Arynes in the Monoarylation of Unprotected Carbohydrate Amines

Article abstract of DOI:10.1021/acs.orglett.7b03741

A CsF-mediated method has been developed for the N-arylation of amino sugars that affords good to excellent yields of arylated products under mild conditions involving the in situ generation of arynes. The reaction conditions tolerate a variety of common carbohydrate protecting groups and also performs exceptionally well on unprotected amino sugar derivatives. The reactions are scalable in moderate to good yields with broad scope.

Full text of DOI:10.1021/acs.orglett.7b03741

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Arynes in the Monoarylation of Unprotected Carbohydrate Amines
Kumar Bhaskar Pal,† Mukul Mahanti,† and Ulf J. Nilsson*
Centre for Analysis and Synthesis Department of Chemistry, Lund University, Box 124, 221 00 Lund, Sweden
S
* Supporting Information
ABSTRACT: A CsF-mediated method has been developed for the
N-arylation of amino sugars that affords good to excellent yields of
arylated products under mild conditions involving the in situ generation
of arynes. The reaction conditions tolerate a variety of common car-
bohydrate protecting groups and also performs exceptionally well on
unprotected amino sugar derivatives. The reactions are scalable in moderate to good yields with broad scope.
he functionalization of carbohydrates is essential in the
synthesis of glycomimetics,1 glycobiological2 studies, and
Hence, we hypothesized that amines, being the more reactive
nucleophile in amino sugar derivatives, O-protected or even
unprotected, would react selectively with arynes to yield N-aryl
derivatives. Herein, we report a room temperature method-
ology to functionalize carbohydrate amines with an aryl group
using in situ generated arynes as the aryl source (Scheme 1).
Initially, the condition dependence of the reaction of 6-amino-
6-deoxy-1,2:3,4-di-O-isopropylidene-α-D-galactopyranose 1a with
benzyne generated in situ from 2-(trimethylsilyl)phenyl triflate
2a was investigated. Treating 1a with precursor 2a and 2 equiv
of CsF in CH3CN at room temperature afforded the monoarylated
product 6-deoxy-1,2:3,4-di-O-isopropylidene-6-N-phenylamino-
α-D-galactopyranoside 3a in 90% isolated yield (Table 1, entry 1)
within 2 h. Interestingly, when the amount of CsF was increased
up to 3 equiv, the yield was similar (entry 2), while increasing
the amount of aryne precursor (entries 3 and 5) or the reaction
temperature (entry 4) gave lower yields mainly due to compet-
ing formation of di-N-arylated product. When the amount of 2a
used (for entry 3 and 5) was 1 and 1.1 equiv, 4% and 16% of di-
N-arylated were obtained, respectively. Elevation of the temper-
ature10p up to 60 °C (entry 4) yielded 22% of di-N-arylated
product, while the choice of THF10r as the solvent was detri-
mental (entry 6). Using KF10e,m (entries 7−9) in the presence
of 18-crown-6 (entries 7, 8) as the fluoride source proved to be
less efficient and gave lower yields, while tetrabutylammonium
fluoride (TBAF)10j gave yields comparable with those of CsF as
a fluoride source (entries 10, 11).
T
natural product synthesis. While chemical O-functionalization
of carbohydrates and glycoconjugates is central and extensively
developed, N-functionalization is less developed despite the
common occurrence of biologically active N-functionalized car-
bohydrate structures.3 Chemical modifications at aminosugar
N-positions mainly involve N-acylation,4 alkylation,5 azidation,6
and Schiff base formation,7 while N-arylation8 has been sparingly
studied. Nevertheless, carbohydrate N-arylation is of significant
interest to carbohydrate sciences as the O/NH isosteric rela-
tionship can be used for structure−activity relationship investi-
gations of protein−glycan interactions, solubility can be improved
in a weakly basic N-analogue, and the extra valency of the
N-analogue can be used to introduce additional affinity and/or
selectivity, enhancing structural moieties into a protein-binding
glycomimetic compound.
A limited number of literature reports on carbohydrate
N-arylation present varying yields and typically require a careful
choice among a limited number of possible O-protecting groups.
