Nickel-catalyzed arylation, alkenylation, and alkynylation of unprotected thioglycosides at room temperature

Article abstract of DOI:10.1002/chem.201302999

Unprotected thioglycosides were effective nucleophiles for Ni ⁰-catalyzed C-S bond-forming reaction with functionalized (hetero)aryl, alkenyl, and alkynyl halides. The functional-group tolerance on the electrophilic partner was typically high a

Full text of DOI:10.1002/chem.201302999

DOI: 10.1002/chem.201302999
Nickel-Catalyzed Arylation, Alkenylation, and Alkynylation of Unprotected
Thioglycosides at Room Temperature
Etienne Brachet, Jean-Daniel Brion, Mouad Alami,* and Samir Messaoudi*[a]
Abstract: Unprotected thioglycosides were effective nucleophiles for Ni0-catalyzed
À
C S bond-forming reaction with functionalized (hetero)aryl, alkenyl, and alkynyl
Keywords: alkenylation · alkynyla-
halides. The functional-group tolerance on the electrophilic partner was typically
tion · arylation · nickel · thioglyco-
high and the anomeric selectivities of the thioglycosides were high in all cases. The
sides
efficiency of this general procedure was well-demonstrated by the synthesis of 4-
methyl-7-thioumbelliferyl-b-d-cellobioside (MUS-CB).
Introduction
The development of transition-metal-catalyzed coupling re-
actions for the facile generation of unprotected polyfunc-
tionalized compounds with useful architectures remains of
great interest to academic and industrial chemists. Such pro-
cesses preclude the need for prior time-consuming protec-
tion and deprotection steps, thus making the overall chemi-
cal transformations highly efficient. We are particularly in-
terested in the development of new methods for the direct
metal-catalyzed coupling of protecting-group-free thioglyco-
sides under mild and operationally simple conditions. Cata-
lytic reactions of this nature would be of great interest for
the construction of molecules that may be sensitive to the
harsh conditions that are often required for glycosidic bond-
forming reactions.
Scheme 1. Coupling reactions of unprotected thioglycosides.
Driven by the exceptional reactivity of sulfur and its im-
portance in biology, medicine, and materials science,[1] we
recently reported the synthesis of arylthioglycosides by
using a protecting-group strategy that was based on the cou-
pling of protected thioglycosides as nucleophile partners
the feasibility of this transformation for the coupling of 4-io-
doanisole with various unprotected thioglycosides (e.g., 1-
thio-b-d-glucopyranose, 1-thio-b-d-galactopyranose, 1-thio-
b-d-ribose, 1-thio-b-d-mannopyranose, 1-thio-b-d-cellobiose,
etc.). However, all of our attempts failed (Scheme 1, path a),
which was not surprising because the unprotected thioglyco-
sides showed limited stability towards high-temperature[3]
and/or basic[4] environments. Conscious of these limitations,
we believe that the development of a robust procedure for
the coupling of unprotected thioglycosides as viable nucleo-
philic partners with various aglycone halides is highly desira-
ble. To this end, a suitable coupling procedure would meet
the following requirements: 1) it should not use expensive
metal catalysts or sophisticated ligands; 2) it should be ach-
ievable at room temperature within a short time and allow
complete stereocontrol over the coupling product; 3) it
should be tolerant of many different functional groups and
should be general with respect to both coupling partners;
and 4) the handling, separation, and purification of the com-
pounds should be facile.
with aryl halides in the presence of a PdACTHNURTGNENG(U OAc)2/Xantphos
(Xantphos=4,5-bis(diphenylphosphino)-9,9-dimethylxan-
thene) catalyst system.[2] In addition, in a single example, we
demonstrated that this procedure also enabled, for the first
time, the efficient coupling of unprotected thioglucose 1a
with 4-iodoanisole in an acceptable 66% yield (Scheme 1,
path a). Because this preliminary result did not require any
protecting-group manipulations, we set out to investigate
[a] E. Brachet, Prof. J.-D. Brion, Dr. M. Alami, Dr. S. Messaoudi
Laboratoire de Chimie Thꢀrapeutique, BioCIS-UMR 8076
LabEx LERMIT, Universitꢀ Paris-Sud, CNRS
Facultꢀ de Pharmacie, 5 rue J.-B. Clꢀment
92296 Chꢁtenay-Malabry (France)
Fax : (+33)146-83-58-28
E-mail: mouad.alami@u-psud.fr
samir.messaoudi@u-psud.fr
Recent notable progress in the use of naturally more-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201302999.
