Photochemical intramolecular amination for the synthesis of heterocycles

Article abstract of DOI:10.1039/c7gc02261a

Polycyclic heterocycles can be formed in good to excellent yields via photochemical conversion of the corresponding substituted aryl azides under irradiation with purple LEDs in a continuous flow reactor. The experimental set-up is tolerant to UV-sensitive functional groups while affording diverse carbazoles, as well as an indole and pyrrole framework, in short reaction times. The photochemical method is presumed to progress through a mechanism differing from the other methods of azide activation involving transition metal catalysis.

Full text of DOI:10.1039/c7gc02261a

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Photochemical intramolecular amination for the
synthesis of heterocycles†
Cite this: DOI: 10.1039/c7gc02261a
Received 25th July 2017,
Accepted 19th September 2017
Shawn Parisien-Collette, Corentin Cruché, Xavier Abel-Snape and
Shawn K. Collins
*
DOI: 10.1039/c7gc02261a
rsc.li/greenchem
Polycyclic heterocycles can be formed in good to excellent yields form nitrogen-based heterocycles concerns amination via
via photochemical conversion of the corresponding substituted azide activation.5 Following the report of Rh-based catalysis for
aryl azides under irradiation with purple LEDs in a continuous flow decomposition of azides and the synthesis of heterocycles by
reactor. The experimental set-up is tolerant to UV-sensitive func- Driver and co-workers,6 examples of Ir,7 Ru8 as well as Fe-
tional groups while affording diverse carbazoles, as well as an based catalysis were reported.9 The decomposition of azides
indole and pyrrole framework, in short reaction times. The photo- via transition metals has led to a variety of methods for the
chemical method is presumed to progress through a mechanism synthesis of carbazoles, indoles, aziridines, pyrroles and pyrro-
differing from the other methods of azide activation involving lidines via either Csp3–H or Csp3–H amination.5–9
transition metal catalysis.
Despite the recent interest in C–H amination transition
metal catalysis, the photochemical activation of azides via,
resulting in a formal C–H amination, initially reported over 60
years ago by Smith and Brown in 1951, could be exploited to
form the same products without added reagents or transition
metal catalysts.10 Further investigation of the photochemical
decomposition of azides for C–H amination has been relegated
to studies of the mechanism,8,11 and further development as a
robust synthetic method to access both common and complex
polycycles has been rare. The scarcity of new photochemical
methods is all the more surprising given their complimentarity
with existing protocols.12 Notably, our group has reported the
photochemical oxidation of diaryl- and triarylamines to form
carbazoles,13 but the existing methods fail to promote hetero-
cycle formation when starting materials possess a free amine.
In the current context of sustainable synthesis, the develop-
ment of practical photochemical amination would be a
welcome addition to the toolbox of synthetic chemists. Herein
we describe a photochemical continuous flow synthesis14 of
unprotected, free N–H, carbazoles, indoles and pyrroles, in
addition to complex polycyclic heterocycles, from their corres-
ponding azido-aryl precursors (Fig. 1).
The drive for ever more sustainable and environmentally
friendly technologies for molecular synthesis has led to a
resurgence in the interest of synthetic photochemistry.1 Light
is an attractive “reagent”, as it is traceless and can be accessed
through wavelength selective, low-energy sources such as light
emitting diode (LEDs). When synthetic photochemistry is
exploited within a continuous flow manifold, issues of light
penetration, over-irradiation and scalability are easily over-
come. Consequently, it is not surprising that photochemical
continuous flow processes are of increasing interest for the
synthesis of high-value pharmaceuticals.2
Polycyclic nitrogen heterocycles are important structural
motifs that are embedded into the core skeletons of natural
products, pharmaceuticals3 and compounds of interest in
materials science.4 Due to the structural complexity often
encountered, chemists are faced with the challenge of develop-
ing synthetic methods that afford high levels of regiocontrol
despite substitution patterns, and are tolerant to the density of
heteroatoms present. Consequently, the synthesis of polycyclic
heterocycles remains a challenging problem in organic syn-
thesis. One of the more recent developments in strategies to
The photochemical decomposition of azidobiaryl 1 was first
studied at 254 nm using a previously reported UV-flow
reactor.15 At a concentration of 30 mM in THF, the corres-
ponding carbazole 4 was obtained in 80% yield with a resi-
dence time of only 10 min (Table 1). With an eye on developing
a photochemical method that would tolerate a variety of func-
Shawn Parisien-Collette, Corentin Cruché, Xavier Abel-Snape and Prof, Dr Shawn
K. Collins, Department of Chemistry and Centre in Green Chemistry and Catalysis,
Université de Montréal, CP 6128 Station Downtown, Montréal, Québec, Canada H3C
3J7. E-mail: shawn.collins@umontreal.ca
tionality,
a chlorinated derivative 2 was also evaluated.
†Electronic supplementary information (ESI) available. CCDC 1555026. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c7gc02261a
Unfortunately, under the identical conditions, a lower yield of
61% was observed along with the formation of dechlorinated
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Fig. 1 Photochemical approach to polycyclic heterocycles.
