Synthesis of heterocycles via Pd-ligand controlled cyclization of 2-chloro-N-(2-vinyl)aniline: Preparation of carbazoles, indoles, dibenzazepines, and acridines

Article abstract of DOI:10.1021/ja107511g

The Pd-catalyzed condensation of 2-bromostyrene and 2-chloroaniline derivatives yields stable diphenylamine intermediates, which are selectively converted to five-, six-, or seven-membered heteroaromatics (indoles, carbazoles, acridines, and dibenzazepines). The selectivity of these intramolecular transformations is uniquely ligand-controlled and offers efficient routes to four important classes of heterocycles from a common precursor.

Full text of DOI:10.1021/ja107511g

Published on Web 09/21/2010
Synthesis of Heterocycles via Pd-Ligand Controlled Cyclization of
2-Chloro-N-(2-vinyl)aniline: Preparation of Carbazoles, Indoles,
Dibenzazepines, and Acridines
Dmitry Tsvelikhovsky and Stephen L. Buchwald*
Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139
Received August 19, 2010; E-mail: sbuchwal@mit.edu
Scheme 1. Proposed Common Precursor for the Synthesis of
Tricyclic Nitrogen-Containing Heterocyclic Cores
Abstract: The Pd-catalyzed condensation of 2-bromostyrene and
2-chloroaniline derivatives yields stable diphenylamine intermedi-
ates, which are selectively converted to five-, six-, or seven-
membered heteroaromatics (indoles, carbazoles, acridines, and
dibenzazepines). The selectivity of these intramolecular trans-
formations is uniquely ligand-controlled and offers efficient routes
to four important classes of heterocycles from a common
precursor.
The biological activity manifested by tricyclic, nitrogen-contain-
ing heterocyclic compounds makes them attractive targets for
synthetic chemists.1 The seven-membered ring 5H-Dibenz[b,f]-
azepine nucleus (1) is a pharmaceutically important structure and
constitutes the key subunit in tricyclic antidepressant drug sub-
stances as Carbamazepine (2) and Oxcarbazepine (3).2 These
anticonvulsant and mood stabilizing drugs are primarily used for
the treatment of epilepsy, bipolar disorder,3 trigeminal neuralgia,4
and other neurological disorders.5 Currently, the most widely
employed method for the construction of dibenzazepine analogs
involves a gas-phase dehydrogenation of iminobibenzyls at high
temperatures.6,7 The crude product in these processes is usually
contaminated with 9-methylacridine.8 Thus, a general and efficient
means for the synthesis of substituted dibenzazepines remains a
challenging problem. In addition, the closely related acridine and
carbazole tricyclic nuclei also feature prominently among natural
products and drug substances.9 Various methods utilizing a number
of synthetic platforms and starting materials are used for the
construction of such heteroaromatic systems.1b,10 While there are
many strategies available for the synthesis of carbazoles,2,11
methods for the preparation of acridines12c,13 are limited and
typically require harsh, functional group-intolerant conditions.
solvent, and temperature. Further examination of these variables
led us to discover that the mode of heterocyclization is almost
exclusively controlled by the ligand employed. We examined a
variety of phosphines (L1-L11)14a and found that DavePhos (L2)
was a highly effective ligand for the 7-endo cyclization of 7 to
form 1. In contrast, TrixiePhos (L3) and L4,16 selectively furnished
1-vinylcarbazole (8) and 9-methylacridine (9), respectively (Scheme
2). An efficient catalyst for all transformations was formed from
the combination of the appropriate ligand, Pd2dba3 and NaOt-Bu
at 100-110 °C. Among the solvents screened, the use of 1,4-
dioxane was superior in terms of conversion and selectivity for the
formation of 5H-dibenzazepine and 1-vinylcarbazole. Regioselective
6-exo cyclization to form 9-methylacridine was achieved using L4
in toluene. It should be noted that no other heterocycles or side
products were formed under the optimized conditions. Other
combinations11b-d of catalyst, ligand, base, and solvent led to the
production of multiple products or gave low yields of the desired
heterocycles.
To the best of our knowledge, our results represent the first cases
of such intramolecular reactions that incorporate a 7-endo cycliza-
tion. Control experiments were performed and demonstrated that
no reactions occurred in the absence of ligand. Interestingly, of all
