Condition-determined multicomponent reactions of 1,3-dicarbonyl compounds and formaldehyde

Article abstract of DOI:10.1021/co5001019

By means of changing the reaction parameters, different products could be generated selectively starting from the same combination of substrates involving 1,3-dicarbonyl compounds and formaldehyde. This strategy enabled us to access diverse molecules with

Full text of DOI:10.1021/co5001019

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Article
Condition-determined multicomponent reactions
of 1,3-dicarbonyl compounds and formaldehyde
Changhui Liu, Meng Shen, Bingbing Lai, Amir Taheri, and Yanlong Gu
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/co5001019 • Publication Date (Web): 15 Oct 2014
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Condition-determined
multicomponent
reactions
of
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1,3-dicarbonyl compounds and formaldehyde
Changhui Liu, Meng Shen, Bingbing Lai, Amir Taheri, and Yanlong Gu*
Graphic Abstract
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Condition-determined
multicomponent
reactions
of
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1,3-dicarbonyl compounds and formaldehyde
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Changhui Liu,a,c Meng Shen,a,c Bingbing Lai,a Amir Taheria and Yanlong Gua,b*
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a
Key Laboratory for LargeꢀFormat Battery Materials and System, Ministry of
Education, School of Chemistry and Chemical Engineering, Huazhong University of
Science and Technology, 430074, Wuhan, China. Phone: (0)86ꢀ(0)27ꢀ87 54 37 32,
Fax: (0)86ꢀ(0)27ꢀ87 54 45 32, Eꢀmail: klgyl@hust.edu.cn
b
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute
of Chemical Physics, Lanzhou, 730000 (P.R. China)
c Changhui Liu and Meng Shen contributed equally to this work.
Abstract: By means of changing the reaction parameters, different products could be
generated selectively starting from the same combination of substrates involving
1,3ꢀdicarbonyl compound and formaldehyde. This strategy enabled us to access
diverse molecules without changing both starting material and reactor, maximizing
thus the multiꢀfunctionality of the synthetic system. For example, starting from
1,3ꢀdicarbonyl compound, formaldehyde and 1,1ꢀdiphenylethylene, two kinds of
products could be selectively formed including (i) a densely substituted dihydropyran,
and (ii) an C2ꢀcinnamyl substituted 1,3ꢀdicarbonyl compound. A oneꢀpot
threeꢀcomponent reaction of phenacylpyridinium salt, 1,3ꢀdicarbonyl compound and
formaldehyde
was
also
investigated,
which
produced
either
2,4ꢀdiacylꢀ2,3ꢀdihydrofuran or 2,4ꢀdiacylꢀ2ꢀhydroxylmethylꢀ2,3ꢀdihydrofuran in good
to excellent yield.
Keywords:
Multicomponent
reactions,
diversityꢀoriented
synthesis,
conditionꢀdetermined MCR, combinatorial chemistry
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Introduction
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Multicomponent reactions (MCRs) are convergent reactions of three or more starting
materials, which have emerged as an efficient method for rapidly generating complex
molecules with diverse functional substituents.1 MCRs have often been used to
establish expedient and ecoꢀfriendly chemical methods for the discovery of new
chemical entities required by pharmaceutical and agrochemical industries.2 The most
of MCRs were established by a reaction sequence involving (i) generation of an active
intermediate through a reaction of the first two or three components, and (ii) trapping
of the intermediate with the same or another component. The generated intermediates
generally have a very high reactivity, which enabled us to construct new molecular
scaffolds sometimes. Therefore, most of the research interests are focusing on either
the exploration of a suitable trapping reagent or derivatization of the intermediate with
the hope of establishing a new reaction sequence.3 However, there is a perceived
challenge in the face of the ever increasing demand for novel medicinally active
compounds. This forced us to think how to maximize the efficiency of establishing
molecule libraries for biological screening.
