[3 + 2]-Cycloadditions of nitrile ylides after photoactivion of vinyl azides under flow conditions

Article abstract of DOI:10.3762/bjoc.9.201

The photodenitrogenation of vinyl azides to 2H-azirines by using a photoflow reactor is reported and compared with thermal formation of 2H-azirines. Photochemically, the ring of the 2H-azirines was opened to yield the nitrile ylides, which underwent a [3 + 2]-cycloaddition with 1,3-dipolarophiles. When diisopropyl azodicarboxylate serves as the dipolarophile, 1,3,4-triazoles become directly accessible starting from the corresponding vinyl azide.

Full text of DOI:10.3762/bjoc.9.201

[3 + 2]-Cycloadditions of nitrile ylides after
photoactivation of vinyl azides under flow conditions
Stephan Cludius-Brandt, Lukas Kupracz and Andreas Kirschning*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 1745–1750.
Institute of Organic Chemistry, Leibniz University Hannover,
Schneiderberg 1b, 30167 Hannover, Germany
doi:10.3762/bjoc.9.201
Received: 23 June 2013
Accepted: 22 July 2013
Published: 26 August 2013
Email:
Andreas Kirschning* - andreas.kirschning@oci.uni-hannover.de
* Corresponding author
This article is part of the Thematic Series "Chemistry in flow systems III".
Associate Editor: M. Rueping
Keywords:
azirines; cycloaddition; flow chemistry; flow reactors; inductive
heating; nitrile ylides; photochemistry; vinyl azides
© 2013 Cludius-Brandt et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
The photodenitrogenation of vinyl azides to 2H-azirines by using a photoflow reactor is reported and compared with thermal forma-
tion of 2H-azirines. Photochemically, the ring of the 2H-azirines was opened to yield the nitrile ylides, which underwent a
[3 + 2]-cycloaddition with 1,3-dipolarophiles. When diisopropyl azodicarboxylate serves as the dipolarophile, 1,3,4-triazoles
become directly accessible starting from the corresponding vinyl azide.
Introduction
Recently, photochemistry has seen a renaissance despite the fact to nitriles, b) the dehydrochlorination of imidoyl chlorides, and
that under batch conditions specialized reaction vessels are c) the photochemical ring opening of strained 2H-azirines 2
required, in which the light source is placed in the centre of the [2-5]. The latter route can be initiated by the photoinduced acti-
reaction mixture: Technically this setup is difficult to control vation of vinyl azides 1, which gives rise to 2H-azirines 2 via
for large scale industrial applications because the issue of trans- vinyl nitrenes after the loss of molecular nitrogen and subse-
ferring a substantial amount of heat has to be addressed. On the quent ring-opening under photochemical conditions to provide
other hand, photochemistry allows to perform many transforma- the nitrile ylides 3 (Scheme 1). For recent examples for the use
tions that are hardly possible under thermal conditions. This of azirines in organic syntheses please refer to [6-15]. Recently,
includes photocatalytic reactions that have seen an immense the Seeberger group has published a flow protocol on the photo-
interest lately [1].
chemical degradation of aryl azides and the subsequent forma-
tion of 3H-azepinones [16].
Nitrile ylides 3 are 1,3-dipoles that have served for the prepar-
ation of different five-membered N-heterocycles in 1,3-dipolar With the emergence of continuous processes involving minia-
cycloaddition reactions. They are commonly formed through turized flow reactors in organic-chemistry laboratories, photo-
three routes which are a) the addition of electrophilic carbenes chemistry has found a wider interest in the chemical commu-
1745

