A visible-light-mediated synthesis of carbazoles

Article abstract of DOI:10.1002/anie.201306920

The photosynthetic preparation of N-aryl- and N-alkyl-bearing carbazoles utilizes continuous flow, visible light, and an in situ formed Cu-based sensitizer (see picture). The method is mild and efficient, and allows the straightforward synthesis of a variety of carbazoles with different substituents, heterocycles, and complex carbon architectures. Copyright

Full text of DOI:10.1002/anie.201306920

Angewandte
Chemie
DOI: 10.1002/anie.201306920
Photochemistry
Hot Paper
AVisible-Light-Mediated Synthesis of Carbazoles**
Augusto C. Hernandez-Perez and Shawn K. Collins*
Carbazole, discovered over 100 years ago,[1,2] is a privileged
heterocyclic motif whose electronic and structural features
have allowed its derivatives to find numerous applications. In
addition to its abundance in natural products[3] and bioactive
molecules,[4] carbazole has been a key motif in the develop-
ment of organic light-emitting materials because of its wide
band gap, high luminescent efficiency, and flexibility to
modify its parent skeleton.[5] It has been found to be
particularly useful in the preparation of highly efficient
light-emitting[6] and charge-transporting/host materials.[7]
Recently, catalytic transition-metal-based syntheses of
carbazoles, involving oxidative pathways through N activa-
tion, have become increasingly attractive (Figure 1). These
(C4a!C4b) for the synthesis of carbazoles from diaryl-
ꢀ
amines. In contrast to the C N bond formation strategies,
ꢀ
only one oxidative Pd-catalyzed C C bond-forming route
toward carbazoles has been reported with a synthetically
useful substrate scope, albeit with high reaction temperatures
and under highly acidic conditions (PivOH as solvent).[9a]
ꢀ
While other C C bond-forming strategies, such as an
[9b]
ꢀ
oxidative Pt-catalyzed C H activation
and a UV-light-
mediated Mallory-type reaction,[10,11] have been described,
the methods have not been further developed into robust
synthetic methods.
Photoredox catalysis[12] for oxidative C C bond coupling
ꢀ
would be an attractive synthetic method for the synthesis of
carbazoles from the corresponding di- or triarylamines, and
would benefit from direct access to these amines through
relatively mild cross-coupling methods.[13] When compared to
ꢀ
other oxidative C C bond-forming routes to carbazoles, the
photoredox strategy would employ lower temperatures and
avoid the use of high-energy UV light. Herein, we describe
a photoredox oxidation, utilizing visible light and a continu-
ous-flow strategy to transform arylamines into functionalized
carbazoles.
We initially used the common sensitizer [Ru(bpy)3](PF6)2
to promote the synthesis of carbazoles from di- or triaryl-
amines (Table 1, entries 1 and 2). While no reaction was
observed with diphenylamine (1) as substrate,[14] triphenyl-
amine (TPA, 2) was converted to 4 to some extend (27% yield
of isolated product). We next turned our attention to Cu-
based complexes that have been previously reported as
sensitizers in photoredox transformations and in which the
bisphosphine and diamine ligands influence the photophys-
ical properties of the sensitizers (Table 1).[15] In addition to the
low cost of these complexes, they can be rapidly screened
using an in situ synthesis.[15] The investigated CuI-based
sensitizers were formed in situ by sequential addition of
a bisphosphine ligand, such as Xantphos, and a diamine
ligand, such as 2,9-dimethyl-1,10-phenanthroline (dmp), to
a [Cu(MeCN)4]BF4 precursor to afford Cu-based complexes,
such as 5. The Cu-based sensitizer 5 (formed in situ) catalyzed
the formation of N-phenyl carbazole 4 from 2 in 56% yield
(Table 1, entry 3). The reaction was conducted in the dark at
reflux, to examine whether any thermal activation was
possible,[16] but formation of 4 was not observed. Utilizing
other phosphine or amine ligands for the sensitizer, such as
combinations of DPEphos 7 or the diamine 2,2’-bipyrazine
(bpz, 9),[17] had no beneficial effect on the reaction (Table 1,
entries 5–7). Finally, the reaction was performed for 14 days
under optimized conditions, resulting in carbazole 4 in an
excellent yield of 85% (Table 1, entry 5). Despite the
promising yields obtained in the synthesis of carbazole 4,
the long reaction times prohibited a time-efficient screening
for optimized reaction conditions or an investigation of the
Figure 1. Synthetic strategies toward carbazoles.
