Continuous flow photolysis of aryl azides: Preparation of 3H-azepinones

Article abstract of DOI:10.3762/bjoc.7.129

Photolysis of aryl azides to give nitrenes, and their subsequent rearrangement in the presence of water to give 3H-azepinones, is performed in continuous flow in a photoreactor constructed of fluorinated ethylene polymer (FEP) tubing. Fine tuning of the reaction conditions using the flow reactor allowed minimization of secondary photochemical reactions.

Full text of DOI:10.3762/bjoc.7.129

Continuous flow photolysis of aryl azides:
Preparation of 3H-azepinones
Farhan R. Bou-Hamdan‡, François Lévesque‡, Alexander G. O'Brien‡
and Peter H. Seeberger*
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1124–1129.
Max Planck Institute of Colloids and Interfaces, Department of
Biomolecular Systems, Am Mühlenberg 1, 14476 Potsdam, Germany
and Freie Universität Berlin, Institute for Chemistry and Biochemistry,
Arnimallee 22, 14195 Berlin, Germany
doi:10.3762/bjoc.7.129
Received: 31 May 2011
Accepted: 02 August 2011
Published: 17 August 2011
Email:
Peter H. Seeberger* - peter.seeberger@mpikg.mpg.de
This article is part of the Thematic Series "Chemistry in flow systems II".
Guest Editor: A. Kirschning
* Corresponding author ‡ Equal contributors
Keywords:
© 2011 Bou-Hamdan et al; licensee Beilstein-Institut.
License and terms: see end of document.
azepinones; azides; continuous flow; nitrenes; photochemistry
Abstract
Photolysis of aryl azides to give nitrenes, and their subsequent rearrangement in the presence of water to give 3H-azepinones, is
performed in continuous flow in a photoreactor constructed of fluorinated ethylene polymer (FEP) tubing. Fine tuning of the reac-
tion conditions using the flow reactor allowed minimization of secondary photochemical reactions.
Findings
Although photochemical rearrangements are an important class tion conditions and the continuous removal of products inherent
of reactions for heterocycle synthesis [1,2], their use is often in flow systems can offer improved yields and selectivities
hindered by technical difficulties, both in research laboratories [8,15].
and in industry, particularly when large quantities of material
are required [3,4]. In response, there has been a recent growth in Nitrenes generated by aryl azide photolysis are important tools,
the application of continuous flow techniques [5-7] for the both for preparative heterocycle synthesis [16,17] and for
deployment of photochemical reactions [8-13]. As, from the photoaffinity labeling of proteins [18-20]. The photolysis of
Beer–Lambert law, the intensity of light decreases exponen- aryl azide 1 [21], a well-studied and widely used reaction [22-
tially with increasing distance from the light source, minimiza- 30], generates the singlet aryl nitrene intermediate 12
tion of the path length in a continuous flow photoreactor (Scheme 1). Ring expansion of 12, via 2H-azirine 3, affords
ensures efficient and uniform irradiation of the sample [14], and didehydroazepine 4, which can be trapped by variety of nucleo-
scaling up is simple to achieve by running the reactor over an philes to provide the corresponding azepine 5. Alternatively,
extended period. Additionally, the precise control of the reac- intersystem crossing (ISC) of 12 gives rise to 32, which can
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Beilstein J. Org. Chem. 2011, 7, 1124–1129.
dimerize to form diazo compound 6. Performing the reaction in tubing was observed, which was attributed to the poor solu-
the presence of water typically affords 3H-azepinone 7 [31-34], bility of the substrate in water. Running the reaction with a
a moiety present in natural products [35,36] and in azepinone- reduced water content (THF/H2O, 4:3) obviated this problem
derived pharmaceuticals [37,38]. Despite the importance of and resulted in a 62% conversion of the starting azide to
these 7-membered nitrogen-containing heterocycles, there 3H-azepinone 9a, after a residence time of 30 min (Table 1,
remain few methods for their preparation [39-44]. Overall, aryl entry 2). Further reduction in the water content had a detri-
azides, which are simple to prepare from the corresponding mental effect on the conversion. An inverse dependence of the
aniline derivative, are convenient precursors for the synthesis of conversion on substrate concentration was observed (Table 1).
azepine derivatives. However, the utility of the process is offset Although the highest conversion was observed at 0.015 M,
by the long reaction times required and by the low yields arising higher productivity was obtained at 0.030 M (0.38 mmol h−1).
from poor selectivity and decomposition of the reaction mix- Representing the best balance between conversion and produc-
ture. We report herein the development of a continuous flow tivity, 0.030 M was selected as the optimum concentration for
variant of the process and show how the reaction can be further further optimization. The use of other polar, aprotic, water-
optimized using a flow system [45,46].
miscible solvents for the reaction was explored. Maintaining a
residence time of 30 min, no significant change in conversion
For this study a 14 mL photoreactor was used, constructed from was observed upon replacing THF with DME or 1,4-dioxane;
fluorinated ethylene polymer (FEP) tubing, wrapped around a decreased conversion (22%) was observed with acetonitrile as
450 W medium pressure Hg lamp, surrounded by a cooling the organic solvent.
jacket and Pyrex filter (see Supporting Information File 1).
Continuous flow photochemical reactors based upon FEP
tubing are simple to construct and are seeing increasing use in
photochemical synthesis [47-49]. A recirculating cryostat main-
tained an apparatus temperature of 25 °C for all experiments,
and a back pressure regulator (6.9 bar) was used to suppress the
