Palladium-catalyzed Sonogashira coupling of amides: Access to ynones: Via C-N bond cleavage

Article abstract of DOI:10.1039/c6cc06428k

The first palladium-catalyzed Sonogashira coupling of amides has been developed, which proceeds via a selective cleavage of the N-acylsaccharin C-N bond. Notably, the new approach employs N-acylsaccharins as coupling partners to give ynones in good to excellent yield. This protocol can be efficiently utilized in the synthesis of a broad array of ynones under low catalyst loading and Cu-free conditions.

Full text of DOI:10.1039/c6cc06428k

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Palladium-Catalyzed Sonogashira Coupling of Amides: Access to
Ynones via C-N Bond Cleavage
Ming Cui,a Hongxiang Wu,a Junsheng Jian,a Hui Wang,a Chao Liu,b Stelck, Daniel,c Zhuo Zeng*ab
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
The first palladium-catalyzed Sonogashira coupling of amides has carbonylative Sonogashira couplings provided an alternative
been developed, which proceeds a selective cleavage of N- approach to afford ynones.10 However, palladium-catalyzed
acylsaccharin C-N bond. Notably, the new approach employs N- carbonylative reactions often require elevated CO pressures
acylsaccharins as coupling partners to give ynones in good to and higher temperatures. Also, there is the toxicity of CO to
excellent yield. This protocol can be efficiently utilized in synthesis consider. With this in mind, a variety of CO surrogates were
a broad array of ynones under low catalyst loadings and Cu-free used for carbonylative Sonogashira coupling, which provides a
condition.
new protocol to generate ynones under relatively mild
conditions.11 In recent years, a number of synthetic methods
have been devoted to this transformation. Transition-metal-
catalyzed cross-coupling reactions between terminal alkynes
and acylation reagents, including carboxylic acids,12 esters,13
and aldehydes14 to prepare a broad array of ynones were
developed.
The carbon-nitrogen bond is widely present in many
bioactive natural products and biomacromolecules.1 The
construction of the C-N bond is of significance, therefore,
transition-metal-catalyzed C-N formation reactions have been
greatly developed.2 Although transition-metal-catalyzed C-N
bonds cleavage has attracted much attention, it is still a major
challenge in organic chemistry, due to the high C-N bond
dissociation energy.3 Moreover, transition-metal-catalyzed
cleavage of C-N bonds would generate two useful
nucleophiles, which could be employed as coupling partners
for new transformations.4
(a) Suzuki coupling of amides
O
Ar B(OH)2
O
R1
R
N
Ni or Pd Catalysis
O
R
Ar
R2
Bn
Ph
R1, R2
=
N
N
N
,
Ynones are important building blocks in synthetic chemistry
because they widely exist in many biologically active
compounds.5 They are often used as key intermediates, which
are employed in the construction of various heterocyclic
,
Boc
O
Ts
(b) Heck coupling of amides
O
[Pd cat]
-CO,-NHR1R2
R3
R1
R
R3
N
R2
R
structures6 and even more complex natural products.7
A
O
traditional route to prepare ynones involves the reaction of
alkyne metal reagents with acyl halides.8 In fact, the typical
synthetic protocol to form ynones is the Pd(PPh3)2Cl2 and CuI
bimetallic systems catalyzed cross coupling of acyl chlorides
and terminal alkynes.9 The disadvantage of this catalyst system
is that the requirement of high catalyst loadings and the use of
R1, R2
=
N
O
(c) This work:The Sonogashira coupling of amides
O
O
1 mol% Pd(PPh3)3Cl2
R1
R3
R
N
R
Et3N,THF,65 °C
R2
R3
the
co-catalyst
CuI.
Recently,
palladium-catalyzed
R = Alkyl,aryl,thienyl,cinnamyl
R3 = Alkyl,aryl,thienyl,cycloalkyl
O
First Sonogashira coupling of amides
Copper-free, low catalyst loading
new method to synthesize ynones,
including those linear ynones
R1, R2
=
N
S
O
O
Scheme 1 Transition-metal-catalyzed Cross-Coupling of amides
(a) Suzuki coupling of amides. (b) Heck coupling of amides. (c)
This work: First Sonogashira coupling of amides with terminal
alkynes to ynones.