À
abundant and extremely cheap nickel catalysts in C S bond-
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FULL PAPER
Table 1. Optimization of the coupling reaction between compounds 1a
with 2a.[a]
forming reaction has found wide applications in organic syn-
thesis.[5] Although the Ni-catalyzed arylation of thiophenols
to form diaryl sulfides has been extensively studied, only
a few examples of the use of aliphatic thiols have been re-
ported to date.[5c,e,g] Moreover, to the best of our knowledge,
there are no reports regarding the Ni-catalyzed S-arylation
or heteroarylation of unprotected thiosugars. Herein, we
report a general and robust coupling reaction of unprotected
Entry
Ni catalyst
L
Base Solvent Conversion[b]
[%]
Yield[c]
[%]
1
2
3
4
5
6
7
8
NiCl2
NiCl2·dme
NiBr2
Bipy Py MeOH 95
Bipy Py MeOH 96
56
78
–
thioglycosides with (hetero)aryl halides, as well as alkenyl
2
À
À
and alkynyl halides. We found that the C
G
Bipy Py MeOH
0
0
S bonds could be stereoselectively formed under mild condi-
tions in the presence of a catalytic amount of Ni0 in MeOH
at room temperature (Scheme 1, path b). This procedure
successfully met each of the requirements described above.
[NiCl
N
–
NiCl2·dme
NiCl2·dme
NiCl2·dme
NiCl2·dme
–
–
–
–
Py MeOH 100
99[d]
–
Et3N MeOH
0
71
75
Py
Py
EtOH
water
23
26
[a] A mixture of Zn (1 equiv), NiX2 (30 mol%), bipyridine (90 mol%),
and Py (300 mL) was heated at 558C for 15 min to generate [Ni0-
AHCTUNGTERG(NNNU Bipy)2(Py)]. A solution of compound 1a (0.25 mmol) and compound 2a
Results and Discussion
(0.5 mmol) in solvent (1 mL) was added dropwise to the Ni0 complex and
the mixture was stirred at 208C for 1 h. [b] Conversion was determined
by 1H NMR spectroscopy of the crude reaction mixture and was based
on the chemical shift of the signal of the anomeric proton of the sugar
moiety. [c] Yield of isolated compound 3a. [d] The reaction was stirred at
208C for 2 h.
Our initial efforts focused on the coupling reaction between
unprotected 1-thio-b-d-glucopyranose 1a and 4-iodoanisole
(2a) with various nickel catalysts, ligand sources, bases, and
solvents. Representative results from this study are summar-
ized in Table 1. We found that the reaction of compound 1a
(1 equiv) with compound 2a (2 equiv) in MeOH at room
bly, the polyhydroxylated moieties on compounds 1a and
3a, which were able to coordinate to the Ni catalyst, did not
have a deleterious effects on the outcome of the reactions.
With our catalyst system in hand, we explored its versatili-
ty in the coupling reactions of unprotected 1-thio-b-d-gluco-
pyranose (1a) with various (hetero)aryl iodides. As shown
in Scheme 2, 1-thio-b-d-glucopyranose 1a was readily cou-
pled with aryl iodides that contained para and meta elec-
tron-donating or electron-withdrawing substituents to give
thioglycosylated products 3a–3g and 3i–3m in good-to-ex-
cellent yields with complete b selectivity. In addition, the
sterically demanding ortho-substitution pattern was tolerat-
ed in the coupling reaction with compound 1a, thus leading
to b-thioglycosylated derivatives 3h and 3n in good yields,
regardless of the electronic nature of the substituents. As
shown in Scheme 2, the presence of hydroxy, free-amino, or
boronic-acid groups on the aryl-halide partner did not inter-
fere with the outcome of the reaction (compounds 3c–3e).
In particular, reactive electrophilic functional groups, such
as aldehyde, ester, hydrazone, and bromo substituents, were
well-tolerated, which should be instrumental for the further
derivatization of the thus-obtained b-arylthioglycosides (3i–
3n).
