Synthesis of densely substituted α,β,γ,δ-dienones via the PdII-catalyzed allylation, H-migration, and aerobic oxidative δ-hydride elimination cascade

Article abstract of DOI:10.1021/ol203444g

A novel protocol for the highly stereoselective synthesis of E,E-α,β,γ,δ-unsaturated dicarbonyl compounds is presented. Starting from the readily available allylic alcohols and 1,3-diketones, an array of E,E-α,β,γ,δ-dienones can be efficiently synthesized

Full text of DOI:10.1021/ol203444g

ORGANIC
LETTERS
2012
Vol. 14, No. 5
1218–1221
Synthesis of Densely Substituted r,β,γ,
δ-Dienones via the PdII-Catalyzed
Allylation, H-Migration, and Aerobic Oxidative
δ-Hydride Elimination Cascade
Feng-Quan Yuan†,‡ and Fu-She Han*,†,§
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin
Street, Changchun 130022, Jilin, P. R. China, Graduate School of Chinese Academy of
Sciences, Beijing 100864, P. R. China, and State Key Laboratory of Fine Chemicals,
Dalian 116024, P. R. China
fshan@ciac.jl.cn
Received December 25, 2011
ABSTRACT
A novel protocol for the highly stereoselective synthesis of E,E-r,β,γ,δ-unsaturated dicarbonyl compounds is presented. Starting from the readily
available allylic alcohols and 1,3-diketones, an array of E,E-r,β,γ,δ-dienones can be efficiently synthesized in high yields via Pd-catalyzed
dehydrative allylation, H-migration, and aerobic oxidative δ-hydride elimination cascade. In addition to the novel reaction mechanism, the use of
1:1 allylic alcohol and 1,3-diketone as reactant, 5 mol % of PdCl2 as catalyst, and 1 atm of environmentally benign O2 as oxidant, as well as the
generation of only H2O byproduct, makes this protocol rapid, simple, atom-efficient, and clean.
R,β,γ,δ-Unsaturated carbonyl compounds are impor-
tant synthetic intermediates in a wide spectrum of chemical
transformations. They are versatile precursors for 1,6- or
1,4-addition,1 DielsꢀAlder reaction,2 cycloaddition,3 and
so forth. The most popular methods for the synthesis of
R,β,γ,δ-dienones relied mainly on the Knoevenagel con-
densation of R,β-unsaturated aldehyde with methylene
active compound4 and HornerꢀWadsworthꢀ-Emmons
olefination (HWE) of R,β-unsaturated phosphate with
aldehyde.2 However, the reactions of the corresponding
ketone substrates were sluggish or produced Michael addi-
tion byproduct. Recently, some elegant protocols for the
synthesis of R,β,γ,δ-dienones via the Pd-5 and Rh-
catalyzed6 direct cross-coupling of alkenes and acrylates
have been reported (eq 1). However, a relatively high Pd
catalyst loading (10ꢀ20 mol %) and inorganic salt as co-
oxidants were required. Consequently, effective protocols
for the synthesis of highly substituted (eq 2, R1 ¼ H)
R,β,γ,δ-dienone derivatives are very rare.
† Changchun Institute of Applied Chemistry.
‡ Graduate School of Chinese Academy of Sciences.
§ State Key Laboratory of Fine Chemicals.
(1) For some examples of 1,6-addition, see: (a) Nishimura, T.;
Yasuhara, Y.; Sawano, T.; Hayashi, T. J. Am. Chem. Soc. 2010, 132,
7872. (b) Harutyunyan, S. R.; den Hartog, T.; Geurts, K.; Minnaard,
A. J.; Feringa, B. L. Chem. Rev. 2008, 108, 2824. (c) den Hartog, T.;
Harutyunyan, S. R.; Font, D.; Minnaard, A. J.; Feringa, B. L. Angew.
Chem., Int. Ed. 2008, 47, 398. For examples of 1,4-addition, see: (d)
Singh, R.; Ghosh, S. K. Org. Lett. 2007, 9, 5071 and references cited
therein.
