Pd-Catalyzed Ortho-Directed C—H Glycosylation of Arenes Using N-linked Bidentate Auxiliaries

Article abstract of DOI:10.1002/cjoc.202000500

A set of Pd-catalyzed ortho-directed C—H glycosylation reactions with glycosyl chloride donors using various N-linked bidentate auxiliaries has been developed for synthesis of C-aryl glycosides. A broad range of pyranose and furanose moieties can be installed on the ortho position of arylamine, carbazole, indole and benzylamine type substrates in high yield and with high regio- and diastereoselectivity. These auxiliaries can be readily installed and removed under relatively mild conditions.

Full text of DOI:10.1002/cjoc.202000500

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Pd-catalyzed Ortho-Directed C-H Glycosylation of Arenes Using N-linked
Bidentate Auxiliaries
Authors: Quanquan Wang, Wanjun Zhu, Qikai Sun, Gang He,* and Gong Chen*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000500.
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published online in Early View: http://dx.doi.org/10.1002/cjoc.202000500.
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Chinese Journal
of Chemistry
C-H glycosylation, palladium catalysis, C-glycoside, bidentate auxiliary
Report
CJC
中
国 化 学 - An International Journal
Pd-catalyzed Ortho-Directed C-H Glycosylation of Arenes Using N-linked
Bidentate Auxiliaries
Quanquan Wang, Wanjun Zhu, Qikai Sun, Gang He,* and Gong Chen*
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071, China
Cite this paper: Chin. J. Chem. 2019, 37, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion A set of Pd-catalyzed ortho-directed C-H glycosylation reactions with glycosyl chloride donors using various
N-linked bidentate auxiliaries has been developed for synthesis of C-aryl glycosides. A broad range of pyranose and furanose moieties can be installed on
the ortho position of arylamine, carbazole, indole and benzylamine type substrates in high yield and with high regio- and diastereoselectivity. These
auxiliaries can be readily installed and removed under relatively mild conditions.
2 equiv of tetrabenzyl-mannosyl chloride donor a in the presence
Background and Originality Content
of 2 mol% of Pd(OAc)2, 1.5 equiv of KOAc and 30 mol% of amino
Structures of C-aryl glycosides are prevalent in natural and
o
acid additive Ac-Ile-OH in toluene at 60 C for 12 hours gave 3a in
synthetic compounds.1 For example, C2-α-mannosylation of
93% isolated yield with exclusive α diastereoselectivity. The sugar
tryptophan (Trp) provides an intriguing means for post-
translational modification (PTM) of proteins (Scheme 1A).2 Gliflozin
compounds are highly successful glycomimetic drugs for the
treatment of diabetes. In comparison with the myriad of methods
for synthesis of O and N-linked glycosides, chemistry for synthesis
of C-glycosides is much less developed.3-5 Recently, we reported a
C-H functionalization strategy for the stereoselective synthesis of
C-aryl glycosides via palladium-catalyzed ortho-directed C(sp2)−H
glycosylation of arenes and heteroarenes with glycosyl chloride
donors (Scheme 1B).6,7 The ortho C-H bonds of arylcarboxamide or
2-arylacetamide substrates equipped with amide-linked N,N-
bidentate auxiliary 8-aminoquinoline (AQ or Q) can be activated to
form 5 or 6-membered palladacycle intermediates, which then
react with glycosyl chloride donors via oxidative addition and
reductive elimination to give the corresponding C-glycosides in
good to excellent yield and with excellent diastereoselectivity.8-14
Phenol type substrates can undergo similar ortho C-H glycosylation
using a carbamate-linked AQ auxiliary. Herein, we report an
extension of this Pd-catalyzed ortho-directed C-H glycosylation
reaction strategy to arylamine, benzylamine and N-heteroarene
substrates using various urea-linked or amide-linked bidentate
auxiliaries.
ring of compound 3a adopts a 1C4 conformation based on 1H-NMR
Scheme 1 Synthesis of C-aryl-glycosides via Pd-catalyzed ortho-directed C-
H glycosylation with glycosyl chlorides.
Results and Discussion
Encouraged by the success of ortho C-H glycosylation reaction
of phenol substrates, we questioned whether arylamines bearing a
urea-linked AQ auxiliary can undergo similar transformations via 6-
membermed palladacycle intermediate.15 As outlined in Table 1,
AQ 1 can be readily converted to carbamate intermediate 2 (X =
OPhe) or chloroformate intermediate 2’ (X = Cl). Condensation of 2
or 2’ with m-toluidine in the presence of base gave model substrate
3 in good yield. We were pleased to find that the reaction of 3 with
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First author et al.
