Triphenylphosphine: A catalyst for the synthesis of C-aryl furanosides from furanosyl halides

Article abstract of DOI:10.1016/j.tetlet.2013.12.035

An array of C-aryl furanosides was prepared in good yields from furanosyl halides and aryl Grignard reagents in Et₂O using PPh₃ as a catalyst.

Full text of DOI:10.1016/j.tetlet.2013.12.035

Accepted Manuscript
Triphenylphosphine: a catalyst for the synthesis of C-aryl furanosides from fur-
anosyl halides
Lionel Nicolas, Patrick Angibaud, Ian Stansfield, Lieven Meerpoel, Sébastien
Reymond, Janine Cossy
PII:
S0040-4039(13)02110-2
DOI:
http://dx.doi.org/10.1016/j.tetlet.2013.12.035
TETL 43949
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 August 2013
1 December 2013
9 December 2013
Please cite this article as: Nicolas, L., Angibaud, P., Stansfield, I., Meerpoel, L., Reymond, S., Cossy, J.,
Triphenylphosphine: a catalyst for the synthesis of C-aryl furanosides from furanosyl halides, Tetrahedron
Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.12.035
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Triphenylphosphine: a catalyst for the
synthesis of C-aryl furanosides from
furanosyl halides
Lionel Nicolas, Patrick Angibaud, Ian Stansfield, Lieven Meerpoel, Sébastien Reymond* and Janine Cossy*
O
O
O
X
Ar
Ar
PPh3 (5 mol %)
Et2O
R1O
R1O
R1O
Ar MgBr
(1.5 equiv)
+
R2O
R2O
R2O
+
X = Cl, Br
45 - 95%
dr = 2.5:1 to > 9:1

1
Tetrahedron Letters
jo u rn al ho me p ag e : w ww .e lse vie r .c om
Triphenylphosphine: a catalyst for the synthesis of C-aryl furanosides from
furanosyl halides
a
Lionel Nicolas,a Patrick Angibaud,b Ian Stansfield,b Lieven Meerpoel,c Sébastien Reymond* and Janine
a
Cossy*
a Laboratoire de Chimie Organique, ESPCI ParisTech, UMR CNRS 7084, 10, rue Vauquelin, 75231 Paris Cedex 05, France.
b Janssen Research & Development, a Division of Janssen-Cilag, BP615 – Chaussée du Vexin, 27106 Val de Reuil Cedex, France.
c Janssen Research & Development, a Division of Janssen Pharmaceutica N.V., Turnhoutsweg 30, 2340 Beerse, Belgium.
ARTICLE INFO
ABSTRACT
Article history:
Received
An array of C-aryl furanosides was prepared in good yields from furanosyl halides and aryl
Grignard reagents in Et2O using PPh3 as a catalyst.
Received in revised form
Accepted
2009 Elsevier Ltd. All rights reserved.
Available online
Keywords:
C-furanosides
Cross-coupling
Organocatalysis
Triphenylsphosphine
Grignard reagents
1. Introduction
triphenylphosphine as a catalyst in the synthesis of C-aryl
furanosides from furanosyl halides and Grignard reagents.
Substituted tetrahydrofurans are ubiquitous in bioactive
natural products, and C-nucleosides. These latter can be
considered as stabilized isosteres of N-nucleosides and provide
research opportunities for the study and probing of
nucleobases.1,2 Although numerous methods exist to prepare
C-furanosides, the development of catalytic methods to access
these compounds is still of importance. Among different
methods,3 the metal-catalyzed cross-coupling between furanosyl
halides and organometallic reagents constitutes a method of
choice for the preparation of C-aryl furanosides.4,5,6,7,8 As part of
our synthetic approach to natural products from carbohydrate-
based building blocks9 and development of eco-friendly metal-
catalyzed reactions,10 we would like to report herein the role of
2. Results and discussion
During our investigations on iron-catalyzed cross-coupling for
the preparation of C-aryl glycosides,10b,c our primary results led
to the development of a Fe(OAc)2/XantPhos (3 mol % : 6 mol %)
catalytic system (Scheme 1).11 The cross-coupling of C-bromo
mannopyranose
1
and C-bromo mannofuranose
3 with
phenylmagnesium bromide yielded the desired products 2 and 4
respectively with good diastereoselectivities (> 9:1) but in
moderate yields.
