A one-pot, copper-catalyzed cascade route to 2-indolyl-C-glycosides

Article abstract of DOI:10.1002/ejoc.201201208

An efficient and high-yielding, one-pot, Cu-catalyzed synthesis of 2-indolyl-C-glycosides is delineated. The sequence involves a cascade Sonogashira type coupling and a hydroamination reaction between sugar-derived alkynes and N-tosyl-o-iodoaniline follow

Full text of DOI:10.1002/ejoc.201201208

FULL PAPER
DOI: 10.1002/ejoc.201201208
A One-Pot, Copper-Catalyzed Cascade Route to 2-Indolyl-C-glycosides
Parthasarathi Subramanian[a] and Krishna P. Kaliappan*[a]
Dedicated to Professor G. S. R. Subba Rao on the occasion of his 75th birthday
Keywords: Carbohydrates / C-glycosides / Nitrogen heterocycles / Alkynes / Copper / Domino reactions
An efficient and high-yielding, one-pot, Cu-catalyzed syn-
thesis of 2-indolyl-C-glycosides is delineated. The sequence
involves a cascade Sonogashira type coupling and a hydro-
amination reaction between sugar-derived alkynes and N-
tosyl-o-iodoaniline followed by removal of the N-tosyl group
to provide a library of 2-indolyl-C-glycosides in moderate to
excellent yields.
Introduction
The C-aryl glycosides[1] constitute an important class of
C-glycosides, and comprise a large number of biologically
active natural products that have an aromatic ring linked to
the anomeric carbon of a sugar through a C–C bond. When
a nitrogen heterocycle is attached to the anomeric carbon
of the sugar through a C–C bond, it leads to another inter-
esting class of C-glycosides[2] that display potent antiviral
and anticancer activities due to their structural similarity to
the naturally-occurring N-nucleosides. 2-Indolyl-C-glycos-
ides (Scheme 1) represent one such class of C-glycosides
with a heteroaryl aglycon, exhibiting interesting biological
activities.[3]
Although several methods are available for the synthesis
of 2-indole derivatives,[4] there are only a handful of reports
on the synthesis of 2- and 3-indolyl-C-glycosides, which
mostly involve the addition of N-protected lithio-indoles
onto sugar-derived lactones or lactols followed by reduction
or cyclization.[5] Recently, as a part of their synthetic studies
on α-C-mannosyltryptophan,[6] Nishikawa and co-workers
reported a three-step protocol for the construction of 2-
indolyl-C-glycosides[7] that involves a Pd-mediated Sonoga-
shira coupling of sugar-derived alkynes with N-tosyl-o-
iodoaniline, a Cu-mediated Castro cyclization, and subse-
quent tetrabutylammonium fluoride (TBAF)-assisted cleav-
age of the N-tosyl group (Scheme 2). Although this proto-
col serves as a general method for the synthesis of a variety
of 2-indolyl-C-glycosides, it requires three individual steps
to construct the indole skeleton. As part of our ongoing
Scheme 1. Proposed structures of 2-indolyl-C-glycosides 2 and 3
from Isatis indigotica.
interest in the synthesis of C-aryl glycosides[8] and also in
view of the biological importance of 2-indolyl-C-glycosides,
herein, we report a mild, inexpensive, CuI-catalyzed one-
pot synthesis of 2-indolyl-C-glycosides from N-tosyl-
iodoaniline and various ethynyl C-glycosides. This method
employs a domino C–C bond formation to internal alkynes
followed by a hydroamination/annulation reaction and
TBAF-mediated N-tosyl deprotection. During the course of
our preliminary studies on this work, Kotora and co-
workers[9] reported a Pd-catalyzed, two-step methodology
for the construction of 2-indolyl-C-glycosides that involves
a Pd-mediated Sonogashira coupling, followed by a Pd-cat-
alyzed hydroamination/cyclization (Scheme 2). This proto-
col also requires a couple of steps for the construction of
the indole framework, and use of the costly JohnPhos li-
gand was imperative for the hydroamination.
[a] Department of Chemistry, Indian Institute of Technology
Bombay,
Powai, Mumbai 400076, India
E-mail: kpk@chem.iitb.ac.in
Homepage: http://www.chem.iitb.ac.in/~kpk
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201201208.
Eur. J. Org. Chem. 2013, 595–604
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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P. Subramanian, K. P. Kaliappan
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Scheme 2.
To test the premise, we selected galactose-derived alkyne the formation of the desired product, N-tosyl-2-indolyl-C-
4[8a] and 2-iodoaniline 5 (R = H) as our model substrates galactoside 6 (R = Ts), the yield (18%) was far from satis-
to identify suitable reaction conditions for the one-pot syn- factory. Nevertheless, encouraged by the formation of the
thesis of 2-indolyl-C-glycosides. To our surprise, all desired product, we then optimized the reaction conditions
attempts to perform the reaction under various Pd-cata- to improve the yield. Thus, this reaction was attempted un-
lyzed reaction conditions[10] failed (Scheme 3, Table 1) and, der Microwave irradiation conditions,[10b] which led to a
instead, led to the formation of an intractable mixture from significant improvement in the yield of the reaction, afford-
which even traces of the desired product could not be iden- ing the required product in modest yield (55%; entry 7). In
tified (entries 1–4). We then turned our attention to the one- our efforts to optimize the reaction conditions further, we
pot reaction conditions reported by Oskooie, Heravi and next looked at copper-based catalysts and chose the Venkat-
co-workers[11] for the synthesis of 2-phenyl indoles. Under araman catalyst[13a] [Cu(Phen)(PPh3)2]NO3, which has been
these conditions, the reaction proceeded smoothly but successfully used in one-pot syntheses of benzofurans and
stopped at the Sonogashira-coupled product 8 (R = H) with 2-indole derivatives from 2-iodophenol and 2-iodoaniline,
concomitant partial epimerization at the glycosidic center respectively, by the group of Venkataraman[13] and Cac-
(87%, dr 3:1) (entry 5). These results substantiate the chi.[14]
requirement for an electron-withdrawing group on the ni-
When we attempted the reaction of 4 with 2-iodoaniline
trogen atom for the concomitant annulation by enhancing under the reported conditions (entry 8), only the Sonoga-
the acidity of NH in N-tosyl-o-iodoaniline 5 (R = Ts). Thus, shira type coupling product 8 (R = H) (67%), with partial
the reaction of N-tosylated o-iodoaniline 5 (R = Ts) with epimerization at the glycosidic center (dr 1.75:1) (entry 8),
galactose-derived alkyne 4 under Larock’s conditions[12] was obtained. This observation further underlines the im-
(entry 6) was attempted. Although it was heartening to see portance of having an electron-withdrawing group on the
Scheme 3. Cascade synthesis of 2-indolyl-C-glycosides.
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One-Pot Synthesis of 2-Indolyl-C-glycosides
Table 1. Reaction optimization for the synthesis of galactose de- through the addition of an external reagent. In our search
rived N-tosyl-2-indolyl-C-glycoside 6 (R = Ts) from galactose de-
for compatible conditions to cleave the N-tosyl group, we
rived alkyne 4 and N-tosyl-iodoaniline 5.
found TBAF-mediated removal to be suitable.[15] Thus, the
Enty
1
R
H
Reaction conditions
Yield of 6 (%)[a] Yield of 8 (%)[a]
one-pot cascade reaction of alkyne 4 and 5 (R = Ts) in the
presence of 10 mol-% [Cu(Phen)(PPh3)2]NO3 and K3PO4
(3 equiv.) at 110 °C provided N-tosyl-2-indolyl-C-glycoside
6, and subsequent addition of TBAF (5 equiv.) at 110 °C
promoted the formation of the desired 2-indolyl-C-galact-
oside 7 in 89% yield (Scheme 4). It should be noted that
the above one-pot reaction involves three sequential trans-
formations: the Sonogashira-type coupling, cyclative-hydro-
amination, and TBAF-mediated removal of N-Ts group.
These optimized procedures were then applied to a vari-
ety of sugar-derived alkynes 4a–i in combination with N-
tosyl-iodoaniline 5 (R = Ts) to generate a library of 2-
indolyl-C-glycosides 7a–i (Table 2, R = H) through a one-
pot reaction. In a similar way, N-tosyl-2-indolyl-C-glycos-
ides 6a–i were also synthesized from alkynes 4a–i in the
absence of TBAF (Table 2, R = Ts). Thus, d-glucose-de-
rived alkyne 4a,[8a] under the optimized one-pot conditions,
afforded 2-indolyl-C-glycoside 7a in excellent yield (81%).
