Desulfitative C-arylation of glycals by using benzenesulfonyl chlorides

Article abstract of DOI:10.1002/ejoc.201403195

The palladium-catalyzed stereoselective synthesis of 2,3-deoxy-C-aryl glycosides was investigated. The strategy is based on the Pd-catalyzed desulfitative Heck coupling of arylsulfonyl chlorides and glycals with good leaving groups. An attempt was made to

Full text of DOI:10.1002/ejoc.201403195

Job/Unit: O43195
/KAP1
Date: 09-12-14 15:22:44
Pages: 5
SHORT COMMUNICATION
DOI: 10.1002/ejoc.201403195
Desulfitative C-Arylation of Glycals by Using Benzenesulfonyl Chlorides[‡]
Anil Kumar Kusunuru,[a,b] Syed Khalid Yousuf,[c] Madhubabu Tatina,[a,b] and
Debaraj Mukherjee*[a,b]
Keywords: Synthetic methods / C–C coupling / Cross-coupling / Sulfur / Palladium / Glycosides
The palladium-catalyzed stereoselective synthesis of 2,3-de-
oxy-C-aryl glycosides was investigated. The strategy is
An attempt was made to establish the reaction mechanism,
which may involve PdII/Pd0 interconversion under basic con-
based on the Pd-catalyzed desulfitative Heck coupling of ar- ditions.
ylsulfonyl chlorides and glycals with good leaving groups.
heteroatom elimination if the glycals are protected by good
Introduction
leaving groups such as acetate, and 2-deoxy-C-glycosides
are the main products formed through β-hydride elimi-
nation if glycals are protected by poor leaving groups such
as silyl or benzyl. High electron density in the phenyl ring
and the presence of ligands are prerequisites for such a
transformation. Further, in the case of Pd(OAc)2-catalyzed
cross-coupling reactions of boronic acids with glycals, ring
opening is one of the major side reactions.[11] In recent
years, the search for alternatives to boronic acid chemistry
has been under intense investigation. This has led to the
unraveling of several new reagent systems for the arylation
of glycals. These typically comprise aromatic carboxylic
acids[12] and phenylhydrazines.[13] Palladium-mediated de-
carboxylative C-arylation of glycals by using aromatic carb-
oxylic acids has been well studied by Liu et al. The same
group has exploited phenylhydrazines for the oxidative C-
arylation of glycals (Figure 1).[7]
The past decade has witnessed a renaissance in C–C
bond-forming reactions. On the one hand, new advances
have been made in already developed methods, and on the
other hand, a number of reagents have been discovered that
offer easy and scalable C–C bond transformations.[1] In
carbohydrate chemistry, C–C bond generation mostly im-
plies C-glycosylation,[2] a process to join monosaccharide
units to form new C-glycosides either of industrial/bio-
logical importance or of synthetic/natural origin. Amongst
the various C-aryl glycosides,[3] that is, C-glycosides with
aryl ring at the anomeric position, 2,3-deoxy-C-aryl glyco-
sides have attracted substantial attention,[3,4] because they
are regularly found in natural products of pharmacological
importance, show potential to serve as enzyme inhibitors
and carbohydrate mimics, possess greater metabolic sta-
bility than O-glycosides, and promise to serve as useful chi-
ral starting materials for synthetic chemistry. This has made
them a target for synthetic chemists. The various strategies
that are used[5] for their synthesis involve electrophilic sub-
stitution reactions of glycals with electron-rich arenes,[6]
transition-metal-catalyzed glycosylations,[7] de novo synthe-
sis of carbohydrate units,[8] and O–C aryl migration reac-
tions.[9] Among the reported methods, transition-metal-cat-
alyzed Heck-type reactions have gained special attention
owing to the use of stable and moisture friendly reagents.[10]
In this case, the product distribution is case sensitive. For
example, 2,3-deoxy-C-glycosides are generated through β-
[‡] Iiim no.: IIIM/1749/2014
[a] Academy of Scientific and Innovative Research,
Canal Road, Jammu-Tawi 180001, India
[b] Indian Institute of Integrative Medicine, CSIR-IIIM,
Jammu 180001, India
E-mail: dmukherjee@iiim.ac.in
www.iiim.res.in
[c] Indian Institute of Integrative Medicine,
Srinagar 190005, India
Figure 1. Recent developments in C-arylation of glycals under
Heck conditions.