Metal-catalyzed C−N cross coupling with amino sugars requires
a catalyst8 or elevated temperature9 (Scheme 1) Arynes10 are
Scheme 1. Approaches To Introduce Aryl Functional Groups
at Carbohydrate Amines
With optimized reaction conditions for the selective mono
N-arylation of 1a with benzyne (Table 1), the amino sugar
scope was investigated. A panel of furanose and pyranose struc-
tures with different protecting groups, both acid and base
sensitive, were reacted under the optimized conditions to give
the corresponding unsubstituted phenyl derivatives in good to
high yields (Scheme 2). Noteworthy is the reaction sensitivity
to the nitrogen nucleophilicity, this being reflected in the fact
that amino sugars having electron-withdrawing groups (i.e., to
give 3g, 3l, and 3m) reacted slowly with the benzyne, whereas
electron-donating groups (i.e., to give 3h, 3i, and 3k) accelerated
highly electrophilic in nature, and the highly strained carbon−
carbon triple bond reacts rapidly with nucleophiles like alcohols,11
amines,12 amides,13 aldehydes,14 thiols,15 and carboxylic acids10,16
with a high sensitivity toward the nucleophilicity of the nucleophile.
Received: December 1, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03741
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Reaction Conditions Optimization of Mono-N-
phenylation of 6-Amino-6-deoxy-1,2:3,4-di-O-
isopropylidene-α-D-galactopyranose 1a
Scheme 2. Selective Mono-N-phenylation of Different
a
Amino Sugars (1a−q) with 2a
isolated yield
(%)
2a
(equiv)
time
(h)
entry F− source (equiv)
solvent
3a
7a
b
b
1
2
3
4
5
6
7
8
9
CsF (2)
CsF (3)
CsF (2)
CsF (2)
CsF (2)
CsF (2)
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
THF
0.98
0.98
1
2
4
90
94
NO
NO
4
2
80
a
0.98
1.1
1
45
22
2
65
16
b
c
0.98
0.98
0.98
0.98
0.98
0.98
12
24
24
24
4
<10
NR
NR
NR
70
NO
NR
NR
NR
NO
NO
c
c
c
KF/18-Crown-6 (2) THF
c
KF/18-Crown-6 (2) CH3CN
c
KF (2)
CH3CN
CH3CN
THF
b
b
10 TBAF (2)
11 TBAF (2)
4
72
a
b
c
Reaction at 60 °C. Not observed. No reaction.
the reaction, causing the complete conversion of the corre-
sponding starting amine 1 into product within 1−2 h.
Compellingly, unprotected sugar amines also underwent
smooth coupling reactions with 2a leading to the formation of
the mono-N-phenylated sugar derivatives (i.e., 3n, 3o, 3p, and
3q) as the sole isolated product in high yields. Moreover, no
traces of the O-arylation product were observed, which again
demonstrated that N-arylation advances faster than O-arylation
on partially protected carbohydrate derivatives. The trimethyl-
silyl group of 1l and 1p remained intact during the N-arylation
process, the corresponding N-arylated products 3l and 3p being
obtained, under our optimized reaction conditions, even in the
presence of fluoride. Thus, this method is suited perfectly to
various kind of protecting groups.
To investigate the electronic and steric effects of substituents,
2-(trimethylsilyl)phenyl trifluoromethanesulfonates carrying elec-
tron-withdrawing and -donating groups (2b−g) were used in the
arylations of 1q (Scheme 3). The reactions worked well in all
cases to provide the corresponding products 4a−f in 59−68%
yield. Symmetrical arynes generated from the precursors 2b and
2c afforded the mono-N-arylated product, while the reaction
with the unsymmetrical aryne obtained from 2f and 2g afforded
a mixture of regioisomers in a 1:1 (4e:4e′) and 3:1 (4f:4f′) ratio,
respectively. However, the unsymmetrical arynes generated from
2d and 2e furnished 3-chloro-phenyl amino sugar, 4c (65%)
and 3-nitrophenyl amino sugar, 4d (63%), respectively, with a
complete regioselectivity. The electron-withdrawing nature of
the Cl and NO2 groups likely directs the formation of meta
regioisomer as the sole isolated product, rather than formation
of the ortho regioisomer.10a Additional examples of substituted
arynes reacting with different amino sugars 1 corroborated the
observations discussed above (Figure 1).
a
Isolated yields.
mono-N-arylation of the symmetric diamine 3-amino thiodigal-
actoside 1v in the presence of 0.85 equiv of 2a afforded the
monoarylated product 6e in 70% yield (Figure 2), while treat-
ment of 1v with 1 equiv of 2a gave a trace (10%) of symmet-
rical bis-mono-N-arylated product 6g together with the desired
monoarylated 6e (52%), whereas on treatment of 1v with
1.8 equiv of the 2-(trimethylsilyl)aryl triflates afforded 6g and
6h at 74% and 77% yield, respectively. Thus, the present
method also allows the mono-N-arylation selectively on one
amino group in a carbohydrate diamine, which opens the pos-
sibility of fashioning the disaccharides with an N-aryl group
with different substitution patterna. Hence, both symmetrical
(6g, 6h) and unsymmetrical N-arylated (6f) amino sugars were
readily accessible.
