Palladium-catalyzed primary amine-directed regioselective mono- and di-alkynylation of biaryl-2-amines

Article abstract of DOI:10.1039/c7cc09308j

The first example of the palladium-catalyzed primary amine-directed C(sp²)-H alkynylation of biaryl-2-amines has been developed by using (bromoethynyl)triisopropylsilane as an alkynylating reagent. This protocol exhibits a broad substrate scope, excellent regioselectivity and gram-scale synthesis. Significantly, the versatility of this straightforward method was further demonstrated by controlled mono- and di-alkynylation.

Full text of DOI:10.1039/c7cc09308j

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
first methanofullerene derivatives of Sc
3
N@C2n (2n
=
68 and 80). Synthesis of the
3
N@D5h-C80
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Palladium-Catalyzed Primary Amine-Directed Regioselective
Mono- and Di-Alkynylation of Biaryl-2-Amines
Received 00th January 20xx,
Accepted 00th January 20xx
Guangbin Jiang, Weigao Hu, JianXiao Li, Chuanle Zhu, Wanqing Wu,* Huanfeng Jiang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
2
The first example of palladium-catalyzed primary amine-directed group to construct C(sp )-C(sp ) bonds has been studied well.
2
10
2
C(sp )-H alkynylation of biaryl-2-amines has been developed by For instance, Daugulis and co-workers reported that primary
using (bromoethynyl)triisopropylsilane as an alkynylating reagent. amine could be used successfully as a chelating group in
This protocol exhibits broad substrate scope, excellent diarylation reactions. Huang group described a rhodium-
regioselectivity and gram-scale synthesis. Significantly, the catalyzed amidation of 2-aminobiaryls with diazo. In contrast,
x
versatility of this straightforward method was further as for C(sp )-C(sp) bond construction, no example has been
demonstrated by the controlled mono- and di-alkynylation.
reported.
During the past decades, haloalkynes have been recognized
as versatile and powerful building blocks due to their diversity,
Alkynes are significant structural motifs in materials chemistry
1
and bioactive compounds, and they can be utilized as useful
2
and important precursors for further transformations. In this
1
1
easy availability, practicability, and high reactivity. Therefore,
to date, transition-metal-catalyzed or transition-metal free
reactions involving haloalkynes have already attracted
respect, transition metal-catalyzed direct alkynylation of
unactivated C-H bonds has emerged as one of the most
powerful methods for the construction of C-C bonds over the
1
2
widespread attention. Previously, we have developed a
series of palladium-catalyzed alkynylation reactions of
3
1
3
14
past decades. In 2014, a palladium-catalyzed alkynylation of
alkynes and olefin with haloalkynes as alkynylated reagents.
As part of our continuous studies on the transformation of
N-vinylacetamides was elegantly developed by Loh and co-
3
workers. Very Recently, the groups of Waster, Sigman,
f
3a
3h
haloalkynes, herein, we disclose
a palladium-catalyzed,
3
i
Fu, et.al used copper, palladium or ruthenium salt as catalyst
to achieve the alkynylation of various substrates. Among them,
directing groups (DGs) assisted C-H alkynylation reactions are
particularly attractive due to their excellent regioselectivity
primary amine-directed regioselective mono- and di-
alkynylation
of
biaryl-2-amines
with
(bromoethynyl)triisopropylsilane using haloalkynes as the
limiting reagents (Scheme 1b).
4
and reactivity. Therefore, a series of nitrogen-containing
6
5
directing groups, including 8-aminoquinoline, pyrimidine,
7
8
9
PIP, TAM, and Pico, have been extensively studied under
palladium, cobalt, nickel or manganese catalysis (Scheme 1a).