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Control of the reaction selectivity, for example, chemoꢀ, stereoꢀ, and
regionꢀselectivity, is one of the most important objectives of organic chemistry.4
Many different reaction parameters such as temperature, pressure, solvent, as well as
catalyst type, and other factors can be utilized to modulate the selectivity of organic
reactions. Because three or more substrates were involved in a MCR, it is conceivable
that by carefully manipulating the reaction parameters, it might be possible to
establish two or more MCRs with the same combination of substrates. This strategy
can increase the number of MCRs without increasing the number of substrates.
Previously, a few reports have disclosed some individual examples on the synthesis of
different products from the same substrates.5 It offered an effective means to us for
enriching the diversity of the MCR product libraries, which in turn facilitates
biological screening.
We are attracted by the unique advantages of this strategy and started a research
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program on this topic some time ago. To utilize this strategy, we have to find a
suitable intermediate, which not only has a high reactivity but also is amenable to
diversified reaction modes, allowing us to trap it in different reaction pathways.
Recently, Knoevenagel reaction of 1,3ꢀdicarbonyl compound and formaldehyde has
been used to create MCRs.6 The generated 2ꢀmethyleneꢀ1,3ꢀdicarbonyl intermediate
not only acts as a oxoꢀdiene in DielsꢀAlder reaction but also serves as Michael
acceptor in conjunction with some Michael donors, favoring thus construction of
many MCRs.7 We are attracted by the multifunctionality of this intermediate, and
started our MCR investigation with a combination of 1,3ꢀdicarbonyl compound and
formaldehyde.
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Results and discussion
Initially, a threeꢀcomponent reaction of 1,1ꢀdiphenylethylene 1a, acetoacetone 2a
and formaldehyde was investigated. As shown in Scheme 1, when formalin was used
as HCHO source, a dihydropyran 3a was obtained in 75 % of yield after 5 hours of
o
reaction at 80 C in acetonitrile. The reaction is very clean, and the unreacted
1,1ꢀdiphenylethylene can be fully recovered. Interestingly, when paraformaldehyde
was used as the HCHO source, a different compound, 4a was obtained in 80 % of
yield in the presence of toluenesulfonic acid (PTSA) at 60 oC. These results imply that
the source of HCHO and the reaction conditions played key role in controlling the
reaction selectivity.
Scheme 1. Threeꢀcomponent reaction of 1a, 2a and formaldehyde.
These results gave us also impetus to investigate the reaction mechanism. It is well
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known that 3a was formed through a tandem Knoevenagel/oxo DielsꢀAlder reaction
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pathway, in which 1a acted as
a
dienophile to trap the generated
3ꢀmethyleneꢀ2,4ꢀpantadione (intermediate I, Figure 1).8 In order to shed light on the
mechanism for the formation of 4a, several control experiments were then carried out.
Firstly, although the Prins cyclization product of 1a and paraformaldehyde, 5a could
be formed with the aid of PTSA catalyst, it cannot be converted into 4a under the
reaction conditions (Scheme 2). Because 3a could be also detected during the reaction
of forming 4a (Figure 2), we therefore treated 3a with PTSA in acetonitrile. After 5
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hours of reaction at 80 C, 4a was formed in 80 % of yield. However, this result is
insufficient to lead us to draw a conclusion for the formation of 4a because kinetic
investigation of the reaction between 1a, 2a and paraformaldehyde revealed that no
significant accumulation of 3a was observed during the reaction (Figure S2). In
addition, monitoring of the reaction progress by means of 1H NMR manifested that (i)
intermediate I was generated quickly in the first 30 minutes of the reaction; then, it’s
concentration gradually decreased; and (ii) the formation of 4a occurred in the
beginning of the reaction, and it lasted all 12 hours as the concentration of 4a
increased gradually during the reaction. All these results led us to deduce that 4a
might be formed through a direct Michael reaction of the intermediate I and 1a.
