General Approach to Five-Membered Nitrogen Heteroaryl C-Glycosides Using a Palladium/Copper Cocatalyzed C-H Functionalization Strategy

Article abstract of DOI:10.1021/acs.orglett.7b01583

A general approach to the synthesis of diverse heteroaryl-C-Δ^1,2-glycosides has been developed by employing the Pd(OAc)₂/CuI cocatalyzed direct cross-coupling of five-membered nitrogen heterocycles with 1-iodoglycals in a C-H activation manner. Using this method, 27 examples of heteroaryl-C-Δ^1,2-glycosides, containing indoles, thiazoles, benzothiazoles, imidazoles, benzimidazoles, and benzoxazoles as aglycones were obtained in 43-99% yield.

Full text of DOI:10.1021/acs.orglett.7b01583

Letter
pubs.acs.org/OrgLett
General Approach to Five-Membered Nitrogen Heteroaryl
C‑Glycosides Using a Palladium/Copper Cocatalyzed C−H
Functionalization Strategy
Shuo Zhang,† You-Hong Niu,† and Xin-Shan Ye*
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Road No.
38, Beijing 100191, China
S
* Supporting Information
ABSTRACT: A general approach to the synthesis of diverse
heteroaryl-C-Δ1,2-glycosides has been developed by employing the
Pd(OAc)2/CuI cocatalyzed direct cross-coupling of five-membered
nitrogen heterocycles with 1-iodoglycals in a C−H activation manner.
Using this method, 27 examples of heteroaryl-C-Δ1,2-glycosides,
containing indoles, thiazoles, benzothiazoles, imidazoles, benzimida-
zoles, and benzoxazoles as aglycones were obtained in 43−99% yield.
onjugation of five-membered nitrogen heterocycles such as
indoles, thiazoles, imidazoles, benzimidazoles, and benzo-
thiazoles to the anomeric carbon of glycopyranoses, through a
C−C bond, creates heteroaryl C-glycosides, an important
subclass of C-glycoside. Such heteroaryl C-glycosides, either of
natural or synthetic origin, possess a wide range of biological
activities (Figure 1).1 For example, C-glycosides containing
significance of heteroaryl C-glycosides is also exemplified by
glycopyranosyl-2-benzoimidazoles and other heterocycles that
include imidazoles, thiazoles, and benzothiazoles, which display
various activities such as glycosidase/glycogen phosphorylase
inhibition, as well as antibacterial and antifungal activities.
Due to their tremendous potential in the treatment of diseases,
diverse synthetic methods have been developed to construct
heteroaryl C-glycosides. Most syntheses rely upon one of the
following two approaches. The first approach involves the
formation of a C-glycosidic bond by the sequential addition of a
carbanion to gluconolactone and reductive deoxygenation.1d,3a
The second approach involves nitrogen heterocyclic ring
formation,6 which employs the reaction of the pyranosyl one
carbon unit with the corresponding benzene derivatives (Scheme
1). Some of these syntheses are not straightforward, and some are
carried out under harsh conditions. Moreover, these syntheses
are usually compatible with only a narrow range of heterocycles.
Therefore, a general synthetic approach to this type of nitrogen
heteroaryl C-glycoside and structurally similar compounds would
be highly valuable.
Transition-metal-catalyzed C−H activation has emerged as
one of the most sustainable and powerful platforms for the step-
economical construction of organic molecules with various
substitution patterns over the last two decades.7 Among these
transformations, arylation of five-membered heterocycles such as
indole,8 thiazole,9 benzoxazole,10 and other heterocyles11 has
been achieved by Pd(II)- or Cu(I)-catalyzed direct C−H
activation, and the functionalization of heterocycles with simple
aryl iodides has afforded diverse 2-arylheterocycles.
