Photochemistry of ortho -Azidocinnamoyl Derivatives: Facile and Modular Synthesis of 2-Acylated Indoles and 2-Substituted Quinolines under Solvent Control

Article abstract of DOI:10.1055/s-0036-1590861

The light-promoted potential of ortho -azidocinnamoyl compounds is evaluated for heterocycle synthesis. Depending on the nature of the solvent, 2-acylated indoles were obtained under aprotic conditions, whereas the use of a protic medium led to 2-substituted quinolines. The synthetic significance of this metal-free method is that, by simply changing the solvent, the reaction outcome can be directed towards different key heterocyclic scaffolds.

Full text of DOI:10.1055/s-0036-1590861

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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
S. Chaabouni et al.
Letter
Synlett
Photochemistry of ortho-Azidocinnamoyl Derivatives: Facile and
Modular Synthesis of 2-Acylated Indoles and 2-Substituted Quino-
lines under Solvent Control
S. Chaabounia,b,c,1
N. M. Pinkertona,1
S. Abidb
C. Galaupc
S. Chassaing*a
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0
0
0
0-
0
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1
5-
8
4
2
5-
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8
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a Institut des Technologies Avancées en Sciences du Vivant (ITAV), Université
de Toulouse, CNRS, UPS, 1 place Pierre Potier, 31106 Toulouse Cedex 1,
France
stefan.chassaing@itav.fr
b Laboratoire de Chimie Appliquée: HGP, Université de Sfax, Faculté des
Sciences, Sfax 3000, Tunisia
c Laboratoire de Synthèse et Physicochimie de Molécules d’Intérêt Biologique
(SPCMIB), CNRS-UMR5068, Université Paul Sabatier-Toulouse III, 118 route
de Narbonne, 31062 Toulouse Cedex 9, France
Received: 03.05.2017
Accepted after revision: 11.07.2017
Published online: 17.08.2017
In this context, and due to our recent interest in the po-
tential of cinnamoyl derivatives for heterocycle synthesis,10
we herein report a solvent-dependent photochemical, met-
al-free approach for the construction of both 2-acylindole
and 2-substituted quinoline scaffolds, starting from readily
prepared ortho-azidocinnamoyl derivatives 1 as nitrene
sources.
DOI: 10.1055/s-0036-1590861; Art ID: st-2017-d0321-l
Abstract The light-promoted potential of ortho-azidocinnamoyl com-
pounds is evaluated for heterocycle synthesis. Depending on the nature
of the solvent, 2-acylated indoles were obtained under aprotic condi-
tions, whereas the use of a protic medium led to 2-substituted quino-
lines. The synthetic significance of this metal-free method is that, by
simply changing the solvent, the reaction outcome can be directed to-
wards different key heterocyclic scaffolds.
R'
Previous works
R
N
O
H
2
O
Key words photochemistry, azides, indoles, quinolines, nitrenes, sol-
vent effect, rearrangement
m = Cu, Fe, Rh, Ru - Ref. 7
hν - Ref. 8
metal m
or hν
R'
R
N3
R
1
Organic azides are highly valuable building blocks in or-
ganic synthesis.2 Their use as 1,3-dipoles in cycloaddition
reactions has received significant and ever-increasing inter-
est in the last decade, particularly with the advent of the
copper-catalyzed azide-alkyne cycloaddition reaction
(CuAAC) as the archetypal ‘click’ reaction.3 Of further signif-
icance are the photolysis/thermolysis and transition-metal-
mediated decomposition of aryl azides, yielding highly re-
active species, nitrenes and nitrenoids, respectively, that
participate in a large range of organic reactions, including
rearrangement, (cyclo)addition and insertion reactions.4 In
particular, the potential of aryl azides 1 as nitrene/nitrenoid
sources has been exploited for the synthesis of 2-acylated
indoles 25 and 2-substituted quinolines 3,6 two heterocyclic
scaffolds of synthetic and biological relevance (Scheme 1).
