Three-component reactions of aromatic aldehydes and two different nucleophiles and their leaving ability-determined downstream conversions of the products

Article abstract of DOI:10.1002/adsc.201300790

Many three-component reactions of aromatic aldehydes with activated methylene derivatives and an associated nucleophile have been developed by using l-proline as the catalyst. Nucleophiles, such as indoles, thiophenols, mercaptans, 2-methylfuran and benze

Full text of DOI:10.1002/adsc.201300790

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DOI: 10.1002/adsc.201300790
Three-Component Reactions of Aromatic Aldehydes and Two
Different Nucleophiles and their Leaving Ability-Determined
Downstream Conversions of the Products
Minghao Li,a Amir Taheri,a Meng Liu,a Shaohuan Sun,a and Yanlong Gua,b,*
a
Key Laboratory for Large-Format Battery Materials and System, Ministry of Education, Huazhong University of Science
and Technology (HUST), 1037 Luoyu road, Hongshan District, Wuhan 430074, Peopleꢀs Republic of China
Fax : (+86)-(0)27-8754-4532; e-mail: klgyl@hust.edu.cn
State Key Laboratory for Oxo Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Lanzhou
b
730000, Peopleꢀs Republic of China
Received: August 31, 2013; Revised: October 16, 2013; Published online: January 31, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300790.
Abstract: Many three-component reactions of aro- carbon-carbon and carbon-heteroatom bonds in
matic aldehydes with activated methylene derivatives these molecules are indeed possible, which opens an
and an associated nucleophile have been developed avenue to access some new SN1-type reactions. Par-
by using l-proline as the catalyst. Nucleophiles, such ticularly, when the MCR product of an aromatic al-
as indoles, thiophenols, mercaptans, 2-methylfuran dehyde, dimedone and thiophenol was treated with
and benzenesulfinic acid, could be successfully used an acid catalyst in the presence of an appropriate nu-
in the reactions while the activated methylene deriv- cleophile, cleavage of the carbon-sulfur bond oc-
atives can be 1,3-cyclohexanedione, dimedone, 1,3- curred preferentially, thus providing many complex
cyclopentanedione, 1-phenyl-3-methyl-5-pyrazolone, molecules that cannot be attained by other known
4-hydroxycoumarin, 4,6-dihydroxy-2-mercaptopyri- methods.
midine, 4-hydroxy-1-methyl-2quinolone, 4-hydroxy-
6-methyl-2-pyrone and 2-hydroxy-1,4-naphthoqui-
none. Investigation of the downstream utilization of Keywords: carbon-carbon bond formation; leaving
the products from the above multicomponent reac- groups; l-proline; SN1 reactions; three-component
tions (MCRs) revealed that selective cleavages of reactions
Introduction
proline is one of the most versatile compounds for es-
tablishing these reactions.[4]
Maximizing synthetic efficiency by designing com-
In the past five years, many nucleophiles have been
plexity-generating diversity-oriented synthesis is gain- proved to be capable of acting as leaving groups,[5]
ing more and more importance in organic synthesis and some of them have been frequently used in
and in drug discovery endeavors. For this purpose, the MCRs. Because of this good leaving ability, the ob-
development and utilization of multi-component reac- tained MCR products should be competent to con-
tions (MCRs) are of prime importance.[1] Electrophil- struct many types of carbon-carbon and carbon-
ic reactions of aldehyde with two different nucleo- heteroACHTNUTRGNEaNUG tom bonds. However, a literature survey re-
philes are known to be able to construct MCR com- vealed that this strategy has been rarely used in or-
pounds. However, research along this line often en- ganic synthesis.[6] It might result partially from the
countered a notorious difficulty in controlling the re- lack of an adequate method for controlling the selec-
action’s selectivity. In order to address this issue, tivity of the MCR.
much effort has been paid to design an efficient cata-
We have recently reported that dimedone can act
lyst that favors the assembly of all the starting sub- as a leaving group in the presence of an appropriate
strates toward the target compound.[2] In this context, catalyst.[7] Additionally, dibenzoylmethane, N,N-dime-
small organic molecules like amino acids and Cincho- thylbarbituric acid and Meldrumꢀs acid have also
na alkaloids[3] have been widely used for developing been useful in organic synthesis by virtue of their
new MCRs. Among all the various organocatalysts, l- good leaving group capabilities.[8] On the basis of
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exist in many natural products,[12] and the related
compounds are considered as venerable pharmaco-
phores and have a wide range of biological applica-
tions.[13] Therefore indole was chosen as the first nu-
cleophile in our research. As shown in Table 1, the re-
action was messy under catalyst-free conditions in
ethanol, and two by-products resulting from aldehyde
and the same nucleophile could be observed by TLC
monitoring (entry 1, and also see the details in the
Supporting Information, Scheme S1). Strong acids,
such as TsOH, Amberlyst 15 and ScACTHNUTRGNEUNG(OTf)3 (entries 2–
4), and weak acids including montmorillonite K-10,
LiBr, and H3BO3 (entries 5–7) were all ineffective for
this reaction. We then turned to the use of basic cata-
lysts, such as NEt3, DABCO, and K2CO3. It was found
that the model reaction proceeded well with all of
these catalysts (entries 8–10). Especially, when
DABCO was used, the desired product, 4a, was ob-
Scheme 1. Schematic illustration of our work.
these results, we envisioned that the three-component tained in 90% yield within 4 h in ethanol (entry 9).
reaction of an aromatic aldehyde, an activated meth- With the hope of further increasing the reaction yield,
ylene derivative, and an associated nucleophile might some amphoteric catalysts, natural amino acids, were
be an effective means to synthesize some molecules then employed. To our great delight, this type of cata-
that can be further converted to valuable products lyst showed an outstanding ability for promoting the
through SN1-type substitution reactions. Particularly, model reaction. Particularly, the reaction with l-pro-
if the activated methylene compound and the associ- line as catalyst furnished an almost quantitative prod-
ated nucleophile could both be used as leaving uct yield within only 6 min (entry 11). Although we
groups, the formed products would probably have an had recently reported that l-proline is a powerful cat-
intrinsically high reactivity that may enable us to de- alyst for MCRs of salicylaldehydes, 1,3-cyclohexane-
velop some interesting synthetic reactions. Based on diones and indole nucleophiles,[14] considering the fol-
these considerations, some time ago we started a re- lowing facts: (i) the obtained product, 4a, is much
search program on this topic. Herein, we disclose the more attractive for organic synthesis as compared
successful outcome of these endeavors, in which an ar- with the MCR products of salicylaldehydes; and (ii)
omatic aldehyde reacted selectively with an activated the hitherto unprecedented high efficiency of l-pro-
methylene compound and an associated nucleophile line for this catalysis, this result is quite remarkable.
in the presence of l-proline (Scheme 1). Interestingly, Further investigation revealed that the performance
the formed products could be converted to various of l-proline was also affected by the solvent (en-
useful molecules that cannot be obtained by conven- tries 15–19), temperature (entry 20) and catalyst
tional methods. The leaving group abilities of both amount (entry 21). Finally, the optimal conditions
the activated methylene derivative and the associated were found to be as follows: catalyst amount:
nucleophile play a key role in determining the reac- 10 mol%, solvent: ethanol, temperature: 808C
tion pathway for the downstream conversions of the (entry 21).
MCR products.
With the optimized conditions in hand, we then ex-
plored the substrate scope of the l-proline/ethanol
system (Scheme 2). It was found that the reactions
catalyzed by l-proline were able to provide a variety
of 3-substituted indoles. The electronic nature of the
Results and Discussion
Our experimentation commenced with the three-com- substituents on the indole ring had only limited influ-
ponent reaction of 2-chlorobenzaldehyde, dimedone, ence on the reaction (4a–4i). Most of the reactions
and indole, with which a 3-substituted indole, 4a, could be completed in less than 1 hour. Furthermore,
could be hopefully obtained through a Yonemitsu- various aromatic aldehydes were successfully applied
type reaction (Table 1). Although some similar reac- to this system (4j–4w). The reaction time could be sig-
tions involving the use of Meldrumꢀs acid,[9] 1,3-dime- nificantly decreased when aromatic aldehydes that
thylbarbituric acid,[10] and linear 1,3-bifunctional car- contain a single halogen (F, Cl, Br) substituent in the
bonyl derivatives[11] as substrates have been reported, ortho position (4a, 4j, 4k) were employed. With these
1,3-cyclohexanediones have never been employed in aldehydes, the reactions could be accomplished within
this type reaction so far. Additionally, 3-substituted 20 min whilst the other aldehydes need several hours
indole moieties are of great importance because they to reach the same conversions. Electronic effects of
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Table 1. Condition optimization for the reaction of 1a, 2a, and 3a.[a]
Entry
Catalyst
Solvent
Time
Yield [%][d]
1
2
3
4
5
6
7
8
–
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
neat
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
4 h
6 min
2 h
4 h
30 min
4 h
4 h
4 h
4 h
messy[e]
trace
trace
trace
trace
20
35
85
90
80
99
90
85
95
10
30
68
80
TsOH·H2O
Amberlyst 15
Sc
montmorillonite K-10
LiBr·H2O
H3BO3
N(Et)3
DABCO·6H2O
K2CO3
l-proline
sarcisine
l-pipecolic acid
glycine
l-proline
l-proline
l-proline
l-proline
l-proline
l-proline (10 mol%)
l-proline (10 mol%)
l-proline (10 mol%)
(OTf)3
9
10
11
12
13
14
15
16
17
18
19
20[b]
21
22[c]
H2O
CH3CN
toluene
DCE
EtOH
EtOH
EtOH
4 h
4 h
15 min
15 min
85
messy[e]
99
97
[a]
1a/2a/3a=1.0/1.0/1.0, reaction scale: 1.0 mmol, solvent: 1.0 mL, catalyst amount: 20 mol%, 808C.
Room temperature.
Reaction scale: 20.0 mmol.
Isolated yield.
[b]
[c]
[d]
[e]
For the exact composition of the mixture, please see Scheme S1 in the Supporting Information.
the aromatic aldehydes were not notable upon com- ogy offers an efficient way to construct this kind of
paring the yields with several electron-rich aldehydes skeleton with better product diversity. Some other
such as benzaldehyde, and para-methylbenzaldehydes 1,3-cyclohexanediones were also employed successful-
(4m, 4n) with those of para-chloro- and para- ly in the title reaction, and the desired products were
trifluoroACHTUNGTRENNUNGmethylbenzaldehyde, (4o, 4p) and meta-nitro- obtained in good to excellent yields (4x, 4y, 4z). The
benzaldehyde (4q). The reaction proceeded also very reaction can also be effectively scaled up with similar
well in the case of cinnamaldehyde (4t), which indi- efficiency. For example, a large scale (20.0 mmol) re-
cated that it could be extended to conjugated alde- action of 1a, 2a, and 3a gave the corresponding prod-
hydes. Moreover, l-proline worked quite well for the uct, 4a, in 97% yield (7.3 g, Table 1, entry 22).
reaction with some heteroaromatic aldehydes, such as
2-pyridaldehyde, 3-bromopicolinaldehyde, and 4-pyri- tives are amenable to the three-component reaction
dinecarboxaldehyde (4u, 4v, 4w), affording the corre- of aromatic aldehyde and indole in the l-proline/etha-
sponding pyridyl(indolyl)methane derivatives in ex- nol system. As shown in Table 2, 1,3-cyclopentane-
cellent yields. It is worth noting that pyridyl- dione, 4,6-dihydroxy-2-mercaptopyrimidine, 1-phenyl-
(indolyl)methane is an important unit in numerous 3-methyl-5-pyrazolone, 4-hydroxy-6-methyl-2-pyrone,
drug molecules and materials.[15] Previously, this kind 4-hydroxycoumarin,
2-hydroxy-1,4-naphthoquinone
Furthermore, various activated methylene deriva-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
of substance was generally synthesized by nucleophil- and 4-hydroxy-1-methyl-2-quinolone reacted smooth-
ic substitution of a-hydroxy or halomethylpyridine ly with benzaldehydes and indoles, affording the cor-
derivatives.[16] However, these methods suffer from responding adducts in good to excellent yields (en-
the lack of structural diversity. The present methodol- tries 1–7). However, a limitation was found when ace-
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Scheme 2. Substrate scope of aromatic aldehydes, indoles, and 1,3-cyclohexanediones.
tylacetone was used as the substrate, which cannot
Aldehydes and secondary amines can easily form
give the expected product with l-proline catalyst an imine ion.[17] Taking this scenario into account, we
under the optimal conditions (entry 8).
hypothesized a plausible mechanism for the model re-
action. As shown in Figure 1, the reaction commenced
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Three-Component Reactions of Aromatic Aldehydes and Two Different Nucleophiles
Table 2. Yonemitsu-type reactions of other cyclic active methylene compounds.[a]
Entry
1
Carbonyl Compounds
Product
Yield [%][c]
5a
5b
62
2[b]
96
3
4
5c
67
81
5d
5[b]
5e
5f
5g
98
52
88
6
7
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Table 2. (Continued)
Entry
Carbonyl Compounds
Product
Yield [%][c]
8
5h
0
[a]
General conditions: aldehyde/indole/cyclic active methylene compounds=1.0/1.0/1.0, reaction scale: 1.0 mmol, solvent:
1.5 mL, l-proline: 20 mol%, 808C, 4 h, the desired product was isolated by preparative TLC.