Of note is the fact that the mono-N-arylation depends on
the amount of 2-(trimethylsilyl)aryl triflate added to the reac-
tion mixture. Only the monoarylated product is formed if the
2-(trimethylsilyl)aryl triflate is 0.98 equiv with respect to the
amine, while a mixture of mono- and diarylated products is
formed if the 2-(trimethylsilyl)aryl triflate is increased up to
1.1 equiv. Thus, in order to investigate if amino sugars are reac-
tive enough to form di-N,N′-arylated products in good yields,
we carried out the reaction with amino sugars in the presence
of 2 equiv of 2-(trimethylsilyl)aryl triflate and 4 equiv of CsF at
room temperature. Di-N,N′-arylated products 7a, 7b, 7c, and
The applicability of the reaction to more complex struc-
tures, i.e., di- and trisaccharides, was subsequently investigated,
which demonstrated that the reaction performed equally well
on such amines (Figure 2). Furthermore, attempted selective
B
DOI: 10.1021/acs.orglett.7b03741
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Selective Mono-N-arylation of 1q with Different
a
2-(Trimethylsilyl)aryl Triflates (2b−g)
Figure 2. Selective mono-N-arylation of di- and trisaccharide amines
(1r−1v). Isolated yields.
a
Isolated yields. Regioisomers were separated by HPLC.
Figure 3. Di-N,N′-arylation of amino sugars. Isolated yields.
sugars under ambient conditions in high yields. The conditions
of the method tolerate many common carbohydrate protecting
groups. Furthermore, they can be used for N-arylation at any
given position of the amino group on the sugar moiety. The
reactions with unprotected carbohydrate amines proceeded
chemoselectively without the formation of any O-arylated
byproducts and the methodology could be expanded to the
selective mono-N-arylation of diamino sugar derivatives. Fur-
thermore, di-N,N′-aryl derivatives are accessible with this method
simply by increasing the 2-(trimethylsilyl)aryl triflate concen-
trations. Hence, the method reported here opens up an efficient
access to N-arylated amino sugars as a novel and largely
unexplored structural class of glycomimetic compounds, which
we expect will be important for discovery and the development
of glycomimetic drugs.
Figure 1. Selective mono-N-arylation of different amino sugars with
different 2-(trimethylsilyl)aryl triflates. Isolated yields.
7d were obtained in satisfying yields after 12 h (Figure 3). More-
over, an increased reaction temperature to 60 °C shortened the
reaction time to 1 h with virtually no effect on the yields.
In summary, an efficient, mild, CsF-mediated method for the
mono- and di-N-arylation of amino sugars is reported. 2-(Tri-
methylsilyl)aryl triflates with both electron-withdrawing and
donating groups afford the desired mono-N-arylated amino
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.7b03741.
■
S
Detailed experimental procedures and spectral data
(PDF)
C
DOI: 10.1021/acs.orglett.7b03741
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(d) Titz, A.; Radic, Z.; Schwardt, O.; Ernst, B. Tetrahedron Lett. 2006,
47, 2383−2385.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: ulf.nilsson@chem.lu.se.
ORCID
́
(7) (a) Costamagna, J.; Barroso, N. P.; Matsuhiro, B.; Villagran, M.
Inorg. Chim. Acta 1998, 273, 191−195. (b) Costamagna, J.; Lillo, L. E.;
Matsuhiro, B.; Noseda, M. D.; Villagran, M. Carbohydr. Res. 2003, 338,
1535−1542.
́
(8) (a) Bruneau, A.; Brion, J. D.; Alami, M.; Messaoudi, S. Chem.
Commun. 2013, 49, 8359−8361. (b) Tao, C.; Liu, F.; Zhu, Y.; Li, Y.;
Liu, X.; Zhao, J. Tetrahedron Lett. 2012, 53, 7093. (c) Otsuka, Y.;
Yamamoto, T.; Fukase, K. Tetrahedron Lett. 2017, 58, 3019−3023.
(d) Tao, C.; Liu, F.; Xu, B.; Cao, Z.; Wang, H.; Liu, W. J. Carbohydr.
Chem. 2013, 32, 411−423.
Ulf J. Nilsson: 0000-0001-5815-9522
Author Contributions
†K.B.P. and M.M. contributed equally.
Notes
The authors declare no competing financial interest.
