Ru-Catalysed synthesis of fused heterocycle-pyridinones and -pyrones

Article abstract of DOI:10.1039/c7ob01497j

The synthesis of fused heterocycle-pyridinones has been achieved by oxidative coupling of N-unprotected primary heterocycle-amides with internal alkynes. The reaction, which is catalysed by Ru(ii) and assisted by Cu(ii), takes place through C-H and N-H bo

Full text of DOI:10.1039/c7ob01497j

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DOI: 10.1039/C7OB01497J
Journal Name
ARTICLE
Ru-catalysed synthesis of fused heterocycle-pyridinones and -
pyrones
S. Ruiz,a C. Carrera,a P. Villuendas,a and E. P. Urriolabeitia*a
Received 00th January 20xx,
Accepted 00th January 20xx
The synthesis of fused heterocycle-pyridinones has been achieved by oxidative coupling of N-unprotected primary
heterocycle-amides with internal alkynes. The reaction, which is catalysed by Ru(II) and assisted by Cu(II), takes place
through C–H and N–H bond activation of the heterocyclic unit. The scope of the reaction includes a variety of alkynes,
electron-rich thiophenes, furan and pyrrole, and even electron-poor pyridines. The reaction is fully regioselective with
respect to the position of the C–H bond activation due to the directing effect of the amide group. In the same way, the
synthesis of fused heterocycle-pyrones (isocoumarins) has been developed by Ru-catalysed oxidative coupling of
heterocyclic carboxylic acids and internal alkynes. The reaction involves C–H and O–H bond activation. This reaction also has
a broad scope, from electron-rich thiophenes, furans and pyrroles to electron-deficient pyridines and quinolines.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Heterocyclic compounds that contain pyridinone or pyrone
units fused with another heterocycle (Figure 1a) are of great
interest due to their biological and pharmacological activities.1,2
The strong and diverse activity of these compounds prompted
the development of a variety of synthetic methods and the
intensive search for new pathways continues today. The
synthesis of fused heterocycle-pyridinones can be achieved by
general classical methods, such as those used for isoquinolones
and isoquinolines (Pomeranz–Fritsch, Bischler–Napieralski and
Pictet–Spengler), which involve two disconnections between
the carbonyl carbon and either the N atom or the aromatic ring
(Figure 1b).3 There are also specific methods (Figure 1c) and
these include a Curtius rearrangement followed by cyclisation,4c
the condensation of 3-aminothiophene derivatives with isatines
and Meldrum's acid,4f cyclisation of dehydroamino acids,4g
domino reactions of dimethylaminopropenoyl-cyclopropanes
with Lawesson's reagent,4b or the cyclisation of ortho-
methylbenzamide by lithiation and reaction with DMF,4h
amongst others. Developments in this area also include the use
of transition metal catalysts.4 Similarly, the synthesis of
isocoumarins has been carried out using many different
methods, including those promoted by transition metals.5,6
Most of these methods, however, share a common structural
Figure 1. General molecular skeletons of fused heterocycle-pyridinones and -
pyrones, and some classical methods for their synthesis
Despite their general character, these syntheses suffer from
some disadvantages: (a) they take place under harsh conditions;
(b) the substrates must be highly prefunctionalized to achieve
high reactivity and selectivity, even in the presence of transition
metal catalysts; (c) the reactions are multi-step and generate
considerable waste; (d) most of the reagents are not
commercially available and usually have complex syntheses,
they are highly toxic or difficult to handle (e.g., phosgene). For
these reasons – and given the general interest in this type of
compound – other synthetic methods have been explored.
starting point, which is a benzene ring with a b-functionalized
alkyl chain and a C1 group ortho to the alkyl chain: for instance,
the condensation of homophthalic acids or the intramolecular
cyclisations of o-alkynylbenzoates.5,6
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The most successful alternative synthesis of pyridinones and pyrroles) to electron-poor (pyridines or isoquinolines), despite
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DOI: 10.1039/C7OB01497J
isocoumarins has probably been the directed functionalization the known reluctance of electron-deficient heterocycles to
of C–H bonds catalysed by transition metals, because this undergo functionalization.17 The second advantage is that the
approach allows non-classical disconnections under relatively synthesis of fused heterocycles is achieved directly from the
mild conditions. The use of catalytically directed C–H bond corresponding unprotected precursors, which are usually
activation processes is a well-established procedure in organic commercially available or easily prepared, thus reducing the
synthesis.7 The synthesis of pyridinones and isocoumarins has number of synthetic steps and minimizing the production of
been achieved through N–H/C–H or O–H/C–H oxidative waste.