Extending this method to the heteroarylation of com-
pound 1a was also successful. 3-Iodopyridine, 2-iodo-5-bro-
moindole, and 3-bromoquinolinone were good partners for
the coupling reaction with compound 1a under our opti-
mized conditions, thereby furnishing the desired thioglyco-
sides (3o–3q) in acceptable yields (45–65%).
In a further set of experiments, we investigated the scope
of this method with respect to mono- and dithiosaccharides
1a–3e (Figure 1). As shown in Scheme 3, the coupling reac-
tions proceeded cleanly in high yields, without the presence
of any side reactions, such as anomerization of the resulting
ACTHNUTRGNEUNG
temperature in the presence of [Ni0(Bipy)2(Py)][5c,6]
(30 mol%, Bipy=bipyridine, Py=pyridine) as the catalyst,
which was readily generated in situ from a mixture of NiCl2
(30 mol%), bipyridine (90 mol%), and Zn0 (1 equiv) in pyr-
idine (300 mL) at 558C (see the Supporting Information), af-
forded the expected b-arylthioglycoside (3a) in 56% yield
(Table 1, entry 1). Next, the screening conditions were em-
ployed with various other nickel sources. The catalytic activ-
ity of NiCl2·dme (dme=dimethoxyethane) was found be su-
perior to that of NiCl2, thus leading to the formation of
compound 3a in a higher yield (78%; Table 1, entry 2).
However, the use of other nickel sources, such as NiBr2 or
[NiCl2ACHTUNGTRENNUNG(PPh3)2], did not promote the S-arylation of com-
pound 1a (Table 1, entries 3 and 4). Pleasingly, we found
that the bipyridine ligand was not required, because a reac-
tion between compounds 1a and 2a without bipyridine
under otherwise-identical conditions led to the formation of
compound 3a in quantitative yield (Table 1, entry 5). Finally,
after a brief screening of other parameters (base and sol-
vent; Table 1, entries 6–8), optimal conditions were found,
that is: compound 1a (1 equiv), compound 2a (2 equiv),
[Ni0
ACHTUNGTRENNUNG(dme)(Py)] as the catalyst (which was generated in situ
from a mixture of NiCl2·dme (30 mol%), Zn0 (1 equiv), and
pyridine (300 mL) at 558C, according to a similar procedure
ACTHNUTRGNEUNG
for the generation of [Ni0(Bipy)2(Py)][5c]) in MeOH at room
temperature for 2 h (Table 1, entry 5). Accordingly, com-
pound 3a was formed in 99% yield, without the formation
of any side products that would result from competitive O-
arylation reactions under Ni catalysis.[7] Notably, this reac-
tion was not limited to small-scale syntheses (0.25 mmol); it
could be conveniently performed on a 1.2 g scale (5 mmol;
20-fold scale-up) with only 5 mol% Ni0 in 76% yield, thus
indicating that this procedure is practically valuable. Nota-
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M. Alami, S. Messaoudi et al.
Figure 1. Thiosaccharides 1a–1e that were used in this study.
Scheme 3. Nickel-catalyzed coupling reactions of unprotected thiosac-
charides 1a–1g with various aryl iodides (2). Reaction conditions: A mix-
ture of Zn (1 equiv), NiCl2·dme (30 mol%), and Py (300 mL) was heated
at 558C to generate [Ni0
ACTHNUTRGNEU(GN dme)2(Py)]. A solution of compound 1a–1g
(0.25 mmol) and compound 2 (0.5 mmol) in MeOH (1 mL) was added
dropwise to the Ni0 complex and the mixture was stirred at 208C for 2 h.
[a] 10 mol% NiCl2·dme was used.
Scheme 2. Ni-catalyzed coupling reactions of unprotected 1-thio-b-d-glu-
copyranose (1a) with various (hetero)aryl halides (2). Reaction condi-
tions: A mixture of Zn (1 equiv), NiCl2·dme (30 mol%), and Py (300 mL)
was heated at 558C to generate [Ni0
ACTHNUTRGNEN(UG dme)2(Py)]. A solution of compound
good yields were obtained from the coupling reactions of 4-
iodoanisole with 1-thio-a-d-glucopyranose (1d) and 1-thio-
b-d-glucopyranose (1a; 80% and 99% yields, respectively).