Similarly, d-glucose-derived alkyne 4b with a free hydroxy
group was also found to be compatible with these condi-
Pd(OAc)2, PPh3,
K2CO3, LiCl, DMF
Pd(OAc)2, PPh3,
K2CO3, Bu4NBr, DMF
Pd(OAc)2, Et3N, NMP
PdCl2, Na2CO3, LiCl,
DMF
–
–
2
H
–
–
3
4
H
H
–
–
–
–
5
6
H
Pd(PPh3)2Cl2, CuI,
Et3N,
DMF
–
87 (3:1)[b]
Ts Pd(OAc)2, PPh3,
nBu4NBr, Na2CO3,
DMF
18
–
7
8
Ts Pd(OAc)2, Et3N, NMP,
MW (100 W, 125 °C)
55
–
–
H
[Cu(PPh3)2phen]NO3,
Cs2CO3, 110 °C,
67 (1.75:1)[b]
toluene, then tBuONa
9
Ts [Cu(PPh3)2phen]NO3,
K3PO4, 110 °C, toluene
83
–
[a] Isolated yield. [b] Diastereomeric ratio given in parentheses.
nitrogen atom to facilitate the subsequent cyclative-hydro- tions, affording the required product 7b in 90% yield. It is
amination through effective stabilization of the η2 amine- noteworthy that the free hydroxy group was unaffected un-
acetylene-Cu complex. Thus, after extensive optimization der these reaction conditions. Furthermore, d-ribose-de-
with N-tosyl-2-iodoaniline 5 (R = Ts), we were pleased to rived alkynes 4c–f furnished the corresponding 2-indolyl-C-
find exclusive formation of the desired N-tosyl-2-indolyl-C- glycoside 7c–f in good yields. In the case of alkyne 4d, the
galactoside 6 (R = Ts) (entry 9) in excellent yield (83%) in required glycoside product 7d was obtained in 83% yield
the presence of [Cu(Phen)(PPh3)2]NO3 (10 mol-%) catalyst accompanied by concomitant cleavage of the TBS group, as
and K3PO4 after heating at reflux in toluene.
anticipated. The diastereomeric mixture of ribose-derived
Although our primary aim was to realize the synthesis propargyl alkyne 4e (α,β; 2.4:1) afforded the desilylated
of 2-indolyl-C-glycosides without amine protection through product α-7e in 67% yield as the major product, and the
a cascade reaction, the requirement for an electron-with- minor product, 2-indolyl-C-β-glycoside β-7e, was isolable
drawing group (Ts) proved to be crucial (see above). There- from the other impurities. However, in the absence of
fore, we sought to remove the temporary masking group TBAF, glycosides α-6e and β-6e were obtained in an ap-
(Ts) in the same pot upon formation of the indole skeleton proximate 2:1 ratio in favor of the former. Moreover, the
Scheme 4. One-pot synthesis of 2-indolyl-C-glycosides.
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P. Subramanian, K. P. Kaliappan
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Table 2. Cu(I)-catalyzed synthesis of 2-indolyl-C-glycosides.
one-pot reaction of alkyne 4e required prolonged heating at
elevated temperature (32 h, 140 °C) to approach completion
to afford the required product β-7e. When we attempted to
extend the scope of this strategy to the synthesis of bis-
indolyl-C-glycoside from bis-alkyne 4f, surprisingly, only se-
lective formation of the mono indolyl-C-glycoside 7f was
observed (92%), with the propargyl moiety remaining in-
tact.
Remarkably, to the best our knowledge, this is the first
report on selective formation of mono indolyl-C-glycoside
from a bis-alkynyl sugar derivative. Subsequently, mannose-
derived alkynes 4g and 4h[8a] were also found to undergo
the one-pot reaction under the optimized conditions to fur-
nish indolyl glycosides 7g and 7h in 86 and 85% yields,
respectively.
When we attempted to extent to one-pot reaction to
include the biologically important nucleoside substrate, β-
thymidine-derived alkyne 4i, however, disapointingly, an in-
tractable complex mixture was obtained. Nevertheless, the
corresponding N-tosyl-indolyl-C-glycoside 6i could be ob-
tained from 4i in 76% yield in the absence of TBAF.
Conclusions
We have accomplished the synthesis of a variety of N-
tosyl-2-indolyl-C-glycosides through a cascade reaction of
C-alkynyl glycosides that involves a sequential Sonogashira
type coupling and cyclative-hydroamination. We have also
extended this strategy to develop a one-pot synthesis of 2-
indolyl-C-glycosides through TBAF-mediated removal of
the N-tosyl group. Notable features of this protocol include
tolerance to sensitive functional groups, and the selective
functionalization of sugar-derived bis-alkyne. Thus, the de-
scribed method serves as a straightforward alternative pro-
tocol for the synthesis of 2-indolyl-C-glycosides, and also
facilitates the synthesis of related natural products. Further
efforts to extend the scope of this methodology will include
the total synthesis of α-C-mannosyl-tryptophan and its an-
alogues by taking advantage of a precedent report.[16]
Experimental Section
General Methods: Unless and otherwise noted, all starting materi-
als and reagents were obtained from commercial suppliers and used
after further purification as detailed below. N-Methyl-2-pyrrol-
idone (NMP), N,N-dimethylformamide, and triethylamine were
freshly distilled from calcium hydride. All solvents for routine isola-
tion of products and chromatography were reagent grade and glass
distilled. Reaction flasks were dried in an oven at 100 °C for 12 h.
Air- and moisture-sensitive reactions were performed under an ar-
gon/UHP nitrogen atmosphere. Column chromatography was per-
formed using silica gel (100–200 mesh, Aceme) with indicated sol-
vents. All reactions were monitored by thin-layer chromatography
carried out on 0.25 mm E. Merck silica plates (60F-254) using UV
light to visualize the spots, and aqueous phosphomolybdic acid
containing concd. H2SO4 and heat as developing agents. Optical
rotation was recorded with an Autopol IV automatic polarimeter.
IR spectra were recorded with a Thermo Nicolet Avater 320 FTIR
and a Nicolet Impact 400 machine. Mass spectra were obtained
with a Waters Micromass-Q-Tof microTM (YA105) spectrometer.
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One-Pot Synthesis of 2-Indolyl-C-glycosides
1H and 13C NMR spectra were recorded with a Bruker AV
400 MHz. NMR spectroscopic data is given in the order: chemical
shift, multiplicity (s, singlet; br. s, broad singlet; d, doublet; t, trip-
let; q, quartet; m, multiplet), coupling constant in Hertz (Hz), and
number of protons.
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 114.3, 84.9, 84.7,
84.3, 81.6, 63.5, 60.9, 35.5, 27.6, 26.0, 25.7, 18.5, –5.1, –5.3 ppm. IR
(neat): ν = 3504, 3019, 2931, 2858, 1256, 1216, 1074, 758, 669 cm–1.
˜
HRMS (ESI): calcd. for C16H32O5NaSi [M + Na] 355.1917; found
355.1905.
Synthesis of Ribose-Derived Alkyne 4e
Ribose-Derived TBS Ether Alkyne 4e: To a stirred solution of
alcohol 11 (1.2 mg, 3.61 mmol) in CH3CN (20 mL) was added 2-
iodoxybenzoic acid (IBX; 2.51 g, 9.03 mmol) at room temp. and
the resulting suspension was heated to reflux for 5 h. The reaction
mixture was filtered through a Celite pad and washed with ethyl
acetate (10 mL). The combined filtrates were dried with anhydrous
Na2SO4 and concentrated under reduced pressure to give the alde-
hyde (1.0 g), which was used in the next step without further purifi-
cation.
Ribose Derived Ester 10: To a solution of lactol 9 (2.4 g, 8.21 mmol)
in CH3CN was added ethoxycycarbonlymethylenetriphenyl phos-
phorane (5.72 g, 16.43 mmol) followed by Et3N (1.71 mL,
12.32 mmol) at room temp. and the mixture was stirred for 24 h.
The reaction mixture was concentrated under reduced pressure and
the resulting residue was purified by column chromatography to
obtain ester 10 (2.6 g, 88%) as a pale-yellow liquid. [α]2D0 = –11.40
(c = 4.91, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.59 (dd, J =
6.5, 3.1 Hz, 1 H), 4.37 (dd, J = 6.3, 4.4 Hz, 1 H), 4.25 (dd, J =
11.1, 6.6 Hz, 1 H), 4.14–4.05 (m, 2 H), 4.00 (q, J = 6.5, 3.3 Hz, 1
H), 3.63 (d, J = 3.1 Hz, 2 H), 2.55 (d, J = 6.3 Hz, 2 H), 1.47 (s, 3
H), 1.27 (s, 3 H), 1.18 (t, J = 7.16 Hz, 3 H), 0.83 (s, 9 H), 0.00 (s,
6 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 170.7, 113.7, 84.9,
84.7, 82.1, 81.3, 63.9, 60.5, 38.9, 27.5, 60.0, 25.6, 18.4, 14.2, –5.2,
To a suspension of anhydrous K2CO3 (840 mg, 6.06 mmol) in anhy-
drous MeOH (20 mL) under nitrogen, was added dimethyl (1-di-
azo-2-oxopropyl)phosphonate (1.04 mL, 6.06 mmol) at room temp.
