Photochemical Synthesis of Carbazoles Using an [Fe(phen)3](NTf2)2/O2 Catalyst System: Catalysis toward Sustainability

Article abstract of DOI:10.1021/acs.orglett.6b02456

An increasingly sustainable photochemical synthesis of carbazoles was developed using a catalytic system of Fe(phen)₃(NTf₂)₂/O₂ under continuous flow conditions and was demonstrated on gram-scale using a numbering-up strategy. Photocyclization of triaryl and diarylamines into the corresponding carbazoles occurs in general in higher yields than with previously developed photocatalysts.

Full text of DOI:10.1021/acs.orglett.6b02456

Letter
pubs.acs.org/OrgLett
Photochemical Synthesis of Carbazoles Using an [Fe(phen)3](NTf2)2/
O2 Catalyst System: Catalysis toward Sustainability
Shawn Parisien-Collette, Augusto C. Hernandez-Perez, and Shawn K. Collins*
Dep
Queb
́
artement de Chimie, Centre for Green Chemistry and Catalysis, Universite
ec H3C 3J7 Canada
́ ́ ́
de Montreal, CP 6128 Station Downtown, Montreal,
́
S
* Supporting Information
ABSTRACT: An increasingly sustainable photochemical synthesis of
carbazoles was developed using a catalytic system of Fe(phen)3(NTf2)2/
O2 under continuous flow conditions and was demonstrated on gram-
scale using a numbering-up strategy. Photocyclization of triaryl and
diarylamines into the corresponding carbazoles occurs in general in
higher yields than with previously developed photocatalysts.
setup. Despite the good yields and wide substrate scope, several
key drawbacks were identified (Figure 1), especially when scale-
hotocatalysis has experienced a resurgence in interest as a
Ptool for organic synthesis, particularly as the use of light as an
energy source is widely viewed as a green technology.1 The
harvesting of light by sensitizers and subsequent electron transfer
to different molecules can promote a number of important
organic transformations via catalysis. In parallel, continuous flow
methods have complemented the development of new photo-
chemical technologies, allowing faster reactions times and
improved scale-up to synthetically relevant scales.2 Among
metal-based sensitizers for photoredox catalysis, Ru- and Ir-based
complexes possessing polypyridine and associated ligands have
demonstrated utility in a host of transformations.3 However,
questions of sustainability have led to the exploration of
Figure 1. Limitations of the Cu-based sensitizer/I2 catalyst system and
targets for a new catalyst system.
4
up would be considered. Although copper remains a more
abundant and cheaper metal than Ru or Ir, both metal and ligand
costs would have to be revisited. A change from molecular iodine
to molecular oxygen or air would permit a more benign oxidant
system. Lastly, the copper-catalyzed reaction required relatively
long residence times for a continuous flow process, and
decreasing the residence time through either chemical reactivity
or reaction engineering would be valued. Herein, we report the
synthetic utility of a soluble Fe-based sensitizer complex for a
photocatalytic oxidative transformation under continuous flow
conditions.
The first goal was to survey photocatalysts that could
efficiently form the carbazole nucleus using molecular oxygen
as an oxidant. Molecular oxygen can accept an electron and act as
a reagent to promote organic oxidative transformations.9 As such,
a variety of sensitizers were evaluated in an oxidative cyclization
to form 9-phenylcarbazole employing molecular oxygen (Figure
2). All reactions were performed in continuous flow using
household lightbulbs as the light source. To achieve the goal of
using molecular oxygen as the stoichiometric oxidant,10 a tube-
heterogeneous photocatalysis via sensitized TiO2 or meso-
porous carbon nitride polymers,5 as well as homogeneous
photocatalysis using organic dyes.6
The use of Cu-based sensitizers7 has now attracted attention as
a cheaper and more abundant metal source for photocatalysis,
although they remain underexplored in comparison to their Ru-
and Ir-based counterparts. Our group previously described the
use of heteroleptic copper complexes for the synthesis of
carbazole heterocycles (Scheme 1).8 The complex Cu-
(Xantphos)(neo)BF4 formed in situ promoted the oxidative
cyclization of di- and triarylamines to the corresponding
carbazoles using visible light irradiation and a continuous flow
Scheme 1. Photoredox Synthesis of Carbazoles Using a Cu-
Based Sensitizer/I2 Catalyst System
Received: August 16, 2016
© XXXX American Chemical Society
A
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previously used to trap any acidic byproducts, improved the
isolated yield of 2 to 95%.
