Dual heterogeneous catalysis for a regioselective three-component synthesis of Bi-and Tri(hetero)arylpyridines

Article abstract of DOI:10.1002/adsc.201200412

We have designed a new, user-friendly oxidative dual heterogeneous catalytic system capable of promoting polysubstituted pyridines as unique products from simple activated Michael acceptors, 1,3-dicarbonyls and ammonium acetate. This metal-free environmentally-respectful and totally regioselective domino reaction proved to be a great strategy to access bi- and triaryl-type pyridines as well as challenging bi- and triheteroaryl-type pyridines in a single operation. Copyright

Full text of DOI:10.1002/adsc.201200412

UPDATES
DOI: 10.1002/adsc.201200412
Dual Heterogeneous Catalysis for a Regioselective Three-
Component Synthesis of Bi- and Tri(hetero)arylpyridines
AHCTUNGTRENNUNG
Christophe Allais,a Frꢀdꢀric Liꢀby-Muller,a Thierry Constantieux,a,*
and Jean Rodrigueza,*
a
Aix-Marseille Universitꢀ, UMR CNRS 7313 iSm2, Campus Saint Jꢀrꢁme, service 531, 13397 Marseille, France
Fax : (+33)-(0)491-289-187; phone: (+33)-(0)491-288-933; e-mail: thierry.constantieux@univ-amu.fr or
jean.rodriguez@univ-amu.fr
Received: May 9, 2012; Revised: June 18, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200412.
Abstract: We have designed a new, user-friendly ox-
idative dual heterogeneous catalytic system capable
of promoting polysubstituted pyridines as unique
products from simple activated Michael acceptors,
1,3-dicarbonyls and ammonium acetate. This metal-
free environmentally-respectful and totally regiose-
lective domino reaction proved to be a great strat-
egy to access bi- and triaryl-type pyridines as well
as challenging bi- and triheteroaryl-type pyridines
in a single operation.
nitriles largely leads the way for the synthesis of pyri-
dines.[13] However, despite recent spectacular advan-
ces,[14] the low availability of some catalysts and sub-
strates associated with the lack of regioselectivity[15]
constitute major drawbacks of this methodology. Al-
ternatively, bimolecular or multicomponent metal-
free synthetic methods based on the direct condensa-
tion of carbonyl compounds with a source of ammo-
nia constitute an interesting complement but still
suffer from substrate limitations,[16] require an oxida-
tive agent,[17] or an elimination step.[18] In this context,
the development of new one-pot regiodefined synthe-
ses of highly substituted pyridine nuclei from simple
starting materials is of significant value.
Keywords: biaryls; 1,3-/1,2-dicarbonyls; dual heter-
ogeneous catalysis; multicomponent recations; pyri-
dines
For several years, our group has been strongly in-
volved in the development of new molecular sieves
(MS)-promoted domino[19] multicomponent reactions
(MCRs)[20] providing high molecular complexity and
diversity[21] while combining economical[22] and envi-
ronmental aspects,[23] to reach, in a stereoselective
Introduction
Since its discovery 166 years ago,[1] pyridine has manner, polyfunctionalized nitrogen-containing het-
become one of the most studied nitrogen-containing erocycles[24] from 1,3-dicarbonyls.[25] Among these
heterocycles. This important building block is found methodologies, we recently reported preliminary re-
in numerous natural biological systems such as vita- sults on the regioselective metal-free three-compo-
min B6 or nicotine. Pyridines and their derivatives nent access to pyridine derivatives (Scheme 1).[26]
have gained considerable attention due to their cen-
This flexible environmentally-friendly strategy in-
tral roles in the biological activity of natural substan- volved the direct open flask condensation of 1,3-dicar-
ces, as well as in the design of therapeutic agents.[2] bonyls 1 with Michael acceptors 2 and ammonium
Moreover, the pyridine ring is recurrent in numerous acetate 3 under heterogeneous catalysis by 4 ꢂ MS in
drugs with a large panel of bioactivities.[3] These scaf- its “classical conditions” (Scheme 1, method A). More
folds are also of widespread interest in agrochemis- recently, we successfully extended this reaction to the
try,[4] coordination[5] and supramolecular[6] chemistry, first use of b,g-unsaturated-a-keto carbonyl deriva-
material sciences,[7] polymers,[8] catalysis,[9] organoca- tives as Michael acceptors in an MCR.[27] The success
talysis[10] and synthesis of natural products.[11] Because of this transformation relied on the development of
of this large spectrum of fascinating applications, the “dual heterogeneous catalysis”, i.e., combination of
selective synthesis of highly functionalized pyridine molecular sieves with activated carbon under an
derivatives remains an attractive challenge in modern oxygen atmosphere, allowing the incorporation of
synthetic organic chemistry.[12] Currently the metal- great molecular diversity at strategic C-2[28] and C-4[29]
catalyzed [2+2+2]cycloisomerization of alkynes with positions (Scheme 1, method B).
