Gold-Catalyzed Carbazolation Reactions of Alkynes

Article abstract of DOI:10.1021/acs.orglett.0c01719

Herein, we report on a Au(I)-catalyzed reaction of alkynes with carbazoles that enables a one-step synthesis of vinyl carbazoles that are important molecules for applications as photoluminescent materials. This reaction proceeds under mild conditions at r

Full text of DOI:10.1021/acs.orglett.0c01719

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Letter
Gold-Catalyzed Carbazolation Reactions of Alkynes
Sripati Jana, Feifei He, and Rene M. Koenigs*
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ABSTRACT: Herein, we report on a Au(I)-catalyzed reaction of
alkynes with carbazoles that enables a one-step synthesis of vinyl
carbazoles that are important molecules for applications as
photoluminescent materials. This reaction proceeds under mild
conditions at room temperature, without the need of external
bases, and can be employed to a variety of aromatic and aliphatic
alkynes in monohydroamination and poly-hydroamination reactions. We conclude with photophysical studies of the vinyl carbazole
products, which feature distinct fluorescence properties.
Scheme 1. (a) Hydroamination Reactions of N-
Heterocycles; (b) Synthesis of N-Vinyl Carbazoles; (c)
Gold-Catalyzed Hydroamination of Alkynes with
Carbazoles
he high prevalence of the C−N bond in natural products,
Tagrochemicals, drugs, or materials renders the catalytic
formation of new C−N bonds as one of the most important
reactions in organic synthesis.1,2 With the recent advances of
metal-catalyzed cross-coupling reactions, methods for the
coupling of aryl halides with nitrogen nucleophiles became
one of the most important strategies for this purpose.
However, mandatory prefunctionalization of at least one
reaction partner hampers the overall process efficiency.2 On
the contrary, the hydroamination allows for direct C−N
coupling reactions of amines with unsaturated bonds via
activation of the π-system of the unsaturated reaction
partner.3,4 Hydroamination reactions have consequently
developed as an important timely strategy to conduct atom-
efficient C−N coupling reactions. The currently available
synthetic repertoire covers the reaction of a diverse set of
olefins and alkynes with nitrogen nucleophiles, such as amines,
amides, or anilines.3,4 On the contrary, hydroamination
reactions of unprotected aromatic N-heterocycles are much
less developed.5−8 Different groups described the catalytic
hydroamination of alkynes with indole or pyrrole heterocycles
using catalysts based on Cu(I) yet requiring high reaction
temperatures and strong base to achieve this reaction and
giving the product of endo-dig addition (Scheme 1a).5,6
Echavarren, Verma, and Larock reported on the intramolecular
hydroamination of indole.7 Li and co-workers reported on an
intermolecular reaction of anilines with alkynes using a Au(III)
catalyst at high temperatures to give the formal hydro-
amination product of indole and phenylacetylene. However,
careful mechanistic experiments have shown that this reaction
does not proceed via a hydroamination route (Scheme 1a).8
Based on our interest in the functionalization of N-
heterocycles via carbene intermediates,9 we hypothesized that
the hydroamination of carbazole heterocycles with alkynes
should provide an elegant entry into N-vinyl-substituted
carbazoles (Scheme 1b). N-Vinyl carbazoles are important
building blocks in the synthesis of carbazole-based electro-
Received: May 20, 2020
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© XXXX American Chemical Society
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luminescent materials,10 and currently available synthesis
methods involve cross-coupling of vinyl bromides,11 oxidative
coupling of olefins,12 addition reactions under strongly basic
conditions,13 or carbene transfer of tosylhydrazones (Scheme
1b).14 The direct synthesis of vinyl carbazoles from readily
available starting materials at ambient conditions thus remains
a challenge in organic synthesis, and the development of a
hydroamination reaction of alkynes with unprotected carbazole
would open up an direct approach toward this important
structural element (Scheme 1c).
coordinating solvents have a detrimental effect on the product
yield. In contrast to previous reports on Cu(I)-catalyzed high-
temperature hydroamination reactions of pyrrole, we could
observe the selective formation of the exo-addition product.13
With the optimized conditions in hand, we embarked on the
applicability of this hydroamination reaction and studied
different terminal alkynes 11 in the reaction with carbazole
10a. Aromatic alkynes bearing electron-donating or halogen
substituents in the para- or meta-position underwent the
hydroamination reaction in high isolated yield even on a 3
mmol scale (see Scheme 2, 12a−h, 2 mol % (XPhos)AuCl and
We set out our studies toward the hydroamination reaction
of N-heterocycles by studying the reaction of carbazole 10a
and phenylacetylene 11a in DCM solvent. Different Cu, Ag,
Rh, or Pd catalysts proved unreactive or inefficient as
Scheme 2. Substrate Scope of Alkynes
1
determined by H NMR analysis of crude reaction mixtures
(for details, see the Supporting Information).15 A notable
difference was observed when employing Au(I) catalysts.16
While only trace amounts of the desired hydroamination
product 12a were observed using the bidentate dppf ligand,
moderate reaction yields could be obtained even at room
temperature when employing phosphite or the sterically
demanding tri-tert-butyl phosphine ligand (Table 1, entries
Table 1. Optimization of Reaction Conditions
a
b
no.
