Formation of four different aromatic scaffolds from nitriles through tandem divergent catalysis

Article abstract of DOI:10.1002/anie.201403698

A zinc bromide complex, formed by the sequential reaction of nitriles with a Reformatsky reagent and terminal alkynes, is used as an intermediate for divergent palladium-catalyzed reactions. The reaction pathway of the intermediate is precisely controlled by the choice of the reaction solvent or the palladium catalyst to quickly form four different aromatic scaffolds - arylamines, aminoindenes, pyrroles, and quinolines - starting from readily available nitriles.

Full text of DOI:10.1002/anie.201403698

Angewandte
Chemie
DOI: 10.1002/anie.201403698
Tandem Reactions
Formation of Four Different Aromatic Scaffolds from Nitriles through
Tandem Divergent Catalysis**
Ju Hyun Kim, Jean Bouffard, and Sang-gi Lee*
Abstract: A zinc bromide complex, formed by the sequential
reaction of nitriles with a Reformatsky reagent and terminal
alkynes, is used as an intermediate for divergent palladium-
catalyzed reactions. The reaction pathway of the intermediate is
precisely controlled by the choice of the reaction solvent or the
palladium catalyst to quickly form four different aromatic
scaffolds—arylamines, aminoindenes, pyrroles, and quino-
lines—starting from readily available nitriles.
D
ivergent catalytic reactions provide quick access to
structurally different compounds from a common precursor
through controlled reaction pathways, and are highly attrac-
tive tools in the discovery of drugs and functional materi-
als.[1,2] A more promising, yet challenging strategy that
remains largely unexplored is tandem divergent catalysis,
which combines the key advantages inherent to both tandem
reactions[3] and divergent catalysis to provide a rapid access to
different structures from the same simple reagents while
minimizing the generation of waste. In the course of our
studies on the tandem use of the Blaise reaction in catalysis,[4]
we envisoned that the zinc bromide complex A, formed by the
sequential reaction of nitriles with a Reformatsky reagent and
1-alkynes,[5] may serve as a viable intermediate for divergent
Scheme 1. A tandem strategy for the divergent conversion of nitriles to
arylamines, aminoindenes, pyrroles, and quinolines.
Optimization of the reaction parameters (Table S1) showed
that the catalytically active Pd0 species is best obtained from
Pd(OAc)2 (5 mol%) and PPh3 (15 mol%), and that the
outcome of the tandem catalytic reaction is determined by the
reaction solvent. Ultimately, the choice of N-methyl-2-
pyrrolidinone (NMP) in the presence of 2.0 equiv of Bu4NI
at 1358C for 6 h was optimal for the tandem synthesis of 3a
(78% overall yield, Scheme 2a). A significant finding is the
formation of aminoindenene 4a when the tandem reaction is
conducted in DMF/H2O. Rather than merely accelerating the
reduction of Pd(OAc)2 to Pd0,[9] the tandem catalytic reaction
pathways of A1 in this solvent mixture are redirected to give
the hydrodehalogenated aminoindene 4a in 72% yield
(Scheme 2b).[10]
À
À
catalysis involving selective C C and C N bond-forming
reactions. Herein, we report a strategy based on divergent
palladium catalysis that provides four distinct compound
classes—arylamines, aminoindenes, pyrroles, and quino-
lines—from simple nitriles (Scheme 1).[6]
Our investigations began with the Pd-catalyzed intra-
molecular C C bond-forming reactions of A1 (R = o-
1
À
C6H4Br, R2 = Ph), formed by the sequential reaction of
2-bromobenzonitrile, a Reformatsky reagent, and 1-phenyl-
acetylene. When the intermediate A1 was reacted in the
presence of a catalytic amount of [Pd(PPh3)4] in DMF,
1-aminonaphthalene 3a was isolated in 22% yield (entry 1,
Table S1).[7,8] A cursory inspection of the skeletal framework
of intermediate A1 and 1-aminonaphthalene 3a showed that
These results point toward a Heck-type 5-exo-trig carbo-
palladation, giving the s-bonded complex B as a second
À
an unusual 1,2 migration of a C C bond had occurred.
