Metal free carboamination of internal alkynes - An easy access to polysubstituted quinolines

Article abstract of DOI:10.1039/c5cc10460b

A metal free carboamination of unactivated alkynes towards highly substituted quinolines was realized in the presence of a synergistic Br?nsted acid catalyst system. Supported by mechanistic probes, the reaction proceeds via a highly reactive vinyl cation in a C-C bond formation - Schmidt reaction sequence. The irreversible extrusion of N₂, as a powerful driving force, allows for a general conversion of poorly nucleophilic aliphatic alkynes.

Full text of DOI:10.1039/c5cc10460b

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Metal Free Carboamination of Internal Alkynes –
an Easy Access to Polysubstituted Quinolines
Received 00th January 20xx,
Accepted 00th January 20xx
T. Stopka and M. Niggemann*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A metal free carboamination of unactivated alkynes towards
highly substituted quinolines was realized in the persence of a
synergistic Brønsted acid catalyst system. Supported by
mechanistic probes, the reaction proceeds via a highly reactive
vinyl cation in a C-C bond formation - Schmidt reaction sequence.
The irreversible extrusion of N2, as a powerful driving force, allows
for a general conversion of poorly nucleophilic aliphatic alkynes.
Substituted quinolines represent an important structural motif in
numerous biologically active natural products and pharma-
ceutcials.1 Due to their wide utility much effort has been devoted to
the efficient synthesis of these compounds. Traditional conden-
sations, such as the Friedlander reaction and related protocols,2
have been extensively studied. Nevertheless, harsh reaction
conditions such as the necessity for extended heating in strongly
basic or acidic media severely limit functional group tolerance and
often impart modest reaction selectivity. Allowing for milder
reaction conditions, and avoiding self-condensation side reactions
associated with classical Friedlander substrates, the coupling of
alkynes with anilines and derivatives has recently become
increasingly popular.3 Despite remarkable progress, most protocols
are still confined to terminal4 or activated alkynes bearing one or
two carboxylate groups.5 Therefore, new procedures, providing
general access to highly substituted quinolines from internal
alkynes under mild reaction conditions are highly desirable.
Scheme 1 Reaction of azides with internal, unativated alkynes.
metric electrophile - they call for the preformation of alkyne
tethered azide building blocks.
In this context, we reasoned, that in an ideal synthetic strategy
towards highly substituted quinolines from alkynes the C-C bond
formation for the synthesis of the cyclization precursor is combined
with the activation of the alkyne for the subsequent Schmidt
reaction, resulting in a bifunctionalizing formal carboamination of
the unactivated, internal alkyne (Scheme 1, eqn. 3). In this reaction
alcohol I is ionized to a benzylic carbocation II which is readily
reacting with the alkyne to form a vinylcation III.9 Nucleophilic
addition of the azide to the vinylcation induces the loss of nitrogen
and a simple deprotonation yields the corresponding quinoline IV.
Addressing the above mentioned shortcomings of the existing
quinoline syntheses, our new protocol adds not only a valuable
transformation to the toolbox of scarcely explored carboamination
reactions of alkynes10 but also combines several further benefits.
Expensive, sensitive and potentially toxic metal catalysts are
unnecessary. Water and N2 are the only byproducts of the process.
Last but not least, from a more fundamental view point, merging
the intermolecular vinyl cation forming C-C bond formation process
with a powerful driving force, such as the irreversible expelling of
nitrogen in the Schmidt reaction, represents an ideal playground for
The activation of alkynes by noble metal catalysts lately established
powerful concepts for the synthesis of complex structures also from
unactivated internal alkynes.6 Here especially, the acetylenic
Schmidt reaction, catalyzed by cationic Au(I)-species, drew our
attention, as it is highly effective for the synthesis of nitrogen
heterocycles (f. ex. Scheme 1, eqn. 1).7 Alternatively, strong
electrophiles, such as iodine donors have been successfully applied
(f. ex. Scheme 1, eqn. 2).8 Apart from the obvious drawbacks of
these methods - the need of expensive TM-catalysts, or a stoichio-
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Table 2 Scope of azidesa,b
.
a further expansion of the knowledge on highly reactive vinyl
cations.