However, these nitrogen-containing DGs suffer from a multi-
step operation for the preparation of starting materials. Given
the atom economy, practicality
and subsequent
transformation of the directing groups, the application of
2
simple DG in direct C(sp )-H
primary amine as
a
2
functionalization/C(sp )-C(sp)-coupling processes is a highly
valuable goal. Previously, using primary amine as a directing
2
Scheme 1. Transition metal-catalyzed C(sp )-H Alkynylation Using
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School
of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, China. E-mail: cewuwq@scut.edu.cn; jianghf@scut.edu.cn
Fax: +86 20-87112906; Tel: +86 20-87112906
Nitrogen-Containing Group as a Directing Group
Initially, [1,1'-biphenyl]-2-amine
(
1a,
0.2 mmol) and
Electronic supplementary information (ESI) available: Experimental section,
(bromoethynyl)triisopropylsilane (2a, 0.2 mmol) were chosen
1
13
characterization of all compounds, and copies of H and C NMR spectra for
selected compounds. For ESI and other electronic format See
DOI:10.1039/x0xx00000x
as the model substrate to optimize the monoalkynylation
conditions in the presence of Pd(OAc)
(0.01 mmol) and
2
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Cu(OAc)
ChemComm
o
(0.4 mmol) in toluene (1.5 mL) at 100 C for 12 h. desired products could be obtained in 73-78% yields (3h
2
-3j).
Unfortunately, no desired alkynylated product 3a was 2'-Fluoro-[1,1'-biphenyl]-2-amine also furnished the products
detected (see entry 1 of Table S1 in the Supporting 3k) in 87% yield. To our delight, the alkynylation reaction was
Information (SI)). To our surprise, 3a was detected in 76% GC compatible with 2-(naphthalen-2-yl)aniline and 2-(6-
yield by replacing Cu(OAc) with AgOAc (Table S1, entry 2). methoxynaphthalen-2-yl)aniline to give the corresponding
Subsequently, a variety of different palladium catalysts were products in 83% (3l) and 53% (3m) yields, respectively.
tested, and the optimal result was obtained in the presence of Meanwhile, heteroaromatic substrate containing
Pd(OAc) (Table S1, entries 3-4). Switching the solvents to DCE benzothiophene scaffolds could be transformed to the target
and CH CN had no satisfactory results on the reaction product 3n in moderate yield. It is worth noting that 2-(pyren-
efficiency (Table S1, entries 5-6). This transformation did not 1-yl)aniline was also tolerated in this reaction, which gave the
occur in the absence of either Pd(OAc) or AgOAc (Table S1, desired product 3o in 72% yield. The relative configuration of
(
2
2
3
2
entries 7-8). Moreover, when the chosen substrate ratio was 3o was unambiguously confirmed by crystallographic analysis
changed, the GC yield of 3a increased from 76% to 84% (Table (see the Supporting Information for details). Significantly, 3'-
S1, entry 2 vs 9). With chloroalkyne 2b or iodoalkyne 2c as the chloro biphenyl-2-amine was successfully alkynylated as well
substrate, the alkynylated product 3a was also isolated in
(3p), providing a synthetically useful alkynylated synthon.
1
reasonable yield (Table S1, entries 10-11). It is noteworthy to Finally, substrates bearing different R substituents worked
mention that the alkynylated products 3a (monoalkynylation) well under the standard reaction conditions and the
and 4a (dialkynylation) could be selectively isolated by alkynylated products (3q
adjusting the stoichiometry of 1a 2a and AgOAc. Therefore, good yields.
-3w) were formed in moderate to
,
when 2.5 equivalents of 2a and 4 equivalents of AgOAc were
used, the dialkynylated product was obtained in 82% isolated
yield (see the Supporting Information for details).
a,b
Table 2. Dialkynylation of Biaryl-2-Amines
a,b
Table 1. Monoalkynylation of Diaryl-2-Amines
R1
R1
NH2
H
TIPS
Pd(OAc)2 (5 mol %)
H2N
R2
TIPS
+
R2
Br
AgOAc (2 equiv), toluene
1
2a
3
H2N
TIPS H2N
TIPS H2N
Cl
TIPS H2N
TIPS H2N
O
TIPS
Cl
R
3
3
3
3
3
3
a, R = H, 80%
b, R = Ph, 79%
c, R = Et, 75%
d, R = F, 82%
3
g. 83%
3h, 76%
3i, 78%
3j, 73%
TIPS
H2N
H2N
F
TIPS
H2N
TIPS
H3CO
S
e, R = CF3, 85%
f, R = Ac, 76%
TIPS
H2N
3k, 87%
3l, 83%
3m, 53%
3n, 51%
H2N
TIPS
H2N
TIPS H2N
TIPS H2N
TIPS
a
Cl
Reaction conditions: a mixture of 1 (0.2 mmol), 2a (0.5 mmol), AgOAc (0.8
3
o, 72%
X-ray of 3o
3p, 61%
3q, 76%
3r, 73%
mmol, 4 equiv), Pd(OAc) (0.01 mmol, 5 mol %) and toluene (1.5 mL) were
2
COOEt
b
COOEt
TIPS H2N
F
CF3
Cl
Cl
sealed in a 25 mL Schlenk tube at 100 °C for 12 h under N2. Isolated yields.
