Ferrier-type alkynylation reaction mediated by indium

Article abstract of DOI:10.1021/ol701480x

An efficient Ferrier-type alkynylation reaction between glycals and iodoalkynes using Barbier conditions is described. These conditions require In⁰, In¹, or In¹¹ and lead to α-2,3-unsaturated-C-glycosides with good stereos

Full text of DOI:10.1021/ol701480x

ORGANIC
LETTERS
2007
Vol. 9, No. 18
3679-3682
Ferrier-Type Alkynylation Reaction
Mediated by Indium
Nade`ge Lubin-Germain,* Agne`s Hallonet, Florent Huguenot, Sara Palmier,
Jacques Uziel, and Jacques Auge´
Laboratoire de Synthe`se Organique Se´lectiVe et Chimie Organome´tallique,
UMR 8123 CNRS-UCP-ESCOM, UniVersite´ de Cergy-Pontoise, 5 mail Gay-Lussac,
95031 Cergy-Pontoise cedex, France
nadege.lubin-germain@u-cergy.fr
Received July 2, 2007
ABSTRACT
An efficient Ferrier-type alkynylation reaction between glycals and iodoalkynes using Barbier conditions is described. These conditions require
In0, InI, or InII and lead to
-2,3-unsaturated-C-glycosides with good stereoselectivity. When glycosyliodoalkynes are used, trehalose-derived
compounds and -(1 6)-C-disaccharides are obtained.
r
r
f
Addition of alkynyl derivatives to carbonyl compounds is
an important reaction.1 We have recently shown that iodo-
alkynes add to carbonyl compounds in the presence of a
stoichiometric amount of metallic indium to afford propar-
gylic alcohols.2 Depending on the conditions of the reaction,
an in situ oxidation of the propargylic alcohol can take place
to give propargylic ketones.3 As organoindium species were
found to be tolerant of ester groups, this reaction could be
applied in carbohydrate chemistry using acetate protecting
groups. Thus, we realized the synthesis of C-glycosides4
through the alkynylation of formylglycosides. We were also
interested in the direct creation of the carbon-carbon bond
at the anomeric center using indium-promoted alkynylation
reaction5 by a Ferrier rearrangement.
Minehan’s group8 recently published the addition of triaryl,
trivinyl, and trialkynylindium reagents to glycals. The authors
emphasized the attraction of such reagents toward function-
alized compounds and then their use in synthesis. The
method9 implies the transmetalation of trialkynylmagnesium
bromide in the presence of indium trichloride, prior to the
addition of the organometallic species.
We tried Barbier conditions,10 mixing 2 equiv of iodophen-
ylacetylene with tri-O-acetyl-D-glucal in the presence of 2.4
equiv of metallic indium. After 4 h under reflux of dichlo-
(6) (a) Isobe, M.; Phoosaha, W.; Saeeng, R.; Kira, K.; Yenjai, C. Org.
Lett. 2003, 5, 4883. (b) Procopio, A.; Dalpozzo, R.; De Nino, A.; Nardi,
M.; Russo, B.; Tagarelli, A. Synthesis 2006, 332. (c) Yadav, J. S.; Raju, A.
K.; Sunitha, V. Tetrahedron Lett. 2006, 47, 5269.
(7) (a) Yadav, J. S.; Reddy, B. V.; Rao, C. V.; Reddy, M. S. Synthesis
2003, 247. (b) Saeeng, R.; Sirion, U.; Sahakipitchan, P.; Isobe, M.
Tetrahedron Lett. 2003, 44, 6211.
C-Glycosylation by silylacetylene addition to glucals using
Lewis acids had been previously reported.6 Iodine was also
efficient as a catalyst in this reaction.7
(8) Price, S.; Edwards, S.; Wu, T.; Minehan, T. Tetrahedron Lett. 2004,
45, 5197.
(9) Baker, L.; Minehan, T. J. Org. Chem. 2004, 69, 3957.
(1) Guillarme, S.; Ple´, K.; Banchet, A.; Liard, A.; Haudrechy, A. Chem.
ReV. 2006, 106, 2355.
(2) Auge´, J.; Lubin-Germain, N.; Seghrouchni, L. Tetrahedron Lett. 2002,
(10) In a typical procedure, indium (2 g, 17.5 mmol) was stirred during
30 min under a vacuum/argon in a sealed tube. Then, a solution of
iodophenylacetylene (3.35 g, 14.7 mmol) and tri-O-acetyl-D-glucal (2 g, 1
mmol) in anhydrous CH2Cl2 (40 mL) was introduced to the medium which
was refluxed for 4 h. The mixture was treated with a saturated solution of
NaHCO3 (70 mL) and extracted with CH2Cl2. The combined organic phases
were dried (MgSO4). The crude product was purified by flash chromatog-
raphy on silica gel (Cyclohexane-EtOAc, 85:15), and the compound 1b
was obtained as a yellow solid (1.83 g, 79%).
42, 5255.
(3) Auge´, J.; Lubin-Germain, N.; Seghrouchni, L. Tetrahedron Lett. 2003,
44, 819.
(4) Picard, J.; Lubin-Germain, N.; Uziel, J.; Auge´, J. Synthesis 2006,
979.
(5) Auge´, J.; Lubin-Germain, N.; Uziel, J. Synthesis 2007, 1739.
10.1021/ol701480x CCC: $37.00
© 2007 American Chemical Society
Published on Web 08/02/2007

