Palladium-Catalyzed Oxygenative Cross-Coupling of Ynamides and Benzyl Bromides by Carbene Migratory Insertion

Article abstract of DOI:10.1002/anie.201712795

A palladium-catalyzed oxygenative cross-coupling of ynamides and benzyl bromides has been developed. After subsequent hydrogenation, α,α-disubstituted amide derivatives were obtained in good yields. Migratory insertion of α-oxo palladium carbene species, generated by intermolecular oxidation, is proposed as the key step in this reaction. The study demonstrates the potential of ynamides to serve as carbene precursors in palladium-catalyzed C?C bond-forming cross-coupling reactions.

Full text of DOI:10.1002/anie.201712795

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
Chemie
International Edition
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Accepted Article
Title: Palladium-Catalyzed Oxygenative Cross-Coupling of Ynamides
and Benzyl Bromides via Carbene Migratory Insertion
Authors: Yunpeng Gao, Guojiao Wu, Qi Zhou, and Jianbo Wang
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201712795
Angew. Chem. 10.1002/ange.201712795
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10.1002/anie.201712795
Angewandte Chemie International Edition
DOI: 10.1002/anie.200((will be filled in by the editorial staff))
Cross-Coupling
Palladium-Catalyzed Oxygenative Cross-Coupling of Ynamides and
Benzyl Bromides via Carbene Migratory Insertion**
Yunpeng Gao, Guojiao Wu, Qi Zhou and Jianbo Wang*
Abstract: A Pd-catalyzed oxygenative cross-coupling of ynamides
and benzyl bromides has been developed. After subsequent
hydrogenation, α,α-disubstituted amide derivatives were obtained in
good yields. Migratory insertion of α-oxo palladium carbene species
generated by intermolecular oxidation is proposed as the key step in
this reaction. The study demonstrates the potential of ynamides as
carbene precursors in Pd-catalyzed C-C bond-forming cross-
coupling reactions.
In recent years, cross-coupling through metal carbene intermediates
have been rapidly evolving as general methods for C-C bond
construction.[1,2] The key steps in these transformation are the
formation of the metal carbene intermediate and the subsequent
migratory insertions. In the majority of these coupling reactions, the
diazo compounds (or their precursors N-tosylhydrazones) are served
as the precursors for metal carbene generation (Scheme 1A). In
addition to diazo compounds, the unsaturated compounds that can
be utilized as metal carbene precursors in transition-metal-catalyzed
reactions have attracted significant attentions in recent years.[3] Thus,
in principle these unsaturated compounds can also be used as
reaction partners in carbene-based cross-coupling reactions. In this
context, we have previously demonstrated the palladium-catalyzed
cross-coupling of enynones and arylhalides. The enynones readily
undergo cyclization with aryl palladium species to generate
palladium carbenes, which further undergo migratory insertion
(Scheme 1B).[4,5] In another example, we have demonstrated that
allenyl ketones react similarly with arylhalides in the presence of
Scheme 1. Transition-metal-catalyzed cross-coupling with various carbene
precursors
palladium catalyst.[6]
Alkynes represent a type of unsaturated compounds that can be
utilized as metal carbene precursors, typically initiated by
nucleophilic attack on the metal-activated triple bonds. In this
context, gold-catalyzed transformations of alkynes via α-oxo and
α-imino carbenes have recently attracted significant attentions.[7] In
particular, Zhang and others have established the gold-catalyzed
intermolecular oxidation approaches with N-O bond oxidants
(Scheme 1C).[8] The in situ generated α-oxo gold carbenes undergo
typical carbene transformations, such as cyclopropanation, X-H
bond insertion, 1,2-migration and ylide reaction, which renders
readily available alkynes as effective alternatives of α-carbonyl
diazo compounds. Aside from intramolecular approaches, several
reports also highlight the intermolecular trapping process of α-oxo
gold carbenes generated with external oxidants.[9]
In connection to our interest in cross-coupling with carbene
pre-cursors, we conceived the possibility of incorporating
intermolecular oxidation of C-C triple bond with carbene migratory
insertion process to achieve oxygenative coupling. However,
compared to gold, palladium is a weaker Lewis acid when activating
C-C triple bonds.[10] Therefore, the generation of palladium carbenes
from simple alkyne is rare.[11] Recently, ynamides have emerged as
versatile and easily accessible building blocks in organic
synthesis.[12] Due to its strongly polarized C-C triple bond, ynamide
can be converted to keteniminium ion with Lewis or Brønsted acids.