C
Figure 1. Some examples of bioactive five-membered nitrogen
heteroaryl C-glycosides.
indoles display significant cytotoxic activities against a series of
cancer cells due to their DNA modulatory properties.2 Such
molecules also serve as potent inhibitors of sodium/glucose
cotransporter 2 (SGLT2)3 and phosphorylase4 and could be of
potential value as drugs for the treatment of type 2 diabetes
mellitus, from which approximately four hundred million people
suffer worldwide. α-C-Mannosyltryptophan, a sugar amino acid,
is a key structural unit of several biologically important proteins
such as recombinant interleukin 12 (IL-12),5a proteins of the
human complement system,5b,c human platelet thrombospon-
din-1,5d,e and the recombinant erythropoietin receptor.5f The
Due to the similar reactivity between iodobenzene and 1-
iodoglycals established in our previous work,12 we envisioned
Received: May 25, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b01583
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Letter
heteroaryl-C-Δ1,2-glycosides by the Pd/Cu cocatalyzed C−H
functionalization of heterocycles with 1-iodoglycals.
Scheme 1. Methods for the Preparation of Five-Membered
Nitrogen Heteroaryl C-Glycosides
Our investigation commenced with an optimization of the
coupling between 1 and 2 to obtain 3a (Table 1). N-Tosylindole
(2) was chosen because the tosyl protective group possesses
strong electron-withdrawing properties, which leads to low
nucleophilicity for C-3. The oxygen atom of the tosyl protective
group might also have a weak coordination ability, which would
result in the C-2 glycosidation of the indole as the major product.
In addition, if we could find the optimal reaction conditions for
the coupling of indole with 1-iodoglycals, these conditions could
be applied to the other nitrogen heterocycles. Experiments were
carried out using different catalysts, bases, ligands, solvents, and
temperatures, and the results are summarized in Table 1. Using
Pd(OAc)2 as the catalyst and dioxane as the solvent, we initially
screened various bases such as Na2CO3, K2CO3, and t-BuOLi to
couple 1-iodoglucal 1 with indole 2, but no desired product was
obtained, even after the addition of 1,10-phenanthroline17 as a
ligand (entries 1−4). Using CuI as the catalyst instead of
Pd(OAc)2, the coupling reaction did not take place either (entry
5). According to the work of Sames and Daugulis,8b,10 either
Pd(OAc)2 or CuI was needed for the 2-arylation of indoles and
benzoxazoles. We speculated that use of Pd(OAc)2 and CuI as a
bimetallic catalysis system might promote the coupling reaction.
When the reaction was run with Pd(OAc)2, CuI, and t-BuOLi in
dioxane at 100 °C, the 2-glycosylation product of indole was
obtained in 64% yield (entry 6). To further increase the yield,
different solvents such as DMF and DMA (entries 7 and 8) were
tried, but no coupling product was detected in the reactions,
suggesting that in our screening, 1,4-dioxane was the most
suitable solvent for this C−H activation and functionalization.
Simply by changing the ratio of 1 to 2 from 2:1 to 1:2, we found
that the desired product was furnished in 81% yield (entry 9).