coupling between, respectively, amides or acids and internal
alkynes (Figure 2).8-14
Previous work
O
O
Results and discussion
1. Catalytic synthesis of fused heterocycle-pyridinones.
R2
R2
R1
N
H
OH
O
H
O
R2
R2
H
H
ONR2
OOR
R3
Rh[11] Ru[12]
R3
R4
R3
R4
The first step was to optimize the reaction conditions on a
model system, for which the coupling between thiophene-2-
carboxamide 1a and 3-hexyne 2a (Table 1) was selected. The
conditions employed were those optimized for related
precursors, such as benzylamines and naphthylamines: 1 mmol
of substrate, 2 mmol of alkyne, [Ru(cymene)Cl2]2 (10% mol) as
catalyst, KPF6 (10% mol) and Cu(OAc)2 (1 equiv.) as additives,
Pd[8]
Rh[9] or Ru[10]
R4
O
H
O
O
Rh[11b]
R3
Rh[11a]
R2
R2
R4
R1
H(R1)
R3
O
N
N
Ru[12e]
O
H
R3
R3
R2
R3
COOH
R4
R4
R4
R1 = alkyl, alkoxy groups
R4
N-substituted amide; blocked N-reactivity
Aryl rings, few heterocycles
Electron-rich rings, very few electron-deficient
Aryl rings, few heterocycles
Electron-rich, very few electron-deficient
methanol as solvent and 100 °
C as the reaction temperature.18
This work
O
O
O
O
After 24 hours under these conditions an equimolar mixture of
1a and 4,5-diethylthieno[2,3-c]pyridin-7(6H)-one 3aa was
obtained following the workup procedure described in the
Experimental Section (entry 1).
H
X
Y
X
Y
X
Y
X
Y
[Ru]
[Ru]
OH
O
O
NH2
N
N
R2
R2
R2
R2
R3
R3
H
H
R4
O
R4
O
O
O
H
Z
Y
Z
Y
Z
OH
[Ru]
Z
Y
NH
2 [Ru]
Table 1. Optimization of the conditions for the coupling reaction between 1a and 2aa
Y
X
X
R3
X
R3
X
H
H
R4
R4
Focused on fused heterocycle-pyrone
O
O
Focused on fused heterocycle-pyridinone
All heterocycles (electron-rich AND deficient)
N-unsubstituted free amides
O
All heterocycles (electron-rich AND deficient)
O-unsubstituted free acids
Ru catalyst: cheaper compared with Pd or Rh
[Ru(cym)Cl2]2 10 % mol
H
S
S
KPF6 10% mol
N
NH2
S
+ others
+
NH2
Et
Et
+
Ru catalyst: cheaper compared with Pd or Rh
Additive
Solvent
T ºC/t, h
Et
Et
Et
3aa
Et
4a
Figure 2. Previous work on the synthesis of isoquinolones and isocoumarins, and
1a
2a
relationship with the study reported here.
Entry Solvent Oxidant
additive
/
T
°
C
NMR ratiob (%)
1a 3aa
4a/othersc
/
/
Previous work on the synthesis of pyridinones and
isoquinolones has shown that Pd,8 Rh,9 and Ru10 are the most
efficient metals to promote this coupling. As for the synthesis of
isoquinolones, the mono-insertion and subsequent coupling
only takes place when the N atom of the amide is protected.
Attempts to use primary amides resulted in no reaction or in the
formation of polycyclic compounds. In addition, a few examples
of fused pyridinones have been found. The synthesis of
isocoumarins by metal-catalysed C–H bond activation has been
performed mainly with rhodium11 and ruthenium12 catalysts.