Except the transformations via α-oxo gold carbenes,[13] oxygenative
reactions of ynamides using zinc[14] or Brønsted acid[15] as the
activating reagent are also known. Thus, we conceived that
palladium may be able to activate the triple bonds of ynamides, thus
allowing the carbene-based coupling to proceed. Herein we report
our investigation on the palladium-catalyzed oxygenative
cross-coupling of ynamides and benzyl bromides via sequential
intermolecular oxidation and carbene migratory insertion process
(Scheme 1D).
[]
Y. Gao, Dr. G. Wu, Q. Zhou, Prof. Dr. J. Wang
Beijing National Laboratory of Molecular Sciences (BNLMS) and
Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, College of Chemistry
Peking University, Beijing 100871, China
Fax: (+8610) 6275-1708; Email: wangjb@pku.edu.cn
Prof. Dr. J. Wang
The State Key Laboratory of Organometallic Chemistry,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032, China
Our initial investigations were focused on the reaction of ynamide
1a and 4-methylbenzyl bromide 2b with the treatment of pyridine
N-oxide 3a and K2CO3 in toluene. Pd(OAc)2 and P(2-furyl)3 were
utilized as catalyst and ligand respectively (Table 1).[16] The reaction
[] The project is supported by the Natural Science Foundation of
China (Grant 21332002, 21472004) and the National Basic
o
was carried out at 90 C for 4 h, the target product 4a was obtained
Research
Program
of
China
(973
Program,
No.
in 38% yield (entry 1). Lowering the temperature to 70 oC and
prolonging the reaction time resulted in a slightly increased yield
(entry 2). However, around half of the starting 1a was recovered
2015CB856600).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
o
unchanged at 60 C even after prolonged reaction time (entry 3).
1
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10.1002/anie.201712795
Angewandte Chemie International Edition
electron-withdrawing groups (5g-k) were both well tolerated in this
transformation. Cross-coupling products with fluorine-containing
groups at different positions (5g-j) were smoothly generated in
54-77% yields. Bromomethylnaphthalenes were also suitable
substrates. Compared with -substituted substrate (2n), significant
steric effect retarded the reaction when utilizing α-substrate (2m),
which led to a diminished yield of 39%.
Changing the ratio of substrates led to significant improvement.
Using 1.5 equivalents of 2b and 2.0 equivalents of 3a improved the
yield to 62% (entry 5). Subsequently, the effect of the oxidant was
investigated. A series of substituted pyridine N-oxides and quinoline
N-oxides
were
screened.[17]
For
the
N-oxide
with
electron-withdrawing group (3b), most of 1a was recovered
unchanged, presumably due to the decreased nucleophilicity of the
negatively charged oxygen (entry 6). Pyridine N-oxides with
electron-donating groups also led to diminished yields due to the
undesirable oxidation of 2b (entries 7 and 8). When screening
quinoline N-oxides, we found that keto imide byproduct 4aa was
obtained using 3f as oxidant (entry 10). Interestingly, addition of 1
equivalent of water dramatically suppressed the over-oxidation,
affording the product 4a in 72% yield (entry 11). Using the oxidant
with bulky i-Pr group on 8-position of the quinoline ring gave
similar result (entry 12). The yield was slightly diminished when the
loading of the catalyst was reduced to 5 mol% (entry 13). Thus, the
reaction conditions given in entry 11 were chosen as the optimized
conditions.