Product was isolated by filtration.
Isolated yield.
[b]
[c]
with the formation of an imine intermediate 6a from a sole by-product in most cases. Therefore, we de-
the aromatic aldehyde and l-proline. This intermedi- duced that although both pathways are theoretically
ate underwent a nucleophilic reaction with dimedone possible, pathway A is the prefered route for the for-
(pathway A) or indole (pathway B) to form the corre- mation of the final product.
sponding Mannich-type intermediate 7a, 8a and
It is worthwhile to note that almost all the products
Knoevenagel-type intermediate 7b, 8b, which were could be isolated without the use of silica column
susceptible towards nucleophilic attack of the other chromatography. All reactants dissolved well in etha-
nucleophile to form the final product. In the course of nol at the initial stage of the reaction. Interestingly, at
our substrate scope study, we found that when moder- the end of the reaction, a large amount of solid was
ate yields were obtained, 4b could be detected as formed (see Figure S1 in the Supporting Information).
Figure 1. Proposed mechanism for the model reaction.
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Moreover, aromatic aldehydes with both electron-do-
nating and electron-withdrawing groups showed a sim-
ilar performance in this system, and all the target
molecules could be obtained in excellent yields. The
reaction works equally well with the other 1,3-cyclo-
hexanediones. Importantly, almost all the NMR pure
sulfide products could be directly obtained by filtra-
tion, which eliminated the use of silica column chro-
matography and organic solvents.
We then examined the capability of l-proline/etha-
nol system for assembling aromatic aldehydes, 1,3-cy-
clohexanediones and some other nucleophiles. As
shown in Scheme 3, 2-methylfuran and benzenesulfin-
ic acid participated readily in the three-component re-
action. These examples demonstrated that l-proline/
ethanol is indeed a versatile system for the title three-
component reactions.
Having these results in hand, we then started to in-
vestigate the synthetic applications of the obtained
MCR products. Because compound 4a contains a di-
medone fragment which can act as a leaving group,[7]
we therefore examined its reactivity toward 5-bro-
Figure 2. Conformational structure of 4a with the lowest
energy by density functional approach (DFT) theory calcu-
lation.
This behavior not only enables us to isolate all the moindole in the presence of a Lewis acid catalyst. As
products by means of filtration, but also imparts the shown in Scheme 4, an unsymmetrical bisindolylme-
synthetic methodology with green credentials. On the thane 11a was obtained in 93% yield with the aid of
basis of this fact, we deduced that the precipitation MnBr2/PPh3 in nitromethane. In this system, PPh3
might be one of the main powers of the reaction that might play the role of a hydrogen bond acceptor to
significantly shift the equilibrium to the right side. weaken the intramolecular hydrogen bond and confer
The result of density functional theory (DFT) calcula- a good flexibility to the dimedone fragment of 4a, al-
tions at the 6-31+G* level using Gaussian 98 showed lowing thus an easy interaction of the substrate with
that the conformational structure of 4a with the MnBr2 catalyst.[7] This example not only opens an al-
lowest energy contained, at least, four intramolecular ternative way to the synthesis of unsymmetrical bisin-
hydrogen bonds (see the dotted line of Figure 2, and dolylmethanes[20] but also demonstrates the feasibility
details in Supporting Information), which endowed 4a of using our MCR products as starting material to
a rigid structure that might be responsible for the low construct carbon-carbon bonds.
solubility in ethanol.[18] In the three-component reac-
Encouraged by this successful endeavor on using di-
tion, it seems that, for most substrates, the density of medone as a leaving group, and with the hope of de-
the intramolecular hydrogen bonds in the product has veloping some new organic transformations, we then
a subtile influence on the reaction time, and multiple scrutinized the reactivity of compound 9a, which con-
intramolecular hydrogen bond interactions favor tains two cleavable chemical bonds in the molecule,
shorter reaction times. Reactions with 2-substituted in the presence of acid catalysts.[21] It was found that,
indoles generally needed a long reaction time, where- in the presence of an appropriate nucleophile, thio-
as 2-unsubstituted indoles were assembled rapidly phenol has priority to act as a leaving group, whereas
with an aldehyde that has an ortho halogen substitu- the dimedone moiety was delivered uneventfully into
ent and dimedone.
the final product. For example, 9a reacted with anti-
Thiophenols are an important class of heteroatom- pyrine and 1-methylpyrrole smoothly in the presence
containing nucleophiles. In view of the fact that the of MnCl2·4H2O in nitromethane, providing the corre-
thiophenol fragment is often found in many biologi- sponding SN1-type substitution products, 12a and 12b,
cally active compounds,[19] we then investigated the in 93% and 80% yields, respectively (Scheme 5). In
feasibility of using thiophenols as nucleophiles to addition, 1,3-cyclohexanedione can also react with 9a
react with aromatic aldehydes and 1,3-cyclohexane- to generate an unsymmetrical 3,4,5,6,7,9-hexahydro-9-
diones. As evidenced by the results in Table 3, the l- phenyl-1H-xanthene-1,8-(2H)-dione, 12c, in 94%
proline/ethanol system was proved again to be suita- yield in acetic acid. Because all these products cannot
ble for this three-component reaction. Thiophenols be synthesized directly through three-component re-
with different substituents, such as methyl, methoxy, actions even in l-proline/ethanol system, the strategy
isopropyl, chloro, all reacted well. Mercaptans were shown in Scheme 5 offers thus an effective means to
found to be a little less competent than thiophenols. access such compounds.
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Table 3. Substrate scope of aromatic aldehydes, thiophenols, and 1,3-cyclohexa-
nediones.[a]
[a]
General conditions: aldehyde/thiophenol/cyclohexane-1,3-dione=1.0/1.0/1.0,
reaction scale: 1.0 mmol, EtOH: 1.0 mL, l-proline: 10 mol%, room temper-
ature (about 308C), 6 h, the products were isolated by filtration.
The products were isolated by filtration after adding a few drops of water.
[b]
[c]
0.3 mmol scale and the products were isolated by preparative TLC.
Scheme 3. Three-component reactions of aromatic aldehydes, 1,3-cyclohexanediones and some other nucleophiles.
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Scheme 4. SN1-type substitution of 4a by using dimedone as a leaving group.
Scheme 5. SN1-type substitution of 9a with different nucleophiles.
The good leaving group ability of thiophenol also was used as substrate instead of n-butyl vinyl ether,
allowed us to develop a new method for synthesizing no product was obtained under Linꢀs conditions.
densely substituted dihydropyrans. As shown in Therefore, our present method not only offers an ef-
Scheme 6, dihydropyrans 13a to 13i could be obtained fective way to synthesize the densely substituted dihy-
in moderate to excellent yields by using 9a and styr- dropyrans, 13a to 13i, but also displays a good com-
enes as starting materials. This reaction begins with plementarity to the previous method. All the results
an elimination of thiophenol from 9a, which results in in Scheme 4, Scheme 5 and Scheme 6 demonstrated
the formation of a 2-benzylidene-1,3-cyclohexane- that, thanks to the good leaving group ability of some
dione derivative (I) that can act as an oxodiene to special nucleophiles, this strategy to use the MCR
react with styrene to give the final product (Figure 3). product of an aldehyde with two different nucleo-
In the literature, some analogous dihydropyrans have philes as the substrate for SN1-type reactions can be
been synthesized by Lin, who developed a three-com- an effective method for constructing carbon-carbon
ponent reaction of benzaldehyde, dimedone and n- bonds.
butyl vinyl ether by using ethylenediamine diacetate
as catalyst.[22] However, we found that when styrene
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Scheme 6. Synthesis of dihydropyrans from 9a and styrenes.
Figure 3. Proposed mechanism for the formation of dihydropyrans
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Conclusions
General Procedure for the Reactions of Aromatic
Aldehydes, 1,3-Cyclohexanediones and Sulfides
l-Proline/ethanol was proved to be a versatile and an
effective system for three-component reactions of
benzaldehydes, activated methylene derivatives, and
an associated nucleophile. When dimedone was used,
the formed three-component adducts are eligible sub-
strates to participate SN1-type substitution reactions.
Interestingly, the product synthesized through three-
component reaction of benzaldehydes, dimedone and
thiophenol can be used as an important building
block for organic synthesis. Cleavage of carbon-sulfur
bond is preferential under suitable conditions, while
the dimedone fragment can be delivered uneventfully
into the final product. This strategy offers an effective
means for the synthesis of various complex molecules
that cannot be attained by conventional methods.
Given that a large number of MCR products can be
synthesized in the l-proline/ethanol system, it is quite
reasonable to expect that this strategy may be widely
used in organic synthesis in the near future.
Reaction conditions: aldehyde/thiophenol/1,3-cyclohexane-
dione=1.0/1.0/1.0, reaction scale: 1.0 mmol or 0.3 mmol,
EtOH: 1.0 mL, l-proline: 10 mol%, room temperature
(about 308C), 6 h. The products were isolated by the above
mentioned methods.
General Procedure for the Reactions of Aromatic
Aldehydes, 1,3-Cyclohexanediones and 2-Methylfuran
or Benzenesulfinic Acid
Reaction conditions: aldehyde/dimedone/2-methylfuran or
benzenesulfinic acid=1.0/1.0/1.0, reaction scale: 0.5 mmol,
EtOH: 1.5 mL, l-proline: 10 mol% or 20 mol% respectively,
room temperature (about 308C), 6 h. The products were iso-
lated by prepared TLC with an eluting solvent composed of
ethyl acetate and petroleum ether (EA/PE=1/5 v/v).
Procedure for the Synthesis of Unsymmetrical
Bisindolylmethane 11a
A mixture of 4a (0.3 mmol), 5-bromoindole (1.2 equiv.),
MnBr2 (10 mol%), PPh3 (10 mol%) and nitromethane
(1.5 mL) was stirred at 1008C for 6 h. After completion of
the reaction, the solution was subjected to isolation with
preparative TLC using a mixture of ethyl acetate and petro-
leum ether as eluent (EA/PE=1/5 v/v).
Experimental Section
General
Melting points were determined on a microscopic melting
point apparatus and are uncorrected. IR spectra were re-
corded on a Bruker FT-IR (EQUINOX 55) using KBr pel-
General Procedure for Reaction of 9a with Anti-
pyrine, 1-Methylpyrrole, or 1,3-Cyclohexanedione
1
lets or neat liquid technology. H and 13C NMR spectra were
recorded on a Bruker AV-400. 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 V-
type flask equipped with triangle magnetic stirring.
A
mixture of 9a (0.3 mmol), nucleophile (0.36 mmol),
MnCl2·4H2O (0.06 mmol, if necessary), nitromethane
(1.5 mL) or acetic acid (1.5 mL) was stirred at 1008C or
808C for the specified number of hours. After the reaction
was completed (monitored by TLC), the mixture was sub-
jected to prepared TLC and the product was isolated by
using ethyl acetate/petroleum as eluent (EA/PE=1/4 v/v).
General Procedure for the Reactions of Aromatic
Aldehydes, 1,3-Cyclohexanediones and Indoles
General Procedure for the Synthesis of
Dihydropyrans from 9a and Styrenes
A mixture of aldehyde (1.0 mmol), 1,3-cyclohexanedione
(1.0 mmol), indole (1.0 mmol) and l-proline (0.1 mmol) in
ethanol (1.0 mL) was stirred at 808C until the reaction was
completed (monitored by TLC). After completion, the mix-
ture was kept in the refrigerator (48C) for 4 h, and then sub-
jected to filtration. The residue was washed with ethanol
(2.0 mLꢂ3). After drying under air, the pure product was
obtained, in the most cases, as a white powder.