H2N
TIPS H2N
TIPS H2N
TIPS H2N
TIPS
Next, the scope of this dialkynylation protocol was evaluated to a
series of biaryl-2-amines (Table 2). The transformation was well
3
s, 82%
3t, 84%
3u, 73%
3v, 64%
3w, 70%
tolerated with substrates containing electron-donating and
-
a
Reaction conditions: a mixture of 1 (0.2 mmol), 2a (0.14 mmol), AgOAc
0.28 mmol, 2 equiv), Pd(OAc) (0.007 mmol, 5 mol %) and toluene (1.5 mL)
withdrawing substituents at the 4'-position, affording the desired
dialkynylated products 4a-4i in 57-84% yields. Delightfully, the
disubstituted substrates also proceeded well in this catalytic system
(
2
b
were sealed in a 25 mL Schlenk tube at 100 °C for 12 h under N
yields.
2
. Isolated
(
4j, 4k). It was noted that 3'-chloro-[1,1'-biphenyl]-2-amine gave
With the optimized conditions in hand (Table S1, entry 9),
we examined the scope of substituted biaryl-2-amines
amenable to this primary amine directed alkynylation
reactions (Table 1). Pleasingly, substrates with electron-rich or
comparably lower yield, probably owing to the steric effects (4l).
Notably, the corresponding product 4m was also accessed, albeit in
4
7% yield. Gratifyingly, 5-chloro-3-fluoro-[1,1'-biphenyl]-2-amine
was suitable substrate and converted to the desired product 4n in
5% yield. Moreover, the transformation of 4-methyl-substituted
-
poor groups on the 4'-position could undergo this
transformation smoothly, delivering the corresponding
products with excellent yields (3a 3f). Notably, a vinyl group
7
and 5-methyl-substituted substrates also afforded the target
products 4o and 4p with 73% and 76% yields, respectively. The 5-
chloro group could tolerate the catalytic system, making further
application on the scaffold possible (4q). Finally, electron-
-
which is sensitive to palladium-catalyzed coupling reactions
could also remain under the optimal conditions (3g). When
using the disubstituted biaryl-2-amines as the substrates, the
2
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3
withdrawing substituents such as COOEt and CF , were also well (Scheme 3a). This result indicated that the mechanism of
tolerated to isolate the desired dialynylated products 4r, 4s, and 4t present method should not be a radical process. To better
in 80, 83, and 67% yields, respectively. The structure of the understand the mechanism of this transformation, we
1
dialkynylated product has been confirmed by single-crystal X-ray conducted the reaction using the bimetallic complex
A
, which
1
0f
analysis of 4b (for detailed information, see the Supporting was prepared according to the literature. Surprisingly, the
Information). corresponding product 3a was obtained in 77% yield (Scheme
Next, in a gram-scale experiment, the C(sp )-H alkynylation of 3b). The stoichiometric conversion from
biphenyl-2-amine catalyzed by Pd(OAc) could also proceed conditions also delivered the corresponding products 3a, albeit
smoothly to give the mono- or di-alkynylated products in moderate in 34% yield (Scheme 3c). In addition, when 3a and
2
1
A
under the same
2
yields (Scheme 2).
(bromoethynyl)triisopropylsilane (2a) were treated in toluene
using AgOAc as additive, the dialkynylated product 4a was
isolated in 89% yield (Scheme 3d). This observation suggested
that 3a might be a possible intermediate in this dialkynylation
reaction. Moreover, the protocol exhibited intermolecular
TIPS
H2N
Pd(OAc)2 (0.25 mmol, 5 mol %)
H2N
TIPS
+
H
AgOAc (10 mmol, 2 equiv), toluene (10 ml)
Br
00 oC, 12 h
1
1
a, 7.2 mmol 2a, 5 mmol
67% (3a, 1.17 g)
kinetic isotope effect both in monoalkynylation (k
H D
/k = 2) and
TIPS
H2N
H
NH2
in dialkynylation reaction (k /k = 5) (Scheme 3e, f), implying
D
Pd(OAc)2 (0.25 mmol, 5 mol %)
H
+
TIPS
TIPS
H
2
AgOAc (20 mmol, 4 equiv), toluene (10 ml)
o
that the cleavage of C(sp )-H bond of biphenyl-2-amine is likely
to be the rate-determining step in the catalytic process.