ꢀ
synthetic methods utilize the formation of a C N bond
(C8a!N9) as the final step in the formation of the carbazole
nucleus. Such oxidative pathways typically exploit a Pd- or
Cu-based catalyst system in combination with a stoichiometric
oxidant (either Cu salts or hypervalent iodine reagents) and
have been used with a wide variety of substrates.[8] Disap-
pointingly, relatively little progress has been made in the
ꢀ
alternative retrosynthetic disconnection of a C C bond
[*] A. C. Hernandez-Perez, Prof. Dr. S. K. Collins
Department of Chemistry and Centre for Green Chemistry and
Catalysis, Universitꢀ de Montrꢀal, CP 6128 Station Downtown,
Montrꢀal, Quꢀbec H3C 3J7 (Canada)
E-mail: shawn.collins@umontreal.ca
[**] The authors acknowledge the Natural Sciences and Engineering
Research Council of Canada (NSERC), Universitꢀ de Montreal, the
Xerox Research Centre of Canada, and the Centre for Green
Chemistry and Catalysis (CGCC) for generous funding. The
Canadian Foundation for Innovation (CFI) is acknowledged for
generous funding of the flow-chemistry infrastructure.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201306920.
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Table 1: Optimization of photocyclization of aryl amines to carbazoles.
Table 2: Optimization of the photocyclization of arylamines to carba-
zoles using a continuous-flow reactor.
Entry
Catalyst
system
Oxidant
system
Yield
[%]
Recovered
2 [%]
1
2
3
Cu
Cu
Cu
I2 (1 equiv)
O2 (1 atm)
(MV)(PF6)2 (15 mol%)
O2 (1 atm)
75
55
65
0
3
0
Entry
Photocatalyst
R
Yield
[%]
Recovered
1 or 2 [%]
4
5
6
Ru
Ru
Ru
I2 (1 equiv)
O2 (1 atm)
(MV)(PF6)2 (15 mol%)
O2 (1 atm)
53
16
22
14
27
21
1
2
[Ru(bpy)3](PF6)2
[Ru(bpy)3](PF6)2
H
0
27
56[b]
85
14
32
30
>99
69
44
0
61
40
47
Ph
Ph
Ph
Ph
Ph
Ph
3[a]
4[c]
5
[Cu(Xantphos)(dmp)]BF4
[Cu(Xantphos)(dmp)]BF4
[Cu(DPEphos)(dmp)]BF4
[Cu(Xantphos)(bpz)]BF4
[Cu(DPEphos)(bpz)]BF4
[a] In the absence of light, 94% of 2 was recovered. [b] In the absence of
Cu-based catalyst and with an excess of I2 (5 equiv), 4 was isolated in
only 16% yield (61% of 2 was recovered).
6[a]
7[a]
Unless stated otherwise, reactions were performed using the discreet
preformed catalyst. [a] Catalyst formed in situ. [b] Repeating the reaction
at reflux instead of using visible light did not afford any product. Purging
the mixture with N2 before and during the reaction lowered the yield to
24%. [c] Reaction was left for 14 days. bpy=2,2’-bipyridine.
material 2 when compared to I2 as oxidant system (Table 2,
entries 5 and 6).
With these optimized conditions in hand, with which the
model triphenylamine afforded the desired carbazole 4 in
75% yield (Table 2, entry 1), the scope of the synthesis of
carbazoles was investigated (Table 3). Assuming an oxidative
mechanism, electron-rich triarylamines were initially
substrate scope. Consequently, photoreactions in a batch
reactor (round-bottom flask) were abandoned and replaced
by reactions conducted in a continuous-flow reactor.
The most important advantages of using a continuous-
flow reactor for synthetic photochemistry[18] is the ability to
dramatically increase the exposure of the reaction mixture
(surface area) to ambient light or a focused-light source.
During the optimization of the continuous-flow reaction, both
the Cu-based sensitizer 5 (formed in situ) and the Ru-based
sensitizer [Ru(bpy)3](PF6)2 were surveyed with various oxi-
dant systems (Table 2). In addition, the flow rate was chosen
to target a residence time of 10 hours (0.05 mLminꢀ1, interior
diameter of tubing 0.5 mm, a 12-fold reduction in reaction
time from the batch reactor). The transposition of the
reaction conditions from batch to continuous flow for the
synthesis of 4 from 2 proceeded smoothly with Cu-based
sensitizer 5 to afford carbazole 4 in 75% yield of isolated
product (3.3 mghꢀ1; Table 2, entry 1). The oxidant (I2) could
be replaced by an O2 atmosphere, but with slightly lower
yields (55% yield of isolated carbazole 4; Table 2, entry 2).
