A procedure for fast and regioselective copper-free click chemistry at room temperature with p-toluenesulfonyl alkyne

Article abstract of DOI:10.1055/s-0029-1216744

Sulfonyl alkyne group can undergo copper-free cyclization at room temperature with diverse azido compounds. In solventfree conditions the reaction was fast, yielding 1,4-disubstituted regioisomers with high regioselectivity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1216744

LETTER
1409
A Procedure for Fast and Regioselective Copper-Free Click Chemistry at
Room Temperature with p-Toluenesulfonyl Alkyne
A
Procedure
f
é
a
nd
b
Regioselecti
a
ve Copper-
s
F
ree Click
t
Chem
i
istry en G. Gouin,* José Kovensky
Department of Chemistry, Laboratoire des Glucides UMR CNRS 6219, Institut de Chimie de Picardie, Université de Picardie Jules Verne,
33 Rue Saint-Leu, 80039 Amiens, France
Fax +33(3)22827560; E-mail: sebastien.gouin@u-picardie.fr
Received 27 January 2009
F
Abstract: Sulfonyl alkyne group can undergo copper-free cycliza-
tion at room temperature with diverse azido compounds. In solvent-
F
free conditions the reaction was fast, yielding 1,4-disubstituted
regioisomers with high regioselectivity.
X
OH
cyclooctyne
1
2
Key words: cycloadditions, regioselectivity, copper-free click
chemistry, solvent-free reaction, p-toluenesulfonyl alkyne
Figure 1 Structure of the cyclooctynes derivatives 1 and 2, respec-
tively, developed by Bertozzi and Boons groups
groups have been appended to the ring, respectively, by
the groups of Bertozzi15 and Boons.16
The click chemistry term initially coined by Sharpless, re-
fers to a series of simple reactions that can rapidly create
molecular diversity without complex workup and purifi-
cation procedures.1 Among the few reactions that fulfill
such criteria (i.e., Diels–Alder cycloadditions, thiol–ene
coupling, nucleophilic opening of epoxides and aziri-
dines), the Huisgen 1,3-dipolar cycloaddition between
azides and alkynes has received the most attention during
the last decade. This is mainly due to the independent dis-
covery by Sharpless2 and Meldal3 and co-workers that
Cu(I) catalysis dramatically accelerates the reaction to
form 1,4-disubstitued triazoles with high regioselectivity.
These functionalized cyclooctynes (Figure 1) that require
multistep synthesis have been successfully applied for the
labeling of carbohydrates in living cells. Usefulness of the
present derivatives in chemical synthesis is, however, lim-
ited due to the formation of four isomers during the
cycloaddition process. Identification of alkynes undergo-
ing regioselective copper-free cycloaddition17 in different
solvent systems at room temperature would be of great in-
terest for applications where copper should be avoided for
toxic reasons or if the reaction is low-yielding due to Cu-
catalyzed acetylenic homocoupling,18 oxidative dimeriza-
tion,19 or metal chelation.20 We described herein a proce-
dure for the regioselective copper-free cycloaddition of
Subsequently, the copper-catalyzed azide–alkyne cyclo-
addition (CuAAC)4 has been successfully implemented
for diverse applications such as the design of polymeric
materials,5 the synthesis of bioconjugates,6 the functional-
ization of nanomaterials,7 and the synthesis of multivalent
inhibitors.8 The reaction owes its usefulness to its high
compatibility with a broad range of functional groups in
different solvents including water. New recyclable cata-
lysts where copper has been immobilized onto various
supports, that is, zeolites,9 activated charchoal,10 and alu-
minum oxyhydroxide nanofibers11 have also been devel-
oped. Interestingly, Fokin and co-workers have found a
ruthenium catalyst producing 1,5-disubstituted triazoles
regioselectively.12
diverse azides with p-toluene sulfonyl alkyne21
3
(Table 1) at room temperature.
We selected compound 3 for the strong withdrawing ef-
fect of the sulfonyl group that should lower the activation
energy barrier for the [3+2] cycloaddition. Moreover, 3
offers the possibility of introducing directly a chemical
group on the aromatic ring for grating synthetic moieties.
