Copper-catalysed synthesis of alkylidene 2-pyrrolinone derivatives from the combination of α-keto amides and alkynes

Article abstract of DOI:10.1039/c8ob02205d

A Cu(i)-catalysed addition and cyclisation sequence has been developed for the synthesis of (E)-alkylidene pyrrolinone derivatives. The reactions incorporate simple α-keto amides and alkynes as substrates, and employ a commercially available Cu(i) catalyst. The process tolerates good variation of both starting materials, and delivers the desired pyrrolinones in good yields, with high levels of stereocontrol.

Full text of DOI:10.1039/c8ob02205d

Organic &
Biomolecular Chemistry
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Copper-catalysed synthesis of alkylidene
2-pyrrolinone derivatives from the combination of
Cite this: Org. Biomol. Chem., 2018,
16, 7797
α-keto amides and alkynes†
Received 6th September 2018,
Accepted 12th October 2018
a
Qian Wen Tan,a Praful Chovatiab and Michael C. Willis
*
DOI: 10.1039/c8ob02205d
rsc.li/obc
A Cu(I)-catalysed addition and cyclisation sequence has been and the inherent atom economy of these reactions.12 As such,
developed for the synthesis of (E)-alkylidene pyrrolinone deriva- the use of hydroamination or hydroamidation reactions, which
tives. The reactions incorporate simple α-keto amides and alkynes combine amines or amides, respectively, with either alkenes or
as substrates, and employ a commercially available Cu(I) catalyst. alkynes, presents an attractive and versatile method for the for-
The process tolerates good variation of both starting materials, mation of nitrogen-containing organic compounds. Although
and delivers the desired pyrrolinones in good yields, with high these reactions can potentially produce a wide range of nitro-
levels of stereocontrol.
gen-containing heterocycles, they have yet to be exploited fully
in this context. Many hydroamination and hydroamidation
reactions display a narrow substrate scope and require non-
trivial, or precious metal catalysts.13 The development of
alkene and alkyne hydroamination reactions using earth-abun-
dant copper catalysts has been significant in recent years,14
with notable examples being reported from the Buchwald lab-
oratory based on the use of Cu(I)-hydride chemistry.15
However, systems for copper-catalysed hydroamidation are less
common.16,17
We took on the challenge of developing a system that uti-
lises copper-catalysed hydroamidation to synthesise 2-pyrroli-
none motifs using simple and readily accessible starting
materials. In earlier work, we reported a copper-catalysed route
to ylidenebutenolides from the combination of alkynes and
α-oxo acids, which we proposed proceeds via an initial hydro-
Nitrogen-based heterocycles feature in almost 60% of FDA-
approved drugs.1 In addition, they are common motifs in agro-
chemicals,2 in new materials,3 and can function as versatile
synthetic intermediates.4 These attributes drive efforts to
deliver efficient atom-economic methods for the synthesis of
N-heterocycles using readily available starting materials.
Towards this goal, we were interested in exploring routes to
substituted 2-pyrrolinones. These unsaturated amide-contain-
ing heterocycles are present in a diverse range of biologically
active natural products and pharmaceutical compounds
(Scheme 1),5 and their multiple functional groups make them
attractive synthetic building blocks.
Classically, the pyrrolinone core is synthesised using Wittig
reactions
on
maleimides,6
or
by
treating
γ-alkylidenebutenolides with amines,7 while the cyclisation of
unsaturated substrates such as dienamides8 and iodoaceta-
mides is also known.9 More recently, methods have been
reported employing rhodium catalysts for the addition and
cyclisation of α,β-unsaturated oximes to isocyanates,10 or acryl-
amides to gem-difluoroacrylates.11 Despite the range of
approaches available, these protocols often require complex
starting materials that require multi-step synthesis, resulting
in increased costs, and significant waste generation.
The use of simple addition processes to facilitate bond for-
mation is attractive due to the rapid increase in complexity
aDepartment of Chemistry, University of Oxford, Chemistry Research Laboratory,
Mansfield Road, Oxford, OX1 3TA, UK. E-mail: michael.willis@chem.ox.ac.uk
bEvotec, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c8ob02205d
Scheme 1 Selected examples of natural products and pharmaceutical
compounds containing 2-pyrrolinone derivatives.
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Performing the reaction at a slightly higher concentration
(1.0 M) increased the yield to 69%. The use of alternative
copper catalysts or solvents, the addition of supporting nitro-
gen- or phosphorous-based ligands, or the addition of base,
failed to improve the yield further. Selected optimization data
are shown in Table 1, with full details available in the ESI.†
Importantly, in all cases, only the (E)-isomer of pyrrolinone 3a
was formed.20
We next explored variation of the N-substituent of the
α-keto amides, keeping 1-octyne constant as the second reac-
tion component (Table 2). N-Sulfonyl α-keto amides were
Scheme 2 Cu(I)-Catalysed preparation of ylidenebutenolides and alky-
lidene 2-pyrrolinones.
carboxylation of the alkyne (Scheme 2a).18 We speculated that
the use of α-keto amides as substrates in a related reaction
would deliver a new route to 2-pyrrolinone derivatives, based
on simple addition chemistry, and by analogy to our earlier
Table 2 Evaluation of α-keto-amide N-substituent in the synthesis of
alkylidene 2-pyrrolinonesa
work, would proceed by
a
hydroamidation pathway
(Scheme 2b). At the outset of this work we noted that a signifi-