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Scheme 1. 4ꢂ MS-promoted three-component reaction (3-
CR) synthesis of polysubstituted pyridines.
The purpose of this article is to present how this
methodology proved to be a great strategy to access
bi- and triaryl-type pyridines as well as challenging bi-
and triheteroaryl-type pyridines in a single operation.
Currently, metallo-catalyzed cross-coupling[30] and oxi-
Figure 1. 1,3-Dicarbonyls 1 and g-arylated activated Michael
acceptors 6–8 used in the MCRs.
[31]
À
dative C H functionalization
reactions lead the
way in the synthesis of aryl-substituted pyridines.
However, the use of metal catalysts combined with
the production of halogenated waste is not compati-
ble with sustainable chemistry, and regioselectivity in
[32]
À
direct C H arylation is not always satisfying. Con-
sequently, we strongly thought that our methodology
may be a robust complementary synthetic route to
access biaryl- or triaryl-type pyridines in a single oper-
ation, from easily accessible substrates, without the
use of any metal.
Results and Discussion
Application of “Dual Heterogeneous Catalysis” to
the Synthesis of Bi- and Triaryl-Type Pyridines 5
We focused our efforts on the synthesis of 4-arylpyri-
dines that are less accessible from metal-catalyzed
protocols. For this purpose, we prepared (see Figure 1
and Experimental Section)[33–35] a series of b,g-unsatu-
rated-a-keto esters 6, a-ketophosphonate 7 and a-
keto amides 8[36] bearing an aryl substituent at the ter-
minal position.
A library of 4-arylpyridines 5 was synthesized be-
tween these activated Michael acceptors and various
1,3-dicarbonyl derivatives 1 (Figure 1). The efficiency
of this method to access such challenging biaryl deriv-
atives is clearly demonstrated by the results reported
in Figure 2. Thus, 4-phenyl-substituted pyridine 5a
was efficiently formed from a-keto ester 6a and
methyl acetoacetate (1a). Gratifyingly, this metal-free
transformation proved to be very tolerant in regard to
the substitution on the phenyl ring. Indeed, both elec-
tron-donating (4-MeO, 5b) and electron-withdrawing Figure 2. 4-Arylpyridines obtained from the 3-CR.
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Dual Heterogeneous Catalysis for a Regioselective Three-Component Synthesis
(2-NO2, 5c) functionalities were tolerated in the reac-
tion although a moderate yield was obtained for 5c,
presumably due the ortho-steric hindrance provided
by the nitro group. 2-Trifluoromethylated biarylpyri-
dine 5d was also isolated in good yield when 1b was
the Michael donor. 4-Arylnicotinamide derivatives
such as 5e and 5f were successfully obtained from sec-
ondary b-keto amide 1c and b,g-unsaturated-a-keto
esters 6a and 6b, respectively. Finally, the tertiary
amide 1d gave 5g in excellent yield. The use of g-
phenyl-b,g-unsaturated a-ketophosphonate 7 was not
as successful as expected, and the corresponding
phosphorus-containing 4-phenylpyridines 5h and 5i
were obtained from methyl acetoacetate (1a) and ace-
toacetanilide (1c) with a yield that does not exceed
22%. Finally, we used b,g-unsaturated a-keto amides
8 in this MCR, allowing the rapid generation of an
important panoply of pyridines 5j–s bearing an amide
function on position 2, known as picolinamide deriva-
tives. In addition to their great biological significance,
these pyridine scaffolds are of widespread interest in
Figure 3. 2,4-Biarylpyridines obtained from b-keto ester 1e
or b-keto amide 1f.