A mixture of 9a (0.3 mmol), styrene (0.45 mmol), ZnCl2
(20 mol%) in nitromethane (1.5 mL) was stirred at 808C for
8 h. After the reaction was completed, the mixture was sub-
jected to preparative TLC. The product was obtained by
using ethyl acetate and petroleum ether as eluent (EA/PE=
1/5 v/v).
The large scale synthesis of 4a was performed using an
analogous procedure.
Spectroscopic Data for the Obtained Compounds
2-[(2-Chlorophenyl)(1H-indol-3-yl)methyl]-3-hydroxy-5,5-di-
methylcyclohex-2-enone (4a): White solid; mp 231–2338C;
1H NMR (DMSO-d6): d=1.02 (s, 6H), 2.25 (br, 4H), 5.93 (s,
1H), 6.83–6.87 (m, 2H), 7.01–7.05 (m, 3H), 7.12 (q, J=
8.0 Hz, 2H), 7.31–7.35 (m, 2H), 10.74 (s, 1H); 13C NMR
(DMSO-d6): d=28.4, 31.9, 34.3, 111.8, 115.1, 115.4, 118.5,
118.9, 121.1, 124.7, 125.9, 127.2, 127.3, 128.9, 132.6, 133.1,
136.8, 142.1; IR: n=3341, 3172, 3060, 2958, 2922, 2887, 2597,
1565, 1464, 1380, 1265, 1155, 1100, 1032, 750, 612 cmÀ1; HR-
General Procedure for the Reactions of Aromatic
Aldehydes, Indoles and Other Activated Methylene
Derivatives
Reaction conditions: aldehyde/indole/activated methylene
derivative=1.0/1.0/1.0, reaction scale: 1.0 mmol, solvent:
1.5 mL, l-proline: 10 mol, 808C, 4 h. The desired product
was isolated by preparative TLC or filtration (in the case of
filtration, the product was washed with petroleum).
Adv. Synth. Catal. 2014, 356, 537 – 556
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
547

FULL PAPERS
Minghao Li et al.
MS (ESI): m/z=402.1230, calcd for C23H2235ClNNaO2 [M+
Na]+: 402.1237.
HR-MS (ESI): m/z=416.1384, calcd. for C24H2435ClNNaO2
[M+Na]+: 416.1393.
2-[(5-Bromo-1H-indol-3-yl)(2-chlorophenyl)methyl]-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (4b): White solid; mp
275–2788C; H NMR (DMSO-d6): d=1.01 (s, 6H), 2.26 (br,
2-[(2-Chlorophenyl)(2-phenyl-1H-indol-3-yl)methyl]-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (4g): White solid; mp
236–2388C; H NMR (DMSO-d6): d=0.94 (s, 6H), 2.13 (br,
1
1
4H), 5.89 (s, 1H), 6.93 (d, J=1.6 Hz, 1H), 7.08–7.17 (m,
5H), 7.33 (dd, Ja =1.6 Hz, Jb =8.0 Hz, 2H), 11.00 (d, J=
2.0 Hz, 1H); 13C NMR (DMSO-d6): d=28.4, 31.9, 34.1,
111.2, 113.9, 114.8, 115.4, 120.9, 123.6, 126.1, 126.4, 127.5,
129.1, 129.2, 132.3, 133.2, 135.5, 141.6; IR: n=3424, 3286,
2955, 2923, 2885, 2601, 1608, 1567, 1465, 1382, 1319, 1252,
1155, 1115, 1031, 887, 748, 622 cmÀ1; HR-MS (ESI): m/z=
480.0334. calcd. for C23H2179BrClNNaO2 [M+Na]+:
480.0342.
4H), 5.97 (s,1H), 6.84 (dt, Ja =0.8 Hz, Jb =7.2 Hz, 1H), 7.03
(dt, Ja =0.8 Hz, Jb =7.2 Hz, 1H), 7.10–7.13 (m, 2H), 7.23–
7.28 (m, 2H), 7.29–7.39 (m, 5H), 7.46 (dd, Ja =1.6 Hz, Jb =
7.2 Hz, 2H), 10.31 (br, 1H), 11.11 (s, 1H); 13C NMR
(DMSO-d6): d=28.4, 31.7, 36.0, 111.5, 112.8, 114.6, 118.8,
120.8, 121.1, 126.4, 127.2, 127.5, 128.5, 128.7, 129.0, 129.1,
131.7, 132.9, 133.9, 135.9, 136.4, 143.3; IR: 3444, 3068, 2957,
2889, 2601, 1659, 1625, 1455, 1374, 1311, 1268, 1057, 1008,
822, 760, 621 cmÀ1; HR-MS (ESI): m/z=478.1539, calcd. for
C29H2635ClNNaO2 [M+Na]+: 478.1550.
2-((2-Chlorophenyl)(5-methoxy-1H-indol-3-yl)methyl)-3-
hydroxy-5,5-dimethylcyclohex-2-enone (4c): White solid; mp
2-[(2-Chlorophenyl)(1-methyl-2-phenyl-1H-indol-3-yl)-
1
224–2268C; H NMR (DMSO-d6): d=1.01 (s, 6H), 2.33 (br,
methyl]-3-hydroxy-5,5-dimethylcyclohex-2-enone
(4h):
1
4H), 3.59 (s, 3H), 5.85 (s, 1H), 6.48 (d, J=2.4 Hz, 1H), 6.68
(dd, Ja =2.4 Hz, Jb =8.8 Hz, 1H), 6.81 (d, J=1.6 Hz, 1H),
7.06 (dt, Ja =1.2 Hz, Jb =7.2 Hz, 1H), 7.11 (dt, Ja =2.0 Hz,
Jb =7.6 Hz, 1H), 7.17 (dd, Ja =2.0 Hz, Jb =7.6 Hz, 1H), 7.23
(d, J=8.8 Hz, 1H), 7.32 (dd, Ja =1.2 Hz, Jb =7.6 Hz, 1H),
10.57 (d, J=1.6 Hz, 1H); 13C NMR (DMSO-d6): d=28.4,
31.9, 34.4, 55.7, 101.2, 110.8, 112.4, 115.0, 115.2, 125.4, 126.0,
127.3, 127.6, 129.0, 132.1, 132.4, 133.1, 141.9, 153.1; IR: n=
3432, 3298, 3059, 2951, 2925, 2884, 2523, 1568, 1483, 1465,
1380, 1258, 1205, 1046, 748, 639 cmÀ1; HR-MS (ESI): m/z=
432.1337, calcd for C24H2435ClNNaO3 [M+Na]+: 432.1342.
2-[(2-Chlorophenyl)(6-methyl-1H-indol-3-yl)methyl]-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (4d): Brown liquid;
1H NMR (CDCl3): d=1.12 (s, 6H), 2.29–2.40 (m, 4H), 2.46
(s, 3H), 6.21 (s, 1H), 6.40 (s, 1H), 6.95 (d, J=8.0 Hz, 1H),
7.12 (s, 1H), 7.11–7.25 (m, 2H), 7.31–7.40 (m, 3H), 8.62 (s,
1H); 13C NMR (CDCl3): d=21.6, 28.2, 31.6, 34.5, 111.5,
114.3, 115.3, 118.7, 121.6, 122.7, 124.2, 126.6, 127.8, 128.6,
129.9, 132.7, 134.4, 137.6, 139.4; IR: n=3291, 3064, 2958,
2928, 2870, 2646, 2247, 1725, 1608, 1465, 1375, 1259, 1151,
1038, 909, 803, 733 cmÀ1; HR-MS (ESI): m/z=416.1384,
calcd. for C24H2435ClNNaO2 [M+Na]+: 416.1393.
White solid; mp 229–2318C; H NMR (DMSO-d6): d=0.91
(s, 6H), 2.03 (br, 4H), 3.45 (s, 3H), 5.76 (s, 1H), 6.88 (t, J=
7.2 Hz, 1H), 7.03–7.12 (m, 3H), 7.17–7.21 (m, 3H), 7.28 (br,
2H), 7.37–7.40 (m, 4H); 13C NMR (DMSO-d6): d=28.4,
30.9, 31.6, 35.9, 110.0, 113.0, 114.5, 119.0, 120.5, 121.2, 126.2,
127.1, 127.9, 128.2, 128.3, 128.9, 130.7, 131.8, 132.4, 132.9,
137.0, 138.6, 142.8; IR: n=3437, 3053, 2953, 2887, 2618,
1555, 1468, 1371, 1263, 1153, 1031, 889, 744, 702, 593,
483 cmÀ1
;
HR-MS (ESI): m/z=492.1697, calcd. for
C30H2835ClNNaO2 [M+Na]+: 492.1706.
2-[(2-Chlorophenyl)(1-ethyl-2-phenyl-1H-indol-3-yl)meth-
yl]-3-hydroxy-5,5-dimethylcyclohex-2-enone (4i): White
solid; mp 212–2158C; 1H NMR (DMSO-d6): d=0.91 (s,
6H), 1.06 (t, J=8.8 Hz, 3H), 2.00 (br, 4H), 3.89 (q, J=
7.6 Hz, 2H), 5.74 (s, 1H), 6.86 (t, J=7.6 Hz, 1H), 7.01–7.10
(m, 3H), 7.13–7.26 (m, 5H), 7.37–7.42 (m, 4H), 10.16 (br,
1H); 13C NMR (DMSO-d6): d=15.5, 29.0, 31.6, 35.8, 38.2,
110.0, 113.1, 114.4, 118.9, 120.5, 121.1, 126.1, 127.1, 128.2,
128.3, 128.4, 128.5, 128.8, 130.7, 130.8, 132.0, 132.6, 132.9,
135.8, 138.1, 142.8; IR: n=3437, 3060, 2957, 2709, 1570,
1466, 1373, 1280, 1248, 1157, 1030, 742, 703, 593 cmÀ1; HR-
MS (ESI): m/z=506.1858, calcd. for C31H3035ClNNaO2 [M+
Na]+: 506.1863.
2-[(2-Chlorophenyl)(6-fluoro-1H-indol-3-yl)methyl]-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (4e): White solid; mp
2-[(2-Fluorophenyl)(1H-indol-3-yl)methyl]-3-hydroxy-5,5-
dimethylcyclohex-2-enone (4j): White solid; mp 211–2318C;
1H NMR (DMSO-d6): d=1.00 (s, 6H), 2.26 (s, 4H), 5.98 (s,
1H), 5.84–5.94 (m, 3H), 7.00–7.05 (m, 2H), 7.10–7.14 (m,
3H), 7.34 (d, J=8.4 Hz, 1H), 10.73 (s, 1H); 13C NMR
1
215–2178C; H NMR (DMSO-d6): d=1.02 (s, 6H), 2.09 (br,
4H), 5.90 (s, 1H), 6.72 (dt, Ja =2.4 Hz, Jb =8.0 Hz, 1H),
6.86–6.88 (m, 1H), 6.97 (dd, Ja =1.6 Hz, Jb =8.8 Hz, 1H),
7.10–7.16 (m, 4H), 7.32 (d, J=7.6 Hz, 1H), 10.25 (br, 1H),
10.82 (s, 1H); 13C NMR (DMSO-d6): d=28.3, 29.5, 32.0,
(DMSO-d6): d=28.3, 29.5, 32.0, 111.8, 114.7 (d, JC,F
22.2 Hz), 115.2, 115.6, 118.5, 118.8, 121.1, 123.3 (d, JC,F
=
=
111.8, 114.7 (d, JC,F =22.3 Hz), 115.2, 115.6, 118.6 (d, JC,F
=
20.6 Hz), 121.1, 123.3 (d, JC,F =2.5 Hz), 124.6, 127.3, 127.4,
131.5, 131.9, 132.0, 136.6, 159.5 (d, JC,F =220.4 Hz); IR: n=
3389, 3330, 3173, 2956, 2873, 1721, 1611, 1566, 1378, 1255,
1225, 1145, 1097, 1030, 745, 602 cmÀ1; HR-MS (ESI): m/z=
420.1137, calcd. for C23H2135ClFNNaO2 [M+Na]+: 420.1143.