the ligands screened, L2 was unique in promoting the cascade
synthesis17 of 5H-dibenzazepine (Scheme 3). This direct transfor-
mation was achieved via a tandem reaction of 2-bromostyrene with
2-chloroaniline, which proceeded smoothly in the presence of
Pd2(dba)3, L2, and NaOt-Bu, to provide 1 in 99% isolated yield.
Other ligands (L1, L3-L11) afforded a diarylamine intermediate
as the only observed product. As shown in Table 1, our protocol
for the tandem synthesis of 5H-dibenzazepine derivates is quite
general.
An examination of a series of tricyclic heteroaromatic compounds
led us to the realization that 5H-dibenzazepines (4), 9-methy-
lacridines (5), and vinylcarbazoles (6) might be derived from a
common precursor via controlled intramolecular cyclizations. The
key precursor (7) was prepared in 91% yield via a C-N coupling
reaction14,15 of commercially available 2-bromostyrene and 2-chlo-
roaniline, as shown in Scheme 1.
Following the initial survey of ligands (L3 and L4 for the
formation of carbazoles and acridines respectively) and optimization
of Pd sources, we next prepared a range of vinyldiarylamines (as
We reasoned that four major factors would control the regiose-
lectivity of the Pd(0)-catalyzed transformation of 7: ligand, base,
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C O M M U N I C A T I O N S
Scheme 2. Pd/Ligand Controlled Selective Cyclizations
Table 1. Pd-Catalyzed Tandem Formation of Dibenzazepines
a Reaction conditions: Isolated yields (average of two runs). 1.0
mmol of styrene, 1.2 mmol of amine, 1 mL of dry 1,4-dioxane, 3.0
mmol of NaOt-Bu, 0.0075 mmol of Pd2(dba)3, 0.023 mmol of L2; Ar
atmosphere; 110 °C, 24 h. b Reaction time: 6 h. c Reaction proceeded to
85% conversion (GC). d Reaction conditions: 2.5 mol % Pd2(dba)3 and 8
mol % of L2 are required.
Table 2. Synthesis of Diarylamine Intermediatesa
shown in Table 2). The intermediates so prepared were then
subjected to Pd-catalyzed cyclization conditions to provide a range
of vinylcarbazoles and acridines in a highly regioselective manner
and in good to excellent yields (Table 3). Notably, both electron-
rich and electron-deficient vinyldiarylamines were transformed in
an efficient manner.
a Reaction conditions: 1.0 mmol of 2-bromostyrene, 1.2 mmol of
amine, 0.0075 mmol of Pd2(dba)3, 0.023 mmol of L1 (BrettPhos), 1.0
mL of dry 1,4-dioxane, 1.5 mmol of NaOt-Bu; Ar atmosphere; 110 °C,
4 h. Isolated yields.
As an expansion of this study, we explored the preparation of
N-arylindoles through the use of an oxidative cyclization.1b,18 Using
the same precursors as above, the construction of arylindoles was
achieved via intramolecular C-N bond formation. These reactions
proceed in the presence of Pd(OAc)2, Cu(OAc)2, and acetic acid
in DMF at 100 °C, to provide 2-chloro-N-arylindoles in excellent
yields (Table 4).
Scheme 3. One-Pot Direct Synthesis of 5H-Dibenzazepine
In Scheme 4 we suggest plausible mechanisms for the
transformations described above. The dibenzazepine, vinylcar-
bazole, and acridine syntheses are likely initiated by the oxidative
addition of Pd(0) to 7. Carbon-carbon bond formation, in the
construction of 5H-dibenzazepine, may proceed via intermediate
A to form eight-membered palladacycle B, which then undergoes
reductive elimination to afford 1 (pathway I, green).19 With L3,
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Table 3. Selective Formation of Acridines and Carbazolesa
Scheme 4. Possible Mechanistic Pathways
a Reaction conditions: Isolated yields (average of two runs). 1.0
mmol of intermediate, 1.5 mmol of NaOt-Bu, 110 °C, 24 h. For
acridines: 1 mL of dry toluene, 0.025 mmol of Pd2(dba)3, 0.075 mmol
of L3. For vinylcarbazoles: 1 mL of dry 1,4-dioxane, 0.0075 mmol of
Pd2(dba)3, 0.023 mmol of L4.
derivates. Our future efforts will be devoted to obtaining a clearer
understanding of the mechanism of these highly ligand-dependent
transformations.
Table 4. Pd(II)-Catalyzed Synthesis of N-Arylindolesa
Acknowledgment. This research was financially supported by
the National Institutes of Health (NIH) (GM-58160) and Novartis
AG.
Supporting Information Available: Experimental details for the
synthesis of all new compounds and spectral data. This information is
available free via the Internet at http://pubs.acs.org.
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