Photochemical Synthesis of Complex Carbazoles: Evaluation of Electronic Effects in Both UV- and Visible-Light Methods in Continuous Flow

Article abstract of DOI:10.1002/chem.201502661

An evaluation of both a visible-light- and UV-light-mediated synthesis of carbazoles from various triarylamines with differing electronic properties under continuous-flow conditions has been conducted. In general, triarylamines bearing electron-rich groups tend to produce higher yields than triarylamines possessing electron-withdrawing groups. The incorporation of nitrogen-based heterocycles, as well as halogen-containing arenes in carbazole skeletons, was well tolerated, and often synthetically useful complementarity was observed between the UV-light and visible-light (photoredox) methods.

Full text of DOI:10.1002/chem.201502661

DOI: 10.1002/chem.201502661
Full Paper
&
Photochemistry
Photochemical Synthesis of Complex Carbazoles: Evaluation of
Electronic Effects in Both UV- and Visible-Light Methods in
Continuous Flow
Augusto C. Hernandez-Perez, Antoine Caron, and Shawn K. Collins*[a]
Abstract: An evaluation of both a visible-light- and UV-light-
mediated synthesis of carbazoles from various triarylamines
with differing electronic properties under continuous-flow
conditions has been conducted. In general, triarylamines
bearing electron-rich groups tend to produce higher yields
than triarylamines possessing electron-withdrawing groups.
The incorporation of nitrogen-based heterocycles, as well as
halogen-containing arenes in carbazole skeletons, was well
tolerated, and often synthetically useful complementarity
was observed between the UV-light and visible-light (photo-
redox) methods.
Introduction
a UV-light continuous-flow set-up and demonstrated its utility
in the formation of derivatives of carprofen, a carbazole-based
drug used for the treatment of pain in veterinarian science.[9]
In addition, our group has reported that visible-light photore-
dox catalysis can be used to prepare carbazoles through a CÀC
bond-forming process.[10] The transformation used a Cu-based
sensitizer 3 and exploited continuous-flow conditions to im-
prove the yields and reaction time. The visible-light-mediated
reaction was shown to afford trisubstituted N-aryl or N-alkyl
carbazoles, but no effort was made to explain the regiochemi-
cal preferences observed during the synthesis of complex car-
The synthesis of complex, highly functionalized carbazoles has
been an active field of study due to their application in both
pharmaceuticals[1] and materials science.[2] Recent advances in
synthetic strategies, which involve functionalization of carbon–
hydrogen (CÀH) bonds has provided chemists with new tools
for the formation of the parent carbazole skeleton, as well as
their late-stage functionalization. One of the more popular
strategies for carbazole synthesis involves formation of
a carbon–nitrogen (CÀN) bond from an amino-functionalized
biaryl to form the central five-membered ring of the carbazole.
Oxidative transformations under palladium catalysis can pre-
pare carbazoles in good to excellent yields employing
Cu(OAc)2/O2 or hypervalent iodine reagents as stoichiometric
oxidants. Alternatively, rhodium catalysis can be employed to
transform azide-functionalized biaryls to carbazoles in a redox
neutral process. Each of the aforementioned technologies
studied the effects of substitution on the outcome of the
transformation. In particular, the effect of a substituent placed
in a meta-position of the biaryl can afford mixtures of products
(see R1 and products 2para and 2ortho, Figure 1). Photochem-
ical strategies are attractive synthetic routes to carbazoles as
light is viewed as a “green” reagent. The synthesis of carba-
zoles via a UV-mediated electrocyclic process has been known
since the 1970s,[3] and despite considerable interest in the reac-
tion mechanism,[4,5] has been only used sparingly in the prepa-
ration of natural products.[6–8] In 2014, our group reported
[a] Dr. A. C. Hernandez-Perez, A. Caron, Dr. S. K. Collins
DØpartement de Chimie
Centre for Green Chemistry and Catalysis
UniversitØ de MontrØal, CP 6128 Station Downtown
MontrØal, QuØbec H3C 3J7 (Canada)
E-mail: shawn.collins@umontreal.ca
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201502661.
