Palladium-catalyzed: C -glycosylation and annulation of o -alkynylanilines with 1-iodoglycals: Convenient access to 3-indolyl- C -glycosides

Article abstract of DOI:10.1039/d0ob01812k

An efficient and practical approach for the synthesis of 3-indolyl-C-Δ1,2-glycosides through a palladium-catalyzed annulation/C-glycosylation sequence of o-alkynylanilines with 1-iodoglycals has been developed. This methodology has a wide scope of substra

Full text of DOI:10.1039/d0ob01812k

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DOI: 10.1039/D0OB01812K
COMMUNICATION
Palladium-catalyzed C-glycosylation and annulation of o-
alkynylanilines with 1-iodoglycals: convenient access to 3-indolyl-
C-glycosides
Received 00th January 20xx,
Accepted 00th January 20xx
Jianchao Liu,* Xiao Xiao, Puren Han, Huiwen Zhou, Qi-Shuang Yin and Jian-Song Sun*
DOI: 10.1039/x0xx00000x
An efficient and practical approach for the synthesis of 3-indolyl-C- highly efficient for the synthesis of indole-C-glycosides. In this
1,2–glycosides through
palladium-catalyzed annulation/C- regard, sequential Sonogashira/heteroannulation reaction of
∆
a
glycosylation sequence of o-alkynylanilines with 1-iodoglycals has sugar terminal alkynes and 2-iodoanilines was developed to
been developed. This methodology has a wide scope of substrates construct 2-indolyl-C-glycosides (Scheme 1a).7c,8 In 2017, Ye
and gives access to 3-indolyl-C-∆1,2–glycosides in high yields. group reported
a
palladium/copper cocatalyzed C−H
Furthermore, the product obtained here exhibiting high utility for functionalization of indoles with 1-iodoglycals (Scheme 1b).9
further transformations.
Recently, Chen and co-workers developed the elegant
palladium catalyzed ortho-directed C−H glycosylation of
indoles with glycosyl chloride donors (Scheme 1c).10 Despite
these advances, most reported methods involve the
construction of 2-indolyl-C-glycosides, and only one report on
the efficient synthesis of 3-indolyl-C-glycosides has been
published.10a Therefore, the development of general and facile
protocols for the synthesis of 3-indolyl-C-glycosides is still
highly desirable.
C-aryl glycosides represent a metabolically stable class of
saccharides that widely occur in natural products, biologically
active compounds, and pharmaceutical agents.1 In particular,
indole-C-glycosides with structural similarity to the natural N-
nucleosides2 have attracted plenty of synthetic and biological
studies due to the frequent occurrence of such structural cores
in biologically important proteins,3 as well as their potential
anticancer and antiviral activities.4 For instance (Fig. 1), α-C-
mannosyltryptophan was discovered from the Trp7 of
ribonuclease 2, as the first naturally occurring C-glycosyl amino
acid found in protein.3a 2-Indolyl-C-glycosides I and II isolated
from Isatis indigotica, which exhibited cytotoxic activities
against human myeloid leukemia HL-60 cells, human liver
cancer HepG2 cells and human myeloid leukemia Mata cells.4b
3-Indolyl-C-glycosides III and IV have also been disclosed as
sodium-dependent glucose co-transporter 2 (SGLT2) inhibitors
and exhibits great potential in the treatment of type 2
diabetes.4c-e Accordingly, diverse synthetic methods have been
developed for the synthesis of these valuable scaffolds, such as
the reaction of lithio-indoles with sugar lactones4c,5 or 1,2-
anhydro sugars,6 C-glycosylation of indole derivatives with
glycosyl donors.7 However, these traditional strategies also
suffer from some limitations such as multiple-step
manipulations, harsh reaction conditions or a narrow substrate
scope. Meanwhile, transition-metal-catalyzed transformation
of carbohydrate derivatives has been demonstrated to be
OH
OH
CN
CN
OMe
O
O
HO
HO
HOOC
HO
HO
Me
N
N
OH
NH2
H
OH
II
OMe
OH
I
O
HO
OMe
N
H
HO
OH
F
-C-mannosyltryptophan

OH
N
O
N
O
HO
OH
HO
OH
III
OH
IV
OH
Fig. 1 Selected bioactive molecules containing indole-C-
glycoside scaffolds.
