Palladium-catalyzed carbonylative Sonogashira coupling between aryl triazenes and alkynes

Article abstract of DOI:10.1039/c5ob00502g

We developed a palladium-catalyzed carbonylative Sonogashira reaction with aryl triazenes and alkynes as substrates and methanesulfonic acid as the additive. A series of α,β-ynones were synthesized by this alternative procedure. Notably, bromides, iodides

Full text of DOI:10.1039/c5ob00502g

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Palladium-catalyzed carbonylative Sonogashira
coupling between aryl triazenes and alkynes†
Cite this: Org. Biomol. Chem., 2015,
13, 5090
Wanfang Li and Xiao-Feng Wu*
Received 13th March 2015,
Accepted 27th March 2015
DOI: 10.1039/c5ob00502g
www.rsc.org/obc
We developed a palladium-catalyzed carbonylative Sonogashira reac- good stability and facile conversion to other functional
tion with aryl triazenes and alkynes as substrates and methanesul- groups.13 For example, aryl triazenes have often been employed
fonic acid as the additive. A series of α,β-ynones were synthesized in the Sonogashira reactions for the synthesis of some phenyl-
by this alternative procedure. Notably, bromides, iodides and hydroxyl acetylene oligomers,14 molecular wires15 and annulenes.16 To
groups could be well-tolerated under these reaction conditions.
the best of our knowledge, carbonylative Sonogashira coupling
using aryl triazenes has been hitherto unreported in the litera-
ture. Herein, we report the palladium-catalyzed carbonylation of
aryl triazenes with alkynes and carbon monoxide.
At the outset, we carried out carbonylation between 3,3-
diethyl-1-(p-tolyl)triaz-1-ene (1a) and phenylacetylene (2a) as
the model reaction in the presence of a catalytic amount of
Pd(OAc)2 to optimize the reaction conditions. When the Lewis
acid BF3·OEt2 was added as the activator for 1a, only a trace
amount of 3-phenyl-1-(p-tolyl)prop-2-yn-1-one (3aa) was
detected on a GC (entry 1, Table 1). Under the same ligand-
α,β-Ynones are an important class of compounds with many
special biological activities.1 Besides, they provide versatile
intermediates for numerous heterocycle2 and natural product
syntheses.3 Traditionally, these structures were obtained from
the nucleophilic addition of acetylide reagents to aldehydes4
or carboxylic acid derivatives,5 which required either a two-step
procedure or laborious work-up. The cross-coupling between
acid chlorides and alkynes or alkynylboronates under metal-
catalyzed6 or metal-free7 conditions represents a more con-
venient way to their synthesis, but the poor substrate stability
and narrow functional group tolerance often curtailed this
methodology for synthetic applications.
Since the seminal work by Kobayashi and Tanaka in 1981,8
palladium-catalyzed carbonylative Sonogashira coupling using
aryl (pseudo)halides has become an efficient route to
α,β-ynones.9 Aryl amines are relatively inexpensive and abun-
dantly available chemicals and usually act as nucleophiles in
many organic reactions. However, after being converted to dia-
zonium salts by some well-known procedures, they become
more active than aryl halides in many palladium-catalyzed
cross-coupling reactions.10 One of the practical concerns while
dealing with diazonium salts is their instability and explosive
potential.11 To overcome these disadvantages, in 2011, some
of us developed a carbonylative Sonogashira protocol with
in situ generated diazonium salts from aryl amines and tert-butyl
nitrite in the presence of acetic acid.12 Recently, the use of
triazenes as diazonium precursors or directing groups has
attracted much attention due to their easy preparation and
Table 1 Optimization of the reaction conditionsa
Entry
Acid
Ligand
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
BF3·OEt2
HCOOH
CH3COOH
CF3COOH
TsOH·H2O
MeSO3H
MeSO3H
MeSO3H
MeSO3H
MeSO3H
MeSO3H
MeSO3H
MeSO3H
MeSO3H
MeSO3H
MeSO3H
MeSO3H
MeSO3H
No
No
No
No
No
No
DPPP
DPEPhos
XantPhos
n-BuPAd2
PPh3
P(p-FC6H5)3
P(p-OC6H5)3
PCy3
P(o-tolyl)3
P(o-tolyl)3
P(o-tolyl)3
P(o-tolyl)3
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
tBuOMe
DME
Trace
Trace
Trace
33
48
55
11
5
7
51
60
41
57
58
66
11
9
10
11
12
13
14
15
16
17
18
55
THF
76c (71d)
a Reaction conditions: 1a (57.4 mg, 0.3 mmol), 2a (50 µL, 0.45 mmol),
MeSO3H (20 µL, 0.33 mmol), Pd(OAc)2 (2.02 mg, 9 µmol) and solvent
(2 mL). 20 bar CO, 70 °C. b Determined by GC using n-hexadecane as
the internal standard. c Corresponds to 73% isolated yield. d The CO
pressure was 10 bar.
Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Strasse
29a, 18059 Rostock, Germany. E-mail: xiao-feng.wu@catalysis.de
†Electronic supplementary information (ESI) available: NMR spectra and data,
and the reaction procedure. See DOI: 10.1039/c5ob00502g
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free conditions, several other protic acids were screened acids were more effective than other acids and MeSO3H was
(entries 2–6, Table 1). Formic acid and acetic acid were as the best additive, which furnished 3aa in 55% yield (entry 6,
inefficient as BF3·OEt2. Trifluoroacetic acid, which has often Table 1).
been used as an activator for triazenes, led to only 33% yield
To further improve the yield of 3aa, we tried to add some
of 3aa (entry 4, Table 1). Finally we discovered that sulfonic ligands to the catalytic system. When bidentate phosphine
Table 2 Palladium-catalyzed carbonylative Sonogashira coupling of various aryl triazenes and alkynesa
R′ = Et
R′ = Et
R′ = –(CH2)4
1j (Ar = Ph)
1k (Ar = 3-CH2OH-Ph)
1l (Ar = 4-MeO-Ph)
1m (Ar = 4-Me-5-CN-Ph)
R′ = –(CH2)5
1n (Ar = 4-I-Ph)
1o (Ar = 3,4,5-tri-MeO-Ph)
1p (Ar = 3-PhO-Ph)
1a (Ar = 4-Me-Ph)
1b (Ar = 4-Cl-Ph)
1c (Ar = 4-CF3-Ph)
1d (Ar = 4-CN-Ph)
1e (Ar = 4-COOMe-Ph)
1f (Ar = 3-I-Ph)
1g (Ar = 2-MePh)
1h (Ar = 2-Br-Ph)
1i (Ar = 1-Naphthyl)
NR′ = 4-methylpiperidiyl
2
1q (Ar = 4-Br-Ph)
Structure of the alkynes 2a–s
2a (R = Ph)
2b (R = 3-Me-Ph)
2c (R = 4-Et-Ph)
2d (R = 4-n-Pr-Ph)
2e (R = 4-n-Bu-Ph)
2f (R = 4-n-Hex-Ph)
2g (R = 2-Br-Ph)
2h (R = 4-CF3-Ph)
2i (R = 4-Ac-Ph)
2k (R = 3-thienyl)
2l (R = ferrocenyl)
2m (R = Bn)
2n (R = TIPS)
2o (R = n-Bu)
2p (R = CH2OPh)
2q (R = CH2OH)
2r (R = (CH2)2OH)
2s (R = (1-cyclohexanol)yl)
2j (R = 1-naphthyl)
a Reaction conditions: 1 (0.6 mmol), 2 (0.9 mmol), MeSO3H (40 µL, 0.66 mmol), Pd(OAc)2 (4.04 mg, 18 µmol), P(o-Tol)3 (11.0 mg, 36 µmol), and
solvent (4 mL), 70 °C, 20 h. Isolated yield. b The product was contaminated with some unreacted 2i.
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ligands like DPPP, DPEPhos and XantPhos were employed, the
yield of 3aa decreased to a very low level (entries 7–9, Table 1).
Therefore, we tried to use some monophosphines instead.
n-BuPAd2, which has been used in many palladium-catalyzed
carbonylations of aryl halides,17 led to a somewhat lower yield
of 3aa (51% vs. 55%) than ligand-free conditions (entry 10,
Table 1). Substituted triphenylphosphines with either electron-
donating or electron-withdrawing groups on the phenyl rings
did not show much improvement for this reaction (entries
11–13, Table 1). The electron-richer ligand like tricyclohexyl-
phosphine (PCy3) led to 58% yield of 3aa. To our satisfaction,
when P(o-tolyl)3 was used in place of PPh3, the yield of 3aa
increased from 60% to 66% under the same conditions (entry
11 vs. 15, Table 1). When the solvent was changed from
dioxane to THF, the yield of 3aa was increased further to 76%.
