Catalytic syntheses of N-heterocyclic ynones and ynediones by in situ activation of carboxylic acids with oxalyl chloride

Article abstract of DOI:10.1002/anie.201103296

Breaking the bottleneck: α-Keto carboxylic acids and N-heterocyclic carboxylic acids are activated in situ with oxalyl chloride then catalytically alkynylated to give ynediones and N-heterocyclic ynones efficiently in a one-pot fashion. 5-Acylpyrazoles and 2-phenylaminopyrimidines, potentially interesting for pharmaceutical applications, are readily synthesized in concise one-pot, three-component syntheses. Copyright

Full text of DOI:10.1002/anie.201103296

Communications
DOI: 10.1002/anie.201103296
One-Pot Reactions
Catalytic Syntheses of N-Heterocyclic Ynones and Ynediones by In
Situ Activation of Carboxylic Acids with Oxalyl Chloride**
Christina Boersch, Eugen Merkul, and Thomas J. J. Mꢀller*
Dedicated to Professor Kenkichi Sonogashira on the occasion of his 80th birthday
Ynones are highly reactive Michael systems and can be
smoothly reacted with various mono- and binucleophiles in
addition and addition–cyclocondensation processes. Conse-
quently, they have received considerable attention as valuable
building blocks in heterocycle[1] and natural-product[2] syn-
thesis. Ynediones contain a 1,2-dione motif and are even more
densely functionalized electrophiles, thus enabling a more
multifaceted transformation profile towards heterocycles.[3,4]
Despite their auspicious synthetic potential, ynediones have
remained scarcely explored owing to a lack of a general and
practical preparative access.[5] Therefore, a direct, simple, and
efficient route to this class of compounds would be highly
desirable.
Aryl-substituted ynones can be easily prepared by stoi-
chiometric or catalytic acylation of organometallic reagents,
especially by Sonogashira coupling.[6,7] However, an essential
limitation of this methodology to date is the lack of an
efficient method for the preparation of ynones with N-
heterocyclic substituents.[8,9] N-Heteroarenes are pervasive in
numerous natural products[10] and in biologically active agents
in medicinal chemistry, and the quest for nitrogen-containing
building blocks is enormous. However, the often observed low
reactivity in cross-coupling reactions resulting from substrate
or product inhibition by coordination to transition metals[11]
has fostered the necessity to develop a convincing and robust
methodology for breaking this bottleneck. For instance,
pyridine or quinoline carboxylic acid chlorides, which are
highly interesting building blocks in medicinal chemistry, are
often not readily available and thus, their transformation to
ynones under modified Sonogashira coupling conditions[12]
was not considered to be practical. On the other hand, N-
heterocyclic carboxylic acids are the immediate precursors of
acid chlorides. Therefore, a one-pot access to ynones starting
directly from carboxylic acids could overcome the short-
comings of acid chloride preparation and isolation, and a
valuable, conceptually new synthetic tool for ynone prepara-
tion could evolve.
Aromatic carboxylic acids have received considerable
attention as aryl-nucleophile precursors in metal-catalyzed
cross-couplings,[13] which in most cases proceed under decar-
boxylation.[14,15] Cross-couplings of carboxylic acids using an
excess of anhydrides or carbonates for activation allow for the
carbonyl group to be maintained but result in the formation of
simple alkyl and aryl ketones.[16]
At the same time, the activation of carboxylic acids with
oxalyl chloride is a widespread, mild, and clean method for
the preparation of acid chlorides, which produces only
gaseous by-products (carbon monoxide, carbon dioxide, and
hydrogen chloride).[17] Thus, an in situ conversion of carbox-
ylic acids to acid chlorides using oxalyl chloride followed by
alkyne coupling in a one-pot fashion can be considered as an
activation–alkynylation sequence to ynones and ynediones.
To our knowledge this straightforward alkynylation method-
ology is unprecedented to date.
Recently, we disclosed conceptually novel approaches to
ynones and ynediones initiated by glyoxylation of electron-
rich heteroaromatic p nucleophiles with oxalyl chloride and
subsequent alkyne coupling. The Pd/Cu-catalyzed decarbon-
ylative Sonogashira coupling gives rise to the formation of
ynones,[9] whereas the Cu-catalyzed Stephens–Castro cou-
pling maintains both carbonyl groups and results in the
generation of ynediones (Scheme 1).[4]
Inspired by the alkynylation of in situ generated glyoxylyl
chlorides, we set out to design one-pot activation–alkynyla-
tion sequences that either start from a-keto carboxylic acids 1
and apply Castro conditions for the synthesis of ynediones 3
or from carboxylic acids 4 using Sonogashira conditions for
the generation of ynones 5 (Scheme 2), especially addressing
notoriously difficult transformations of N-heterocyclic car-
boxylic acids.
For the optimization of the activation–alkynylation
sequence phenylglyoxylic acid (1a) and phenylacetylene
[*] M. Sc. C. Boersch, Dipl.-Chem. E. Merkul, Prof. Dr. T. J. J. Mꢀller
Institut fꢀr Organische Chemie und Makromolekulare Chemie
Heinrich-Heine-Universitꢁt Dꢀsseldorf
Universitꢁtsstrasse 1, 40225 Dꢀsseldorf (Germany)
E-mail: thomasjj.mueller@uni-duesseldorf.de
[**] The authors cordially thank Merck Serono, Darmstadt, for the
financial support, and the Fonds der Chemischen Industrie.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201103296.
Scheme 1. One-pot three-component glyoxylation–alkynylation synthe-
ses of ynones and ynediones.
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Angew. Chem. Int. Ed. 2011, 50, 10448 –10452

