Chemoselective hydration of glycosyl cyanides to C-glycosyl formamides using ruthenium complexes in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2015.09.040

[RuCl₂(DMSO)₄] in the presence of N-benzylated 1,3,5-triaza-7-phosphaadamantane efficiently catalyzed the hydration of glycosyl cyanides to the corresponding formamide derivatives in water or water-N-methylpyrrolidone solvent mixture

Full text of DOI:10.1016/j.tetlet.2015.09.040

Accepted Manuscript
Chemoselective hydration of glycosyl cyanides to C-glycosyl formamides using
ruthenium complexes in aqueous media
Anup Kumar Misra, Éva Bokor, Sándor Kun, Evelin Bolyog-Nagy, Ágnes
Kathó, Ferenc Joó, László Somsák
PII:
S0040-4039(15)30082-4
DOI:
Reference:
http://dx.doi.org/10.1016/j.tetlet.2015.09.040
TETL 46712
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
29 June 2015
11 September 2015
14 September 2015
Please cite this article as: Misra, A.K., Bokor, É., Kun, S., Bolyog-Nagy, E., Kathó, Á., Joó, F., Somsák, L.,
Chemoselective hydration of glycosyl cyanides to C-glycosyl formamides using ruthenium complexes in aqueous
media, Tetrahedron Letters (2015), doi: http://dx.doi.org/10.1016/j.tetlet.2015.09.040
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Chemoselective hydration of glycosyl cyanides to
C-glycosyl formamides using ruthenium complexes
in aqueous media
Leave this area blank for abstract info.
Anup Kumar Misra, Éva Bokor, Sándor Kun, Evelin Bolyog-Nagy, Ágnes Kathó, Ferenc Joó, László Somsák*

1
Tetrahedron Letters
journal homepage: www.els evier.com
Chemoselective hydration of glycosyl cyanides to C-glycosyl formamides using
ruthenium complexes in aqueous media
Anup Kumar Misra,a,b Éva Bokor,b Sándor Kun,b Evelin Bolyog-Nagy,c Ágnes Kathó,c Ferenc Joó,a,c
László Somsákb*
aMTA-DE Homogeneous Catalysis and Reaction Mechanisms Research Group, H-4010 Debrecen, POB 7, Hungary
bDepartment of Organic Chemistry, University of Debrecen, H-4010 Debrecen, POB 20, Hungary
cDepartment of Physical Chemistry, University of Debrecen, H-4010 Debrecen, POB 7, Hungary
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
[RuCl2(DMSO)4] in the presence of N-benzylated 1,3,5-triaza-7-phosphaadamantane efficiently
catalyzed the hydration of glycosyl cyanides to the corresponding formamide derivatives in
water or water–N-methylpyrrolidone solvent mixtures at 105 ºC. O-Acetyl, O-benzoyl, and O-
benzyl protecting groups, anomeric bromide and azide substituents as well as double bonds were
shown to be compatible with these reaction conditions.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
C-glycoside
amide
nitrile
ruthenium complex
water
———
*Corresponding author. Tel.: +3652512900 ext 22348; Fax: +3652512744; E-mail: somsak.laszlo@science.unideb.hu

2
Tetrahedron Letters
C-Glycosyl formamide (anhydro-aldonamide) derivatives
reaction conditions has been reported from one of our
laboratories using a combination of a water soluble catalyst,
are an important class of molecules used in the synthesis of
several C-glycosylated and glycosylidene-spiro-heterocyclic
[RuCl2(DMSO)4],
and
N-benzylated
1,3,5-triaza-7-
compounds
which possess
promising pharmaceutical
phosphaadamantane (pta-Bn)Cl, as a ligand (catalyst:ligand ratio;
applications.1,2 The most straightforward and atom economical
approach for the preparation of these compounds is the hydration
1:3).12
Expanding on this earlier report, herein, we disclose the
application of this catalyst system for the preparation of C-
glycosyl formamide derivatives from glycosyl cyanides (Table
1). Initially a combination of [RuCl2(DMSO)4] (10 mol%) and
(pta-Bn)Cl (30 mol%) were added to a suspension of O-
peracetylated β-D-galactopyranosyl cyanide (1a; 100 mg) in
water (5 mL) and the reaction mixture stirred vigorously at 105
°C. A clear solution was observed after 10 min, and the C-
galactosyl formamide derivative 2a was formed cleanly in 85%
yield after 2 h. After optimizing the reaction conditions, it was
established that a combination of 5 mol% catalyst and 15 mol%
ligand in water (4 mL/100 mg of substrate) was sufficient to
obtain compound 2a in 85% yield. Application of the optimized
conditions to other O-acetyl protected glycosyl cyanides (1b,c)
furnished the corresponding products 2b,c with excellent yields
(Table 1).13
of
glycosyl
cyanides
(anhydro-aldononitriles).