Because the isolation of pure intermediate I is not possible, methyl vinyl ketone 6a
was therefore used as a Michael acceptor, which has a relatively low reactivity than
the intermediate I. As shown in Scheme 2, the expected product 7a was obtained in
80 % of yield. This result implies that 4a might be formed through a tandem
Knoevenagel/Michael reaction pathway. Incidentally, as Knoevenagel/oxo
DielsꢀAlder reaction is a nonꢀcatalytic reaction sequence, formation of 3a is therefore
inevitable during the synthesis of 4a. A Knoevenagel/oxo DielsꢀAlder/ringꢀopening
reaction sequence may be also operative for the formation of 4a (Figure 1). The
ringꢀopening reaction pathway is able to convert 3a into 4a, ensuring thus a good
selectivity of 4a.
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Scheme 2. Control experiments for understanding the mechanism of 4a formation.
Figure 1. Proposed mechanism for the formations of 3a and 4a.
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Figure 2. Progress of a PTSAꢀcatalyzed reaction of 1a, 2a and paraformaldehyde monitored by 1H
NMR.
The PTSA/acetonitrile system was successfully used to establish the
threeꢀcomponent reactions of a wide range of 1,3ꢀdicarbonyl compounds, (HCHO)n,
and 1,1ꢀdiarylethylenes, and the results are shown in Figure 3. Many linear
βꢀketoesters or 1,3ꢀdiketones reacted readily with 1a and paraformaldehyde, affording
the corresponding products in generally excellent yields. Cyclopropyl and methoxy
groups are tolerable in this system (4g). A secondary βꢀketoamide can also be used
uneventfully (4i). Some other 1,1ꢀdiphenylethylene derivatives could also be used.
Particularly, a diarylethylene with thienyl group participated readily in this reaction as
well (4l). It is significant to note that 1a could be replaced by 1,1ꢀdiphenylethanol,
which is lessꢀexpensive as compared with 1a, in this reaction. This offered a
costꢀeffective alternative route to access 4aꢀtype product (Scheme 3). It should be
noted also that, although the same products in Figure 3 could be synthesized by many
reported methods, most of which involve the use of harsh conditions, expensive
reagents and suffer from the lack of simplicity and also the yields and selectivities
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reported are sometimes far from satisfactory.
Therefore, the present
threeꢀcomponent reaction opened a simple and effective route to access these
compounds. However, attempts to use normal 1ꢀarylethylenes, such as
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4ꢀmethylstyrene and αꢀmethylstyrene, as substrates in PTSA/acetonitrile system were
in vain. The reactions suffered from the lack of selectivity as messy mixtures were
formed in these cases. By the same token, formaldehyde cannot be replaced by other
aliphatic or aromatic aldehyde in this reaction.
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Figure 3. PTSAꢀcatalyzed threeꢀcomponent reaction of 1,1ꢀdiarylethylene, 1,3ꢀdicarbonyl
compound and (HCHO)n.
Scheme 3. PTSAꢀcatalyzed threeꢀcomponent reaction of 1,1ꢀdiphenylethanol, 2a and
paraformaldehyde.
The aboveꢀmentioned results demonstrated that the development of
conditionꢀdetermined MCRs based on a combination of 1,3ꢀdicarbonyl compound and
formaldehyde is indeed possible. Encouraged by these results, we then investigated
the
condensation
reaction
of
Nꢀphenacylpyridinium
bromide
7a,
1,3ꢀcyclohexanedione 2b and formaldehyde, which can hopefully produce a
2,4ꢀdiacylꢀ2,3ꢀdihydrofuran derivative, 8a through a cascade Knoevenagel / [4+1]
annulation reaction under appropriate conditions.10 The reaction was also triggered
by a Knoevenagel condensation of 2b with formaldehyde, which generated a
2ꢀmethyleneꢀ1,3ꢀcyclohexanedione intermediate (II) that can be trapped by
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phenacylpyridinium salt through [4+1] annulation reaction (Figure 4). As shown in
Table 1, a product was indeed formed in the presence of an inorganic base,
.