coordination chemistry,[37] catalysis[9b] and organocata- chemicals and material sciences and have been en-
lysis.[10a,c] Furthermore, the application of such activat- countered in some natural products. Consequently,
ed Michael acceptors in this transformation increased the straightforward access to these scaffolds remains
the functional diversity introduced at the C-2 position a great challenge in modern organic synthesis.[38] In
of the pyridine ring. In combination with methyl ace- this field, cross-coupling reactions between heteroaryl
toacetate (1a), substrates 8a–g allowed the formation halides and metallated heteroaryl substrates have
of 4-phenylpicolinamides bearing primary 5j or secon- been described[39] and C H bond functionalization
À
dary 5k–o amide functionalities. The yield significant- has been studied over the past few years.[40] However,
ly dropped when tertiary a-keto amide 8g reacted the currently preferred synthetic route to biheteroaryl
with 1a to form pyridine 5p, highlighting the dramatic compounds is the selective metal-catalyzed dehydro-
role of the NH moiety in the activation process. Final- genative cross-coupling reaction between heteroar-
ly, this methodology proved to be a short and efficient enes, which avoids formation of halogen-containing
way to polyfunctionalized picolinamide-nicotinamide waste.[41] Nonetheless, in the particular case of pyri-
hybrid derivatives 5q–s in good yields from secondary dines, we feel this elegant transformation still suffers
or tertiary b-keto amides 1c and 1d.
from several drawbacks: (i) use of transition metal
To further demonstrate the high synthetic potential catalysts does not completely fulfil sustainable
of this methodology, we prepared a series of triaryl- chemistry demands, (ii) electron-poor pyridine N-
type pyridines 5t–x. When 1,3-dicarbonyl substrates oxides have to be used in this process, requiring an
1 and activated Michael acceptors 6 or 8 were judi- additional deprotection step, (iii) several equivalents
ciously chosen, triaryl products were formed by con- of pyridine N-oxides are usually involved; and (iv)
struction of the central pyridine ring (Figure 3). only the activated 2-position of the pyridine ring can
Indeed, a-keto esters 6 could be combined with b- be substituted by another heterocycle. We thus envi-
keto ester 1e or b-keto amide 1f to lead regioselec- sioned extending the three-component reaction to the
tively to triarylpyridines 5t and 5u in 70% and 92% synthesis of valuable bi- and triheteroaryl-type pyri-
yields, respectively. Additionally, when a-keto amides dines to answer this challenge and provide a viable
8 were used, triaryl-type picolinamide-nicotinamide metal-free alternative.
hybrid derivatives 5v–x were easily accessed in syn-
thetically useful yields starting from 1e and 1f.
To reach this goal, heteroaryl substituents have to
be introduced in the correct position either in the sub-
strate of the acceptor structure for biheteroaryl tar-
gets, or in both reactants for triheteroaryl products.[42]
With the appropriate substrates in hand, we first stud-
ied the synthesis of 4-heteroaryl-substituted pyridines
that are not accessible from dehydrogenative cross-
coupling transformations. We thus used furan-contain-
Application of Optimized “Dual Heterogeneous
Catalysis” to the Synthesis of Bi- and Triheteroaryl-
Type Pyridines 5
Heteroaromatic biaryl compounds are of great inter- ing a-keto amides 8h–j in the user-friendly metal-free
est in many areas including pharmaceuticals, agro- MCR (Scheme 2).
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Scheme 2. 4-Furylpyridines 5aa–ac obtained from the 3-CR.
Scheme 3. Synthesis of 2-furylpyridines under “classical”
and “dual heterogeneous catalysis” conditions.
Gratifyingly, the totally regioselective process al-
lowed the formation of pyridines 5aa–ac bearing
a furyl substituent at the C-4 position in 48% to 63%
yield. Once again, the sequence tolerated both b-keto
ester 1a (R2 =OMe) and b-keto amide 1c (R2 =
NHPh).
Efforts were also made to rapidly synthesize 2-het-
eroaryl-substituted pyridines by adequately choosing
the 1,3-dicarbonyl derivative 1 or the Michael accept-
ors 2 and 8. Thus, “classical conditions” were only
suitable for the synthesis of 2-furylpyridine 5ad from
b-keto ester 1g and b-unsubstituted enal 2, whereas it
was necessary to apply “dual heterogeneous catalysis”
when starting from pyruvate derivative 8 for the syn-
thesis of pyridine 5ae (Scheme 3).
Stimulated by these results, we then extended the
functional diversity of the methodology to several
other heterocycles starting with the metal-free synthe-
sis of 2,2’-bipyridines. To elaborate these extremely
useful scaffolds, notably in organometallic chemis-
try,[5a,43] two synthetic routes proved to be highly effi-
cient (Scheme 4).
Scheme 4. Synthetic routes to 2,2’-bipyridines from this 3-
CR.
The first one was the construction of the pyridine
ring by using b-keto ester 1h [Scheme 4, Eq. (1)]. the remarkable functional diversity at the C-2 posi-
Under the optimized conditions, we were pleased to
obtain the 2,2’-bipyridine 5af from activated Michael
acceptor 8f in a satisfactory 81% yield. The second
strategy involved the b,g-unsaturated a-ketopyridine
9 as reaction partner in combination with b-keto ester
1a or b-keto amide 1c [Scheme 4, Eq. (2)]. These
transformations provided 2-pyridinylpyridines 5ag
and 5ah in excellent yields, supporting that nitrogen-
containing heterocycles could be great activators of
the Michael acceptor.
