Microwave enhancement of a 'one-pot' tandem azidation-'click' cycloaddition of anilines

Article abstract of DOI:10.1055/s-2008-1078019

The practical and efficient one-pot azidation of anilines with the reagent combination t-BuONO and TMSN₃ has become a useful addition to the click-chemistry toolbox. Herein we report a modification of this methodology, using microwave radiation

Full text of DOI:10.1055/s-2008-1078019

LETTER
2089
Microwave Enhancement of a ‘One-Pot’ Tandem Azidation–‘Click’
Cycloaddition of Anilines
‘One-Pot’
T
andem
d
Azidation–‘
a
C
lick’ Cyc
l
oaddition of
Anilines D. Moorhouse, John. E. Moses*
School of Chemistry, University of Nottingham, University Park, Nottingham NG7 2RD, UK
Fax +44(115)9513564; E-mail: john.moses@nottingham.ac.uk
Received 21 May 2008
Dedicated to ‘The Prof’: Sir Jack Baldwin, FRS, on the occasion of his 70th birthday
the corresponding 1,4-triazole linkage. Examples include
three-component azide substitution with NaN3 on reactive
alkyl and aryl halides,8 epoxides,9 and Baylis–Hilman ad-
ducts.10 Copper triflate has also been used as a catalyst for
Abstract: The practical and efficient one-pot azidation of anilines
with the reagent combination t-BuONO and TMSN3 has become a
useful addition to the click-chemistry toolbox. Herein we report a
modification of this methodology, using microwave radiation to
significantly enhance the rate of formation of 1,4-triazoles from in both azidation of benzylic acetates and subsequent Cu(I)
reaction in one pot.11 Aliphatic and aromatic primary
situ generated azides.
amines have also been used in conjunction with TfN3 as a
diazo transfer reagent,12 along with our own diazotiza-
tion–azidation procedure utilising t-BuONO and TMSN3
with anilines.13
Key words: click chemistry, aromatic azides, Huisgen cycloaddi-
tion, chemoselectivity, 1,4-triazoles
Aromatic azides are valuable synthetic intermediates with
immediate application in organic and bioorganic chemis-
try.1 Although organic azides are often stable under most
reaction conditions, compounds with low molecular
weight can sometimes be explosive, and so-called ‘azi-
dophobia’ has perhaps, until recently, resulted in a neglect
of this functional group by the modern organic chemist.2
However, with the recent advent of ‘click’ chemistry2 and
discovery of the powerful 1,4-triazole forming Cu(I)-
catalysed Huisgen reaction,3 there is a growing demand
for new methodology to facilitate access to this function-
ality. This powerful fusion process has found widespread
application in drug discovery,4,5 materials science,5,6 and
bioconjugation amongst others.5,7
In order to minimise the potential explosive hazard,2 pro-
cedures which enable the in situ generation of organic
azides followed by their immediate reaction, is an attrac-
tive option. In the context of ‘click’ chemistry, several
procedures have recently been reported where in situ
azide formation is followed immediately by azide–alkyne
cycloaddition under Cu(I)-mediated conditions, to yield
In our previous work, ambient conditions for the Cu(I)-
catalysed cycloaddition stage of the reaction were de-
scribed. Although good yields for a selection of triazole
products were obtained, for some combinations of starting
materials, the reaction was hampered by undesirable long
reaction times and low yields. We now report a conve-
nient and reliable modification using microwave radiation
to reduce reaction times from hours to minutes, with
greatly increased yields. Scheme 1 illustrates a direct
comparison with two examples, where 4-aminobenzoni-
trile was reacted with 4-ethynylanisole and 3-ethynylpyri-
dine. In both cases, reaction times were dramatically
reduced and product yields greatly increased.
To investigate the generality of this protocol, a variety of
1,4-triazole products was synthesised from a selection of
readily available anilines and acetylenes. Many of these
combinations were not amenable to room-temperature
conditions. In each case overall reaction times were sig-
nificantly reduced, ranging from 15 minutes to 2.5 hours,
a dramatic improvement lending itself to high-throughput
t-BuONO, TMSN3
MeCN
N
N
NH2
OMe
N
then Cu(I), H2O
NC
4-ethynylanisole
a or b
a) 67%
b) 91%
1
NC
t-BuONO, TMSN3
MeCN
N
N
N
NH2
N
then Cu(I), H2O
3-ethynylpyridine
a or b
NC
a) 65%
b) 97%
2
NC
Scheme 1 Reagents and conditions: (a) r.t., overnight; (b) MW heating, 80 °C (125 W max.), 10 min.
SYNLETT 2008, No. 14, pp 2089–2092
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2
.0
8
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0
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Advanced online publication: 31.07.2008
DOI: 10.1055/s-2008-1078019; Art ID: D16808ST
© Georg Thieme Verlag Stuttgart · New York