K2HPO4 3H2O, in DMSO, however, it was the hydroxymethylation product of the
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expected one, 8a'. Because compound 8a was also detected at the end of the reaction,
we therefore deduced that 8a' might be formed through a cascade Knoevenagel / [4+1]
annulation / hydroxymethylation reaction (Figure 4). Indeed, treatment of 8a in
DMSO in the presence of paraformaldehyde resulted in an evident formation of 8a'
(Scheme 4). To our great delight, the quasi fourꢀcomponent reaction was found to be
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very efficient, and the yield of 8a' reached 83 % after 4 hours of reaction at 80 C
(entry 1). This observation encouraged us to scrutinize the effects of reaction
parameters including base, solvent and reaction temperature. No or only trace amount
.
of product was obtained with inorganic bases, such as K3PO4 3H2O and K2CO3
(entries 2 and 3). Organic bases like NEt3 and DBU were also ineffective for this
reaction (entries 4 and 5). Among different solvents tested in the reaction, DMSO
clearly stood out, producing 8a' with the highest yield, with DMF and acetonitrile in a
distant second place (ca. 40 % yields). PEG400, ionic liquid [BMIm]BF4, and water
resulted in significantly lower efficiency of the reaction (entries 8 to 10). Ratio of
7a/2b/HCHO can also significantly affect the yield of 8a', and the best is
7a/2b/HCHO = 1.0/2.0/2.5. Poor yields were obtained with much excess amount of
2b or HCHO, which might result from an extensive formation of a byꢀproduct through
Knoevenagel / Michael reaction of 2b and HCHO (entries 11 and 12). Interestingly,
when ratio of 7a/2b/HCHO was changed to 1.0/1.5/2.0, 8a was produced as a major
product, and 8a' was formed only in tiny amount (entry 13). These results imply that
substrate ratio has a subtle influence on the reaction selectivity, and amounts of 2b
and formaldehyde are both important to determine the reaction selectivity. It offered
us a possible means to control the reaction selectivity by tuning the reaction
parameters. It should be noted that, in all the previous reports on Knoevenagel / [4+1]
annulation sequential reaction of phenacylpyridinium salt, the use of aromatic
aldehyde is mandatory in order to facilitate controlling of the reaction selectivity.11
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The present synthesis of 8aꢀlike 2,3ꢀdihydrofuran represents the first example of using
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nonꢀaromatic aldehyde as substrate. Additionally, the reaction was also affected by
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temperature and reaction time, and the maximum yield of 8a' was obtained at 80 C
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after 4 hours of reaction (entries 14 to 16). It is worthwhile to note that, under the
optimal conditions, effort to replace paraformaldehyde with either formalin (37 wt %)
or trioxymethylene was in vain (entries 17 and 18).
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Table 1. Threeꢀcomponent reaction of Nꢀphenacylpyridinium bromide, acetylacetone and
formaldehyde under different conditions.a
yield (%)
ratio of
entry
solvent
temp. (oC)
base
7a/2b/HCHO
8a׳
8a
<5
<5
0
.
1
2
K2HPO4 3H2O DMSO
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/1.0/2.0
1.0/2.5/3.0
1.0/1.5/2.0
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
80
80
80
80
80
80
80
80
80
80
80
80
80
50
100
80
80
80
83
<5
0
.
K3PO4 3H2O
K2CO3
DMSO
DMSO
DMSO
DMSO
3
4
Et3N
8
5
5
DBU
0
0
.
6
K2HPO4 3H2O DMF
<5
<5
<5
9
36
39
<5
<5
<5
67
22
<5
5
.
7
K2HPO4 3H2O CH3CN
.
8
K2HPO4 3H2O PEG400
.
9
K2HPO4 3H2O [BMIm]BF4
.
10
11
12
13
14
15
16b
17c
18d
K2HPO4 3H2O H2O
8
.
K2HPO4 3H2O DMSO
<5
9
.
K2HPO4 3H2O DMSO
.
K2HPO4 3H2O DMSO
80
0
.
K2HPO4 3H2O DMSO
.
K2HPO4 3H2O DMSO
5
10
51
11
0
.
K2HPO4 3H2O DMSO
24
< 5
0
.
K2HPO4 3H2O DMSO
.