2-[(2-Chlorophenyl)(2-methyl-1H-indol-3-yl)methyl]-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (4f): Brown liquid;
1H NMR (CDCl3): d=1.10 (s, 6H), 1.97 (s, 3H), 2.28–2.38
(m, 4H), 6.17 (s, 1H), 6.94–7.00 (m, 2H), 7.09 (dt, Ja =
1.2 Hz, Jb =8.0 Hz, 1H), 7.18–7.26 (m, 3H), 7.36 (ddd, Ja =
2.0 Hz, Jb =3.6 Hz, Jc =7.6 Hz, 1H), 8.67 (s, 1H); 13C NMR
(CDCl3): d=11.9, 28.4, 31.7, 35.1, 108.0, 110.8, 114.9, 118.3,
119.7, 121.5, 126.7, 127.5, 128.1, 129.2, 130.1, 133.6, 134.9,
135.4, 139.2; IR: n=3392, 3300, 3060, 2959, 2871, 2648, 2247,
2.5 Hz), 124.6, 127.3 (d, JC,F =9.4 Hz), 131.5, 131.9, 132.0,
136.6, 160.7 (d, JC,F =243.3 Hz); IR: n=3348, 3114, 2961,
2888, 2550, 1564, 1485, 1383, 1267, 1224, 1100, 1030, 754,
612 cmÀ1
;
HR-MS (ESI): m/z=386.1518, calcd. for
C23H22FNNaO2 [M+Na]+: 386.1532.
2-[(2-Bromophenyl)(1H-indol-3-yl)methyl]-3-hydroxy-5,5-
dimethylcyclohex-2-enone (4k): White solid; mp 205–2068C;
1H NMR (DMSO-d6): d=1.02 (s, 6H), 2.04–2.06 (m, 4H),
5.85 (s, 1H), 6.84 (dt, Ja =0.8 Hz, Jb =7.6 Hz, 2H), 7.00–7.04
(m, 3H), 7.07 (dt, Ja =1.2 Hz, Jb =7.6 Hz, 1H), 7.16 (dd, Ja =
2.0 Hz, Jb =8.0 Hz, 1H), 7.34 (d, J=8.0 Hz, 1H), 7.49 (dd,
Ja =1.6 Hz, Jb =8.0 Hz, 1H), 10.73 (d, J=1.6 Hz, 1H);
13C NMR (DMSO-d6): d=33.3, 36.6, 41.8, 116.6, 119.8,
120.5, 123.3, 123.7, 125.9, 128.8, 129.4, 131.2, 132.0, 132.4,
137.0, 137.7, 141.6, 148.5; IR: 3329, 3056, 2956, 2927, 2869,
1723, 1609, 1463, 1373, 1308, 1253, 1152, 1040, 909, 735 cmÀ1
;
548
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2014, 356, 537 – 556

FULL PAPERS
Three-Component Reactions of Aromatic Aldehydes and Two Different Nucleophiles
2590, 1721, 1610, 1569, 1462, 1378, 1265, 1153, 1098, 1022,
127.7, 127.8, 128.3, 130.4, 131.7, 136.6, 138.5, 149.9; IR: n=
3058, 3026, 2959, 2879, 2621, 1552, 1468, 1371, 1322, 1256,
1158, 1116, 1065, 1019, 903, 822, 722, 593 cmÀ1; HR-MS
(ESI): m/z=526.1959, calcd. for C31H28F3NNaO2 [M+Na]+:
526.1970.
748 cmÀ1
;
HR-MS (ESI): m/z=446.0727, calcd. for
C23H2279BrNNaO2 [M+Na]+: 446.0732.
2-[(2-Chloro-6-fluorophenyl)(1H-indol-3-yl)methyl]-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (4l): White solid; mp
1
210–2128C; H NMR (DMSO-d6): d=1.03 (s, 6H), 2.24–2.30
3-Hydroxy-5,5-dimethyl-2-[(1-methyl-2-phenyl-1H-indol-
3-yl)(2-nitrophenyl)methyl]cyclohex-2-enone (4q): White
solid; mp 241–2438C; 1H NMR (DMSO-d6): d=0.87 (s,
6H), 1.90 (br, 2H), 2.12 (br, 2H), 3.49 (s, 3H), 6.17 (s, 1H),
6.92 (t, J=7.6 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 7.19 (d, J=
8.0 Hz, 1H), 7.27–7.45 (m, 9H), 7.40 (d, J=7.6 Hz, 1H),
10.37 (s, 1H); 13C NMR (DMSO-d6): d=31.0, 31.4, 33.7,
39.4, 110.2, 114.0, 119.3, 120.4, 121.4, 123.8, 126.5, 127.5,
128.4, 130.8, 131.5, 131.9, 132.1, 137.2, 139.2, 139.5, 149.6;
IR: n=3400, 3054, 2954, 2868, 2612, 1559, 1522, 1367, 1262,
1154, 1024, 883, 784, 746, 700, 595 cmÀ1; HR-MS (ESI):
m/z=503.1939, calcd. for C30H28N2NaO4 [M+Na]+:
503.1947.
(m, 2H), 2.54–2.67 (m, 2H), 5.36 (s,1H), 6.87 (t, J=8.0 Hz,
1H), 6.98 (t, J=8.0 Hz, 1H), 7.15 (d, J=2.4 Hz, 1H), 7.18
(dd, Ja =2.0 Hz, Jb =7.2 Hz, 1H), 7.25–7.33 (m, 4H), 10.90
(d, J=2.0 Hz, 1H); 13C NMR (DMSO-d6): d=26.2, 27.0,
28.7, 31.6, 49.9, 111.5, 112.7, 115.3, 116.1, 118.2 (d, JC,F
=
27.8 Hz), 120.4, 123.4, 124.4, 125.3 (d, JC,F =10.4 Hz), 128.4,
134.6 (d, JC,F =3.8 Hz), 150.6, 163.4 (d, JC,F =240.2 Hz),
195.5; IR: n=3332, 3082, 3058, 2960, 2928, 1639, 1573, 1452,
1376, 1232, 1179, 1146, 1102, 895, 798, 740, 557 cmÀ1; HR-
MS (ESI); m/z=420.1139, calcd. for C23H2135ClFNNaO2
[M+Na]+: 420.1143.
3-Hydroxy-5,5-dimethyl-2-[(1-methyl-2-phenyl-1H-indol-
3-yl)
N
2-[(2,3-Dichlorophenyl)(1-methyl-2-phenyl-1H-indol-3-
1
mp 190–1918C; H NMR (DMSO-d6): d=0.94 (s, 6H), 2.00
(br, 2H), 2.25 (br, 2H), 3.47 (s, 3H), 5.65 (s,1H), 6.86–6.89
(m, 4H), 7.16–7.26 (m, 6H), 7.33–7.35 (m, 2H), 7.39–7.41
(m, 2H), 10.11 (s, 1H); 13C NMR (DMSO-d6): d=30.9, 31.0,
31.1, 31.7, 37.0, 110.2, 114.8, 116.0, 119.1, 120.8, 121.2, 127.4,
127.7, 128.3, 128.5, 130.5, 131.0, 131.7, 137.2, 138.7, 145.0;
IR: n=3037, 3010, 2937, 2860, 2615, 1555, 1467, 1374, 1255,
yl)methyl]-3-hydroxy-5,5-dimethylcyclohex-2-enone
(4r):
1
White solid; mp 233–2348C; H NMR (DMSO-d6): d=0.93
(s, 6H), 2.03 (br, 4H), 3.46 (s, 3H), 5.77 (s, 1H), 6.93 (t, J=
7.6 Hz, 1H), 7.07 (t, J=8.0 Hz, 1H), 7.13 (t, J=7.6 Hz, 1H),
7.26–7.32 (m, 4H), 7.38–7.42 (m, 4H), 10.27 (s, 1H);
13C NMR (DMSO-d6): d=30.9, 31.3, 31.6, 37.0, 110.1, 112.6,
114.1, 119.2, 120.3, 121.3, 127.0, 127.6, 127.7, 128.3, 128.4,
130.4, 130.6, 130.7, 131.2, 132.2, 137.1, 138.7, 145.8; IR: n=
3044, 2952, 2885, 2616, 1559, 1468, 1412, 1368, 1260, 1150,
1026, 883, 744, 700, 592, 482 cmÀ1; HR-MS (ESI): m/z=
526.1312, calcd. for C30H2735Cl2NNaO2 [M+Na]+: 526.1317.
2-[(5-Bromo-2-fluorophenyl)(1-methyl-2-phenyl-1H-indol-
3-yl)methyl]-3-hydroxy-5,5-dimethylcyclohex-2-enone (4s):
1145, 1025, 860, 814, 742 cmÀ1
458.2089, calcd. for C30H29NNaO2 [M+Na]+: 458.2096.
3-Hydroxy-5,5-dimethyl-2-[(1-methyl-2-phenyl-1H-indol-
3-yl)(para-tolyl)methyl]cyclohex-2-enone (4n): White solid;
mp 183–1858C; H NMR (DMSO-d6): d=0.93 (s, 6H), 2.16
(br, 4H), 2.22 (s, 3H), 3.47 (s, 3H), 5.59 (s, 1H), 6.81 (t, J=
3.2 Hz, 1H), 6.92 (s, 4H), 7.06 (t, J=7.2 Hz, 1H), 7.17 (d,
J=8.0 Hz, 1H), 7.32–7.43 (m, 4H), 10.05 (s, 1H); 13C NMR
(DMSO-d6): d=21.0, 30.9, 31.1, 31.7, 36.6, 109.7, 114.4,
116.2, 118.5, 120.9, 122.0, 127.8, 128.1, 128.3, 128.4, 128.5,
131.0, 132.6, 133.7, 137.1, 138.7, 142.0; IR: n=3047, 3015,
2947, 2885, 2625, 1553, 1467, 1374, 1255, 1148, 1025, 879,
818, 742, 703, 593, 481 cmÀ1; HR-MS (ESI): m/z=472.2246,
calcd. for C31H31NNaO2 [M+Na]+: 472.2252.
1
White solid; mp 145–1478C; H NMR (DMSO-d6): d=0.91
(s, 6H), 1.98 (br, 2H), 2.19 (br, 2H), 3.47 (s, 3H), 5.37 (s,
1H), 6.90–6.96 (m, 2H), 7.12–7.16 (m, 2H), 7.24–7.32 (m,
4H), 7.39–7.44 (m, 4H), 10.43 (s, 1H); 13C NMR (DMSO-
d6): d=18.3, 30.2, 30.5, 55.8, 109.5, 111.1, 113.5, 114.9, 115.0,
116.3 (d, JC,F =23.6 Hz), 118.6, 119.6, 120.7, 126.8, 127.7 (d,
J
C,F =9.1 Hz), 129.3, 129.4, 130.2, 131.5, 133.0, 133.1, 136.3,
138.1, 160.0 (d, JC,F =244.3 Hz); IR: n=3051, 2956, 2888,
2-[(4-Chlorophenyl)(1-methyl-2-phenyl-1H-indol-3-yl)-
2622, 1557, 1427, 1366, 1259, 1153, 1027, 877, 811, 742, 698,
methyl]-3-hydroxy-5,5-dimethylcyclohex-2-enone
(4o):
590 cmÀ1
;
HR-MS (ESI): m/z=554.1101, calcd. for
White solid; mp 200–2028C; H NMR (DMSO-d6): d=0.93
(s, 6H), 2.11 (br, 4H), 3.48 (s, 3H), 5.61 (s, 1H), 6.87 (t, J=
7.6 Hz, 1H), 7.01 (d, J=8.4 Hz, 2H), 7.09 (t, J=8.0 Hz,
1H), 7.15 (d, J=8.4 Hz, 2H), 7.24 (d, J=8.0 Hz, 1H), 7.32–
7.34 (m, 2H), 7.38–7.42 (m, 4H), 10.31 (s, 1H); 13C NMR
(DMSO-d6): d=28.4, 30.9, 31.7, 36.6, 109.8, 113.5, 115.6,
118.8, 121.1, 121.6, 127.5, 127.6, 128.3, 128.4, 129.6, 130.2,
131.0, 132.4, 137.2, 138.9, 144.4; IR: 3059, 2959, 2871, 2623,
1561, 1467, 1371, 1314, 1267, 1157, 1085, 1030, 1013, 858,
817, 740, 699, 600, 526 cmÀ1; HR-MS (ESI): m/z=492.16997,
calcd. for C30H2835ClNNaO2 [M+Na]+: 492.1706.