This
transformation is conventionally performed using harsh acidic
reaction conditions (e.g. HBr-AcOH3 or TiCl4 ), involving the
4
requirement of several additional precautionary measures.
Therefore, it is quite pertinent to develop a mild, neutral and user
friendly reaction to obtain these versatile intermediates.
A
large number of reports have appeared regarding
chemoselective hydration of the nitrile group using a variety of
reaction conditions.5 Among several approaches, metal catalyzed
reactions have attracted special attention due to the fact that
metal ions are able to activate the nitrile group and water as the
nucleophile by forming a coordination transition state complex.
Efforts have been made to develop transition metal catalyzed
homogeneous6 and heterogeneous7 reaction conditions. Besides
these, chitosan supported ruthenium catalyst,8 potassium tert-
butoxide mediated hydration,9 and microwave assisted hydration
of nitriles10 were also studied. Several reports have also appeared
on the use of biocatalysis for this transformation.11 Recently, the
hydration of aromatic and aliphatic nitriles under aqueous
Table 1. Chemoselective hydration of glycosyl cyanides.
[RuCl2(DMSO)4] (5 mol%)a
(pta-Bn)Cl (15 mol%)a
O
O
CN
CONH2
Gly
Gly
Solvent A: H2Ob
Solvent B: H2O-NMPc
105 °Cd
1a-n
2a-n
Gly-CN
Solvent
A
Time
(h)
Ref.
Gly-CN
Solvent
Time
(h)
Ref.
2
2
yielde
(%)
yielde
(%)
4
16
2
85
Ag
B
55
30
50
74
(84)f
D-Glcp
D-Galp
h
a
13
h
AcO
AcO
OAc
O
A
A
3
3
82
87
Ag
B
4
3
-
-
h
-
CN
D-Xylp
b
AcO
Br
i
3b
-
Ag
B
60
48
-
52i
D-Arap
j
c
3b
h
17
2h
Ag
B
60
20
65
82
Ag
B
72
8
-
72j
D-Glcp
d
k
14
Ag
B
50
5
68
80
A
2
84
D-Xylp
l
e

3
B
B
4
3
80
84
-
A
6
80
-
-
m
D-Ribp
f
15
h
Ag
B
48
48
-
h
-
D-Ribf
g
n
a See structures below for [RuCl2(DMSO)4] and (pta-Bn)Cl (N-benzylated 1,3,5-triaza-7-phosphaadamantane); b 4 mL/100 mg; c N-
f
Methyl-2-pyrrolidone (2:1 v/v; 3 mL/100 mg); d Oil bath temp.; e Isolated yield; Yield obtained using 2 g of the substrate; g Sodium
dodecyl sulphate (SDS, 5 mol%) was added; h Starting material consumed to produce a complex reaction mixture; i Starting material not
fully consumed and was recovered (20%); j Reaction carried out using [RuCl2(DMSO)4] (15 mol%) in the absence of (pta-Bn)Cl.
When O-perbenzoylated β-D-glucopyranosyl cyanide 1d was
treated with the catalyst combination in water at 105 °C the
reaction mixture did not become homogeneous and the
compound remained suspended even after 48 h, with TLC
indicating no transformation. It was reasoned that the failure of
the reaction could be due to the significantly lower solubility of
the O-benzoyl derivatives in comparison to that of the O-
acetylated compounds. Therefore, sodium dodecyl sulphate
(SDS, 5 mol%) was added to the reaction mixture as a surfactant
resulting in the formation of the corresponding formamide
derivative 2d in 65% yield after 60 h. Addition of SDS was also
beneficial in the cases of 1e and the O-perbenzylated 1h, which
gave the corresponding formamide derivatives 2e and 2h in good
yields (Table 1).
cyano groups could form a coordination complex with the Ru
atom, which could support the hydration of this nitrile.