K2HPO4 3H2O DMSO
a: 1a: 1.0 mmol, paraformaldehdye was used as HCHO source, solvent: 1.0 ml, reaction time: 4 h.
b: reaction time: 2 h.
c: aqueous solution of formaldehyde was used as HCHO source.
d: trioxymethylene was used as HCHO source.
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Figure 4.Proposed mechanism for the formations of 8a and 8a'.
Scheme 4. Hydroxymethylation of 8a to 8a'.
We also probed the scope of the reaction with respect to both the pyridinium
bromide and the 1,3ꢀdicarbonyl compounds. As evidenced by the results in Table 2,
Nꢀphenacylpyridinium bromides with both electronꢀdonating and moderately
electronꢀwithdrawing
groups
smoothly
reacted
with
2b,
producing
2ꢀhydroxymethylated 2,3ꢀdihydrofurans derivatives in generally good yields (entries 1
to 5). By means of decreasing the ratio of 7/2/HCHO, we are able to suppress the
hydroxymethylation. Particularly, when Nꢀ(4ꢀmethoxyphenacyl)pyridinium bromide
was used, yield of the tandem Knoevenagel/[4+1] annulation product, 8e, reached
95 % with the ratio of 7/2/HCHO = 1.0/1.5/2.0. However, increasing the ratio to
1.0/2.0/2.5 was in vain to obtain its hydroxymethylated counterpart, 8e'. In this case,
much excess amount of paraformaldehyde has to be used in order to get a good yield
of 8e' (entry 4). Acetoacetone 2a reacted readily with 7a and formaldehyde, however,
extra effort has to be paid to control the reaction selectivity because change of the
substrate ratio cannot alter significantly the product distribution. Addition of solvent
amount of xylene, which constructed a biphasic system along with DMSO, was
proved to be an effective way to suppress the hydroxymethylation reaction of 8g
o
(entry 6). In order to get 8g', the reaction has to be performed at 30 C. Fortunately,
when the other Nꢀphenacylpyridinium bromide derivatives were used to react with 2a,
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it is quite easy to control the reaction selectivity. In the presence of a large excess
amount of paraformaldehyde, the hydroxymethylated product will be preferentially
formed as usual. Whereas, the major products are the nonꢀhydroxymethylated
2,3ꢀdihydrofurans when the ratio of 7/2b/HCHO is 1.0/2.0/2.5 (entries 7 to 14). This
strategy is particularly effective for tuning the selectivity of condensation between
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60
Nꢀ(4ꢀphenylphenacyl)pyridinium
bromide,
2a
and
formaldehyde.
Both
hydroxymethylated and nonꢀhydroxymethylated products could be obtained in more
than 90 % of yields in this case (entry 10). 1ꢀ(2ꢀNaphthoylmethyl)pyridinium bromide
was also proved to be an eligible substrate that reacted smoothly with either 2b or 2a,
providing both hydroxymethylated and nonꢀhydroxymethylated products in good
yields (entries 5 and 11). It should be noted that OH group in the phenacylpyridinium
salt can be delivered uneventfully (entry 12). This facilitates further conversions of
the obtained 2,3ꢀdihydrofurans. Heterocyclic group, such as thienyl, is also tolerable
in the present reaction (entry 13). Reactions with βꢀketoesters proceeded also very
well, and the products succeeded the ester moieties without any damage (entries 14 to
17). Ether fragment in 2ꢀmethoxyethyl acetoacetate is also tolerable. Due to an
insusceptibility of the reaction toward the change of the substrate ratio, DMSO/xylene
biphasic system was employed when methyl isobutyrylacetate and 2ꢀmethoxyethyl
acetoacetate were used to react with 7a (entries 16 and 17). It should be noted that
when an aqueous solution of acetaldehyde was used instead of paraformaldehyde, no
expected substituted dihydrofuran derivative was formed.