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403195
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1

Job/Unit: O43195
/KAP1
Date: 09-12-14 15:22:44
Pages: 5
A. K. Kusunuru, S. K. Yousuf, M. Tatina, D. Mukherjee
SHORT COMMUNICATION
Arylsulfonyl chlorides can be easily obtained from oxy- group or an electron-withdrawing group (Figure 2, see com-
halogenation of the corresponding aryl thiol under green pounds 3–9) reacted smoothly to yield the corresponding
condition.[14] Owing to the ease of their synthesis, aryl- aryl glycosides in moderate yields with Ͼ99% selectivity.
sulfonyl chlorides have found application as aryl sources in Further, to diversify the substrate scope glycals other than
various organic transformations.[15,16] With our continuous glucal were examined.
interest in C-glycoside synthesis,[17] herein we would like to
disclose the desulfitative direct C-arylation of glycals from action with various arylsulfonyl chlorides under the stan-
Thus, the tri-O-acetyl-d-galactal was subjected to the re-
arylsulfonyl chlorides.
dardized reaction conditions to yield C-aryl galactosides in
moderate yields (Figure 2, see compounds 11–14). Reaction
of deoxysugars such as 3,4-di-O-acetyl-l-rhamnal and 3,4-
di-O-acetyl-l-fucal with benzenesulfonyl chloride afforded
Results and Discussion
To find experimental support for our idea, commercially the desired glycosides in yields of 54 and 45%, respectively,
available 3,4,6-tri-O-acetyl-d-glucal (1) was allowed to react with β-selectivity (Figure 2, see compounds 16–18). Next,
with benzenesulfonyl chloride in the presence of various we were interested in examining the effect of other protect-
palladium catalysts (Table 1). It was observed that the na- ing groups on the glucal moiety. It was observed that the
ture of the base and the solvent directly affected product benzoyl (Bz) group reacted almost similarly to the acetyl
formation. For example, the use of Pd(PPh3)2Cl2 and (Ac) group to yield the corresponding C-aryl glycoside in
Cs2CO3 in dioxane at 100 °C (oil bath temperature) did not moderate yield (Figure 2, see compound 15). In the case of
work, even after stirring for 40 h. Increasing the oil bath ether protection such as 3,4,6-tri-O-benzyl-d-glucal, a
temperature to 140 °C led to the formation of the desired ketone-type C-glycoside (Figure 2, see compound 19) in-
product in 34% yield. The use of other palladium catalysts stead of the normal C-Ferrier product was obtained
such as Pd(CH3CN)2Cl2 and Pd2(dba)3 (dba = dibenz- through β-hydride elimination of the intermediate σ adduct
ylideneacetone) did not improve the yield of the reaction. and cleavage of the benzyl (Bn) group, as reported in the
We were delighted to note, however, that a change in the literature under similar conditions.[18c]
base from Cs2CO3 to Li2CO3 increased the yield of the de-
On the basis of previous literature[10,5] on palladium-cat-
sired product dramatically to 65% with high stereoselecti- alyzed C-glycosylation, we propose the mechanism outlined
vity. However, the amount of the base used was found to in Figure 3. To start, the PdII species is reduced to Pd0 un-
be critical, as the use of 6 equivalents of Li2CO3 lowered der basic conditions;[18b] this is followed by a sequence of
the yield to only 40%. Next, we screened other solvents for four steps: One, oxidative addition of the arylsulfonyl chlor-
the reaction and concluded that dioxane was the best in ide to Pd0[15] to form PdII species A. Two, subsequent elimi-
terms of yield and selectivity. Thus, the use of Pd(PPh3)2Cl2 nation of SO2 and Cl under heating conditions to generate
(10 mol-%) and Li2CO3 (2 equiv.) in dioxane at 140 °C (oil ArPd cation complex B. Three, the addition of B to the
bath temperature) was found to be the optimal conditions double bond of the glucal triacetate to generate π complex
for the generation of aryl glycosides 2.
C, which results in the formation of glucal palladium cat-
With these standardized reaction conditions in our hand, ionic complex D. In this step, the ArPd species attacks from
we examined the substrate scope of the coupling reaction. the opposite side of the C-3 substituent, which results in
For this, a series of sulfonyl chlorides were allowed to react anomeric selectivity. Four, reductive elimination of the PdII
with 3,4,6-tri-O-acetyl-d-glucal (1). It was found that all ar- complex under basic conditions[18] along with anti-β-3-OAc
ylsulfonyl chlorides containing either an electron-donating elimination to afford desired C-aryl glycoside 2. It is evident
Table 1. Standardization of the reaction conditions for the C-arylation of glycals with benzenesulfonyl chloride.
Entry
Catalyst[a]
Base (equiv.)
T [°C]
Solvent[b]
Time [h]
Yield[c] [%]
α/β[d]
1
2
3
4
5
6
Pd(Ph3P)2Cl2
Pd(Ph3P)2Cl2
Pd(CH3CN)2Cl2
Pd2(dba)3
Pd(PhCN)2Cl2
Pd(OAc)2
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Cs2CO3 (2)
Li2CO3 (6)
Li2CO3 (2)
100
140
140
140
140
140
140
140
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
48
40
40
40
40
40
40
40
–
34
trace
25
12
10
–
99:1
–
–
–
–
99:1
99:1
7
Pd(Ph3P)2Cl2
Pd(Ph3P)2Cl2
43
65
8[e]
[a] In all cases, 10 mol-% of catalyst was used. [b] Solvent used was 5 mL for 1 mmol of substrate. [c] Yield obtained after column
1
chromatography. [d] Detected by H NMR spectroscopy. [e] Standardized reaction conditions.
