F. Stazi et al. / Tetrahedron Letters 51 (2010) 5385–5387
5387
Table 1
in continuous flow. The tight control of the reaction variables com-
bined with the advantages offered by the continuous flow applica-
tion for the reaction scale-up, made this process of undoubted
synthetic utility.
Synthesis of various 1,2,3-aryltriazoles in a continuous flow reactor12
a
b
Entry
R
R0
t1 (min)
t2 (min)
Product
Yield (%)
1
2
3
4
5
6
7
8
9
4-Br
4-MeO
3-CN
iPr
iPr
iPr
iPr
iPr
iPr
Ph
20
30
20
20
20
20
20
30
30
13
19
13
13
13
13
13
19
19
3a
3b
3c
3d
3e
3f
3g
3h
3i
72
59
57
65
79
70
74
68
54
Acknowledgment
4-CF3
4-COOEt
4-COMe
4-CF3
4-CF3
4-CF3
We gratefully acknowledge Ornella Curcuruto (Analytical
Chemistry) for the support given in the MS analysis.
CF3
tBu
a
t1: residence time reactor 1.
t2: residence time reactor 2.
Supplementary data
b
Supplementary data associated with this article can be found, in
achieved with DBU and 1,4-dioxane at 80 °C. After as little as
10 min, the reaction was complete, without solid formation. Figure
2 depicts the instrument set-up to carry out the process in the flow
system.
References and notes
1. (a) Baxendale, I. R.; Ley, S. V.. In Seeberger, P. H., Blume, T., Eds.; New Avenues
to Efficient Synthesis—Emerging Technologies; Springer: Berlin, Heidelberg,
2007; Vol. 3, pp 151–185; (b) Yoshida, J.; Nagaki, A.; Yamada, T. Chem. Eur. J.
2008, 14, 7450–7459; (c) Baxendale, I. R.; Hayward, J. J.; Lanners, S.; Ley, S. V. In
Microreactors in Organic Synthesis and Catalysis; Wirth, T., Ed.; Wiley-VCH:
Weinheim, 2008; pp 84–122. Chapter 42; (d) Hodge, P. Curr. Opin. Chem. Biol.
2003, 7, 362–373; (e) Mason, B. P.; Price, K. E.; Steinbacher, J. L.; Bogdan, A. R.;
McQuade, D. T. Chem. Rev. 2007, 107, 2300–2318.
2. For recent applications: (a) Baumann, M.; Baxendale, I. R.; Ley, S. V. Synlett
2008, 2111–2114; (b) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.;
Smith, C. D. Org. Biomol. Chem. 2008, 6, 1577–1586; (c) Baumann, M.;
Baxendale, I. R.; Nikbin, N.; Ley, S. V.; Smith, C. D. Org. Biomol. Chem. 2008, 6,
1587–1593; (d) Baxendale, I. R.; Ley, S. V.; Smith, C. D.; Tamborini, L.; Voica, A.-
F. J. Comb. Chem. 2008, 10, 851–857; (e) Baxendale, I. R.; Ley, S. V.; Mansfield, A.
C.; Smith, C. D. Angew. Chem., Int. Ed. 2009, 48, 4017–4021; (f) Baumann, M.;
Baxendale, I. R.; Martin, L. J.; Ley, S. V. Tetrahedron 2009, 65, 6611–6625; (g)
Baxendale, I. R.; Schou, S. C.; Sedelmeier, J.; Ley, S. V. Chem. Eur. J. 2010, 10, 89–
94; (h) Hopkin, M. D.; Baxendale, I. R.; Ley, S. V. Chem. Commun. 2010, 2450–
2452; (i) Tamborini, L.; Conti, P.; Pinto, A.; De Micheli, C. Tetrahedron:
Asymmetry 2010, 21, 222–225.
3. Boyer, J. H.; Moriarty, R.; de Darwent, B.; Smith, P. A. S. Chem. Eng. News 1964,
42, 6–9.