Scheme 2. Conceptual access to ynediones and ynones by sequential
activation–alkynylation.
Scheme 3. One-pot synthesis of ynediones 3 by an activation–Ste-
phens–Castro alkynylation sequence. All reactions were carried out on
a 2.00 mmol scale [c(1)=0.2m] and yields refer to isolated and
purified compounds. [a] The potassium carboxylate was used as a
substrate. Ph=phenyl, TIPS=triisopropylsilyl, Me=methyl.
(2a) were chosen as model substrates furnishing 1,4-diphe-
nylbut-3-yne-1,2-dione (3a; Table 1). Different ethereal sol-
vents were examined and parameters such as temperature,
reaction time, order of reagent addition, and amount of CuI
were modified (for experimental details and full optimization,
see the Supporting Information).
With this new and mild activation–Stephens–Castro
alkynylation sequence it was possible to prepare aryl (3a–
c), heteroaryl (3d,e), and alkenyl ynediones (3 f,g) in
moderate to good yields starting directly from a-keto
carboxylic acids 1 or their carboxylates. This novel, valuable
sequence convincingly complements the glyoxylation–Ste-
phen–Castro coupling sequence,[4] because electron-neutral
and even sterically hindered substrates (see formation of 3c)
can be transformed uneventfully.
Likewise, the one-pot in situ activation–alkynylation
scenario was transposed to carboxylic acids 4 in the presence
of 2 mol% [PdCl2(PPh3)2] and 4 mol% CuI as a catalyst
system, leading to the successful formation of ynones 5 in
moderate to excellent yields (Scheme 4).[19] Expectedly, the
reaction times under Sonogashira conditions are considerably
shorter, and complete conversion was achieved after only 1 h
at room temperature.
Table 1: Selected optimization trials for the synthesis of ynedione 3a.
Entry First reaction step[a] Second reaction step
Yield [%][b]
1
2
3
4
5
6
1.0 equiv NEt3, THF 5 mol% CuI, 2.0 equiv NEt3 39
THF
1,4-dioxane
5 mol% CuI, 3.0 equiv NEt3 43
5 mol% CuI, 3.0 equiv NEt3 65
1,4-dioxane/DMF[c] 5 mol% CuI, 3.0 equiv NEt3 51
1,4-dioxane
1,4-dioxane
2 mol% CuI, 3.0 equiv NEt3 47
10 mol% CuI, 3.0 equiv NEt3 64
[a] Reaction temperature: 508C, reaction time: 4 h. [b] Yield of isolated
product on a 2.0 mmol scale. [c] Addition of 2 mol% N,N-dimethylfor-
mamide.
The activation–Sonogashira alkynylation sequence start-
ing from heterocyclic carboxylic acids and carboxylates 4
furnishes a broad variety of the corresponding ynones 5. Most
remarkably, Sonogashira coupling of commercially available
pyridine-3-carbonyl chloride hydrochloride (Merck KGaA)
to give ynone 5a under identical reaction conditions failed
completely, even if the reason for this strange observation is
yet unknown.
For sodium nicotinate (4a) it was demonstrated that the
variation of the alkyne 2 was feasible. Besides phenylacety-
lene, 1-hexyne, and TIPS-acetylene, also N-heterocyclic
alkynes can be efficiently coupled to yield highly functional-
ized building blocks (see formation of 5d,e). The example of
the ynone 5e shows that even the highly labile Boc protective
group on the 7-azaindolyl moiety is preserved.
Substituents in 2-, 5-, and 6- as well as in 2,6-positions of
the pyridine core are well tolerated (5 f–i and 5l). Bromine in
3-position of pyridine (5g) remains untouched under these
gentle conditions, ready for addressing this ynone in further
functionalizations. It could also be shown that dinicotinic acid
can be activated and coupled to give a bis(ynone) (5j) in a
good yield. In addition to pyridine-containing carboxylic
acids, this method can be well applied to convert a whole
The addition of triethylamine in the first step for
deprotonation of the carboxylic acid in the chlorination step
or scavenging the generated hydrogen chloride is not
necessary (Table 1, entries 1 and 2). The most significant
increase of the yield of isolated product from 43 to 65% was
observed upon changing the solvent from THF to 1,4-dioxane
(entry 3). It is known that 1,4-dioxane and oxalyl chloride
form oligomeric complex chains of alternating 1,4-dioxane
and oxalyl chloride molecules by coordination of the oxygen
atoms of 1,4-dioxane to the chlorine atoms of oxalyl
chloride.[18] Presumably, the enhanced reactivity is caused by
an activation of the reagent by destabilization of the chlorine–
carbon bond of oxalyl chloride. We also attempted to exploit
the known catalytic effect of DMF on the chlorination with
oxalyl chloride by addition of 2 mol% of DMF; however, the
obtained yield was lower (entry 4). The variation of the CuI
loading in the alkynylation step from 2 to 10 mol% revealed
an optimum with 5 mol% of the catalyst (entries 3, 5, and 6).
These optimized conditions were successfully applied to one-
pot syntheses of several ynediones 3, which were obtained in
moderate to good yields (Scheme 3).[19]
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www.angewandte.org 10449