Scheme 1. Iron-catalyzed cross-coupling between 1 and 3
with PhMgBr.
———
* Corresponding authors. Tel.: (+33)140794429; fax: (+33)140794660;
e-mail: janine.cossy@espci.fr; sebastien.reymond@espci.fr

2
Tetrahedron Letters
Grignard reagents13 (Table 2, entries 1-3). In all cases, the
Fe(OAc)2 (3 mol %)
XantPhos (6 mol %)
O
Br
O
expected C-aryl furanosides were isolated in good yields and
diastereoselectivities. 2-Thienylmagnesium bromide was also
reactive however, providing the expected cross-product in
moderate yield (45%) (Table 2, entry 4). No coupling product
was observed when aryl zinc reagents (Table 1, entry 5), aryl
lithium derivatives (Table 1, entry 6) and heteroaryl Grignard
reagents were used (Table 2, entry 7). We have to point out that
alkenyl and alkyl Grignard reagents did not react under these
conditions and the starting material was recovered.
AcO
AcO
AcO
AcO
+
+
BrMg
(1.5 equiv)
OAc
OAc
0 °C → rt, THF
OAc
OAc
30 %
1
2
O
O
O
O
Fe(OAc)2 (3 mol %)
XantPhos (6 mol %)
O
O
Br
BrMg
(1.5 equiv)
0 °C → rt, Et2O
O
O
O
O
62 %
4 (α/β > 9:1)
3
In order to broaden the substrate scope of the PPh3-catalyzed
cross-coupling, orthogonally protected furanoside halides
5-11 were prepared and subjected to the cross-coupling with 1.5
equiv of phenylmagnesium bromide (Table 3). When 5 was
reacted with 1.5 equiv of phenylmagnesium bromide in Et2O, the
β-C-aryl furanoside was isolated in 31% yield and unreacted 5
was recovered in 49%. We have to point out that the α-
furanoside was also observed but not isolated (Table 3, entry 1).
When 5 mol % of PPh3 were added to the reaction, the
conversion of 5 was complete, the β-furanoside was isolated in
68% yield and the α-furanoside was formed in 14% (Table 3,
entry 2). With furanosyl bromide 6 an increase in the yield of the
α-furanoside from 56% to 80% was obtained when 5 mol % of
PPh3 were added to the reaction (Table 3, entries 3 and 4). When
O
PPh2
PPh2
XantPhos
During the course of our optimization process, control
experiments were performed, and the cross-coupling between
phenyl magnesium bromide and C-bromo mannofuranoside 3
was studied (Table 1). When the reaction was performed without
any catalyst or any ligand, in THF at room temperature, no
reaction occurred and, at reflux, decomposition of 3 to
unidentified products was observed (Table 1, entry 1). In the
presence of 5 mol % of PPh3, the desired α-product 4 was
obtained in a low 39% yield (Table 1, entry 2). Surprisingly,
when the reaction was conducted in Et2O, at room temperature
without any catalyst or additive, the yield was increased to 68%
chloro-ribofuranose
7
was reacted with 1.5 equiv of
phenylmagnesium bromide and in the presence of 5 mol % of
PPh3, the reaction was complete and the desired aryl-furanosides
were obtained in 74% isolated yield with a dr of 2.5:1 in favor of
the α-product (Table 3, entries 5, 6). It is worth noting that 7 was
widely used in the synthesis of C-aryl nucleosides by reaction
with diaryl copper7 or toxic diaryl cadmium reagents, and that a
mixture of α- and β-products was obtained.8a,d Therefore, the
PPh3-facilitated cross-coupling is a good alternative for the
preparation of substituted furanosides. However, when the
benzoylated furanosyl bromide 8 and the protected furanosyl
bromides 9, 10 and 11 were involved in the cross-coupling, the
desired products were not obtained and, unidentified compounds
coming from the decomposition of bromides 8 and 9 were
obtained whereas, 10 and 11 were recovered (Table 3, entries 7, 8
and 9).