Unsaturated compounds 1l and 1m furnished the respective
formamides 2l (84%) and 2m (80%) in water without the
requirement of the surfactant additive (SDS). The enol-ester type
1n did not furnish any of the expected product under the
examined reaction conditions.
In order to check the role of the ligand in the reaction,
compound 1a was treated with [RuCl2(DMSO)4] (varied
quantities from 5 to 15 mol%) in water as well as mixed solvent
in the absence of the (pta-Bn)Cl ligand. Under these conditions
only decomposition of 1a was observed even after a prolonged
reaction time of 2 days, while formation of the expected product
2a could not be detected by TLC.
An additional method to improve the solubility of the
It is worth mentioning that no trace of the corresponding
carboxylic acid resulting from over-hydrolyzed product was
observed under the reaction conditions. The C-glycosyl
formamide derivatives were identified by NMR and mass
spectral analysis.18 The reaction was successfully applied in a
scaled up preparation of C-glycosyl formamide 2a (84 % yield in
a 2 g batch). In the cases of compounds 1a-c,l,m the catalyst
combination present in the aqueous phase after reaction work-up
was recycled up to three times without any significant loss of the
catalytic potential.
substrates by adding
a co-solvent was also tried. Thus,
compounds 1d-h were treated with the catalyst combination in a
mixed solvent [water-NMP (N-Methyl-2-pyrrolidone) = 2:1 v/v]
at 105 °C. In these cases the reaction mixtures became clear after
5 min and smooth formation of the corresponding formamide
derivatives 2d-h was achieved in very good yields and
significantly shorter times (Table 1).
Next, more complex substrates with bromo (1i,j) and azido
(1k) substituents as well as double bonds (1l-n) were studied
under the optimized conditions. Using water as the solvent and
SDS (5 mol%) as the additive, the reactions of compounds 1i-k
produced complex mixtures from which the expected products
could not be detected by TLC. In the mixed water-NMP solvent,
O-acetylated 1i also gave a complex mixture, however, the
analogous O-benzoylated 1j produced the corresponding
formamide 2j in 52% yield together with unreacted starting
material. Since these substrates contained bromo and azido
groups, which might have cross reactivity with the (pta-Bn)Cl
ligand, the reactions were then carried out in the absence of (pta-
Bn)Cl. However, bromo-cyanide 1i produced a complex mixture
upon treatment with [RuCl2(DMSO)4] (15 mol%) both in water
and the mixed solvent. Although the reaction in water resulted in
formation of a complex mixture, gratifyingly azido-cyanide 1k
furnished the corresponding formamide derivative 2k in 72%
yield after 8 h upon treatment with [RuCl2(DMSO)4] (15 mol%)
in the mixed solvent. It is presumed that the adjacent azido and
Typical procedure using water as solvent: To a solution of
compound 1a (100 mg, 0.28 mmol) in water (4 mL) were added
[RuCl2(DMSO)4] (7 mg, 0.014 mmol) and (pta-Bn)Cl (12 mg,
0.042 mmol) and the reaction mixture was stirred at 105 °C (bath
temperature) for 2 h. The mixture was cooled to room
temperature and extracted with EtOAc (20 mL). The organic
layer was dried (Na2SO4) and concentrated under reduced
pressure. The crude product was crystallized from EtOH to give
pure 2a (90 mg, 85%). The aqueous layer was reused for another
batch of reaction by adding 1a (100 mg, 0.28 mmol) and stirring
at 105 °C for 2 h to give 2a (90 mg, 85%). Similar recycling of
the catalyst system was applied for the preparation of 2b,c,l,m to
furnish the products as mentioned in Table 1.