Table 1 Survey of photochemical protocols
Fig. 2 Photochemical reactors for irradiation at 394 nm (purple LEDs)
(on, left, off right). The temperature within purple LED reactor can
increase over time (temperature reaches a maximum of 24.6 °C) A
cooling fan was installed at the bottom of the reactor to maintain the
temperature.
Entrya
Time
Solvent
Wavelength (nm)
Yield (%)
1
2
3
4
5
6
7
8
9
1
1
2
3
1
1
2
2
3
3
10 min
10 min
10 min
10 min
2 h
2 h
2 h
4 h
4 h
4 h
THF
EtOAc
THF
THF
THF
EtOAc
EtOAc
THF
THF
EtOAc
254
254
254
254
394
394
394
394
394
394
80b
70
61
45
80c,d
80d
62d
81d
80d
69d
10
a Yields following flash chromatography. b 74% of 4 at 75 mM. c 63% of
4 at 75 mM. d Mass balance is unreacted azide.
by-products. When an analogous brominated azide 3 under-
went irradiation with light at 254 nm, the desired bromo-car-
bazole 6 was isolated in only 45%. After examining various
wavelengths, it was found that the irradiation from purple
LEDs (394 nm) overlapped with the tail end of the absorption
of azidobiaryl 1 (Fig. 2 and 3).
Furthermore, irradiation from the purple LEDs in either
EtOAc or THF as solvent was an efficient photochemical pro-
cedure for the decomposition of azides (Table 1).16 The chlori-
nated carbazole 5 was isolated in 81% (THF, 4 h) while
Fig. 3 Overlapping the absorption spectrum for 2-azido-1,1’-biphenyl
(1, black) with the emission spectrum of the purple LED (purple) at the
concentration used for the photochemical decomposition of the azide
(30 mM in THF).
irradiation of the bromo azide 3 in EtOAc afforded an during any of the irradiations. It should be noted that a recent
increased yield of the desired carbazoles (69% compared to report aiming to evaluate that “greenness” of various solvents
45% at 254 nm) and the yield could be further increased when classified THF as “problematic” and EtOAc as “rec-
using THF (80%). In many instances, under the 394 nm ommended”.17 While in many cases the yields are superior in
irradiation, the remainder of the mass balance was unreacted THF, the difference in yield when using EtOAc is generally
azide precursor.
within 10%, and in some cases demonstrated below, the yields
Further attempts to optimize the yield of carbazoles were can be better with EtOAc. Some differences in yield may be
not fruitful: either increasing or decreasing the concentration due to the difference in UV cutoff values for the two solvents
of the reaction mixture gave lower yields, alternative solvents (EtOAc 256 nm, THF 212 nm). Having optimized the con-
produced lower yields and increasing the flow rate gave lower ditions for the intramolecular photochemical amination at two
yields, albeit again the mass balance was recovered azide start- different wavelengths in continuous flow, the scope of the
ing material. Furthermore, no azo side-products were observed transformation was explored with regards to both electron-
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Table 2 Scope of the photochemical amination: electronic effectsa
Next, the influence of alkyl group substitution was explored
(Table 3). A sterically encumbered alkyl group, i-Pr, was investi-
gated and afforded the corresponding carbazole in moderate
yields (53 and 51% at 254 and 394 nm irradiation respectively).
Interestingly, carbazole 14 was formed as the sole product and
no product resulting from C–H insertion were observed. Also
noteworthy, the photochemical amination provided higher
yields than existing methods involving palladium-catalyzed
azide decomposition18 and a bimolecular aryne/nitrosoarene
addition,19 in which the latter also afforded a mixture of regio-
isomers. In exploring the influence of alkyl substituents, a
methyl group could be appended to the azidobiphenyl precur-
sor in either the para-, meta- or ortho-positions and typically
afforded the products in good yields.
Interestingly, the photochemical decomposition of azidobi-
phenyls provides facile access to polycyclic heteroaromatic
skeletons (Table 4). For example, 4H-thieno[3,2-b]indole 18,
previously investigated as a more electron-rich analogue of car-
bazole for dye-sensitized solar cells, could be formed via the
photochemical amination in up to 76% yield (394 nm
irradiation). The yield fits within a range of yields found in the
literature for the preparation of 18 via other methods,9a,20,21
but has the distinction of not requiring transition metal cataly-
sis. In addition to benzothiophene, naphthalene, indazole and
a Yields following flash chromatography. b In EtOAc.
withdrawing and electron-donating substituents (Table 2).
Each of the cyclizations was performed at both 254 and
394 nm irradiation and in general, conversion to the desired
product afforded higher yields when the latter protocol was
used. In some instances, EtOAc afforded higher yields than
THF as solvent for irradiation of the azidobiphenyls at 394 nm.