Figure 1. Synthesis of carbazoles via transition-metal catalysis and photo-
chemical pathways.
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bazoles. Herein, we describe a full account of the substrate
scope with regards to the visible-light-mediated synthesis of
carbazoles employing a copper-based sensitizer, with an em-
phasis on exploring the electronic effects of substituent. In ad-
dition, we report a comparative study of the synthesis and
substituent effects in the preparation of complex carbazoles
by using a UV-light-mediated strategy.[11]
group as a typical electron-donating substituent was also
made considering the number of biologically active carbazole
natural products that contain such a motif.[13] Using either visi-
ble-light-mediated photoredox cyclization or UV-light-mediat-
ed electrocyclization, a series of triarylamines adorned with
methoxy substituents were prepared and evaluated
(Table 1).[14] First, triarylamine derivatives bearing a single me-
thoxy substituent in either the ortho-, meta-, or para-positions
of one of the N-aryl groups were examined. When the me-
thoxy group was in the para position (triarylamine 4), visible-
light-mediated photoredox cyclization afforded a 70% yield of
products as a 90:10 ratio of 5exo/5endo. Interestingly, the UV-
light-mediated cyclization afforded a 81% yield of products,
with the opposite regiochemical preference for cyclization
(10:90 5exo/5endo). When the meta-methoxy triaylamine 6
was subject to both photochemical syntheses, an endo product
was favored in both cases. However, under visible-light photo-
redox conditions, the carbazole 7endo1 was obtained in the
highest yield, whereas UV-light electrocyclization gave the
7endo2 as the favored product. When the methoxy substitu-
Results and Discussion
The synthesis of carbazoles from the corresponding tri-
arylamine derivatives under photochemical conditions was car-
ried out in continuous-flow conditions. The use of continuous-
flow photochemistry has been shown to result in significant re-
ductions in reaction time and rendering scale-up more “user-
friendly”.[12] In the visible-light-mediated synthesis of carba-
zoles, continuous-flow conditions resulted in an approximately
12-fold decrease in reaction time.[10] The photoredox method-
ology exploited the in situ formation of a copper-based sensi-
tizer 3, which outperformed other sensitizers for the process
(Scheme 1a). Continuous-flow conditions were also responsible
for the ability to explore a UV-light-mediated synthesis of car-
bazoles. Using a previously developed flow system,[9] cycliza-
tions could be performed at various wavelengths with even
shorter reaction times than observed for the analogous photo-
redox methods (Scheme 1b).
Table 1. Photocyclization of electron-rich triarylamines.
Triarylamine
Product conditions,[a] yield,[b] ratio (exo/
endo)
Scheme 1. Synthesis of an unsubstituted carbazole by a) visible-light-mediat-
ed photoredox catalysis and b) UV-light-mediated photocyclization.
The following study employed the identical oxidant system
used in the visible-light syntheses under irradiation at 300 nm.
In the cyclization of triarylamines to form carbazoles, the incor-
poration of the substituted aryl group is defined as the “endo”
product, whereas exclusion of the substituted aryl (which be-
comes in the N-aryl group in the resulting carbazole) is defined
as the “exo” substituent.
[a] A) Visible light, [Cu(Xantphos)(dmp)](BF4), 3 in situ (5 mol%), visible
light, I2 (1 equiv), propylene oxide (50 equiv), THF, 218C, residence time
20 h, (0.05 mLminÀ1); B) UV Light 300 nm, I2 (1 equiv), propylene oxide
(50 equiv), THF, 218C, residence time 15 min (2 mLminÀ1). [b] Yields are
based on chromatography.