(2) For examples, see: Dockendorff, C.; Sahli, S.; Olsen, M.; Milhau,
L.; Lautens, M. J. Am. Chem. Soc. 2005, 127, 15028 and references cited
therein.
(3) Horie, H.; Kurahashi, T.; Matsubara, S. Angew. Chem., Int. Ed.
2011, 50, 8956.
(4) He, Y.-H.; Hu, Y.; Guan, Z. Synth. Commun. 2011, 41, 1617 and
extensive references therein.
To overcome this problem, we have initiated an inves-
tigation into the development of a novel protocol for the
r
10.1021/ol203444g
Published on Web 02/09/2012
2012 American Chemical Society

synthesis of polysubstituted R,β,γ,δ-unsaturated dicarbon-
yl compounds. Herein, we disclose that, starting from
readily available allylic alcohols7 and 1,3-dicarbonyl
compounds (eq 2), the synthesis of R,β,γ,δ-unsaturated
dicarbonyl compounds bearing substituents (R1 ¼ H) in the
inner double bond could be achieved not only in high yields
but also in E,E-form of selectivity via PdII-catalyzed tan-
dem reactions, involving the dehydrative allylation,
H-migration, and aerobic oxidative δ-hydride elimination.
Moreover, the reaction proceeded smoothly in the presence
of only 1:1 ratio of reactants, 5 mol % of PdCl2 catalyst,
and 1 atm of environmentally benign O2 oxidant. In
addition, only H2O was generated as byproduct. These
advantanges make the new protocol highly efficient in
terms of atom-economic and environmental impact.8 To
the best of our knowledge, such a novel protocol has not
been reported.
On the basis of the proposed mechanism, we screened
the reaction parameters using allylic alcohol 1a and 1,3-
diketone 2a as a model reaction (Scheme 2). Some im-
portant information was obtained after numerous experi-
ments. Namely, the reaction is dramatically influenced by
the basicity of the reaction system. We found that the PdII-
catalyzed allylation of 1a and 2a proceeds smoothly to
provide the allylated product 3a in the absence of base but
was suppressed completely when base was present. In con-
trast, base was indispensable for the formation of R,β,γ,
δ-dienone 4a from 3a. In addition, the conversion of 3a to
4a is accelerated remarkably by O2 as compared to that
under air and N2 atmosphere.
Scheme 2. Real Pathway for the PdII-Catalyzed Synthesis of
R,β,γ,δ-Dienones
The initial synthetic strategy is illustrated in Scheme 1.
Based on our recent experiences on Pd-catalyzed allyla-
tion reaction of heteroarenes and allylic acetates,9 as
well as other reports on the Lewis acid-catalyzed allylic
substitutions,10ꢀ13 we assumed that the Pd cation-
catalyzed allylation of allylic alcohol A and 1,3-dicarbo-
nyl compounds B would occur to afford C. Its tautomer
D undergoes oxidative hydride elimination via the alkene-
Pd coordination (E), CꢀPd bond formation (F), and β-
hydride elimination to produce the R,β,γ,δ-unsaturated
carbonyl compound G.
Scheme 1. Tentatively Proposed Mechanism for the PdII-
Catalyzed Synthesis of R,β,γ,δ-Dienones
To clarify the reasons, we carried out some control experi-
ments. The results revealed that in contrast to our initially
proposed mechanism (Scheme 1), 3a was indeed converted
to dienol 5 very rapidly in the presence of base in almost
quantitative yield. The structure of 5 was unambiguously
determined by NMR and X-ray single-crystal analyses
(see Scheme 2).14 Treatment of 5 in the presence of PdII
and 1 atm of O2 afforded E,E-R,β,γ,δ-unsaturated dicar-
bonyl compound 4a as a single stereoisomer whose struc-
ture was also clearly demonstrated by NMR and X-ray
single-crystal analyses (see Scheme 2).14 These results
inorganic oxidants with molecular oxygen has been recognized as the
most effective ways for efficient synthesis. For some reviews, see: (a)
Dondoni, A.; Massi, A. Angew. Chem., Int. Ed. 2008, 47, 4638. (b)
Nicolaou, K. C.; Chen, J. S. Chem. Soc. Rev. 2009, 38, 2993.