The first cycloadditions trials were performed between
alkynyl-armed 3 and azido-diethylene glycol 4 to generate
the cycloadduct as a mixture of regioisomers 5a and 5b
(Table 1). The 1,4- and 1,5-disubstituted triazole struc-
tures were identified by the respectively large and small
D(dC-4 – dC-5) values observed in the corresponding 13C
NMR spectra for the triazole carbon atoms.22
Despite the tremendous and growing success of CuAAC,
high cytotoxicity of copper(I) for bacteria and mammalian
cells preclude in vitro or in vivo applications wherein cells
must remain viable. Bertozzi and co-workers13 proposed
an interesting copper-free azide–alkyne cycloaddition ap-
proach using the intrinsic ring strain of cyclooctynes.14 To
increase the rate of the reaction, fluoride or aromatic
Under conventional heating at 100 °C (Table 1, entry 1)
5a and 5b were isolated with low regioselectivity and an
overall yield of 42%. Conducting the same reaction under
microwave irradiation allowed a reduction of the reaction
time from 5.5 hours to 2 hours with a significant yield im-
provement (entry 2). Interestingly, the cycloaddition
could also be conducted at room temperature with good
regioselectivity (entry 3). However, the reaction was slug-
gish and 48 hours were necessary for a total consumption
SYNLETT 2009, No. 9, pp 1409–1412
x
x.
x
x.
2
0
0
9
Advanced online publication: 04.05.2009
DOI: 10.1055/s-0029-1216744; Art ID: G01909ST
© Georg Thieme Verlag Stuttgart · New York

1410
S. G. Gouin, J. Kovensky
LETTER
Table 1 Initial Attempts for the Copper-Free Cyclization
O
S
N
N
N
OH
O
O
O
2
N3
2 OH
O
S
1,4-regioisomer (5a)
4
+
copper-free
O
O
3
O
S
N
N
2 OH
O
N
1,5-regioisomer (5b)
Entry
Solvent
Temp (°C)
Time (h)
Yield (%)a
Ratio of 5a/5b
1
2
3
4
5
dioxane
dioxane
CH2Cl2
100
5.5
2
42
60
81
80
79
63:37
57:43
89:11
92:8
100 (MW)
16
16
16
48
2
b
–
c
–
2
95:5
a After isolation of both regioisomers by flash chromatography.
b Reactants were mixed in CH2Cl2 and the solvent quickly removed on rotavapor (less than 5 min for a complete evaporation).
c Reactants were mixed in dioxane–H2O (3:1) and the solvent quickly removed on rotavapor (less than 10 min for a complete evaporation).
of the starting materials. To overcome this problem, we ed cycloadducts were observed, meaning that the sulfonyl
tried to perform the same experiment under solvent-free group plays a crucial role in the cyclization process.
conditions. Stoichiometric quantities of alkyne 3 and azi-
do-ethylene glycol 4 were dissolved in a minimum of
The interesting results obtained with alkyne 3 under sol-
vent-free conditions led use to investigate the cycloaddi-
dichloromethane to mix the reagents, and the solution was
tion with a set of organic azides presented in Table 2.
subsequently evaporated under reduced pressure (20
The cyclization proceeded with high yield and short reac-
mbar) at 16 °C (entry 4). The solvent was evaporated in
tions time even with hindered tertiary azides (entry 4).
However, azido-lactoside 12 (entry 3) was much less re-
less than 5 minutes, and after 2 hours, a complete conver-
sion into the expected products with high regioselectivity
active and the experiment should be conducted for 52
was observed.23 This soft procedure is as fast as a micro-
1
hours to be driven to completion. A possible explanation
would be a high electron deficiency of the azide due to the
specific anomeric position and the presence of several de-
activating acetate groups on the saccharide. The regiose-
lectivity was also very high for the different structures
regardless to the nature of the scaffold and the two iso-
mers obtained were separable by flash chromatography on
silica gel. A single 1,4-disubstitued regioisomer were ob-
served by NMR when the experiment was conducted with
azido-adamantane 13 or synthetic iminosugar 14.24
wave-assisted heating at 100 °C. The H and 13C NMR
spectra of the crude material indicated a very clean pro-
cess and the absence of side products. The present exam-
ple also shows that the electron-deficient alkyne is
compatible with free hydroxyl groups, and thus protection
is unnecessary. The starting materials can also be dis-
solved in different solvent systems prior to evaporation
without affecting yields or selectivity as shown in entries
4 and 5. We assign the increased reaction rate to the high
concentration of reactants when the solvent is evaporated
and not to a pressure effect. Indeed, we obtained similar
results at atmospheric pressure after quick removal of the
solvent on a rotavapor.