that the direct coupling of 1-iodoglycals (in spite of them being
more complicated substrates than iodoarenes) with indoles and
other heterocycles would provide a reliable approach to
construct various 2-heteroaryl-C-Δ1,2-glycosides. If the reaction
proceeded as we anticipated, it would have several advantages
that would include (1) high generality, (2) high reaction
efficiency because it would use C−H activation, and (3)
diversified subsequent modifications by it allowing conversion
of the double bond into other functional groups such as 2-
deoxysugars by hydrogenation.13 It would also allow the ready
introduction of hydroxyl,14 nitrogen,15 or halogen16 groups and
expand the diversity of 2-heteroaryl-C-glycosides that could be
prepared for the screening of bioactive compounds. Based on this
design, we report our results on the synthesis of various 2-
a
Table 1. Optimization of the Reaction Conditions
b
entry
1/2
catalyst
Pd(OAc)2
base
ligand
solvent
t (°C)
yield (%)
1
2
3
4
5
6
7
8
9
2/1
2/1
2/1
2/1
2/1
2/1
2/1
2/1
K2CO3
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
DMF
100
100
100
100
100
100
100
100
100
100
100
100
100
90
0
0
Pd(OAc)2
Cs2CO3
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
Pd(OAc)2
0
Pd(OAc)2
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
PPh3
Bpy
0
CuI
0
Pd(OAc)2, CuI
Pd(OAc)2, CuI
Pd(OAc)2, CuI
Pd(OAc)2, CuI
Pd(OAc)2, CuI
Pd(OAc)2, CuI
Pd(OAc)2, CuI
Pd(OAc)2, CuI
Pd(OAc)2, CuI
Pd(OAc)2, CuI
Pd(OAc)2, CuI
Pd(OAc)2, CuBr
Pd(OAc)2, CuOAc
64
0
DMA
0
c
1/2
1/2
1/2
1/2
1/2
1/2
1/2
1/2
1/2
1/2
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
1,4-dioxane
81
65
3
d
10
e
11
12
13
14
15
16
17
18
6
59
39
76
70
67
70
Phen
Phen
Phen
Phen
Phen
110
120
100
100
a
Reaction conditions: 1 (0.054 mmol), 2 (0.027 mmol), base (6.0 equiv), Pd catalyst (10 mol %), Cu catalyst (20 mol %), ligand (0.2 equiv), solvent
b
c
d
e
(0.5 mL), under an argon atmosphere, 24 h. Isolated yield. Reaction conditions: 1 (0.027 mmol), 2 (0.054 mmol). Phen (0.4 equiv) was used. t-
BuOLi (4.0 equiv) was used. Phen = 1,10-phenanthroline. Bpy = 2,2-bipyridine.
B
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Increasing the amount of Phen from 0.2 to 0.4 equiv, decreasing
the amount of base, or using PPh3 and 2,2-bipyridine as ligands
rather than Phen resulted in a drop in the yield of the product
(entries 10−13). Reaction temperature was also screened to
improve the coupling yield, but none of the reactions was able to
achieve a yield higher than 81% (entries 14−16). Finally,
different copper salts such as CuBr and CuOAc were tested, but
the yield did not increase further (entries 17 and 18). Before
evaluating the scope of substrates, the standard conditions were
applied to the coupling of 1 with 4-methylthiazole, with the
desired product 6a (Figure 2) obtained in almost quantitative
yield. This suggested that the optimum conditions would be
applicable to the coupling of the azole substrate with 1-
iodoglycals.
As the optimal reaction conditions had been determined, we
evaluated the generality of this new method for the synthesis of
five-membered nitrogen heteroaryl C-glycosides using three
different 1-iodoglycals with heterocycles that included indoles,
thiazoles, benzothiazoles, imidazoles, benzimidazoles, and
benzoxazoles (Figure 2). Besides indole 2, other substituted
indoles were subjected to the coupling reaction. For example,
when 5/6-methyl-1-tosyl-1H-indole and 5-methoxy-1-tosyl-1H-
indole, which are even more electron-rich, were employed to
react with 1-iodoglucal 1 under the standard conditions, desired
products 7a, 8a, and 9a were obtained in 79, 83, and 80% yields,
respectively. Coupling of 5-fluoro-substituted indole with 1 was
also performed, and the corresponding product 10a was
furnished in 77% yield. It should be noted that if there is a
strong electron-withdrawing group (nitro group) on the indole
ring, the coupling reaction with 1-iodoglucal 1 failed to give the
product. Furthermore, when other 1-iodoglycals 4 and 5 derived
from D-galactose and L-rhamnose were applied to the direct C−H
activation and the functionalization of N-tosylindole derivatives,
they afforded the corresponding products 11b, 12c, and 13c in
moderate to good yields. All of these results indicated that our
approach shows good generality in the preparation of 1-indolyl
glycosides.