Table 2. Substrate scope of threeꢀcomponent reaction of Nꢀphenacylpyridinium bromides,
1,3ꢀdicarbonyl compounds and paraformaldehyde.a
entry
1
major product
yield (%)b
74 (12)
1/2/HCHO
major product
Yield (%)b
60 (14)
1/2/HCHO
Cl
Cl
O
O
1.0/1.5/2.0
8b
1.0/2.0/2.5
8b'
O
O
O
O
OH
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5
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7
8
9
F
F
O
O
2
3
1.0/1.5/2.0
1.0/1.5/2.0
1.0/1.5/2.0
1.0/1.5/2.0
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/2.5
8c
8d
8e
8f
62 (9)
70 (8)
1.0/2.0/2.5
1.0/2.0/2.5
1.0/2.0/7.0
1.0/2.0/7.0
1.0/2.0/2.5
1.0/2.0/7.0
1.0/2.0/7.0
1.0/2.0/7.0
1.0/2.0/7.0
1.0/2.0/7.0
1.0/2.0/7.0
1.0/2.0/7.0
1.0/2.0/7.0
1.0/2.0/7.0
8c'
8d'
8e'
8f'
68 (13)
70 (10)
71 (19)
76 (14)
85d (7)
70 (11)
51 (9)
O
OH
O
O
O
C6H5
C6H5
O
O
O
O
OH
O
O
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
MeO
MeO
O
4
95 (< 1)
86 (7)
O
OH
O
O
O
O
5
O
O
O
O
OH
O
O
6
8g
8h
8i
82c (6)
69 (16)
73 (8)
8g'
8h'
8i'
O
OH
O
O
O
F
F
O
O
7
O
OH
O
O
O
Cl
Cl
O
O
8
O
OH
O
O
O
C
H
5
6
C6H5
O
O
9
8j
94 (< 5)
72 (12)
65 (17)
75 (11)
81 (10)
49 (8)
8j'
93 (< 5)
57 (18)
62 (15)
50 (13)
61 (16)
54 (< 5)
71 (7)
O
OH
O
O
O
O
O
10
11
12
13
14
15
8k
8l
8k'
8l'
O
O
O
O
OH
MeO
MeO
O
O
O
OH
O
O
O
HO
HO
O
O
8m
8n
8o
8p
8m'
8n'
8o'
8p'
O
OH
O
O
O
O
O
S
S
O
OH
O
O
O
O
O
OMe
OEt
OMe
OEt
O
O
O
O
OH
O
O
60 (14)
O
O
O
O
OH
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O
O
4
5
6
7
8
9
OMe
OMe
16
17
1.0/2.0/2.5
1.0/2.0/2.5
8q
8r
50c (9)
1.0/2.0/2.5
1.0/2.0/2.5
8q'
8r'
76 (13)
O
O
OH
O
O
O
O
50c (11)
97 (< 1)
O
O
O
O
OH
O
O
OMe
OMe
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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29
30
31
32
33
34
35
36
37
38
39
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47
48
49
50
51
52
53
54
55
56
57
58
59
60
a: Nꢀphenacylpyridinium bromide: 0.5 mmol, DMSO: 1.0 ml; K2HPO4·3H2O: 1.0 mmol; 80 oC, 4 h.
b: value in parentheses is the yield of the minor product.
c: xylene was added.
d: 30 oC.
Because the hydroxymethylated products contain some reactive groups, we
therefore suspected that these molecules might be susceptible under acidic conditions.
As we expected, treatment of 8g' in ethanol in the presence of Sc(OTf)3 resulted in
selective formation of diphenyl derivative 9a (Scheme 5). The existence of hydroxyl
group in 8g' was proved to be crucial for rendering this reaction possible because no
reaction was observed when 8g was used as substrate under the identical conditions.
Initial step of the reaction might be an intramolecular ringꢀopening and ringꢀclosing
reaction of 8g' with the aid of acid catalyst, which generated an epoxide intermediate
(IV). The following ringꢀopening of (IV) with ethanol produced an intermediate (V)
that underwent an intramolecular aldol reaction12 and subsequent retroꢀClaisen
condensation13 to form the final product 9a. This reaction not only displayed an
interesting reaction sequence but also offered us the first example that can get
aromatic ether from fiveꢀmember ring heterocycles without oxidation.14
Scheme 5. Conversion of 8g' to 9a.
