Palladium catalyzed stereocontrolled synthesis of C-aryl glycosides using glycals and arenediazonium salts at room temperature

Article abstract of DOI:10.1039/c8ob01393d

A stereocontrolled synthesis of aryl-C-glycosides was achieved using glycals and aryldiazonium salts in the presence of palladium acetate. A wide range of glycals including d-glucal, d-galactal, l-rhamnal, d-xylal and d-ribal underwent C-arylation at the anomeric carbon in the presence of different aryldiazonium tetrafluoroborates and gave synthetically useful 2,3-deoxy-3-keto-α-aryl-C-glycosides in good to excellent yields. Broad substrate scope, simple operation and room temperature reactions make this protocol very attractive in organic synthesis.

Full text of DOI:10.1039/c8ob01393d

View Article Online
View Journal
Organic &
Biomolecular
Chemistry
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: J. Kandasamy and
A. K. Singh, Org. Biomol. Chem., 2018, DOI: 10.1039/C8OB01393D.
This is an Accepted Manuscript, which has been through the
Volume 14 Number
1 7 January 2016 Pages 1–372
Royal Society of Chemistry peer review process and has been
accepted for publication.
Organic &
Biomolecular
Chemistry
www.rsc.org/obc
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
author guidelines.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the ethical guidelines, outlined
in our author and reviewer resource centre, still apply. In no
event shall the Royal Society of Chemistry be held responsible
for any errors or omissions in this Accepted Manuscript or any
consequences arising from the use of any information it contains.
ISSN 1477-0520
COMMUNICATION
Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
rsc.li/obc

Page 1 of 11
Organic & Biomolecular Chemistry
View Article Online
DOI: 10.1039/C8OB01393D
Palladium catalyzed stereocontrolled synthesis of C-aryl
glycosides using glycals and arenediazonium salts at room
temperature
Adesh Kumar Singh and Jeyakumar Kandasamy*
Department of Chemistry, Indian Institute of Technology (BHU), Varanasi,
Uttar Pradesh-221005
ABSTRACT: A stereocontrolled synthesis of aryl-C-glycosides was achieved using glycals
and aryldiazonium salts in the presence of palladium acetate. A wide range of glycals
including D-glucal, D-galactal, L-rhamanal, D-xylal and D-ribal underwent C-arylation at the
anomeric carbon in the presence of different aryldiazonium tetrafluoroborates and gave
synthetically useful 2,3-deoxy 3-keto α-aryl-C-glycosides in good to excellent yields. Broad
substrate scope, simple operation and room temperature reactions make this protocol very
attractive in organic synthesis.
Carbohydrates play an important role in biological system, which are used not only as source
of energy, but also drugs, diagnostic tools, vaccines, drug targets, etc.1 Aryl C-glycoside is
one of the distinct motifs found in various bio-active molecules and natural products, thus
attracted tremendous interest in synthetic organic chemistry (Figure 1).2 Aryl glycosides are
typically achieved by Friedel-Crafts alkylation of electron-rich arenes with glycosyl donors3
or by the reaction of protected aldonolactones with organometallic reagents such as
aryllithium or Grignard reagents.4 Alternatively, coupling reaction between glycosyl
bromides and arylzinc reagent has been reported to provide β-arylated glycosides.5 On the
other hand, palladium catalysed coupling reaction of glycals with various aryl donors such as
10
arylboronic acids,6 arylhydrazines,7 arylzinc reagents,8 aryl halides,9 etc.2,
have been
recently demonstrated for the preparation of various aryl C-glycosides.
Figure 1. Structures of some bioactive aryl C-glycosides.
1