The mixture was stirred at room temp. for 30 min, then the above
aldehyde dissolved in MeOH (20 mL) was added and the mixture
was stirred for 5 h. The reaction mixture was filtered through a
Celite pad and washed with MeOH (10 mL). The combined fil-
trates were dried with anhydrous Na2SO4, concentrated under re-
duced pressure, and purified by column chromatography to give
alkyne 4e (710 mg, 61%; α,β 2.4:1) as an oil. [α]2D0 = –15.80 (c =
0.82, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.75 (d, J =
6.1 Hz, 1 H), 4.65 (t, J = 4.3 Hz, 1 H), 4.19 (q, J = 11.0, 7.0 Hz, 1
H), 4.02 (t, J = 3.6 Hz, 1 H), 3.67–3.63 (m, 2 H), 2.47 (dd, J = 7.0,
2.4 Hz, 2 H), 1.95–1.94 (m, 1 H), 1.42 (s, 3 H), 1.29 (s, 3 H), 0.83
(s, 9 H), 0.00 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
112.5, 84.6, 83.2, 82.1, 81.7, 81.1, 69.4, 65.0, 26.4, 25.9, 25.1, 19.7,
–5.4 ppm. IR (neat): ν = 2983, 2954, 2932, 2858, 1740, 1472, 1258,
˜
1080, 837, 778 cm–1. HRMS (ESI): calcd. for C18H35O6Si [M + H]
375.2203; found 375.2209.
Ribose-Derived Alcohol 11:[17] To a suspension of LiAlH4 (296 mg,
7.99 mmol) in diethyl ether (10 mL) at 0 °C, was added ester 10
(1.5 g, 3.99 mmol) dissolved in anhydrous diethyl ether (15 mL).
The reaction mixture was stirred at the same temperature for
30 min, then quenched by slow addition of saturated Na2SO4 solu-
tion at 0 °C and the resulting milky emulsion was stirred up to give
a clear solution at room temp. This mixture was filtered through a
Celite pad and washed with ethyl acetate. The combined filtrates
were dried with anhydrous Na2SO4, concentrated under reduced
pressure, and purified by column chromatography to afford alcohol
11 as a colorless liquid (1.22 g, 92%). [α]2D0 = –10.28 (c = 1.28,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 4.65 (dd, J = 6.7,
18.2, –5.4, –5.3 ppm. IR (neat): ν = 3313, 2953, 2931, 2858, 1643,
˜
1382, 1257, 1097, 1077, 838, 777, 638 cm–1. HRMS (ESI): calcd.
for C17H31O4Si [M + H] 327.1992; found 327.2007.
Synthesis of Ribose-Derived Alkyne 4f
Ribose-Derived Alkyne 13: To a solution of dimethyl (1-diazo-2-
3.5 Hz, 1 H), 4.37 (dd, J = 6.7, 5.3 Hz, 1 H), 4.06 (m, 2 H), 3.79 oxopropyl)phosphonate (0.86 mL, 4.97 mmol) in MeOH (15 mL)
(t, J = 5.3 Hz, 2 H), 3.74 (dd, J = 3.5, 1.0 Hz, 2 H), 1.95–1.81 (m,
2 H), 1.53 (s, 3 H), 1.35 (s, 3 H), 0.89 (s, 9 H), 0.07 (s, 3 H), 0.06
under nitrogen was added anhydrous K2CO3 (690 mg, 4.97 mmol)
at room temp. The mixture was stirred at room temp. for 30 min,
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then aldehyde 12[18] (530 mg, 1.99 mmol) dissolved in MeOH
(10 mL) was added and the mixture was stirred for 5 h. The reac-
tion mixture was filtered through a Celite pad and washed with
MeOH (10 mL). The combined filtrates were dried with anhydrous
Na2SO4, concentrated under reduced pressure, and purified by col-
umn chromatography to give alkyne 13 (350 mg, 83%) as an oil.
azo-2-oxopropyl)phosphonate (1.14 mL, 6.63 mmol) at room temp.
The mixture was stirred at room temp. for 30 min, then the above
aldehyde dissolved in MeOH (20 mL) was added and the mixture
was stirred for 5 h. The reaction mixture was filtered through a
Celite pad and washed with MeOH (15 mL). The combined fil-
trates were dried with anhydrous Na2SO4, concentrated under re-
duced pressure, and purified by column chromatography to give
1
[α]2D0 = –11.16 (c = 1.20, CHCl3). H NMR (400 MHz, CDCl3): δ
= 4.74 (dd, J = 6.1, 3.9 Hz, 1 H), 4.67 (dd, J = 6.1, 1.3 Hz, 1 H), alkyne 4i (760 mg, 61%) as a viscous oil. [α]2D0 = 77.25 (c = 0.35,
1
4.18–4.07 (m, 2 H), 3.69–3.61 (m, 2 H), 2.61 (dd, J = 2.6, 1.6 Hz,
1 H), 2.59 (dd, J = 2.6, 1.3 Hz, 1 H), 2.03 (t, J = 2.6 Hz, 1 H), 1.50
(s, 3 H), 1.35 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
113.1, 84.6, 82.5, 81.2, 80.9, 79.7, 69.7, 62.3, 26.4, 25.2, 19.5 ppm.
CHCl3). H NMR (400 MHz, CDCl3): δ = 9.84 (br. s, 1 H), 7.66–
7.48 (m, 4 H), 7.48–7.34 (m, 6 H), 6.56 (dd, J = 8.4, 5.8 Hz, 1 H),
4.62 (t, J = 1.0 Hz, 1 H), 4.51 (d, J = 4.2 Hz, 1 H), 2.61 (d, J =
2.2 Hz, 1 H), 2.47 (dd, J = 13.7, 5.8 Hz, 1 H), 2.05–1.94 (m, 1 H),
1.88 (d, J = 1.0 Hz, 3 H), 1.10 (s, 9 H) ppm. 13C NMR (100 MHz,
IR (neat): ν = 3460, 3303, 2983, 2933, 1739, 1382, 1212, 1163, 1105,
˜
1037, 869, 759, 667 cm–1. HRMS (ESI): calcd. for C11H16O4Na [M CDCl3): δ = 164.3, 150.6, 135.7, 135.7, 132.7, 132.5, 130.2, 130.2,
+ Na] 235.0946; found 235.0950.
128.0, 128.0, 111.2, 86.9, 80.3, 78.6, 77.5, 77.2, 40.3, 26.8, 19.0,
12.8 ppm. IR (neat): ν = 3299, 3018, 2932, 2859, 1694, 1471, 1112,
˜
Ribose-Derived Bis-alkyne 4f: To a stirred solution of alcohol 13
(320 mg, 1.50 mmol) in CH3CN (15 mL) was added 2-iodoxybenz-
oic acid (IBX; 1.04 g, 3.77 mmol) at room temp. and the resulting
suspension was heated to reflux for 3 h. The reaction mixture was
filtered through a Celite pad and washed with ethyl acetate
(10 mL). The combined filtrates were dried with anhydrous Na2SO4
and concentrated to give the aldehyde (300 mg), which was used in
the next step without further purification.
758, 702, 508 cm–1. HRMS (ESI): calcd. for C27H31N2O4Si [M +
H] 475.2053; found 475.2049.
General Procedures for 2-Indolyl-C-glycosides
Procedure A: [Pd(PPh3)2Cl2] (3 mg, 3 mol-%), 2-iodoaniline (30 mg,
0.75 mmol), CuI (2 mg, 6 mol-%), triethylamine (0.025 mL,
0.182 mmol), galactose derived alkyne 4 (28 mg, 0.109 mmol), and
DMF (5 mL) were heated to reflux for 24 h under an N2 atmo-
sphere. The reaction mixture was diluted with saturated aqueous
ammonium chloride and the product was extracted with ethyl acet-
ate. The organic layer was dried with Na2SO4 and filtered. The
crude product was purified by silica gel column chromatography to
afford diastereomeric product 8 (27 mg, dr 3:1, 87%) as a brown
syrup. Rf = 0.40 (20% ethyl acetate in hexanes). [α]2D0 = +3.38 (c =
To a suspension of anhydrous K2CO3 (500 mg, 3.56 mmol) in anhy-
drous MeOH (10 mL) under nitrogen, was added dimethyl (1-di-
azo-2-oxopropyl)phosphonate (0.61 mL, 3.56 mmol) at room temp.