2090
A. D. Moorhouse, J. E. Moses
LETTER
synthesis (Table 1). The initial azidation reaction with one The procedure with electron-deficient anilines was found
equivalent of t-BuONO followed by one equivalent of to work equally well with both electron-deficient (e.g., en-
TMSN3 proceeded cleanly to completion in less than five tries 1, 4, 8, 13, 15, 19, 20) and electron-rich acetylenes
minutes for both 4-nitroaniline and 4-aminobenzonitrile. (e.g., entries 3, 5, 7, 9, 12).
In the case of iodoaniline slightly longer reaction times of
In summary, this approach offers a genuinely quick and
30 minutes were required with the same reagent ratios.
reliable procedure for the synthesis of a variety of 1,4-tri-
Aniline was found to be sluggish under these conditions,
azole products. The procedure is particularly amenable to
requiring up to 16 hours, although this could be reduced
electron-deficient anilines, and works well with a wide
to two hours using slight excess of reagents (1.5 equiv of
variety of alkynes including aromatic, conjugated, ali-
phatic, electron-rich and electron-deficient varieties. The
t-BuONO followed by 1.2 equiv of TMSN3).14 After com-
plete azide formation (as indicated by TLC analysis), an
products were rapidly isolated by precipitation and filtra-
aqueous solution of CuSO4·5H2O and sodium ascorbate
tion directly from the reaction mixture with no further pu-
was added to generate the [Cu(I)] catalyst in situ, followed
rification. This procedure offers advantages over current
by the corresponding terminal acetylene. The reaction vi-
methodologies in terms of safety, ease of execution, and
als were capped and heated in the microwave at 80 °C, un-
efficiency, and should prove especially useful when un-
til full conversion of azide as indicated by TLC analysis
stable, low molecular weight, and polyvalent aromatic
(maximum 10 min). The products were isolated by simple
azides are required.
filtration and in most cases required no further purifica-
tion.
Table 1 Results for One-Pot Azidation and Cu(I)-Catalysed Huisgen Reaction
Entry
Aniline
Alkyne
Product
Yield (%)
85a,d
N
O
N
N
NH2
NH2
NH2
NH2
NH2
O
1
3
4
5
6
7
OEt
OEt
S
NC
NC
N
N
N
N
N
S
2
3
4
5
>99d
94d
NC
NC
NC
NC
N
N
C5H11
C5H11
NC
O
N
N
O
94d
NC
N
N
N
C6H13
96d
C6H13
NC
NC
OH
N
N
N
N
NH2
NH2
6
8
96d
OH
NC
NC
NC
NC
N
N
7
8
9
92d
N
O
N
N
O
NH2
10
82b,d
OEt
OEt
Synlett 2008, No. 14, 2089–2092 © Thieme Stuttgart · New York

LETTER
‘One-Pot’ Tandem Azidation–‘Click’ Cycloaddition of Anilines
2091
Table 1 Results for One-Pot Azidation and Cu(I)-Catalysed Huisgen Reaction (continued)
Entry
9
Aniline
Alkyne
Product
Yield (%)
84d
N
N
N
N
NH2
NH2
C6H13
C6H13
11
12
N
N
10
11
88d
85d
OH
N
N
N
N
NH2
13
OH
N
N
C5H11
NH2
12
13
14
15
80d
96e
C5H11
N
N
O
OEt
N
N
NH2
NH2
NH2
NH2
NH2
NH2
O
OEt
O2N
O2N
O2N
O2N
O2N
O2N
O2N
O2N
O2N
O2N
O2N
O2N
N
N
OMe
86d
89e
OMe
14
15
16
17
N
N
N
N
O
N
N
O
N
N
S
S
16
17
18
19
20
18
19
20
21
22
94e
96d
82d
91c,e
92d
N
N
N
N
C6H13
C6H13
N
N
O
N
N
NH2
O
OEt
O
OEt
I
I
I
I
N
N
NH2
O
Synlett 2008, No. 14, 2089–2092 © Thieme Stuttgart · New York