Organic & Biomolecular Chemistry
Page 2 of 11
View Article Online
DOI: 10.1039/C8OB01393D
Arenediazonium salts are highly useful aryl donors which can be easily obtained from
corresponding anilines.11 Aryl diazonium salts have been identified as an efficient alternative
to arylhalides and arylboronic acids in Pd-catalyzed cross-coupling reactions.11a Recently,
palladium mediated Heck-type cross coupling between glycal and arylboronic acid was
explored by Ye et al.6a, 6c and Mukherjee et al.6b In this context, we have envisioned that
arenediazonium salts can be used as an efficient alternative to arylboronic acids to prepare
aryl-C-glycosides,12 because, the inherent electrophilicity of diazonium salts might allow the
coupling reaction under mild reaction conditions in the absence of ligand or base.11a,11bAs
part of our ongoing research on glycosylation reactions,13 here we report an efficient
preparation of synthetically useful 2,3-deoxy 3-keto α-aryl-C-glycosides from the
corresponding glycals and aryldiazonium salts in the presence of palladium catalyst.
At the outset, the glycosylation of O-permethylated glucal (1aa) was investigated with 4-
bromobenzenediazonium tetrafluoroborate (2aa) in various solvents in the presence of
different palladium salts (Table 1). Initially, the reaction was performed with 5 mol% of
palladium acetate in methanol at room temperature without any base or ligand. The reaction
underwent smoothly resulting in a new product within 60 mins (Table 1, entry 1). Going by
the previously reported literature pertaining to boronic acid and the glycal,6a, 6c, 6e one of the
Ferrier rearrangement products (A-C) was only expected as shown in Table 1. Surprisingly,
unlike boronic acid, the reaction provided 2,3-deoxy 3-keto α-aryl-C-glycoside (3aa)
exclusively with 91% yield. In fact, formation of similar ketone product was previously
reported with arylboronic acids, however, in the presence of external oxidants such as
benzoquinone (BQ) or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ).6c Encouraged, we
further tested the reaction in other solvents including DCM, dioxane, THF, acetonitrile,
toluene and acetic acid (Table 1, entries 2-7). Among them, THF provides 3aa in ~ 10% yield
(Table 1, entry 4), while other solvents failed to provide the desired product. Further, the
reaction was tested with water mixed DCM, methanol and acetonitrile in the presence of 5
mol% of Pd(OAc)2 at room temperature (Table 1, entries 8-10). Interestingly, acetonitrile-
water (3:1) was found to be equally good as of methanol and gave the desired product 3aa in
90% yield within 1.5 h (Table 1, entry 10). Further, the optimal conditions were investigated
with other typically used Pd(0) and Pd(II) catalysts such as Pd(dba)2, Pd(PPh3)4, Pd(TFA)2,
PdCl2 and PdCl2(CH3CN)2 (Table 1, entry 11-15). Among them, Pd(dba)2 and Pd(TFA)2
showed equal efficiency to that of palladium acetate (Table 1, entry 11 & 13), while other
catalysts gave the desired product 3aa in a low yield (i.e. <30%).
2

Page 3 of 11
Organic & Biomolecular Chemistry
View Article Online
Table 1. Optimization of the reaction condition with 4-bromobenzenediazonium
DOI: 10.1039/C8OB01393D
tetrafluoroborate.a
aReaction condition: Glucal 1aa (95 mg, 0.5 mmol) and diazonium salt 2aa (152 mg, 0.56
mmol, 1.1 equiv.) were stirred in a solvent (4 mL) following which the catalyst (0.025 mmol)
was added. bIsolated yield.
Although, methanol was seen to be an efficient medium, it provides dimethyl acetal 4ab as
the product during the reaction of glucal 1aa with 2-chlorobenzenediazonium
tetrafluoroborate (2ab) (Table 2, entry 1). In fact, other active catalysts such as Pd(dba)2 and
P(TFA)2 also gave 4ab as the only product in similar yields (Table 2, entries 2 & 3).
Nevertheless, the desired product 3ab was successfully obtained in 89% yield when the
reaction was performed in acetonitrile-water medium (Table 2, entry 4). Under this condition,
palladium acetate was found to be slightly better than Pd(dba)2 and P(TFA)2 (Table 2, entries
5 & 6).
3

Organic & Biomolecular Chemistry
Page 4 of 11
View Article Online
Table 2. Optimization of reaction condition with 2-chlorobenzenediazonium
DOI: 10.1039/C8OB01393D
tetrafluoroborate.a
aReaction condition: Glucal 1aa (95 mg, 0.5 mmol) and diazonium salt 2ab (125 mg, 0.55
mmol, 1.1 equiv.) were stirred in a solvent (4 mL) following which the catalyst (0.025 mmol)
was added. bIsolated yield.
Having established the optimized condition, the reaction of permethylated glucal (1aa) with
different aryldiazonium tetrafluoroborates was investigated and the results are summarized in
Table 3. The unsubstituted phenyl and naphthyldizaonium salts as well as aryldizaonium salts
bearing electron donating and withdrawing groups at the para- position underwent coupling
reaction with glucal and gave the desired products 3ac-3an in 69-90% yields. It was observed
that strongly electron withdrawing groups (e.g. NO2, CF3, CO2Me, COCH3 and CN)
functionalized phenyldiazonium salts gave the desired products (i.e. 3ag-3ak) in slightly
lower yields (i.e. 69-80%). Further, the C-arylation of glucal 1aa was investigated with
sterically hindered, i.e. ortho-functionalized phenyldiazonium salts. To our delight, the
reactions were preceded with efficiency similar to that of para-substituted diazonium salts
and gave the desired products 3ao-3aq in 71-81% yields. Likewise, C-arylation of glucal
(1aa) with meta-substituted diazonium salts was successfully accomplished to obtain the
desired products 3ar-3az in 61-89% yields.
Having studied the reaction with permethylated glycal (1aa) with different diazonium
tetrafluoroborate salts, we further investigated the coupling of benzyl, ethyl and MOM-
protected glucals (1ab-1ad) with different diazonium salts. All these reactions were preceded
smoothly and gave the 3-keto C-aryl glucals 3ba-3bj in 60-90% yields, which demonstrates
the broad scope of the methodology. However, glycosylation was unsuccessful with tri-O-
4