C30H2779BrFNNaO2 [M+Na]+: 554.1107.
1
(E)-3-Hydroxy-5,5-dimethyl-2-[3-phenyl-1-(2-phenyl-1H-
indol-3-yl)allyl]cyclohex-2-enone (4t): White solid; mp 252–
1
2548C; H NMR (DMSO-d6): d=1.11 (s, 6H), 2.18–2.23 (m,
2H), 2.32 (d, J=15.6 Hz, 1H), 2.41 (d, J=17.2 Hz, 1H),
3.78 (dt, Ja =4.8 Hz, Jb =13.6 Hz, 1H), 4.11 (d, J=4.0 Hz,
1H), 5.20 (d, J=11.2 Hz, 1H), 6.99 (d, J=7.6 Hz, 2H), 7.05
(t, J=7.6 Hz, 1H), 7.15 (t, J=7.6 Hz, 3H), 7.23 (d, J=
7.2 Hz, 2H), 7.29 (q, J=7.2 Hz, 2H), 7.32–7.36 (m, 2H),
7.41 (d, J=8.0 Hz, 1H), 7.59 (d, J=8.0 Hz, 1H), 11.45 (s,
1H); 13C NMR (DMSO-d6): d=28.0, 29.0, 32.3, 34.5, 69.8,
110.1, 110.8, 112.1, 119.8, 120.2, 122.3, 126.5, 126.9, 128.2,
128.3, 128.4, 128.6, 128.9, 131.8, 136.0, 136.7, 145.3, 171.5,
196.2; IR: n=32.11, 3186, 3055, 2957, 1601, 1453, 1399, 1364,
1341, 1229, 1143, 1059, 764, 740, 697, 630 cmÀ1; HR-MS
(ESI): m/z=470.2089, calcd. for C31H29NNaO2 [M+Na]+:
470.2096.
3-Hydroxy-5,5-dimethyl-2-{(1-methyl-2-phenyl-1H-indol-
3-yl)[4-(trifluoromethyl)phenyl]methyl}cyclohex-2-enone
1
(4p): White solid, mp 130–1338C; H NMR (DMSO-d6): d=
0.93 (s, 6H), 2.13 (br, 4H), 3.48 (s, 3H), 5.68 (s, 1H), 6.88 (t,
J=7.6 Hz, 1H), 7.11 (t, J=7.6 Hz, 1H), 7.19 (d, J=8.0 Hz,
2H), 7.27–7.30 (m, 3H), 7.39–7.42 (m, 4H), 7.45 (d, J=
8.0 Hz, 2H), 10.41 (s, 1H); 13C NMR (DMSO-d6): d=27.8,
30.3, 31.2, 36.6, 78.8 (q, J=1.2 Hz), 109.3, 112.3, 114.8, 118.3,
120.6, 120.7, 123.9, 124.0, 126.7, 126.9 (q, JCÀF =230.1 Hz),
2-[(1H-Indol-3-yl)(pyridin-2-yl)methyl]-3-hydroxy-5,5-di-
methylcyclohex-2-enone (4u): White solid; mp 248–2508C;
1H NMR (DMSO-d6): d=0.93 (s, 6H), 2.25 (dd, Ja =16.8 Hz,
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FULL PAPERS
Minghao Li et al.
Jb =22.8 Hz, 4H), 6.05 (s, 1H), 6.82 (d, J=1.6 Hz, 1H), 6.86
(t, J=8.0 Hz, 1H), 6.99–7.03 (m, 1H), 7.29 (d, J=8.0 Hz,
2H), 7.39 (ddd, Ja =0.8 Hz, Jb =5.2 Hz, Jc =7.6 Hz, 1H), 7.65
(d, J=8.0 Hz, 1H), 7.92 (dt, Ja =1.6 Hz, Jb =7.6 Hz, 1H),
8.53 (dd, Ja =0.8 Hz, Jb =5.2 Hz, 1H), 10.78 (s, 1H);
13C NMR (DMSO-d6): d=31.1, 37.8, 111.4, 114.1, 115.2,
118.3, 118.5, 121.1, 122.6, 122.7, 123.8, 126.2, 136.3, 139.6,
146.8, 162.1; IR: n=3219, 3058, 2957, 2922, 2684, 2432, 1593,
1430, 1369, 1263, 1147, 1109, 1010, 741 cmÀ1; HR-MS (ESI):
m/z=347.1754, calcd. for C22H23N2O2 [M+H]+: 347.1760.
2-[(3-Bromopyridin-2-yl)(1H-indol-3-yl)methyl]-3-hy-
2-[(2-Chlorophenyl)(1-methyl-2-phenyl-1H-indol-3-yl)-
methyl]-3-hydroxy-5-isopropylcyclohex-2-enone (4z): White
1
solid; mp 202–2038C; H NMR (DMSO-d6): d=0.81 (d, J=
6.4 Hz, 6H), 1.41–1.53 (m, 2H), 1.85–2.17 (m, 4H), 3.44 (s,
3H), 5.78 (s, 1H), 6.85 (t, J=7.6 Hz, 1H), 7.01–7.11 (m,
4H), 7.21–7.23 (m, 2H), 7.29 (br, 2H), 7.38–7.40 (m, 4H),
10.18 (s, 1H); 13C NMR (DMSO-d6): d=9.8, 19.9, 30.8, 31.4,
36.0, 109.9, 118.9, 120.4, 121.1, 126.2, 127.2, 127.9, 128.2,
128.9, 130.8, 132.5, 137.0, 138.5; IR: n=3056, 3026, 2963,
2859, 2598, 1559, 1467, 1367, 1272, 1153, 1121, 1032, 746,
700, 606, 514 cmÀ1; HR-MS (ESI): m/z=506.1851, calcd. for
C31H3035ClNNaO2 [M+Na]+: 506.1863.
droxy-5,5-dimethylcyclohex-2-enone (4v): White solid; mp
1
2-[(2-Chlorophenyl)(1-methyl-2-phenyl-1H-indol-3-yl)-
methyl]-3-hydroxycyclopent-2-enone (5a): Pink solid; mp
182–1848C; 1H NMR (CDCl3): d=2.23 (br, 4H), 3.54 (s,
3H), 5.56 (s, 1H), 7.01 (dt, Ja =0.8 Hz, Jb =3.6 Hz, 1H),
7.11–7.25 (m, 4H), 7.27–7.33 (m, 4H), 7.35–7.39 (m, 4H);
13C NMR (CDCl3): d=30.7, 35.2, 109.2, 109.6, 117.5, 119.5,
119.9, 121.9, 126.4, 126.6, 127.8, 128.2, 128.3, 129.8, 129.9,
130.4, 131.6, 134.2, 137.1, 138.9, 139.6; IR: n=3459, 3048,
2921, 2851, 2566, 2396, 1554, 1369, 1272, 1020, 918, 740,
238–2408C; H NMR (DMSO-d6): d=1.01 (s, 6H),2.03–2.81
(m, 2H), 2.39 (br, 2H), 5.85 (s, 1H), 6.90 (t, J=7.2 Hz, 1H),
6.97 (d, J=1.6 Hz, 1H), 7.05 (t, J=7.2 Hz, 1H), 7.19 (d, J=
7.6 Hz, 1H), 7.24 (d, J=8.0 Hz,1H), 7.35 (d, J=8.0 Hz,
1H), 7.40 (d, J=7.6 Hz, 1H), 7.58 (t, J=7.6 Hz, 1H), 10.86
(s, 1H), 11.15 (br, 1H); 13C NMR (DMSO-d6): d=27.8, 28.7,
32.1, 38.1, 111.9, 114.4, 116.0, 118.8, 118.9, 121.4, 122.6,
124.3, 125.4, 127.3, 136.5, 139.9, 140.1, 166.1; IR: n=3416,
3217, 3086, 2959, 2930, 2868, 2680, 2507, 1591, 1433, 1406,
1361, 1260, 1166, 1125, 1016, 744, 735 cmÀ1; HR-MS (ESI):
m/z=425.0857, calcd. for C22H2279BrN2O2 [M+H]+:
425.0865.
2-[(1H-indol-3-yl)(pyridin-4-yl)methyl]-3-hydroxy-5,5-di-
methylcyclohex-2-enone (4w): White solid; mp 205–2078C;
1H NMR (DMSO-d6): d=1.00 (s, 6H), 2.29 (br, 4H), 5.78 (s,
1H), 6.89 (t, J=7.2 Hz, 1H), 6.97 (d, J=2.0 Hz, 1H), 7.02–
7.07 (m, 3H), 7.21 (d, J=8.0 Hz, 1H), 7.35 (d, J=8.0 Hz,
1H), 8.32 (d, J=6.0 Hz, 2H), 10.84 (s, 1H); 13C NMR
(DMSO-d6): d=28.3, 32.1, 34.8, 111.8, 114.4, 116.1, 118.7,
118.8, 121.2, 123.9, 124.7, 127.7, 136.3, 149.0, 154.5; IR: n=
3407, 3255, 3055, 2957, 2869, 1623, 1372, 1259, 1214, 1112,
1011, 736, 614 cmÀ1; HR-MS (ESI): m/z=347.1749, calcd.
for C22H23N2O2 [M+H]+: 347.1760.
699 cmÀ1
;
HR-MS (ESI): m/z=450.1231, calcd. for
C27H2235ClNNaO2 [M+Na]+: 450.1237.
5-[(2-Chlorophenyl)(1-methyl-2-phenyl-1H-indol-3-yl)-
methyl]-6-hydroxy-2-thioxo-2,3-dihydropyrimidin-4(1H)-one
1
(5b): White solid; mp 152–1548C; H NMR (DMSO-d6): d=
3.46 (s, 3H), 5.56 (s, 1H), 6.90 (t, J=8.0 Hz, 1H), 7.07–7.35
(m, 11H), 7.41- 7.43 (m, 2H), 11.50 (s, 2H); 13C NMR
(DMSO-d6): d=23.7, 35.6, 100.1, 102.1, 114.9, 116.9, 124.0,
125.1, 126.1, 131.1, 132.4, 132.9, 133.7, 135.4, 136.5, 136.7,
137.7, 141.8, 143.6, 145.9, 176.0, 177.9, 178.0; IR: n=3511,
3369, 3191, 2967, 1602, 1544, 1469, 1393, 1198, 1135, 1048,
746 cmÀ1
;
HR-MS (ESI); m/z=496.0851, calcd. for
C26H2035ClN3NaO2S [M+Na]+: 496.0862.
4-[(1H-indol-3-yl)(pyridin-2-yl)methyl]-3-methyl-1-
phenyl-1H-pyrazol-5-ol (5c): Colorless liquid; 1H NMR
(CDCl3): d=2.31 (s, 3H), 5.35 (s, 1H), 6.91 (d, J=1.6 Hz,
1H), 6.98–7.07 (m, 3H), 7.12–7.18 (m, 2H), 7.35 (t, J=
8.0 Hz, 2H), 7.46 (d, J=8.0 Hz, 1H), 7.54 (d, J=8.0 Hz,
1H), 7.65 (dt, Ja =1.6 Hz, Jb =7.6 Hz, 1H), 7.83 (d, J=
7.6 Hz, 2H), 8.28 (d, J=5.2 Hz, 1H), 8.75 (s, 1H); 13C NMR
(CDCl3): d=12.8, 41.0, 111.6, 117.3, 118.5, 119.4, 121.4,
121.8, 122.3, 122.9, 123.5, 125.5, 125.9, 128.9, 136.6, 138.9,
147.1, 147.3, 163.2; IR: n=3228, 3062, 2961, 2930, 2868,
2555, 1590, 1456, 1429, 1369, 1304, 1260, 1146, 1103, 1011,
892, 806, 754, 609 cmÀ1; HR-MS (ESI): m/z=381.1704,
calcd. for C24H21N4O [M+H]+: 381.1715.