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Amides are a common functional group and are vital building did not affected the yield, and 3aa afforded a 92 % yield (Table
blocks in biologically active compounds and 1, entries 18). However, in presence of 0.5 mol % of
biomacromolecules. Actually, Weinreb reported the use of N- Pd(PPh3)2Cl2, the yield of 3aa decreased to a 42 % yield (Table
methoxy-N-methylamides as acylation reagents for synthesis 1, entries 19). Thus, the optimized reaction conditions for
of ynones via a reaction between a Weinreb amide and an Sonogashira coupling of amides were set as
alkyne metal reagent.15 This transformation requires an Pd(PPh3)2Cl2, Et3N (4 equiv) in dry THF at 65 ˚C.
1
mol%
equimolar terminal alkyne metal reagent to furnish ynones via
Under the optimized reaction conditions, a range of
a two-step procedure. Transition-metal-catalyzed selectively electronically and sterically different amides were tested
cleavage of amides C-N bonds are always a difficult problem, (Scheme 2). N-arylated substrates 4a and 4c were found to be
due to the resonance stability of the amide C-N bond.16 In not suitable for this methodology. Weinreb`s N-OMe-N-Me
2015, Garg demonstrated an elegant nickel-catalyzed amides 4b couldn`t generate the ynone products. The coupling
activation of amides C-N bond methodology which could of the distorted cyclic imides 4d-f was completely unsuccessful.
convert amides to esters.17 Following this strategy, nickel- These results demonstrate
a unique activity of the N-
catalyzed alkylation of amide derivatives has been acylsaccharins in this transformation.
developed.18 Independently, Zou, Szostak and Garg reported
the transition-metal-catalyzed carbonylative Suzuki coupling of
amides (Scheme 1, a).19 At the same time, palladium-catalyzed
Heck reaction of amides were demonstrated by Szostak
(Scheme 1, b).20 However, there has not been reports so far
which utilized amides as efficient electrophile coupling
partners to afford ynones via palladium-catalyzed Sonogashira
coupling reaction, directly (Scheme 1, c).
Herein, we first report our progress on palladium-catalyzed
Sonogashira coupling of terminal alkynes with amides to
access ynones. Transition-metal-catalyzed cleavage of amides
C-N bond has been reported by exploiting the ground state
amides distortion.21 Inspired by these advances and using the
electron-withdrawing property of saccharin which gives the
Scheme 2 Evaluating different amides
superior reactivity of N-acylsaccharin, we considered that N-
acylsaccharin can be harnessed as electrophile coupling
With the optimized conditions in hand, we turned to explore
partner can be efficiently synthesized from saccharin, a readily
available and low cost commodity. To investigate the reactivity
the functional-group tolerance of this palladium-catalyzed
Sonogashira coupling. First, different terminal alkynes were
applied as substrates to react with 1a under the optimized
reaction conditions (Scheme 3). The reaction of para-methyl,
meta-methyl, and para-n-propyl-substituted phenylacetylene
all proceeded well and furnished the corresponding ynones in
of
N-acylsaccharin,
N-benzoylsaccharin
1a
and
phenylacetylene 2a were employed as the model substrates.
Optimization of the reaction is shown in Table 1 in the
Supporting Information. Initially, we attempted to achieve this
transformation in the present of 5 mol % Pd(PPh3)2Cl2 catalyst
with K3PO4 as base resulted in the corresponding ynone in 61%
yield. Notably, other catalysts did not show good compatibility
with this reaction, Pd(PPh3)2Cl2 was the most active catalyst in
this transformation (Table 1, entries 1-4). Various phosphine
ligands were then screened in combination with Pd(OAc)2 as
the catalyst precursor, and the steric hindered ligands were
found to be not suitable for this reaction (Table 1, entries 5, 6).
good yields
(3ab-3ad). Phenylacetylene showed better
reactivity in this reaction and afforded the corresponding
product with 92% yield (3aa). Delightfully, halide substituents
such as Cl, Br were both tolerated in this transformation, thus
providing a potential possibility for further functionalization of
ynones (3ae, 3af). A slight yield decreased was found for the
reaction of electron-deficient phenylacetylene (3ag). However,
the reaction of electron-rich p-methoxylphenylene proceeded
well and furnished the corresponding ynone in 80% yield (3ah).