yield in favor of the α-product 4 (Table 1, entry 3). When a
phosphine, such as XantPhos (6 mol %) or PPh3 (5 mol %), was
used without any metal catalyst, the cross-product 4 (α/β > 9:1)
was isolated in 79% and 89% respectively (Table 1, entries 4 and
5). A polymer bound PPh3 was also used without decreasing the
yield in the coupling product (88%) (Table 1, entry 6).
Table 1. PPh3-catalyzed cross-coupling of PhMgBr and 3a
O
O
O
O
O
O
cat.
Br
+
solvent
BrMg
(1.5 equiv)
O
O
O
O
4(α/β > 9:1)
3
Table 2. Scope of the PPh3-facilitated cross-coupling of 3
b
entry cat. (mol %)
solvent
temperature yield of 4 (%)
with various organometallics.a
c
-
O
O
O
O
O
O
1
2
3
None
THF
THF
Et2O
reflux
reflux
RT
PPh3 (5 mol %)
R-M (1.5 equiv)
O
O
O
Br
R
R
PPh3 (5 mol %)
None
39
68
+
0 °C to RT, Et2O
O
O
O
O
O
O
4
5
XantPhos (6 mol %)
PPh3 (5 mol %)
Et2O
Et2O
RT
RT
79
89
3
α-4
β-4
b
c
entry organometallics
dr (α/β)
yield (%)
93
PPh3 polymer bound
(5 mol %)
OMe
6
Et2O
RT
88
1
2
3
4
5
> 9:1
BrMg
a) Conditions: 3 (0.1 M), cat. (x mol %) then PhMgBr (3 M in Et2O, 1.5
equiv) was added at 0 °C; the reaction medium was warmed to RT and stirred
until no more conversion was observed by GC/MS. b) Yield of the isolated
product,
unidentified products.
> 9:1
> 9:1
> 9:1
_
>95
85
BrMg
α
- and
β
-isomers. c) Decomposition of 3 and formation of
Cl
To our knowledge, a non-metal-catalyzed cross-coupling has
never been developed for the preparation of C-aryl furanosides,
and this unexpected catalytic activity of PPh3 in Et2O12 could
represent an eco-friendly alternative to access such substituted
furanosides. The scope of the PPh3-catalyzed cross-coupling was
extended to electron-rich, electron-poor and sterically hindered
BrMg
d
45
BrMg
S
LiCl.ClZn

3
A. A.; Remesberg, F. E. Curr. Opin. Chem. Bio. 2003,
e
6
7
_
_
-
7, 727-733. (d) Kool, E. T.; Morales, J. C.; Guckian, K.
M. Angew. Chem, Int. Ed. 2000, 39, 990-1009. (e) Kool,
E. T. Acc. Chem. Res. 2002, 35, 936-943.
Li
no reaction,
50% of the
Cl
LiCl.ClMg
N
2. For examples, see: (a) Franchetti, P.; Cappellacci, L.;
Griffantini, M.; Barzi, A.; Nocentini, G.; Yang, H. Y.;
O’Connor, A.; Jayaram, H. N.; Carrell, C.; Golstein, B.
M. J. Med. Chem. 1995, 38, 3829-3837. (b) Walker, J.
A.; Liu, W.; Wise, D. S.; Drach, J. C.; Towsend, J. C. J.