2-[(2-Chlorophenyl)(1-methyl-2-phenyl-1H-indol-3-yl)-
methyl]-3-hydroxycyclohex-2-enone (4x): White solid; mp
210–2128C; 1H NMR (DMSO-d6): d=1.68 (br, 2H), 2.09
(br, 4H), 3.45 (s, 3H), 5.78 (s, 1H), 6.85 (t, J=7.2 Hz, 1H),
7.03 (d, J=8.0 Hz, 1H), 7.07–7.10 (m, 3H), 7.20–7.24 (m,
2H), 7.30 (br, 2H), 7.36–7.42 (m, 4H), 10.22 (s, 1H);
13C NMR (DMSO-d6): d=20.8, 30.8, 36.0, 109.9, 113.1,
115.9, 118.9, 120.5, 121.0, 126.3, 127.2, 128.0, 128.2, 128.9,
130.8, 131.8, 132.5, 133.2, 137.0, 138.5, 142.5; IR: n=3408,
3250, 3054, 2955, 2926, 2870, 2542, 1593, 1478, 1429, 1377,
1326, 1267, 1248, 1132, 1109, 1010, 759, 739, 687, 597 cmÀ1
;
HR-MS (ESI): m/z=464.1389, calcd. for C28H2435ClNNaO2
3-[(2-Chlorophenyl)(1H-indol-3-yl)methyl]-4-hydroxy-6-
methyl-2H-pyran-2-one (5d): Red solid; mp 78–808C;
1H NMR (CDCl3): d=2.09 (s, 3H), 5.82 (s, 1H), 6.17 (s,
1H), 6.61 (d, J=1.6 Hz, 1H), 7.03 (t, J=7.6 Hz, 1H), 7.09
(t, J=7.6 Hz, 1H), 7.11–7.18 (m, 2H), 7.28–7.31 (m, 2H),
7.36 (dd, Ja =1.2 Hz, Jb =8.0 Hz, 2H), 8.64 (s, 1H);
13C NMR (CDCl3): d=19.6, 36.0, 101.4, 102.4, 111.7, 114.2,
119.1, 122.6, 123.9, 126.5, 128.0, 129.6, 130.0, 134.2, 136.9,
138.9, 161.3, 166.0, 167.9; IR: n=3403, 3062, 2983, 2922,
2674, 1732, 1673, 1576, 1407, 1277, 1036, 747 cmÀ1; HR-MS
(ESI): m/z=388.0709, calcd. for C21H1635ClNNaO3 [M+
Na]+: 388.0716.
[M+Na]+: 464.1393.
2-[(2-Chlorophenyl)(1-methyl-2-phenyl-1H-indol-3-yl)-
methyl]-3-hydroxy-5-methylcyclohex-2-enone (4y): White
1
solid; mp 222–2238C; H NMR (DMSO-d6): d=0.92 (d, J=
6.4 Hz, 3H), 1.92–2.21 (br, 5H), 3.45 (s, 3H), 5.76 (s, 1H),
6.86 (t, J=7.6 Hz, 1H), 7.07–7.11 (m, 4H), 7.12–7.22 (m,
2H), 7.30 (br, 2H), 7.36–7.40 (m, 4H), 10.22 (s, 1H);
13C NMR (DMSO-d6): d=20.9, 27.9, 30.9, 36.0, 109.9, 113.0,
115.4, 119.0, 120.5, 121.0, 126.2, 127.2, 128.0, 128.2, 128.9,
130.8, 131.8, 132.4, 133.1, 137.0, 138.5, 142.6; IR: n=3058,
3013, 2948, 2873, 2614, 1561, 1466, 1378, 1336, 1305, 1276,
1254, 1159, 1101, 1036, 777, 739, 703 cmÀ1; HR-MS (ESI);
m/z=478.1542, calcd. for C30H2835ClNNaO2 [M+Na]+:
478.1550.
3-[(2-Chlorophenyl)(1-methyl-2-phenyl-1H-indol-3-yl)-
methyl]-4-hydroxy-2H-chromen-2-one (5e): White solid; mp
1
192–1948C; H NMR (DMSO-d6): d=3.48 (s, 3H), 5.98 (s,
550
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Three-Component Reactions of Aromatic Aldehydes and Two Different Nucleophiles
1H), 6.89 (t, J=3.2 Hz, 1H), 7.10–7.16 (m, 3H), 7.23–7.31
(m, 10H), 7.44 (d, J=8.0 Hz, 1H), 7.53 (t, J=8.0 Hz, 1H),
7.91 (d, J=8.0 Hz, 1H); 13C NMR (DMSO-d6): d=35.7,
42.8, 111.2, 115.0, 116.5, 121.2, 121.6, 124.2, 124.9, 126.2,
128.4, 128.6, 131.4, 132.4, 132.5, 133.0, 133.1, 133.8, 135.3,
136.6, 136.7, 136.8, 137.8, 141.8, 143.9, 146.2, 157.3, 167.1;
IR: n=3222, 3066, 3037, 2932, 1678, 1619, 1468, 1394, 1202,
1165, 1108, 894, 754 cmÀ1; HR-MS (ESI): m/z=514.1181,
calcd. for C31H2235ClNNaO3 [M+Na]+: 514.1186.
(d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H); 13C NMR
(DMSO-d6): d=28.1, 32.0, 42.4, 56.0, 111.1, 115.0, 121.4,
126.7, 126.9, 127.9, 128.1, 129.8, 130.9, 141.5, 156.5; IR: n=
3456, 3062, 3006, 2957, 2871, 2632, 1582, 1475, 1375, 1310,
1243, 1150, 1090, 1072, 1019, 748, 594 cmÀ1; HR-MS (ESI):
m/z=403.1122, calcd. for C22H2435ClO3S [M+H]+: 403.1135.
2-[(4-Chlorophenyl)(ortho-tolylthio)methyl]-3-hydroxy-
5,5-dimethylcyclohex-2-enone (9d): White solid; mp 67–
698C; 1H NMR (CDCl3): d=0.94 (s, 6H), 2.28 (br, 7H),
5.67 (s, 1H), 7.02–7.16 (m, 4H), 7.28 (d, J=8.4 Hz, 2H),
7.45 (d, J=8.4 Hz, 2H); 13C NMR (CDCl3): d=20.4, 28.1,
32.0, 44.3, 115.0, 126.0, 126.9, 128.1, 128.3, 129.8, 130.4,
131.1, 136.9, 137.7, 141.4; IR: n=3205, 3059, 3010, 2958,
2871, 2627, 1585, 1488, 1467, 1374, 1314, 1258, 1149, 1090,
1013, 829, 787, 744, 565 cmÀ1; HR-MS (ESI): m/z=387.1178,
calcd. for C22H2435ClO2S [M+H]+: 387.1186.
2-[(2-Chlorophenyl)(1-methyl-2-phenyl-1H-indol-3-yl)-
methyl]-3-hydroxynaphthalene-1,4-dione (5f): Dark red
liquid; 1H NMR (CDCl3): d=3.59 (s, 3H), 6.31 (s, 1H),
7.09–7.24 (m, 4H), 7.28–7.32 (m, 4H), 7.40 (dd, Ja =8.4 Hz,
Jb =17.6 Hz, 3H), 7.49–7.52 (m, 2H), 7.62 (t, J=7.2 Hz,
1H), 7.70 (t, J=6.4 Hz, 1H), 7.99 (d, J=7.6 Hz, 1H), 8.06
(d, J=7.6 Hz, 1H); 13C NMR (CDCl3): d=30.7, 37.5, 109.5,
110.5, 119.7, 120.1, 121.7, 123.0, 125.8, 126.2, 127.0, 127.5,
127.6, 128.0, 128.4, 128.9, 129.2, 130.7, 131.7, 132.0, 132.6,
132.9, 133.5, 134.8, 137.1, 139.7, 140.1, 183.5; IR: n=3358,
2-{(4-Chlorophenyl)[(2,4-dimethylphenyl)thio]methyl}-3-
hydroxy-5,5-dimethylcyclohex-2-enone (9e): White solid; mp
1
141–1448C; H NMR (CDCl3): d=0.93 (s, 6H), 2.18 (s, 3H),
3059, 2937, 2248, 1654, 1468, 1370, 1272, 1043, 908, 730 cmÀ1
;
2.24–2.25 (m, 7H), 5.56 (s, 1H), 6.86 (d, J=8.0 Hz, 1H),
6.98 (d, J=8.0 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.42 (d, J=
8.4 Hz, 2H); 13C NMR (CDCl3): d=20.5, 20.8, 28.2, 32.0,
45.2, 114.9, 127.5, 128.0, 129.7, 129.8, 130.9, 131.2, 134.0,
135.7, 137.6, 141.8; IR: n=3402, 2964, 2566, 1570, 1484,
1379, 1312, 1263, 1150, 1018, 824, 795, 603 cmÀ1; HR-MS
(ESI) m/z=401.1333, calcd. for C23H2635ClO2S [M+H]+:
401.1342.
HR-MS (ESI): m/z=526.1179, calcd. for C32H2235ClNNaO3
[M+Na]+: 526.1186
3-[(2-Chlorophenyl)(1-methyl-2-phenyl-1H-indol-3-yl)-
methyl]-4-hydroxy-1-methylquinolin-2(1H)-one (5g): White
solid; mp 188–1908C; 1H NMR (CDCl3): d=3.54 (s, 3H),
3.64 (s, 3H), 6.58 (s, 1H), 7.05 (t, J=7.2 Hz, 2H), 7.10–7.13
(m, 2H), 7.20–7.32 (m, 11H), 7.40 (d, J=8.4 Hz, 1H), 7.56
(dt, Ja =1.6 Hz, Jb =7.6 Hz, 1H), 7.94 (dd, Ja =1.2 Hz, Jb =
8.0 Hz, 1H); 13C NMR (CDCl3): d=29.6, 30.8, 38.5, 108.7,
109.9, 111.8, 113.7, 116.0, 119.5, 120.4, 121.4, 122.4, 123.4,
126.4, 126.7, 128.2, 128.3, 128.4, 129.6, 130.0, 130.1, 130.7,
131.2, 135.1, 137.3, 139.0, 139.1, 140.4, 158.0, 162.4; IR: n=
3325, 3051, 2934, 1624, 1464, 1422, 1329, 1266, 1154, 1041,
742, 701 cmÀ1; HR-MS (ESI): m/z=527.1493, calcd. for
C32H2535ClN2NaO2 [M+Na]+: 527.1502.
2-{(4-Chlorophenyl)[(4-hydroxyphenyl)thio]methyl}-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (9f): White solid; mp
1
132–1348C; H NMR (DMSO-d6): d=1.08 (s, 6H), 2.39 (s,
4H), 5.65 (s, 1H), 6.84 (d, J=8.0 Hz, 2H), 7.30 (d, J=
8.0 Hz, 2H), 7.40 (d, J=8.0 Hz, 2H), 7.60 (d, J=8.0 Hz,
2H); 13C NMR (DMSO-d6): d=28.2, 32.0, 47.9, 115.3, 116.4,
128.0, 130.0, 130.9, 133.6, 142.1, 157.2; IR: n=3437, 3250,
3092, 2957, 2870, 2663, 1624, 1491, 1377, 1267, 1057, 1006,
822, 758, 620, 526 cmÀ1; HR-MS (ESI): m/z=389.0969,
calcd. for C21H2235ClO3S [M+H]+: 389.0978.
2-[(4-Chlorophenyl)(phenylthio)methyl]-3-hydroxy-5,5-di-
methylcyclohex-2-enone (9a): White solid; mp 162–1648C;
1H NMR (CDCl3): d=0.93 (s, 6H), 2.25 (t, J=18.0 Hz, 4H),
5.71 (s, 1H), 7.12 (t, J=6.8 Hz, 1H), 7.18–7.30 (m, 6H), 7.45
(d, J=8.4 Hz, 2H); 13C NMR (CDCl3): d=28.1, 32.1, 44.9,
114.9, 126.1, 128.2, 128.6, 129.4, 129.8, 131.1, 138.8, 141.5;
IR: n=3428, 3072, 3046, 2962, 2882, 2563, 1902, 1574, 1485,
1345, 1318, 1240, 1195, 1146, 1090, 1019, 834, 727, 690, 599,
2-{(4-Chlorophenyl)[(3,5-dimethylphenyl)thio]methyl}-3-
hydroxy-5,5-dimethylcyclohex-2-enone (9g): White solid; mp
1
138–1408C; H NMR (CDCl3): d=0.93 (s, 6H), 2.16 (s, 6H),
2.24 (br, 4H), 5.69 (s, 1H), 6.74 (s, 1H), 6.81 (s, 2H), 7.28
(d, J=8.4 Hz, 2H), 7.44 (d, J=8.4 Hz, 2H); 13C NMR
(CDCl3): d=21.2, 28.2, 32.0, 45.7, 114.7, 126.2, 127.7, 128.0,
129.8, 130.9, 138.4, 138.5, 141.8; IR: n=3402, 3012, 2959,
2615, 1576, 1487, 1377, 1319, 1262, 1240, 1191, 1147, 1090,
1017, 833, 594 cmÀ1; HR-MS (ESI): m/z=401.1333, calcd.
for C23H2635ClO2S [M+H]+: 401.1342.