The mixture was stirred at room temp. for 30 min, then the above
aldehyde dissolved in MeOH (10 mL) was added and the mixture
was stirred for 5 h. The reaction mixture was filtered through a
Celite pad and washed with MeOH (10 mL). The combined fil-
trates were dried with anhydrous Na2SO4, concentrated under re-
duced pressure and purified by column chromatography to give
alkyne 4f (92 mg, 30%) as an oil. [α]2D0 = –33.04 (c = 1.26, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 4.82 (d, J = 5.9 Hz, 1 H), 4.77
(dd, J = 5.9, 3.4 Hz, 1 H), 4.71 (d, J = 2.2 Hz, 1 H), 4.14 (td, J =
7.3, 3.4 Hz, 1 H), 2.64 (dt, J = 7.3, 2.9 Hz, 2 H), 2.49 (d, J =
2.2 Hz, 1 H), 2.04 (t, J = 2.9 Hz, 1 H), 1.47 (s, 3 H), 1.34 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 113.2, 86.4, 80.4, 80.3,
1
0.78, CHCl3). H NMR (400 MHz, CDCl3): δ = 7.27 (dd, J = 7.5,
1.5 Hz, 1 H), 7.15 (dt, J = 7.5, 1.5 Hz, 1 H), 6.65 (dd, J = 7.68,
0.64 Hz, 1 H), 6.63 (dt, J = 7.68, 0.64 Hz, 1 H), 5.60 (d, J = 5.1 Hz,
1 H), 4.81 (d, J = 2.2 Hz, 1 H), 4.67 (dd, J = 7.68, 2.6 Hz 1 H),
4.47 (br. s, 2 H), 4.38–4.35 (m, 2 H), 1.58 (s, 3 H), 1.53 (s, 3 H),
1.39 (s, 3 H), 1.35 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 149.4, 132.1, 130.2, 117.5, 114.1, 109.9, 109.1, 106.93, 96.6, 89.8,
83.8, 73.2, 71.03, 70.2, 61.1, 26.3, 26.2, 25.0, 24.9 ppm. IR (neat):
ν = 3479, 3369, 2927, 2855, 2232, 1619, 1216, 1070, 901, 767,
˜
669 cm–1. HRMS (ESI): calcd. for C19H24NO5 [M + H] 346.1654;
found 346.1650.
79.6, 79.3, 75.7, 73.7, 69.8, 26.1, 25.2, 18.4 ppm. IR (neat): ν =
˜
3295, 2988, 2939, 1658, 1378, 1216, 1163, 1088, 869, 759, 649 cm–1.
HRMS (ESI): calcd. for C12H14O3Na [M + Na] 229.0841; found
229.0848.
Procedure B: [Pd(OAc)2] (2 mg, 5 mol-%), nBu4NBr (63 mg,
0.196 mmol), Na2CO3 (104 mg, 0.984 mmol), N-tosyl-o-iodoaniline
5
(146 mg, 0.236 mmol), galactose-derived alkyne 4 (50 mg,
Synthesis of Thymidine-Derived Alkyne 4i
0.196 mmol), and PPh3 (2 mg, 5 mol-%) were taken in DMF
(10 mL) and heated at 100 °C for 30 h under an N2 atmosphere.
The reaction mixture was diluted with diethyl ether and washed
with saturated aqueous NH4Cl and H2O. The organic layer was
dried with Na2SO4, the reaction mixture was filtered and concen-
trated, and the product was purified by column chromatography to
provide N-tosyl-indolyl-C-galactoside 6 (18 mg, 18%).
Thymidine-Derived Alkyne 4i: To a stirred solution of alcohol 14[19]
(1.37 g, 2.85 mmol) in CH3CN (50 mL) was added 2-iodoxybenzoic
acid (IBX; 2 g, 7.13 mmol) at room temp. and the resulting suspen-
sion was heated to reflux for 2.5 h. The reaction mixture was fil-
tered through a Celite pad and washed with ethyl acetate (30 mL).
The combined filtrates were dried with anhydrous Na2SO4 and con-
centrated to give the aldehyde (1.27 mg), which was used in the
next step without further purification.
Procedure C: [Pd(OAc)2] (7 mg, 30 mol-%), N-tosyl-o-iodoaniline 5
(146 mg, 0.236 mmol), galactose-derived alkyne
4
(50 mg,
To a suspension of anhydrous K2CO3 (916 mg, 6.63 mmol) in anhy-
drous MeOH (20 mL) under nitrogen, was added dimethyl (1-di-
0.196 mmol), and triethylamine (0.05 mL, 0.393 mmol) were taken
in NMP (3 mL) and the reaction was heated under microwave con-
600
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© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 595–604

One-Pot Synthesis of 2-Indolyl-C-glycosides
ditions (100 W, 125 °C) [CEM focused microwave oven, model Dis-
coverer] for 50 min. The reaction mixture was diluted with diethyl
ether and washed with saturated aqueous NH4Cl and H2O. The
organic layer was dried with Na2SO4 and the crude product was
purified by column chromatography to provide N-tosyl-2-indolyl-
C-galactoside 6 (54 mg, 55%).
(26 mg, 0.096 mmol) and N-tosyl-o-iodoaniline 5 (30, 0.08 mmol).
Column chromatography on silica gel gave the title compound 6a
(41 mg, 98%) as a colorless liquid. Rf = 0.30 (10% ethyl acetate in
hexanes); [α]2D0 = +109.43 (c = 1.79, CHCl3). H NMR (400 MHz,
1
CDCl3): δ = 8.17 (d, J = 8.4 Hz, 1 H), 7.59 (d, J = 8.4 Hz, 2 H),
7.48 (d, J = 7.32 Hz, 1 H), 7.31 (td, J = 8.4, 1.3 Hz, 1 H), 7.24 (td,
J = 7.3, 1.1 Hz, 1 H), 7.20–7.12 (m, 5 H), 6.97 (d, J = 8.4 Hz, 2
H), 6.95 (s, 1 H), 6.06 (d, J = 3.7 Hz, 1 H), 5.82 (d, J = 2.1 Hz, 1
H), 4.69 (d, J = 3.7 Hz, 1 H), 4.53 (d, J = 2.1 Hz, 1 H), 4.35 (d, J
= 11.7 Hz, 1 H), 4.19 (d, J = 11.7 Hz, 1 H), 2.30 (s, 3 H), 1.59 (s,
3 H), 1.37 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.1,
137.40, 137.3, 135.7, 135.4, 130.0, 128.6, 128.4, 127.8, 127.8, 126.4,
124.6, 123.9, 121.1, 114.8, 112.4, 112.1, 104.6, 84.0, 83.1, 77.6, 72.8,
Procedure D: To a suspension of [Cu(phen)(PPh3)2]NO3 (8 mg,
10 mol-%), 2-iodoaniline (20 mg, 0.091 mmol), galactose derived
alkyne 4 (28 mg, 0.109 mmol) in toluene (5.0 mL), was added
Cs2CO3 (60 mg, 0.182 mmol) under an N2 atmosphere, and the re-
action was stirred at 110 °C for 24 h. When the reaction was com-
plete, tBuONa (18 mg, 0.183 mmol) was added under an N2 atmo-
sphere, and the reaction mixture was further stirred at 110 °C for
2 h. Sat. NH4Cl solution (25 mL) was added, the mixture was ex-
tracted with CH2Cl2, and the combined organic phase was dried
with anhydrous Na2SO4, filtered, and the solvent was removed. The
solid residue was purified by column chromatography to afford
Sonogashira type diastereomeric product 8 as a syrup (67%, dr
1.75:1).
27.3, 26.6, 21.7 ppm. IR (neat): ν = 3020, 2932, 1597, 1452, 1374,
˜
1218, 1091, 1025, 758, 580, 548 cm–1. HRMS (ESI): calcd. for [M
+ H] C29H30NO6S 520.1794; found 520.1791.
N-Tosyl-2-indolyl-C-glucoside 6b: Following the General Procedure
E, the reaction was carried out between glucose-derived alkyne 4b
(18 mg, 0.096 mmol) and N-tosyl-o-iodoaniline
5
(30 mg,
Procedure E: To a solution of sugar-derived alkyne (0.096 mmol,
1.2 equiv.) and N-tosyl-o-iodoaniline 5 (30 mg, 0.08 mmol, 1 equiv.)
in toluene (4 mL) was added [Cu(Phen)(PPh3)2]NO3catalyst (7 mg,
0.08 mmol). Column chromatography on silica gel gave the title
compound 6b (31 mg, 91%) as a white solid. Rf = 0.25 (20% ethyl
acetate in hexanes); m.p. 122–126 °C; [α]2D0 = +77.96 (c = 1.81,
1
10 mol-%), then anhydrous K3PO4 (51 mg, 0.241 mmol, 3 equiv.) CHCl3). H NMR (400 MHz, CDCl3): δ = 8.14 (d, J = 8.2 Hz, 1
under an N2 atmosphere, and the reaction mixture was heated at
110 °C for 9–11 h. When the starting material was consumed, the
reaction was diluted with ethyl acetate and washed with water, the
aqueous layer was washed with ethyl acetate and the combined
organic layers were dried with anhydrous Na2SO4 and concen-
trated.