Other aromatic alkynes were also tolerated in this
methodology. 4-Ethynyl-1,1'-biphenyl was successfully
transformed to desirable products with 85% yield (3ai). 2-
Ethynylthiophene and 3-ethynylthiophene were also applied in
this transformation in moderate to good yields. 3-
The solvent played
a vital role in palladium-catalyzed
Sonogashira coupling of 1a and 2b. THF was found to be the
most suitable solvent for this reaction, the reaction with THF
as solvent gave a higher yield than polar solvents such as
CH3CN and 1,4-dioxane (Table 1, entries 7-9). It is important to
select an appropriate base for this transformation, the desired
product couldn`t be obtained by the reaction between N-
benzoylsaccharin 1a and phenylacetylene 2a under base free
conditions. The use of K2CO3, Cs2CO3, pyridine, DBU, DABCO
delivered the product in very low yields. Et3N was found to be
the most efficient base, which increased the yield of desired
product markedly (Table 1, entries 11-17). Furthermore,
decreasing the amount of Pd(PPh3)2Cl2 from 5 mol % to 1 mol %
ethynylthiophene was obtained in decent yields (3aj: 69 %; 3ak
89 %). The reactivity of aliphatic terminal alkynes are slightly
decreased and gave the desired ynones in moderate to good
:
yields (3al
2l and ethynylcyclopropane 2n generated the corresponding
ynones with 81% and 69% yields, respectively (3al 3an).
-3an). It is worthy of noting that 4-phenyl-1- butyne
,
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Scheme 3 alkynes scope in palladium-catalyzed Sonogashira
coupling of amidesa,b
Scheme 4 Amides scope in palladium catalyzed Sonogashira
coupling of amidesa,b
aReaction conditions: a mixture of N-benzoylsaccharin (0.5
mmol), Pd(PPh3)2Cl2 (1 mol %), terminal alkyne(0.75 mmol),
aReaction condition: a mixture of N-acylsaccharin (0.5 mmol),
Pd(PPh3)2Cl2 (1 mol %), terminal alkyne (0.75 mmol), Et3N (2
Et3N (2 mmol), and 3 mL of THF was stirred at 65
bisolated yield.
℃ for 24 h.
mmol ), and 3 mL of THF was stirred at 65
bisolated yield.
℃ for 24 h.
Next, we began to test the generality of the catalyst system
for a variety of amides under optimized conditions (Scheme 4).
The para-, meta-, and ortho-methoxyl substituted N-
acylsaccharin were all suitable in this transformation and
Based on our observations on transition-metal-catalyzed C-
N bond cleavage, a possible mechanism for the palladium-
catalyzed Sonogashira coupling of amides is proposed (Scheme
5).
provided the corresponding ynones in moderate yields (3ca
-
3ea). Due to the steric effect, the substrates bearing an ortho-
group resulted in lower yields compared to meta- and para-
substituted substrates. The N-4-methylbenzoylsaccharin also
showed similar reactivity in this reaction (3ba). The halide
substituents F, Cl, Br were all tolerated in this catalyst system,
and N-4-chlorobenzoylsaccharin afforded the desired products
in 86% yield (3fa
were tolerated in this reaction and afforded the desired
products in 51%-64% yields (3ia 3ka). Other N-acylsaccharins
also showed good reactivity in this transformation. N-2-
naphthoylsaccharin 1l showed good reactivity in this
transformation and obtained the desired product in 78% yield
3la). N-2-thiophene-2-carbonylsaccharin 1m could efficiently
-3ha). The electron-poor substrates (1i-1k)
-
a
(
provide the corresponding product in 62% yield (3ma). Notably,
N-cinnamoylsaccharin 1n seemed to facilitate this
transformation, and the corresponding ynone were isolated
nearly quantitatively (3na, 98%). To the best of our knowledge,
there are few reports that can convert N-alkanoylsaccharin
into linear ynone products. However, N-acetylsaccharin 1o and
N-dodecanoylsaccharin 1p were all tolerated in this catalyst
system and provided the desired products in 48% and 58%
Scheme
5 Proposed Mechanism for palladium-catalyzed
Sonogashira coupling of amides
yields (3oa, 3pa), respectively.
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the palladium-catalyzed Sonogashira coupling of amides with
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N-acylsacchrins were selectively converted into the
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The authors gratefully acknowledge the support of National
Natural Science Foundation of China (21272080). The Scientific
Research Foundation for the Returned Overseas Chinese
Scholars, State Education Ministry.
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