In a last set of experiment we investigated the possibility
to perform the solvent and copper-free cyclization in the
presence of amino group (Table 3). No traces of cycload-
ducts were observed due to the very fast and total addition
of amino group onto the alkyne. These results indicates
We further explored this solvent-free protocol with azido-
EG 4 and alkynes 6–9 (Figure 2). No traces of the expect-
MeO
F
MeO
N
7
9
6
8
Figure 2 Structure of the commercial alkynes 6–9
Synlett 2009, No. 9, 1409–1412 © Thieme Stuttgart · New York

LETTER
A Procedure for Fast and Regioselective Copper-Free Click Chemistry
1411
Table 2 Cycloaddition with a Set of Organic Azides
Entry Azide
Product
Time Yield
Ratio of
(h)
(%)
1,4/1,5
O
S
N
N
N
N
1
2
10
11
17
18
3
83a
88:12
N3
O
N
O
N3
O
N
O
S
O
O
81a
85:15
O
O
2
O
O
O
O
O
OAc
AcO
OAc
O
OAc
AcO
OAc
O
OAc
O
AcO
OAc
O
AcO
O
3
12
19
52
88a
96a
85:15
>95:5
N
N
O
O
AcO
N
AcO
S
N3
AcO
N
AcO
O
N
N
O
4
5
13
14
20
21
3
2
S
N3
O
Bn
N3
O
N
CN
O
S
quant.b >95:5
O
N
N
N
N
O
O
O
Bn
NC
a After isolation of both regioisomers by flash chromatography.
b Based on the crude material. Reactions were carried out at 20 °C.
Table 3 Cycloaddition attempts with unprotected amino groups
Entry
1
Amine
Product
Time (s)
<30
Yielda
quant.
N3
N3
O
N
NH2
15
22
H
S
N3
N3
O
O
N
H
2
16
23
<30
quant.
S
NH2
O
a Based on the crude material
that substrates should not contain unprotected amino
groups to give cycloadducts.
Acknowledgment
This work was carried out with financial support from the Centre
National de la Recherche Scientifique, the Ministère Délégué à
l’Enseignement Supérieur et à la Recherche and the Conseil Régio-
nal de Picardie.
To our knowledge, the present work is the second exam-
ple of copper-free azide alkyne cyclization at room tem-
perature not driven by the intrinsic ring strain of
cyclooctynes.17 We demonstrated that sulfonyl alkyne 3
could undergo regioselective and fast cyclization with a
set of azides if the reaction was performed under solvent-
free conditions. These results are of interest for the future
development of a regioselective copper-free cycloaddi-
tion strategy in chemical synthesis.
References and Notes
(1) For reviews, see: (a) Kolb, H. C.; Finn, M. G.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2001, 40, 2004. (b) Gil, M. V.;
Arévalo, M. J.; López, Ó. Synthesis 2007, 1589.
(2) Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless,
K. B. Angew. Chem. Int. Ed. 2002, 41, 2596.
(3) Tornøe, C. W.; Christensen, C.; Meldal, M. J. Org. Chem.
2002, 67, 3057.
Synlett 2009, No. 9, 1409–1412 © Thieme Stuttgart · New York

1412
S. G. Gouin, J. Kovensky
LETTER
(4) Bock, V. D.; Hiemstra, H.; van Maarseveen, J. H. Eur. J.
Org. Chem. 2006, 51.
(21) Acetylenic sulfones undergo a variety of cylizations, see:
(a) Zhai, H.; Parvez, M.; Back, T. G. J. Org. Chem. 2007, 72,
3853. (b) Weston, M. H.; Nakajima, K.; Back, T. G. J. Org.
Chem. 2008, 73, 4630. (c) Wei, H.; Cai, G.; Ma, D. Org.
Lett. 2005, 7, 5545. (d) Vokressensky, L. G.; Borisova,
T. N.; Listratova, A. V.; Kulikova, L. N.; Titov, A. A.;
Varlamov, A. V. Tetrahedron Lett. 2006, 47, 4585.