H), 7.63 (d, J = 8.4 Hz, 2 H), 7.48 (d, J = 7.5 Hz, 1 H), 7.31 (td,
J = 7.5, 1.3 Hz, 1 H), 7.23 (td, J = 8.2, 0.9 Hz, 1 H), 7.18 (d, J =
8.4 Hz, 2 H), 6.93 (s, 1 H), 6.05 (d, J = 3.6 Hz, 1 H), 5.88 (d, J =
1.4 Hz, 1 H), 4.67 (d, J = 3.6 Hz, 2 H), 2.32 (s, 3 H), 1.61 (s, 3 H),
1.38 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.3, 137.5,
135.4, 134.4, 130.1, 129.4, 126.4, 125.0, 124.0, 121.1, 114.7, 112.6,
112.2, 104.5, 85.2, 78.2, 75.8, 27.2, 26.5, 21.7 ppm. IR (neat): ν =
˜
General One-pot Reaction Procedure F: To a solution of sugar-de-
rived alkyne (0.096 mmol, 1.2 equiv.), and N-tosyl-o-iodoaniline 5
(30 mg, 0.08 mmol) intoluene (4 mL), was added[Cu(Phen)(PPh3)2]-
NO3 (7 mg, 10 mol-%) catalyst, then anhydrous K3PO4 (51 mg,
0.241 mmol, 3 equiv.) under an N2 atmosphere. The reaction mix-
ture was heated at 110 °C for 9–11 h. When the starting material
N-tosyl-o-iodoaniline 6 was consumed (reaction monitored by
TLC), the reaction mixture was brought to room temp., TBAF (1 m
in THF, 5–7 equiv.) was added and the mixture was further heated
at 110 °C for 2–3 h. The reaction was then diluted with ethyl acet-
ate and washed with water. The aqueous layer was extracted with
ethyl acetate, and the combined organic layers were dried with an-
hydrous Na2SO4 and then concentrated.
3020, 2932, 1597, 1452, 1374, 1218, 1091, 1025, 758, 580, 548 cm–1.
HRMS (ESI): calcd. for [M + H] C22H24NO6S 430.1324; found
430.1335.
N-Tosyl-2-indolyl-C-riboside 6c: Following General Procedure E,
the reaction was carried out between ribose-derived alkyne 4c
(19 mg, 0.096 mmol) and N-tosyl-o-iodoaniline
5
(30 mg,
0.08 mmol). Column chromatography on silica gel gave the title
compound 6c (35.4 mg, 100%) as a white solid. Rf = 0.42 (15%
ethyl acetate in hexanes); m.p. 138–142 °C; [α]2D0 = –49.34 (c = 1.30,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 8.01 (d, J = 8.2 Hz, 1
H), 7.70 (d, J = 8.4 Hz, 2 H), 7.47 (d, J = 8.2 Hz, 1 H), 7.26–7.19
(m, 2 H), 7.17 (d, J = 8.4 Hz, 2 H), 6.88 (s, 1 H), 5.68 (d, J =
3.7 Hz, 1 H), 5.18 (dd, J = 5.8, 3.7 Hz, 1 H), 5.05 (s, 1 H), 4.69 (d,
J = 5.8 Hz, 1 H), 3.37 (s, 3 H), 2.31 (s, 3 H), 1.37 (s, 3 H), 1.28 (s,
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.8, 136.8, 135.8,
135.8, 129.7, 129.7, 126.6, 124.3, 123.5, 120.9, 114.5, 112.7, 111.7,
Synthesis of N-Tosyl-2-indolyl-C-glycosides
N-Tosyl-2-indolyl-C-galactoside 6: Following General Procedure E,
the reaction was carried out between galactose-derived alkyne 4
(25 mg, 0.096 mmol) and N-tosyl-o-iodoaniline
5
(30 mg,
106.3, 85.1, 80.6, 76.7, 54.8, 26.0, 24.9, 21.5 ppm. IR (neat): ν =
˜
0.08 mmol). Column chromatography on silica gel gave the title
compound 6 (33 mg, 82%) as a pale-yellow solid. Rf = 0.40 (20%
ethyl acetate in hexanes); m.p. 66–70 °C; [α]2D0 = +3.38 (c = 0.78,
2983, 2935, 2835, 1597, 1453, 1372, 1174, 1092, 1029, 751, 575,
545 cm–1. HRMS (ESI): calcd. for C23H25NO6S [M + H] 444.1481;
found 444.1492.
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 8.02 (d, J = 8.1 Hz, 1
H), 7.58 (d, J = 8.4 Hz, 2 H), 7.43 (dd, J = 7.0, 1.7 Hz, 1 H), 7.23–
7.17 (m, 2 H), 7.14 (d, J = 8.4 Hz, 2 H), 6.85 (s, 1 H), 5.83 (s, 1
H), 5.73 (d, J = 5.2 Hz, 1 H), 4.74 (d, J = 1.9 Hz, 1 H), 4.74 (s, 1
H), 4.44 (dd, J = 1.9, 5.2 Hz, 1 H), 2.29 (s, 3 H), 1.64 (s, 3 H), 1.45
(s, 3 H), 1.39 (s, 3 H), 1.29 (s, 3 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 144.8, 137.5, 137.3, 135.2, 130.4, 129.8, 126.5, 124.4,
123.9, 121.1, 115.3, 113.0, 109.4, 109.0, 97.4, 72.8, 71.5, 70.9, 65.1,
N-Tosyl-2-indolyl-C-riboside 6d: Following the General Procedure
E, the reaction was carried out between ribose-derived alkyne 4d
(30 mg, 0.096 mmol) and N-tosyl-o-iodoaniline
5
(30 mg,
0.08 mmol). Column chromatography on silica gel gave the title
compound 6d (41 mg, 93%) as a syrup. Rf = 0.40 (10% ethyl acet-
ate in hexanes); [α]2D0 = +3.59 (c = 1.69, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.95 (d, J = 8.0 Hz, 1 H), 7.70 (d, J =
8.4 Hz, 2 H), 7.45 (dd, J = 6.9, 2.2 Hz, 1 H), 7.21 (dd, J = 8.0,
1.6 Hz, 1 H), 7.18 (dd, J = 6.9, 1.6 Hz, 1 H), 7.14 (d, J = 8.4 Hz,
2 H), 6.87 (d, J = 0.8 Hz, 1 H), 5.88 (dd, J = 4.5, 0.8 Hz, 1 H),
5.26 (dd, J = 5.9, 4.9 Hz, 1 H), 4.92 (d, J = 5.9 Hz, 1 H), 4.33 (t,
J = 3.1 Hz, 1 H), 3.87 (dd, J = 3.1, J = 11.0 Hz, 1 H), 3.81 (dd, J
26.2, 26.1, 25.1, 24.5, 21.6 ppm. IR (neat): ν = 3356, 3258, 2924,
˜
2853, 1597, 1452, 1372, 1299, 1090, 901, 580, 534 cm–1. HRMS
(ESI): calcd. for C26H30NO7S [M + H] 500.1743; found 500.1755.
N-Tosyl-2-indolyl-C-glucoside 6a: Following General Procedure E,
the reaction was carried out between glucose-derived alkyne 4a
Eur. J. Org. Chem. 2013, 595–604
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
601

P. Subramanian, K. P. Kaliappan
FULL PAPER
= 3.1, 11.0 Hz, 1 H), 2.31 (s, 3 H), 1.29 (s, 3 H), 1.28 (s, 3 H), 0.94
(s, 9 H), 0.11 (s, 6 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
144.7, 138.4, 136.9, 136.1, 129.9, 129.8, 126.8, 124.1, 123.4, 120.9,
114.5, 112.5, 110.7, 84.0, 83.6, 83.0, 80.5, 65.5, 26.2, 26.1, 25.2,
0.08 mmol). Column chromatography on silica gel gave the title
compound 6g (32 mg, 89%) as a white solid. Rf = 0.42 (15% ethyl
acetate in hexanes); m.p. 168–172 °C; [α]2D0 = 149.76 (c = 1.50,
CHCl3). 1H NMR (400 MHz, CDCl3): δ = 8.01 (dd, J = 8.1,
0.7 Hz, 1 H), 7.71 (d, J = 8.4 Hz, 2 H), 7.47 (dd, J = 7.2, 1.7 Hz,
21.6, 18.4, –5.2, –5.3 ppm. IR (neat): ν = 2931, 2857, 1597, 1453,
˜
1371, 1174, 1091, 838, 747, 580 cm–1. HRMS (ESI): calcd. for 1 H), 7.23 (dd, J = 8.1, 1.4 Hz, 1 H), 7.20 (dd, J = 7.2, 1.3 Hz, 1
C29H40NO6SSi [M + H] 558.2346; found 558.2347.