Beilstein J. Org. Chem. 2013, 9, 1745–1750.
Scheme 1: Formation of azirines 2 from vinyl azides 1, photoinduced ring-opening to the nitrile ylides 3, and 1,3-dipolar cycloaddition to the penta-
cyclic N-heterocycles 5.
nity [17,18]. Particularly large-scale photochemical syntheses Results and Discussion
can simply be achieved by numbering-up miniaturized flow As the generation of azirines 2 can be conducted under thermal
reactors in a parallel set-up. Uniform irradiation can be guaran- as well as under photochemical conditions, we first evaluated
teed when the penetration depth of light is kept small both processes with respect to their suitability under flow condi-
(100–1000 µm). Furthermore, the production rate of a photo- tions (Scheme 3). The thermal reaction was studied in the pres-
chemical flow process can be controlled by varying the irradi- ence of an external oscillating magnetic field of medium
ation power, or by increasing or decreasing of the flow rate. frequency (15–25 kHz). The best reactor set-up for inducing
Finally, miniaturized flow reactors have high heat-transfer coef- heat in a medium frequency field was found to be a steel capil-
ficients so that the cooling of the photochemical process can lary reactor (volume: 1.0 mL, inner diameter = 1.0 mm) with a
efficiently be achieved.
steel core, which is encased by the inductor. An internal pres-
sure of at least 250 psi allows transformations well above the
These facts led us to initiate an investigation on the photochem- boiling point of the solvent, and this was secured by placing a
ical activation of vinyl azides and the trapping of the intermedi- backpressure regulator behind the flow system. In contrast, the
ate nitrile ylides 3 [19] by different dipolarophiles exploiting photochemical flow-reactor was composed of a Teflon (FEP)
the advantages of photo flow-chemistry [20,21]. Here, we tubing (volume: 3.0 mL, inner diameter = 0.75 mm) and
report on the first photochemical transformation of vinyl azides a Pyrex filter. These were placed onto the water-cooled
to pyrrole derivatives under continuous-flow conditions.
quartz immersion well (type UV-RS-1, Heraeus) equipped
with a medium-pressure mercury lamp (type TQ 150,
Only recently, we reported the two-step preparation of vinyl λ = 190–600 nm). The reaction mixture was fed into the tubing
azides 1 in mircrostructured flow reactors starting from alkenes by using a pump and collected in a flask after having passed
6, using the solid-phase bound iodine azide transfer-reagent 7 through the reactor.
followed by HI elimination using immobilized DBU as fixed
bed material (Scheme 2) [9,22,23]. All vinyl azides used in this In essence 2H-azirines can be prepared continuously in good
report were prepared by azido-iodination of the corresponding yields under thermal as well as under photochemical conditions
alkenes followed by DBU-mediated HI elimination (for details in appropriate flow reactor devices (Table 1). Complete conver-
see the Supporting Information File 1).
sion was achieved at 190 °C after 1 min in dichloromethane. At
higher temperatures as well as at reduced flow rates the amount
of decomposition products increased. The photochemical trans-
formation required longer reaction times, but the products were
formed under thermally mild conditions in improved yields and
with higher purity. Therefore, we decided to continue our
studies with the photochemical flow-reactor and to extend these
studies to the photoinduced nitrile ylide formation and the
1,3-dipolar cycloaddition. We initially chose to photolyze
methyl 4-(1-azidovinyl)benzoate (1a) in the presence of acrylo-
nitrile (4a) (Table 2). A solution of 1a and 4a in the respective
solvent was passed through the photochemical flow-reactor
with 5.5 mL volume and a pyrex filter.
Scheme 2: Solid-phase assisted synthesis of vinyl azides 1 from
alkenes 6 under flow conditions [9].
1746

Beilstein J. Org. Chem. 2013, 9, 1745–1750.
Scheme 3: Schematic presentation of the flow set-up for the synthesis of 2H-azirines 2 under inductive heating (IH, left) and photochemical (hν, right)
conditions.
Table 1: Continuous synthesis of 2H-azirines 2 under inductive heating and photochemical conditions. The experiments were conducted at a concen-
tration of 0.05 M.
entry
producta
isolated yield (hν) [%]b,c
isolated yield (IH) [%]c,d
1
97
82
2a
2b
2
90
79
3
4
92
95
72
2d
2g
42e
aPrecursor vinyl azides and 2H-azirines are found in Scheme 4; bphoto flow-conditions: toluene, 10 min (residence time), rt; cisolated yields are given;
dinductive heating conditions: CH2Cl2, 1 min (residence time), 190 °C; ealthough the transformation was very rapid, we encountered substantial
decomposition under thermal conditions.
1747