such as dichloromethane or dichloroethane,2,3 contrary to the
usual indium-mediated Barbier processes using aqueous
media.
Table 1. Barbier Alkynylation of Tri-O-acetyl-D-glucal with
Iodophenylacetylene
We were interested in testing indium in other oxidation
states with the aim of knowing which oxidation states of
the organoindium intermediates are involved in the reaction.
Thus, InI was found to be very efficient for the catalysis of
the reaction, and particularly, the reaction rate was increased
with InBr (Table 1, entry 2). Then the reaction was performed
at room temperature, but the yield did not improve (Table
1, entry 3). An InII salt led rapidly to the C-glycoside with
a good yield (Table 1, entry 5). InII is now commercially
available, and to our knowledge, it has not been mentioned
in the literature in such reactions. However, the determination
of the oxidation states of organoindium intermediates is under
investigation.
entry
metal
In0
InBr
InBrb
InCl
InCl2
Mn0
Zn0
In0/Mn0
In0/Zn0
time
4 h
0.5 h
2 h
4 h
4 h
42 h
4 days
7 h
yield (%)
R/â selectivity
1
2
3
4
5
6
7
8a
9a
79
57
50
24
77
traces
30
46
35
90/10
82/18
70/30
90/10
83/17
-
88/12
84/16
83/17
On the other hand, as we had previously mentioned an
In0 catalytic system for allylation reactions,12 we tried to
transpose a similar system to the alkynylation reaction to
avoid the use of a substoichiometric amount of indium. We
first verified the absence or the low efficiency of Mn0 and
Zn0 in the alkynylation (Table 1, entries 6 and 7). Then, when
10% In0 was added, the C-glycoside was formed with modest
yields (Table 1, entries 8 and 9).
5 h
a 10 mol % of In0/2.4 equiv of metal. b Room temperature.
romethane, the C-alkynylglycoside 1b6b was obtained in 79%
yield with 90/10 R/â selectivity (Table 1). The need of the
iodine atom of the alkyne was verified for this reaction as
we observed the lack of reactivity when terminal alkyne was
used in the presence of indium tribromide and triethyl-
amine.11 Concerning the choice of the solvent, this alkynyl-
ation reaction takes place efficiently in chlorinated solvents
In a second part of this work, we tried to apply the
conditions to various alkynes. In0 was chosen as the best
compromise between reactivity and cost for a synthetic
application (Table 2). The iodoalkynes 1a, 2a, 3a, 4a, 5a,
6a, 8a, and 9a were all prepared from the corresponding
Table 2. Alkynylation Reaction of Tri-O-acetyl-D-glucal with In0
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Org. Lett., Vol. 9, No. 18, 2007