[*] Dr. J. H. Kim, Prof. J. Bouffard, Prof. S.-g. Lee
Department of Chemistry and Nano Science (BK 21 plus)
Ewha Womans University
Seoul 120-750 (Korea)
E-mail: sanggi@ewha.ac.kr
[**] This work was financially supported by the Korea Research
Foundation (NRF-2011-0016344 and NRF-2009-0083525). We thank
Dr. Y. Kim for X-ray analysis and the Daegu branch of the Korea Basic
Science Research Center for mass spectrometric analyses.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201403698.
Scheme 2. Pd/solvent-controlled selective tandem synthesis of 1-ami-
nonaphthalene 3a and indenes 4a and 5a from a common nitrile 1a.
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Table 1: Tandem synthesis of arylamines and aminoindenes from
nitriles.[a]
Scheme 3. Proposed reaction pathways for the formation of 3a in
NMP and 4a in DMF/H2O.
common intermediate,[11] which may be in equilibrium with its
imine tautomer C (Scheme 3). In the absence of b-hydrogen
À
atoms, a b-carbon cleavage from C (C1 C2 bond cleavage),
which affords the stabilized palladium enolate, is among
plausible reaction pathways.[12–13] The latter would undergo
À
a subsequent 6-endo cyclization of D, forming the Cexo C1
bond, and b-H elimination/aromatization would afford 3a-
ZnBr and HPdBr. Closure of the catalytic cycle would then
occur upon regeneration of Pd0 and liberation of amino-
naphthalene 3a, as observed in NMP as solvent. The
formation of aminoindene 4a in DMF/H2O is ascribed to
the protonative and reductive trappings of alkylpalladium
B.[14] When the same reaction was conducted in deuterium-
labelled [D7]DMF/H2O, 75% deuterium was incorporated in
place of one of the protons in the exocyclic methyl group,
implying the intermediacy of a palladium formate such as F,
which undergoes decarboxylation followed by reductive
elimination to afford the deuterium labeled [D75%]-4a.
Reactions performed in DMF/D2O and [D7]DMF/D2O gave
25% and 100% deuterium incorporation, respectively, in 4a.
These labeling experiments suggest that dimethylammonium
formate, generated from DMF and H2O, can effect either the
protolysis of B or its reduction with a rate ratio of k1/k2 = 3.[15]
The intermediacy of s-carbopalladate B offers an addi-
tional opportunity for increasing the diversity of amino-
indenes obtained in this tandem reaction if its interception
with a suitable carbon nucleophile occurs at a rate compet-
itive with the hydrodehalogenation sequence. To our delight,
the tandem Pd-catalyzed reaction of A1 with 2.0 equivalents
of phenylacetylene in the presence of 3.0 equivalents K3PO4
in DMF/H2O satisfied these requirements, affording 5a in
79% yield within 1 h (Scheme 2c).
[a] For details on the reaction conditions, see the Supporting Informa-
tion. Yields of isolated products are given.
indenes 5 can be selectively synthesized from nitriles
(Table 1). The tandem reaction of A1, prepared starting
from 2-bromobenzonitrile with phenylalkynes that bear
either electron-donating or electron-withdrawing groups
afforded the corresponding 1-aminonaththalenes 3b–3 f in
excellent yields. Alkyl alkynes such as 1-hexyne and
4-phenylbutyne were also successfully incorporated to pro-
vide 4-alkyl-substituted 1-aminonaphthalenes 3g and 3h,
albeit with slightly lower yields. Variation of the nitrile moiety
enabled the rapid synthesis of polysubstituted arylamines 3i–
3o in excellent yields in a tandem one-pot manner. Switching
to the conditions optimized for the trapping of B gave
aminoindenes with methyl (4a–4e) and phenyl propargyl
(5a–5e) substituents from the same nitriles and alkynes. The
incorporation of 3-ethynylpyridine (5 f) and cyclohexenyne
(5g) groups highlights the rapid generation of molecular
diversity through these tandem one-pot catalytic sequences.