It should be noted that the excited states of polypyridyl
complexes of the type *FeL32+ are short compared to analogous
Ru-based analogues16,17 and hence should not operate via the
single electron transfer mechanisms common in photoredox
catalysis. Given the abundance of literature data which support
that photoredox catalysis via metal-to-ligand charge transfer for
Fe(II)−polypyridyl complexes is not possible in solution,18 it is
reasonable to assume that some other mechanism must be
promoting the photochemical transformation. It may also be
possible that catalysis is achieved through Fe(III)-based
impurities. A control experiment was performed where
commercially available Fe(II)Cl2 was purified using a reported
protocol to remove any Fe(III)-based impurities, and the
corresponding catalyst 3 was prepared. Once again, the
transformation (1 → 2) occurred in high yield (∼80% of 2)
and required visible light irradiation (in the absence of light, 5%
2, 94% recovered 1). Given the necessity of the iron complex,
light, and oxygen for the reaction to occur, the oxidation of the
amines to carbazoles could proceed mechanistically via
formation of superoxide.19 The improved mixing of O220 made
possible via the flow tube-in-tube system likely helps accelerate
the reaction rate. In addition, when the transformation (1 → 2)
was performed with Fe(III)(phen)3PF6 in either catalytic or
stoichiometric quantities, no productive formation of the desired
carbazole 2 was observed.
A second goal to improve the synthesis of carbazoles was to
decrease the reaction time. The use of continuous flow
techniques is crucial to the success of the Fe(phen)3(NTf2)2/
O2 photocatalytic system. When the analogous carbazole
synthesis (1 → 2) was performed in batch with a reaction time
of 6.67 h, only traces of 2 could be isolated from the reaction
mixtures. When a reaction time of 50 h was used, the desired
carbazole could be isolated in 15% yield. In addition, in the
absence of the tube-in-tube reactor, the yields of the carbazole 2
ranged from 46 to 95% yield, highlighting the need for efficient
dissolution of molecular oxygen in the reaction media. To
decrease the residence time, modifications to the continuous
flow reactor were made so that the tubing was no longer in an
interwoven pattern. Consequently, improved irradiation allowed
a decrease in the residence time to 3.33 h, while maintaining high
yields of 2 (91%) (Scheme 2).
Figure 2. Optimization evaluation of photocatalysts for the synthesis of
9-phenylcarbazole. Yields following flash chromatography. Recovered
starting material 1 indicated in brackets.
in-tube reactor11 was used to ensure a high concentration of
dissolved oxygen in THF.12 For convenience, a flow rate of 0.15
mL/min (irradiation time = 6.67 h) was employed. First, the
synthesis of carbazole 2 was performed in the dark, and >90% of
the starting material 1 was recovered. In addition, attempts to
promote the reaction thermally also failed (heating in batch, 80%
recovered 1). The reaction also failed to afford significant yields
of carbazole 2 (13% 2, 86% recovered 1) when performed in the
absence of any photocatalyst. When a Ru- [Ru(bpy)3Cl2] and Ir-
based sensitizer [Ir(ppy)3] were studied, each afforded modest to
low yields of the desired carbazole (46 and 10% yield,
respectively). Next, a previously developed Cu-based sensitizer
[Cu(Xantphos)(neo)BF4, 34% yield] and an organic sensitizer
(eosin Y,13 26% yield) were also evaluated but provided low
yields, as well. An Fe-based catalyst [Fe(bpy)3(NTf2)2]14
afforded a 37% yield of carbazole 2. The NTf2− counterion was
chosen specifically to augment the solubility of the Fe complex
for its use in continuous flow. Other Fe-based complexes were
also investigated, and the phen-derived complex 315 provided the
desired carbazole in the highest yield (74%). Finally, further
optimization via the removal of the propylene oxide additive,
Scheme 2. Improved Irradiation with Reactor Design
To probe the efficiency of the Fe(phen)3(NTf2)2/O2 system, a
series of carbazoles were prepared from the corresponding diaryl-
or triarylamines (Table 1). First, triarylamines bearing an
electron-donating OMe or Me substituent were cyclized using
the optimized conditions. The carbazoles 4 and 5 were isolated in
85 and 81% yields, respectively. The synthesis of carbazoles
B
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Letter
the yields were all higher when the Fe-based sensitizer/O2
catalyst system was employed and performed in a much shorter
reaction time (residence times 3.33 vs 20 h for Fe- vs Cu-based
catalyst systems).
