Modular synthesis of propargylamine modified cyclodextrins by a gold(iii)-catalyzed three-component coupling reaction

Article abstract of DOI:10.1039/c7ra00249a

An efficient modular approach for the synthesis of propargylamine modified β-cyclodextrins has been developed. Using mono-(6-benzylamino-6-deoxy)-β-cyclodextrins, formaldehyde, and alkynes, mono-(6-(benzylpropargyl)amino-6-deoxy)-β-cyclodextrins have been synthesized through a three-component coupling reaction catalyzed by gold(iii) salt in water at 40 °C.

Full text of DOI:10.1039/c7ra00249a

RSC Advances
View Article Online
View Journal | View Issue
PAPER
Modular synthesis of propargylamine modified
cyclodextrins by a gold(III)-catalyzed three-
component coupling reaction†
ab
Cite this: RSC Adv., 2017, 7, 14477
Tsz-Wai Hui,‡ab Jian-Fang Cui‡ab and Man-Kin Wong
*
Received 7th January 2017
Accepted 24th February 2017
An efficient modular approach for the synthesis of propargylamine modified b-cyclodextrins has been
developed. Using mono-(6-benzylamino-6-deoxy)-b-cyclodextrins, formaldehyde, and alkynes, mono-(6-
(benzylpropargyl)amino-6-deoxy)-b-cyclodextrins have been synthesized through a three-component
coupling reaction catalyzed by gold(III) salt in water at 40 ꢀC.
DOI: 10.1039/c7ra00249a
rsc.li/rsc-advances
Cyclodextrins (CDs) are naturally occurring cyclic oligosaccha- acids/halides and azides containing molecules offer an easy
rides consisting of a-1,4-D-glucopyranose units. The commonly access to multifunctional molecules. Moreover, alkyne contain-
used cyclodextrins with six, seven, and eight glucopyranose ing cyclodextrins function as versatile building blocks for the
units are referred to as a-, b-, and g-cyclodextrins, respectively synthesis of multifunctional cyclodextrins through click reaction,
(Fig. 1a). Cyclodextrin is an amphipathic molecule bearing 1,3-dipolar cycloaddition, and Sonogashira cross-coupling
a hydrophilic exterior surface and a hydrophobic interior cavity
(Fig. 1b). Owing to the hydrophilic surface, cyclodextrins are
water-soluble. The hydrophobic cavity of cyclodextrins allows
“host–guest” inclusion complex formation with a wide variety of
guest molecules through hydrophobic interaction. Therefore,
the use of cyclodextrins and their modied derivatives as
versatile supramolecular hosts has been widely employed in
supramolecular catalysis, enzymatic mimics, analytical chem-
istry, and the pharmaceutical and food industry.1–9
Fig. 1 Chemical structures of cyclodextrins.
In general, modied cyclodextrins exhibit distinctive proper-
ties compared with native cyclodextrins. Modication of cyclo-
dextrins provides novel derivatives with unique structures and
functions to support the development of different research
elds.1,4–9 In the past decades, various methods for cyclodextrin
modication have been developed to ne-tune their physico-
chemical properties (solubility, inclusion complexation proper-
ties, etc.). In particularly, 6-OTs monosubstituted cyclodextrins
have been employed as orthogonal handle for conjugation with
different functional molecules (Scheme 1a).10–12 Through trans-
formation of the OTs group of the mono[6-O-(p-toluenesulfonyl)]-
cyclodextrin (6-OTs-CD), amine and alkyne functionalities could
be easily introduced into cyclodextrins. Further synthetic elabo-
rations through amidation and click reaction with carboxylic
aThe Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen, PR
China
bState Key Laboratory of Chirosciences, Department of Applied Biology and Chemical
Technology, The Hong Kong Polytechnic University, Hung Hom, Hong Kong, PR China.
E-mail: mankin.wong@polyu.edu.hk; Fax: +852 2364 9932
Scheme 1 (a) Typical synthetic strategies for multifunctional cyclo-
dextrins via amino and alkynyl groups; (b) gold(III) catalyzed synthesis of
propargylamine modified cyclodextrins.