(e) Back, T. G.; Nakajima, K. J. Org. Chem. 2000, 65, 4543.
(f) For a review, see: Back, T. G. Tetrahedron 2001, 57,
5263.
(22) Rodios, N. A. J. Heterocycl. Chem. 1984, 21, 1169.
(23) General Procedure for the Copper-Free Cycloaddition
p-Toluenesulfonyl alkyne 3 (31 mg, 171 mmol) and 8-azido-
3,6-dioxaoctadecanol 4 (30 mg, 171 mmol) were dissolved in
CH2Cl2 (1 mL). The solvent was evaporated under reduced
pressure at 16 °C (rotavapor, 20 mbar). Complete evap-
oration was observed in less than 5 min, and the stirring was
continued under the same conditions for 2 h. The residue was
purified by flash chromatography on SiO2 (2:3 cyclohexane–
EtOAc to EtOAc, then 39:1 EtOAc–MeOH) to give 5a (45
mg, 74%) and 5b (4 mg, 6%) as colorless oils.
(5) (a) Ladmiral, V.; Mantovani, G.; Clarkson, G. J.; Cauet, S.;
Irwin, J. L.; Haddleton, D. M. J. Am. Chem. Soc. 2006, 128,
4823. (b) Helms, B.; Mynar, J. L.; Hawker, C. J.; Fréchet,
J. M. J. J. Am. Chem. Soc. 2004, 126, 15020. (c) Review:
Lutz, J.-F. Angew. Chem. Int. Ed. 2007, 46, 1018.
(6) (a) Link, A. J.; Tirell, D. A. J. Am. Chem. Soc. 2003, 125,
11164. (b) Wang, Q.; Chan, T. R.; Hilgraf, R.; Fokin, V. V.;
Sharpless, K. B.; Finn, M. G. J. Am. Chem. Soc. 2003, 125,
3192.
(7) (a) Polito, L.; Monti, D.; Caneva, E.; Delnevo, E.; Russo, G.;
Prosperi, D. Chem. Commun. 2008, 621. (b) Review:
Nandivada, H.; Jiang, X.; Lahann, J. Adv. Mater. 2007, 19,
2197.
(8) (a) André, S.; Sansone, F.; Kaltner, H.; Casnati, A.; Kopitz,
J.; Gabius, H.-J.; Ungaro, R. ChemBioChem 2009, 9, 1649.
(b) Gouin, S. G.; Vanquelef, E.; García Fernández, J. M.;
Ortiz Mellet, C.; Dupradeau, F.-Y.; Kovensky, J. J. Org.
Chem. 2007, 72, 9032. (c) Diot, J.; García-Moreno, M. I.;
Gouin, S. G.; Ortiz Mellet, C.; Haupt, K.; Kovensky, J. Org.
Biomol. Chem. 2009, 7, 357. (d) Lindhorst, T. K.; Patel, A.
Carbohydr. Res. 2006, 341, 1657.
1-[8-Hydroxy-3,6-dioxaoctyl]-4-[p-toluenesulfonyl]-
[1,2,3]-triazole (5a)
(9) Chassaing, F.; Kumarraja, M.; Sani Souna Sido, A.; Pale, P.;
Sommer, J. Org. Lett. 2007, 9, 883.
(10) Lipshutz, B. H.; Taft, B. R. Angew. Chem. Int. Ed. 2006, 45,
8235.
(11) Park, I. S.; Kwon, M. S.; Kim, Y.; Lee, J. S.; Park, J. Org.
Lett. 2008, 10, 497.
(12) Boren, B.; Narayan, S.; Rasmussen, L. K.; Zhang, L.; Zhao,
H.; Lin, Z.; Jia, G.; Fokin, V. V. J. Am. Chem. Soc. 2008,
130, 8923.
(13) (a) Agard, N. J.; Prescher, J. A.; Bertozzi, C. R. J. Am. Chem.
Soc. 2004, 126, 15046. For reviews, see: (b) Baskin, J. M.;
Bertozzi, C. R. QSAR Comb. Sci. 2007, 26, 1211. (c) Lutz,
J.-F. Angew. Chem. Int. Ed. 2008, 47, 2182.