478 cmÀ1
;
HR-MS (ESI) m/z=373.1018, calcd. for
C21H2235ClO2S [M+H]+: 373.1029.
2-{(4-Chlorophenyl)[(4-methoxyphenyl)thio]methyl}-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (9b): White solid; mp
142–1458C; 1H NMR (CDCl3): d=0.93 (s, 6H), 2.24 (br,
7H), 3.69 (s, 3H), 5.51 (s, 1H), 6.84 (d, J=8.8 Hz, 2H), 7.20
(d, J=8.8 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.42 (d, J=
8.4 Hz, 2H); 13C NMR (CDCl3): d=28.1, 32.0, 47.3, 55.5,
115.0, 128.0, 128.6, 129.9, 130.9, 132.5, 132.7, 141.8, 158.8;
IR: n=3356, 3059, 3004, 2962, 2937, 2877, 2532, 1842, 1563,
1492, 1346, 1315, 1258, 1211, 1152, 1024, 831, 779, 641, 596,
2-{(4-Chlorophenyl)[(4-isopropylphenyl)thio]methyl}-3-
hydroxy-5,5-dimethylcyclohex-2-enone (9h): White solid;
1
mp 152–1558C; H NMR (CDCl3): d=0.92 (s, 6H), 1.12 (d,
J=6.8 Hz, 6H), 2.38 (dd, Ja =17.2 Hz, Jb =18.4 Hz, 4H),
5.66 (s, 1H), 7.12 (s, 4H), 7.28 (d, J=8.8 Hz, 2H), 7.45 (d,
J=8.8 Hz, 2H); 13C NMR (CDCl3): d=24.2, 24.3, 28.2, 32.0,
33.3, 115.0, 127.4, 128.1, 129.2, 129.8, 131.0, 135.6, 141.8,
146.6; IR: n=3430, 3016, 2960, 2927, 2870, 2568, 1900, 1570,
1490, 1339, 1239, 1148, 1091, 1018, 816, 596 cmÀ1; HR-MS
(ESI): m/z=415.1492, calcd. for C24H2835ClO2S [M+H]+:
415.1499.
2-[(Benzylthio)(4-chlorophenyl)methyl]-3-hydroxy-5,5-di-
methylcyclohex-2-enone (9i): White solid; mp 133–1358C;
1H NMR (DMSO-d6): d=0.93 (s, 6H), 2.21 (br, 4H), 3.59
(d, J=13.2 Hz, 1H), 3.65 (d, J=13.2 Hz, 1H), 5.21 (s,1H),
527 cmÀ1
;
HR-MS (ESI): m/z=403.1126, calcd. for
C22H2435ClO3S [M+H]+: 403.1135.
2-{(4-Chlorophenyl)[(2-methoxyphenyl)thio]methyl}-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (9c): White solid; mp
54–568C; 1H NMR (DMSO-d6): d=0.95 (s, 6H), 2.26 (br,
4H), 3.78 (s, 3H), 5.93 (s,1H), 6.81 (dt, Ja =0.8 Hz, Jb =
7.6 Hz, 1H), 6.93 (d, J=8.0 Hz, 1H), 6.97 (dd, Ja =1.6 Hz,
Jb =7.6 Hz, 1H), 7.10 (dt, Ja =1.6 Hz, Jb =8.4 Hz, 1H), 7.29
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FULL PAPERS
Minghao Li et al.
7.18–7.29 (m, 7H), 7.41 (d, J=8.4 Hz, 2H); 13C NMR
(DMSO-d6): d=28.2, 31.9, 37.2, 42.2, 114.8, 127.1, 128.0,
128.6, 129.2, 130.1, 130.8, 139.0, 141.9; IR: n=3429, 3060,
3031, 2956, 2925, 2557, 1551, 1487, 1419, 1377, 1317, 1265,
1158, 1090, 1012, 828, 707 cmÀ1; HR-MS (ESI): m/z=
387.1178, calcd. for C22H2435ClO2S [M+H]+: 387.1186.
2-[(4-Chlorophenyl)(cyclohexylthio)methyl]-3-hydroxy-
2-{[(4-Chlorophenyl)thio][4-(trifluoromethyl)phenyl]-
methyl}-3-hydroxy-5,5-dimethylcyclohex-2-enone
(9o):
1
White solid; mp 166–1688C; H NMR (DMSO-d6): d=0.95
(s, 6H), 2.28 (br, 4H), 5.81 (s, 1H), 7.24 (d, J=8.8 Hz, 2H),
7.31 (d, J=8.4 Hz, 2H), 7.62 (d, J=8.4 Hz, 2H), 7.68 (d, J=
8.0 Hz, 2H); 13C NMR (DMSO-d6): d=28.1, 32.0, 45.5, 46.5,
1
114.5, 123.4, 125.2, 125.3, 127.5 (q, JCÀF =269.8 Hz), 128.7,
129.3, 130.4, 130.9, 137.6, 146.9; IR: n=3430, 3062, 3034,
2965, 2931, 2891, 2870, 2553, 1851, 1616, 1551, 1474, 1412,
1357, 1326, 1266, 1246, 1153, 1122, 1068, 1016, 843, 823, 785,
721, 644, 601, 482 cmÀ1; HR-MS (ESI): m/z=441.0899,
calcd. for C22H2135ClF3O2S [M+H]+: 441.0903.
5,5-dimethylcyclohex-2-enone
(9j):
Colorless
liquid;
1H NMR (CDCl3): d=1.02 (s, 6H), 1.26–1.44 (m, 5H), 1.55
(br, 1H), 1.69–1.74 (m, 2H), 1.81–1.84 (m, 1H), 1.97 (br,
1H), 2.31 (br, 4H), 2.60–2.67 (m, 1H), 5.59 (s, 1H), 7.19 (d,
J=8.4 Hz, 2H), 7.27 (d, J=8.4 Hz, 2H); 13C NMR (CDCl3):
d=25.5, 25.6, 25.9, 28.1, 31.8, 32.5, 33.0, 40.9, 44.6, 111.3,
128.6, 129.2, 132.9, 138.3; IR: n=3060, 2929, 2853, 2656,
2247, 2897, 1704, 1591, 1488, 1375, 1258, 1148, 1091, 1013,
910, 831, 732, 646, 594, 527, 477 cmÀ1; HR-MS (ESI): m/z=
379.1493, calcd. for C21H2835ClO2S [M+H]+: 379.1499.
2-{(4-Acetylphenyl)[(4-chlorophenyl)thio]methyl}-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (9p): White solid; mp
1
124–1268C; H NMR (DMSO-d6): d=1.08 (s, 6H), 2.37 (s,
3H), 2.40 (br, 4H), 5.85 (s, 1H), 7.13 (d, J=8.4 Hz, 2H),
7.36 (d, J=8.4 Hz, 2H), 7.45 (d, J=8.4 Hz, 2H), 7.59 (d, J=
8.4 Hz, 2H); 13C NMR (DMSO-d6): d=21.3, 28.2, 32.1, 45.2,
114.8, 121.6, 128.9, 129.3, 130.3, 139.5, 149.2, 169.6; IR: n=
3432, 3065, 2960, 2877, 2619, 1771, 1568, 1504, 1476, 1372,
1262, 1243, 1205, 1095, 1016, 913, 810, 597, 484 cmÀ1; HR-
MS (ESI): m/z=415.1124, calcd. for C23H2435ClO3S [M+
H]+: 415.1135.
2-{(4-Chlorophenyl)[(furan-2-ylmethyl)thio]methyl}-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (9k): White solid; mp
1
120–1228C; H NMR (DMSO-d6): d=0.94 (s, 6H), 2.23 (br,
4H), 3.59 (d, J=14.4 Hz, 1H), 3.65 (d, J=14.4 Hz, 1H),
5.23 (s,1H), 6.18 (d, J=3.2 Hz, 1H), 6.34 (dd, Ja =2.0 Hz,
Jb =2.3 Hz, 1H), 7.27 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.8 Hz,
2H), 7.52 (t, J=0.8 Hz, 1H); 13C NMR (DMSO-d6): d=
28.2, 29.1, 32.0, 42.2, 107.8, 110.9, 114.8, 128.0, 130.0, 130.8,
141.8, 142.7, 152.1; IR: n=3500, 3112, 3079, 2957, 2926,
2564, 1897, 1555, 1378, 1319, 1264, 1154, 1092, 1011, 826,
740, 597 cmÀ1; HR-MS (ESI): m/z=377.0969, calcd. for
C20H2235ClO3S [M+H]+: 377.0978.
2-{[(4-Chlorophenyl)thio](4-methoxyphenyl)methyl}-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (9q): White solid; mp
1
126–1288C; H NMR (DMSO-d6): d=1.07 (s, 6H), 2.39 (br,
4H), 3.81 (s, 3H), 5.79 (s, 1H), 6.78 (d, J=7.6 Hz, 2H), 6.97
(d, J=7.6 Hz, 2H), 7.17 (s, 1H), 7.37 (d, J=8.0 Hz, 2H),
7.43 (d, J=8.0 Hz, 2H); 13C NMR (DMSO-d6): d=28.1,
32.0, 45.5, 55.9, 112.5, 115.2, 120.4, 129.2, 129.6, 129.9, 130.4,
132.9, 138.6, 145.5, 147.3; IR: n=3435, 3062, 2999, 2959,
2836, 2619, 1611, 1568, 1509, 1476, 1354, 1245, 1178, 1152,
2-{[(4-Chlorophenyl)thio](para-tolyl)methyl}-3-hydroxy-
5,5-dimethylcyclohex-2-enone (9l): White solid; mp 139–
1
1418C; H NMR (DMSO-d6): d=1.06 (s, 6H), 2.36 (s, 3H),
1095, 1030, 831, 812, 599 cmÀ1
; HR-MS (ESI): m/z=
2.37 (br, 4H), 5.83 (s, 1H), 7.16 (d, J=7.2 Hz, 2H), 7.32 (d,
J=8.0 Hz, 2H), 7.42 (d, J=8.0 Hz, 2H), 7.46 (d, J=7.2 Hz,
2H); 13C NMR (DMSO-d6): d=21.0, 28.2, 32.0, 45.3, 115.0,
127.8, 128.8, 129.2, 130.0, 130.3, 135.6, 138.6, 139.2; IR: n=
3436, 3016, 2961, 2933, 2875, 2560, 2857, 1632, 1548, 1473,
1348, 1312, 1266, 1241, 1210, 1150, 1091, 1018, 832, 755, 611,
403.1123, calcd. for C22H2435ClO3S [M+H]+: 403.1135.
2-{[(4-Chlorophenyl)thio](2-methoxyphenyl)methyl}-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (9r): White solid; mp
1
143–1458C; H NMR (DMSO-d6): d=1.07 (s, 6H), 2.36 (br,
4H), 3.77 (s, 3H), 6.17 (s, 1H), 6.95 (d, J=7.6 Hz, 1H), 7.00
(d, J=8.4 Hz, 1H), 7.30 (d, J=8.4 Hz, 2H), 7.41 (d, J=
8.4 Hz, 2H), 7.88 (d, J=7.6 Hz, 1H); 13C NMR (DMSO-d6):
d=28.1, 31.9, 55.7, 110.9, 113.9, 119.9, 127.9, 129.0, 130.0,
130.3, 138.5, 156.8; IR: n=3423, 3068, 3008, 2960, 2925,
2881, 2651, 1565, 1481, 1370, 1310, 1282, 1256, 1093, 1026,
1012, 810, 761, 484 cmÀ1; HR-MS (ESI): m/z=403.1123,
calcd. for C22H2435ClO3S [M+H]+: 403.1135.
486 cmÀ1
;
HR-MS (ESI): m/z=387.1178, calcd. for
C22H2435ClO2S [M+H]+: 387.1186.