Rewardingly, other heterofunctionalized Michael
acceptors 10a and 10b provided access to a new class
of heterocyclic biaryl products by this methodology.
Thus, 2-imidazoyl-4-arylpyridines 5ai–ak were synthe-
sized in a single operation from methyl acetoacetate
(1a) and acetoacetanilide (1c) (Figure 4).
To further demonstrate the versatility of this metal-
free MCR in biheteroaryl synthesis while highlighting metal-free 3-CR.
Figure 4. 2-Imidazoylpyridines 5ai–5ak obtained from the
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Dual Heterogeneous Catalysis for a Regioselective Three-Component Synthesis
Table 1. Optimization of experimental conditions to access 2-oxazoline-pyridine 5al.
Entry
Solvent
Additive
Atmosphere[a]
Time [h]
5al [%][b]
12 [%][b]
1
2
3
4
toluene/AcOH (4/1)
toluene
toluene
act. C[c]
–
O2
air
O2
air
48
16
29
6
–
8
47
57
–
50
14
–
act. C[c]
[d]
toluene
MnO2
[a]
Reaction conducted under air or oxygen atmosphere.
Yield after purification by flash chromatography on silica gel.
Activated carbon 50% weight.
[b]
[c]
[d]
One equivalent.
tion of the pyridine ring, we successfully extended the
process to the use of a-ketooxazoline 11. However,
a slight improvement of the procedure was necessary
because of the instability of the oxazoline ring under
acidic conditions (Table 1).
Indeed, in the presence of acetic acid, neither the
pyridine mono-oxazoline 5al nor the corresponding
dihydropyridine 12 were observed by NMR analysis
(Table 1, entry 1). We then switched to the “classical
conditions” of the MCR that allowed the formation
of 12 in 50% yield whereas pyridine 5al was obtained
with a poor 8% yield (entry 2). When optimized
Scheme 5. Synthesis of 2,4-triheteroaryl-type picolinamide
5am from this 3-CR.
“dual heterogeneous catalysis” conditions were em- by the formation of pyridine 5am (Scheme 5). When
ployed in this transformation without acetic acid as a mixture of b-keto ester 1g, b,g-unsaturated a-keto
co-solvent (i.e., activated carbon 50% weight under amide 8k and ammonium acetate (3a) was submitted
oxygen atmosphere), pyridine 5al was isolated as the to our optimized “dual heterogeneous catalysis” con-
major product in a mixture with a non-negligible ditions, 2,4-bisfuryl-picolinamide 5am was obtained in
amount of corresponding DHP (Entry 3). The yield of a single operation in 57% yield. This result further
this 2-oxazoline pyridine 5al was ultimately increased demonstrated the high synthetic potential of this re-
to 57% without any trace of 12 when one equivalent gioselective and user-friendly methodology.
of manganese dioxide was added to the mixture of
the three partners in refluxing toluene (entry 4).
Moreover the reaction time was considerably short- Conclusions
ened under these optimized conditions. Despite the
moderate yield, a quick access to this type of pyridine We have developed a new, metal-free, three-compo-
mono-oxazoline is not trivial since they are useful li- nent reaction from 1,3-dicarbonyl derivatives, Michael
gands commonly synthesized in several steps. Pyridine acceptors and ammonium acetate, allowing the access
bis-oxazoline (PYBOX) is certainly the most popular to polyfunctionalized pyridines with a total control of
class in this ligand family and is widely involved in or- regioselectivity. This environmentally-friendly ap-
ganometallic chemistry.[44] Notably, various other li- proach is in accordance with many stringent criteria
gands with a similar structure to 5al have been recent- of sustainable chemistry such as step- and atom-econ-
ly utilized in highly enantioselective Fujiwara–Morita- omy. The transformation proved to be extremely tol-
ni annelations, but were synthesized in six steps.[45]
erant in regard to reaction partners, leading either to
Finally, the challenging metal-free construction of pyridines from b-keto esters or to nicotinamide deriv-
heterocyclic triaryl compounds was also possible atives from b-keto amides and to picolinamides with
through this versatile methodology as demonstrated a-keto amides.
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D. Crouzier, Enguehard- C. Gueiffier, A. Gueiffier, F.
Nachon, B. Lefebvre, F. Fauvelle, Eur. J. Med. Chem.
2009, 44, 3509–3518; c) V. Onnis, M. T. Cocco, R.