In addition, the coupling procedure was not only limited to
monothioglycosides; it also worked successfully with chal-
lenging 1-thiodisaccharides, such as 1-thio-b-d-cellobiose
(1e). Exclusive 1,2-trans b-diholosides 4h and 4i were ob-
tained in 69% and 66% yields, respectively, and the stereo-
chemistry of the 1-4’-O-glycosidic bond remained intact.
With the aim of further pushing the limit of this nickel-
catalyzed S-(hetero)arylation reaction of thiosugars, we ex-
amined the coupling reactions of unprotected a- or b-thio-
glycosides 1a–1e with alkenyl iodides and alkynyl bromides
as aglycone partners (Scheme 4). Delightfully, if E- or Z-al-
1a (0.25 mmol) and compound 2 (0.5 mmol) in MeOH (1 mL) was added
dropwise to the Ni0 complex and the mixture was stirred at 208C.
[a] 5 mol% NiCl2·dme was used.
arylthioglycosides. This reaction was found to be general
with respect to the configuration of the sugar, because 1-
thio-b-d-galactopyranose (1c) and N-acetyl-1-thio-b-d-ami-
noglucopyranose (1b) gave their corresponding products
(4a–4e) in excellent yields. Our coupling procedure was not
limited to thioglycosides with an anomeric b configuration;
it also worked successfully with thiol 1d, which had an
anomeric a configuration. Moreover, there were no signifi-
cant differences in reactivity between the a and b anomers;
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Arylation, Alkenylation, and Alkynylation of Thioglycosides
FULL PAPER
stituted alkynyl bromides were examined as aglycon cou-
pling partners. Alkynylated thioglycoside products 6a and
6b were obtained diastereoselectively in acceptable yields.
The synthesis of compounds 5 and 6 that feature alkenyl or
alkynyl substituents on the sulfur atom of the sugar moiety
have not previously been reported, perhaps owing to the dif-
ficulty in their preparation by using standard procedures.[8]
Finally, the synthetic potential of this procedure was well-
illustrated by the preparation of 4-methyl-7-thioumbellifer-
yl-b-d-cellobioside (MUS-CB),[9] a fluorescent non-hydrolyz-
able analogue of cellulases. The key step in this synthesis
was the coupling reaction between 7-iodocoumarin (7)[10]
and fully deprotected b-d-disaccharide 1e under our opti-
mized conditions to give MUS-CB (8) in an excellent 65%
yield, with exclusive b selectivity (Scheme 5). In addition,
subjecting iodophenstatin 9 to the coupling reaction with
compound 1a under our reaction conditions similarly result-
ed in the rapid preparation of thioglycoside 10, an analogue
of phenstatin[11] and isocombretastatin A-4 (isoCA-4),[12] two
highly promising cytotoxic and antitubulin agents.
Conclusion
In conclusion, we have demonstrated that unprotected thio-
glycosides could be used as viable nucleophilic partners with
aglycone halides. A catalyst system based on Ni0 allowed
the efficient S-arylation, alkenylation, and alkynylation of
unprotected thioglycosides at room temperature. This reac-
tion was highly diastereoselective, functional-group tolerant,
step-economical, and proceeded stereoselectively in good-
to-excellent yields. The value of this transformation has
been highlighted in the synthesis of biologically interesting
thioglycosylated compounds 8 and 10. We expect that this
simple and general procedure will be of broad utility for the
synthesis and development of new medicinal agents.
Scheme 4. Nickel-catalyzed coupling reactions of thiosaccharides 1a–1g
with alkenyl and alkynyl halides. Reaction conditions: A mixture of Zn
(1 equiv), NiCl2·dme (30 mol%), and Py (300 mL) was heated at 558C to
generate [Ni0
ACHTUNGTRENNUNG(dme)2(Py)]. A solution of compound 1a–1g (0.25 mmol)
and compound 2 (0.5 mmol) in MeOH (1 mL) was added dropwise to the
Ni0 complex and the mixture was stirred at 208C for 2 h.
kenyl iodides were employed, the coupling reactions with
compounds stereoselectively 1a–1e afforded the desired al-
kenylthioglycoside derivatives (5a–5j) in good yields with-
out any thermal isomerization, thereby clearly demonstrat-
ing the mild nature of this selective coupling reaction. In ad-
dition to the alkenyl halides that were evaluated above, sub-
Experimental Section
General procedure for the nickel-catalyzed coupling of unprotected thio-
glycosides with (hetero)aryl, alkenyl, and alkynyl halides: NiCl2·dme
(16.5 mg,0.075 mmol) was added to a stirring slurry of Zn (16.5 mg,
Scheme 5. Synthesis of (MUS-CB) and phenstatin analogue 10.