formation of a separate gaseous phase from the evolved
nitrogen. THF and water were pumped simultaneously into the
Scheme 2: Optimisation of the photolysis of aryl azide 8a.
reactor at the specified rates through a commercially available
Vapourtec R2 pump, [50] and mixed by a PTFE T-mixer.
Increasing the residence time improved the conversion of 8a
Aryl azide 8a bearing a p-methyl ester substituent, prepared by (Figure 1), although this was accompanied by increased
treatment of the corresponding aniline with NaNO2/HCl–NaN3, concomitant formation of the byproduct 10. Lactam 10 was
was selected for initial optimization of the reaction (Scheme 2). obtained upon re-exposure of purified 9a to the reaction condi-
During preliminary experiments under the conditions reported tions and is believed to result from photochemical disrotatory
by Smalley (0.05 M in THF/H2O, 1:1) [31], blockage of the electrocyclization of the 3H-azepinone diene moiety [51-54]
Scheme 1: Products of aryl azide photolysis.
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Beilstein J. Org. Chem. 2011, 7, 1124–1129.
solution of 8a in THF/H2O 4:3, giving analytically pure 9a in
45% yield. Only traces of the diazo product were observed in
the NMR spectrum of the crude mixture.
Table 1: Effect of aryl azide concentration on conversion.
Entry
[8a] (M)
Conversion (%)a
Isolated Yield (%)
1
2
3
4
0.100
0.050
0.030
0.015
39
62
78
90
29
35
45
48
A variety of other 3H-azepinones was prepared in moderate to
good yields under the optimized reaction conditions (Scheme 4,
Table 2). Residual starting material was easily recovered by
silica column chromatography. Rearrangements of aryl azides
bearing electron withdrawing substituents are better repre-
sented in the literature than their electron donating congeners
[31], and this was reflected in our compound selection. Methyl
aBy 1H NMR analysis of the crude product mixture after a residence
time of 30 min.
(Scheme 3). Instead of making a direct comparison between 2-azidobenzoate (8b), the corresponding acid 8c and dimethyl
reaction progress in batch and flow, the effects of longer resi- 2-azidoterephthalate (8d) each reacted favorably compared to
dence times reported for batch photolysis were evaluated in a the model substrate 8a. We were particularly interested in the
stopped-flow experiment by irradiating a solution of 8a for preparation of 5-aryl-3H-azepinones 9e–g, examples of which
3.5 h in the same FEP photoreactor (Figure 1). Analysis of the have seen recent interest as γ-secretase inhibitors for the treat-
composition of the crude mixture showed significantly ment of Alzheimer’s disease [37]. Photolysis of methyl 2-azido-
increased conversion of 9a to 10 accompanied by a slight 5-phenylbenzoate 8e under the optimized conditions afforded a
increase in the proportion of the starting material 8a, which complex mixture of products. Upon shortening the residence
likely reflects decomposition of both of the reaction products. time to 15 min, 3-methoxycarbonyl-5-phenyl-3H-azepinone
Overall, a residence time of 30 min was selected for a 0.030 M (9e) was obtained in 35% yield. While both the corresponding
acid 8f and 4-azidobiphenyl 8g decomposed upon photolysis,
8h gave the corresponding 5-chloro-3H-azepinone 9h, bearing a
handle for further functionalization. To explore the preparation
of bicyclic products, we studied the photolysis of 3-azidoquino-
line (8i) to give the corresponding benzodiazepinone. Although
the substrate decomposed under the original optimized condi-
tions, reaction of 8i in NaOMe–MeOH [55,56] afforded 9i in
good yield. Although yields were similar to those reported for
batch processes [31,34,56], performing the reaction in contin-
uous flow allows simple scaleup.
Figure 1: Relationship between residence time and relative compos-
ition of the crude reaction mixture.
Scheme 4: General conditions for the photolysis of aryl azides in
continuous flow.
In summary, the photochemical syntheses of 3H-azepinones and
related azepines were performed and optimized in continuous
flow through a photoreactor made from FEP tubing. Secondary
photochemical reactions were minimized through careful
control of the residence time. Although isolated yields were
variable, a variety of aryl azides bearing electron withdrawing
substituents underwent photolysis in good yield. Modification
Scheme 3: Preparation of side product 10.
of the procedure allowed the preparation of benzodiazepine 9i.
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Beilstein J. Org. Chem. 2011, 7, 1124–1129.
Table 2: 3H-azepinone derivatives prepared by photolysis of aryl azides in continuous flow.
Entry
Substrate
Product
Yield (%)a
1
8a
9a
45 (51)
2
3
8b
8c
9b
9c
75 (77)
50 (62)
4
8d
9d
74 (80)
5b
8e
8f
9e
9f
35 (47)
6
0
0
7
8g
9g
8
8h
8i
9h
9i
70
9c
44d
aYields in parentheses are based on recovered starting material. bThe residence time was reduced to 15 min. cThe photolysis was performed with a
0.030 M solution of 8i in 1.0 M NaOMe–MeOH. dDetermined by 1H NMR of the crude mixture.
1127

Beilstein J. Org. Chem. 2011, 7, 1124–1129.
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Supporting Information
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Supporting Information File 1
Description of the flow reactor setup, experimental
procedures and spectroscopic data of all compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-129-S1.pdf]
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Acknowledgements
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We gratefully thank the Max Planck Society, AstraZeneca
R&D, Macclesfield, UK and Fonds de Recherche sur la Nature
et les Technologies, Québec (postdoctoral scholarship to F. L.)
for generous funding.
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