Direct copper(I)-catalyzed cycloaddition of organic azides with TMS-protected alkynes

Article abstract of DOI:10.1055/s-0030-1258120

A methodology for the direct use of trimethylsilyl-protected alkynes in the copper(I)-mediated alkyne-azide cycloaddition reaction without the need of a previous deprotection step is reported. This methodology is selective for the trimethylsilyl in front of other silicon-based C(sp)-H protecting groups. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0030-1258120

LETTER
1873
Direct Copper(I)-Catalyzed Cycloaddition of Organic Azides with
TMS-Protected Alkynes
C
ycloaddition
é
of
O
rganic
l
A
zide
s
i
w
ith T
x
M
S-Protecte
d
A
lk
C
yne
s
uevas,a Ana I. Oliva,a Miquel A. Pericàs*a,b
a
Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain
Fax +34(977)920222; E-mail: mapericas@iciq.es
b
Departament de Química Orgànica, Universitat de Barcelona (UB), 08028 Barcelona, Spain
Received 4 May 2010
In this communication we whish to report the successful
implementation of a catalytic tandem desilylation–
CuAAC of 1-trimethylsilyl-1-alkynes mediated by CuBr.
Abstract: A methodology for the direct use of trimethylsilyl-pro-
tected alkynes in the copper(I)-mediated alkyne–azide cycloaddi-
tion reaction without the need of a previous deprotection step is
reported. This methodology is selective for the trimethylsilyl in
front of other silicon-based C(sp)–H protecting groups.
According to our expectations, when 1-phenyl-2-trimeth-
ylsilylacetylene (1a) was treated with benzyl azide (2) in
the presence of CuBr (15 mol%) in DMF at room temper-
ature under argon, the formation of the triazole product 3a
was observed, and this compound could be isolated in
41% yield after 40 hours reaction (Table 1, entry 1). The
addition of one equivalent of N-methylmorpholine
(NMM) to the reaction mixture led to a slightly improved
yield (entry 2), much probably by increasing the solubility
of the putative Cu(I) acetylide intermediate.11 Yield could
be further improved and reaction time very significantly
shortened by performing the reaction at 100 °C (entries 3
and 4).
Key words: alkynes, azides, cycloaddition, tandem reaction, click
chemistry
The copper-catalyzed alkyne–azide cycloaddition reac-
tion (CuAAC)1 has become the archetypal example of
‘click chemistry’,2 and the process has found application
in almost every field of chemistry.3 The efficiency and se-
lectivity of this transformation are a direct consequence of
the reactivity of in situ generated copper(I) acetylides, and
therefore CuAAC is usually limited to terminal acety-
lenes, which produce only 1,4-disubstituted triazoles.4
The influence of different amines (entries 5–10) and sol-
vents (entries 11–16) on the course of the reaction was
next studied. In general, yield was not importantly affect-
ed by the nature of the employed amine, although results
obtained in the presence of 1 equivalent of triethylamine
(entry 5) were consistently better. Only in the case of us-
ing o-phenantroline as ligand (entry 10) the cycloaddition
yield decreased considerably. This is probably due to the
formation of a stable phenantroline–Cu complex, likely
less active in the desilylation of the starting alkyne.
Trimethylsilyl-protected alkynes (TMS-alkynes) are very
useful intermediates for the synthesis of complex mole-
cules through CuAAC cycloadditions, but a previous
deprotection step is required to generate the reactive, ter-
minal alkyne. Methods involving treatment of the TMS-
alkyne with fluoride5 or with silver salts,6 or the use of
K2CO3 in methanol7 are most frequently used, and even
‘one-pot’ deprotection–CuAAC tandem procedures have
been reported.8
Although the transformation of TMS-alkynes into cop-
per(I) acetylides by the use of Cu(I) salts has been report-
ed,9 this methodology has not been studied in connection
with CuAAC reactions. In the context of our own research
in this domain,10 we wondered whether TMS-alkynes,
when submitted to the usual conditions for the CuAAC re-
action, could generate a catalytic amount of the copper(I)
acetylide intermediate and this could enter the cycloaddi-
tion catalytic cycle, as represented in Scheme 1. This
would allow using disubstituted 1-trimethylsilyl-1-
alkynes as direct substrates for the CuAAC avoiding any
previous deprotection step.