(9) (a) Ohkubo, M.; Kawamoto, H.; Ohno, T.; Nakano, M.;
Morishima, H. Tetrahedron 1997, 53, 585−592. (b) Ohkubo, M.;
Nishimura, T.; Jona, H.; Honma, T.; Morishima, H. Tetrahedron 1996,
ACKNOWLEDGMENTS
■
́ ́
52, 8099−8112. (c) Messaoudi, S.; Anizon, F.; Leonce, S.; Pierre, A.;
This work was supported by the Swedish Research Council
(Grant No. 621-2012-2978), the Royal Physiographic Society,
Lund, a project grant awarded by the Knut and Alice
Wallenberg Foundation (KAW 2013.0022), and by Galecto
Biotech AB, Lund, Sweden.
Pfeiffer, B.; Prudhomme, M. Eur. J. Med. Chem. 2005, 40, 961−971.
(10) (a) Bunnett, J. F. J. Chem. Educ. 1961, 38, 278−285. (b) Heaney,
H. Chem. Rev. 1962, 62, 81−97. (c) Warmuth, R. Angew. Chem., Int.
Ed. Engl. 1997, 36, 1347−1350. (d) Wenk, H. H.; Winkler, M.; Sander,
W. Angew. Chem., Int. Ed. 2003, 42, 502−528. (e) Tadross, P. M.;
Stoltz, B. M. Chem. Rev. 2012, 112, 3550−3577. (f) Pavlicek, N.;
́ ́
Perez, D.; Guitian, E.; Pena, D.; Gross, L. Nat. Chem. 2015, 7, 623−
̃
REFERENCES
■
628. (g) Yoshida, H.; Shirakawa, E.; Honda, Y.; Hiyama, T. Angew.
Chem., Int. Ed. 2002, 41, 3247−3249. (h) Jin, T.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2007, 46, 3323−3325. (i) Tambar, U. K.; Stoltz, B. M.
J. Am. Chem. Soc. 2005, 127, 5340−5341. (j) Zhang, L.; Geng, Y.; Jin,
Z. J. Org. Chem. 2016, 81, 3542−3552. (k) Yoshida, H.; Sugiura, S.;
Kunai, A. Org. Lett. 2002, 4, 2767−2769. (l) Pintori, D. G.; Greaney,
M. F. Org. Lett. 2010, 12, 168−171. (m) Aithagani, S. K.; Dara, S.;
Munagala, G.; Aruri, H.; Yadav, M.; Sharma, S.; Vishwakarma, R. A.;
Singh, P. P. Org. Lett. 2015, 17, 5547−5549. (n) Hirsch, M.; Dhara, S.;
Diesendruck, C. E. Org. Lett. 2016, 18, 980−983. (o) Haber, J. C.;
Lynch, M. A.; Spring, S. L.; Pechulis, A. D.; Raker, J.; Wang, Y.
Tetrahedron Lett. 2011, 52, 5847−5850. (p) Bhojgude, S. S.; Bhunia,
A.; Biju, A. T. Acc. Chem. Res. 2016, 49, 1658−1670. (q) Thangaraj,
M.; Gaykar, R. N.; Roy, T.; Biju, A. T. J. Org. Chem. 2017, 82, 4470−
4476. (r) Thangaraj, M.; Bhojgude, S. S.; Jain, S.; Gonnade, R. G.; Biju,
A. T. J. Org. Chem. 2016, 81, 8604−8611.
(1) (a) Ghirardello, M.; Rivas, M. D. L.; Lacetera, A.; Delso, I.;
Navarrete, E. L.; Tejero, T.; Santamaría, S. M.; Guerrero, R. H.;
Merino, P. Chem. - Eur. J. 2016, 22, 7215−7224. (b) Vidal, P.; Rolds,
V.; Alonso, M. D. C. F.; Vauzeilles, B.; Bleriot, Y.; Canada, F. J.; Andre,
́
̃
S.; Gabius, H.-J.; Barbero, J. J.; Espinosa, J. F.; Santamara, S. M. Chem.
́
- Eur. J. 2013, 19, 14581−14590. (c) Mikkelsen, L. M.; Hernaiz, M. J.;
Pastor, M. M.; Skrydstrup, T.; Barbero, J. J. J. Am. Chem. Soc. 2002,
124, 14940−14951. (d) Ernst, B.; Magnani, J. L. Nat. Rev. Drug
Discovery 2009, 8, 661−677.
(2) (a) Blow, N. Nature 2009, 457, 618−620. (b) Bies, C.; Lehr, C.
M.; Woodley, J. F. Adv. Drug Delivery Rev. 2004, 56, 425−435.
(c) Couldrey, C.; Green, J. E. Breast Cancer Res. 2000, 2, 321−323.