2092
A. D. Moorhouse, J. E. Moses
LETTER
Table 1 Results for One-Pot Azidation and Cu(I)-Catalysed Huisgen Reaction (continued)
Entry
21
Aniline
Alkyne
Product
Yield (%)
98e
N
N
N
NH2
23
I
I
a Reaction conditions (azidation): TMSN3 (1 equiv), t-BuONO (1 equiv), MeCN, r.t., 2 min.
b Reaction conditions (azidation): TMSN3 (1.2 equiv), t-BuONO (1.5 equiv), MeCN, r.t., 2 h.
c Reaction conditions (azidation): TMSN3 (1 equiv), t-BuONO (1 equiv), MeCN, r.t., 30 min.
d Reaction conditions [Cu(I) step]: CuSO4·5H2O (0.1 equiv), sodium ascorbate (0.5 equiv), acetylene (1.5 equiv), MW, 80 °C (125 W max), 10
min.
e Reaction was complete, MW, 80 °C (125 W max), 2 min.
(11) Fukuzawa, S.-I.; Shimizu, E.; Kikucki, S. Synlett 2007,
Acknowledgment
2436.
We thank EPSRC and The University of Nottingham for funding
JEM and ADM. We thank Professor K. B. Sharpless for fruitful dis-
cussions and Professor C. J. Moody for helpful advice. Thanks are
also due to Dr. R. Stockman for use of his microwave reactor.
(12) Beckmann, H. S. G.; Wittmann, V. Org. Lett. 2007, 9, 1.
(13) Barral, K.; Moorhouse, A. D.; Moses, J. E. Org. Lett. 2007,
9, 1809.
(14) Typical Procedure – Synthesis of 4-{4-(4-Methoxyphen-
yl)-[1,2,3]triazol-1-yl}benzonitrile (1)
To a stirred solution of 4-aminobenzonitrile (200 mg, 1.69
mmol) in MeCN (2 mL) was added t-BuONO (0.22 mL, 1.69
References and Notes
mmol) at 0 °C in a 2–5 mL microwave reaction vial. To this
solution was added TMSN3 (0.20 mL, 1.69 mmol) dropwise
at 0 °C. The solution was stirred for 2 min at r.t., before
completion of transformation to azide (monitored by TLC).
At this point, 1-ethynyl 4-methoxybenzene (0.33 mL, 2.54
mmol) was added to the reaction mixture, followed by the
addition of CuSO4·5H2O (42 mg, 0.169 mmol) and sodium
ascorbate (167 mg, 0.845 mmol) in H2O (1 mL). The vial
was capped, then placed in a microwave reactor, and heated
to 80 °C (125 W max) (Biotage® Initiator 2.0, 400 W). The
reaction mixture was stirred at this temperature for 10 min
before completion of reaction was observed by TLC
(1) (a) Bräse, S.; Gil, C.; Knepper, K.; Zimmermann, V. Angew.
Chem. Int. Ed. 2005, 44, 5188. (b) Scriven, E. F. V.;
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K. B. Angew. Chem. Int. Ed. 2002, 41, 2596.
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715. (b) Tron, G. C.; Pirali, T.; Billington, R. A.; Canonico,
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analysis. The product was then precipitated by the addition
of H2O (25 mL). The product was isolated by filtration then
washed with H2O (2 × 10 mL), then PE (40–60, 2 × 10 mL).
This gave the product as an orange powder (423 mg, 91%).
IR (CHCl3): 3010.24 (CH), 2234.19 (C≡N) cm–1. 1H NMR
(400 MHz, DMSO): d = 3.81 (s, 3 H, CH3), 7.07 (d, J = 8.9
Hz, 2 H, 2 × CH), 7.86 (d, J = 8.9 Hz, 2 H, 2 × CH), 8.11 (d,
J = 9.0 Hz, 2 H, 2 × CH), 8.17 (d, J = 9.0 Hz, 2 H, 2 × CH),
9.32 (s, 1 H, CH). 13C NMR (100 MHz, DMSO): d = 55.1,
110.8, 114.4, 118.0, 118.6, 120.1, 122.2, 128.7, 134.2,
139.4, 147.6, 159.4. HRMS: m/z calcd for C16H13N4O:
277.1084; found: 277.1076. Anal. Calcd for C16H12N4O: C,
69.55; H, 4.38; N, 20.28; Found: C, 69.32; H, 4.32; N, 20.11.
(5) Moses, J. E.; Moorhouse, A. D. Chem. Soc. Rev. 2007, 36,
1249.
(6) (a) Binder, W. H.; Kluger, C. Curr. Org. Chem. 2006, 10,
1791. (b) Hawker, C. J.; Fokin, V. V.; Finn, M. G.;
Sharpless, K. B. Aust. J. Chem. 2007, 60, 381. (c) Lutz,
J.-F. Angew. Chem. Int. Ed. 2007, 46, 1018.
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47, 3897.
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G.; Narasimha Chary, D. Tetrahedron Lett. 2007, 9, 8773.
(10) Chandrasekhar, S.; Basu, D.; Rambabu, C. Tetrahedron Lett.
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Synlett 2008, No. 14, 2089–2092 © Thieme Stuttgart · New York

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