Br
1
00 C, 12 h
1
a, 5 mmol 2a, 12.5 mmol
7
3% (4a, 1.93 g)
Scheme 2. Gram-Scale Experiment
Subsequently, the synthetic utility of this protocol was
demonstrated by further transformation of the product 3a (Table
15
3
). Gratifyingly, the chemoselective removal of the TIPS of 3a was
easily realized under the straightforward reaction conditions.
Valuable 6-methylphenanthridine (6a) was obtained in 78% yield via
a hydrolysis and cyclization process. Under the treatment of KSCN,
3a was transformed smoothly to the corresponding product 7a in
89% yield. Finally, 2'-(1-benzyl-1H-1,2,3-triazol-4-yl)-[1,1'-biphenyl]-
2-amine (8a) and 1-(2'-amino-[1,1'-biphenyl]-2-yl)ethan-1-one (9a)
were synthesized in excellent yields (see the Supporting
16
Information for details).
Table 3. Further Synthetic Applications
Scheme 3. Control Experiments
Based on our experimental results and related literature
8
,17
Reaction conditions: a) 3a (0.2 mmol), TBAF (1 M in THF, 0.4 mL), THF (1 mL), reports, we proposed that the transformation may proceed
rt, 3 h. b) i) 3a was hydrolyzed to 5a. ii) 5a (0.1 mmol), PdCl
2
(5 mol %),
through a Pd(II)/Pd(IV) catalytic process (Scheme 4). Initially,
Pd(OAc) was coordinated by the biphenyl-2-amine to form
the active palladium(II) species. Subsequently, directed C(sp )-
10 mol %), DMF (2 mL), 80 C, 12 h; e) 3a (0.2 mmol), KOH (3 equiv), DMSO H activation leads to the formation of bimetallic Pd(II)-Pd(II)
o
CH
3
CN 100 C, 12 h; c) 3a (0.3 mmol), KSCN (2 equiv); Cu(OTf)
2
(20 mol %),
.
o
2
TMEDA (20 mol %), BF
3
Et
2
O (2 equiv), DMSO (1 ml), O
2
balloon, 100 C, 24 h;
2
d) i) 3a was hydrolyzed to 5a. ii) 5a (0.2 mmol), benzylazide (0.2 mmol), CuI
o
(
(
o
2 mL), 100 C, 12 h.
intermediate
To gain more insight into this palladium-catalyzed (bromoethynyl)triisopropylsilane (2a) to intermediate
alkynylation reaction, a range of mechanistic experiments the corresponding Pd(IV) species
which underwent
A
.
Next, the oxidative addition of
A
gives
B,
were conducted (Scheme 3). First, when 3 equivalents of reductive elimination to afford the alkynylation product 3a
radical scavenger TEMPO (2,2,6,6-tetramethyl-1-piperidinyloxy) along with regeneration of palladium(II) catalyst.
was employed in the reaction condition A, the corresponding
In summary, we have successfully developed a primary
monoalkynylated product 3a was obtained in 75% yield amine directed alkynylation reaction of biaryl-2-amines with
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palladium(II) catalysis. This novel protocol provides a practical
and robust method for the formation of mono- and
dialkynylated biaryl-2-amines in excellent yields. The
transformation has remarkable features, including excellent
regioselectivity, good functional group compatibility, and
gram-scale synthesis. Further studies regarding the synthetic
applications are currently underway in our laboratory.
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The authors thank the National Key Research and
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National Natural Science Foundation of China (21490572 and
1
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DOI: 10.1039/C7CC09308J
Palladium-catalyzed primary amine-directed controlled alkynylation of
biaryl-2-amines has been developed by using haloalkynes as an alkynylating reagent.