Communications
(5v), now opening access to heterocyclic derivatives of
flavones.
Both activation–alkynylation sequences for the prepara-
tion of ynediones 3 and ynones 5 are preparatively very
simple, mild, and straightforward to perform. In particular,
they open an entry to derivatives that are not accessible or
difficult or expensive to access with known methods. Carbox-
ylic acids are easily available, stable, and generally nontoxic
compounds. Moreover, oxalyl chloride is a liquid which can be
conveniently handled. Both sequences use simple standard
catalyst systems. Neither exotic ligands nor additives are
required, and the alkynylation steps proceed smoothly at
room temperature. Finally, all reactants and reagents are used
in strictly equimolar amounts without the need for excess
reagents.
As an illustration of the applicability of ynediones and
ynones as intermediates, one-pot three-component hetero-
cycle syntheses of N-Boc-5-acylpyrazoles 6 and 2-amino-
pyrimidines 8 were conceived. In a consecutive three-
component fashion the in situ generated ynediones 3 can be
selectively transformed to N-Boc-protected 5-acylpyrazoles 6
with N-Boc-hydrazine. After deprotection, the 5-acylpyra-
zoles 7a–c are isolated as analytically pure products
(Scheme 5).
Scheme 5. One-pot three-component access to 5-acylpyrazoles 6.
Likewise, the cyclocondensation of o-tolyl guanidinium
nitrate with the in situ generated trimethylsilyl (TMS) ynones
concludes the one-pot three-component synthesis of 2-o-
tolylaminopyrimidines 8 (Scheme 6). 4-(3-Pyridyl)-2-o-toly-
laminopyrimidine (8a) is the pharmacophore of the block-
buster drugs imatinib (Gleevec)[21] and nilotinib (Tasigna),[22]
both acting as tyrosine kinase inhibitors in cancer chemo-
therapy. This new sequence allows the rapid assembly of the
phenylaminopyrimidine scaffold in a one-pot fashion using
simple and cheap starting materials, whereas other known
procedures take two or more steps and use more elaborate
precursors.[23] Most remarkably, the analogue 8b possesses
two activated chlorine atoms that have remained untouched,
again emphasizing the high compatibility with other function-
alities and the mild reaction conditions of the presented
methodology.
Scheme 4. One-pot synthesis of ynones 5 by an activation–Sonoga-
shira alkynylation sequence. All reactions were carried out on a
2.00 mmol scale [c(4)=0.2m] and yields refer to isolated and purified
compounds. [a] The sodium carboxylate was used as a substrate.
nBu=n-butyl, Py=pyridyl, Boc=tert-butyloxycarbonyl.
variety of 6-membered N-heterocyclic carboxylic acids, such
as isonicotine, pyrimidine, quinoline, and cinnoline carboxylic
acid (see formation of 5k–q). Also azoles such as indole,
pyrazole, and indazole carboxylic acids can be successfully
carried through the sequence (see formation of 5r–t).
It is noteworthy that the indazole derivative 5t is
accessible neither by the carbonylative Sonogashira cou-
pling[2] nor by the glyoxylation–decarbonylative alkynylation
sequence.[9] Therefore, it is quite remarkable that there is no
limitation with respect to the electronic nature of the
substrates. Electron-poor (5a–q) as well as electron-rich
(5r–t) ynones are accessible. Interestingly, the antimicrobial
nalidixic acid[20] (4p) can also be functionalized (5u) as well as
a chromone carboxylic acid (4q) to give a chromenyl ynone
In conclusion, we have developed new one-pot activation–
alkynylation sequences starting from a-keto carboxylic acids
or carboxylic acids as versatile and efficient approaches to
ynediones and N-heterocyclic ynones, respectively. The one-
pot three-component syntheses of 5-acylpyrazoles and 2-o-
tolylaminopyrimidines illustrate the implementation of this
10450 www.angewandte.org
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2011, 50, 10448 –10452