The nature of the solvent, in turn, exerted a dramatic influ-
ence on the performance of the reaction. While the use of
DMF, our initial guess, appears to be optimal, acetonitrile
and ethanol gave only moderate yields (entries 11 and 12),
and solvents such as toluene, THF, 1,2-dichloroethane,
and water had deleterious effects on the course of the
reaction (entries 13–16).
In an attempt to reduce the amounts of CuBr and triethyl-
amine employed in the reaction, some additional experi-
ments were performed. When 15 mol% of CuBr and 30
mol% of triethylamine were used, a slight decrease of the
yield of the reaction was observed (entry 17). This yield
was maintained when only 5 mol% of CuBr and 10% of
triethylamine were used, although a longer reaction time
(5 h) was required (entry 18). Even working with only 2
mol% of catalyst and 4 mol% of triethylamine, the reac-
tion took place in synthetically acceptable yield (entry
19). Finally, the use of microwave irradiation was studied
under the optimal reaction conditions (15 mol% CuBr,
100 mol% triethylamine, 100 °C) to reduce reaction time.
N
N
R2N3
Cu(I)
R1
[Cu]
R1
TMS
N
R1
R2
Scheme 1 Direct CuAAC reaction with 1-trimethylsilyl-1-alkynes
SYNLETT 2010, No. 12, pp 1873–1877
x
x
.x
x
.2
0
1
0
Advanced online publication: 30.06.2010
DOI: 10.1055/s-0030-1258120; Art ID: G12510ST
© Georg Thieme Verlag Stuttgart · New York

1874
F. Cuevas et al.
LETTER
Gratifyingly, the reaction can carried out to completion in 5 illustrates another advantage of the use of this method-
30 minutes under these conditions with practically no de- ology: compound 3e could not be easily prepared through
crease in yield (entry 20).
the traditional CuAAC methodology given the gaseous
nature of propyne.
Table 1 Screening of Reaction Conditions for the Tandem Desily-
It is noteworthy that when bis(trimethylsilyl)acetylene
was used as starting material the reaction product was
4-trimethylsilyltriazole 3h (entry 8, method A). This fact
indicates that only one trimethylsilyl group is removed
before the reaction takes place, and that trimethylsilyltria-
zoles are stable under the reaction conditions involved in
the tandem desilylation–CuAAC reaction. In full agree-
ment with these observations, when trimethylsilylacety-
lene was used as starting material, 3h was again obtained
in high yield (entry 9, method A), and the same stands for
the preparation of 3j from triisopropylsilylacetylene (en-
try 10, method A). Thus, whenever a C(sp)–H bond is
present in the starting alkyne, a direct CuAAC takes place,
irrespective of the presence on the substrate of a C(sp)–
TMS unit.
lation–CuAAC of 1-Trimethylsilyl-1-alkynes
Ph
TMS
1a
CuBr (15 mol%)
amine (1 equiv)
N
N
Ph
+
N
Ph
solvent
N3
3a
Ph
2
Entry Solvent
Conditions
r.t., 40 h
Amine
–
Yield (%)
1
2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
EtOH
toluene
THF
41
68
63
83
94
86
88
83
86
r.t., 40 h
NMM
–
3
100 °C, 1.5 h
100 °C, 1.5 h
100 °C, 2 h
100 °C, 2 h
100 °C, 2 h
100 °C, 2 h
100 °C, 2 h
100 °C, 2 h
100 °C, 2 h
100 °C, 2 h
100 °C, 2 h
100 °C, 2 h
4
NMM
Et3N
Keeping in mind the possibility of developing chemose-
lective cycloaddition processes on differently protected
poliynes, the possible participation in the tandem desily-
lation–CuAAC reaction of 1-silyl-1-alkynes bearing bulk-
ier trialkylsilyl substituents was studied (entries 11 and
12). Very interestingly, 1-triisopropylsilyl-1-alkynes and
1-tert-butyldimethyl-silyl-1-alkynes do not react at all,
being quantitatively recovered upon reaction workup,
while the corresponding triazole products are not detect-
ed. It is thus confirmed that trialkysilyl substituents other
than trimethylsilyl are not cleaved under the studied reac-
tion conditions and, hence, that the direct CuAAC reac-
tion with 1-silyl-1-alkynes is selective for trimethylsilyl
substituted acetylenes.