Page 5 of 11
Organic & Biomolecular Chemistry
View Article Online
acetyl-D-glucal (1ae) in the presence of 4-methylbenzenediazonium tetrafluoroborate under
DOI: 10.1039/C8OB01393D
optimized conditions (Table 3, 3bk).
Table 3. Reaction of protected glucal with different aryldiazonium salts.a,b
aReaction condition: Glucal (0.5 mmol) and diazonium salt (1.1 equiv.) were stirred in
AcCN:H2O (4 mL, 3:1) following which the catalyst Pd(OAc)2 (5.5 mg, 0.025 mmol) was
added. bIsolated yield.c Pd(OAc)2 (11 mg, 0.05 mmol) was used.
5

Organic & Biomolecular Chemistry
Page 6 of 11
View Article Online
Encouraged by the results obtained with differently protected glucals and diazonium salts, the
DOI: 10.1039/C8OB01393D
reaction of protected galactal was studied under optimized conditions (Table 4). Initially, C-
arylation of permethylated galactal (1af) was investigated with aryldiazonium
tetrafluoroborates bearing electron donating and withdrawing groups. To our delight, C-aryl
glycosylation proceeded smoothly at room temperature and resulted in the desired products
3bl-3bt in 52-65% yields. Similarly, sterically hindered ortho-substituted diazonium salts as
well as meta-substituted diazonium salts also underwent glycosylation with galactal (1ae) and
provided 3bu-3bw in 40-55% yields. To increase scope of the methodology, perbenzylated
galactal (1ag) was subjected for glycosylation with different diazonium salts, which provided
the desired ketones 3bx-3bz in >50% yields. Over all, it was observed that the reaction of
galactals (1af and 1ag) with aryldiazonium salts provided lower yields to that of glucals (1aa-
1ad).
Table 4. Reaction of protected galactal with different aryl diazonium salts.a,b
aReaction condition: Galactal (0.5 mmol) and diazonium salt (1.1 equiv.) were stirred in
AcCN:H2O (4 mL, 3:1) following which the catalyst Pd(OAc)2 (11 mg, 0.05 mmol) was
added. bIsolated yield.
6

Page 7 of 11
Organic & Biomolecular Chemistry
Table 5. Reaction of benzyl protected L-rhamnal 1ah with diazonium salts.a,b
View Article Online
DOI: 10.1039/C8OB01393D
aReaction condition: Rhamnal (0.5 mmol) and diazonium salt (1.1 equiv.) were stirred in
AcCN:H2O (4 mL, 3:1) following which the catalyst Pd(OAc)2 (11 mg, 0.05 mmol) was
added. bIsolated yield.
In order to study the versatility of this protocol, C-glycosylation of other hexose such as
perbenzylated L-rhamnal and D-xylal (1ah and 1ai, respectively) was investigated with
different diazonim salts (Table 5 and Scheme 1). Similar to glucal, the reaction of L-rhamnal
(1ah) with different diazonim salts proceeded smoothly under optimized conditions and gave
the α-C-arylated products 3ca-3cc in good to excellent yields (64-72%). Likewise, benzyl
protected D-xylal (1ai) underwent C-arylation with 4-methylphenyldiazonium
tetrafluoroborate successfully and gave the desired product 3cd in 41% yield (Scheme 1).
Scheme 1. Reaction of benzyl protected D-xylal 1ai with 4-methylbenzenediazonium
tetrafluoroborate.
Considering the biological significance of 2-deoxypentose sugars, 4-methylphenyldiazonium
tetrafluoroborate was subjected for glycosylation with benzyl protected D-ribal (1aj). To our
delight, similar to pyranose glycals, the desired 2,3-deoxy 3-keto α-C-glycosylated product
7

