Pd-Catalyzed cyclization reaction: A convenient domino process for synthesis of α-carbonyl furan derivatives

Article abstract of DOI:10.1039/c1ob06105d

The design and development of a new efficient two-step one pot protocol for the preparation of novel bicyclic a-carbonyl furans from readily accessible propargyl alcohols and commercially available 1,3-dicarbonyl compounds is presented. The reaction scope

Full text of DOI:10.1039/c1ob06105d

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Pd-Catalyzed cyclization reaction: a convenient domino process for synthesis
of a-carbonyl furan derivatives†
Hua Cao,a,b Huan-Feng Jiang,*b Hua-Wen Huangb and Jin-Wu Zhaob
Received 7th July 2011, Accepted 5th September 2011
DOI: 10.1039/c1ob06105d
Today Pd-catalyzed reactions are probably the most versatile
and extensively used processes for the synthesis of hetero-
cyclic compounds in one single operation without isolation of
intermediates.1–11 Due to their synthetic efficiency they have
attracted significant attention in modern organic synthesis.12–14
Therefore, the discovery of new and convenient transformations
for the synthesis of various heterocyclic compounds through Pd-
catalyzed reactions continues to attract broad interest. In this
paper, we have described an efficient Pd-catalyzed process to
construct a-carbonyl furan derivatives.
Scheme 1 Transition metal-catalyzed synthesis of furans by our group.
Furans are extremely important heterocyclic compounds15–20
and worth our attention because they exhibit a wide range of
biological activities,21–27 and the furan skeleton often exists as a key
structural unit in many drugs and natural products.28–30 In addi-
tion, furan derivatives can be extensively used not only as synthetic
building blocks for the synthesis of more complex compounds, but
also as communicating moieties in materials science. Generally,
there are mainly two routes to obtain furan derivatives:31–42 (i)
cyclization of allenyl ketones,43,44 alkynyl ketone,45,46 enynols,47,48
alkynyl epoxides49 or propargyl ethers;50 (ii) cyclization of 1,4-
dicarbonyl compounds (Paal–Knorr synthesis).
Recently, our group has reported convenient one-pot domino
processes for regiospecific synthesis of highly functionalized poly-
substituted furans through different transition metal-catalyzed cy-
clizations (Scheme 1).39–42 These furans derivatives were obtained
through intramolecular Claisen rearrangement from substrates
electron-deficient alkynes and 2-yn-1-ols. With these fruitful
results in hand, we attempted to explore the scope of these
transformations. Thus, we anticipated to design and develop a
new efficient two-step one pot protocol for the preparation of
novel bicyclic a-carbonyl furans from readily accessible propargyl
alcohols and commercially available 1,3-dicarbonyl compounds
(Scheme 2).
Scheme 2 New synthetic route to a-carbonyl furans.
catalyzed by iron(III) p-toluenesulfonate in DCE for 12 h at
◦
80 C to give intermediate product 3a51,52 under an atmosphere
of nitrogen. Our endeavors centered on optimizing the reaction
conditions for the transformation of 3a into 4aa. The results were
summarized in Table 1. Initially, various Cu(I) and Fe(III) catalysts
used in our previous work were tested. As seen in Table 1, FeIII
catalysts such as Fe(C7H7SO3)3, Fe(ClO4)3, FeCl3 were of no effect
(Table 1, entries 1–3), and trace amounts of the product were
detected under the catalysis of CuI or nano-Cu2O (entries 4, 5).
The cyclization reaction of 3a could not proceed when various
palladium species were respectively used as catalysts alone (entries
6–8). Excitingly, the desired product 4aa was produced in 41% yield
in the presence of PdCl2 with CuI as co-catalyst (entry 9). Then,
other co-catalysts, such as CuCl, CuBr and FeCl3, were evaluated
and it was found that they were inferior to CuI (entries 10–12). To
improve the transformation under the catalysis of PdCl2 with CuI
as co-catalyst, we attempted to employ various additives in the
reaction system (entries 13–20). Our investigations indicated that
Bu4N+Cl- was the most helpful (entry 18). Finally, with regard
to the solvent, DMF, DMSO and DMA proved to be suitable in
the presence of PdCl2/CuI and 3aa was given in 60–65% yields,
while other solvents such as toluene (entry 23), 1,2-dichloroethane
(entry 24), 1,4-dioxane (entry 25) led to lower yields.