5
6
DIPEA
7
benzylamine
TMEDA
8
9
piperidine
10
11
12
13
14
15
16
17a
18b
19c
20d
o-phenantroline 31
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
Et3N
70
53
11
11
7
As a consequence of this behavior, the protection of two
or more terminal triple bonds in a molecule with
trimethylsilyl and other trialkylsilyl groups becomes or-
thogonal towards the tandem desilylation–CuAAC of 1-
trimethylsilyl-1-alkynes. This fact can be used, in prac-
tice, for the ready control of triple-bond reactivity. We il-
lustrate this concept in Scheme 2, where the preparation
of a molecule containing two differently substituted 1,2,3-
triazole moieties is presented. Starting from an orthogo-
nally protected diyne 4, it is possible to use the tandem
desilylation–CuAAC of 1-trimethylsilyl-1-alkynes to ob-
tain selectively a monotriazole intermediate at the trime-
thylsilyl-protected alkyne moiety 5 without affecting the
triisopropylsilyl-protected one. Then, the desilylation
with tetrabutylammonium fluoride in THF of the TIPS
group and the subsequent CuAAC reaction afforded the
bistriazole derivative 6 in excellent yield (Scheme 2).
1,2-DCE 100 °C, 2 h
H2O
100 °C, 2 h
100 °C, 3.5 h
100 °C, 5 h
100 °C, 5 h
100 °C, 0.5 h
9
DMF
DMF
DMF
DMF
78
79
68
84
a Conditions: 15 mol% of CuBr, 30 mol% of Et3N.
b Conditions: 5 mol% of CuBr, 10 mol% of Et3N.
c Conditions: 2 mol% of CuBr, 4 mol% of Et3N.
d Conditions: under MW irradiation.
The scope of the tandem desilylation–CuAAC of 1-trime-
thylsilyl-1-alkynes was studied with a family of alkynes
featuring triple bonds with different electronic character-
istics (Table 2), using in all cases the previously opti-
mized reaction conditions [method A: CuBr 15 mol%,
Et3N (1 equiv) in DMF at 100 °C].12 As it can be seen, the
process is compatible with the presence of different fun-
tional groups in the alkyne, and good yields are obtained
in all cases (entries 1–7, method A). The example in entry
To trace the origin of the hydrogen atom at C-5 in the tri-
azole products and the fate of the trimethylsilyl group on
the starting alkyne, the reaction was performed in a NMR
tube in DMF-d7 under the optimal reaction conditions
[CuBr (15 mol%), Et3N (1 equiv), 100 °C] with 1a and 2.
By monitoring the progress of the reaction, the formation
of the nondeuterated triazole 3a could be observed
Synlett 2010, No. 12, 1873–1877 © Thieme Stuttgart · New York

LETTER
Cycloaddition of Organic Azides with TMS-Protected Alkynes
1875
Table 2 Scope of the Tandem Desilylation–CuAAC of 1-Trimethylsilyl-1-alkynes
R
TMS
CuBr (15 mol%)
Et3N (1 equiv)
1
N
N
Ph
+
N
R
DMF, 100 °C
N3
3
Ph
2
Entry
1
Alkyne
Product
Time (h)
2
Yield (%) Aa/Bb
94/97
N
N
N
Ph
Ph
N
TMS
1a
3a
O
O
H
H
N
2
3
2.5
2.5
82/93
82/84
N
TMS
1b
3b
N
N
Ph
N
I
TMS
I
1c
3c
N
N
Ph
4
5
2.5
2.5
76/85
69/56
N
TMS
3d
1d
N
N
Ph
TMS
N
1e
3e
N
N
Ph
N
TMS
6
7
1.5
2.5
94/87
85/76
O
O
1f
3f
N
N
O
O
O
Ph
N
TMS
O
3g
1g
N
N
N
N
Ph
TMS
TMS
8
9
2.5
2.5
2.5
2.5
2.5
57/43
77/37
91/88
n.d.c
N
TMS
1h
3h
N
Ph
Ph
TMS
TIPS
N
TMS
1i
1j
3h
N
10
11
12
N
TIPS
3j
N
N
N
Ph
TIPS
N
Ph
3a
1k
1l
N
n.d.c
Ph
TBDMS
N
Ph
3a
a Method A: in DMF.