Typical procedure using water-NMP as solvent: To a
solution of compound 1d (100 mg, 0.16 mmol) in water-NMP (3
mL; 2:1 v/v) were added [RuCl2(DMSO)4] (4 mg, 0.008 mmol)

4
Tetrahedron Letters
9. Midya, G. C.; Kapat, A.; Maiti, S.; Dash, J. J. Org. Chem. 2015, 80,
and (pta-Bn)Cl (7 mg, 0.024 mmol) and the reaction mixture
4148-4151.
was stirred at 105 °C (bath temperature) for 20 h. The mixture
was cooled to room temperature, diluted with H2O (30 mL) and
extracted with EtOAc (20 mL). The organic layer was dried
(Na2SO4) and concentrated under reduced pressure. The crude
product was crystallized from EtOH to give pure 2d (85 mg,
82%). Similar reaction conditions were applied for the
preparation of 2e-h,j,k.
10. Tu, T.; Wang, Z.; Liu, Z.; Feng, X.; Wang, Q. Green Chem. 2012, 14,
921-924.
11. (a) Kovacs, J. A. Chem. Rev. 2004, 104, 825-848; (b) Kobayashi, M.;
Shimizu, S. Curr. Opin. Chem. Biol. 2000, 4, 95-102.
12. Bolyog-Nagy, E.; Udvardy, A.; Joó, F.; Kathó, Á. Tetrahedron Lett.
2014, 55, 3615-3617.
13. McMillan, K. G.; Tackett, M. N.; Dawson, A.; Fordyce, E.; Michael
Paton, R. Carbohydr. Res. 2006, 341, 41-48.
14. Somsák, L.; Bokor, É.; Czibere, B.; Czifrák, K.; Koppány, C.; Kulcsár,
L.; Kun, S.; Szilágyi, E.; Tóth, M.; Docsa, T.; Gergely, P. Carbohydr.
Res. 2014, 399, 38-48.
15. Buffel, D. K.; Simons, B. P.; Deceuninck, J. A.; Hoornaert, G. J. J. Org.
Chem. 1984, 49, 2165-2168.
16. DeShong, P.; Soli, E. D.; Slough, G. A.; Sidler, D. R.; Elango, V.;
Rybczynski, P. J.; Vosejpka, L. J. S.; Lessen, T. A.; Le, T. X.; Anderson,
G. B.; von Philipsborn, W.; Vöhler, M.; Rentsch, D.; Zerbe, O. J.
Organometallic Chem. 2000, 593-594, 49-62.
17. Somsák, L.; Sós, E.; Györgydeák, Z.; Praly, J.-P.; Descotes, G.
Tetrahedron 1996, 52, 9121-9136.
In summary, efficient chemoselective reaction conditions have
been developed for the hydration of glycosyl cyanides to C-
glycosyl formamide derivatives using a water soluble ruthenium
complex in aqueous media. These conditions can be considered
as practical alternatives to the existing protocols for this
transformation due to their environmental compatibility, mild
conditions, operational simplicity, high yields with excellent
chemoselectivity, and applicability in the presence of the acid
and base sensitive functional groups used in carbohydrate
derivatization.
18. Analytical data for the compounds which have not been reported earlier:
25
Compound 2c: Rf = 0.2 (hexane-EtOAc; 2:3); [α]D −53.1 (c 1.0,
1
CHCl3); H NMR (360 MHz, CDCl3): δ 6.46 (br s, 1 H, NH), 6.12 (br s,
Acknowledgments
1 H, NH), 5.40 (pseudo t, J = 8.0 Hz, 1 H, H-3), 5.32 (br s, 1 H, H-5),
5.13 (dd, J = 11.0, 3.5 Hz, 1 H, H-4), 4.09 (dd, J = 12.5, 4.0 Hz, 1 H, H-
6a), 3.84 (d, J = 8.0 Hz, 1 H, H-2), 3.77 (dd, J = 12.5, 2.5 Hz, 1 H, H-6b),
2.16, 2.08, 2.02 (3 s, 9 H, 3 COCH3); 13C NMR (90 MHz, CDCl3): δ
170.1, 169.9 (CONH2, COCH3), 76.7 (C-2), 70.7 (C-4), 67.9 (C-5), 67.3
(C-6), 66.8 (C-3), 20.8, 20.7, 20.5 (COCH3); ESI-MS: 326.0 [M+Na]+;
Anal. Calcd for C12H17NO8: C, 47.53; H, 5.65; N, 4.62. Found: C, 47.68;
H, 5.77; N, 4.69.