Evaluation of electron-rich substrates
In evaluating the transformation of electron-rich triarylamines
to the corresponding carbazoles, the choice of a methoxy
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ent was placed in an ortho-position on the N-aryl group (triar-
ylamine 8), both photochemical reaction conditions gave a sim-
ilar ratio of products, slightly favoring the exo-product, 9exo
(60:40 9exo/9endo in both cases); however, the UV-mediated
method gave higher yields (98 vs. 64% yield).
light-mediated cyclization of the more electron-rich substrate
12 gave a low 10% yield, with selectivity for a single isomer
13endo2. When the retention time was decreased from 15 to
6 min, a yield of 56% was observed. In addition, at a reduced
retention time, all three possible products were observed
(10:26:64 13exo/13endo1/13endo2), suggesting that certain
products degrade more rapidly than others under the reaction
conditions (although 13endo2 was the major product in
either case). Finally, when a triarylamine derivative having two
of its N-aryl groups para-substituted with methoxy groups
(14), the endo product was isolated as the major product
under either photochemical conditions (photoredox: 84%,
35:65 15exo/15endo, UV light: 81%, 41:59 15exo/15endo).
Next, more complex patterns of methoxy-substituted triaryl-
amines were examined (Table 2). A triarylamine bearing a 3,5-
dimethoxy N-aryl group 10 was evaluated. Although a single
meta-methoxy group exhibited preference in forming endo-
products, no selectivity was now observed under visible-light
conditions (75%, 50:50 11 exo/11 endo). Similar ratios were ob-
served under UV-light irradiation (43:57 11 exo/11 endo), but
the very electron-rich compounds were formed in lower yield
(55%). The lower yields may be due to sensitivity of the final
products to the UV-light conditions. When a similarly electron-
rich triarylamine bearing a 3,4-dimethoxy N-aryl group 12 was
evaluated, very little productive cyclization occurred in either
photochemical manifold. Visible-light-mediated photoredox
cyclization afforded only traces of cyclized carbazoles with sig-
Evaluation of electron-poor substrates
Next, triarylamine derivatives bearing a methyl ester substitu-
ent were examined to determine the effects of an electron-
withdrawing group on the photochemical cyclizations to form
carbazoles (Table 3). A methyl ester group was again placed in
either the ortho-, meta-, or para-positions of one of the N-
aryl groups of the corresponding triarylamines. The only
cyclization, which proceeded with the formation product
was when the methyl ester substituent was placed in the
meta-position of an N-aryl group, in which cyclization could
be observed under visible-light using the Cu-based sensitiz-
er (37% of 19exo). Irradiation of the triarylamines having
a methyl ester group was in the ortho- or para-positions did
not result in cyclization under either visible-light-mediated
photoredox cyclization or UV-light-mediated electrocycliza-
tion conditions (in general, quantitative recovery of starting
material was observed). Because the photoredox transfor-
mation is thought to proceed through a nitrogen-centered
radical cation, it was believed that the presence of a strong
electron-withdrawing group renders the amine too elec-
tron-poor to undergo oxidation. In addition, two triaryla-
mines were prepared having an N-aryl group with both an
electron-donating and -withdrawing substituent (22 and
24), but both photochemical conditions failed to produce
significant quantities of carbazole products.[15]
1
nificant amounts of by-products observed by H NMR. The UV-
Table 2. Photocyclization of complex electron-rich triarylamines.
Triarylamine
Product conditions,[a] yield,[b] ratio
(exo/endo)
Evaluation of heterocycle-containing substrates
Complex carbazoles having additional nitrogen atoms
within their framework form an important class of heterocy-
cles. For example, both a- and b-carbolines[16] are prevalent
in biologically active natural products. The photocyclization
of triarylamines having a nitrogen heterocycle as an N-aryl
group were explored under the photochemical conditions
(Table 4). The photochemical transformation of the pyridine-
substituted 26 was first explored and afforded a 55% yield
of 27endo under visible-light conditions. UV-light-mediated
cyclization afforded an excellent yield, again with selectivity
for the 27endo isomer (98%). For the pyrimidine-substitut-
ed derivative 28, both the visible-light and UV-light condi-
tions afforded solely the 29endo product in similar yield
(60 vs. 64% respectively).