Table 1. Optimization of reaction conditions.[a]
Entry
T, oC
1a:2b:3
Oxidant 3, R =
t, h
4a, %[b]
1
2
3
4
5
6
7
90
70
60
70
70
70
70
1:1:1
1:1:1
3a, H
3a, H
4
38
46
35[c]
10
18
10
10
10
10
1:1:1
3a, H
1:1.5:1.5
1:1.5:2
1:1.5:2
1:1.5:2
3a, H
50
3a, H
62
3b, 2,6-Cl2
3c, 4-Me
trace
44
8
70
70
70
70
70
70
1:1.5:2
1:1.5:2
1:1.5:2
1:1.5:2
1:1.5:2
1:1.5:2
3d, 4-OMe
3e, H
10
10
10
10
10
10
37
48
9
10
3f, Me
37[d]
11[e]
12[e]
13[e,f]
3f, Me
72
3g, i-Pr
3f, Me
71
Scheme 2. The reaction scope of benzyl bromides. The reaction was carried out
on 0.2 mmol scale. All yields refer to the isolated products after chromatography.
Except the cases of 5m and 5n, hydrogenation was repeated twice under the
same conditions due to incomplete hydrogenation.
62
[a] The reaction was carried out on 0.1 mmol scale. [b] The yields refer to the
combined yield of both isomers. Determined by 1H NMR using CH2Br2 as the
internal standard. [c] 1a was recovered in 53% yield. [d] Keto imide byproduct
4aa was isolated in 26% yield. [e] 1 equiv of H2O was added. [f] The loading of
Pd(OAc)2 and P(2-furyl)3 was 5 mol% and 20 mol%, respectively.
Next, a variety of ynamides (1b-l) bearing different substituents
on the aryl ring was submitted to this transformation (Scheme 3).
Substrates with methyl group on the meta- and para-position of the
aryl ring gave similar results (6a and b), while ortho-substituted
analog gave trace product with the substrate remained (6c), which
suggests that the steric effect of the ynamide side is much larger
than the benzyl bromide side. Then the electronic effect was
investigated. Substrates with electron-donating groups (6d and e)
and weak electron-withdrawing fluoride substituent (6f and g)
afforded the corresponding products in good yields, yet strong
electron-withdrawing groups (6h and i) resulted in diminished yields.
Naphthalene substituent was also tolerated in this reaction (6k).
With the optimized conditions in hand, we started to investigate
the substrate scope of this reaction. Since the E and Z isomers of the
alkene products cannot be isolated by flash column chromatography,
subsequent hydrogenation was carried out on the crude coupling
products, affording hydrogenated products. First, we explored the
reaction scope with various benzyl bromides (2a-n) by utilizing
ynamide 1a as the carbene precursor (Scheme 2). For most
examples the α,α-disubstituted amide derivatives were obtained with
moderate to good yields under optimized reaction conditions. The
reaction with benzyl bromide gave the corresponding product (5a)
in 80% yield. The position of substituents on the aromatic ring had
little influence on this reaction. Benzyl bromides bearing methyl
groups on different positions were employed in this reaction, and
64-72% yields were obtained (5b-d). Electron-donating (5b-f) and
2
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10.1002/anie.201712795
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Scheme 5. Cross-coupling of diazo compound 8 and benzyl bromide. The
reaction was carried out on 0.1 mmol scale. [a] Yield and E/Z ratio were
determined by 1H NMR using CH2Br2 as the internal standard. [b] The reaction
was conducted without H2O. [c] E:Z = 4:1. [d] E/Z ratio was not determined.
Scheme 3. The reaction scope of aryl substituents of ynamides. The reaction
was carried out on 0.2 mmol scale. All yields refer to the isolated products after
chromatography. Except the cases of 6g and 6h, hydrogenation was repeated
twice under the same conditions due to incomplete hydrogenation.