(9) Yuan, F.-Q.; Gao, L.-X.; Han, F.-S. Chem. Commun. 2011, 47,
5289.
(10) For AuCl3-catalyzed reactions, see: Rao, W.; Chan, P. W. H.
Org. Biomol. Chem. 2008, 6, 2426.
(11) For Mo(II)-catalyzed reactions, see: Malkov, A. V.; Davis, S. L.;
(5) (a) Hatamoto, Y.; Sakaguchi, S.; Ishii, Y. Org. Lett. 2004, 6, 4623.
(b) Xu, Y.-H.; Lu, J.; Loh, T.-P. J. Am. Chem. Soc. 2009, 131, 1372. (c)
Yu, H.; Jin, W.; Sun, C.; Chen, J.; Du, W.; He, S.; Yu, Z. Angew. Chem.,
Int. Ed. 2010, 49, 5792. (d) Xu, Y.-H.; Wang, W.-J.; Wen, Z.-K.; Hartley,
J. J.; Loh, T.-P. Tetrahedron Lett. 2010, 51, 3504. (e) Xu, Y.-H.; Chok,
Y. K.; Loh, T.-P. Chem. Sci. 2011, 2, 1822.
ꢀ
ꢁ
Baxendale, I. R.; Mitchell, W. L.; Kocovsky, P. J. Org. Chem. 1999, 64,
2751.
(6) Besset, T.; Kuhl, N.; Patureau, F. W.; Glorius, F. Chem.;Eur. J.
2011, 17, 7167.
(12) For Ca(II)-catalyzed reactions, see: Niggemann, M.; Meel, M. J.
Angew. Chem., Int. Ed. 2010, 49, 3684.
(13) For In(III)-catalyzed allylations, see: (a) Yasuda, M.; Somyo,
T.; Baba, A. Angew. Chem., Int. Ed. 2006, 45, 793. (b) Yadav, J. S.;
Reddy, B. V. S.; Rao, K. V.; Rao, P. P.; Raj, K. S.; Prasad, A. R.;
Prabhakar, A.; Jagadeesh, B. Synlett 2006, 3447.
(7) Allylic alcohols are commercially available or can be readily
prepared according to the known methods; see: (a) Siddiqui, N.; Alam,
P.; Ahsan, W. Arch. Pharm. Chem. Life Sci. 2009, 342, 173. (b)
Crawford, J. J.; Henderson, K. W.; Kerr, W. J. Org. Lett. 2006, 8,
5073. (c) Ueda, M.; Miyaura, N. J. Org. Chem. 2000, 65, 4450.
(8) In modern organic synthesis, the combination of a multistep
synthesis into a one-pot tandem operation or replacement of organic/
(14) CCDC 847602 and 847601 contain the supplementary crystal-
lographic data of compounds 4a and 5, respectively.
Org. Lett., Vol. 14, No. 5, 2012
1219

suggested that the real pathway for the formation of 4a from
3a proceeds indeed via a base-mediated enolization and 1,3-H
migration to form 5, followed by a PdII-catalyzed aerobic
oxidative δ-hydride elimination.
Table 1. Optimization of the Reaction Conditions for the One-
Pot Synthesis of 4aa
b
catalyst
(% mol)
t1/t2
yieldc
(%)
entry
additive
solvent
DMF
(h)
1
2
3
4
5
6
7
PdCl2 (10) K2CO3
PdCl2 (10) K2CO3
PdCl2 (10) K2CO3
PdCl2 (10) KHCO3
PdCl2 (10) K3PO4
2/10
51
dioxane 10/24 traced
toluene 9/24
trace
54
DMF
DMF
DMF
2/16
2/20
2/6
49
61e
59e
˚
PdCl2 (10) K2CO3 /4 A MS
˚
PdCl2 (5) K2CO3 /4 A MS DMF
2/8
a Reaction conditions: allylic alcohol 1a (0.5 mmol), 1,3-diketone 2a
(0.5 mmol, 1.0 equiv), O2 at 1 atm, and PdCl2 catalyst in solvent(3 mL) at
100 °C; then base (0.5 equiv) was recharged in stiu and heated at 100 °C.
b t1 and t2 stand for the reaction time for the formation of 3a from 1a and
2a and the subsequent formation of 4a from 3a, respectively. c The yield
of 4a was determined by 1H NMR spectroscopy because of the con-
tamination of a small amount of furan byproduct 6a (Scheme 2).
d Monitored by TLC. e Isolated yield.