Nevertheless, whereas various examples of efficient metal-
mediated approaches have been reported so far in the liter-
ature,7 photochemical approaches8 are much less docu-
mented.9
N
R'
3
m = Cu, Rh, Ru - Ref. 7
hν: no reference
R'
This work
R
O
N
O
H
hν
2
R'
and/or
R
solvent
control
N3
R
1
N
R'
3
Scheme 1 Photo- and metal-mediated approaches towards 2-acylated
indoles 2 and 2-substituted quinolines 3 from 2-azidocinnamoyl deriva-
tives 1
We started our investigations by focusing on the photo-
conversion of azides 1 to indoles 2. To establish the reaction
conditions, an initial series of experiments was conducted
on readily available ortho-azido ethyl cinnamate (1a)11 as
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
S. Chaabouni et al.
Letter
Synlett
the model substrate (Table 1). Based on preliminary work
reported by Gairns et al.,8b irradiation of 1a was performed
in acetonitrile as solvent using a LED-based multi-wave-
length monochromatic light source.12 Four excitation wave-
lengths, λ = 420, 385, 365 and 315 nm, were evaluated and
it was observed that the shorter the wavelength and thus
the more energetic the radiation, the faster the photocon-
version into the expected indole 2a occurred (Table 1, en-
tries 1 and 2 vs entries 3 and 4). Performing the illumina-
tion at λ = 315 nm proved to be the best conditions, both in
terms of conversion and efficiency (Table 1, entry 4). The
molar concentration of 1a also played a significant role with
the highest yield of 2a (68%) obtained at [1a] of 3.2 mM (Ta-
ble 1, entry 4 vs entries 5 and 6). Various solvents were
then screened but without any improvement in efficiency.
The reaction occurred in dichloromethane, ethyl acetate,
cyclohexane and tetrahydrofuran, but was less efficient
than in acetonitrile (Table 1, entries 7–10 vs entry 4). In a
protic solvent such as ethanol, the reaction course drasti-
cally changed, leading to a lower yield of 2a (29%) and to the
formation of a mixture of unidentified products bearing an
aromatic moiety as revealed by 1H NMR analysis of the
crude product (Table 1, entry 11).
With these reaction conditions in hand, we then ex-
plored the scope and limitations of this process for the con-
struction of 2-acylated indoles (Scheme 2). To do so, we
prepared diverse ortho-azidocinnamoyl derivatives (1b–k;
Figure 1), which were subsequently submitted to the opti-
mal photochemical conditions described in the entry 4 of
Table 1. We first examined the influence of the substituents
R1 and R2 on the reaction progress. In the ethyl ester series
(i.e. R1 = OEt), the light-promoted activation of diester 1b
(i.e. R2 = CO2Et) enabled the synthesis of the 2,3-disubstitut-
ed indole 2b but with lower efficiency than the process in-
volving the model monoester 1a, whereas indole 2c was ob-
tained in a similar yield starting from the 2-methylated de-
rivative 1c. Changing from monoester 1a (i.e. R1 = OEt,
R2 = H) to its monoacetylated analogue 1d (i.e. R1 = Me, R2 =
H) resulted in a net decrease of the efficiency, with only a
29% yield of the 2-acetylated indole 2d being obtained.
However, 2,3-diacylated indoles 2e,f were obtained in the
same efficient way as for their diester equivalent 2b.