4. For a review see: (a) Biffin, M. E. C.; Miller, J.; Paul, D. B. In The Chemistry of
Azido Group; Patai, S., Ed.; Wiley: New York, 1971; pp 147–176; (b) Takahashi,
M.; Suga, D. Synthesis 1998, 7, 986–990.
5. (a) Urben, P. G. In Bretherick’s Handbook of Reactive Chemical Hazards, 6th ed.;
Butterworth Heinemann Ltd: Oxford, 1999; Vol. 2.; (b) Ullrich, R.; Grewer, T.
Thermochim. Acta 1993, 225, 201–211.
6. Barral, K.; Moorhouse, A. D.; Moses, J. E. Org. Lett. 2007, 9, 1809–1811.
7. Malet-Sanz, L.; Madrzak, J.; Holvey, R. S.; Underwood, T. Tetrahedron Lett. 2009,
50, 7263–7267. and int. reference.
Stream 1, containing TMSN3 in acetonitrile and Stream 2, con-
taining the aniline in acetonitrile, were mixed through a T-piece
and flowed into the first loop reactor, with an internal volume of
10 ml, pre-heated at 50 °C. The reactor output was mixed to Stream
3, the b-ketoester and DBU solution in 1,4-dioxane and flowed into
a second loop reactor with an internal volume of 10 ml pre-heated
to 80 °C. The system was fitted with a back pressure regulator (Bpr)
of 250 psi. The collected stream was quenched with a saturated
solution of NH4Cl, ready for the work-up procedure. After extrac-
tion and purification by flash chromatography, the 1,2,3-triazoles
were isolated (Fig. 3). Taking advantage of some initial trials, the
flows were adjusted in order to have a residence time of 20–
30 min in the first reactor (arylazide formation). Consequently,
the second residence time resulted in being between 13 min and
19 min.11 These reactor set-ups were deemed necessary in the light
of the variable reaction time for the second step.
We ascribed this variability to the ring substitution: anilines with
electron-donating groups (EDG) needed a residence time almost
double for the cyclization step. In fact, the cyclization reaction im-
plied, at first, the b-ketoester enolate attack to the azide in a way that
the starting electron-rich anilines corresponded to a slightly lower
reactivity than electron-poor anilines (entries 2 and 3).
We were delighted to find out that the cycloaddition step was
completely regioselective and the yields of the products were good
to excellent, considering they were calculated on isolated products
over two steps (Table 1). We extended the substitution pattern of
the desired triazoles, by reacting the 4-CF3-aniline with differently
substituted acetoacetate (entries 7–9): in the case of ethyl trifluo-
roacetoacetate and ethyl tert-butylacetoacetate the second step
took longer, probably for either electronic or steric effects.
In conclusion, we set up a reliable procedure for a two steps-
synthesis of aryl 1,2,3-triazoles from the corresponding anilines
8. Bogdan, A. R.; Sach, N. W. Adv. Synth. Catal. 2009, 351, 849–854.
9. (a) Da Settimo, A.; Livi, O.; Biagi, G.; Primofiore, G.; Masoni, G. Farmaco Ed. Sc.
1982, 37, 728–739; (b) Da Settimo, A.; Livi, O.; Ferrarini, P. L.; Tonetti, I.;
Ciabattini, E. Farmaco Ed. Sc. 1979, 34, 371–382; (c) Livi, O.; Ferrarini, P. L.;
Tonetti, I.; Smaldone, F.; Zefola, G. Farmaco Ed. Sc. 1979, 34, 217–228.
10. Vapourtec R2+/R2/R4 units are available from Vapourtec Ltd, Place Farm,
11. Reactions were first tried on a batch mode to determine the residence time for
the cyclization step. For all the compounds reported in Table 1 the formation of
the azide was completed in 20 min. A prolonged reaction time (30 min) had no
impact on the purity of the intermediate azide, at least by NMR.
12. See Supplementary data general procedures and compounds’ characterization.