Report
5
No base
ND
6
K2CO3 (1.5 equiv) as base
without Ac-Ile-OH
35%
53%
86%
76%
45%
51%
22%
95%
7
8
Ac-Ile-OH replaced with Phth-Gly-OH
Ac-Ile-OH replaced with PivOH
Addition of AgOAc (2 equiv)
45 oC
9
10
11
12
13
10 mol% of Pd, 25 oC
Under air atmosphere
a) Yields are based on 1H-NMR analysis of crude reaction mixture using
1,1,2,2-tetrachloroethane as internal standard at 0.1 mmol scale. b)
Isolated yield. ND: not detected.
analysis. Reaction in solvents like 1,2-dichloroethane (DCE), CH3CN
or THF gave diminished yield (entries 2-4). The addition of base is
necessary and the use of K2CO3 gave lower reactivity (entries 5, 6).
3a was obtained in 53% yield in the absence of any acid additive
(entry 7). Ac-Ile-OH performed consistently better than other
carboxylic acid additive over a range of substrates tested.16
Addition of silver additive diminished the reactivity (entry 10).
Reaction with 10 mol% of Pd catalyst at rt gave 3 in 22% yield (entry
12). Reaction under air atmosphere gave similar results (entry 13).
As shown in Scheme 2, a range of arylamines undergo an ortho
C−H mannosylation reaction with donor
a to give the
corresponding C-glycosides in good to excellent yield and with
excellent α diastereoselectivity under optimized conditions. In
general, electron-rich arenes are more reactive and react well at
relatively low temperatures (conditions A with 2 mol% of Pd, 60 oC).
For example, reaction of m-anisidine gave 4a in 94% yield. Reaction
of p-tert-butylaniline gave 7a as a mixture of mono- and di-
mannosylated product. Ortho-substituted substrates are less
reactive than meta- or para-substituted ones and work better with
higher loading of Pd catalyst (5 mol%) and increased reaction
o
temperature (110 C) (conditions B). For example, reaction of o-
Table 1. Reaction optimizations
anisidine gave 6a in 92% yield. Reaction of m-CF3-aniline did not
give any desired product 9a under conditions B. As shown by
compounds 12a and 14a, arylamine equipped with urea-linked
ortho-methylthiolaniline (SA) or 2-pyridylmethylamine (PM)
auxiliaries reacted well under conditions C with 10 mol% of Pd.
Unlike the facile preparation of 3, the installation of urea-linked AQ
auxiliary on secondary arylamine substrate can be problematic due
to steric hindrance. For example, synthesis of product 10a was
Scheme 2 Ortho-directed C-H glycosylation using urea-linked auxiliarya
Entry Change from standard conditions
Yield of 3a (%)a
1
2
3
4
No change
>95% (93%b)
45%
DCE as solvent
CH3CN as solvent
THF as solvent
40%
70%
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Chin. J. Chem. 2019, 37, XXX－XXX
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Running title
Chin. J. Chem.
unsuccessful due to the difficulty of making the corresponding
starting material. In comparison, the PM auxiliary can be more
easily installed onto the secondary amine starting material of 11a
using a chloroformate intermediate, which is analogous of 2’ (see
SI for detail). Mono-mannosylation products 11a and 15a were
obtained in good yields under conditions C at 110 oC. As shown in
16a-19a, indole and carbazole also can undergo C-H glycosylation
using urea-linked AQ or PM auxiliary. For example, AQ-directed
reaction of 3-methylindole selectively took place at C2 position
(18a), whereas PM-directed reaction gave a mixture of mono-
mannosylated product at C2 or C7 and di-mannosylated product.
Reaction of m-toluidine bearing a urea-linked benzyl group did not
give any ortho-C-H glycosylation product 13a, underscoring the
critical role of bidentate auxiliary for this Pd-catalyzed C-H
glycosylation reaction.
As shown in Scheme 2B, reaction of 3 with pyranomannose
chloride donors in other protected forms also work well (3b, 3d).
The disarmed tetraacetate-protected donor showed little
reactivity (3c). Reaction with other pyranose donors including D-
glucose (3e, 3f), D-galactose (3g), D-arabinose (3h) and L-rhamnose
(3i) proceeded in high yield and excellent α diastereoselectivity. No
neighboring group participation effect was observed for 3f.