We also anticipated that the intermediate A2, generated
using 2-chloroaryl alkynes, may serve as a common precursor
À
Under these reaction conditions, various kinds of amino-
naphthalenes 3, aminoindenes 4, and the alkynylated amino-
for catalyst-controlled selective C N bond-forming reactions
to provide both pyrroles 6 and quinolines 7 selectively,
2
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through oxidative intramolecular olefin amination[16] and
redox-neutral arylamination reactions,[17] respectively. After
screening different reaction conditions (see Table S2), we
found that the treatment of intermediate A2, generated from
benzonitrile and o-chlorophenylacetylene, with 10 mol%
Pd(OAc)2 in the presence of Cu(OAc)2 (2.0 equiv) and
AcOH (2.0 equiv) in DMF at 908C for 2 h afforded pyrrole
6a selectively in 62% yield.[18,19] The catalytic reaction
pathway of A2 can be redirected by using a Pd0 catalyst
ligated with a sterically hindered electron-rich phosphine,
[Pd{P(tBu3)}2] (5 mol%), and tBuOK (1.1 equiv) at 1008C in
DMF to afford quinoline 7a in 60% yield.[20] With a set of
optimized reaction conditions in hand for the selective
synthesis of pyrroles 6 and quinolines 7, several pairs of
these heterocycles were successfully synthesized through
tandem reactions of the intermediate A2, generated from
various nitriles 1, a Reformatsky reagent, and 2-chloro
arylacetylene 2 (Table 2).
Scheme 4. Proposed mechanisms for the formation of a) pyrroles 6,
and b) quinolines 7.
Table 2: Tandem Pd-catalyst-controlled divergent conversion of
common nitriles to pyrroles 6 and quinolines 7.[a]
pyrroles 6. The PdII species can be regenerated by oxidation of
Pd0 with Cu(OAc)2 and O2/AcOH.[22] Nucleophilic substitu-
tion pathways forming the g-C-palladate F, followed by
nucleophilic substitution, reductive elimination, and isomer-
ization in sequence cannot be ruled out at present. For the
formation of quinoline through a typical Buchwald–Hartwig
catalytic cycle (Scheme 4b), oxidative addition of Pd0 to Ar-
Cl first affords I. Deprotonation of the amine with tBuOK
forms J, which leads to Pd0 and N-arylated K through
reductive elimination. Finally, the latter undergoes aromati-
zation to produce the targeted quinoline 7.
In summary, we have developed tandem divergent
catalytic methods for the selective conversion of simple
nitriles to four distinct classes of aromatic compounds. The
zinc bromide complexes of b-enaminoesters, generated by the
sequential reaction of nitriles with a Reformatsky reagent and
1-alkynes, are used as common intermediates. The catalytic
reaction pathways of the intermediates are precisely con-
trolled by a simple change of the reaction solvents or
palladium catalysts to selectively afford arylamines, amino-
indenes, pyrroles, and quinolines. This tandem divergent
catalytic approach is shown to be particularly useful to rapidly
elaborate simple molecules into different complex structures.
Received: March 25, 2014
Published online: && &&, &&&&
[a] For details on the reaction conditions, see the Supporting
Information. Yields of isolated products are given.
Keywords: aromatics · divergency · nitriles · palladium ·
.
tandem reactions
Mechanistic proposals for the formation of pyrroles 6 and
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pyrrole 6 (Scheme 4a), the transformation begins with
a ligand substitution with Pd(OAc)2, resulting in amino-
palladate complex C. A 5-endo-trig cyclization[21] through
either a syn or anti aminopalladation of D gives the
intermediate E, and subsequent b-H elimination affords
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Angew. Chem. Int. Ed. 2014, 53, 1 – 5
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Communications
Tandem Reactions
Four roads diverged: A zinc bromide
complex, generated by the sequential
reaction of nitriles with a Reformatsky
reagent and 1-alkynes, is used as an
intermediate for divergent palladium-cat-
alyzed reactions. The reaction pathway
depends on the choice of reaction sol-
vents and palladium catalysts. The
method provides a simple and efficient
approach to four different frameworks
starting from readily available nitriles.
J. H. Kim, J. Bouffard,
S.-g. Lee*
&&&& — &&&&
Formation of Four Different Aromatic
Scaffolds from Nitriles through Tandem
Divergent Catalysis
Angew. Chem. Int. Ed. 2014, 53, 1 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
These are not the final page numbers!