1H NMR (300 MHz, CDCl3): d = 8.48 (1 H, s, CHTri), 7.91
(2 H, d, J = 8.5 Hz, arom. H), 7.30 (2 H, d, arom. H), 4.54 (2
H, t, J = 4.6 Hz, CH2CH2N), 3.80 (2 H, t, J = 4.8 Hz, CH2)
3.73 (2 H, t, J = 4.8 Hz, CH2), 3.58–3.53 (6 H, m, 3 × CH2),
2.37 (3 H, s, CH3). 13C NMR (75 MHz, CDCl3): d = 149.0
(CqTri), 145.0 (CqAr), 137.2 (CqAr), 129.9 (CHAr), 128.1
(CHAr), 127.5 (CHTri), 72.7, 72.5, 70.4, 70.2, 68.6 (CH2),
61.7 (CH2OH), 50.1 (CH2N), 21.7 (CH3Ar). HRMS (ES+):
m/z calcd for C15H21N3O5NaS: 378.1100; found: 378.1105.
1-[1¢,2¢:3¢,4¢-Di-O-isopropylidene-6-deoxy-a-D-
galactopyranosid-6-yl]-4-[p-toluensulfonyl]-[1,2,3]-
triazole (18)
[a]D –58 (c 0.5, CH2Cl2). 1H NMR (300 MHz, CDCl3):
d = 8.31 (1 H, s, CHTri), 7.92 (2 H, d, J = 8.1 Hz, arom. H),
7.30 (2 H, d, J = 8.1 Hz, arom. H), 5.50 (1 H, d, J1,2 = 4.9 Hz,
H-1), 4.64 (1 H, dd, J5,6 = 3.7 Hz, J6,6¢ = 14.0 Hz, H-6), 4.63
(1 H, dd, J2,3 = 2.6 Hz, J3,4 = 7.8 Hz, H-3), 4.48 (1 H, dd,
(14) Turner, R. B.; Jarett, A. D.; Goebel, P.; Mallon, B. J. J. Am.
Chem. Soc. 1973, 95, 790.
(15) Codelli, J. A.; Baskin, J. M.; Agard, N. J.; Bertozzi, C. R.
J. Am. Chem. Soc. 2008, 130, 11486.
(16) Ning, X.; Guo, J.; Wolfert, M. A.; Boons, G.-J. Angew.
Chem. Int. Ed. 2008, 47, 2253.
(17) To our knowledge, only one previous report has shown that
1,3-dipolar cycloaddition reaction with azides could be
carried out at room temperature in water with electron-
deficient alkynes. See: Li, Z.; Seo, T. S.; Ju, J. Tetrahedron.
Lett. 2004, 45, 3143.
J5,6¢ = 8.5 Hz, H-6¢), 4.34 (1 H, dd, H-2), 4.18 (1 H, dd,
J4,5 = 1.9 Hz, H-4), 4.12 (1 H, ddd, H-5), 2.40 (3 H, s, CH3),
1.52, 1.37, 1.34, 1.32 (12 H, 4 ´ s, 4 ´ isop. CH3). 13C NMR
(75 MHz, CDCl3): d = 148.9 (CqTri), 145.0 (CqAr), 137.0
(CqAr), 129.9 (CHAr), 128.3 (CHAr), 127.2 (CHTri), 110.0
[C(CH3)2], 109.1 [C(CH3)2], 71.0, 70.3, 67.0, 66.7 (C-2,
C-3, C-4, C-5), 51.1 (C-6), 25.8, 24.9, 24.6 (CH3), 21.6
(CH3Ar). HRMS (ES+): m/z calcd for C21H27N3O7NaS:
488.1467; found: 488.1474.
(18) For a review. see: Siemsen, P.; Livingston, R. C.; Diederich,
F. Angew. Chem. Int. Ed. 2000, 39, 2632.
(19) Angell, Y.; Burgess, K. Angew. Chem. Int. Ed. 2007, 46,
3649.
(24) Moura, M.; Delacroix, S.; Postel, D.; Van Nhien, A. N.
Tetrahedron 2009, 65, 2766.
(20) Rodionov, V. O.; Fokin, V. V.; Finn, M. G. Angew. Chem.
Int. Ed. 2005, 127, 2210.
Synlett 2009, No. 9, 1409–1412 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.