Scheme 6. One-pot three-component synthesis of 4-pyridyl-2-o-tolylaminopyrimidines 8. Tol=tolyl.
179.3 ppm (Cquat); elemental analysis calcd. (%) for C18H11NO
(257.3): C 84.03, H 4.31, N 5.44; found: C 83.86, H 4.40, N 5.51.
highly efficient methodology in multicomponent syntheses of
pharmaceutically important heterocycles. Further methodo-
logical studies are currently underway.
Received: May 13, 2011
Published online: September 9, 2011
À
Keywords: alkynylation · carboxylic acids · C C coupling ·
heterocycles · one-pot reactions
.
Experimental Section
3a: Phenylglyoxylic acid (1a, 306 mg, 2.00 mmol) in dry 1,4-dioxane
(10 mL) was placed under argon atmosphere in a screw-cap Schlenk
vessel with septum. Argon was passed through the solution for 5 min.
Then, oxalyl chloride (0.18 mL, 2.00 mmol) was added dropwise to
the reaction mixture at room temperature (water bath). The mixture
was stirred for 4 h at 508C in a preheated oil bath and then cooled to
room temperature. CuI (20 mg, 0.10 mmol), phenylacetylene (2a,
0.23 mL, 2.00 mmol), and dry triethylamine (0.84 mL, 6.00 mmol)
were successively added to the mixture, and stirring at room
temperature was continued for 24 h. After complete conversion,
water (10 mL) was added and the mixture was extracted with
dichloromethane. The combined organic layers were dried with
anhydrous sodium sulfate. After removal of the solvents in vacuum
the residue was adsorbed on Celite and purified by flash chromatog-
raphy on silica gel (petroleum ether/ethyl acetate = 50:1; Rf = 0.14) to
give the analytically pure 1,4-diphenylbut-3-yne-1,2-dione (3a,
302 mg, 65%) as a yellow oil. 1H NMR (CDCl3, 500 MHz): d =
7.39–7.43 (m, 2H), 7.48–7.56 (m, 3H), 7.63–7.70 (m, 3H), 8.07–
8.10 ppm (m, 2H); 13C NMR (CDCl3, 125 MHz): d = 87.0 (Cquat), 99.1
(Cquat), 119.1 (Cquat), 128.7 (CH), 128.9 (CH), 130.5 (CH), 131.5 (Cquat),
131.7 (CH), 133.6 (CH), 134.9 (CH), 178.5 (Cquat), 188.4 ppm (Cquat);
elemental analysis calcd (%) for C16H10O2 (234.3): C 82.04, H 4.30;
found: C 82.13, H 4.31.
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1,4-dioxane (10 mL) was placed under argon atmosphere in a screw-
cap Schlenk vessel with septum. Argon was passed through the
solution for 5 min. Then, oxalyl chloride (0.18 mL, 2.00 mmol) was
added dropwise to the reaction mixture at room temperature (water
bath). The mixture was stirred for 4 h at 508C in a preheated oil bath
and was cooled to room temperature. [PdCl2(PPh3)2] (28 mg,
0.04 mmol), CuI (15 mg, 0.08 mmol), phenylacetylene (2a, 0.23 mL,
2.00 mmol), and dry triethylamine (0.84 mL, 6.00 mmol) were suc-
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continued for 1 h. After complete conversion, water (10 mL) was
added, and the mixture was extracted with dichloromethane. The
combined organic layers were dried with anhydrous sodium sulfate.
After removal of the solvents in vacuum the residue was adsorbed on
Celite and purified by flash chromatography on silica gel (petroleum
ether/ethyl acetate = 6:1, Rf = 0.22) to give the analytically pure 3-
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1
brown solid. M.p. 938C; H NMR (CDCl3, 300 MHz): d = 7.38–7.56
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8.93–9.02 (m, 1H), 9.12–9.19 ppm (m, 1H); 13C NMR (CDCl3,
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124.4 (CH), 125.9 (CH), 129.1 (CH), 129.4 (CH), 130.3 (CH), 130.4
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