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Conclusion
5
6
7
8
Some conditionꢀdetermined MCRs of 1,3ꢀdicarbonyl compound and formaldehyde
were reported. Reaction of 1,3ꢀdicarbonyl compound, formaldehyde and
1,1ꢀdiphenylethylene produced either a densely substituted 3,4ꢀdihydropyran or a
C2ꢀcinnamyl substituted 1,3ꢀdicarbonyl compound. A pseudo fourꢀcomponent
reaction of Nꢀphenacylpyridinium bromide, 1,3ꢀdicarbonyl compound and
formaldehyde was also developed, which involved a hitherto unreported
Knoevenagel/[4+1] annulation/hydroxymethylation reaction sequence. All these
examples demonstrated that the concept of conditionꢀdetermined MCR is indeed
useful for divergenceꢀoriented organic synthesis.
9
10
11
12
13
14
15
16
17
18
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21
22
23
24
25
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27
28
29
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31
32
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34
35
36
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42
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49
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51
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59
60
Experimental Section
General
Melting points were determined by microscopic melting pointmeter and were
uncorrected. IR spectra were recorded on a FTꢀIR Bruker (EQUINOX 55) using KBr
pellets or neat liquid technology. 1H and 13C NMR spectra were recorded on a Bruker
AVꢀ400. Chemical shifts are expressed in ppm relative to Me4Si in solvent. All
chemicals used were of reagent grade and were used as received without further
purification. All reactions were conducted in a 10 mL of Vꢀtype flask equipped with
triangle magnetic stirring.
Reaction of 1,1-diarylethylene, 1,3-dicarbonyl compound and (HCHO)n
In a typical reaction, 1,3ꢀdicarbonyl compound (0.2 mmol) was mixed with
paraformaldehyde (0.2 mmol), 1,1ꢀdiarylethylene (0.25 mmol) and PTSA (0.02 mmol,
3.8 mg, 10 % mol) in acetonitrile (1.0 mL), The mixture was then stirred at 60 oC for
12 hours. After reaction, the mixture was cooled to room temperature, and the product
was obtained by isolation with preparative TLC (eluting solution: petroleum ether /
ethyl acetate = 5 / 1 (v/v)). Tests for substrate scope were all performed with an
analogous procedure.
Three-component reaction of N-phenacylpyridinium bromides, 1,3-dicarbonyl
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compounds and (HCHO)n
5
6
7
8
NꢀPhenacylpyridinium bromide (0.25 mmol) was mixed with 1,3ꢀdicarbonyl
compound (0.375 mmol), and paraformaldehyde (0.5 mmol), The mixture was then
9
o
stirred at 80 C for 4 hours. After reaction, the mixture was cooled to room
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
temperature, and the product 2,4ꢀdiacylꢀ2,3ꢀdihydrofuran derivative was obtained by
isolation with preparative TLC (eluting solution: petroleum ether / ethyl acetate = 10 /
1 (v/v)). Tests for substrate scope were all performed with an analogous procedure.
The hydroxymethylation product was obtained only change the ratio of
Nꢀphenacylpyridinium bromide, 1,3ꢀdicarbonyl compound and paraformaldehyde to
1.0/2.0/2.5.
Synthesis of 9a from 8g׳
8g, (52 mg, 0.2 mmol) and Sc(OTf)3 (10 mg, 10 % mol) was added to ethanol (1 mL),
o
and the mixture was then stirred at 80 C for 4 hours. After reaction, the product 9a
was obtained by isolation with preparative TLC (eluting solution: petroleum ether /
ethyl acetate = 20 / 1 (v/v)) with yield 61 %.
Acknowledgements
The authors thank for National Natural Science Foundation of China for the financial
support (21173089 and 21373093) and also for the Analytical and Testing Center of
HUST. Chutian Scholar Program of the Hubei Provincial Government and the
Cooperative Innovation Center of Hubei Province are also acknowledged. This work
is also supported by the Fundamental Research Funds for the Central Universities of
China (2014ZZGH019).