Organic & Biomolecular Chemistry
Page 8 of 11
View Article Online
3ce was obtained in 31% yield under optimized condition (Scheme 2). Overall, this protocol
DOI: 10.1039/C8OB01393D
shows excellent substrate scope in C-aryl glycosylation reactions.
.
Scheme 2. Reaction of benzyl protected D-ribal 1aj with 4-methylbenzenediazonium
tetrafluoroborate tetrafluoroborate.
Of the two anomers of aryl-C-glycosides (i.e. α/β), β-isomers were most commonly found in
natural products.2 While attempting hydrolysis of dimethyl acetal 4ab, we observed a mixture
of anomeric products 3ab (α-isomer) and 5ab (β-isomer) in 6:1 ratio (Scheme 3). We propose
that this acid catalyzed anomerization might be useful for the preparation of β-aryl-C-
glycosides from corresponding α-glycosides.
Scheme 3. Acid catalyzed hydrolysis of dimethyl acetal 4ab.
The resulted ketone compounds (i.e. 3aa-3ce) are expected to have wide applications in
carbohydrate synthesis. For instance, these compounds can serve as the starting materials for
the preparation of 2-deoxy C-aryl glycosides. Thus, we have attempted the reduction of the
ketones 3ba and 3bf using sodium borohydride in methanol. To our delight, the reaction
proceeded smoothly at room temperature and gave 2-deoxy-α-aryl D-allose derivatives 4ba
and 4bf in >70%, as a single isomer (Scheme 4).14
Scheme 4. Reduction of 3ba and 3bf using sodium borohydride.
8

Page 9 of 11
Organic & Biomolecular Chemistry
View Article Online
A plausible mechanism of the palladium catalyzed C-arylation of glycal is shown in Scheme
DOI: 10.1039/C8OB01393D
5.11 At first, the oxidative addition of the palladium to the aryldiazonium salt in the presence
of glycal provides the intermediate X which undergoes β-elimination to form palladium enol
ether Y.11c Palladium-hydride reinsertion provides the intermediate Z which undergoes
reductive elimination to provide the desired ketone and palladium (0).
Scheme 5. Plausible mechanism for palladium catalyzed C-arylation of glycals
In summary, we have demonstrated a new reaction of diazonium salts with glycals in the
presence of palladium catalysts. A wide range of glycals including protected D-glucals,
D-
galactals, L-rhamanal, -xylal and -ribal underwent stereocontrolled C-glycosylation with
D
D
different aryldiazonium tetrafluoroborates in the presence of 5-10 mol% of palladium acetate
at room temperature. All the reactions provide 2,3-deoxy-3-keto α-aryl C-glycosides in good
to excellent yields in a stereo-controlled manner under optimized condition. This simple
method does not require base or ligand or additives, and thus providing scope for wide
applications in organic synthesis.
ASSOCIATED CONTENT
Supporting Information
Experiment procedures and Copies of 1H NMR and 13C NMR of 1aa-1aj, 3aa-3ce, 4ab, mixture
of 3ab+5ab, 4ba, 4bf, and 5ba.
AUTHOR INFORMATION
Corresponding Author
Email: jeyakumar.chy@iitbhu.ac.in
DEDICATION
Dedicated to Professor Peter H. Seeberger on the occasion of his 50th birthday
9