Based on the results, the following mechanism is proposed
(Scheme 6). Pd(OAc)2 is first reduced to Pd(0) species A, then
oxidative addition of benzyl bromide 2 to Pd(0) takes place to
generate benzylpalladium(II) species B. The C-C triple bond of
ynamide 1 is activated by B, which leads to the generation of
reactive keteniminium ion D. Intermolecular oxidation by 3f affords
intermediate E, which undergoes γ-elimination and then the
nucleofugal part of the oxidant is expelled. A subsequent migratory
insertion occurs to Pd(II) carbene species F, thus forming Pd(II)
species G. Finally, with the aid of base, Pd(0) catalyst A is
regenerated by β-H elimination and the coupling product 4 is
formed.
It is worth mentioning that the substituents on the nitrogen have
significant influence on the reactivity of the ynamides. Thus, the
scope of N-substituents was preliminarily studied (Scheme 4). Since
chiral oxazolidinone auxiliaries are widely used in stereoselective
construction of chiral molecules,[18] auxiliaries derived from
L-phenylalanine and L-valine were introduced to ynamides and
resulted in moderate yields (7a and b). However, only a low
diastereoselectivity of 3:2 for 7a and 1:1 for 7b was observed after
the hydrogenation. The structure of the (S,S) diastereoisomer of 7b
was unambiguously established by X-ray crystallography.[16]
Ynamides bearing sulfonyl groups were also proved to be suitable
substrates for this reaction (7c and 7d).
Scheme 4. The reaction scope of N-substituents of ynamides. The reaction was
carried out on 0.2 mmol scale. All yields refer to the isolated products after
chromatography. Diastereomeric ratio was determined by isolated products.
To gain insights into the mechanism of this reaction, diazo
compound 8 was prepared and submitted to the palladium-catalyzed
reaction with benzyl bromide. As shown in Scheme 5, it was
observed that 8 reacted smoothly with benzyl bromide 2a, affording
4a with 75% yield. A similar ratio of two isomers (E:Z = 4:1) with
the reaction of 1a and 2a (E:Z = 3:1) was also obtained. Then, 1.0
equivalent of 8-methylquinoline N-oxide (3f) was added to simulate
the standard conditions of the investigated reaction. It is noteworthy
that a slightly improved yield of 85% was obtained. This
phenomenon could be explained by the stabilization effect due to the
electron donation from heteroaromatic N-oxide to the palladium
carbene species.[19] Moreover, a similar water effect was also
observed. In the absence of water, the yield of 4a decreased
significantly and the keto imide byproduct 4aa was formed.
Scheme 6. Proposed reaction mechanism.
In conclusion, we have developed a novel palladium-catalyzed
oxygenative cross-coupling between ynamides and benzyl bromides.
The reaction is a straightforward method for the efficient synthesis
of α,α-disubstituted amide derivatives. Mechanistically, an
intermolecular oxidation and carbene migratory insertion sequence
is involved. This methodology reveals the possibility of utilizing
alkynes as α-oxo palladium carbene precursors, which is a
significant expansion of gold-catalyzed oxidative transformations of
alkynes. This study also demonstrates the generality of carbene
migratory insertion process in C-C bond formation regardless of
carbene precursors.
Received: ((will be filled in by the editorial staff))
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10.1002/anie.201712795
Angewandte Chemie International Edition
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Published online on ((will be filled in by the editorial staff))
Keywords: cross-coupling, ynamides, carbenes, intermolecular
oxidation, palladium.
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4
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10.1002/anie.201712795
Angewandte Chemie International Edition
Cross-Coupling
Yunpeng Gao, Guojiao Wu, Qi Zhou,
and Jianbo Wang*
Page – Page
Palladium-Catalyzed
Cross-Coupling of Ynamides and
Benzyl Bromides via Carbene
Migratory Insertion
Oxygenative
Ynamide as palladium carbene precursor: A palladium-catalyzed oxygenative
cross-coupling between ynamides and benzyl bromides is reported. An orderly
organized intermolecular oxidation/carbene migratory insertion sequence is most
likely involved in the mechanism, which renders ynamide as a novel palladium
carbene precursor.
5
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