alkynes in the presence of iodine and morpholine in benzene.4
The treatment of tri-O-acetyl-D-glucal with these iodoalkynes
provided the C-pseudoglycals 1b, 2b,13 3b, 4b,14 5b, and
6b in a few hours under reflux of dichloromethane. In each
case, the R-anomer was predominantly obtained. The deter-
mination of the R-selectivity was based on the NMR
observations of H-5 and C-5. In fact, Isobe6a,15 established
an empirical rule dealing with the chemical shielding of H-5
between 4.07 and 4.09 ppm for the R-anomer and between
3.74 and 3.77 for the â-anomer. Moreover, the R-anomer
presents a chemical shift8 for the C-5 lower than 75 ppm. In
the case of alkynylation with trimethylacetylene, Isobe
explained the R selectivity by electronic effects on the
oxocarbenium intermediates involved in the transformation.
To demonstrate the generality of the reaction, the tri-
methylsilylethynyl-C-glycoside 4b was transformed into
iodoethynyl-C-glycoside 7a by treatment with silver nitrate
and iodine (Scheme 1). The product 7a was then involved
on tri-O-acetyl-D-glucal (Table 2, entry 8) and by addition
of the organoindium species derived from 9a on tri-O-acetyl-
D-glucal (Table 2, entry 9).
Finally, the reaction was applied to other glycosidic
electrophiles (Table 3). The first reaction was carried out
Table 3. Other Glycalsa
Scheme 1. Preparation of 7a
a All reactions were carried out at reflux of dichloromethane (0.166 M
solution) with 2 equiv of In(0) and 2.4 equiv of iodophenylacetylene.
with tri-O-acetyl-D-galactal, and the corresponding C-
pseudogalactal 10b6b was isolated with a good yield of 95%.
Acetylated lactal 13a was also found to be a good substrate
for the reaction, furnishing C-alkynylglycoside 13b.
in the Ferrier reaction with tri-O-acetyl-D-glucal and led to
the C-disaccharide 7b (Table 2, entry 7).
Scheme 2. Synthesis of C-Disaccharide 17
Figure 1. Trehalose derivatives.
Other C-disaccharides 8b and 9b (Figure 1) were obtained,
by the simultaneous addition of 1,8-diiodoocta-1,7-diyne 8a
(11) Sakai, N.; Hirasawa, M.; Konahara, T. Tetrahedron Lett. 2003, 44,
4171. Under the conditions described here, no C-pseudoglucal was observed
after 4 days in refluxing toluene.
(12) Auge´, J.; Lubin-Germain, N.; Marque, S.; Seghrouchni, L. J.
Organomet. Chem. 2003, 679, 79.
(13) Isobe, M.; Nishizawa, R.; Nishikawa, T.; Yoza, K. Tetrahedron Lett.
1999, 40, 6927.
(14) Isobe, M.; Saeeng, R.; Nishizawa, R.; Konobe, M.; Nishikawa, T.
Chem. Lett. 1999, 6, 467.
(15) (a) Tanaka, S.; Tsukiyama, T.; Isobe, M. Tetrahedron Lett. 1993,
34, 5757. (b) Tanaka, S.; Isobe, M. Tetrahedron 1994, 50, 5633.
We also showed that pivaloyl and benzyl protecting groups
could be used in this reaction, the time of reaction depending
Org. Lett., Vol. 9, No. 18, 2007
3681

on the leaving-group ability of the protecting group em-
ployed. It is reasonable to think that the mechanism of the
reaction is close to that given by Minehan’s group8 under
Grignard conditions, as we also observed that the selectivity
does not depend on the nature of the protected sugar.
in the presence of Pd/C and further acetylation, the disac-
charide 17 was formed in 66% yield. The configuration was
confirmed by NMR spectroscopy.
In conclusion, we have demonstrated that indium-mediated
alkynylation offers a convenient access to C-glycosides with
good yields and diastereoselectivities.
To assess the scope of the reaction, we attempted the
coupling with glycosyliodoalkyne with the aim to build a
C-disaccharide (Scheme 2). Glycosyl alkyne 1416 was
iodinated as described above, and iodoalkyne 15 was used
for the coupling reaction. After 3 h, the C-disaccharide 16
was identified by TLC and isolated by flash chromatography
in a very good yield of 84%. After hydrogenolysis-reduction
Acknowledgment. This research was supported by the
French Ministry of Research and the CNRS.
Supporting Information Available: General experimen-
tal procedures for reactions, NMR (1H and 13C), characteriza-
tion data for new compounds. This material is available free
of charge via the Internet at http://pubs.acs.org.
(16) Che´nede´, P.; Pothier, P.; Sollogoub, M.; Fairbanks, A. J.; Sinay¨, P.
J. Chem. Soc., Chem. Commun. 1995, 1373.
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