In the past decades, palladium-catalyzed cyclization of o-
alkynylanilines with organic (pseudo) halides has attracted
great attention as one of the most powerful methods to
assemble C3-substituted indoles with high atom and step
economy.11 The key steps of these transformations are that
the intramolecular nucleophilic attack of the nitrogen atom
across the activated carbon-carbon triple bond to afford the σ-
indolyl-σ-organopalladium intermediates, which could furnish
3-aryl,12 alkynyl,13 carbonyl14 or alkyl15 indoles through a
reductive elimination. However, to the best of our knowledge,
the cyclization of o-alkynylanilines for the construction of
National Engineering Research Center for Carbohydrate Synthesis, Jiangxi Normal
University, 99 Ziyang Avenue, Nanchang 330022, China. E-mail: jcliu@jxnu.edu.cn,
jssun@jxnu.edu.cn.
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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Journal Name
Ph
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Ph
Pd(PPh3)4, L
biologically interesting 3-glycosyl indoles has not been
discovered. As part of our continuing interest in the synthesis
of C-glycosides,16 we envisioned that the heterocyclization of
o-alkynylanilines with easily accessible 1-iodoglycals under Pd-
catalysis would allow the formation of 3-indolyl-C-glycosides
(Scheme 1d). Herein, we report the details of this study.
NH
I
O
TIPSO
TIPSO
DOI: 10.1039/D0OB01812K
O
TIPSO
+
Base, Solvent
T
NHR1
1 = COCF3
TIPSO
OTIPS
1a
2a,
R
OTIPS
R
1 = H
3aa
2a',
Yield
Solvent
Entry
Ligand
Base
(%)b
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20c
21d
22e
23f
PPh3
Binap
Xantphos
dppf
Xphos
K2CO3 1,4-dioxane
K2CO3 1,4-dioxane
K2CO3 1,4-dioxane
K2CO3 1,4-dioxane
K2CO3 1,4-dioxane
K2CO3 1,4-dioxane
73
68
55
73
57
72
79
53
77
59
20
69
25
23
37
67
85
a) Sonogashira coupling/heteroannulation of sugar alkynes with 2-iodoanilines
O
GPO
I
O
1) [Pd]/CuI
GPO
+
N
NHR1
2) [Cu] or [Au]
R1
b) Palladium/Copper cocatalyzed cross-coupling of 1-iodoglycals with indoles
P(o-tol)3
O
GPO
O
I
[Pd]/[Cu]
P(p-MeOPh)3 K2CO3 1,4-dioxane
P(2-furyl)3
GPO
+
N
R1
N
R1
K2CO3 1,4-dioxane
K2CO3 1,4-dioxane
K2CO3 1,4-dioxane
PCy3
--
c) Pd-catalysed ortho-directed C-H glycosylation of indoles
R1
N
AQ (8-aminoquinoline)
P(p-MeOPh)3 Na2CO3 1,4-dioxane
P(p-MeOPh)3 Cs2CO3 1,4-dioxane
P(p-MeOPh)3 Ag2CO3 1,4-dioxane
QAOC
O
COAQ
N
R1
GPO
O
Cl
[Pd]
P(p-MeOPh)3
Et3N
1,4-dioxane
CH3CN
Toluene
THF
GPO
NHi3QA
P(p-MeOPh)3 K2CO3
P(p-MeOPh)3 K2CO3
P(p-MeOPh)3 K2CO3
P(p-MeOPh)3 K2CO3
P(p-MeOPh)3 K2CO3
P(p-MeOPh)3 K2CO3
P(p-MeOPh)3 K2CO3
P(p-MeOPh)3 K2CO3
P(p-MeOPh)3 K2CO3
NHi3QA
N
O
GPO
R1
i3QA
(isoquinoline-3-carboxylic acid)
N
R1
DCE
DMF
THF
THF
THF
THF
trace
62
65
90
82
d) Cyclization of o-alkynylanilines with1-Iodoglycals (This work)
Ar
NR1
Ar
I
O
[Pd]
R2
O
R2
GPO
+
GPO
NHR1
trace
aReaction conditions, unless otherwise noted: 1a (0.18 mmol),
2a (0.15 mmol), Pd(PPh3)4 (5 mol %), Ligand (10 mol %), Base (2
equiv), Solvent (2 mL), T = 90 °C, N2 atmosphere, 4 h. bIsolated
Scheme 1 Transition-metal-catalyzed synthesis of indole-C-
glycosides.