H), 7.17 (d, J = 8.4 Hz, 2 H), 6.88 (t, J = 0.9 Hz, 1 H), 5.68 (d, J
= 3.8 Hz, 1 H), 5.18 (dd, J = 5.8, 3.8 Hz, 1 H), 5.05 (s, 1 H), 4.69
(d, J = 5.80 Hz, 1 H), 3.37 (s, 3 H), 2.32 (s, 3 H), 1.37 (s, 3 H),
1.28 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 144.8, 136.8,
135.8, 135.8, 129.7, 129.7, 126.6, 124.3, 123.5, 120.9, 114.5, 112.7,
111.7, 106.3, 85.1, 80.6, 76.7, 54.8, 26.0, 24.9, 21.5 ppm. IR (neat):
N-Tosyl-2-indolyl-C-ribosides α-6e and β-6e: Following the General
Procedure E, the reaction was carried out between ribose-derived
alkyne 4e (31 mg, 0.096 mmol) and N-tosyl-o-iodoaniline 5 (30 mg,
0.08 mmol). Column chromatography on silica gel gave the title
compounds, α-6e (31 mg, 68%; Rf = 0.50, 10% ethyl acetate in
hexanes) and β-6e (12 mg, 26%; Rf = 0.52, 10% ethyl acetate in
hexanes) as syrups.
ν = 2983, 2933, 2851, 1597, 1453, 1213, 1174, 1092, 1029, 749,
˜
575, 545 cm–1. HRMS (ESI): calcd. for C23H25NO6SNa [M + Na]
466.1300; found 466.1297.
α-6e: [α]2D0 = –45.57 (c = 0.89, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 8.14 (d, J = 8.3 Hz, 1 H), 7.63 (d, J = 8.4 Hz, 2 H),
7.39 (d, J = 7.8 Hz, 1 H), 7.26–7.14 (m, 4 H), 6.54 (s, 1 H), 4.83
(d, J = 6.1 Hz, 1 H), 4.77 (dd, J = 6.1, 3.9 Hz, 1 H), 4.59 (quint, J
= 3.9 Hz, 1 H), 4.10 (t, J = 3.8 Hz, 1 H), 3.68 (dd, J = 3.9, 2.05 Hz,
2 H), 3.49 (dd, J = 16.1, 3.8 Hz, 1 H), 3.24 (dd, J = 16.1, 7.9 Hz,
1 H), 2.31 (s, 3 H), 1.54 (s, 3 H), 1.38 (s, 3 H), 0.87 (s, 9 H), 0.04
(s, 3 H), 0.02 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ =
144.7, 138.9, 137.3, 136.1, 130.1, 129.9, 126.5, 124.0, 123.6, 120.5,
115.0, 112.3, 110.8, 84.5, 83.3, 82.3, 81.1, 64.7, 30.1, 26.5, 26.0,
N-Tosyl-2-indolyl-C-glycoside 6h: Following the General Procedure
E, the reaction was carried out between mannose-derived alkyne
4h (16 mg, 0.096 mmol) and N-tosyl-o-iodoaniline
5 (30 mg,
0.08 mmol). Column chromatography on silica gel gave the title
compound 6h (30 mg, 90%) as a syrup. Rf = 0.35 (10% ethyl acet-
ate in hexanes); [α]2D0 = 20.39 (c = 0.71, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 7.99 (d, J = 8.2 Hz, 1 H), 7.68 (d, J =
8.9 Hz, 2 H), 7.47 (d, J = 7.1 Hz, 1 H), 7.26–7.19 (m, 2 H), 7.16
(d, J = 8.9 Hz, 2 H), 6.89 (s, 1 H), 5.22 (d, J = 3.5 Hz, 1 H), 5.17
(dd, J = 5.9, 3.5 Hz, 1 H), 4.91 (dd, J = 5.9, 3.6 Hz, 1 H), 4.19 (d,
J = 10.6 Hz, 1 H), 3.69 (dd, J = 10.6, 3.60 Hz 1 H), 2.31 (s, 3 H),
1.38 (s, 3 H), 1.29 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 144.9, 137.0, 136.1, 135.8, 129.9, 126.7, 124.4, 123.7, 121.1, 114.7,
112.5, 111.8, 99.9, 81.6, 81.5, 79.6, 72.5, 26.1, 25.0, 21.7 ppm. IR
25.3, 21.7, 18.3, –5.3, –5.4 ppm. IR (neat): ν = 2930, 2857, 1597,
˜
1453, 1371, 1175, 1091, 838, 584, 544 cm–1. HRMS (ESI): calcd.
for C30H41NO6SSiNa [M + Na] 594.2322; found 594.2318.
β-6e: [α]2D0 = –1.79 (c = 1.81, CHCl3). 1H NMR (400 MHz, CDCl3):
δ = 8.14 (d, J = 7.6 Hz, 1 H), 7.61 (d, J = 8.4 Hz, 2 H), 7.42 (d, J
= 7.3 Hz, 1 H), 7.27–7.21 (m, 2 H), 7.16 (d, J = 8.4 Hz, 2 H), 6.58
(d, J = 0.6 Hz, 1 H), 4.68 (dd, J = 6.5, 3.4 Hz, 1 H), 4.45 (dd, J =
6.5, 4.4 Hz, 1 H), 4.40–4.35 (m, 1 H), 4.08 (dd, J = 7.2, 4.4 Hz, 1
H), 3.73 (d, J = 3.4 Hz, 2 H), 3.37 (dd, J = 16.8, 6.0 Hz, 1 H), 3.27
(dd, J = 16.8, 6.0 Hz, 1 H), 2.32 (s, 3 H), 1.55 (s, 3 H), 1.34 (s, 3
H), 0.91 (s, 9 H), 0.08 (s, 3 H), 0.07 (s, 3 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 144.8, 138.0, 137.2, 136.3, 130.0, 127.9,
126.4, 124.2, 123.6, 120.6, 114.9, 114.0, 110.5, 85.2, 84.9, 83.4, 82.1,
(neat): ν = 2930, 1673, 1454, 1370, 1216, 759, 580 cm–1. HRMS
˜
(ESI): calcd. for C22H24NO5S [M + H] 414.1375; found 414.1364.
Thymidine-Derived N-Tosyl-2-indolyl-C-glycoside 6i: Following Ge-
neral Procedure E, the reaction was carried out between thymidine-
derived alkyne 4i (46 mg, 0.096 mmol) and N-tosyl-o-iodoaniline 5
(30 mg, 0.08 mmol). Column chromatography on silica gel gave the
title compound 6i (44 mg, 76%) as a white solid. Rf = 0.20 (50%
ethyl acetate in hexanes); m.p. 109–113 °C; [α]2D0 = 77.25 (c = 0.35,
1
CHCl3). H NMR (400 MHz, CDCl3): δ = 8.15 (d, J = 8.4 Hz, 1
63.9, 33.8, 27.6, 26.1, 25.7, 21.7, 18.5, –5.0, –5.2 ppm. IR (neat): ν
˜
= 3019, 2930, 2851, 1452, 1372, 1216, 1092, 759, 669 cm–1. HRMS
(ESI): calcd. for C30H41NO6SSiNa [M + Na] 594.2322; found
594.2313.
H), 8.11 (s, 1 H), 7.77 (d, J = 6.9 Hz, 2 H), 7.61 (dd, J = 7.9,
1.2 Hz, 2 H), 7.54 (d, J = 7.1 Hz, 2 H), 7.43–7.31 (m, 6 H), 7.26–
7.21 (m, 4 H), 7.07 (d, J = 6.9 Hz, 2 H), 6.53 (t, J = 7.2 Hz, 1 H),
6.27 (br. s, 1 H), 5.65 (br. s, 1 H), 4.88 (t, J = 3.1 Hz, 1 H), 2.47
(ddd, J = 13.8, 7.2, 3.1 Hz, 1 H), 2.27 (s, 3 H), 2.17–2.04 (m, 1 H),
1.59 (s, 3 H), 1.08 (s, 9 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 163.2, 150.2, 145.2, 137.4, 135.9, 135.7, 132.7, 130.2, 130.1, 129.5,
128.3, 128.0, 127.9, 127.2, 125.8, 123.9, 121.3, 115.2, 110.9, 85.4,
N-Tosyl-2-indolyl-C-riboside 6f: Following General Procedure E,
the reaction was carried out between ribose-derived alkyne 4f
(20 mg, 0.096 mmol) and N-tosyl-o-iodoaniline
5
(30 mg,
0.08 mmol). Column chromatography on silica gel gave the title
compound 6f (34 mg, 94%) as a syrup. Rf = 0.40 (10% ethyl acetate
in hexanes); [α]2D0 = +190.23 (c = 0.81, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.12 (d, J = 8.2 Hz, 1 H), 7.81 (d, J =
8.4 Hz, 2 H), 7.44 (d, J = 7.5 Hz, 1 H), 7.30 (td, J = 8.2, 1.3 Hz, 1
H), 7.23 (td, J = 7.5, 1.0 Hz, 1 H), 7.14 (d, J = 8.4 Hz, 2 H), 6.61
(s, 1 H), 5.78 (s, 1 H), 5.24 (d, J = 6.0 Hz, 1 H), 4.71 (dd, J = 6.0,
3.8 Hz, 1 H), 4.23 (td, J = 6.9, 3.8 Hz, 1 H), 2.71–2.67 (m, 2 H),
2.30 (s, 3 H), 2.06 (t, J = 8.0 Hz, 1 H), 1.41 (s, 3 H), 1.25 (s, 3
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 145.2, 137.6, 137.6,
135.0, 129.8, 129.4, 126.9, 125.2, 124.2, 121.1, 115.2, 112.9, 111.2,
86.9, 81.8, 80.9, 80.6, 79.8, 69.7, 26.4, 25.2, 21.7, 19.1 ppm. IR
82.0, 75.7, 40.6, 27.0, 21.6, 19.2, 12.3, 0.17 ppm. IR (neat): ν =
˜
3020, 2929, 2860, 2110, 1693, 1216, 1113, 669 cm–1. HRMS (ESI):
calcd. for C40H42N3O6SSi [M + H] 720.2564; found 720.2560.