A.K.M. thanks the Indian National Science Academy (INSA), the
Hungarian Academy of Science (HAS), and Bose Institute,
Kolkata, India for financing his stay at the University of
Debrecen. The work was supported by the Hungarian Scientific
Research Fund (OTKA PD105808) as well as the BAROSS
REG_EA_09-1-2009-0028 (LCMS_TAN) project. Dr. A. Kiss-
Szikszai is thanked for recording the mass spectra and elemental
analyses.
25
Compound 2f: Rf = 0.2 (hexane-EtOAc; 3:2); [α]D −41.4 (c 1.0,
1
CHCl3); H NMR (360 MHz, CDCl3): δ 8.10-7.29 (m, 15 H, Ar-H), 6.47
(br s, 1 H, NH), 6.15-6.13 (m, 1 H, H-4), 5.82 (br s, 1 H, NH), 5.62 (dd, J
= 7.8, 2.4 Hz, 1 H, H-3), 5.50-5.45 (m, 1 H, H-5), 4.53 (d, J = 7.8 Hz, 1
H, H-2), 4.27 (dd, J = 9.3, 4.5 Hz, 1 H, H-6a), 4.04 (t, J = 9.3 Hz each, 1
H, H-6b); 13C NMR (90 MHz, CDCl3): δ 170.2, 165.2, 165.1 (CONH2,
PhCO), 133.5, 133.4, 133.2, 129.9, 129.8, 129.7, 129.5, 129.2, 129.0,
128.6, 128.4, 128.3 (Ar-C), 73.9 (C-2), 68.7 (C-3), 68.4 (C-4), 67.1 (C-
5), 63.8 (C-6); ESI-MS: 512.1 [M+Na]+; Anal. Calcd for C27H23NO8: C,
66.25; H, 4.74; N, 2.86. Found: C, 66.32; H, 4.80; N, 2.80.
References and notes
1. a) Somsák, L.; Czifrák, K.; Tóth, M.; Bokor, É.; Chrysina, E. D.;
Alexacou, K.-M.; Hayes, J. M.; Tiraidis, C.; Lazoura, E.; Leonidas, D.
D.; Zographos S. E.; Oikonomakos, N. G. Curr. Med. Chem. 2008, 15,
2933-2983; (b) Somsák, L.; Nagy, V.; Hadady, Z.; Docsa, T.; Gergely, P.
Curr. Pharm. Design, 2003, 9, 1177-1189; (c) Somsák, L. Comptes
Rendus Chimie 2011, 14, 211-223.
25
Compound 2m: Rf = 0.18 (hexane-EtOAc; 7:3); [α]D −21.8 (c 0.5,
1
CHCl3); H NMR (360 MHz, CDCl3): δ 8.05-7.38 (m, 15 H, Ar-H), 6.51
(br s, 1 H, NH), 6.30 (d, J = 2.7 Hz, 1 H, H-3), 6.12 (br s, 1 H, NH), 5.90
(strongly coupled m, 1 H, H-4), 5.81 (dd, J = 6.7, 5.3 Hz, 1 H, H-5),
4.85-4.81 (m, 1 H, H-6), 4.78-4.67 (m, 2 H, H-7ab); 13C NMR (90 MHz,
CDCl3): δ 166.1, 165.4, 165.0 (PhCO), 162.7 (CONH2), 146.5 (C-2),
133.7, 133.4 (2), 129.9, 129.8, 129.7, 129.3, 129.2, 128.8, 128.5 (2),
128.4 (Ar-C), 103.6 (C-3), 75.3 (C-4), 67.3 (C-5), 67.2 (C-6), 61.5 (C-7);
ESI-MS: 524.1 [M+Na]+; Anal. Calcd for C28H23NO8: C, 67.06; H, 4.62;
N, 2.79. Found: C, 67.30; H, 4.75; N, 2.76.