Scheme 1 Proposed reaction mechanism.
t
But in other ether solvents like BuOMe and DME, the yields
were much lower (entries 16 and 17, Table 1). At an elevated
temperature of 80 °C, the yield in THF dropped from 76% to
65%, which may be caused by the partial decomposition of the
diazonium methanesulfonate that was likely to be presented
as an intermediate during the reaction. In other solvents like
MeCN, toluene and DMSO, the yields of 3aa were 44, 15 and
62% respectively. Therefore, THF was the optimal solvent for
the carbonylation between 1a and 2a. Besides, the lower CO
pressure caused a decrease in the yield.
Having the optimized reaction conditions in hand, we next
examined the substrate scope of the above procedure with
other triazenes and commercially available alkynes (Table 2).
These triazenes (1a–q) were easily prepared from the corres-
ponding anilines and secondary amines in high yields (see the
Experimental section). Firstly, we carried out the reactions
between several ortho and para-substituted aryl triazenes and
phenyl acetylenes. Obvious lower yields were found when ortho
substituents were on the phenyl group. Aryl triazenes with
some electron-withdrawing groups on para positions gave
higher yield of the products. These may be attributed to the
less stability of these aryl triazenes with electron rich or ortho
groups.11 Next, 1-(phenyldiazenyl)pyrrolidine (1j) was reacted
with several substituted phenyl acetylenes and good to excel-
lent yields were obtained. For example, when 1-ethynyl
naphthene (2j) was employed, 3jj was isolated in 87% yield.
Notably, 3jl was obtained from ferrocenylethyne (2l) in 49%
yield, which has some potential applications in photoactive
semiconductors and liquid crystals.18 More investigation on
of gaseous acetylene, (triisopropylsilyl)acetylene (2n), was
smoothly converted to a protected aryl ethynyl ketone, which
is a very versatile intermediate for many organic syntheses.20
Besides, the alkynols (2q–s) were also coupled with aryl tria-
zenes but the yields were even lower.
Based on these results, a most possible reaction mechan-
ism has been proposed. As shown in Scheme 1, the aryl tria-
zenes were first transformed into the corresponding aryl
diazonium salts with the assistance of methane sulfonic acid.
Then the formed aryl diazonium salts underwent oxidative
addition with Pd(0) to give an arylpalladium complex which
gave the acylpalladium intermediate after the coordination
and insertion of one molecule of CO. Then the terminal
alkynes were produced which formed a new Pd–C bond with
the assistance of MeSO3−, which gave the desired alkynones
after reductive elimination and also Pd(0) for the next catalytic
cycle. In this procedure, methane sulfonic acid might have
three roles: (1) producing aryl diazonium salts from aryl tria-
−
zenes; (2) MeSO3 deprotonates terminal alkynes and re-forms
methane sulfonic acid; (3) the regenerated methane sulfonic
acid reacts with the pre-released free amines to avoid the
nucleophilic attack of the amines to the acylpalladium inter-
mediate and produce non-desired amides.
Conclusions
the substituent effect on both aryl triazenes and aryl alkynes In conclusion, we have developed a carbonylative Sonogashira
was performed and we were glad to see that aryl iodide (1n) procedure for the synthesis of α,β-ynones using aryl triazenes,
and bromides (1h, 1q, 2g) were well tolerated. These aryl which have been transformed to aryl diazonium salts in the
halides could undergo further palladium-catalyzed cross- presence of methane sulfonic acid. This procedure has the
couplings to introduce various functional groups.19 The free following features: (1) acidic conditions are used instead of
hydroxyls in 1k and 2q–s were also tolerated under these basic conditions and aryl bromides and iodides remained
acidic conditions. Unfortunately, some basic functional unreactive; (2) aryl triazenes are easily prepared and stable to
groups like pyridines and amines were not tolerated under be stored for a long time; (3) free alcohols in the substrates
our conditions.
can be tolerated. Owing to these advantages, we believe
Finally, we tried the carbonylative Sonogashira reactions that this alternative method will be useful in the synthesis
with some aliphatic alkynes (2m–s) and the yields were in of some special functionalized ynones for multiple step
overall lower than the aryl counterparts. The masked form synthesis.
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