R1
R2
R3
R3'
1a
1b
1c
1d
OEt
OEt
OEt
Me
H
CO2Et
Me
H
H
H
H
H
H
H
H
Table 1 Screening of the Reaction Conditions for the Photoconversion
of Ethyl 3-(2-Azidophenyl)acrylate (1a) to Ethyl 1H-Indole-2-carboxylate
(2a)a
H
R3'
R3
COR1
1e
1f
Me
OEt
OEt
OEt
OEt
COMe
CO2Et
H
H
H
H
H
H
H
R2
N3
1g
1h
1i
CF3
NMe2
H
1a–k
hν
H
CO2Et
CO2Et
CO2Et OMe OMe
H
solvent, rt
N
N3
1j
Me
Me
COMe CF3
COMe NMe2
H
H
H
1a
2a
1k
[2a] (mM) Time (h)b Yield (%)c
Figure 1 Structures of ortho-azidocinnamoyl derivatives 1a–k
Entry
Solvent
λ (nm)
1
2
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
CH2Cl2
EtOAc
C6H12
THF
420
385
365
315
315
315
315
315
315
315
315
3.2
3.2
3.2
3.2
6.4
1.6
3.2
3.2
3.2
3.2
3.2
3
52
49
54
68
42
56
62
59
58
52
29d
3
Azides 1g–k bearing various aryl substitution patterns
were then evaluated as possible substrates (Scheme 2). Ex-
posure of 1g–k to our illumination conditions provided the
expected indoles 2g–k in poor to good yields. Interestingly,
the method proved effective for the facile synthesis of mo-
no- to highly substituted scaffolds such as indoles 2i–k.
Nevertheless, the obtained results revealed contrasting re-
sults regarding electronic effects, as illustrated by the pro-
cess efficiency of the series 2a,g,h in relation to the series
2e,j,k. It is noteworthy that analyses of crude mixtures re-
sulting from all these reactions proved clean with the de-
sired indole 2 as the only aromatic photoproduct, thus sim-
plifying the column purification.13
Intrigued by the result obtained in EtOH (Table 1, entry
11), we decided to study in more detail the photochemical
behavior of azides 1 under protic conditions. The readily ac-
cessible azide 1e was chosen as the model substrate for this
study (Table 2). This choice was motivated by the fact that
1e previously was a suitable substrate for indole synthesis
(Scheme 2), and by our hypothesis that 1e could form a
3
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
4
5
6
7
8
9
10
11
EtOH
a Reactions were run in a quartz tube with 1a under argon using a multi-
wavelength monochromatic bench-top light source.12
b Reaction time corresponding to complete conversion, as revealed by TLC
and 1H NMR analysis of the crude product.
c 1H NMR yields were determined with 1,3,5-trimethylbenzene added after
photolysis as internal standard.
d Formation of unidentified aromatic by-products was observed.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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S. Chaabouni et al.
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Table 2 Screening of Reaction Conditions for the Photoconversion of
3-(2-Azidobenzylidene)pentan-2,4-dione (1e)a
R2
COR1
R3
Me
O
N
H
hν
315 nm
COR1
O
or
R3
COR1
R2
R2
MeCN
N3
N
H
Me
rt, 1.5 h
1a–k
R1
hν
2e
COMe
COMe
N
or
H
O
solvent, rt
2a–j
N3
Me
1e
H
CO2Et
Me
CO2Et
N
Me
CO2Et
CO2Et
N
H
3e
N
N
H
H
68%
H
44%
62%
2a
2b
2c
Me
Entry
Solvent
Ratio 2e:3eb
Yield of 3e (%)c
Me
O
O
O
e
1
2
3
4
5
6
7
8
9
MeCNd
EtOHd
EtOHf
H2Of
100:0
55:45
53:47
29:71
41:59
48:52
37:63
0:100g
0:100g
–
O
27
37
40
46
40
45
30
16
CO2Et
N
H
Me
N
N
H
Me
H
2d 29%
2e 56%
2f 43%
CO2Et
CO2Et
EtOH–H2O (1:1)f
EtOH–H2O (2:1)f
EtOH–H2O (1:2)f
AcOH–H2O 1:4f
AcOH–H2O (4:1)f
H
H
MeO
MeO
CO2Et
Me
CO2Et
N
N
H
N
F3C
Me2N
O
H
H
2g 63%
2h 27%
2i 63%
Me
O
O
O
a Reactions were run in a quartz tube with 1e under argon ([1e] = 3.2 mM).
b Ratio was determined by 1H NMR analysis of the crude product.
c 1H NMR yields were determined with 1,3,5-trimethylbenzene as internal
standard.