To further examine the scope of other heterocycle substrates,
coupling reactions of some thiazole derivatives with 1 and 1-
iodo-L-rhamnal 5 were carried out under the standard conditions,
affording the corresponding products 14a, 15a, and 16c in
moderate to excellent yields (99, 62, and 93%, respectively).
Interestingly, when methyl 4-methylthiazole-5-carboxylate was
used, it was found that the coupling and transesterification
reactions took place simultaneously, and the product with a t-
butyl ester was isolated in 62% yield. The moderate yield for 15a
might result from hydrolysis of the methyl ester. Synthesis of
benzothiazole-containing C-glycosides by our approach was
further assessed. Reactions of benzothiazoles bearing different
substituents such as Br, OCH3, and Cl with various 1-iodoglycals
worked very well, furnishing the desired products 17a−24c in
72−99% yield. It was gratifying to find that the bromo group was
compatible with the reaction conditions. Due to the structural
similarity and probability of sharing common properties, we then
expanded our method to other heterocycle substrates such as
imidazoles, benzimidazoles, and benzoxazoles. 1-Methyl-1H-
imidazole and 1-methyl-1H-benzimidazole were applied to the
coupling reaction employing the Pd/Cu catalysis system, and the
corresponding products 25a, 26b, and 27a were formed in 60, 98,
and 95% yields. Benzoxazole also smoothly underwent the
coupling reaction with different 1-iodoglycals under the catalytic
system to produce 28a and 31c in 43 and 56% yields,
respectively. By comparison, when 5-bromobenzoxazole was
Figure 2. Scope of substrates and five-membered nitrogen heteroaryl C-
a
glycosides. Isolated yield when 20.0 mg of the 1-iodoglycal was used.
bIsolated yield in brackets when approximately 1 mmol of the 1-
iodoglycal was used.
used to couple with 1 and 4, products 29a and 30b were obtained
in even higher yields. Note that the reaction of benzothiazole was
more efficient than the reaction of bromo-substituted
benzothiazole (17a vs 18a, 22c vs 23c), but reaction of
benzoxazole gave a yield lower than that of 5-bromobenzoxazole
(28a vs 29a). We think the reason is that the electron-
withdrawing effect of the bromine might reduce the electron
density of the nitrogen atom, thus weakening the coordination of
copper to the nitrogen in the benzothiazole. However, in bromo-
substituted benzoxazole, the bromine atom might reduce the
C
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electron-donating effect of the oxazole ring, making deprotona-
tion at the 2-proton and formation of the lithium salt on the
oxazole ring easier, thus leading to a difference in yield. In all of
the coupled products, the glycals became attached to the
heterocycles at the C-2 position, suggesting that our method
shows high regioselectivity. To further investigate the practicality
of this protocol, nine coupling reactions involving all types of 1-
iodoglycal and heterocycle were performed, in which the
substituent effects were also considered. These reactions were
conducted on an approximately 1 mmol scale under the
optimized conditions, and the coupling yields of products 6a,
7a, 13c, 19a, 21b, 22c, 25a, 27a, and 31c were almost consistent
with the yields of the small-scale reactions.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b01583.
■
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Experimental procedures and characterization data for all
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: xinshan@bjmu.edu.cn.
ORCID
Xin-Shan Ye: 0000-0003-4113-506X
Author Contributions
†S.Z. and Y.-H.N. contributed equally.
Notes
(17) Qin, X.; Cong, X.; Zhao, D.; You, J.; Lan, J. Chem. Commun. 2011,
47, 5611.
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was financially supported by the National Natural
Science Foundation of China (Grant No. 21232002) and Grant
2013CB910700 from the Ministry of Science and Technology of
China.
D
DOI: 10.1021/acs.orglett.7b01583
Org. Lett. XXXX, XXX, XXX−XXX