Figure 1. Synthesis of various R,β,γ,δ-dienones from alkyl 1,3-
dicarbonyl compounds. aReaction conditions: allylic alcohol 1
(0.5 mmol), 1,3-diketone 2 (0.5 mmol, 1.0 equiv), O2 at 1 atm,
and PdCl2 (5 mol %) in DMF (3 mL) at 100 °C; then K2CO3 (0.5
equiv) was recharged in situ and heated at 100 °C; isolated yield.
bt1 and t2 stand for the reaction time of allylation and dienone
formation, respectively. cDienone formation was carried out at
60 °C. dThe corresponding allylic acetate was used for allylation
in CH2Cl2 catalyzed by Cu(OTf)2, and dienone formation was
carried out in DMF at 60 °C catalyzed by PdCl2.
Withthesekeyreactionparametersaswell asthereaction
mechanism established, our efforts were devoted to
optimizing the reaction conditions aimed at realizing the
synthesis of R,β,γ,δ-unsaturated carbonyl compounds via
a one-pot operation. Here, the key relies on an appropriate
combination of catalyst, oxidant, and base that enables the
tandem transformations to proceed efficiently without
affecting the activity of the catalysts. Table 1 summarized
some representative results. Extensive trials showed that
PdCl2 (10 mol %) was a highly active catalyst, affording
the desired product 4a in 51% yield in the presence of 1:1
molar ratio of 1a and 2a (Table 1, entry 1). In addition, a
trace amount of furan derivative 6a was formed (Scheme 2).
A screening of solvents (entries 1ꢀ3) and bases (entries 1, 4,
and 5) indicated that DMF and K2CO3 were better options.
Further optimization toward lowering the catalyst load-
Having established the optimized conditions, we exam-
ined the general applicability of this protocol. An array of
allylic alcohols reacted smoothly with the alkyl-substituted
1,3-diketone 2a to afford the desired R,β,γ,δ-unsaturated
dicarbonyl compounds. As shown in Figure 1, allylic alco-
hols substituted by simple phenyl groups reacted well with
2a to give 4a and 4b in good isolated yields. The fused
aromatic systems such as R- and β-naphthyl substituents are
also tolerated, delivering 4c and 4d in 74% and 71% yields,
respectively. In addition, substrates either with electron-
deficient Br and NO2 or with electron-rich OMe functional
groups in the phenyl ring periphery are also viable substrates
as seen from the high yields of the corresponding products
4eꢀh, although allylic acetate was shown to be more ef-
ficient for the allylation reaction of NO2-substituted sub-
strate (4f). Interestingly, bromides, which are well-known to
be good leaving groups in Pd-catalyzed cross-couplings,
remain intact under the reaction conditions. Moreover, the
method is also applicable to acetyl acetate 2b, affording the
desired product 4i/4i0 (E/Z = 1.4/1) in 74% yield. Finally, it
should also be mentioned that the method exhibits excellent
stereoselectivity with the R,β,γ,δ-diene moiety in the pro-
ducts assigned to be E,E.
˚
ing revealed that, by adding 4 A molecular sieves, the
yield of 4a could be improved to about 60% even by
decreasing the catalyst loading from 10 mol % to 5 mol %
(entries 6 vs 7). Thus, the optimized conditions for the
synthesis of 4a via the tandem procedure was a 1:1 molar
ratio of 1a and 2a, 5 mol % of PdCl2 catalyst, O2 at
˚
1 atm, and 4 A MS (ca. 30 wt %) in DMF at 100 °C for
2 h, and then the reaction vessel was recharged in situ
with K2CO3 (0.5 equiv) and further heated under an O2
atmosphere at 1 atm for an additional 8 h. Under these
conditions, 4a was obtained in 59% isolated yield (entry 7). It
should be mentioned that the moderate yield for 4a resulted
from the multitime column purification to remove the small
amount byproduct 6a. Thus, this protocol represents an
efficient method for the synthesis of highly substituted
R,β,γ,δ-unsaturated dicarbonyl compounds in terms of the
simple, rapid, clean, and atom-economic reaction process as
well as the formation of only H2O as byproduct.