N
N
H
Me
Me
F3C
Me2N
H
2k16
2j 23%
33%
d The reaction time was 1.5 h at λ = 315 nm using a multi-wavelength
monochromatic bench-top light source.12
Scheme 2 Scope of the light-triggered conversion of azides 1 to in-
doles 215
e Not detected.
f The reaction time was 6 h using a tungsten household halogen lamp.
g No trace of indole 2e detected.
quinoline. In fact, by changing the reaction solvent from
acetonitrile to ethanol, the quinoline 3e was indeed formed
(Table 2, entry 2 vs entry 1), validating our hypothesis. After
evaluating diverse excitation wavelengths and another light
source (a standard household tungsten lamp), it was found
that irradiation with this alternative light source resulted in
higher yields albeit with longer reaction times (Table 2, en-
try 3 vs entry 2). We then screened diverse protic solvents
to optimize the reaction conditions. In water, conversion
occurred with the same efficiency but a notably higher se-
lectivity towards 3e than in ethanol (Table 2, entry 4 vs en-
try 3). Various ethanol/water mixtures were next examined
as solvents and a 1:1 mixture gave the best result in terms
of efficiency (Table 2, entry 5 vs entries 6 and 7). Perform-
ing the reaction under aqueous acidic conditions was suc-
cessful in terms of selectivity, with no traces of indole 2e
being detected, but unsuccessful in terms of yield (Table 2,
entries 8 and 9).
stituted aryl azides, 1j and 1k respectively, proved suitable
substrates for the transformation, furnishing the corre-
sponding quinolines 3j and 3k in good yields. Notably, 3j
and 3k were formed without any trace of indoles 2j and 2k
as by-products.
The conditions were further evaluated for their poten-
tial to form carbostyril derivatives 4, starting from azides
bearing no acetyl moiety but only ester moieties. While
carbostyril 4a could not be obtained from 1a, photolysis of
1b and 1i resulted in the formation of the expected carbo-
styrils 4b and 4i, although only in low yields. In this ethyl
ester series, indoles remained the major photoproducts in
2:4 measured ratios.
From a mechanistic viewpoint, we hypothesize that
both indole and quinoline/carbostyril routes start with the
photolysis of the azide moiety, thus providing nitrene I1 as
the key intermediate (Scheme 4). The nitrene I1 may then
evolve differently depending on the nature of the solvent. In
an aprotic solvent such as acetonitrile, I1 can rearrange to
the fused intermediate I2 via C–N bond formation. Due to
the non-aromatic feature of I2, a second rearrangement pro-
cess can take place, allowing the rearomatization of I2 to I3
The optimized illumination conditions were then ap-
plied to a range of ortho-azidocinnamoyl derivatives 1
(Scheme 3). Although azide 1d proved again to be a poor
substrate, quinoline 3f could be obtained with similar effi-
ciency to 3e. Trifluoromethyl- and N,N-diethylamino-sub-
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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S. Chaabouni et al.
Letter
Synlett
R2
R1
R2
R3
COR1
N
N3
3
R2
hν
1
R3
or
COR1
hν
EtOH/H2O (1:1)
N2
R2
R2
O
N3
quinoline/
carbostyril
route
rt, 6 h
1a–k
R3
N
R2
H
COR1
4
N
protic
medium
COR1
NH2
CO2Et
Me
I1
COMe
Me
H
I4
indole
route
aprotic
medium
N
N
N
Me
imine or
lactam
formation
46%
13%
39%
3e
3d
3f
R2
(2e:3e = 40:60)
(2d:3d = 75:25)
COMe
Me
(2f:3f = 50:50)
R2
COR1
COR1
N
N
R2
COMe
I2
+ H2O
Me2N
N
Me
F3C
N
N
R1
[1,5]-shift
3k17
3
3j 56%
57%
(no traces of 2k)
H
H
COR1
R2
(no traces of 2j)
R2
or
R2
O
COR1
CO2Et
O
MeO
MeO
CO2Et
O
or
I3
H
+ EtOH
N
N
N
N
H
N
N
H
O
H
H
4
[1,3]-H shift
4a
–
4b 20%
4i 14%
(only 2a detected)
(2b:4b = 70:30)
(2i:3i = 85:15)
R2
COR1
Scheme 3 Scope of the light-promoted conversion of azides 1 to quin-
olines 3 or carbostyrils 415
R2
COR1 or
N
N
2
H
H
Scheme 4 Mechanistic proposal for the construction of indoles 2 and