catalyst
additive
solvent
% yield
1
2
3
4
5
6
7
8
9
10
dppf(AuCl)2
(L1)AuCl
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgSbF6
AgPF6
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
traces
42
no rxn
32
32
60
traces
traces
38
72
82
(IMes)AuCl
(tBu3P)AuCl
(tBuXPhos)AuCl
(XPhos)AuCl
(XPhos)AuCl
(XPhos)AuCl
(XPhos)AuCl
(XPhos)AuCl
(XPhos)AuCl
(XPhos)AuCl
AgBF4
AgNTf2
NaBArF
NaBArF
NaBArF
c
11
12
d
86
a
Reaction conditions: 0.2 mmol (1.0 equiv) of 10a, 0.2 mmol of 11a,
5 mol % of catalyst, and 5 mol % of additive were dissolved in 2.0 mL
of DCM, and the reaction mixture was stirred at rt until the
b
c
completion of the reactions. Isolated yield. 1.5 equiv of 11a was
d
used. 2 equiv of 11a and 10 mol % of NaBArF (sodium tetrakis[3,5-
bis(trifluoromethyl)phenyl]borate) were used. L1 = tris(2,4-di-tert-
butylphenyl)phosphite. IMes = 1,3-dimesitylimidazol-2-ylidene. tBuX-
Phos = 2-di(tert-butyl)phosphino-2′,4′,6′-triisopropylbiphenyl.
1−5). The best yield of 12a was obtained when using XPhos
(2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl) as li-
gand (Table 1, entry 6). Further investigations concerned the
effect of counterion, reaction stoichiometry, temperature, and
solvent.15 A remarkable effect of the counterion was observed
(Table 1, entries 6−10), and no reaction was observed using
BF4 or PF6 anion, indicating a strong influence of the
counterion on the reactivity of the Au(I) complex. We thus
5 mol % NaBArF on 3 mmol scale). When investigating ortho-
substituted arylacetylene derivatives (Scheme 2, 12i−j) or
thiophene-substituted acetylene (Scheme 2, 12k), a slightly
reduced yield was observed. Only in the case of electron-
withdrawing substituents, such as a CF3-substituted phenyl-
acetylenes 11l,m, was a notable reduction in product yield of
−
examined the weakly coordinating BArF anion, which led to
excellent yields of the desired hydroamination product (Table
1, entries 10−12). This observation is also in line with the
results of the solvent screen, which revealed that polar,
B
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the hydroamination product 12l,m observed, which can be
rationalized by the higher reactivity of the hydroamination
product and, consequently, a rapid hydrolysis by trace amounts
of water in the reaction mixture. The limitations of the present
methodology lie within the use of strong electron-withdrawing
groups (e.g., CN) or the use of N-heterocycles (Scheme 2,
11o,p). For both, no product of the hydroamination was
observed, which might be explained by poisoning of the
cationic Au(I) catalyst by the Lewis basic 3-pyridylacetylene or
by hydrolysis of the reaction product in the case of the cyano-
substituted phenylacetylene. Similarly, 1,2-disubstituted al-
kynes (11q,r), styrene (13), or phenylallene (14) did not
react in this hydroamination reaction. An interesting
observation was made with 1-trimethylsilyl-2-phenylacetylene
11n: in this case, the hydroamination reaction proceeded in
moderate yield with concomitant cleavage of the silyl group to
give product 12a.
product were observed when employing [H6]-carbazole (16),
indole (17), or phenothiazine (18) as the reaction partner,
which might be related to the ease of hydrolysis of the reaction
product or poisoning of the electrophilic Au(I) catalyst as
observed by 31P NMR of the Au(I) catalyst in the presence of
heterocycles 17 and 18.15
Based on the importance of carbazole heterocycles in
materials’ applications, we next studied this protocol in multi-
hydroamination reactions (Figure 1). For this purpose, we
Subsequently, we applied this hydroamination protocol
under slightly modified conditions (L1 instead of XPhos; for
the optimization of conditions, see the Supporting Informa-
tion) to aliphatic, terminal alkynes, which reacted in moderate
yield to the desired vinyl-substituted carbazole (12s−w). Even
cyclopropyl acetylene smoothly reacted in this hydroamination
reaction without ring opening of the cyclopropane ring.