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c7ra00249a
‡ These authors contributed equally to this work.
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 14477–14480 | 14477

View Article Online
RSC Advances
Paper
reaction.13,14 However, cyclodextrin modication is still a chal-
lenging task in synthetic chemistry due to the multiple hydroxyl
groups present at the 2-, 3-, and 6-positions competing with
reactants, leading to complex product formation and difficult
product purication. Thus, there remains a signicant interest to
develop new approaches for the synthesis of multifunctional
cyclodextrins.
Over the years, we have been developing gold catalysis for
organic synthesis,15–18 and bioconjugation of oligosaccharides,
peptides and proteins.19–21 Efficient methods for the synthesis of
multifunctional biomolecules via Morita–Baylis–Hillman reaction
and gold catalyzed/mediated reactions have also been developed
in our group.19–22 Particularly, a modular approach for single-site
incorporation of two independent functionalities (amines and
alkynes) into aldehyde-containing oligosaccharides by using a one-
pot gold-mediated three component coupling reaction has been
developed.17,19 As cyclodextrins are cyclic oligosaccharides, it is
envisaged that multifunctional propargylamine modied cyclo-
dextrins could be synthesized from a gold-catalyzed three
component coupling reaction23–25 of amine containing cyclodex-
trins, aldehydes, and alkynes.
Here we rst present an efficient method for the synthesis of
a new class of propargylamine modied b-cyclodextrins through
a modular approach of gold(III)-catalyzed three component
coupling reaction of amine containing cyclodextrins, formalde-
hyde, and alkynes in water at 40 ꢀC (Scheme 1b). Using mono-(6-
benzylamino-6-deoxy)-b-cyclodextrins (1, 6-BA-b-CD), formalde-
hyde, and various alkynes, mono-(6-(benzylpropargyl)amino-6-
deoxy)-b-cyclodextrins (2, 6-BPA-b-CD) have been achieved in
moderate to good yields with excellent purity through convenient
precipitation in acetone and recrystallization in water successively.
Notably, the reaction proceeded with high chemoselectivity for
formaldehyde and remarkable functional group compatibility for
the unprotected hydroxyl groups of mono-(6-benzylamino-6-
deoxy)-b-cyclodextrins 1.
One key challenge for selective modication of cyclodextrins
is the competitive reactions of the hydroxyl groups at the 2-, 3-
and 6-positions. Highly reactive reagents tend to non-selectively
react with the hydroxyl groups of any positions, while less
reactive reagents allow selective modication of the hydroxyl
groups at the 6-position.1 Typically, mono-, and multi-(6-tosyl)
cyclodextrins are the most commonly used precursors for the
synthesis of a wide variety of 6-position modied cyclodextrins.
Therefore, we set out to synthesize mono-(6-benzylamino-6-
deoxy)-b-cyclodextrins (1, 6-BA-b-CD)26 from 6-OTs-b-CD as the
amine component for the gold(III)-catalyzed three component
coupling reaction. In this regard, 6-OTs-b-CD was synthesized
via the reaction of b-cyclodextrin and p-toluenesulfonyl imid-
azole in alkaline aqueous solution according to literature
procedure (Scheme 2).27 Starting from 6-OTs-b-CD, 6-BA-b-CD 1
was synthesized accordingly.28 Upon treatment with benzyl-
amine as solvent and reactant at 70 ꢀC for 16 h, 6-OTs-b-CD was
converted to 6-BA-b-CD 1a with 83% yield. Then, various
substituted benzylamines were used to synthesize 6-BA-b-CDs
(1b–1d) under the same reaction conditions with moderate to
good yields (36–83%, Scheme 2).
Scheme 2 Synthetic route of mono-(6-benzylamino-6-deoxy)-b-
cyclodextrins 1.