b Method B: in DMF–H2O (2 equiv).
c n.d.: not detected.
Synlett 2010, No. 12, 1873–1877 © Thieme Stuttgart · New York

1876
F. Cuevas et al.
LETTER
CN
iment represents an additional argument in favor of the in-
termediacy of copper acetylides in the CuAAC
reaction.1c,4a,13 The different events required for the cata-
lytic cycle to operate are included in the simplified mech-
anistic proposal presented in Scheme 3.
TIPS
TIPS
N
N
N
R1
C
C
TMS
N
R2
1) TBAF, THF
30 min, r.t.
99%
Cu(I)
N
N
CuBr (15 mol%)
Et3N (1 equiv)
R1
H
2) CuI, DIPEA, THF
Ph
N3
R1
N3
C
C Cu
DMF, 100 °C, 2.5 h
method A: 76%
method B: 86%
H2O
N
N
NC
MW, 80 °C, 1 h
91%
N
N
N
N
N
TMS
R2
N
N
R2N3
4
R1
Cu
5
6
Scheme 3 Proposed catalytic cycle for the tandem desilylation–
CuAAC of 1-trimethylsilyl-1-alkynes
Scheme 2 Selective synthesis of differently substituted bistriazoles
Although conventional dry grade DMF usually contains
enough water as to allow the achievement of high conver-
sions under the standard reaction conditions used in this
work (Table 2, method A), the reaction was also studied
in the presence of a slight excess (2 equiv) of water
(Table 2 and Scheme 2, method B). In general, yields re-
corded with method B are higher. As an exception,
alkynes bearing hydrolysis-prone substituents, such as
TMS (entries 8 and 9, method B), or those leading to vol-
atile species upon hydrolysis (entry 5, method B) are more
efficiently converted under the reaction conditions of
method A. Much probably, the presence of excess water
favors hydrolysis of the starting alkynes or of cycloaddi-
tion intermediates in detriment of yield.
(Figure 1). Interestingly, when conversion of the starting
material reached ca. 50%, the reaction importantly slowed
down. We interpreted that traces of water present in the
deuterated solvent had been completely consumed by the
reacting system at that point. In fact, addition of a small
amount of D2O to the reaction mixture led to immediate
reactivation, the formation of 3a deuterated at the triazole
ring being observed from this moment on. In a parallel ex-
periment the reaction was performed in DMF-d7 contain-
ing 2 equivalents of D2O. In this case, the reaction cleanly
progressed to 90% conversion in 2 hours, partially deuter-
ated 3a being formed.
In conclusion, we have described a catalytic, tandem de-
silylation–CuAAC of 1-trimethylsilyl-1-alkynes that
avoids a previous deprotection step. Under the reaction
conditions reported, the intermediate copper(I) acetylide
is formed in situ from the copper(I) species used as cata-
lyst, and subsequently undergoes the cycloaddition reac-
tion with the azide counterpart. From a practical
perspective, this methodology avoids the isolation and
manipulation of the often volatile terminal alkynes, lead-
ing in general to substantially improved yields. Moreover,
this process is selective for trimethylsilyl-protected
alkynes [vs. alkynes bearing bulkier silyl-based C(sp)–H
protecting groups], and this allows using this methodolo-
gy for the controlled synthesis of molecules bearing two
or more differently substituted triazoles.