2. (a) Páhi, A.; Czifrák, K.; Kövér, K. E.; Somsák, L. Carbohydr. Res.
2015, 403, 192-201; (b) Bokor, É.; Szilágyi, E.; Docsa,T.; Gergely, P.;
Somsák, L.Carbohydr. Res. 2013, 381, 179-186; (c) Somsák, L.; Kovács,
L.; Tóth, M.; Ősz, E.; Szilágyi, L.;Györgydeák, Z.; Dinya, Z.; Docsa, T.;
Tóth, B.; Gergely, P. J. Med. Chem. 2001, 44, 2843-2848; (d) Bokor, É.;
Docsa, T.; Gergely, P.; Somsák, L. ACS Med. Chem. Lett. 2013, 4, 612-
615; (e) Felföldi, N.; Tóth, M.; Chrysina, E. D.; Charavgi, M.-D.;
Alexacou, K.-M.; Somsák, L. Carbohydr. Res. 2010, 345, 208-213; (f)
McMillan, K. G.; Tackett, M. N.; Dawson, A.; Fordyce, E.; Paton, R. M.
Carbohydr. Res. 2006, 341, 41-48; (g) Lichtenthaler, F. W.; Nakamura,
K.; Klotz, J. Angew. Chem. Int. Ed. Engl. 2003, 42, 5838-5843; (h) Kiss,
L.; Somsák, L. Carbohydr. Res. 1996, 291, 43-52; (i) Poonian, M. S.;
Nowoswiat, E. F. J. Org. Chem. 1980, 45, 203-208.
3. (a) Myers, R. W.; Lee, Y. C. Carbohydr. Res. 1986, 152, 143-158; (b)
Somsák, L.; Nagy, V. Tetrahedron: Asymmetry 2000, 11, 1719-1727.
4. BeMiller, J. N.; Yadav, M. P.; Kalabokis, V. N.; Myers, R. W.
Carbohydr. Res. 1990, 200, 111-126.
5. (a) Schaefer, F. C. In The Chemistry of the Cyano Group: Nitrile
Reactivity; Rappoport, Z., Ed.; Interscience: New York, 1970; pp 239-
305; (b) Bailey, P. D.; Mills, T. J.; Pettecrew, R. A. in Comprehensive
Organic Functional Group Transformations II; Katritzky, A. R.; Taylor,
R. J. K. Eds., Vol 5, Elsevier, Oxford, 2005, pp 201-294.
6. (a) Kukushkin, V. Y.; Pombeiro, A. J. L. Chem. Rev. 2002, 102, 1771-
1802; (b) Pombeiro, A. J. L.; Kukushkin, V. Y. Comprehensive
Coordination Chemistry II, 2004, 1, 639-660; (c) Yamaguchi, K.;
Matsushita, M.; Mizuno, N. Angew. Chem. Int. Ed. Engl. 2004, 43, 1576-
1580; (d) Ahmed, T. J.; Knapp, S. M. M.; Tyler, D. R. Coord. Chem.
Rev. 2011, 255, 949-974; (e) Garcia-Alvarez, R.; Francos, J.; Tomas-
Mendivil, E.; Crochet, P.; Cadierno, V. J. Organometallic Chem. 2014,
771, 93-104.
7. (a) Tamura, M.; Wakasugi, H.; Shimizu, K. -I.; Satsuma, A. Chem. Eur.
J. 2011, 17, 11428-11431; (b) Liu, Y. -M.; He, L.; Wang, M.-M.; Cao,
Y.; He, H.-Y.; Fan, K.-N.; ChemSusChem 2012, 5, 1392-1396; (c)
Hirano, T.; Uehara, K.; Kamata, K.; Mozuno, N. J. Am. Chem. Soc.
2012, 134, 6425-6433; (d) Battilocchio, C.; Hawkins, J. M.; Ley, S. V.
Org. Lett. 2014, 16, 1060-1063.
8. Matsuoka, A.; Isogawa, T.; Morioka, Y.; Knappett, B. R.; Wheatley, A.
E. H.; Saito, S.; Naka, H. RSC Adv. 2015, 5, 12152-12160.