Organic & Biomolecular Chemistry
Page 10 of 11
View Article Online
DOI: 10.1039/C8OB01393D
NOTES
The authors declare no competing financial interest
ACKNOWLEDGEMENT
J. K. acknowledges Max-Planck Society-Germany and DST-India (DST/INT/MPG/P-
09/2016) for financial support through Indo-Max Planck partner group project. A. K. S.
acknowledges the CSIR for senior research fellowship (SRF). J. K acknowledges Central
Instrumentation Facility Center (CIFC)-IIT BHU for the NMR facilities.
REFERENCES AND NOTES
1.
(a) P. H. Seeberger and D. B. Werz, Nature 2007, 446, 1046-1051; (b) A. Varki,
Essentials of Glycobiology. Cold Spring Harbor Laboratory Press, Cold Spring Harbor: NY,
USA, 1999.
2.
1495-1598; (b) Y. Yang and B. Yu Chem. Rev., 2017, 117, 12281-12356.
3. (a) R. G. dos Santos, A. R. Jesus, J. M. Caio and A. P. Rauter, Curr. Org. Chem.,
2011, 15, 128-148; (b) J. A. Mahling and R. R. Schmidt, Synthesis 1993, 325-328.
4. (a) S. Czernecki and G. Ville, J. Org. Chem., 1989, 54 , 610-612; (b) G. A. Kraus and
(a) K. Kitamura, Y. Ando, T. Matsumoto and K. Suzuki, Chem. Rev., 2018, 118,
M. T. Molina, J. Org. Chem., 1988, 53 , 752-753; (c) H. Streicher, M. Reiner and R. R.
Schmidt, J .Carbohyd. Chem., 1997, 16 , 277-298.
5.
S. Lemaire, I. N. Houpis, T. T. Xiao, J. J. Li, E. Digard, C. Gozlan, R. M. Liu, A.
Gavryushin, C. Diene, Y. C. Wang, V. Farina and P. Knochel, Org. Lett., 2012, 14 , 1480-
1483.
6.
(a) C. F. Liu, D. C. Xiong and X. S. Ye, J. Org. Chem., 2014, 79 , 4676-4686; (b) A.
K. Kusunuru, C. K. Jaladanki, M. B. Tatina, P. V. Bharatam and D. Mukherjee, Org. Lett.,
2015, 17, 3742-3745; (c) D. C. Xiong, L. H. Zhang and X. S. Ye, Org. Lett., 2009, 11 , 1709-
1712; (d) S. H. Xiang, S. T. Cai, J. Zeng and X. W. Liu, Org. Lett., 2011, 13, 4608-4611. (e)
J. Ramnauth, O. Poulin, S. Rakhit and S. P. Maddaford, Org. Lett., 2001, 3 , 2013-2015.
7.
Y. G. Bai, L. M. H. Kim, H. Z. Liao and X. W. Liu J. Org. Chem., 2013, 78, 8821-
8825.
8.
D. P. Steinhuebel, J. J. Fleming and J. Du Bois, Org. Lett., 2002, 4, 293-295.
H. H. Li and X. S. Ye, Org. Biomol. Chem., 2009, 7, 3855-3861.
9.
10.
(a) S. Wagschal, J. Guilbaud, P. Rabet, V. Farina and S. Lemaire, J. Org. Chem.,
2015, 80, 9328-9335; (b) A. K. Kusunuru, S. K. Yousuf, M. Tatina and D. Mukherjee, Eur. J.
10

Page 11 of 11
Organic & Biomolecular Chemistry
View Article Online
Org. Chem., 2015, 459-462; (c) F. Zhu, J. Rodriguez, T. Y. Yang, I. Kevlishvili, E. Miller, D.
DOI: 10.1039/C8OB01393D
Yi, S. O'Neill, M. J. Rourke, P. Liu and M. A. Walczak, J. Am. Chem. Soc., 2017, 139,
17908-17922; (d) D. Yi, F. Zhu and M. A. Walczak Org. Lett., 2018, 20, 1936-1940; e) D. C.
Koester, M.Leibeling, R. Neufeld and D. B. Werz, Org. Lett., 2010, 12, 3934-3937; f) D. C.
Koester and D. B. Werz, Beilstein J. Org. Chem., 2012, 8, 675-682; g) D. C. Koester, E.
Kriemen and D. B. Werz, Angew. Chem. Int. Ed., 2013, 52, 2985-2989.
11.
(a) A. Roglans, A. Pla-Quintana and M. Moreno-Manas, Chem. Rev., 2006, 106,
4622-4643; (b) F. Y. Mo, G. B. Dong, Y. Zhang and J. B. Wang, Org. Biomol. Chem., 2013,
11, 1582-1593; (c) C. Frota, E. C. Polo, H. Esteves and C. R. D. Correia, J. Org. Chem.,
2018, 83, 2198-2209; (d) Y. Wang, L. Deng, Y. Deng and J. Han J. Org. Chem., 2018, 83,
4674-4680; (e) D. H. Kim, J. Lee and A. Lee, Org. Lett., 2018, 20, 764-767.
12.
During the preparation of our manuscript similar work is apperared in organic letters:
S. Tang, Q. Zheng, D. C. Xiong, S. Jiang, Q. Li and X. S. Ye, Org. Lett., 2018, 20, 3079-
3082.
13.
14.
K. B. Mishra, A. K. Singh and J. Kandasamy, J. Org. Chem., 2018, 83, 4204-4212.
The stereochemistry of C-3 carbon in 4ba was assigned in a relative manner. The
compound 4ba was subjected for O-benzylation to obtain 5ba. The NMR of the 5ba is
compared with previously reported 2-deoxy 3,4,6-O-tribenzyl α-phenyl C-glucopyranoside
(see the ref. 6a). The NMR data does not match with glucose derivative thus we have
assigned as allose derivate.
11