yield. cT = 80 °C. dT = 100 °C. eT = 110 °C. with 2a′ (0.15 mmol).
f
Our studies began with the optimization of the reaction
conditions with triisopropylsilyl-protected 1-iodoglucal 1a and
With the optimized reaction conditions in hand (Table 1,
entry 21), we then examined the substrate scope of this
reaction (Scheme 2). First, the reactions of various o-
2a
as
the
model
substrates
(Table
1).
o-
(Phenylethynyl)trifluoroacetanilide (2a) was chosen because
the removable trifluoroacetyl group favor the formation of a
stronger nitrogen nucleophile.11c In the presence of 5 mol %
alkynyltrifluoroacetanilides
2 were investigated using 1-
iodoglucal 1a as the reaction partner. In general, the reaction
had a broad scope. Most of the tested substrates bearing
either electron-donating group (Me) or electron-withdrawing
groups (F, Cl, CO2Me) at the C-4 position of aniline ring were
tolerated and led to their corresponding 3-indolyl-C-glycal
products in good to excellent yields (3aa−3ae). The reaction to
access 3aa could be conducted on a gram scale. Further
investigations indicated that similar results were observed
when the substituents shifted to the C-3 (3af), C-5 (3ag, 3ah),
or C-6 (3ai) position of the aniline ring. In addition, the
transformations of alkynes with 4-MeO (3aj−3ao), 4-Et
(3ap−3as) or 4-Cl (3at−3av) on the phenyl ring could proceed
well, giving the desired products in 68%-92% yields. It worth
noting that the reactions of substrates with 3-methyl on the
aniline ring were relatively sluggish, probably due to the steric
hindrance effect (3af, 3an). Subsequently, the reactions of 1-
iodo-L-rhamnal 1b with various o-alkynyltrifluoroacetanilides 2
were examined. For o-alkynyltrifluoroacetanilides 2 bearing 4-
Me or 5-Me on the aniline ring, target products were obtained
in 83% (3bb) and 82% (3bg) yields, respectively. Substrate
bearing an electron-withdrawing substituent (CO2Me, 3be) at
o
Pd(PPh3)4, 10 mol % PPh3 and K2CO3 (2 equiv) at 90 C under
nitrogen atmosphere, the heterocyclization reaction
proceeded smoothly and the desired product 3aa was
afforded in 73% yield (entry 1). Next, ligand screening (entries
2-9) demonstrated that P(p-MeOPh)3 was the best of choice,
affording 3aa in 79% yield (entry 7). In addition, control
experiments confirmed that the product yield declined
considerably in the absence of ligand (entry 10). Screening of
various bases including Na2CO3, Cs2CO3, Ag2CO3 and Et3N did
not give superior results (entries 11-14). Further investigation
into the effect of solvent (entries 15-19) and temperature
(entries 20-22) showed that the reaction conducted in THF at
o
100 C gives the highest yield (90%, entry 21). Notably, it was
found that 2-(phenylethynyl)aniline 2a′ was not suitable for
the reaction (entry 23).
Table 1 Optimization of reaction conditionsa
2 | J. Name., 2012, 00, 1-3
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the C-4 position of aniline ring also participated smoothly in alkynylaniline was proceeded well to give N-protected C-
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the cyclization reaction, and satisfactory yield was obtained. glycoside in good yield (5ad, 86%). IDnOIa:d10d.i1t0i3o9n/,D0eOleBc0t1r8o12nK-
Additionally, alkynes with 4-MeO (3bk, 3bm, 3bo), 4-Et donating or electron-withdrawing groups at various positions
(3bp−3br) and halogen (3bt, 3bu) still well tolerated and gave of the aniline core (5-Me, 4-Me, 4-CO2Me) were well tolerated.
the desired C-glycoside products in good to excellent yields The resultant cyclization products 5ae−h were obtained in
(78%−93%).
65−82% yields.