We started our investigation reacting 2-azido phenylethanol (1a)
with 1-phenylpropyne (2a, Table 1). To our delight, a first attempt
in the presence of our calcium-based catalyst system afforded the
corresponding quinoline 3a in 36% yield (Table 1, entry 1). Other
Lewis acid catalysts proved less effective, and provided the desired
product in diminished yield, or not at all (Table 1, entries 2-6). As no
catalyst was able to produce the desired product in a satisfying
yield and we generally recovered larger amounts of unreacted
starting material, we suspected product inhibition being responsible
for the incomplete conversion. To substantiate this hypothesis, we
carried out a reaction in the presence of stoichiometric BF3∙OEt2
and indeed obtained the quinoline in 74% yield (Table 1, entry 7).
Searching for milder options, equally effective at preventing
product inhibition, we tested Brønsted acid additives, among which
p-toluenesulfonic acid (pTSA) proved most efficient. Using 10 mol%
of calcium catalyst in the presence of pTSA, the conversion of the
starting material proceeded to completion and we isolated the
product in 58% yield (Table 1, entry 8). The role of the acid might be
seen in the formation of a hydrogen bond to the quinoline’s
nitrogen atom, thereby liberating the catalyst for turnover.11
Me
N
Me Me
Me
Me
MeO
Me
Me
Ph
Ph
N
N
Ph
Me
3b (71%)c
3c (70%)
3d (48%)
Me
Ph
Bu
Cl
Me
Ph
Me
Ph
Me
Ph
N
N
N
3e (63%)
3f (85%)
3g (73%)
a Reaction conditions: HNTf2 (10 mol%) and pTSA (1.5 equiv) were added to the
corresponding azide 1b-g (0.25 mmol) and phenyl propyne 2a (0.75 mmol),
dissolved in DCE (2.5 mL) and stirred at 60 °C for 3h.b Isolated yield.c 2h reaction
time.
With the optimized reaction conditions in hands, the generality of
the transformation was investigated. Therefore, we first reacted
different azides with propyne 2a (Table 2). A wide range of azido
phenylethanol derivatives was tolerated under the reaction
conditions. Substrates bearing an electron-donating group (3b-3c)
lead to the desired products in good yields (71% and 70%). A
substitution in the 3-position, interferes with the Schmidt-type
cyclization and an only moderate yield was observed (3d). On the
other hand, even the more challenging electron-withdrawing
derivative (3e) reacted smoothly to the corresponding quinoline in
an acceptable 63% yield. Furthermore, the reaction easily tolerated
starting materials with sterically more demanding and electronically
varying substituents for R2 (3f-3g).
Table 1 Optimization of the reaction conditions.
Entry
1
Catalyst (mol%)
Ca(NTf2)2 (10)
Zn(OTf)2 (10)
FeCl3∙6H2O (10)
Bi(OTf)3 (10)
Sc(OTf)3 (10)
BF3∙OEt2 (25)
BF3∙OEt2 (120)
Ca(NTf2)2 (10)
---
Additive (mol%)
Time
23h
23h
23h
23h
23h
23h
1h
Yield (%)a
36
Bu4NPF6 (5)
Table 3 Scope of aromatic alkynesa,b
.
2
---
nr
3
Bu4NPF6 (5)
nr
4
---
25
5
Bu4NPF6 (5)
15
6
---
26
7
---
Bu4NPF6 (5) + pTSA (150)
pTSA (150)
TFA (150)
74
8
3h
58
9
3h
19
10
11
12
---
3h
11
89b
HNTf2 (10)
pTSA (150)
3h
HNTf2 (150)
---
3h
82
Reaction conditions: Catalyst and additive were added to azide 1a (0.25 mmol)
and phenyl propyne 2a (0.75 mmol), dissolved in DCE (2.5 mL) and stirred at
60 °C for the indicated time.a NMR-yield based on mesitylene as internal
standard.b Isolated yield.
a Reaction conditions: HNTf2 (10 mol%) and pTSA (1.5 equiv) were added to azide
1a (0.25 mmol) and the corresponding alkyne 2b (0.75 mmol), dissolved in DCE
(2.5 mL) and stirred at 60 °C for 3h.b Isolated yield.