Carbazoles bearing electron-withdrawing groups such as F (7),
cyano (8), CO2Me (9) and CF3 (10) all underwent cyclization (69
to 82% yield) under 394 nm irradiation. Electron-donating
substituents such as NMe2 and OMe afforded carbazoles 11
and 12 products in higher yields when irradiated at 254 nm
(84 to 93% yield), while a TMS afforded the corresponding car-
bazoles 13 in higher yield at 394 nm irradiation (81%).
Table 4 Scope of the photochemical amination: polycyclic
heterocycles.a
Table 3 Scope of the photochemical amination: steric effectsa
a Yields following flash chromatography. b In EtOAc.
a Yields following flash chromatography.
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benzofuran were easily annulated to form the corresponding
tetracyclic heterocycles 19, 20, 21 and 22 as single regioisomers
(47 to 86% yields, 394 nm irradiation). A dibenzofuran22 and a
phenanthrene could be annulated via the decomposition of
the corresponding azides to form pentacyclic heterocycles (23
and 24; 55 to 93% yield).
Lastly, the method could also be extended to the synthesis
of other aza-heterocycles. The synthesis of indole 25 and
pyrrole 26 each occurred in good yields (79 and 83% yield
respectively) via reaction of the corresponding azide. Again,
the yields of the heterocycle products were higher when
decomposition of the azide starting materials occurred under
irradiation at 394 nm (79 and 83%), rather than 254 nm (50
and 66%).
Scheme 2 Proposed mechanism for the photochemical formation of
carbazoles and deuterium labelling studies.
The intramolecular photochemical amination displays
useful functional group tolerance and complimentarity when
compared to existing photochemical methods for the synthesis
of biologically active heterocycles. To illustrate the utility of the
photochemical amination, different photochemical routes to
the carbazole-based drug carprofen were examined
(Scheme 1). First, synthetic routes that proceed via C–C bond
formation were explored and the diaryl amine 27 was treated
with a copper-based sensitizer under continuous flow con-
ditions and irradiated under visible light.13a Following elution
from the flow reactor, the diaryl amine was recovered almost
quantitatively. Alternatively, when the same diaryl amine was
was isolated as the major product in 50% yield (254 nm) and
64% (394 nm), as a sole regioisomer and without any dechlori-
nation observed.
The mechanism of the conversion of the biphenyl azides to
the corresponding carbazoles under UV-irradiation has been
proposed to proceed via formation of a singlet biphenyl
nitrene (I) which undergoes addition to an adjacent aromatic
ring (Scheme 2).23 The formed isocarbazole intermediate (II),24
is proposed to rearrange to afford the corresponding carba-
zoles. In our studies, no observation of any C–H insertion pro-
ducts into an adjacent alkyl group such as Me (see carbazole
17, Table 3) or a i-Pr group (see carbazole 14, Table 3) was
observed, as is proposed to occur with triplet nitrene species.25
It should be noted that the overlap between emission of the
purple LED (394 nm) and the absorption of the biphenyl
azides occurs only in the tail end of spectrum. As such, the for-
mation of carbazoles at 394 nm could proceed via an alterna-
tive mechanism. A deuterium labelling study was performed
and revealed a kinetic isotope effect of 1.04 and 0.96 (for
irradiations at 254 and 394 nm respectively). While the values
are considerably different from those obtained for Fe-cataly-
zed9a and Rh-catalyzed26 aminations, alternative mechanisms
may still be plausible for the process when irradiating at
394 nm. Indeed, other mechanisms involving electrocycliza-
tion and electrophilic aromatic substitution processes still
remain plausible.26a
excited under UV irradiation (continuous flow, 254 nm),13b,15
a
complex mixture forms in which carbazole products are only
formed as minor products and have mostly undergone
dechlorination. Importantly, the carbazoles observed are mix-
tures of regioisomers. When the photochemical amination was
explored using the azido biphenyl 28, the desired carbazole 29
Conclusions
In summary, the photochemical conversion of substituted aryl
or vinyl azides under a low-energy source of irradiation
(394 nm) in a continuous flow reactor represents an increas-
ingly sustainable route to heterocycles in good to excellent
yields. Specifically, the strategy provided access to a range of
carbazoles, including the incorporation of other heterocycles
and/or polycyclic aromatics, as well as demonstrating utility
towards the synthesis of an indole and pyrrole skeleton.
Increased yields and improved functional group tolerance is
observed when irradiation occurs with less energetic 394 nm
light. The utility of the protocol was demonstrated via the
Scheme 1 A comparison of photochemical routes to carprofen.
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photochemical synthesis of substituted carbazoles and
complex tetra- and pentaheterocycles. The method was also
applied to the synthesis of a known pharmaceutical agent, car-
profen, and applied to the formation of indoles and pyrroles.
The photochemical route is proposed to progress through a
mechanism differing from the other methods of azide acti-
vation involving transition metal catalysis. The methods
described herein demonstrate that underexplored photochemi-
cal methods can provide efficient, controlled and scalable
routes, without the need for transition metals, to important
heterocyclic frameworks.
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