2
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43195
/KAP1
Date: 09-12-14 15:22:44
Pages: 5
Desulfitative C-Arylation of Glycals
Figure 2. Substrate scope of the palladium-catalyzed desulfitative C-arylation. In all cases, the selectivity was Ͼ99.
from the above discussion that the stereochemistry of OAc
at C-3 plays a role in controlling the anomeric stereochemis-
try and is the reason behind the α-selectivity for d-glycals
and β-selectivity[7,10b] for l-sugars in this study. Moreover,
the involvement of a PdII/PdIV palladacycle cannot be ruled
out.
Conclusions
In conclusion, we demonstrated a new approach for C-
aryl glycosidic bond formation. Staring from easily avail-
able arylsulfonyl chlorides, several aryl glycosides were pre-
pared in good yield by means of the palladium-catalyzed
desulfitative C-arylation of various glycals.
Experimental Section
General Procedure: A 25 mL, oven-dried Schlenk tube was charged
with glycal (1 mmol), arylsulfonyl chloride (1.5 mmol), Li2CO3
(2 mmol), 1,4-dioxane (2 mL), and Pd(Ph3P)2Cl2 (0.1 mmol). The
mixture was evacuated by vacuum–argon cycles (5ϫ) and stirred at
140 °C (oil bath temperature) for 40 h. After cooling the mixture
to room temperature, the solvent was evaporated under reduced
pressure to get the crude product, which upon purification through
silica gel column chromatography (ethyl acetate/petroleum ether)
afforded the desired product.
Acknowledgments
The authors are thankful to Dr. Ram A Vishwakarma, Director,
IIIM Jammu for generous funding (MLP4015) along with fellow-
ship under INSPIRE Faculty Scheme (IFA-CH-18). M. T. and
A. K. K. thank the Council of Scientific and Industrial Research
(CSIR), New Delhi, for a senior research fellowship.
[1] a) A. Bhunia, S. R. Yetra, A. T. Biju, Chem. Soc. Rev. 2012,
41, 3140; b) C. Devdutt, C. B. Nabin, Curr. Org. Synthesis
2012, 44, 9, 17; c) R. Kumar, E. V. Van der Eycken, Chem. Soc.
Rev. 2013, 42, 1121; d) W. Cabri, I. Candiani, Acc. Chem. Res.
Figure 3. Plausible mechanism for the palladium-catalyzed C-aryl-
ation reaction.
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3

Job/Unit: O43195
/KAP1
Date: 09-12-14 15:22:44
Pages: 5
A. K. Kusunuru, S. K. Yousuf, M. Tatina, D. Mukherjee
SHORT COMMUNICATION
1995, 28, 2; e) A. F. Littke, G. C. Fu, Angew. Chem. Int. Ed.
2002, 41, 4176; Angew. Chem. 2002, 114, 4350; f) J. Hassan,
M. S. Vignon, C. Gozzi, E. Schulz, M. Lemaire, Chem. Rev.
2002, 102, 1359; g) A. de Meijere, F. Diederich (Eds.), Metal-
Catalyzed Cross-Coupling Reactions, 2nd ed., Wiley-VCH,
Weinheim, Germany, 2004.
[10] a) M. Lei, L. Gao, J.-S. Yang, Tetrahedron Lett. 2009, 50, 5135;
b) H.-H. Li, X.-S. Ye, Org. Biomol. Chem. 2009, 7, 3855; c) J.
Ramnauth, O. Poulin, S. Rakhit, S. P. Maddaford, Org. Lett.
2001, 3, 2013; d) S. Xiang, S. Cai, J. Zeng, X.-W. Liu, Org.
Lett. 2011, 13, 4608; e) mass spectra of the crude reaction mix-
ture was taken after 1 h and we observed a mass peak of inter-
mediate D (see the Supporting Information, p. 46).
[2] a) M. Mavlan, K. Ng, H. Panesar, A. Yepremyan, T. G. Mine-
han, Org. Lett. 2014, 16, 2212; b) Y. Suga, H. Fuwa, M. Sasaki,
J. Org. Chem. 2014, 79, 1656; c) A. A. Ansari, R. Lahiri, Y. D.
[11] N. Figuera, P. Forns, J.-C. Fernàndez, S. Fiol, D. Fernández-
Forner, F. Albericio, Tetrahedron Lett. 2005, 46, 7271.