Synthesis of 2-Indolyl-C-glycosides
2-Indolyl-C-galactoside 7: Following General Procedure F, the reac-
tion was carried out between galactose-derived alkyne 4 (25 mg,
0.096 mmol) and N-tosyl-o-iodoaniline 5 (30 mg, 0.08 mmol). Col-
umn chromatography on silica gel gave the title compound 7
(24.7 mg, 89%) as a white solid. Rf = 0.30 (20% ethyl acetate in
hexanes); m.p. 135–140 °C; [α]2D0 = –160.97 (c = 1.15, CHCl3). H
1
(neat): ν = 3294, 2924, 2851, 1740, 1711, 1452, 1373, 1175, 1090,
˜
NMR (400 MHz, CDCl3),: δ = 8.75 (br. s, 1 H), 7.57 (dd, J = 8.7,
0.8 Hz, 1 H), 7.37 (dd, J = 8.1, 0.9 Hz, 1 H), 7.15 (td, J = 8.7,
0.9 Hz, 1 H), 7.06 (td, J = 8.1, 0.8 Hz, 1 H), 6.47 (d, J = 2.0 Hz, 1
H), 5.65 (d, J = 5.0 Hz, 1 H), 5.09 (d, J = 1.5 Hz, 1 H), 4.71 (dd,
J = 7.9, 2.2 Hz, 1 H), 4.50 (dd, J = 7.9, 1.5 Hz, 1 H), 4.38 (dd, J
= 4.96, 2.2 Hz, 1 H), 1.62 (s, 3 H), 1.58 (s, 3 H), 1.38 (s, 3 H), 1.36
752, 579 cm–1. HRMS (ESI): calcd. for C25H26NO5S [M + H]
452.1532; found 452.1528.
N-Tosyl-2-indolyl-C-mannoside 6g: Following General Procedure E,
the reaction was carried out between mannose-derived alkyne 4g
(19 mg, 0.096 mmol) and N-tosyl-o-iodoaniline
5
(30 mg,
602
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 595–604

One-Pot Synthesis of 2-Indolyl-C-glycosides
(s, 3 H) ppm. 13C NMR (100 MHz, CDCl3),: δ = 136.2, 134.6, 4.83 (dd, J = 5.8, 3.4 Hz, 1 H), 4.75 (dd, J = 5.8, 1.4 Hz, 1 H), 4.28
127.7, 122.1, 120.8, 119.7, 111.3, 109.6, 108.9, 101.7, 96.8, 73.7,
(td, J = 5.6, 1.4 Hz, 1 H), 3.71 (d, J = 5.6 Hz, 2 H), 2.00 (br. s, 1
H), 1.62 (s, 3 H), 1.34 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3):
δ = 136.6, 132.9, 127.6, 122.4, 120.9, 119.8, 113.0, 111.3, 102.9,
71.0, 70.9, 64.4, 26.4, 26.2, 25.1, 24.1 ppm. IR (neat): ν = 3454,
˜
2989, 2930, 1457, 1383, 1214, 1068,755 cm–1. HRMS (ESI): calcd.
for C19H24NO5 [M + H] 346.1654; found 346.1651.
84.6, 83.0, 82.6, 77.4, 62.3, 26.7, 24.7 ppm. IR (neat): ν = 3445,
˜
2926, 2855, 1511, 1456, 1100, 910, 737 cm–1. HRMS (ESI): calcd.
for C16H20NO4 [M + H] 290.1392; found 290.1390.
2-Indolyl-C-glucoside 7a: Following General Procedure F, the reac-
tion was carried out between glucose-derived alkyne 4a (26 mg,
0.096 mmol) and N-tosyl-o-iodoaniline 5 (30 mg, 0.08 mmol). Col-
umn chromatography on silica gel gave the title compound 7a
(23.5 mg, 81%) as a syrup. Rf = 0.35 (10% ethyl acetate in hex-
anes). [α]2D0 = –21.70 (c = 1.95, CHCl3). 1H NMR (400 MHz,
CDCl3): δ = 8.74 (br. s, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.29 (dd,
J = 8.0, 0.7 Hz, 1 H), 7.26–7.22 (m, 2 H), 7.18 (td, J = 7.8, 0.7 Hz,
1 H), 7.10 (td, J = 8.0, 0.9 Hz, 1 H), 7.04–7.02 (m, 2 H), 6.53 (d,
2-Indolyl-C-riboside α-7e: Following General Procedure F, the reac-
tion was carried out between ribose-derived alkyne 4e (31 mg,
0.096 mmol) and N-tosyl-o-iodoaniline 5 (30 mg, 0.08 mmol). Col-
umn chromatography on silica gel gave α-7e (16.2 mg, 67%) as a
syrup. Rf = 0.30 (50% ethyl acetate in hexanes). [α]2D0 = –45.57 (c
= 0.46, CHCl3). 1H NMR (400 MHz, CDCl3),: δ = 8.65 (br. s, 1
H), 7.54 (d, J = 7.9 Hz, 1 H), 7.34 (dd, J = 7.9, 0.6 Hz, 1 H), 7.13
J = 1.4 Hz, 1 H), 6.06 (d, J = 3.8 Hz, 1 H), 5.40 (d, J = 2.9 Hz, 1 (td, J = 7.9, 0.6 Hz, 1 H), 7.07 (dt, J = 7.9, 1.2 Hz, 1 H), 6.30 (d,
H), 4.74 (d, J = 3.8 Hz, 1 H), 4.41 (d, J = 11.4 Hz, 1 H), 4.18 (d, J = 1.1 Hz, 1 H), 4.69 (d, J = 6.5 Hz, 2 H), 4.25 (dd, J = 6.5,
J = 11.4 Hz, 1 H), 4.07 (d, J = 2.9 Hz, 1 H), 1.58 (s, 3 H), 1.37 (s, 4.6 Hz, 1 H), 4.19 (tt, J = 14.1, 7.0, 2.0 Hz, 1 H), 3.67–3.58 (m, 2
3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 137.0, 136.5, 132.3,
128.6, 128.2, 128.1, 127.7, 122.2, 120.8, 119.7, 112.0, 111.1, 104.7,
H), 3.17 (dd, J = 7.0, 2.0 Hz, 1 H), 1.80 (br. s, 1 H), 1.61 (s, 3 H),
1.45 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3),: δ = 136.2, 135.8,
128.6, 121.4, 120.0, 119.7, 113.0, 110.7, 101.0, 84.5, 82.7, 81.7, 81.4,
102.4, 84.3, 83.1, 76.3, 72.9, 26.9, 26.3 ppm. IR (neat): ν = 3435,
˜
2930, 1456, 1216, 1164, 1076, 1028, 863, 751, 699 cm–1. HRMS
(ESI): calcd. for C22H24NO4[M + H] 366.1705; found 366.1710.
62.3, 28.7, 26.5, 25.3 ppm. IR (neat): ν = 3412, 2927, 1621, 1457,
˜
1217, 1078, 757, 699 cm–1. HRMS (ESI): calcd. for C17H22NO4 [M
+ H] 304.1549; found 304.1559.
2-Indolyl-C-glucoside 7b: Following General Procedure F, the reac-
tion was carried out between glucose-derived alkyne 4a (18 mg,
0.096 mmol) and N-tosyl-o-iodoaniline 5 (30 mg, 0.08 mmol). Col-
umn chromatography on silica gel gave the title compound 7b
(20 mg, 90%) as a white solid. [α]2D0 = –6.57 (c = 1.85, CHCl3); m.p.