Based on the previous study on etherization of 1,3-dicarbonyl
compounds, 1a (1.0 equiv) was reacted with 2a (1.2 equiv)
aSchool of Chemistry and Chemical Engineering, Guangdong Pharmaceu-
tical University, Guangzhou 510006, P.R. of China. E-mail: gmacaohua@
126.com; Fax: (+)86(760)88207839
bSchool of Chemistry and Chemical Engineering, South China University
of Technology, Guangzhou 510640, P.R. of China. E-mail: jianghf@
scut.edu.cn; Fax: (+)86(20)87112906
With the optimal reaction conditions in hand, we then probed
the generality of the reaction using a variety of 1,3-dicarbonyl
compounds and propargyl alcohols. As depicted in Table 2,
† Electronic supplementary information (ESI) available: Experimen-
tal protocols and NMR spectra for products 4aa–4eg. See DOI:
10.1039/c1ob06105d
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Table 1 Screen of reaction conditionsa
either the electron-rich (2d) or electron-withdrawing groups (2e)
at the aromatic ring of the propargyl alcohols. When asymmetric
ethyl 3-oxo-3-phenylpropanoate was employed, only one regio-
isomer was detected, indicating that this cyclization was highly
regioselective.
Subsequently, we were interested in whether the propargyl vinyl
ethers 3 could be converted to a-CH3 furan derivatives 553 through
intramolecular Claisen rearrangement (Scheme 3).
Entry Catalyst
Additive
Solvent
Yield (%)b
1
2
3
4
5
6
7
8
Fe(C7H7SO3)3
Fe(ClO4)3
FeCl3
CuI
nano-Cu2O
PdCl2
—
—
—
—
—
—
—
—
—
—
—
—
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
—
—
—
trace
trace
—
—
—
41
35
38
—
33
22
35
29
44
65
54
40
63
60
24
Pd(OAc)2
Pd2(dba)3
PdCl2/CuI
PdCl2/CuCl
PdCl2/CuBr
PdCl2/FeCl3
PdCl2/CuI
PdCl2/CuI
PdCl2/CuI
PdCl2/CuI
PdCl2/CuI
PdCl2/CuI
PdCl2/CuI
PdCl2/CuI
PdCl2/CuI
PdCl2/CuI
PdCl2/CuI
PdCl2/CuI
PdCl2/CuI
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Scheme 3 AgBF4/AuCl3 co-catalyzed synthesis of furans.
CH3CO2H
1,10-phenanthroline DMF
Bu4N+Br-
Bu4N+F-
Bu4N+I-
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
DMA
Toluene
The cyclization was completed rapidly with the use of
AuCl3/AgBF4 catalytic system under mild conditions, and gave
the corresponding furan derivatives (5a and 5b) in 45% and 42%
yields respectively. This synthetic route provided a further example
of Au and Ag co-catalyzed C–C and C–O bond formation for
synthesis of a-CH3 furan derivatives.
Bu4N+Cl-
pyridine
DABCO
Bu4N+Cl-
Bu4N+Cl-
Bu4N+Cl-
Bu4N+Cl-
Bu4N+Cl-
1,2-dichloroethane 31
1,4-dioxane 46
On the basis of the experimental results, it was demonstrated
that PdCl2 and CuI were essential for the domino reaction. There-
fore, a plausible mechanism for this transformation is described in
Scheme 4. The dehydration product A was formed in the presence
of iron catalyst. A 6-endo dig addition of the enol ether onto Pd(II)–
alkyne complex B resulted in the formation of intermediate C,
which collapsed into the b-allenic ketone D.54,55 And then, b-allenic
ketone D underwent rearrangement to form carbene intermediate
E56–59 in the presence of copper catalyst. Finally, carbene complex
E underwent sequential dehydrogenation oxidation and carbene-
oxidation 60–62 to give product in the presence of air.