Figure 1
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
It can be concluded from these results that the presence of
traces of water in the solvent (DMF) is necessary for the
reaction to proceed. According to the results obtained
with D2O, water is responsible for the protonation of the
triazolyl–copper intermediate, where the catalytic Cu(I)
species regenerates. It is interesting to note that this exper-
Acknowledgment
This work was funded by MICINN (Grant CTQ2008-00947/BQU),
DIUE (Grant 2009SGR623), Consolider Ingenio 2010 (Grant
CSD2006-0003), Laboratorios del Dr. Esteve, S. A., and ICIQ
Foundation.
Synlett 2010, No. 12, 1873–1877 © Thieme Stuttgart · New York

LETTER
Cycloaddition of Organic Azides with TMS-Protected Alkynes
1877
A.; Jimeno, C.; Pericàs, M. A. Org. Lett. 2008, 10, 337.
(f) Oliva, A. I.; Christmann, U.; Font, D.; Cuevas, F.;
Ballester, P.; Buschmann, H.; Torrens, A.; Yenes, S.;
Pericàs, M. A. Org. Lett. 2008, 10, 1617. (g) Popa, D.;
Marcos, R.; Sayalero, S.; Vidal-Ferran, A.; Pericàs, M. A.
Adv. Synth. Catal. 2009, 351, 1539. (h) Özçubukçu, S.;
Özkal, E.; Jimeno, C.; Pericàs, M. A. Org. Lett. 2009, 11,
4680. (i) Alza, E.; Rodriguez-Escrich, C.; Sayalero, S.;
Bastero, A.; Pericàs, M. A. Chem. Eur. J. 2009, 15, 10167.
(j) Alza, E.; Pericàs, M. A. Adv. Synth. Catal. 2009, 351,
3051.
References and Notes
(1) (a) Meldal, M.; Christensen, C.; Tornoe, C. W. J. Org.
Chem. 2002, 67, 3057. (b) Sharpless, K. B.; Fokin, V. V.;
Green, L. G.; Rostovtsev, V. V. Angew. Chem. Int. Ed. 2002,
114, 2708. (c) Meldal, M.; Tornoe, C. W. Chem. Rev. 2008,
108, 2952.
(2) Kolb, H. C.; Finn, M. G.; Sharpless, K. B. Angew. Chem. Int.
Ed. 2001, 40, 2004.
(3) (a) Macromol. Rapid. Commun. 2008, 29, 943; special
thematic issue. (b) QSAR Comb. Sci. 2007, 26, 1110; special
thematic issue. (c) Angell, Y. L.; Burgess, K. Chem. Soc.
Rev. 2007, 36, 1674. (d) Moses, E.; Moorhouse, A. D.
Chem. Soc. Rev. 2007, 36, 1249. (e) Lutz, J.-F. Angew.
Chem. Int. Ed. 2007, 46, 1018. (f) Wu, P.; Fokin, V. V.
Aldrichimica Acta 2007, 40, 7.
(11) A precipitate forms upon mixture of 1 with CuBr in DMF. In
the presence of NMM, precipitation is much less intense.
(12) General Procedure for the Tandem Desilylation–
CuAAC Reaction of 1-Trimethylsilyl-1-alkynes
Method A
(4) (a) Himo, F.; Lovell, T.; Hilgraf, R.; Rostovtsev, V. V.;
Noodleman, L.; Sharpless, K. B.; Fokin, V. V. J. Am. Chem.
Soc. 2005, 127, 210. For two examples of CuAAC
involving the use of internal alkynes, see: (b) Candelon, N.;
Lastécouères, D.; Diallo, A. K.; Ruiz-Aranzaes, J.; Astruc,
D.; Vincent, J.-M. Chem. Commun. 2008, 741. (c) Díez-
González, S.; Correa, A.; Cavallo, L.; Nolan, S. P. Chem.
Eur. J. 2006, 12, 7558.