6-BA-b-CD (1a) was used as the amine component coupling
with phenylacetylene and various aldehydes, as well as different
solvents and transition-metal catalysts were used to study the
reaction conditions (Table 1). Using 1a (0.1 mmol), benzalde-
hyde (1.0 mmol), and phenylacetylene (1.0 mmol) with KAuCl4
(2.5 mol%) as catalyst in water at 40 ꢀC for 24 h gave no desired
three component coupling product (Entry 1). Benzaldehydes
bearing electron-donating group (4-OMe) and electron-decient
group (4-NO2) on the phenyl ring also did not afford the desired
product (Entries 2 and 3). To our delight, when formaldehyde
was used as the aldehyde component under the same reaction
conditions, the expected product 2a was isolated in 50% yield
(Entry 4). Yet, only a trace amount or no product was obtained
when ACN, THF and toluene were used instead of H2O as
solvent (Entries 5–7). AuCl3 and AuCl gave comparable yield in
46% and 41%, respectively (Entries 8 and 9). A trace amount of
product was obtained by using HAuCl4 as the catalyst (Entry 10).
Other gold(III) complexes [(C^N)AuCl2] and [(C^N)2AuBF4]
(HC^N ¼ 2-phenylpyridine or 2-phenylquinoline) were also
employed as the catalyst for the reaction, but only a trace
amount of coupling product was detected by ESI-MS analysis
(Entries 11 and 12). Note that 34% yield of product was obtained
when Salen-gold(III) complex [(Salen)AuBF4] was used as catalyst
(Entry 13). Then, the catalytic effect of various transition-metal
catalysts, including Cu(OAc)2, Cu(OTf)2, AgOTf, NiBr2, Zn(OAc)2
and RuCl3, for this reaction was examined (Entries 14–19). The
results showed that only RuCl3 catalyzed this reaction to give
product in 25% yield. Furthermore, aliphatic aldehydes, such as
acetaldehyde, butyraldehyde and heptaldehyde, did not give the
corresponding products with combination of amine 1a and
phenylacetylene (Entries 20–22). These results indicated that
this three component coupling reaction proceeded with high
chemoselectivity for formaldehyde and the use of simple gold
salt KAuCl4 as the catalyst and water as the solvent are essential.
Moreover, a primary amine modied cyclodextrin 1aa was
synthesized and employed as amine component coupling with
phenylacetylene and various aromatic and aliphatic aldehydes.
14478 | RSC Adv., 2017, 7, 14477–14480
This journal is © The Royal Society of Chemistry 2017

View Article Online
Paper
RSC Advances
Table 1 Screening conditions of three component coupling reactiona Table 2 Screening of substrate scope of propargylamine modified b-
cyclodextrins and alkynesa
Entry
R
Catalyst
Solvent
Yield of 2b (%)
Entry
R1
R2
Product
Yieldb (%)
1
2
3
4
5
6
7
8
Ph
KAuCl4
KAuCl4
KAuCl4
KAuCl4
KAuCl4
KAuCl4
KAuCl4
AuCl3
H2O
H2O
H2O
H2O
ACN
THF
Toluene
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
H2O
0
0
0
4-OMeC6H4
4-NO2C6H4
H
H
H
H
H
H
H
H
H
H
H
H
H
H
1
2
H
2a
2b
50c
51
50
Tracec
CH3
Tracec
0
46
3
4
5
OCH3
Cl
2c
2d
2e
42
49
50
9
AuCl
41
10
11
12
13
14
15
16
17
18
19
20
21
22
HAuCl4
(C^N)AuCl2
(C^N)2AuBF4
(Salen)AuBF4
Cu(OAc)2
Cu(OTf)2
AgOTf
NiBr2
Zn(OAc)2
RuCl3
Tracec
Tracec
Tracec
H
34
0
0
0
0
0
25
0
0
0
6
7
H
H
2f
67
52
H
H
2g
CH3
n-C3H7
n-C6H13
KAuCl4
KAuCl4
KAuCl4
8
H
2h
26
a
The reaction was conducted with b-CD amine
1
(0.8 mmol),
formaldehyde (8.0 mmol), alkyne (8.0 mmol), KAuCl4 (2.5 mol%) in
b
c
water (10 mL) at 40 ꢀC for 24 h. Isolated yield. b-CD amine 1 (0.1
mmol), formaldehyde (1.0 mmol), alkyne (1.0 mmol).