R3
R3
R2
NR1
I
O
R2
Pd(PPh3)4
Pd(PPh3)4
P(p-MeOPh)3
I
O
TIPSO
TIPSO
R2
O
GPO
NH
+
TIPSO
TIPSO
1
6
P(p-MeOPh)3
K2CO3, THF
R1
O
R2
+
OTIPS
NHR1
100 o
C
1
2
5
K2CO3, THF
GPO
NHCOCF3
R1
1a:
1b:
1-iodoglucal
1-iodo-L-rhamnal
1a
100 o
C
3
5
4
OTIPS
4
2
3
R1
N
Ts
Ph
Ph
Ph
Ts
N
Ph
Ph
NH
NH
Ph
O
NH
N
O
O
O
O
O
TIPSO
TIPSO
TIPSO
TIPSO
TIPSO
TIPSO
TIPSO
TIPSO
TIPSO
TIPSO
TIPSO
Me
Me
Me
TIPSO
R
OTIPS
OTIPS
OTIPS
OTIPS
, R = H, 90%
84% (1.5 mmol scale)
, R = Me, 86%
, R = F, 82%
OTIPS
OTIPS
a
, R1 = Bn, ND
3ag
3af
, 83%
, 72%
NH
5aa
5ab
3aa
, R1 = Ac, ND
a
5ae
, 74%
5ad
, 86% (87%)
5ac, R1 = Bz, ND
Ph
O
Ph
O
NH
3ab
3ac
3ad
3ae
Me
Cl
Et
Et
TIPSO
TIPSO
TIPSO
, R = Cl, 85%
, R = CO2Me, 91%
Ts
F
Ts
Ts
TIPSO
N
N
N
MeO
OTIPS
OTIPS
3ah
O
O
O
TIPSO
TIPSO
TIPSO
TIPSO
TIPSO
TIPSO
, 78%
3ai
, 76%
MeO
NH
MeO
CO2Me
CO2Me
Me
O
OTIPS
OTIPS
OTIPS
TIPSO
TIPSO
NH
NH
5ag
, 82%
5af
5ah
, 65%
, 72%
O
R
O
TIPSO
TIPSO
OTIPS
, R = H, 86%
3ak
, R = Me, 88%
3al
, R = Cl, 85%
TIPSO
TIPSO
Me
3aj
Scheme 3 Synthesis of N-protected C-glycosides. Reaction
conditions: 1a (0.18 mmol), 4 (0.15 mmol), Pd(PPh3)4 (5 mol %),
P(p-MeOPh)3 (10 mol %), K2CO3 (2 equiv), THF (2 mL), N2
atmosphere, for 6 h. Yield of isolated product. ND = not
detected. a0.75 mmol scale.
Me
OTIPS
3an
OTIPS
a
3ao
, 79%
, 68%
3am
, R = CO2Me, 92%
Cl
Et
Et
NH
NH
NH
O
TIPSO
O
O
TIPSO
TIPSO
TIPSO
Me
TIPSO
R
TIPSO
To demonstrate the general synthetic utility of our
methodology, several transformations of the product 5ad
were carried out. As shown in scheme 4, the removal of the
hydroxy-protecting TIPS group in product 5ad formed the
desired O-free C-glycoside 6ad in good yield (77%) under mild
reaction conditions. Furthermore, the C=C double bond of the
glycal moiety of 5ad could be reduced with Pd/C under an
atmosphere of H2, giving corresponding 2-deoxy-C-aryl
glycoside 7ad in moderate yield.17 The stereochemistry of 7ad
was determined via NOESY experiment, the presence of a
NOESY correlation peak between H-1 and H-5 indicated that H-
1 is cis to H-5.18
OTIPS
R
OTIPS
, R =H, 88%
, R = Me, 90%
, R = CO2Me, 86%
OTIPS
3at
, R = H, 82%
, R = Me, 80%
, R = CO2Me, 81%
3ap
3aq
3ar
3au
3as
, 85%
3av
MeO
NH
NH
NH
O
O
O
Me
TIPSO
TIPSO
3ba
R
TIPSO
OTIPS
OTIPS
R
OTIPS
3bk
, R = Me, 84%
, R = H, 89%
, R = Me, 83%
, R = CO2Me, 92%
3bg
, 82%
3bb
3be
3bm
, R = CO2Me, 93%
Cl
Et
MeO
NH
NH
NH
O
O
Ts
Ts
NOE
O
Ph
Ts
Ph
Ph
N
N
N
Me
H
H
TIPSO
TIPSO
3bp
O
H2, Pd/C
R
R
O
O
TIPSO
TBAF
TIPSO
TIPSO
OTIPS
OTIPS
, R = H, 80%
, R = Me, 78%
, R = CO2Me, 86%
HO
HO
1
5
OTIPS
EtOAc/MeOH
rt
THF, rt
TIPSO
3bt
3bu
TIPSO
, R = H, 81%
, R = Me, 79%
3bq
3br
3bo
, 82%
OTIPS
7ad
OH
OTIPS
, 53%
6ad
, 77%
5ad
Scheme 2 Substrate scope. Reaction conditions: 1 (0.18 mmol),
2 (0.15 mmol), Pd(PPh3)4 (5 mol %), P(p-MeOPh)3 (10 mol %),
K2CO3 (2 equiv), THF (2 mL), N2 atmosphere, for 6 h. Yield of
isolated product. afor 10h.