[a] A) Visible light, [Cu(Xantphos)(dmp)](BF4), 3 in situ (5 mol%), visible light,
I2 (1 equiv), propylene oxide (50 equiv), THF, 218C, residence time 20 h,
(0.05 mLminÀ1); B) UV light 300 nm, I2 (1 equiv), propylene oxide (50 equiv),
THF, 218C, residence time 15 min (2 mLminÀ1). [b] Yields are based on chro-
matography.
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Table 3. Photocyclization of electron-poor triarylamines.
Table 4. Photocyclization of heterocycle-containing triarylamines.
Triarylamine
Product conditions,[a] yield,[b] ratio (exo/
endo)
Triarylamine
Product conditions,[a] yield,[b]
ratio (exo/endo)
[a] A) Visible light, [Cu(Xantphos)(dmp)](BF4), 3 in situ (5 mol%), visible light,
I2 (1 equiv), propylene oxide (50 equiv), THF, 218C, residence time 20 h,
(0.05 mLminÀ1); B) UV light 300 nm, I2 (1 equiv), propylene oxide (50 equiv),
THF, 218C, residence time 15 min (2 mLminÀ1). [b] Yields are based on chro-
matography. Only trace products were formed, recovered starting material
was generally isolated.
Finally, a more complex triarylamine having both a pyridine
and an anisole substituent 30 was evaluated. Although three
different products could be obtained, under photoredox condi-
tions, only the endo products 31endo1 and 31endo2 were
obtained (95%, 26:74 respectively). Although the yields of the
cyclization under UV light were lower (46%), similar selectivity
was observed, whereby the endo products were again favored
(33:67 31endo1/31endo2). Given that both photochemical
syntheses involving heterocycles showed a selectivity for inclu-
sion of the heterocycle into the carbazole nuclei, the formation
of the endo products is perhaps not surprising.
[a] A) Visible light, [Cu(Xantphos)(dmp)](BF4), 3 in situ (5 mol%), visible
light, I2 (1 equiv), propylene oxide (50 equiv), THF, 218C, residence time
20 h, (0.05 mLminÀ1); B) UV light 300 nm, I2 (1 equiv), propylene oxide
(50 equiv), THF, 218C, residence time 15 min (2 mLminÀ1). [b] Yields are
based on chromatography.
for the endo-product was observed (10:90 33exo/33endo),
whereas the opposite trend was observed under UV-light-
mediated electrocyclization (87:13 33exo/33endo). Next, the
chloro-derivative 34 was explored. Although the photoredox
conditions under visible light afforded an excellent 95% of
only 35exo, the UV-light conditions failed to give either 35exo
or 35endo. A complex reaction mixture was observed, and
none of the starting chloride 34 was recovered.[18] When the
bromo-derivative 36 was evaluated under the photoredox con-
ditions employing the copper-based sensitizer, only a 19% of
the 37endo carbazole was obtained (the exo has been pre-
ferred for the fluoride and chloride derivatives) Under UV-light
conditions, neither 37exo or 37endo was observed. A small
amount of N-phenylcarbazole was observed (16%), along with
71% of recovered bromoamine 36.[19] Under photoredox con-
ditions, the iodo-derivative 38 gave a 50% of the 39exo carba-
zole. The productive cyclization of 38 is highly advantageous
and provides a handle to install other electron withdrawing via
cross-coupling.[20] In the case of the iodo-derivative 38, the UV-
light conditions afforded a clean reaction mixture, which pro-
duced a 95% of N-phenylcarbazole.[21] It is known that UV-light
conditions can cleave CarylÀX bonds; however, it is difficult to
Evaluation of halogen-containing substrates
Halogens are important substituents in heterocyclic chemistry.
Although chloride, bromide, and iodide substituents can be ex-
ploited in cross-coupling chemistry for further functionalization
of a heterocyclic core, a fluoride substituent can be exploited
in medicinal chemistry to inhibit metabolic degradation.[17]
Consequently, the behavior of triarylamines having a halogen
substituent in the para-position of N-aryl group were explored
under the photochemical conditions (Table 5). Given the diffi-
culty of cyclizing triarylamines to carbazoles with electron-
withdrawing methyl ester substituents, the photochemical
transformation of the fluoride-substituted 32 was initially con-
sidered to be challenging. Surprisingly, excellent yields were
obtained for photocyclization of 32 under visible light (94%)
and UV light (86%). Under photoredox conditions, a preference
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tron-withdrawing groups are also problematic even when pres-
ent on identical rings as an electron-donating group.