Med. Chem. 1998, 41, 1236-1241. (c) Brotschi, C.;
Häberli, A.; Leumann, C. J. Angew. Chem. Int. Ed.
2001, 40, 3012-3014. (d) Cuppelotti, A.; Cho, Y.; Park,
J.-S.; Strässler, C.; Kool, E. T. Bioconjugate Chem.
2005, 16, 528-534.
starting material
recovered
a) Conditions: 3 (0.1 M in Et2O), PPh3 (5 mol %) then R-[M] (1.5 equiv) was
added at a 0 °C; the reaction medium was warmed to RT and stirred until no
1H NMR
mspoercetrocsocnovpeyr.sico)nYwiealds oofbisseorlvaetedd bpyrodGuCctM, αS. b) Determined by
- and
β
-isomers. d) 3 equiv of
2-thienyl magnesium bromide were used, and the reaction was performed at
reflux. e) decomposition of the starting material to unidentified compounds.
3. (a) Wu, Q. P.; Simmons, C. Synthesis 2004, 1533-1552.
For reviews on cross-coupling reactions of nucleosides,
see: (b) Agrofoglio, L. A.; Gillaizeau, I.; Saito, Y.
Chem. Rev. 2003, 103, 1875-1916. (c) Hocek, M. Eur. J.
Org. Chem. 2003, 245-254.
Worthy of note, similar experiments were conducted on
C-bromo mannopyranose 1, however, for this compound, no
beneficial effect of PPh3 was observed.
4. For addition of Grignards reagents to fluorofurans, see:
Yokoyama, M.; Toyoshima, H.; Shimizu, M.; Mito, J.;
Togo, H. Synthesis 1998, 409-412.
The catalytic activity of PPh3 in the coupling reaction between
an aryl Grignard and a furanosyl halide, could be explained by
the displacement of the Schlenk equilibrium toward
Ar2Mg/MgBr2 and the organomagnesium derivative would be
responsible for the formation of the aryl furanosides. However,
when 3 was treated with Ph2Mg in the presence of MgBr2, the
corresponding C-phenyl furanoside was obtained in a lower yield
than when PhMgBr was used in the presence of PPh3, excluding
partially the active role of Ph2Mg in the coupling reaction. One
other explanation would be that α- and β-furanosides can be
obtained from furanosyl halides via a phosphonium intermediate
A, resulting from the attack of PPh3 onto the furanosyl halide.
The formed O,P-acetal A would then be attacked by nucleophiles
such Grignard reagents, regenerating PPh3 in the reaction media.
However, the formation of the oxonium species B from A, which
could be trapped by the Grignard reagent, cannot be ruled out
(Scheme 2).
5. For addition of Grignards reagents to chlorofurans, see:
(a) Crombie, L.; Wyvill, R. D. J. Chem., Soc. Perkin.
Trans. 1 1985, 1971-1981. (b) Doboszewski, B.
Nucleosides Nucleotides Nucleic Acid 2009, 28, 875-
901. (c) Hashmi, S. A. M.; Hu, X.; Immos, C. E.; Lee, S.
J.; Grinstaff, M. W. Org. Lett. 2002, 4, 4571-4574. (d)
Hocek, M.; Pohl, R.; Klepetářová, B. Eur. J. Org. Chem.
2005, 4525-4528. (e) Ogawa, A. K.; Wu, Y.; McMinn,
D. L.; Liu, J.; Schultz, P. G.; Romesberg, F. E. J. Am.
Chem. Soc. 2000, 122, 3274-3287 (f) Chen, D.-W.;
Beuscher, A. E.; Stevens, R. C.; Lerner, R. A.; Janda, K.
D. J. Org. Chem. 2001, 66, 1725-1732. (g) Scheitzer, B.
A.; Kool, E. T. J. Org. Chem. 1994, 59, 7238-7242. (h)
François, P.; Perilleux, D.; Kempener, Y.; Sonveaux, E.
Tetrahedron Lett. 1990, 31, 6347-6350.