(5) (a) Fujino, T.; Marine, G.; Nakamura, E.; Isobe, H. Nucleic
Acids Symp. Ser. 2007, 51, 267. (b) Gadzikwa, T.; Farha,
O. K.; Malliakas, C. D.; Kanatzidis, M. G.; Hupp, J. T.;
Nguyen, S. T. J. Am. Chem. Soc. 2009, 131, 13613.
(6) Valverde, I. E.; Delmas, A. F.; Aucagne, V. Tetrahedron
2009, 65, 7597.
A mixture of the alkyne (0.24 mmol), CuBr (0.04 mmol, 15
mol%), benzylazide (0.26 mmol), and Et3N (0.24 mmol) in
DMF (0.5 mL) was stirred at 100 °C for the time indicated in
Tables 1 and 2. The reaction mixture was cooled at r.t., a sat.
solution of NH4Cl was added and extracted with EtOAc. The
organic layer was washed with H2O, dried over Na2SO4,
filtered, and concentrated under reduced pressure.
Purification by flash chromatography, silica gel, gradient
hexane to EtOAc.
Method B
As described in method A, but additional H2O (2 equiv) was
added.
1-Benzyl-4-phenyl-1H-1,2,3-trizole (3a)
From 1-phenyl-2-trimethylsilylacetylene (1a, 27 mg, 30 mL,
0.15 mmol), CuBr (3.3 mg, 0.02 mmol), benzylazide (22 mg,
21 mL, 0.17 mmol), and Et3N (16 mg, 22 mL, 0.16 mmol) in
DMF (0.5 mL), afforded the titled compound (method A: 34
mg, 94% yield; method B: 97%) as a white solid; mp 134–
136 °C. 1H NMR (400 MHz, CDCl3): d = 7.82 (d, J = 7.2 Hz,
2 H), 7.69 (s, 1 H), 7.37 (m, 5 H), 7.33 (m, 2 H) ppm.
13C NMR (100 MHz, CDCl3): d = 148.35, 134.95, 130.78,
129.31, 129.01, 128.93, 128.34, 128.22, 125.88, 119.86,
54.34 ppm. HRMS (ESI+): m/z calcd for [M + Na]+:
258.1007; found: 258.1001.
(7) Montagnat, O. D.; Lessene, G.; Hugues, A. B. Tetrahedron
Lett. 2006, 47, 6971.
(8) (a) Aucagne, V.; Leigh, D. A. Org. Lett. 2006, 8, 4505.
(b) Hu, M.; Li, J.; Yao, S. Q. Org. Lett. 2008, 10, 5529.
(c) Fiandanese, V.; Bottalico, D.; Marchese, G.; Punzi, A.;
Capuzzolo, F. Tetrahedron 2009, 10573. (d) Beltrán, E.;
Serrano, J. L.; Sierra, T.; Giménez, R. Org. Lett. 2010, 12,
1404.
(9) Ito, H.; Arimoto, K.; Sensui, H.; Hosomi, A. Tetrahedron
Lett. 1997, 38, 3977.
(10) (a) Font, D.; Jimeno, C.; Pericàs, M. A. Org. Lett. 2006, 8,
4653. (b) Font, D.; Bastero, A.; Sayalero, S.; Jimeno, C.;
Pericàs, M. A. Org. Lett. 2007, 9, 1943. (c) Bastero, A.;
Font, D.; Pericàs, M. A. J. Org. Chem. 2007, 72, 2460.
(d) Alza, E.; Cambeiro, X. C.; Jimeno, C.; Pericàs, M. A.
Org. Lett. 2007, 9, 3717. (e) Font, D.; Sayalero, S.; Bastero,
(13) (a) Rodionov, V. O.; Fokin, V. V.; Finn, M. G. Angew.
Chem. Int. Ed. 2005, 44, 2210. (b) Nolte, C.; Mayer, P.;
Straub, B. F. Angew. Chem. Int. Ed. 2007, 46, 2101.
(c) Ahlquist, M.; Fokin, V. V. Organometallics 2007, 26,
4389.
Synlett 2010, No. 12, 1873–1877 © 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.