Further studies focused on the influence of the substitution
pattern of the carbazole heterocycle (Scheme 3). While
Figure 1. Multi-hydroamination reactions (reaction conditions: 5 mol
% of (XPhos)AuCl, 10 mol % of NaBArF, carbazole (1.0 equiv for 19
and 20, 2.0 equiv for 21−23, 3.0 equiv for 24) and acetylene
derivative (for 19 and 20: 11a, 4.0 equiv; for 21−24: 1.0 equiv) were
dissolved in 2.0 mL of DCM and stirred for 12 h at room
temperature).
Scheme 3. Substrate Scope of N-Heterocycles
studied 5,7-dihydroindolo[2,3-b]carbazole in the reaction with
phenylacetylene under the previously optimized conditions,
which gave the double hydroamination product 19 in
moderate yields. The closely related isomer 20 did not react
in the hydroamination reaction. The missing reactivity of 20
might be related to the strong coordinating properties of the
two adjacent nitrogen atoms, which shuts down the catalytic
activity of the Au(I) complex. Next, we employed all isomers
of di(ethynyl)benzene to probe a double hydroamination
reaction onto one alkyne reaction partner. The double
hydroamination products 21 and 22 could indeed be obtained
under the same reaction conditions in good isolated yields for
1,4-di(ethynyl)benzene and 1,3-di(ethynyl)benzene, respec-
tively. On the contrary, no reaction was observed when
studying 1,2-di(ethynyl)benzene (23). Finally, we probed the
hydroamination reaction of 1,3,5-tri(ethynyl)benzene, which
gave the product of triple hydroamination 24 in 49% yield.
From a mechanism perspective, we hypothesize that the
present reaction proceeds via π-coordination of the alkyne to
the cationic Au(I) complex 26 as can be observed by a distinct
shift in 31P NMR upon addition of alkyne 11a to in situ formed
26. A competitive complexation of the Au(I) complex 26 with
carbazole 10a is not likely to occur as no change of chemical
shift in 31P NMR was observed. The Au(I)−alkyne complex 27
then undergoes addition of the carbazole heterocycle leading
to formation of a putative Au(I)−vinyl complex 29.17 Release
of the reaction product by protodeauration refurnishes the
catalytically active Au(I) complex 26 (Scheme 4). The distinct
role of NaBArF in this transformation still remains unclear, and
detailed studies via DFT calculations will be necessary to fully
understand the role of the counterion in this transformation.
substitution in the 2-, 3-, and 6-position of the carbazole
framework had only little influence on the hydroamination
reaction, a pronounced decrease in the reaction yield was
observed for 1-bromocarbazole. In this case, the hydro-
amination product was isolated in only 37% yield, which can
be attributed to steric hindrance of the bromo substituent. In
this context, we also studied bis-carbazole 13j and the
benzannellated carbazole 13i, both of which gave the desired
hydroamination product 14j and 14i in high yield, respectively.
In this context, we also studied the application of different
unprotected N-heterocycles. While the hydroamination prod-
uct 15 of [H4]-carbazole could be isolated in moderate yield,
only trace amounts of the corresponding hydroamination
C
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the photoluminescent properties for potential further applica-
tions.
Scheme 4. Putative Mechanism for the Carbazolation
Reaction of Alkynes
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c01719.
Experimental procedures, reaction optimization tables,
NMR studies of gold complexes, characterization data,
analytical data, NMR spectra for all compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
Rene M. Koenigs − RWTH Aachen University, Institute of
Organic Chemistry, D-52074 Aachen, Germany; orcid.org/
0000-0003-0247-4384; Email: rene.koenigs@rwth-
aachen.de
Given the relevance of carbazole as photoluminescent
materials,10 we performed initial studies on the photochemical
properties of selected products of this hydroamination
reaction. For this purpose, we measured UV−vis and
fluorescence spectra of a selected series of vinyl carbazoles.
Spectra were obtained from 25 μM solution in DCM solvent
with absorbance peaks at 290 nm, disregarding of the
substitution pattern. Fluorescence data of 25 μM solution
(Figure 2) showed a significant influence of the substitution
Authors
Sripati Jana − RWTH Aachen University, Institute of Organic
Chemistry, D-52074 Aachen, Germany
Feifei He − RWTH Aachen University, Institute of Organic
Chemistry, D-52074 Aachen, Germany
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c01719
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
R.M.K. thanks the German Science Foundation and Dean’s
Seed Fund of RWTH Aachen for financial support.
■
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