6. For addition of Grignards reagents to bromofurans, see:
Corey, E. J.; Bakshi, R. K.; Shibata, S.; Chen, C.-P.;
Singh, V. K. J. Am. Chem. Soc. 1987, 109, 7925-7926.
7. For the use of copper-catalyzed cross-coupling with
halogenofurans, see: (a) Thompson, A. S.; Tschaen, D.
M.; Simpson, P.; McSwine, D.; Russ, W.; Little, E. D.;
Verhoeven, T. R.; Shinkai, I. Tetrahedron Lett. 1990,
31, 6953-6956. (b) Thompson, A. S.; Tschaen, D. M.;
Simpson, P.; McSwine, D. J.; Reamer, R. A.;
Scheme 2. Proposed mechanism.
O
O
X
P+Ph3
Br-
R1O
R1O
PPh3
R2O
X = Cl, Br
R2O
A
Verhoeven, T. R.; Shinkai, I. J. Org. Chem 1992, 57,
7044-7052. (c) Hainke, S.; Sinkh, I.; Hemmings, J.;
Seitz, O. J. Org. Chem. 2007, 72, 8811-8819.
ArMgX
PPh3
8. For the addition of organocadnium reagents to
halogenofurans, see: (a) Chaudhuri, N. C.; Kool, E. T.
Tetrahedron Lett. 1995, 36, 1795-1798. (b) Chaudhuri,
N. C.; Kool, E. T. Tetrahedron Lett. 1995, 36, 4909-
4010. (c) Ren, R. X.-F.; Chaudhuri, N. C.; Paris, P. L.
Rumney, S. IV; Kool, E. T. J. Am. Chem. Soc. 1996,
118, 7671-7678. (d) Chaudhuri, N. C.; Rem, R. X.-F.;
Kool, E. T. Synlett, 1997, 341-347. (e) Singh, I.; Hecker,
W.; Prasad, A. K.; Parmar, V. S.; Seitz, O. Chem.
Comm. 2002, 500-501. (f) Zhang, L.; Long, H.; Boldt,
G. E.; Janda, K. D.; Schatz, G. C.; Lewis F. D. Org.
Biomol. Chem. 2006, 4, 314-322. (g) Jiang, Y. L.;
Stivers, S. T. Tetrahedron Lett. 2003, 44, 4051-4055. (h)
Griesang, N.; Richert, C. Tetrahedron Lett. 2002, 43,
8755-8758.
O+
O
Ar
R1O
R1O
ArMgX
R2O
R2O
B
C
3. Conclusion
In conclusion we have developed
a
diastereoselective
triphenylphosphine-catalyzed cross-coupling of furanosyl halides
with aryl Grignard reagents producing C-aryl furanosides in
moderate to good yields. Orthogonally protected furanosyl
halides demonstrated different behaviours as the obtained
selectivities were substrate-dependent.
9. Bensoussan, C.; Rival, N.; Hanquet, G.; Colobert, F.;
Reymond, S.; Cossy, J. Tetrahedron 2013, 69, 7759-
7770.
Acknowledgments
10. (a) Guérinot, A.; Reymond, S.; Cossy, J. Angew. Chem.
Int. Ed. 2007, 46, 6521-6524. (b) Nicolas, L.; Angibaud,
P.; Stansfield, I.; Pascal, B.; Meerpoel, L.; Reymond, S.;
Cossy, J. Angew. Chem. Int. Ed. 2012, 51, 11101-11104.
(c) Nicolas, L.; Butkevich, A.; Guérinot, A.; Corbu, A.;
Reymond, S.; Cossy, J. Pure. Appl. Chem. 2013, 85,
1203-1213.
Janssen Research & Development, a Division of Janssen-
Cilag, is gratefully acknowledged for financial support.
References and notes
11. Dongol, K. G.; Koh, H.; Sau, M.; Chai, C. L. L. Adv.
Synth. Catal. 2007, 349, 1015-1018.