a
Reaction conditions: 1a (0.1 mmol), aldehyde (1.0 mmol),
yields (42–51%, Entries 2–4). Using 1a, various aromatic and
aliphatic alkynes also reacted with formaldehyde to give 2e–2h
in 26–67% yield (Entries 5–8). Notably, the reactive functional
groups (hydroxyl, cyclohexenyl) on the alkynes remain intact
aer the coupling reactions (2f and 2h, Entry 6 and Entry 8).
In conclusion, a new method for convenient preparation of
propargylamine modied b-cyclodextrins has been established
through a gold(III)-catalyzed three component coupling reac-
tion. This modular synthetic strategy would be extended to
conversion of cyclodextrins bearing secondary amine moieties
to propargylamine modied cyclodextrin derivatives. Given the
synthetic utility of propargylamines, it is envisioned that these
propargylamine modied b-cyclodextrins could serve as versa-
tile synthetic building blocks for the development of new
cyclodextrin derivatives as hosts for applications on supramo-
lecular catalysis and drug delivery.
b
c
phenylacetylene (1.0 mmol), 40 ꢀC, 24 h. Isolated yield. Detected by
ESI-MS analysis.
Yet, for all of tested aldehydes, no desired three component
coupling products were obtained (see ESI, Table S1†).
To examine the substrate scope of this three component
coupling reaction, we extended our studies to various combi-
nations of 6-BA-b-CD 1 and alkynes. As depicted in Table 2, this
synthetic strategy works well for a wide range of substrates with
moderate to good yields (up to 67%). Coupling of 1a with
formaldehyde and phenylacetylene led to propargylamine
modied b-cyclodextrin 2a in 50% yield (Entry 1). Coupling
product 2a was characterized by NMR spectroscopic techniques
(including 1H, 13C, COSY, ROESY, HMQC and HMBC experi-
ments) and ESI-MS spectrometry. Using mono-(6-benzylamino-
6-deoxy)-b-cyclodextrins 1b–1d with electron-donating group
(Me, OMe) and electron-decient group (Cl) on the phenyl ring
of the benzyl moieties also proceeded smoothly, and the cor-
responding coupling products 2b–2d were obtained in good
Acknowledgements
The authors gratefully acknowledged the nancial support by
the National Natural Science Foundation of China (21272198),
This journal is © The Royal Society of Chemistry 2017
RSC Adv., 2017, 7, 14477–14480 | 14479

View Article Online
RSC Advances
Paper
´
´
The Hong Kong Polytechnic University (4-BCA4) and State Key 14 F. Ortega-Caballero, J. J. Gimenez-Martınez and A. Vargas-
Laboratory of Chirosciences.
Berenguel, Org. Lett., 2003, 5, 2389–2392.
15 V. K.-Y. Lo, K. K.-Y. Kung, M.-K. Wong and C.-M. Che, J.
Organomet. Chem., 2009, 694, 583–591.
16 V. K.-Y. Lo, Y. Liu, M.-K. Wong and C.-M. Che, Org. Lett.,
2006, 8, 1529–1532.
17 H.-M. Ko, K. K.-Y. Kung, J.-F. Cui and M.-K. Wong, Chem.
Commun., 2013, 49, 8869–8871.
18 K. K.-Y. Kung, V. K.-Y. Lo, H.-M. Ko, G.-L. Li, P.-Y. Chan,
K.-C. Leung, Z. Zhou, M.-Z. Wang, C.-M. Che and
M.-K. Wong, Adv. Synth. Catal., 2013, 355, 2055–2070.
19 K. K.-Y. Kung, G.-L. Li, L. Zou, H.-C. Chong, Y.-C. Leung,
K.-H. Wong, V. K.-Y. Lo, C.-M. Che and M.-K. Wong, Org.