Vankar, ARKIVOC 2013, ii, 316; d) M. Huang, G. E. Garrett, [12] N. Rodríguez, L. Gossen, Chem. Soc. Rev. 2011, 40, 5030.
N. Birlirakis, L. Bohé, D. A. Pratt, D. Crich, Nat. Chem. 2012, [13] Y. Li, W. Liu, Q. Tian, Q. Yang, C. Kuang, Eur. J. Org. Chem.
4, 663.
2014, 3307.
[3] C. Liu, D. Xiong, X. Ye, J. Org. Chem. 2014, 79, 4676.
[4] a) T. Bililign, B. R. Griffith, J. S. Thorson, Nat. Prod. Rep.
2005, 22, 742; b) Z. Wei, Curr. Top. Med. Chem. 2005, 5, 1363;
c) H.-L. Qin, J. T. Lowe, J. S. Panek, J. Am. Chem. Soc. 2007,
129, 38.
[5] For selected examples, see: a) T. Matsumoto, T. Hosoya, K.
Suzuki, Tetrahedron Lett. 1990, 31, 4629; b) G. A. Kraus, M. T.
Molina, J. Org. Chem. 1988, 53, 752; c) J. Ramnauth, O. Poulin,
S. S. Bratovanov, S. Rakhit, S. P. Maddaford, Org. Lett. 2001,
3, 2571; d) S. Lemaire, I. Houpis, T. Xiao, J. Li, E. Digard, C.
Gozlan, R. Liu, A. Gavryushin, Org. Lett. 2012, 14, 1480.
[6] O. R. Martin, C. A. Hendricks, P. P. Deshpande, A. B. Cutler,
S. A. Kane, S. P. Rao, Carbohydr. Res. 1990, 196, 41.
[7] Y. Bai, L. M. H. Kim, H. Liao, X.-W. Liu, J. Org. Chem. 2013,
78, 8821, and references cited therein.
[14] For the preparation of arylsulfonyl chlorides, see: S. Madabhu-
shi, R. Jillella, V. Sriramoju, R. Singh, Green Chem. 2014, 16,
3125–3131.
[15] For some examples of the oxidative addition of arylsulfonyl
chlorides, see: a) K. Yuan, H. Doucet, Chem. Sci. 2014, 5, 392.
[16] C. M. R. Volla, P. Vogel, Angew. Chem. Int. Ed. 2008, 47, 1305;
Angew. Chem. 2008, 120, 1325.
[17] 17; a) A. K. Kusunuru, M. Tatina, S. K. Yousuf, D. Mukherjee,
Chem. Commun. 2013, 49, 10154; b) M. Tatina, A. K. Kusun-
uru, S. K. Yousuf, D. Mukherjee, Chem. Commun. 2013, 49,
11409; c) M. R. Lambu, A. Hussain, D. K. Sharma, S. K. You-
suf, B. Singh, A. K. Tripathi, D. Mukherjee, RSC Adv. 2014,
4, 11023–11028; d) D. Mukherjee, S. K. Sarkar, U. S.
Chowdhuryc, S. C. Taneja, Tetrahedron Lett. 2007, 48, 663.
[18] a) M. Zhang, S. Zhang, M. Liu, J. Cheng, Chem. Commun.
2011, 47, 11522; b) Y. Bai, M. Leow, J. Zeng, X.-W. Liu, Org.
Lett. 2011, 13, 5648; c) D. C. Xiong, L. H. Zhang, X. S. Ye,
Org. Lett. 2009, 11, 1709.
[8] S. B. Rosenblum, R. Bihovsky, J. Am. Chem. Soc. 1990, 112,
2746.
[9] T. Furuta, M. Nakayama, H. Suzuki, H. Tajimi, M. Inai, H.
Nukaya, T. Wakimoto, T. Kan, Org. Lett. 2009, 11, 2233, and
references cited therein.
Received: September 10, 2014
Published Online: ᭿
4
www.eurjoc.org
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43195
/KAP1
Date: 09-12-14 15:22:44
Pages: 5
Desulfitative C-Arylation of Glycals
Arylation
A. K. Kusunuru, S. K. Yousuf, M. Tatina,
D. Mukherjee* .................................. 1–5
Desulfitative C-Arylation of Glycals by Us-
ing Benzenesulfonyl Chlorides
A
highly stereoselective desulfitative
variety of glycals and arylsulfonyl chlorides
participate in the reaction smoothly. C-Ar-
ylation happens possibly through a cata-
lytic cycle involving PdII/Pd0 species.
Keywords: Synthetic methods / C–C cou-
pling / Cross-coupling / Sulfur / Palladium /
Glycosides
C-arylation reaction is developed by using
glycal and arylsulfonyl chlorides in the
presence of bis(triphenylphosphine)pal-
ladium(II) chloride and Li2CO3. A wide
Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5