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[8] Frapper, G.; Bachmann, C.; Gu, Y.; de Sousa, R. C.; Jérôme, F., Mechanisms of
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a twoꢀphase aqueousꢀorganic medium, Tetrahedron Lett. 1991, 32, 2025ꢀ2028;
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synthesis of allylated keto esters: the Palladiumꢀcatalysed haloketone
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[10] (a) Chuang, C. –P.; Chen, K. –P.; Hsu, Y. –L.; Tsai, A. ꢀI.; Liu, S. –T., αꢀNitro
carbonyl compounds in the synthesis of 2,3ꢀdihydrofurans, Tetrahedron, 2008,
64, 7511ꢀ7516; (b) Arai, S.; Nakayama, K.; Suzuki, Y.; Hatano, K. –I.; Shioiri, T.,
Stereoselective synthesis of dihydrofurans under phaseꢀtransfer catalyzed
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conditions, Tetrahedron Lett. 1998, 39, 9739ꢀ9742; (c) Chuang, C. P.; Tsai, A. –I.,
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675ꢀ679; (d) Indumathi, S.; Perumal, S.; Anbananthan, N., A facile ecoꢀfriendly
threeꢀcomponent protocol for the regioꢀ and stereoselective synthesis of
functionalized transꢀdihydrofuro[3,2ꢀc]ꢀquinolinꢀ4(2H)ꢀones, Green Chem. 2012,
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S.; Menéndez, J. C.; Almansour, A. I., Domino reactions in water:
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derivatives, Green Chem. 2012, 14, 750ꢀ757; (f) Chuang, C. –P.; Chen, K. –P.,
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ꢀG., Diastereoselective synthesis of transꢀ2,3ꢀdihydrofurans with pyridinium
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Fan, M.; Mu, R.; Liu, W.; Liang, Y., A facile synthesis of highly functionalized
dihydrofurans based on 1,4ꢀdiazabicyclo[2.2.2]octane (DABCO) catalyzed
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[11] Literature survey stated that while sulfonium ylide and imidazolium ylide
enabled the use of aliphatic aldehyde, the reactions with pyridium ylide are still
not amenable to aliphatic aldehyde: (a) Jiang, Y.; Ma, D., Synthesis of
enantiopure substituted dihydrofurans via the reaction of (S)ꢀglyceraldehyde
acetonideꢀ or Garner aldehyde acetonideꢀderived enones with sulfonium ylides.
Tetrahedron: Asymmetry, 2002, 13, 1033ꢀ1038; (b) Kumar, A.; Srivastava, S.;
Gupta, G., Cascade [4 + 1] annulation via more environmentally friendly
nitrogen ylides in water: synthesis of bicyclic and tricyclic fused dihydrofurans,
Green Chem. 2012, 14, 3269ꢀ3272.
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resolution via intramolecular aldol reactions: Enantioselective synthesis of both
enantiomers of chiral cyclohexenones, Org. Biomol. Chem. 2010, 8, 2627ꢀ2632;
(b) Jin, T.; Yamamoto, Y., Goldꢀcatalyzed intramolecular carbocyclization of
alkynyl ketones leading to highly substituted cyclic enones, Org. Lett. 2007, 9,
5259ꢀ5262.
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[13] Biswas, S.; Maiti, S.; Jana, U., An efficient ironꢀcatalyzed carbon–carbon
singleꢀbond ceavage via RetroꢀClaisen Condensation: a mild and convenient
approach to synthesize a variety of esters or ketones, Eur. J. Org. Chem. 2010,
2861ꢀ2866.
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[ 14 ] Synthesis of aromatic ether from nonꢀaromatic precursor has just been
established by means of oxidative condensation of alcohol and 2ꢀcyclohexenone:
Simon, M. –O.; Girard, S. A.; Li, C. –J., Catalytic aerobic synthesis of aromatic
ethers from nonꢀaromatic precursors, Angew. Chem. Int. Ed. 2012, 51,
7537ꢀ7540.
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