Biomol. Chem., 2012, 10, 925–930.
Notes and references
1 A. R. Khan, P. Forgo, K. J. Stine and V. T. D'Souza, Chem. Rev.,
1998, 98, 1977–1996.
2 F. Bellia, D. La Mendola, C. Pedone, E. Rizzarelli, M. Saviano
and G. Vecchio, Chem. Soc. Rev., 2009, 38, 2756–2781.
3 A. Martinez, C. Ortiz Mellet and J. M. Garcia Fernandez,
Chem. Soc. Rev., 2013, 42, 4746–4773.
4 J. Tang and W. Tang, in Modied Cyclodextrins for Chiral
Separation, ed. W. Tang, S.-C. Ng and D. Sun, Springer
Berlin Heidelberg, Berlin, Heidelberg, 2013, pp. 1–25.
´
5 A. Garcıa, D. Leonardi, M. O. Salazar and M. C. Lamas, PLoS
20 K. K.-Y. Kung, H.-M. Ko, J.-F. Cui, H.-C. Chong, Y.-C. Leung
and M.-K. Wong, Chem. Commun., 2014, 50, 11899–11902.
21 A. O.-Y. Chan, J. L.-L. Tsai, V. K.-Y. Lo, G.-L. Li, M.-K. Wong
and C.-M. Che, Chem. Commun., 2013, 49, 1428–1430.
22 G.-L. Li, K. K.-Y. Kung, L. Zou, H.-C. Chong, Y.-C. Leung,
K.-H. Wong and M.-K. Wong, Chem. Commun., 2012, 48,
3527–3529.
23 C. Wei and C.-J. Li, J. Am. Chem. Soc., 2003, 125, 9584–9585.
24 C.-J. Li, Acc. Chem. Res., 2010, 43, 581–590.
25 N. Uhlig and C.-J. Li, Chem. Sci., 2011, 2, 1241–1249.
26 C. Wang, F. Chen, X.-W. He, S.-Z. Kang, C.-C. You and Y. Liu,
Analyst, 2001, 126, 1716–1720.
One, 2014, 9, e88234.
6 H. Bricout, F. Hapiot, A. Ponchel, S. Tilloy and E. Monier,
Sustainability, 2009, 1, 924–945.
7 Y. Miao, F. Djedaıni-Pilard and V. Bonnet, Beilstein J. Org.
Chem., 2014, 10, 2654–2657.
8 M. Fukudome, K. Yoshikawa, K. Koga, D.-Q. Yuan and
K. Fujita, Chem. Commun., 2007, 3157–3159.
9 W.-K. Chan, W.-Y. Yu, C.-M. Che and M.-K. Wong, J. Org.
Chem., 2003, 68, 6576–6582.
10 H. Yamamura, Y. Sugiyama, K. Murata, T. Yokoi, R. Kurata,
A. Miyagawa, K. Sakamoto, K. Komagoe, T. Inoue and
T. Katsu, Chem. Commun., 2014, 50, 5444–5446.
11 V. Oliveri and G. Vecchio, Chem.–Asian J., 2016, 11, 1648–
1657.
¨
27 R. C. Petter, J. S. Salek, C. T. Sikorski, G. Kumaravel and
F. T. Lin, J. Am. Chem. Soc., 1990, 112, 3860–3868.
28 Y. Liu, C.-C. You, S.-Z. Kang, C. Wang, F. Chen and X.-W. He,
Eur. J. Org. Chem., 2002, 2002, 607–613.
12 Y.-C. Lin, P.-I. Wang and S.-W. Kuo, So Matter, 2012, 8,
9676–9684.
´
´
13 F. G. Calvo-Flores, J. Isac-Garcıa, F. Hernandez-Mateo,
´
´
´
F. Perez-Balderas, J. A. Calvo-Asın, E. Sanchez-Vaquero and
´
F. Santoyo-Gonzalez, Org. Lett., 2000, 2, 2499–2502.
14480 | RSC Adv., 2017, 7, 14477–14480
This journal is © The Royal Society of Chemistry 2017