quinolines/carbostyrils 3/4 from azides 1
via [1,5]-shift of the most readily migratable substituent. In
this study, we observed the following order of relative mi-
gratory aptitudes: H > COMe > CO2Et > alkyl, in agreement
with a previous related work.8b Finally, [1,3]-hydrogen shift
would lead to the indole 2, this step being driven by aroma-
tization of the indole scaffold. By contrast, nitrene I1 should
behave differently in a protic medium. To rationalize our
experimental results, a plausible route would involve the
amination of the nitrene group of I1 to furnish the amino
intermediate I4. Such conversion of nitrenes to amines in
protic media has precedent in the literature, especially in
the field of light-promoted fluorogenic substrates.14 The re-
sulting intermediate I4 would hence be well suited to un-
dergo intramolecular imine (when R1 = Me) or lactam
(when R1 = OEt) formation, thus affording quinoline 3 or
carbostyril 4 with concomitant release of water or ethanol,
respectively. Further work is currently in progress to cor-
roborate our hypothesis and decipher the precise mecha-
nism of this nitrene-to-aniline conversion.
Work is currently in progress to expand the scope of
these metal-free reactions and to apply them in total syn-
thesis.
Funding Information
The authors gratefully acknowledge the CNRS and Université Paul Sa-
batier-Toulouse III for financial support. This work was supported by
the Agence Nationale de Recherche (ANR-13-JS07-0003-01 CiTrON-
Fluo) and the CNRS. S.C. thanks the Campus France Agency and the
Université de Sfax for financial support, and N.M.P. thanks the Fonda-
tion RITC and the Fondation Toulouse Cancer Santé for a post-doctor-
al scholarship.
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Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590861.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
nrtogI
f
rmoaitn
In conclusion, we have developed a photochemical
method for the modular construction of two relevant het-
erocyclic scaffolds starting with readily prepared ortho-azi-
docinnamoyl derivatives as substrates.15–17 The method en-
abled the facile solvent-dependent synthesis of indoles un-
der aprotic conditions and quinolines/carbostyrils under
protic conditions.
References and Notes
(1) S.C. and N.M.P. contributed equally to this work.
(2) Bräse, S.; Banert, K. Organic Azides: Syntheses and Applications;
Wiley: Chichester, 2010.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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S. Chaabouni et al.
Letter
Synlett
(3) For recent reviews dealing with the CuAAC reaction, see: (a) Li,
L.; Zhang, Z. Molecules 2016, 21, 1393/1. (b) Chassaing, S.;
Bénéteau, V.; Pale, P. Catal. Sci. Technol. 2016, 6, 923. (c) Haldon,
E.; Nicasio, M. C.; Perez, P. J. Org. Biomol. Chem. 2015, 13, 9528.
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2015, 32, 1389. (b) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S.
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T. Nat. Prod. Rep. 2010, 27, 1630. (d) Kochanowska-Karamyan, A.
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(11) For details on methods for preparing cinnamoylated azides 1a–k
from commercially available ortho-nitrobenzaldehydes, see the
Supporting Information.
(12) The bench-top light source we used was the LUMOS 43® mar-
keted by Atlas Photonics.
(13) In spite of the crude products giving clean 1H NMR spectra, the
fact that the yields are not higher could be explained by the for-
mation of polymeric by-products due to rearrangement pro-
cesses involving the highly reactive nitrene.
(14) For representative examples dealing with photoaffinity labeling
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W. E. J. Phys. Chem. B 2010, 114, 14157. (b) Voskresenska, V.;
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65, 4949.