Beilstein J. Org. Chem. 2013, 9, 1745–1750.
Table 2: Optimization of the photolysis of vinyl azide 1a and trapping of nitrile ylide with acrylonitrile 4a under flow conditions.
entry
concentration of 1a [M]
ratio (1a:4a)
solvent
flow rate [mL/min]
isolated yield [%] of 5a
1
2
0.025
0.025
0.025
0.025
0.012
0.012
0.012
0.05
1:10
1:10
1:10
1:10
1:10
1:10
1:10
1:10
1:5
toluene
benzene
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
0.05
0.05
0.05
0.1
-
-
3
46
53
82
74
68
96
71
65
4
5
0.05
0.1
6
7
0.2
8
0.05
0.05
0.05
9
0.05
10
0.05
1:2
Scheme 4: Photoinduced cycloadditions of vinyl azides 1a–f and electron-deficient alkenes 4a–d. All experiments were conducted at room tempera-
ture in a photochemical flow-reactor (see above) using Teflon (FEP) tubing (volume: 5.5 mL, inner diameter = 0.75 mm) at a concentration of 0.05 M
in CH3CN; isolated yields are given.
1748

Beilstein J. Org. Chem. 2013, 9, 1745–1750.
Test reactions conducted either in benzene or in toluene resulted
exclusively in the formation of the corresponding 2H-azirine 2a
in yields up to 95%, while no formation of the cycloaddition
product was encountered (Table 2; entries 1 and 2). 2a could
easily be identified by the signal at 1.88 ppm in the 1H NMR
spectrum, which is characteristic for the methylene group of the
newly formed 3-membered ring. This signal corresponds to the
carbon signal at 20.2 ppm in the 13C NMR spectrum. In
contrast, acetonitrile turned out to be the solvent of choice and
methyl 4-(4-cyano-4,5-dihydro-3H-pyrrol-2-yl)benzoate (5a)
was isolated in 46% yield (Table 2, entry 3). By optimizing the
reaction conditions with respect to concentration, flow rate, and
ratio of starting materials (Table 2, entries 4–10), we found that
a concentration of 0.05 mol/L for azide 1a and a flow rate of
0.05 mL/min in the presence of a tenfold access of 4a provided
Scheme 5: Photoinduced cycloaddtion of vinyl azide 1c and diiso-
propyl azodicarboxylate (4e). The experiment was conducted at room
temperature in a photochemical flow-reactor (see above) using Teflon
(FEP) tubing (volume: 5.5 mL, inner diameter = 0.75 mm) at a concen-
tration of 0.05 M in CH3CN.
the cycloaddition product 5a in 96% yield as a single regioiso- Alternatively, the in-situ generated nitrile ylide can be trapped
mer (Table 2, entry 8). Remarkably, after removal of the solvent intramolecularly by a nucleophile such as a hydroxy group [25].
under reduced pressure it was not necessary to further purify the This is demonstrated by the photochemical degradation of vinyl
product.
azide 1g which yielded 2,5-dihydrooxazole 9 in 76% yield
(c = 0.01 M, flow rate = 0.02 mL/min) under flow conditions
Next the scope of the photo-induced 1,3-dipolar cycloaddition (Scheme 7). In this case, benzene turned out to be the solvent of
was examined. With the optimized flow-protocol in hand we choice.
were able to synthesize a variety of dihydropyrroles (5a–5i)
(Scheme 4). The electronic properties of the aromatic ring,
which depend on the substituents have no prinicipal influence
on the outcome of this cascade reaction. Only the pyridyl
substituent in vinyl azide 1e provided dihydropyrrole 5e in
unsatisfactory yield. The relative stereochemistry of 5i was
determined by comparison with literature data [24].
To our delight, this flow protocol also allowed us to prepare
2,3-dihydro-1H-1,2,4-triazole 5j in good yield using diiso-
propyl azodicarboxylate (DIAD, 4e) as the dipolarophile
(Scheme 5).
Additionally, we found that even electron-deficient alkynes
such as 4f can serve as dipolarophiles in these reactions
Scheme 7: Formation of 2,5-dihydrooxazole 9 starting from vinyl azide
1g under flow conditions (c = 0.01 M, flow rate = 0.02 mL/min).
(Scheme 6). However, the resulting pyrrole 5k could only be
isolated in 26% yield.
Scheme 6: Photoinduced cycloaddtion of vinyl azide 1b and alkyne 4f. The experiment was conducted at room temperature in a photochemical flow-
reactor (see above) using Teflon (FEP) tubing (volume: 5.5 mL, inner diameter = 0.75 mm) at a concentration of 0.05 M in CH3CN.
1749