Brønsted acids such as p-TSA or TFA alone proved ineffective, even
in overstoichiometic amounts, due to their poor ability for alcohol
ionization (Table 1, entries 9-10). Remarkably, the desired product
was isolated in excellent 89% yield, when we used a synergistic
mixture of two Brønsted acids, 10 mol% HNTf2 for an efficient
ionization of the alcohol and pTSA as a hydrogen bond donor to
prevent product inhibition (Table 1, entry 11). In contrast, HNTf2
alone, in stoichiometric amounts, lead to a diminished yield, due to
the rise of side reactions, an effect that is even much more
pronounced with more sensitive substrates (Table 1, entry 12).
-
g
Next, we turned our attention to the investigation of different
alkynes (Table 3). A range of different alkynes gave the quinoline
products in good to excellent yields. Alkynes bearing electron
donating as well as electron withdrawing substituents in the arene
moiety (3h-3i) were well tolerated. Noteworthy, also terminal
alkynes reacted smoothly to the desired quinolines (3l), and
heterocyclic alkynes (3m) were readily incorporated.
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Inspired by the results shown above, we were interested if the
intermolecular vinyl cation forming C-C bond formation process
could be sufficiently promoted by the irreversible expelling of
nitrogen in the subsequent Schmidt reaction that non-stabilized
vinyl cations intermediates were accessible. Intermolecular reac-
tions proceeding via vinyl cations that are not stabilized by an
adjacent phenyl group are extremely scarce. Given the fact that
both reactions are extremely fast, we reasoned that the reaction of
the benzylic cation with the alkyne might be merged into a single
(quasi-)concerted process with the subsequent Schmidt
rearrangement – so that the developing cationic character on the
alkyne is already stabilized by an interaction with the azide. To our
Scheme 2 Mechanistic investigations.
In conclusion,
a
new and straightforward route toward
polysubstituted quinolines, allowing a very general substitution
pattern was developed. Addressing the limitation to terminal or
carboxylate activated alkynes in previously published procedures
using alkynes as a building block, an acetylenic Schmidt reaction
was envisaged. To avoid the preformation of an azide tethered
alkyne a C-C bond formation process was combined with the azide
addition - rearrangement sequence. Thereby a challenging, formal
carboamination reaction of internal, unactivated alkynes was
realized. The reaction design does not require the use of expensive,
sensitive and potentially toxic transition metal catalysts and water
and N2 are formed as the only byproducts. Proceeding also via
unstabilized vinyl cation intermediates, this new protocol is highly
interesting also from a more fundamental viewpoint. Therefore, the
presented work is intriguing for both, industry as well as academia.
delight,
a wide range of aliphatic alkynes afforded the
corresponding quinolines in good to excellent yields (Table 4).
Symmetric aliphatic alkynes (3n-o) reacted to the corresponding
quinolines in good yields. When aliphatic alkynes with two
different, yet electronically similar substituents (3p-q) were used,
the products were obtained in good yields but as a mixture of
regioisomers.12 Terminal aliphatic alkynes (3r-s) were found to be
more challenging. Here, the use of stoichiometric BF3∙OEt2 proved
more efficient. In addition, the presence of double bonds (3t) and
oxazolidone moieties (3r) did not interfere with the desired
pathway.
Table 4 Scope of aliphatic alkynesa,b
.
HNTf2 (10 mol%)
pTSA (1.5 equiv)
OH
Me
R2
R2
R1
Me
+
R1
DCE, 60 °C
N3
1a
N
Notes and references
2h-o
3n-u
1
2
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a Reaction conditions: HNTf2 (10 mol%) and pTSA (1.5 equiv) were added to azide
1a (0.25 mmol) and the corresponding alkyne 2h-o (0.75 mmol) dissolved in DCE
(2.5 mL) and stirred at 60 °C.b Isolated yield.c Mixture of regioisomers (see
Supporting Information).d BF3∙OEt2 (1.2 equiv) was used instead of HNTf2 and pTSA.
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hydrolysis of the alkyne to the corresponding ketone or the
conversion of the azide to an amine moiety, that would overall
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probes summarized in Scheme 2 were accomplished. Neither the
reactions of aniline derivatives 4 and 5 with alkyne 2a, nor the
exposure of ketone 6 to the azido phenylethanol 1a gave any
significant conversion to the corresponding quinolones. A direct
reaction of an ionized alkyne with the azide moiety would lead to
an entirely different product. Therefore, the carboamination
protocol presented herein is best accommodated by a mechanism
proceeding via the ionization of the alcohol, vinyl cation formation
and subsequent Schmidt reaction, such as outlined in Scheme 1.
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