1.
For a review on modification of natural DNA see: (a)
Nielsen, P. E. Chem. Biodiversity 2007, 4, 1996-2002.
For reviews on C-nucleosides, see: (b) Wang, L.;
Schultz, P. G. Chem. Commun. 2002, 1-11. (c) Henry,
12. (a) Kim, S.; Kim, Y. C. Synlett 1990, 115-116. (b)
Anders, E.; Hertlein, K.; Stankowiak, A.; Irmer, E.
Synthesis 1992, 577-581. (c) Fujioka, H.; Goto, A.;

4
Tetrahedron Letters
Otake, K.; Kubo, O.; Yahata, K.; Sawama, Y.;
13. A solution of the aryl Grignard reagent in Et2O was
added dropwise to a solution of furanosyl halide (1
equiv, 0.1M) and PPh3 (5 mol %) in Et2O at 0 °C. The
reaction medium was warmed to RT and monitored by
TLC or GC/MS. The reaction was quenched by adding
an aqueous solution of 1M HCl. After extractive
workup, the crude product was purified by silica-gel
chromatography.
Maegawa, T. Chem. Commun. 2010, 46, 3976-3978. For
the preparation of O,P-acetals, see: (a) Maleki, M.;
Miller, A.; Lewer, O. W., Jr. Tetrahedron Lett. 1981, 22,
365-368. (b) Nakamura, E. Tetrahedron Lett. 1981, 22,
663-666. (c) Burkouse, D.; Zimmer, H. Synthesis 1984,
330-331. (d) Tückmantel, W.; Oshima, K.; Utimoto, K.
Tetrahedron Lett. 1986, 27, 5617-5618. (e) Anders, E.;
Hertlein, K.; Meske, H. Synthesis, 1990, 323-326. (f)
Roeschlaub, C. A. Sammes, P. G. J. Chem. Soc., Perkin
Trans. 1 2000, 2243-2248.
Table 3. Scope of the PPh3-catalyzed cross-coupling of furanosyl halides 5-11 with Grignard reagents.a
O
O
O
X
PPh3 (x mol %)
R1O
R1O
R1O
+
+
BrMg
(1.5 equiv)
0 °C to RT, Et2O
R2O
α-12
R2O
R2O
β-12
5, 6, 8-11, X = Br
7, X = Cl
b
c
PPh3
(mol %)
Grignard
reagent
entry
reagent
dr (α/β)
yield (%)
O
Br
TBDPSO
d
1
2
3
4
None
PhMgBr
PhMgBr
PhMgBr
PhMgBr
n.d.
31
O
O
5
5
5 mol %
None
1:4.9
> 9:1
> 9:1
82
O
Br
TBDPSO
e
56
O
O
6
6
5 mol %
80
62
74
O
O
Cl
O
O
5
6
7
none
PhMgBr
PhMgBr
PhMgBr
2.7:1
2.5:1
_
O
7
7
5 mol %
5 mol %
O
O
Br
O
f
-
O
O
8
O
Br
AcO
f
-
8
5 mol %
PhMgBr
_
OAc
AcO
9
O
Br
BzO
2
OBz
5 mol %
no reaction,
9
PhMgBr
_
BzO
g
SM recovered
(2R)-10
(2S)-11
a) Conditions: C-furanosyl halide (0.1 M in Et O), cat. (x mol %) then PhMgBr (3M in Et O, 1.5 equiv) was added at 0 °C; the reaction mαedium was warmed to
material to unidentified compounds. g) The reaction was stirred at reflux.
- and
-product was observed but not isolated, 49% of unreacted 5 were recovered. e) 32% of unreacted 6 were recovered. f) Decomposition of the starting
β
-isomers. d)
2
2
1
RThTeaαnd stirred until no more conversion was observed by GC/MS. b) Determined by H NMR spectroscopy. c) Yield of isolated product,