Scheme 4 Synthetic transformations of 5ad.
On the basis of the previous works,12-15 a mechanism for the
formation of 3 was proposed in Scheme 5. The oxidative
addition of Pd(0) to 1-iodoglycal 1 produces palladium specie A
that coordinates to the triple bond of 2 to give intermediate B.
A subsequent intramolecular cyclization by nucleophilic attack
of the nitrogen atom generates the σ-indolyl-σ-
glycosylpalladium intermediate C. Finally, the resulting
intermediate C undergoes reductive elimination to provide the
The scope of the reaction was further investigated to
construct N-protected 3-indolyl-C-glycosides (Scheme 3). The
adjustment of the N-group of o-alkynylaniline from
trifluoroacetyl to benzyl, acetyl and benzoyl did not deliver the
corresponding products (5aa-c), indicating that the N-
protecting group has a great impact on this cyclization process.
To our delight, the reaction with N-tosyl substituted o-
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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Journal Name
3
4
(a) J. Hofsteenge, D. R. Müller, T. De Beer, A.VLieöwffAlretirc,leWOn.linJe.
Richter and J. F. G. Vliegenthart, BDioOcIh: e10m.1i0s3tr9y/D10O99B401,81323K,
13524; (b) M.-A. Doucey, D. Hess, M. J. J. Blommers and J.
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Wu, Z.-X. Zhang, H. Hu, D. Li, G. Qiu, X. Hu and X. He,
Fitoterapia 2011, 82, 288; (c) C.-H. Yao, J.-S. Song, C.-T. Chen,
T.-K. Yeh, T.-C. Hsieh, S.-H. Wu, C.-Y. Huang, Y.-L. Huang, M.-
H. Wang, Y.-W. Liu, C.-H. Tsai, C. R. Kumar and J.-C. Lee, Eur.
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1, 2007.
intermediate D, which subsequently undergoes deprotection
to give 3.11a
Ar
NCOCF3
O
I
LPd(0)
O
GPO
GPO
GPO
1
D
O
O
PdIL
3
Ar
NCOCF3
A
L
Pd
Ar
GPO
C
KI+KHCO3
NHCOCF3
2
Ar
L
I
Pd
O
GPO
NHCOCF3
K2CO3
B
5
(a) D. Guianvarc'h, J.-L. Fourrey, M.-E. Tran Huu Dau, V.
Guérineau and R. Benhida, J. Org. Chem. 2002, 67, 3724; (b)
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Chem. 2010, 141, 913.
Scheme 5 Proposed reaction mechanism.
6
7
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Sotilla and T. Opatz, Synthesis 2012, 44, 1385.
Conclusions
In summary, we have described a novel palladium-catalyzed
heterocyclization and C-glycosylation sequence of o-
alkynylanilines with 1-iodoglycals. The reaction has a broad
substrate scope, demonstrates good functional group
tolerance and could be scaled up. Structurally diverse 3-
indolyl-C-∆1,2–glycosides were accessed in good to excellent
yields with high step economy. Moreover, the transformations
of representative product 5ad were investigated to
demonstrate the potential synthetic applications of this
method.
8
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Conflicts of interest
There are no conflicts to declare.
9
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Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (Nos. 21807051, 21877055),
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18 See the Supporting Information for spectral details.
4 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Ar
DOI: 10.1039/D0OB01812K
NR1
Ar
Pd(PPh3)4 (5 mol %)
I
O
O
P(p-MeOPh)3 (10 mol %)
R2
GPO
+
GPO
K2CO3 (2 equiv)
NHR1
R2
THF, 100 o
C
39 examples, up to 93% yield
An efficient and practical approach for the synthesis of 3-indolyl-C-glycosides through
a palladium-catalyzed annulation/C-glycosylation sequence of o-alkynylanilines has
been developed.