Next, we extended the method to aryl 1,3-diketones as
represented by 7a and 7b (Figure 2). It was found that
various allylic alcohols decorated by simple phenyl (8aꢀd),
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Org. Lett., Vol. 14, No. 5, 2012

yet hard to synthesize. It should also be mentioned that,
although the detailed results deserve further study, a
preliminary observation showed that compounds 9 and
10, whose structures feature a large delocalized system,
exhibit interesting photoluminescent properties depending
on the size of delocalization. These observations suggested
that the polysubstituted pyridine derivatives can be poten-
tially used as fluorescent probes or materials.
Scheme 3. Efficient Synthesis of Densely Substituted Pyridine
Derivatives from R,β,γ,δ-Unsaturated Dicarbonyl Compounds
In summary, we have developed a novel and efficient
protocol for the synthesis of E,E-R,β,γ,δ-unsaturated di-
carbonyl compounds via the Pd-catalyzed tandem proce-
dure involving allylation, H-migration, and aerobic
oxidative δ-hydride elimination. The mechanism was elab-
orated by NMR and single X-ray analysis. In addition
to the novel reaction mechanism, this method is atom-
efficient, operationally rapid and simple, clean, and highly
stereoselective and, therefore, would find extensive appli-
cations owing to the great importance of polysubstituted
R,β,γ,δ-dienone derivatives in numerous chemical trans-
formations. The preliminary application of the polysub-
stituted R,β,γ,δ-unsaturated dicarbonyl compounds has
been elaborated by the construction of densely substituted
pyridine derivatives. Investigations into the full substrate
scope of this reaction, as well as the further downstream
transformation aimed at investigating the relationship
between the structure and luminescent properties are
currently underway.
Figure 2. Synthesis of various R,β,γ,δ-dienones from aryl 1,3-
dicarbonyl compounds. aReaction conditions: allylic alcohol 1
(0.5 mmol), 1,3-diaryl diketone 7 (0.5 mmol, 1.0 equiv), O2 at
1 atm, and PdCl2 (5 mol %) in DMF (3 mL) at 100 °C; then
K2CO3 (0.5 equiv) was recharged in situ and heated at 100 °C;
isolated yield. bt1 and t2 stand for the reaction time of allylation
c
and dienone formaion, respectively. The dienone formation
was carried out at 60 °C. dThe corresponding allylic acetate was
used for allylation in CH2Cl2 catalyzed by Cu(OTf)2, and
dienone formation was carried out in DMF at 60 °C using
PdCl2 as catalyst.
fused naphthyl (8eꢀg), as well as electron-deficient and
rich aryl groups (8hꢀk), underwent smooth transforma-
tion to afford the desired products both in high isolated
yields and E,E-form of selectivity. In addition, the labile Br
substituent in the phenyl ring is also tolerated (8h).
Finally, to probe the utility of the polysubstituted
R,β,γ,δ-unsaturated dicarbonyl compounds, the synthesis
of 2,3,4,6-substituted pyridine derivatives was performed.
As shown by several representative results in Scheme 3, 4a
and 4c can be converted smoothly to the densely substi-
tuted pyridines 9a and 9c by simply heating with ammo-
nium acetate in EtOH. In addition, N-alkyl-substituted
1,4-dihydropyridine derivatives, 10a, for example, can also
be readily obtained. These results provide an efficient
pathway for the construction of highly substituted N-
heterocycles, which are valuable structural motifsin nature
Acknowledgment. Financial support from the Hundred
Talent Program of CAS and State Key Laboratory of Fine
Chemicals (KF1008) is acknowledged.
Supporting Information Available. Experimental pro-
cedures, 1H and 13C NMR and HRMS data, copies of 1H
and 13C NMR spectra, and X-ray data for compounds 4a
and 5 (CIF). This material is available free of charge via
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 5, 2012
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