The cyclization of 2 was also performed with methyl viologen
(MV) derivative MV(PF6)2 as a catalytic oxidant (Table 2,
entry 3), whose use with Ru-based sensitizers has been well
documented.[19] When the photocatalytic formation of 4 was
investigated with MV(PF6)2, O2, and Cu-based sensitizer 5, 4
was isolated in 65% yield. When the Ru-based sensitizer was
used with I2 as oxidant, 4 was isolated in a 53% yield (Table 2,
entry 4). Once again, switching to O2 or MV(PF6)2 and O2
afforded the product in lower yields, and recovered starting
Table 3: Synthesis of carbazoles from triarylamines.
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explored. The symmetrical carbazole 10, which bears three
methoxy groups, was isolated in good yield (55%), but the
formation of some unwanted by-products was also observed
(very electron-rich triarylamines with low oxidation potential,
such as derivative 10 (0.52 V vs. SCE), could undergo
dimerization, oligomerization, or other unwanted oxidation
pathways). Photoredox cyclization afforded the mesityl-sub-
stituted carbazole 11 in excellent yield (95%).
Next, the photocyclization of unsymmetrical substrates
was investigated. The photocyclization of N-tolyl- and N-
anisyl-substituted derivatives afforded the desired isolated
carbazoles 12 and 13 in identical yields of 70%. Interestingly,
the carbazoles 12 and 13 were isolated as constitutional
isomers in a ratio of 7:1 and 9:1, respectively. In the major
isomers, the electron-rich N-tolyl and N-anisyl rings were not
incorporated in the carbazole nucleus, but were instead in an
“exo” position to the carbazole skeleton. Similar selectivity
was observed in the photocyclization of an iodine-containing
triarylamine, where the corresponding carbazole 14, in which
the iodide substituent provides a convenient handle for
further functionalization, was isolated in 50% yield.
pound under the optimized conditions led to N-methyl-
substituted carbazole 17 in 65% yield, and demethylated
carbazole was not observed.[24]
The cyclization of other N-alkyl-bearing diarylamines was
also examined. Both N-ethyl- and N-isopropyl-bearing car-
bazoles were isolated in good yields: 18 was obtained in 79%
yield and 19 in 65% yield.[25] The photocyclization to form
complex tetracyclic heterocycles was also investigated, and
polycyclic carbazole derivative 20 was isolated in 64% yield
(23% of the starting amine was also recovered). The synthesis
of unsymmetrically substituted carbazoles was also possible.
The 3,9-dimethyl carbazole 23 was isolated in 60% yield.
Similarly, 3-methoxy-9-methylcarbazole 24 was isolated in
63% yield. In addition, the synthesis of heterocyclic motifs
was demonstrated. The N-methyl a-carboline derivative 21
and the pyrimido[5,4-b]indole derivative 22 were isolated in
51% and 53% yield, respectively.
A possible mechanism for the conversion of an arylamine
A into a representative carbazole D is outlined in Scheme 1.
The excited Cu-based sensitizer [Cu(Xantphos)(dmp)]+*
could promote the reduction of I2 to generate the radical
In contrast, the synthesis of carbazoles with precursors
that contain electron-poor heterocyclic aromatic groups
afforded the corresponding carbazoles as a single constitu-
tional isomer in which the heteroaromatic ring was incorpo-
rated into the carbazole framework. Gratifyingly, the pyri-
dine-containing carbazole 15 and the pyrimidine-containing
carbazole 16 were isolated in good yields of 55%[20] and 60%,
respectively, despite the fact that the inclusion of nitrogen
atoms in the aromatic rings of diphenylamines increases their
oxidation potentials.[21] More detailed and thorough mecha-
nistic and experimental work is necessary before the origins of
the selectivity in the photocyclization can be properly
elucidated.
The synthesis of N-alkyl-bearing carbazoles was also
investigated using the photoredox process catalyzed by Cu-
based sensitizer 5 (Table 4). Although the oxidation potential
of N-methyl-N,N-diphenylamine is slightly lower (0.84 V vs.
SCE) than that of 2 (0.98 V vs. SCE),[22] we expected that the
Cu-based sensitizer 5 would promote the oxidation of N-
methyl-N-N-diphenylamine.[23] The cyclization of this com-
Scheme 1. Possible mechanism for the photoredox cyclization of aryl
amines to carbazoles.
dication [Cu(Xantphos)(dmp)]+2. Subsequent oxidation of
the di- or triarylamine by single-electron transfer (SET)
would afford the radical cation B.[26] It is possible that such
a radical could exist as a result of delocalization throughout
the pendant aromatic substituents. The preference for the
radical to be localized in one or another aromatic ring
(labeled with the substituents R2 and R3, Scheme 1) could be
responsible for the observed selectivities for different con-
stitutional isomers (Table 3). It should also be noted that
under electrochemical oxidation conditions, unstable radical
cations such as B often participate in an irreversible
dimerization and loss of protons to form dimers and
oligomeric materials.[27] In contrast, the photoredox cycliza-
tion reported herein preferentially proceeds through intra-
Table 4: Synthesis of carbazoles from diarylamines.