Fadda, C. Congiu, Bioorg. Med. Chem. 2009, 17, 6158–
6165; d) C. D. Duffy, P. Maderna, C. McCarthy, C. E.
Loscher, C. Godson, P. J. Guiry, ChemMedChem 2010,
5, 517–522.
We clearly demonstrated the high potential of this
strategy with the straightforward synthesis of bi- and
triACHTUNGTRENNUNG(hetero)aryl-type pyridines without the use of any
metal-based catalyst. This provides access to new and
potentially useful ligands in coordination chemistry.
Advances in this field will be reported in due course.
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Smejkal, B. Breit, Angew. Chem. 2008, 120, 317–321;
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[7] R. Makiura, S. Motoyama, Y. Umemura, H. Yamanaka,
O. Sakata, H. Kitagawa, Nature Mater. 2010, 9, 565–
571.
[8] N. G. Kang, M. Changez, J. S. Lee, Macromolecules
2007, 40, 8553–8559.
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K. W. Jung, Synlett 2009, 482–486; b) K. Shibatomi, T.
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12, 2536–2539.
[10] For recent examples, see: a) H. Zheng, J. Deng, W. Lin,
X. Zhang, Tetrahedron Lett. 2007, 48, 7934–7937; b) V.
Coeffard, H. Muller-Bunz, P. J. Guiry, Org. Biomol.
Chem. 2009, 7, 1723–1734; c) S. Guizzetti, M. Benaglia,
S. Rossi, Org. Lett. 2009, 11, 2928–2931.
[11] J. P. Michael, Nat. Prod. Rep. 2005, 22, 627–646.
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Experimental Section
General Procedure for the Multicomponent Synthesis
of Pyridines 5 in “Dual Heterogeneous Catalysis”
Conditions (Example of Pyridine 5a)
To a 50-mL, two-necked, round-bottom flask equipped with
reflux condenser, were introduced methyl acetoacetate 1a
(100 mg, 0.86 mmol, 1 equiv.), g-phenyl-b,g-unsaturated a-
keto-methyl ester 6a (1 equiv.), ammonium acetate
3
(2 equiv.), activated carbon (50 mg, 50 wt%) and 4ꢂ molec-
ular sieves (3 g) in a mixture AcOH/toluene (1/4 v/v)
(15 mL). The flask was then placed under an oxygen atmos-
phere. The mixture was stirred at reflux until complete con-
sumption of starting materials (monitored by TLC and MS).
The heterogeneous mixture was then filtered on a short pad
of celite and thoroughly washed with toluene. Sometimes,
an acetate salt is formed after filtration on celite. In this
case, a second filtration is needed. The solvent was then re-
moved by evaporation under reduce pressure to afford
crude 5a which was purified by chromatography on silica gel
(EtOAc/petroleum ether 1/3; Rf =0.18). Pyridine 5a was ob-
tained as an orange solid; yield: 91%; mp 118–1198C). MS
(ESI): m/z (%)=308 [M+Na]+ (100), 286 [M+H]+ (14);
+
HR-MS (ESI): m/z=286.1075, calcd. for C16H16NO4 [M+
H]+: 286.1074; 1H NMR (CDCl3, 300.13 MHz): d=7.80 (s,
1H), 7.19 (br s, 5H), 3.77 (s, 3H), 3.44 (s, 3H), 2.48 (s, 3H);
13C NMR (CDCl3, 75.47 MHz): d=167.9, 164.5, 155.6, 148.3,
147.1, 136.8, 130.4, 128.5, 128.2, 127.2, 122.6, 52.4, 51.8, 22.4.
Acknowledgements
C.A. thanks the French Research Ministry for a fellowship
award. F. L.-M. thanks CNRS and the Conseil Rꢀgional
PACA for providing a doctoral fellowship. Aix-Marseille
University, CNRS (UMR 7313 iSm2 and RDR2 research net-
work) and French Research Ministry are gratefully acknowl-
edged for financial support. We also deeply thank Dr. Andy
Tsai and Jason Abbott for their fruitful advice.
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Christophe Allais et al.
UPDATES
cient peptidic coupling between the easily accessible
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À
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8
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These are not the final page numbers!

UPDATES
Dual Heterogeneous Catalysis for a Regioselective Three-
9
Component Synthesis of Bi- and TriACHTUNTRGNEUNG(hetero)arylpyridines
Adv. Synth. Catal. 2012, 354, 1 – 9
Christophe Allais, Frꢀdꢀric Liꢀby-Muller,
Thierry Constantieux,* Jean Rodriguez*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
9
ÞÞ
These are not the final page numbers!