Table 1. Efficiency of the Fe(phen)3(NTf2)2/O2 System for
the Synthesis of Carbazoles
The improved protocol utilizing molecular oxygen and shorter
residence times was explored on ∼40 mg scales. We decided to
explore the scalability in the photochemical synthesis of
carbazoles up to a gram-scale. Using an experimental setup
which involved five tubing reactors in series, at ∼40 mg scales, the
desired carbazole 2 was obtained in 91%. When the scale of the
reaction was increased to 1 g, the reaction profile remained highly
reproducible (88% of 2). A drawback was the long overall process
time required for the scale-up: the 1 g transformation (1 → 2)
required approximately 50 h to complete. To demonstrate
improved protocols for scale-up, proof-of-principle for the utility
of a “numbering-up” strategy21 was explored (Scheme 3). The
Scheme 3. Numbering-up Strategy for the Synthesis of Simple
and Complex Carbazoles
a
Isolated yields following flash chromatography. Major product is
shown. In the cyclization of substituted triarylamines, the incorpo-
ration of the substituted aryl group is defined as the endo product,
while exclusion of the substituted aryl is defined as the exo substituent.
reaction mixture was first pumped through a tube-in-tube reactor
where the O2 pressure was increased (40 → 100 psi) compared
to smaller scales. After elution from the gas/liquid reactor, the
flow was “split” into the two reactor sequences with two 8 bar
back pressure regulators connected to the end of the flow system.
As such, 2 was obtained in 90% yield, and the overall process time
was reduced by more than 50% (approximately ∼1 g/day). The
optimized photocatalytic synthesis of carbazoles was also applied
to the synthesis of the carbazole core of recently reported
inhibitors of STAT3,22 an emerging biomarker in tumor
therapy.23 The photocyclization of diarylamine 16 was
performed on a >1 mmol scale using the numbering-up reactor
design. The desired and highly substituted carbazole 17 was
obtained in 54% yield.
having an even greater number of electron-donating methoxy
groups could also be prepared. The dimethoxy carbazoles 6 and 7
were prepared in 68 and 76% yields, and the trimethoxy
derivative 8 was isolated in 63% yield. The synthesis of a
pyrimidoindole was also possible as 9 was synthesized in 91%
yield.
When we explored the scope of the synthesis of carbazoles,
two halogenated substrates underwent productive cyclization to
provide halogenated carbazoles 10 and 11 in good yields (76 and
87%, respectively). Both the fluoro- and chlorocarbazoles were
isolated as predominantly the endo isomers. A sterically
encumbered mesityl group was also tolerated and afforded the
carbazole 12 in 77% yield. Three different N-alkylated carbazoles
were also evaluated and isolated in good yields, with the N-Me
carbazole 13 in 80% yield, the N-Et carbazole 14 in 80% yield,
and the tetracyclic heterocycle 15 in 67% yield. In addition, upon
comparison with the previously developed catalyst system
employing a Cu-based catalyst and I2 as molecular oxidant,9
In summary, a new photochemical synthesis of carbazoles has
been developed. Key improvements include the following: (1) a
catalytic system of Fe(phen)3(NTf2)2 allows the use of O2 as a
stoichiometric oxidant; (2) employing a tube-in-tube-type
reactor under continuous flow conditions improved the reaction
C
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numbering-up strategy. The Fe(phen)3(NTf2)2/O2 system
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carbazoles in yields higher than those of the first-generation
copper-based catalyst system. Further fundamental work is
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ASSOCIATED CONTENT
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AUTHOR INFORMATION
Corresponding Author
■
*E-mail: shawn.collins@umontreal.ca.
Notes
The authors declare no competing financial interest.
(17) Fe-based photocatalysts: (a) Gualandi, A.; Marchini, M.;
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ACKNOWLEDGMENTS
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The authors acknowledge the Natural Sciences and Engineering
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program in Continuous Flow Science, the Canadian Foundation
for Innovation for financial support for continuous flow
infrastructure and the Centre for Green Chemistry and Catalysis
(CGCC) for funding. The authors thank Prof. James McCusker
(Michigan State University) for helpful suggestions.
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