Table 5. Photocyclization of halogen-containing triarylamines.
3) The use of electron-poor nitrogen-based heterocycles as
aryl groups on the triarylamine starting materials was well tol-
erated. In general, UV-light irradiation provided higher yields.
The cyclization of a triarylamine having a pendant heterocycle
and an aryl group with an electron-donating methoxy substitu-
ent provided inversed regiochemical preferences depending
on the method of irradiation.
Triarylamine
Product conditions,[a] yield,[b] ratio (exo/endo)
4) The cyclization of the halogen-containing triarylamines
was well tolerated using a photoredox, visible-light-mediated
approach, often with high selectivity for one regioisomer. Al-
though UV-light methods tended to afford higher yields with
the other substrate classes, for most halogen-containing sub-
strates (Cl, Br, and I) photodehalogenation was observed.
Despite the general guidelines provided by the above-de-
scribed study, it is worth noting that copper-based sensitizers
have been known to play distinct and different roles in photo-
catalysis compared to more common Ru- and Ir-based sensitiz-
ers and the above-presented study does elucidate whether
such interaction may be responsible for the observed selectivi-
ties.[24] The study demonstrates the efficiency of photochemical
methods utilizing continuous flow for the synthesis of carba-
zoles, as well as the complementarity that can be obtained be-
tween UV-light and visible-light (photoredox) methods for the
preparation of complex heterocycles. Given the widespread in-
terest in carbazoles in medicinal chemistry, as well as material
science, it is expected that photochemical methods described
herein will interest a wide variety of researchers. The applica-
tion of both UV- and visible-light-mediated strategies to other
heterocyclic skeletons is currently under study.
[a] A) Visible light, [Cu(Xantphos)(dmp)](BF4), 3 in situ (5 mol%), visible
light, I2 (1 equiv), propylene oxide (50 equiv), THF, 218C, residence time
20 h, (0.05 mLminÀ1); B) UV light 300 nm, I2 (1 equiv), propylene oxide
(50 equiv), THF, 218C, residence time 15 min, (2 mLminÀ1). [b] Yields are
based on chromatography.
assess whether in the case of 34, 36, or 38 if the CarylÀX bond
is undergoing homolysis before or after cyclization to the car-
bazole moiety.[22,23]
Acknowledgements
Conclusion
The authors acknowledge the Natural Sciences and Engineer-
ing Research Council of Canada (NSERC), UniversitØ de Mon-
treal, the Centre for Green Chemistry and Catalysis (CGCC) and
the NSERC CREATE program in Continuous Flow Science for
generous funding. The Canadian Foundation for Innovation
(CFI) is acknowledged for generous funding of the flow
chemistry infrastructure.
An evaluation of the visible-light-mediated synthesis of carba-
zoles from various electronically different triarylamines employ-
ing Cu-based sensitizer 3 under continuous-flow conditions
has been conducted. In comparison, all of the triarylamines
were also cyclized under UV-light irradiation using the identical
oxidant system and the yields and regiochemical preferences
have been compared. In general, the following conclusions
come to light:
Keywords: carbazoles · continuous flow · photochemistry ·
photoredox catalysis · UV/Vis spectroscopy
1) The synthesis of carbazoles from triarylamines bearing
electron-rich methoxy groups tend to produce higher yields. In
all cases, UV-light irradiation provided shorter reaction times
and in general, higher yields as well. Preferences for either exo
or endo products tend to be similar except in cases when the
group is located in the para position with respect to the nitro-
gen atom.
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Received: July 7, 2015
Published online on September 23, 2015
Chem. Eur. J. 2015, 21, 16673 – 16678
www.chemeurj.org
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