Beilstein J. Org. Chem. 2013, 9, 1745–1750.
9. Kupracz, L.; Hartwig, J.; Wegner, J.; Ceylan, S.; Kirschning, A.
Beilstein J. Org. Chem. 2011, 7, 1441–1448. doi:10.3762/bjoc.7.168
10.Candito, D. A.; Lautens, M. Org. Lett. 2010, 12, 3312–3315.
doi:10.1021/ol100975b
Conclusion
In summary, we developed a protocol for the one-step photo-
chemical formation of dihydropyrroles under flow conditions
starting from aromatic vinyl azides and activated alkenes. This
transformation was achieved with a photochemical flow reactor
and most likely proceeds via the respective 2H-azirines by
photoinduced in-situ formation and subsequent heterolytic ring
opening. The resulting 1,3-dipole is trapped directly with elec-
tron-deficient alkenes to form the [2 + 3] cycloaddition prod-
ucts. With this method, we were able to prepare a variety of
dihydropyrroles. The electronic properties of the aromatic ring
were of little importance for the principal outcome of the reac-
tion. Notable, azodicarboxylates and electron deficient alkynes
were employed for the first time which provided a 1,2,4-tri-
azole and a pyrrole, respectively. Future work should cover a
further generalization of this flow protocol along with tele-
scoping it with vinyl azide formation.
11.Novikov, M. S.; Amer, A. A.; Khlebnikov, A. F. Tetrahedron Lett. 2006,
47, 639–642. doi:10.1016/j.tetlet.2005.11.131
12.Alves, M. J.; Fortes, A. G.; Costa, F. T. Tetrahedron 2006, 62,
3095–3102. doi:10.1016/j.tet.2006.01.035
13.Palacios, F.; de Retana, A. M. O.; Gil, J. I.; Alonso, J. M. Tetrahedron
2004, 60, 8937–8947. doi:10.1016/j.tet.2004.07.013
14.Timén, A. S.; Somfai, P. J. Org. Chem. 2003, 68, 9958–9963.
doi:10.1021/jo0352326
15.Pinho e Melo, T. M. V. D.; Cardoso, A. L.; Gomes, C. S. B.;
Rocha Gonsalves, A. M. d’A. Tetrahedron Lett. 2003, 44, 6313–6315.
doi:10.1016/S0040-4039(03)01534-X
16.Bou-Hamdan, F. R.; Lévesque, F.; O'Brien, A. G.; Seeberger, P. H.
Beilstein J. Org. Chem. 2011, 7, 1124–1129. doi:10.3762/bjoc.7.129
17.Oelgemöller, M.; Shvydkiv, O. Molecules 2011, 16, 7522–7550.
doi:10.3390/molecules16097522
18.Matsushita, Y.; Ichimura, T.; Ohba, N.; Kumada, S.; Sakeda, K.;
Suzuki, T.; Tanibata, H.; Murata, T. Pure Appl. Chem. 2007, 79,
1959–1968. doi:10.1351/pac200779111959
19.Escolano, C.; Duque, M. D.; Vázquez, S. Curr. Org. Chem. 2007, 11,
741–772. doi:10.2174/138527207780831710
Supporting Information