161–165 °C. 1H NMR (400 MHz, CDCl3): δ = 8.64 (br. s, 1 H),
7.60 (d, J = 7.8 Hz, 1 H), 7.37 (dd, J = 8.1, 0.7 Hz, 1 H), 7.19 (td,
J = 7.8, 0.7 Hz, 1 H), 7.11 (td, J = 8.1, 1.0 Hz, 1 H), 6.48 (t, J =
2-Indolyl-C-riboside 7f: Following General Procedure F, the reac-
tion was carried out between ribose-derived alkyne 4f (20 mg,
0.096 mmol) and N-tosyl-o-iodoaniline 5 (30 mg, 0.08 mmol). Col-
umn chromatography on silica gel gave the title compound 7f
(22 mg, 92%) as a syrup. [α]2D0 = +43.03 (c = 0.29, CHCl3); 1H
NMR (400 MHz, CDCl3): δ = 8.38 (br. s, 1 H), 7.57 (d, J = 7.8 Hz,
1 H), 7.37 (d, J = 8.2 Hz, 1 H), 7.19 (td, J = 7.8, 1.0 Hz, 1 H), 7.11
1.0 Hz, 1 H), 6.09 (d, J = 3.7 Hz, 1 H), 5.48 (d, J = 2.6 Hz, 1 H), (td, J = 8.2, 0.9 Hz 1 H), 6.40 (s, 1 H), 5.32 (s, 1 H), 5.21 (d, J =
4.67 (d, J = 3.7 Hz, 1 H), 4.34 (d, J = 2.6 Hz, 1 H), 1.81 (br. s, 1 6.0 Hz, 1 H), 4.74 (dd, J = 6.0, 3.6 Hz, 1 H), 3.85 (td, J = 7.0,
H), 1.58 (s, 3 H), 1.37 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): 3.6 Hz, 1 H), 2.68 (dd, J = 7.0, 2.6 Hz, 2 H), 2.01 (t, J = 2.6 Hz, 1
δ = 136.22, 132.20, 128.25, 122.44, 120.78, 120.26, 112.27, 111.34, H), 1.58 (s, 3 H), 1.42 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3),:
105.01, 100.89, 100.17, 84.84, 78.02, 27.03, 26.36 ppm. IR (neat): ν
δ = 136.1, 135.0, 128.7, 128.3, 122.5, 120.6, 120.2, 113.1, 111.1,
˜
= 3427, 2927, 2104, 1523, 1375, 1214, 1071, 1071, 754 cm–1. HRMS 100.3, 84.8, 81.0, 79.9, 79.4, 69.8, 26.3, 25.2, 18.7 ppm. IR (neat):
(ESI): calcd. C15H18NO4[M + H] 276.1236; found 276.1246.
ν = 3020, 1216, 1072, 758, 669 cm–1. HRMS (ESI): calcd. for
˜
C18H20NO3 [M + H] 298.1443; found 298.1451.
2-Indolyl-C-riboside 7c: Following General Procedure F, the reac-
tion was carried out between ribose-derived alkyne 4c (19 mg,
0.096 mmol) and N-tosyl-o-iodoaniline 5 (30 mg, 0.08 mmol). Col-
umn chromatography on silica gel gave the title compound 7c
(22 mg, 95%) as an off-white solid. Rf = 0.45 (15% ethyl acetate in
hexanes); m.p. 97–101 °C; [α]2D0 = –20.07 (c = 1.10, CHCl3). 1H
2-Indolyl-C-mannoside 7g: Following General Procedure F, the re-
action was carried out between mannose-derived alkyne 4g (19 mg,
0.096 mmol) and N-tosyl-o-iodoaniline 5 (30 mg, 0.08 mmol). Col-
umn chromatography on silica gel gave the title compound 7g
(20 mg, 86%) as a white solid. Rf = 0.45 (15% ethyl acetate in
NMR (400 MHz, CDCl3): δ = 8.92 (br. s, 1 H), 7.57 (d, J = 7.7 Hz, hexanes); m.p. 109–105 °C; [α]2D0 = –5.14 (c = 1.01, CHCl3). 1H
1 H), 7.33 (dd, J = 8.1, 0.6 Hz, 1 H), 7.18 (td, J = 7.7, 0.6 Hz, 1 NMR (400 MHz, CDCl3): δ = 8.74 (br. s, 1 H), 7.60 (dd, J = 7.9,
H), 7.09 (td, J = 8.1, 1.0 Hz, 1 H), 6.45 (d, J = 1.6 Hz, 1 H), 5.47
0.9 Hz, 1 H), 7.37 (dd, J = 8.2, 0.9 Hz, 1 H), 7.18 (td, J = 7.9,
(s, 1 H), 5.16 (s, 1 H), 4.85 (dd, J = 6.0, 0.6 Hz, 1 H), 4.79 (d, J = 0.9 Hz, 1 H), 7.08 (td, J = 8.2, 0.9 Hz, 1 H), 6.56 (dd, J = 1.9,
6.0 Hz, 1 H), 3.44 (s, 3 H), 1.56 (s, 3 H), 1.33 (s, 3 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 136.9, 136.4, 128.3, 122.4, 120.9,
120.0, 112.9, 111.2, 110.5, 101.6, 85.8, 85.3, 84.2, 55.7, 26.6,
0.7 Hz, 1 H), 5.17 (d, J = 3.2 Hz, 1 H), 5.00 (s, 1 H), 4.85 (dd, J =
5.7, 3.2 Hz, 1 H), 4.68 (d, J = 5.7 Hz, 1 H), 3.40 (s, 3 H), 1.60 (s,
3 H), 1.33 (s, 3 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 136.7,
132.4, 127.6, 122.4, 120.9, 119.8, 112.9, 111.3, 107.1, 103.2, 85.5,
25.1 ppm. IR (neat): ν = 3372, 2930, 1738, 1456, 1217, 1095, 953,
˜
872, 757, 668, 564 cm–1. HRMS (ESI): calcd. for C16H19NO4 [M +
Na] 312.1212; found 312.1220.
81.8, 75.3, 55.1, 26.4, 24.6 ppm. IR (neat): ν = 3373, 2928, 2857,
˜
1646, 1456, 1105, 1095, 660 cm–1. HRMS (ESI): calcd. for
C16H20NO4 [M + H] 290.1392; found 290.1389.
2-Indolyl-C-riboside 7d: Following General Procedure F, the reac-
tion was carried out between ribose-derived alkyne 4d (30 mg,
0.096 mmol) and N-tosyl-o-iodoaniline 5 (30 mg, 0.08 mmol). Col-
umn chromatography on silica gel gave the title compound 7d
(19 mg, 83%) as a syrup. Rf = 0.25 (50% ethyl acetate in hexanes).
2-Indolyl-C-mannoside 7h: Following General Procedure F, the re-
action was carried out between mannose-derived alkyne 4h (16 mg,
0.096 mmol) and N-tosyl-o-iodoaniline 5 (30 mg, 0.08 mmol). Col-
umn chromatography on silica gel gave the title compound 7h
(18 mg, 85%) as a white solid. Rf = 0.20 (10% ethyl acetate in
hexanes); m.p. 142–147; [α]2D0 = –33.13 (c = 0.92, CHCl3). 1H NMR
(400 MHz, CDCl3): δ = 8.80 (br. s, 1 H), 7.59 (d, J = 7.9 Hz, 1 H),
1
[α]2D0 = –54.25 (c = 1.63, CHCl3). H NMR (400 MHz, CDCl3): δ
= 8.76 (br. s, 1 H), 7.60 (d, J = 7.9 Hz, 1 H), 7.38 (dd, J = 8.1,
0.8 Hz, 1 H), 7.18 (td, J = 7.9, 0.8 Hz, 1 H), 7.08 (td, J = 8.1,
1.0 Hz, 1 H), 6.53 (d, J = 1.3 Hz, 1 H), 5.21 (d, J = 3.4 Hz, 1 H), 7.37 (dd, J = 8.2, 0.6 Hz, 1 H), 7.18 (dt, J = 7.9, 0.6 Hz, 1 H), 7.08
Eur. J. Org. Chem. 2013, 595–604
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
603

P. Subramanian, K. P. Kaliappan
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(td, J = 8.2, 0.8 Hz, 1 H), 6.55 (d, J = 1.28 Hz, 1 H), 4.91 (dd, J
= 6.0, 4.0 Hz, 1 H), 4.82 (dd, J = 6.0, 3.3 Hz, 1 H), 4.65 (d, J =
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˜
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Supporting Information (see footnote on the first page of this arti-
1
cle): Copies of H and 13C NMR spectra.
Acknowledgments
We thank the Department of Science and Technology (DST), New
Delhi for financial support. K. P. K. thanks the DST for the award
of a Swarnajayanti fellowship. P. S. S. thanks the University Grants
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Received: September 7, 2012
Published Online: November 30, 2012
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