cant challenge would be the use of α-keto amides as sub-
strates, as they are significantly less acidic then the corres-
ponding α-oxo acids.19 Conversely, our earlier route to ylidene-
butenolides resulted in mixtures of geometrical isomers, and
we speculated that the use of keto amide substrates could lead
to more selective reactions due to steric interactions from the
N-R2 substituent, thus controlling the alkene geometry.
We selected the combination of N-benzyl-2-oxo-2-phenylace-
tamide (1a) and 1-octyne (2a) as a suitable test reaction
(Table 1). Pleasingly, the reaction conditions developed for our
butenolide chemistry were effective with the amide substrate,
with the use of Cu(MeCN)4BF4 (10 mol%) as the catalyst in
toluene at 130 °C, delivering 60% of pyrrolinone 3a.
Table 1 Evaluation of reaction between N-benzyl-2-oxo-2-phenylace-
tamide and 1-octynea
Entry
Variation from above
Yieldb (%)
1
2
3
4
5
6
2.0 equiv. 1a
1.0 M
61%
69%
30%
0%
4%
23%
0%
10%
0%
0%
1.0 equiv. 1a, 2.0 equiv. 2a
Cu2O as catalyst
DMF as solvent
PhCl as solvent
Bipyridine added
dppm added
7c
8c
9d
10d
K2CO3 added
Et3N added
a Reaction conditions: α-Keto amide (0.36 mmol), alkyne (0.30 mmol), a Reaction conditions: α-Keto amide (0.36 mmol), alkyne (0.30 mmol),
[Cu(MeCN)4]BF4 (0.03 mmol), toluene (0.50 mL), 130 °C, 20 h, under [Cu(MeCN)4]BF4 (0.03 mmol), toluene (0.50 mL), 130 °C, 20 h, under
1
N2. b Yields determined using H NMR spectroscopy of the crude reac- N2. Isolated yields. b Gram scale reaction using amide (1.3 g,
tion mixtures with nitromethane as an internal standard. Single 4.32 mmol), 1-octyne (3.60 mmol), [Cu(MeCN)4]BF4 (0.36 mmol),
isomer of product. c 10 mol% ligand added. d 1 equiv. of base added.
toluene (6.0 mL), 130 °C, 20 h.
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effective substrates, although it was apparent that the elec-
We then focused on evaluating variation in the substituents
tronic nature of the sulfonyl group played a role in reaction on the aromatic ring of aryl N-benzyl α-keto amides (Table 3).
efficiency. For example, aryl sulfonamides featuring electron- While both electron-donating (4a,b) and electron-withdrawing
donating substituents (3b,c) delivered higher yielding reac- (4c–f) substituents, positioned meta and para on the aryl ring
tions than those featuring electron-withdrawing groups (3d–f). were tolerated, the isolated yields suggested that reducing the
The N-tosyl example was scaled without issue, delivering electron density on the aryl ring provided more efficient reac-
1.2 grams of pyrrolinone 3b in an improved yield of 83%. tions. Pyrrolinone 4b illustrates this well; moving the OMe sub-
Importantly, the reaction could be used to produce pyrrolinone stituent on the arene from the para to the meta position results
cores with various N-alkyl substituents, including linear alkyl in a non-productive reaction being converted into one that pro-
(3h), 3- and 6-membered carbocycles (3i–l) as well as a methyl- ceeds in 59% yield. Although they were less reactive, alkyl
thienyl group (3m). The scope was also not limited to N-alkyl α-keto amides (4g, 4h) can also be tolerated in the system.
substrates as allylic and aryl substituents (3n, 3o) were also
Variation of the alkyne reaction component was explored
tolerated, delivering the expected products in good yields. next. Both carbocyclic (5a–c) and linear (5d) aliphatic alkynes
A mixture of E : Z isomers was obtained for the N-phenyl were tolerated to give moderate yields of the expected pyrroli-
example, with substrates featuring all other N-substituents nones. However, the presence of nitrile, chloro and phthali-
returning single isomers of product.
mide functional groups in the alkyne did not give any product
when combined with N-benzyl α-keto amide 1a. However,
when the more reactive N-tosyl α-keto amide 1b was employed
in combination with these alkynes it was possible to obtain
low to moderate yields of the targeted functionalized pyrroli-
nones (5f,g). Reactivity could be further increased by employ-
ing an α-keto amide featuring an electron-withdrawing aryl
substituent, with pyrrolinone 5h, combining a nitro-substi-
tuted keto amide with a phthalamide-substituted alkyne,
being obtained in an excellent 81% yield.
Table 3 Evaluation of α-keto-amides and alkynes in the Cu-catalysed
synthesis of alkylidene 2-pyrrolinonesa
Conclusions
In conclusion, we have reported a Cu(I)-catalysed synthesis of
alkylidene pyrrolinones. The reactions combine simple α-keto
amides with alkynes, and deliver E-configured products with
high levels of stereocontrol. The scope of the reaction is good,
with variation of both reaction components possible. Scale up
of the process to >1 gram proceeded without incident. This
simple addition process is notable for the use of an earth-
abundant metal catalyst and the high-degree of functionality
delivered in the products.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
We thank Dr Sangwon Seo (Oxford) for fruitful discussions,
the Agency for Science, Technology and Research (A*STAR),
and the Engineering and Physical Sciences Research Council
(EPSRC) Centre for Doctoral Training in Synthesis for Biology
and Medicine (EP/L015838/1) for the studentship, generously
supported by AstraZeneca, Diamond Light Source, Defense
Science and Technology Laboratory, Evotec, GlaxoSmithKline,
Janssen, Novartis, Pfizer, Syngenta, Takeda, UCB and Vertex.
a Reaction conditions: α-Keto amide (0.36 mmol), alkyne (0.30 mmol),
[Cu(MeCN)4]BF4 (0.03 mmol), toluene (0.50 mL), 130 °C, 20 h, under
N2. Isolated yields of single isomers.
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