The use of other metals such as palladium13 or iridium14 for this
type of C–H/O–H coupling has hardly been reported. However,
once again the synthesis of heterocycles fused with the 2-
pyrone ring is poorly represented despite several specific
contributions.11f,12a
1
2
3
4
5
6
7
8
9
MeOH
tAmOH
HFIP
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
100
100
100
100
120
140
120
120
120
50/50/-/-
46/36/18/-
83/17/-/-
61/39/-/-
25/50/25/-
33/47/20/-
-/60/40/-
-/70/20/10
-/78/9/13
d
d
tAmOH
tAmOH
tAmOH
toluene Cu(OAc)2
toluene Cu(OAc)2
toluene Cu(OAc)2
K2CO3
toluene PhI(OAc)2 + 120
K2CO3
+
10
11
32/68/-/-
-/87/6/7
toluene Cu(OAc)2
2 NaOAc
+
120
We propose here a general method for the synthesis of fused
heterocycle-pyridinones and -pyrones (isocoumarins) based on
the oxidative coupling of primary heterocycle-amides and
heterocyclic acids with internal alkynes. The process is catalysed
by [RuCl2(h6-cymene)]2, assisted by Cu(OAc)2 and NaOAc, and
takes place in toluene. The use of ruthenium is an optimal
choice15 because it combines high activity and selectivity with
low cost.16 The method also has two clear advantages. The main
advantage is that it is general for a large number of
heterocycles, from electron-rich (thiophenes, furans or
a 1a (1 mmol), 2a (2 mmol), [Ru(cymene)Cl2]2 (0.1 mmol), KPF6 (0.1 mmol), Cu(OAc)2 (1
mmol), additive (1 equiv.), solvent (3 mL), temp, 24 h. bNMR ratio determined on the
crude reaction mixture after removal of Cu(II). cOther hydroarylation isomers. d2 mmol.
In an effort to increase the conversion of 1a a short screening
of solvents and temperatures was performed. When the
reaction was carried out in tert-amyl alcohol (entry 2) a similar
conversion was achieved but in addition to 3aa the
hydroarylation product 4a was obtained. The use of
hexafluoroisopropanol as solvent (HFIP, entry 3) led to a further
2 | J. Name., 2012, 00, 1-3
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decrease in the conversion and only 17% of 3aa was obtained. The results show that this method is general for a variety of
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DOI: 10.1039/C7OB01497J
The influence of other reaction parameters was investigated substrates. For example, electron-rich heterocycles such as
t
with AmOH used as the solvent. An increase in the amount of thiophenes (3aa
–
3da), benzothiophene (3ea), furan (3fa) and
N-methylpyrrole (3ga) gave the corresponding fused pyridines
entry 4). However, a slight increase in the reaction temperature in moderate to good yields. The slightly lower yield of the
(120 C, entry 5) gave a notable increase in the conversion to benzannulated derivative 3ea is consistent with previous
afford a mixture of 3aa (50%) and 4a (25%). A further increase results, as is the lower reactivity shown by the furan ring 3fa
in temperature (140
C, entry 6) did not improve these results. compared with that of thiophene or pyrrole.18a,19 In addition,
Since the appropriate choice of solvent in this type of reaction the method tolerates the presence of electron-donating (3ca
Cu(OAc)2 to 2 equivalents led to a lower conversion (39% of 3aa
,
°
°
)
seems to be critical, we expanded the range of solvents studied. and electron-withdrawing (3da) substituents at the 5-position
The use of toluene led to a marked change in the reaction of the thiophene ring, although the reaction works better for
outcome as full conversion was obtained on using Cu(OAc)2 (1 the electron-donating group. The oxidative coupling is selective,
equiv.) at 120
(entry 7). This is a remarkable result because toluene is not a group is in the 2-position (3aa
typical solvent for this class of C–H functionalization.18
synthesis of isomers that cannot be obtained by other routes,
°
C for 24 hours to afford 60% of 3aa and 40% 4a with the C–H bond at the 3-position activated when the amide
,
3ca 3ga). This allows the
–
Once full conversion had been achieved, we attempted to with this fact being especially challenging in the case of furan,
minimize the formation of 4a, which probably occurs by where examples of this type of metallation are still scarce.19,20
protodemetallation of the vinyl derivative formed after Clearly, when the directing group is in the 3-position (3ba) the
migratory insertion of the alkyne. Therefore, the removal of H+ reaction takes place at the very favourable 2-position.