Reaction with protected D-mannofuranose and D-ribofuranose
chloride donors gave 3j and 3k in excellent yield. Product 3l
carrying a disaccharide motif was obtained in excellent yield and
stereoselectivity.
Scheme 3. Ortho-directed C-H glycosylation using amide-linked auxiliary
Isolated yield at 0.1 mmol scale.
Chin. J. Chem. 2019, 37, XXX－XXX
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First author et al.
Report
Isolated yield at a 0.1 mmol scale. a) KOAc replaced with K2CO3, 24 h.
arylamine, carbazole, indole and benzylamine type substrates in
high yield and with high selectivity. These auxiliaries can be readily
installed and removed under relatively mild conditions. Further
extension of this C-H glycosylation strategy to other types of
directing groups and substrates is currently under investigation.
1-Naphthylamine 20 bearing an amide-linked picolinamide (PA)
auxiliary also reacted well with mannose donor a to give C8-
glycosylated product 20a in 92% yield and exclusive
α
diastereoselectivity under conditions C (Scheme 3). The reaction
presumably proceeded through a kinectically favored PA-chelated
Experimental
5-membered
palladacycle
intermediate.
In
contrast,
Representative procedure for synthesis of compound 3a. A
mixture of 3 (27.8 mg, 0.1 mmol), Pd(OAc)2 (0.5 mg, 0.002 mmol),
KOAc (14.7 mg, 0.15 mmol), Ac-Ile-OH (5.2 mg, 0.03 mmol) and
tetrabenzyl mannosyl α-chloride a (112 mg, 0.2 mmol) in 1 mL of
toluene in a 8 mL glass vial (purged with N2, sealed with PTFE cap)
was heated at 60 oC for 12 hours. After being cooled to rt, the
reaction mixture was concentrated in vacuo. The resulting residue
was purified by silica gel flash chromatography to give product 3a
as a colorless oil in 93% yield (Rf = 0.3, 20% ethyl acetate in hexanes).
mannosylation of 1-naphthylamine bearing a urea-linked AQ
occurred exclusively at C2 position (21a). Reactions of 20 with D-
mannofuranose, L-rhamnose, and D-glucose chloride donors gave
20j, 20i and 20f in high yield and with exclusive
α
diastereoselectivity. PA-coupled unsubstituted benzylamine
showed little reactivity (23a). Mannosylation of 1,2,3,4-tetrahydro-
1-naphthylamine gave 24a in 40% yields under slightly modified
conditions. In comparison, product 25a bearing an amide-linked
isoquinoline-1-carboxylic acid auxiliary (i1QA) was obtained in 57%
yield.7a,15i Mannosylation of 1-naphthylmethylamine equipped
with PA or i1QA auxiliary with donor a selectively took place at the
C2 position (26a, 27a).
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2018xxxxx.
As shown in Scheme 4, the urea-linked AQ group of 6a can be
cleaved by Ohshima’s methanolysis with 10 mol% of nickel
bis(2,2,6,6-tetramethyl-3,5-heptanedionate) (Ni(tmhd)2) to give
arylamine product 28.17a The urea-linked PM group of 19a can be
easily cleaved by LiOH in MeOH to give indole 29. The PA group of
20a can be cleaved by a two-step sequnce of Boc activation and
Acknowledgement
G.C. thanks NSFC-91753124, NSFC-21672105, NSFC-21421062,
and NSFC-21725204 for financial support of this work.
17b
cleavage with LiOH/H2O2 at room temperature (30).
Alternatively, the PA group can be cleaved by the treatment of Zn
powder in diluted aq. HCl in THF/H2O to give product 31 in high
yield. 17c, 17d
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We have developed a new set of Pd-catalyzed ortho-directed
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2019
Manuscript revised: XXXX, 2019
Manuscript accepted: XXXX, 2019
Accepted manuscript online: XXXX, 2019
Version of record online: XXXX, 2019
www.cjc.wiley-vch.de
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2019, 37, XXX－XXX
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Running title
Chin. J. Chem.
Entry for the Table of Contents
Page No.
Pd-catalyzed Ortho-Directed C-H Glycosylation
of Arenes Using N-linked Bidentate Auxiliaries
Quanquan Wang, Wanjun Zhu, Qikai Sun, Gang
He,* and Gong Chen*
A new method for diastereoselective synthesis of C-aryl glycosides of aryl amines, carbazoles,
indoles and benzylamines.
Chin. J. Chem. 2019, 37, XXX－XXX
© 2019 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
This article is protected by copyright. All rights reserved.