a Reaction conditions: 1a (1.0 equiv), 2a (1.2 equiv), catalyst (0.1 equiv),
additive (0.1 equiv), CuI : PdCl2 = 1.2 : 1, solvent (2.0 mL mmol-1); b Yield
of isolated product after flash chromatography.
the reaction of 1a with 2a afforded product 4aa in 65% yield
(Table 2, entry 1). As expected, the product 4ab was obtained in
62% yield when 1a reacted with 2b carrying a phenyl group on
the alkynyl carbon. Unfortunately, when unsubstituted propargyl
alcohol was tested, the desired product 4ac was not formed
under the optimized conditions. The reason might be that 2c
was unstable in the presence of Pd and this result was coincident
with our previous studies. We then examined the reaction scope
of this Pd/Cu catalytic system and its tolerance of functional
groups in the case of other cyclic 1,3-dicarbonyl compounds. As
illustrated in Table 2, substrates 1b and 1c were employed and
the desired products 4ba–4ca were formed in 59% to 67% yields
(entry 4–6).
The results mentioned above demonstrated the remarkable
functional group compatibility on both reagents. Other 1,3-
dicarbonyl compounds and propargyl alcohols were employed
as substrates for this Pd/Cu co-catalyzed domino reaction. We
discovered that the reaction of 1,3-diphenylpropane-1,3-dione
(1d) or ethyl phenylpropiolate (1e) with differently substituted
propargyl alcohols (R3 = CH3, phenyl, m-tolyl, 4-methoxyphenyl,
4-nitrophenyl, 2-thienyl) had a beneficial effect on the reaction
outcomes, and in most cases the corresponding products were
obtained in moderate to good yields under our standard experi-
mental conditions (Table 2, entries 7–17). Pleasingly, these results
indicated that this domino reaction tolerated functional groups on
the aromatic ring. There was no effect on this transformation with
Scheme 4 Proposed mechanism.
In summary, a practical and mild new method for the palladium-
catalyzed synthesis of highly functionalized a-carbonyl furan
has been developed. Under these conditions, various functional
groups were well tolerated and the product furans were usually
isolated in moderate to good yields. In addition, this synthetic
route could prepare a variety of a-carbonyl furans which are useful
synthetic intermediates for bioactive and natural compounds.
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Table 2 PdCl2/CuI-Catalyzed Synthesis of a-Carbonyl Furansa
Entry
1
1,3-Dicarbonyl compounds
Propargyl alcohols
Product (yield%)b
1a (R1,R2 = CH2CH2CH2)
2a (R3 = CH3)
2
1a
2b (R3 = Ph)
3
4
1a
2c (R3 = H)
2a
—
1b (R1,R2 = CH2CMe2CH2)
5
6
7
1b
2b
2a
2a
1c (R1,R2 = CH2CHPhCH2)
1d (R1 = R2 = Ph)
8
1d
2b
9
10
1d
1d
2c
—
2d (R3 = C6H4-p-OMe)
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Table 2 (Contd.)
Entry
11
1,3-Dicarbonyl compounds
Propargyl alcohols
Product (yield%)b
1d
2e (R3 = C6H4-p-NO2)
12
13
14
1e (R1 = Ph; R2 = OEt)
2a
2b
2d
1e
1e
15
1e
2e
16
17
1e
1e
2f (R3 = 2-C4H3S)
2g (R3 = C6H4-m-Me)
a Reaction conditions: 1 (1.0 equiv), 2 (1.2 equiv), PdCl2 (0.1 equiv), CuI (0.1 equiv), Bu4N+Cl- (0.1 equiv), DMF 3 mL. b Isolated yields.
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29 K. Cheng, A. R. Kelly, R. A. Kohn, J. F. Dweck and P. J. Walsh, Org.
Lett., 2009, 11, 2703–2706.
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The authors thank the National Natural Science Foundation of
China (20932002), National Basic Research Program of China
(973 Program) (2011CB808600), the Doctoral Fund of the Min-
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