(d) Danussi, C.; Coslovi, A.; Campa, C.; Mucignat, M. T.; Spessotto,
P.; Uggeri, F.; Paoletti, S.; Colombatti, A. Glycobiology 2009, 19,
1056−1067. (e) Demetriou, M.; Granovsky, M.; Quaggin, S.; Dennis,
J. W. Nature 2001, 409, 733−739. (f) Disney, M. D.; Seeberger, P. H.
Chem. Biol. 2004, 11, 1701−1707. (g) Hart, G. W.; Housley, M. P.;
Slawson, C. Nature 2007, 446, 1017−1022. (h) Hecht, M.; Stallforth,
P.; Silva, D. V.; Adibekian, A.; Seeberger, P. H. Curr. Opin. Chem. Biol.
2009, 13, 354−359.
(11) Liu, Z.; Larock, R. C. Org. Lett. 2004, 6, 99−102.
(12) (a) Liu, Z.; Larock, R. C. J. Am. Chem. Soc. 2005, 127, 13112−
13113. (b) Liu, Z.; Larock, R. C. J. Org. Chem. 2006, 71, 3198−3209.
(c) Liu, Z.; Larock, R. C. Org. Lett. 2003, 5, 4673−4675.
(13) Pintori, D. G.; Greaney, M. F. Org. Lett. 2010, 12, 168−171.
(14) Yoshida, H.; Watanabe, M.; Fukushima, H.; Ohshita, J.; Kunai,
A. Org. Lett. 2004, 6, 4049−4051.
(3) (a) Gandhi, N. S.; Mancera, R. L. Chem. Biol. Drug Des. 2008, 72,
455−482. (b) Paulick, M. G.; Bertozzi, C. R. Biochemistry 2008, 47,
6991−7000. (c) Wang, L.-X.; Huang, W. Curr. Opin. Chem. Biol. 2009,
13, 592−600. (d) Bryant, C. E.; Spring, D. R.; Gangloff, M.; Gay, N. J.
Nat. Rev. Microbiol. 2010, 8, 8−14. (e) Taube, S.; Jiang, M.; Wobus, C.
E. Viruses 2010, 2, 1011−1049. (f) Liu, L.; Bennett, C. S.; Wong, C.-H.
Chem. Commun. 2006, 21, 21−33.
(15) Zhao, J.; Larock, R. C. J. Org. Chem. 2007, 72, 583−588.
(16) Xue, J.; Huang, X. Synth. Commun. 2007, 37, 2179−2185.
̈
(4) (a) Biswas, N. N.; Yu, T. T.; Kimyon, O.; Nizalapur, S.; Gardner,
C. R.; Manefield, M.; Griffith, R.; Black, D. S.; Kumar, N. Bioorg. Med.
Chem. 2017, 25, 1183−1194. (b) Chauvier
̀
e, G.; Bouteille, B.; Enanga,
B.; de Albuquerque, C.; Croft, S. L.; Dumas, M.; Per
́
ie, J. J. Med. Chem.
2003, 46, 427−440. (c) Heidlas, J. E.; Lees, W. J.; Pale, P.; Whitesides,
G. M. J. Org. Chem. 1992, 57, 146−151. (d) Wipf, P.; Eyer, B. R.;
Yamaguchi, Y.; Zhang, F.; Neal, M. D.; Sodhi, C. P.; Good, M.; Branca,
M.; Prindle, T., Jr.; Lu, P.; Brodsky, J. L.; Hackam, D. J. Tetrahedron
́
Lett. 2015, 56, 3097−3100. (e) Kozulic, B.; Ries, B.; Mildner, P. Anal.
Biochem. 1979, 94, 36−39. (f) Allen, A.; Kent, P. W. Biochem. J. 1968,
107, 589−598. (h) Etchison, J. R.; Holland, J. J. Anal. Biochem. 1975,
66, 87−92.
(5) Liberek, B.; Melcer, A.; Osuch, A.; Wakiec,
Winiewskia, A. Carbohydr. Res. 2005, 340, 1876−1884.
(6) (a) Tejera, S.; Dorta, R. L.; Vazquez, J. T. Tetrahedron: Asymmetry
́
R.; Milewskib, S.;
́
́
2016, 27, 896−909. (b) Snitynsky, R. B.; Lowary, T. L. Org. Lett. 2014,
16, 212−215. (c) Allman, S. A.; Jensen, H. H.; Vijayakrishnan, B.;
Garnett, J. A.; Leon, E.; Liu, Y.; Anthony, D. C.; Sibson, N. R.; Feizi,
T.; Matthews, S.; Davis, B. G. ChemBioChem 2009, 10, 2522−2529.
D
DOI: 10.1021/acs.orglett.7b03741
Org. Lett. XXXX, XXX, XXX−XXX