20.Knowles, J. P.; Elliott, L. D.; Booker-Milburn, K. I.
Beilstein J. Org. Chem. 2012, 8, 2025–2052. doi:10.3762/bjoc.8.229
21.Hook, B. D. A.; Dohle, W.; Hirst, P. R.; Pickworth, M.; Berry, M. B.;
Booker-Milburn, K. I. J. Org. Chem. 2005, 70, 7558–7564.
doi:10.1021/jo050705p
Supporting Information File 1
Descriptions on the synthesis and analyses of vinyl azides
and as well as on cycloaddition products.
[http://www.beilstein-journals.org/bjoc/bjoc/content/
supplementary/1860-5397-9-201-S1.pdf]
22.Kirschning, A.; Hashem, Md. A.; Monenschein, H.; Rose, L.;
Schöning, K.-U. J. Org. Chem. 1999, 64, 6522–6526.
doi:10.1021/jo990478p
23.Kirschning, A.; Monenschein, H.; Schmeck, C. Angew. Chem., Int. Ed.
1999, 38, 2594–2596.
Acknowledgements
Financial support from a research fellowship from the German
Research Foundation (DFG) for S. Cludius-Brandt is gratefully
acknowledged.
doi:10.1002/(SICI)1521-3773(19990903)38:17<2594::AID-ANIE2594>3
.0.CO;2-U
24.Tsuge, O.; Ueno, K.; Kanemasa, S.; Yorozu, K. Bull. Chem. Soc. Jpn.
1986, 59, 1809–1824. doi:10.1246/bcsj.59.1809
References
1. Griesbeck, A. G.; Steinwäscher, J.; Reckenthäler, M.; Uhlig, J.
25.Padwa, A.; Rasmussen, J. K.; Tremper, A. J. Am. Chem. Soc. 1976,
98, 2605–2614. doi:10.1021/ja00425a033
Res. Chem. Intermed. 2013, 39, 33–42.
doi:10.1007/s11164-012-0629-3
2. Padwa, A. Adv. Heterocycl. Chem. 2010, 99, 1–31.
doi:10.1016/S0065-2725(10)09901-0
License and Terms
3. Palacios, F.; de Retana, A. M. O.; de Marigorta, E. M.;
de los Santos, J. M. Org. Prep. Proced. Int. 2002, 34, 219–269.
doi:10.1080/00304940209356770
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
4. Palacios, F.; de Retana, A. M. O.; de Marigorta, E. M.;
de los Santos, J. M. Eur. J. Org. Chem. 2001, 2401–2414.
doi:10.1002/1099-0690(200107)2001:13<2401::AID-EJOC2401>3.0.C
O;2-U
5. Heimgartner, H. Angew. Chem., Int. Ed. 1991, 30, 238–264.
doi:10.1002/anie.199102381
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
6. Loy, N. S. Y.; Singh, A.; Xu, X.; Park, C.-M. Angew. Chem., Int. Ed.
2013, 52, 2212–2216. doi:10.1002/anie.201209301
7. Khlebnikov, A. F.; Novikov, M. S.; Pakalnis, V. V.; Yufit, D. S.
J. Org. Chem. 2011, 76, 9344–9352. doi:10.1021/jo201563b
8. Palacios, F.; de Retana, A. M. O.; del Burgo, A. V. J. Org. Chem. 2011,
76, 9472–9477. doi:10.1021/jo201932m
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.9.201
1750