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M. Alami, S. Messaoudi et al.
0.25 mmol) in pyridine (0.3 mL) at RT. Then, the temperature was in-
of compound 1a within 30 min. In addition, if PdACTHGNUTRENNU(G OAc)2 (5 mmol%)
creased to 558C and vigorous stirring was continued for 15 min. The re-
was added, compound 1a disappeared within only 15 min.
[4] For the pH-dependent mutarotation of 1-thioaldoses, see: R. Cara-
ballo, L. Deng, L. Amorium, T. Brink, O. Ramstrçm, J. Org. Chem.
2010, 75, 6115–6121.
sulting [Ni0
ACHTUNGTRENNUNG(dme)(Py)] complex was cooled to RT and a solution of the
aryl (or alkenyl/alkynyl) halide (0.5 mmol) and the thioglycoside
(0.25 mmol) in MeOH (1 mL) was added. After stirring for 2 h at RT, the
mixture was filtered through a short plug of silica (CH2Cl2/MeOH) and
concentrated in vacuo. The crude product was purified by flash chroma-
tography on silica gel to afford the desired product.
À
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Synthesis of (2R,3S,4S,5R,6S)-2-(hydroxymethyl)-6-((4-methoxyphe-
nyl)thio)tetrahydro-2H-pyran-3,4,5-triol (3a): Following the general pro-
cedure for the Ni0-catalyzed cross-coupling reaction, a mixture of b-thio-
glucose 1a (58.5 mg, 0.25 mmol) and 4-iodoanisole (0.5 mmol) was stirred
for 2 h. The residue was purified by flash chromatography on silica gel
(CH2Cl2/MeOH, 85:15) to afford the desired product (3a, 75 mg,
0.25 mmol, 99%) as a colorless oil, Rf =0.38 (CH2Cl2/MeOH, 85:15);
[a]2D4 =À41.0 (c=1.0 in MeOH); 1H NMR (300 MHz, [D6]acetone, 258C,
TMS): d=7.52 (d, J=8.8 Hz, 2H), 6.88 (d, J=8.8 Hz, 2H), 4.46 (d, J=
9.6 Hz, 1H), 4.41 (brs, 2H), 3.83 (d, J=10.2 Hz, 1H), 3.78 (s, 3H), 3.66
(d, J=12.3 Hz, 1H), 3.50–3.40 (m, 1H), 3.32 (d, J=5.4 Hz, 2H), 3.16 (t,
J=9.1 Hz, 1H), 3.03 ppm (s, 2H); 13C NMR (75 MHz, [D6]acetone): d=
160.61 (C), 135.89 (2ꢃCH), 124.15 (C), 115.05 (2ꢃCH), 89.02 (CH),
81.38 (CH), 79.38 (CH), 73.19 (CH), 71.26 (CH), 62.90 (CH2), 55.59 ppm
(CH3); IR (neat): n˜ =3331, 3240, 3155, 2533, 2202, 2119, 2020, 2002, 1756,
1592, 1494, 1460, 1287, 1218, 1177, 1106 cmÀ1; HRMS (ESI): m/z calcd
for C13H18NaO6S: 325.0716; found: 325.0708.
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Acknowledgements
The CNRS is gratefully acknowledged for financial support of this re-
search and the French Ministry of Education, Research, and Technology
(MENRT) is acknowledged for a doctoral fellowship to E.B. Our labora-
tory, BioCIS-UMR 8076, is a member of the Laboratory of Excellence,
LERMIT, which is supported by a grant from the ANR (ANR-10-
LABX-33).
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Received: July 30, 2013
Published online: September 24, 2013
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Chem. Eur. J. 2013, 19, 15276 – 15280