(15) Typical Procedure: In a quartz tube under argon were succes-
sively added ortho-azidocinnamoyl derivative 1a–k and the
appropriate solvent to give a concentration of 3.2 mM. The
resulting mixture was then irradiated using either the LUMOS
43® (1.5 h stirring time with CH2Cl2 as solvent) or a conven-
tional tungsten lamp [6 h stirring time with EtOH–H2O (1:1) as
solvent], as light sources. After evaporation of the solvent, puri-
fication of the crude product by column chromatography,
eluting with an appropriate cyclohexane–EtOAc mixture, fur-
nished the desired photocyclized products 2a–k or 3/4 in pure
form.
(16) Analytical Data for 2,3-Diacetyl-6-N,N-dimethylamino-1H-
indole (2k, Scheme 2): Orange solid; mp 176–179 °C; Rf 0.40
(cyclohexane–EtOAc, 70:30). FTIR (ATR, neat): 3322, 2921, 1670
(C=O), 1311 cm–1. 1H NMR (300 MHz, CDCl3): δ = 9.30 (br s, 1 H,
NH), 7.65 (d, J = 9.2 Hz, 1 H), 6.87 (dd, J = 2.3, 9.2 Hz, 1 H), 6.53
(d, J = 2.3 Hz, 1 H), 3.02 (s, 6 H), 2.76 (s, 3 H), 2.62 (s, 3 H). 13C
NMR (75 MHz, CDCl3): δ = 197.8, 191.4, 150.0, 137.3, 132.4,
122.6, 122.1, 117.9, 112.2, 92.4, 40.8, 32.1, 28.7. MS (DCI, +):
m/z (%) = 245 (100) [M + H]+. HRMS (DCI, +): m/z [M + H]+ calcd
for C14H17N2O2: 245.1290; found: 245.1289.
(7) (a) Kong, C.; Jana, N.; Jones, C.; Driver, T. G. J. Am. Chem. Soc.
2016, 138, 13271. (b) Alt, I. T.; Plietker, B. Angew. Chem. Int. Ed.
2016, 55, 1519. (c) Goriya, Y.; Ramana, C. V. Chem. Commun.
2014, 50, 7790. (d) Stokes, B. J.; Liu, S.; Driver, T. G. J. Am. Chem.
Soc. 2011, 133, 4702. (e) Liu, Y.; Wei, J.; Che, C.-M. Chem.
Commun. 2010, 46, 6926.
(8) (a) Li, Z.; Wang, W.; Zhang, X.; Hu, C.; Zhang, W. Synlett 2013,
24, 73. (b) Gairns, R. S.; Moody, C. J.; Rees, C. W. J. Chem. Soc.,
Perkin Trans. 1 1986, 501.
(9) For synthetic methods towards quinolines involving imino-
phosphoranes as alternative intermediates, see: (a) Kim, H. J.;
Jeong, E. M.; Lee, K.-J. J. Heterocycl. Chem. 2011, 48, 965. (b) Han,
E.-G.; Kim, H. J.; Lee, K.-J. Tetrahedron 2009, 65, 9616.
(c) Luheshi, A.-B. N.; Salem, S. M.; Smalley, R. K.; Kennewell, P.
D.; Westwood, R. Tetrahedron Lett. 1990, 31, 6561.
(17) Analytical Data for 2-Methyl-3-acetyl-7-N,N-dimethylami-
noquinoline (3k, Scheme 3): Orange-red solid; mp 118–
121 °C; Rf 0.23 (cyclohexane–EtOAc, 70:30). FTIR (ATR, neat):
2925, 1666 (C=O), 1616, 1511, 1422 cm–1 1H NMR (300 MHz,
.
CDCl3): δ = 8.34 (s, 1 H), 7.66 (d, J = 9.0 Hz, 1 H), 7.12 (dd, J = 2.5,
9.0 Hz, 1 H), 7.05 (d, J = 2.5 Hz, 1 H), 3.13 (s, 6 H), 2.88 (s, 3 H),
2.65 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 198.9, 158.9, 152.9,
150.3, 138.7, 129.4, 126.4, 117.7, 115.6, 105.6, 40.3, 28.7, 26.2.
MS (DCI, +): m/z (%) = 229 (100) [M + H]+. HRMS (DCI, +):
m/z [M + H]+ calcd for C14H17N2O: 229.1341; found: 229.1347.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E