ꢀ
molecular C C bond formation (B!C), and a second
oxidation via an iodide radical (IC!Iꢀ); molecular oxygen
or iodine would be necessary for re-aromatization. The
oxidation could be mediated by the sensitizer or by another
equivalent of the terminal oxidant. Such an oxidative
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quenching mechanism[28] could be supported to a certain
extend when considering the relatively similar yields obtained
in both the cyclizations of 2 using O2 and MV(PF6)2 as
alternate oxidants (Table 2, entries 2 and 3). The latter
oxidant is well precedented to act in oxidative quenching
photoredox processes.[19]
The Cu-based sensitizer [Cu(Xantphos)(dmp)]BF4 has
been exploited in the development of a visible-light-mediated
photoredox synthesis of carbazoles. The novel photochemical
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ꢀ
carbazoles compared to other C N bond-forming strategies.
The reaction rates were greatly accelerated through the use of
continuous-flow conditions. Triarylamines could be converted
to N-aryl-bearing carbazoles (50–95%), and a variety of
tertiary diarylamines could be converted to N-alkyl-bearing
carbazoles (51–79%). A variety of interesting carbazoles
could be prepared, including some heterocyclic skeletons that
have found use in medicinal chemistry. While a more detailed
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systems can be made, this study emphasizes one advantage of
the Cu-based systems. In contrast to the well-defined Ru-
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Received: August 6, 2013
Revised: September 12, 2013
Published online: && &&, &&&&
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Keywords: carbazoles · copper · heterocycles · photochemistry
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demethylation was only productive on dialkylamines or alky-
lated anilines. See: M. Rueping, C. Vila, A. Szadkowska, R. M.
Koenigs, J. Fronert, ACS Catal. 2012, 2, 2810 – 2815.
[25] Problematic substituents at the nitrogen atom included allyl,
propargyl, and benzyl groups; the desired carbazole products
could only be isolated in 20% yield or less.
[26] O. Yurchenko, D. Freytag, L. zur Borg, R. Zentel, J. Heinze, S.
Ludwigs, J. Phys. Chem. B 2012, 116, 30 – 39.
[27] a) K. Sreenath, C. V. Suneesh, V. K. R. Kumar, K. R. Gopidas, J.
Org. Chem. 2008, 73, 3245 – 3251; b) L. M. Moshurchak, C.
Buhrmester, J. R. Dahn, J. Electrochem. Soc. 2008, 155, A129 –
A131; c) T. Morofuji, A. Shimizu, J. Yoshida, Angew. Chem.
2012, 124, 7371 – 7374; Angew. Chem. Int. Ed. 2012, 51, 7259 –
7262.
[19] S. Lin, M. A. Ischay, C. G. Fry, T. P. Yoon, J. Am. Chem. Soc.
2011, 133, 19350 – 19353.
[20] For the UV-light-mediated synthesis of similar derivatives, see:
V. M. Clark, A. Cox, E. J. Herbert, J. Chem. Soc. C 1968, 7, 831 –
833.
[21] The inclusion of nitrogen atoms in the aromatic rings of
diphenylamines increases the oxidation potentials: J. J. Han-
thorn, L. Valgimigli, D. A. Pratt, J. Am. Chem. Soc. 2012, 134,
8306 – 8309.
[28] A reductive quenching mechanism cannot be ruled out without
further data. Reductive quenching of photoactive Cu complexes
that bear one bisphosphine and one diamine ligand has not been
reported. For reductive quenching of complexes that bear two
diamine ligands, see: a) K. L. Cunningham, D. R. McMillin,
Inorg. Chem. 1998, 37, 4114 – 4119; b) A. K. I. Gushurst, D. R.
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1989, 28, 4070 – 4072.
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
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.
Angewandte
Communications
Communications
Photochemistry
A. C. Hernandez-Perez,
S. K. Collins*
&&&& — &&&&
A Visible-Light-Mediated Synthesis of
Carbazoles
The photosynthetic preparation of N-aryl-
and N-alkyl-bearing carbazoles utilizes
continuous flow, visible light, and an
in situ formed Cu-based sensitizer (see
picture). The method is mild and effi-
cient, and allows the straightforward
synthesis of a variety of carbazoles with
different substituents, heterocycles, and
complex carbon architectures.
6
www.angewandte.org
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2013, 52, 1 – 6
These are not the final page numbers!