 9194.
21 B. H. Lipshutz, S. S. Pfeiffer, K. Noson, T. Tamioka, in Titanium
and Zirconium in Organic Synthesis, (Ed.: I. Marek), Wiley-VCH,
Weinheim, 2002, pp 110–148.
Acknowledgements
We thank the MIUR (PRIN 2006), Rome, and the University of
Camerino. G. D. A. gratefully acknowledges Boehringer Ingelheim
Italia S.p.A. for doctoral fellowship. Special thanks are due to
Prof. Marco A. Ciufolini of the University of British Columbia,
Vancouver, for helpful discussions.
22 (a) H. Ito, T. Inoue and K. Iguchi, Org. Lett., 2008, 10, 38; (b) Z. Huang
and E. Negishi, Org. Lett., 2006, 8, 3675–3678.
23 (a) P. J. Campos, B. Garc´ıa and M. A. Rodriguez, Tetrahedron Lett.,
2002, 43, 6111; (b) N. Kamiya, Y. Chikami and Y. Ishii, Synlett, 1990,
675.
24 (a) G. Sabitha, J. S. Yadav, in Encyclopedia of Reagents for Organic
Synthesis, (Ed.: L. A. Paquette), Wiley-VCH, Weinheim, 2006; (b) G.
Bartoli, E. Marcantoni and L. Sambri, Synlett, 2003, 2101.
25 (a) G. Bartoli, G. Di Antonio, R. Giovannini, S. Giuli, S. Lanari, M.
Paoletti and E. Marcantoni, J. Org. Chem., 2008, 73, 1919; (b) G.
Bartoli, J. G. Ferna´ndez-Bolan˜os, G. Di Antonio, G. Foglia, S. Giuli,
R. Gunnella, M. Mancinelli, E. Marcantoni and M. Paoletti, J. Org.
Chem., 2007, 72, 6029; (c) G. Bartoli, R. Giovannini, A. Giuliani, E.
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