from the reaction medium by addition of an external base The reactivity can be extended to the electron-poor pyridine
should, in principle, decrease the amount of 4a and favour the heterocycles. This type of oxidative coupling is very rare in
formation of 3aa. In good agreement with our hypothesis, an electron-deficient heterocycles17 and usually gives alkyne poly-
increase in the Cu(OAc)2 concentration to 2 equivalents (entry insertion9e or requires the prior modification of the
8) increased the amount of 3aa (70%) versus 4a (20%) along heterocycle9a to give the best performance for the mono-
with other hydroarylation compounds in minor quantities insertion of the alkyne. In our case, isonicotinamide 1i and
(10%). Even better results were obtained by replacing 1 nicotinamide 1j reacted with 3-hexyne 2a through C–H bond
equivalent of Cu(OAc)2 by K2CO3 (entry 9, 78% 3aa), while the activation and alkyne mono-insertion to give the corresponding
best base proved to be NaOAc (entry 11, 87% 3aa). The 3,4-diethyl-2,6-naphthyridin-1(2H)-one (3ia), as a single isomer,
presence of Cu(OAc)2 as a source of acetates and oxidant is and the two isomeric compounds 7,8-diethyl-1,6-naphthyridin-
mandatory, because attempts to replace this oxidant by others 5(6H)-one (3ja1) and 3,4-diethyl-2,7-naphthyridin-1(2H)-one
led to failure (entry 10). Once the reaction conditions had been
(3ja2), which were separable by column chromatography, in
optimized we investigated the scope of the reaction using low yields (20–33%). Despite the yields, it is remarkable that a
different heterocycles 1a
–
1l and alkynes 2a
–
2e (see Figure 3).
weak coordinating group, such as the free amide, should be able
to direct the reaction towards its adjacent position even in the
presence of the strongly coordinating pyridine group. This
preferential orientation could be based on the generation of an
anion at the N atom by deprotonation in the initial stages of the
reaction, followed by strong N-bonding of the resulting C(O)NH
group to the Ru centre. This concept has been used recently by
Yu and co-workers to overcome the restrictions imposed by
certain strong bonding groups,21 and it seems that it also applies
in the case reported here. As expected, the carbocyclic 1-
naphthylamide 1l reacted cleanly with 2a to give 3,4-
diethylbenzo[h]isoquinolin-1(2H)-one (3la) in good yield.
[Ru] 10% / KPF6 10%
Cu(OAc)2 / 2 NaOAc
toluene 120 Â˚C 24h
O
O
X
3aa-3ga
3aa-3ae, 5ae
(13 examples)
H
X
R3
N
NH2
R3
2
R1
R2
Y
R1 = R2 = Et 2a, Me 2b, Ph 2e
R2 = Me, R1 = tBu 2c, Ph 2d
Y
R1
H
R2
X = S; Y = CH; R3 = H 1a, Me 1c, Cl 1d, C4H4 1e
X = CH; Y = S; R3 = H 1b
Y = CH; R3 = H; X = O 1f, NMe 1g, NH 1h
O
O
[Ru] 10% / KPF6 10%
Cu(OAc)2 / 2 NaOAc
toluene 120 Â˚C 24h
Z
Z
Y
H
3ia-3la
(4 examples)
Y
N
NH2
X
2
Et
Et
X
2a
H
X = N, Y = Z = CH 1i; X = Z = CH, Y = N 1j
X = Y = CH, Z = N 1k; X = CH, Y-Z = C6H4 1l
O
O
O
O
O
S
H
S
H
S
H
H
O
H
N
N
N
N
N
R
S
We also studied the scope of the reaction by changing the
alkyne. The reaction generally worked well with electron-rich
R = Me 3ca (89%)
R = Cl 3da (51%)
3aa (87%)
3ea (75%)
3ba (92%)
3fa (37%)
O
O
O
O
O
alkynes (3aa
–
3ac) and full conversions were observed, although
3ac were
N
H
N
H
H
H
H
N
N
N
N
N
yields of pure 3ab were low. Compounds 3aa
–
+
N
N
obtained as single isomers. This behaviour is expected for
symmetrical alkynes 2a and 2b, but means that the reaction
takes place with total regioselectivity for 4,4-dimethyl-2-
3ga (77%)
3ia (20%)
3ja1 (25%)
3ja2 (8%)
3la (80%)
O
O
O
O
O
H
pentyne 2c 22
The results of NOESY-1D experiments (see ESI)
.
Ph
Ph
H
S
H
S
H
S
H
S
S
Ph
N
N
N
N
N
show that irradiation of the methyl peak (2.37 ppm) promotes
a strong NOE in the signals at 7.19 ppm (Hthio) and 1.38 ppm (t-
Bu), which implies that the t-Bu group is in the 5-position, close
to the N atom, while the Me group is in the 4-position. This
Ph
3ae (19%)
3aa (87%)
3ab (25%)
3ac (92%)
3ad (28%)
Figure 3. Scope of the synthesis of fused heterocycle-pyridinones 3.
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