2-{(4-Chlorophenyl)[(4-chlorophenyl)thio]methyl}-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (9m): White solid; mp
147–1498C; 1H NMR (CDCl3): d=0.92 (s, 6H), 2.25 (br,
4H), 5.70 (s, 1H), 7.20 (d, J=8.4 Hz, 2H), 7.27 (d, J=
2.0 Hz, 2H), 7.29 (d, J=2.0 Hz, 2H), 7.45 (d, J=8.4 Hz,
2H); 13C NMR (CDCl3): d=28.1, 32.0, 45.2, 114.5, 128.2,
129.3, 129.8, 130.3, 130.7, 131.2, 137.8, 141.2; IR: n=3387,
3022, 2960, 2875, 2604, 1575, 1480, 1383, 1313, 1263, 1155,
1095, 1013, 828, 810, 598, 498 cmÀ1; HR-MS (ESI): m/z=
407.0631, calcd. for C21H2135Cl2O2S [M+H]+: 407.0639.
2-{[(4-Chlorophenyl)thio](4-nitrophenyl)methyl}-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (9n): Yellow solid; mp
2-{[(4-Chlorophenyl)thio][4-(dimethylamino)phenyl]-
methyl}-3-hydroxy-5,5-dimethylcyclohex-2-enone (9s): White
solid; mp 127–1298C; 1H NMR (DMSO-d6): d=0.94 (s,
6H), 2.24 (br, 4H), 2.82 (s, 6H), 5.68 (s, 1H), 6.59 (d, J=
8.8 Hz, 2H), 7.19–7.27 (m, 6H); 13C NMR (DMSO-d6): d=
28.2, 32.0, 40.7, 111.5, 112.3, 115.7, 125.6, 127.6, 128.0, 128.3,
128.6, 129.2, 129.9, 130.0, 149.3; IR: n=3405, 3074, 3053,
2958, 2882, 2800, 1549, 1895, 1613, 1559, 1520, 1479, 1442,
1
1345, 1255, 1211, 1145, 1089, 1023, 775, 739, 597, 480 cmÀ1
;
192–1948C; H NMR (DMSO-d6): d=0.94 (s, 6H), 2.28 (br,
HR-MS (ESI): m/z=416.1443, calcd. for C23H2735ClNO2S
4H), 5.82 (s,1H), 7.24 (d, J=8.4 Hz, 2H), 7.31 (d, J=
8.8 Hz, 2H), 7.71 (d, J=8.8 Hz, 2H), 8.13 (d, J=8.8 Hz,
2H); 13C NMR (DMSO-d6): d=28.1, 32.1, 45.7, 114.1, 123.6,
129.2, 129.4, 130.6, 131.1, 137.2, 146.4, 150.1; IR: n=3402,
3059, 2959, 2927, 2869, 2558, 1842, 1546, 1513, 1344, 1266,
[M+H]+: 416.1451.
2-{[(4-Chlorophenyl)thio](4-hydroxy-3-methoxyphenyl)-
methyl}-3-hydroxy-5,5-dimethylcyclohex-2-enone (9t): White
solid; mp 147–1498C; 1H NMR (DMSO-d6): d=1.07 (s,
6H), 2.39 (br, 4H), 3.81 (s, 3H), 5.79 (s, 1H), 6.78 (d, J=
7.6 Hz, 2H), 6.97 (d, J=7.6 Hz, 2H), 7.17 (s, 1H), 7.37 (d,
J=8.0 Hz, 2H), 7.43 (d, J=8.0 Hz, 2H); 13C NMR (DMSO-
1241, 1206, 1153, 1090, 1011, 834, 790, 645, 600, 487 cmÀ1
;
HR-MS (ESI): m/z=418.0871, calcd. for C21H2135ClNO4S
[M+H]+: 418.0880.
552
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FULL PAPERS
Three-Component Reactions of Aromatic Aldehydes and Two Different Nucleophiles
d6): d=28.1, 32.0, 45.5, 55.9, 112.5, 115.2, 120.4, 129.2, 129.6,
129.9, 130.4, 132.9, 138.6, 145.5, 147.3; IR: n=3492, 3064,
3014, 2958, 2936, 2873, 2633, 1590, 1569, 1512, 1473, 1376,
2-[(2-Chlorophenyl)(5-methyl-2-furyl)methyl]-3-hydroxy-
5,5-dimethylcyclohex-2-enone (10b): Colorless liquid;
1H NMR (CDCl3): d=1.09 (s, 6H), 2.27 (s, 3H), 2.29–2.37
(m, 4H), 5.85 (d, J=2.4 Hz, 1H), 5.89 (d, J=2.4 Hz, 1H),
5.96 (s, 1H), 7.15–7.17 (m, 1H), 7.19–7.22 (m, 2H), 7.36–
7.39 (m, 1H); 13C NMR (CDCl3): d=13.6, 30.8, 31.6, 37.0,
106.2, 109.3, 113.6, 126.8, 128.8, 130.2, 134.4, 138.1, 152.1,
152.5; IR: n=3065, 2958, 2929, 2616, 1719, 1631, 1574, 1376,
1260, 1221, 1148, 1087, 1031, 733, 645, 589 cmÀ1; HR-MS
(ESI): m/z=345.1249, calcd. for C20H2235ClO3 [M+H]+:
345.1257.
5-Bromo-3-[(2-chlorophenyl)(1H-indol-3-yl)methyl]-1H-
indole (11a): Brown liquid; 1H NMR (CDCl3): d=6.36 (s,
1H), 6.53 (t, J=3.2 Hz, 2H), 7.08–7.19 (m, 3H), 7.21–7.24
(m, 2H), 7.28–7.35 (m, 2H), 7.47 (t, J=8.0 Hz, 2H), 7.60
(dd, Ja =2.0 Hz, Jb =2.4 Hz, 1H), 7.91 (d, J=16.4 Hz, 1H),
7.97 (d, J=14.8 Hz, 1H); 13C NMR (CDCl3): d=36.3, 111.1,
112.4, 112.6, 117.5, 119.1, 119.4, 121.8, 121.9, 123.7, 124.6,
125.0, 126.5, 126.6, 127.5, 128.4, 129.4, 129.9, 133.6, 135.1,
136.5, 140.7; HR-MS (ESI): m/z=457.0081, calcd. for
C23H1679Br35ClN2Na [M+Na]+: 457.0083.
1262, 1237, 1201, 1149, 1094, 1031, 1010, 872, 810, 763 cmÀ1
;
HR-MS (ESI): m/z=419.1076, calcd. for C22H2435ClO4S
[M+H]+: 419.1084.
2-{[(4-Chlorophenyl)thio](3,4-dimethoxyphenyl)methyl}-
3-hydroxy-5,5-dimethylcyclohex-2-enone (9u): White solid;
1
mp 129–1318C; H NMR (DMSO-d6): d=1.07 (s, 6H), 2.39
(br, 4H), 3.79 (s, 3H), 3.83 (s, 3H), 5.80 (s, 1H), 6.94 (d, J=
8.0 Hz, 2H), 7.08 (d, J=8.0 Hz, 2H), 7.19 (s, 1H), 7.36 (d,
J=8.0 Hz, 2H), 7.44 (d, J=8.0 Hz, 2H); 13C NMR (DMSO-
d6): d=28.1, 32.0, 45.4, 55.8, 55.9, 111.7, 112.1, 115.1, 120.1,
129.2, 129.6, 129.9, 130.4, 130.5, 134.5, 138.4, 147.8, 148.5;
IR: n=3250, 3000, 2958, 2930, 2567, 1602, 1512, 1467, 1373,
1296, 1260, 1224, 1146, 1092, 1026, 1006, 772, 715, 601,
550 cmÀ1
;
HR-MS (ESI): m/z=433.1232, calcd. for
C23H2635ClO4S [M+H]+: 433.1240.
2-{[(4-Chlorophenyl)thio](2-nitrophenyl)methyl}-3-hy-
droxy-5,5-dimethylcyclohex-2-enone (9v): White solid; mp
1
144–1458C; H NMR (DMSO-d6): d=0.91 (s, 6H), 2.20 (dd,
4-[(4-Chlorophenyl)(2-hydroxy-4,4-dimethyl-6-oxocyclo-
hex-1-en-1-yl)methyl]-1,5-dimethyl-2-phenyl-1H-pyrazol-
3(2H)-one (12a): Colorless liquid; 1H NMR (CDCl3): d=
1.07 (s, 3H), 1.13 (s, 3H), 2.26–2.37 (m, 4H), 2.42 (s, 3H),
3.16 (s, 3H), 5.79 (s, 1H), 7.13 (d, J=8.4 Hz, 2H), 7.18 (d,
J=8.4 Hz, 2H), 7.32–7.38 (m, 3H), 7.44–7.48 (m, 2H), 12.52
(s, 1H); 13C NMR (CDCl3): d=10.8, 26.8, 30.1, 30.8, 31.0,
35.1, 44.8, 50.4, 109.6, 116.7, 125.1, 127.9, 128.1, 128.5, 129.4,
131.4, 133.6, 138.7, 152.9, 165.9, 174.7, 197.7; IR: n=3061,
2958, 2930, 2889, 2506, 1617, 1491, 1416, 1355, 1296, 1250,
1143, 1092, 1013, 911, 862, 731, 645, 580 cmÀ1; HR-MS
(ESI): m/z=473.1605, calcd. for C26H2735ClN2NaO3 [M+
Na]+: 473.1608.
Ja =16.8 Hz, Jb =19.2 Hz, 4H), 6.28 (s, 1H), 7.26 (d, J=
8.8 Hz, 2H), 7.34 (d, J=8.4 Hz, 2H), 7.40 (t, J=7.6 Hz,
1H), 7.59 (t, J=7.2 Hz, 1H), 7.68 (d, J=8.0 Hz, 1H), 8.20
(d, J=8.0 Hz, 1H); 13C NMR (DMSO-d6): d=28.1, 31.6,
41.5, 112.3, 123.9, 128.1, 129.4, 130.5, 131.1, 132.0, 132.1,
134.2, 136.7, 149.6; IR: n=3063, 2960, 2875, 2558, 1571,
1523, 1475, 1375, 1360, 1261, 1236, 1206, 1093, 1014, 864,
827, 783, 763, 725, 676 cmÀ1; HR-MS (ESI): m/z=418.0869,
calcd. for C21H2135ClNO4S [M+H]+: 418.0880.
2-{(4-Chlorophenyl)[(4-chlorophenyl)thio]methyl}-3-hy-
droxycyclohex-2-enone (9w): Yellow solid; mp 152–1548C;
1H NMR (DMSO-d6): d=1.94 (t, J=5.6 Hz, 2H), 2.50 (br,
4H), 5.81 (s, 1H), 7.34 (d, J=8.0 Hz, 2H), 7.41–7.44 (m,
4H), 7.60 (d, J=8.0 Hz, 2H); 13C NMR (DMSO-d6): d=
20.7, 45.4, 115.9, 128.2, 129.3, 129.6, 129.9, 130.4, 130.8,
131.2, 138.0, 141.3; IR: n=3485, 3053, 2949, 2925, 2885,
2582, 1877, 1572, 1480, 1369, 1286, 1195, 1094, 987, 806,
2-[(4-Chlorophenyl)(1-methyl-1H-pyrrol-2-yl)methyl]-3-
hydroxy-5,5-dimethylcyclohex-2-enone
(12b):
Colorless
1
liquid; H NMR (CDCl3): d=1.09–1.10 (m, 6H), 2.25–2.38
(m, 4H), 3.50 (s, 3H), 5.54–5.55 (m, 1H), 5.58 (s, 1H), 6.04
(t, J=3.2 Hz, 1H), 6.71 (t, J=2.0 Hz, 1H), 7.22 (d, J=
8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H); 13C NMR (CDCl3):
d=28.2, 31.7, 33.7, 37.2, 43.2, 50.3, 107.7, 108.0, 113.5, 124.3,
128.7, 129.7, 132.6, 133.6, 128.9; IR: n=3251, 2958, 2888,
498 cmÀ1
;
HR-MS (ESI): m/z=379.0319, calcd. for
C19H1735Cl2O2S [M+H]+: 379.0326.
2-{(4-Chlorophenyl)[(4-chlorophenyl)thio]methyl}-3-hy-
droxy-5-isopropylcyclohex-2-enone (9x): Colorless liquid;
1H NMR (DMSO-d6): d=0.87 (d, J=6.8 Hz, 6H), 1.44–1.49
(m, 1H), 1.72–1.75 (m, 1H), 2.13–2.18 (m, 2H), 2.43–2.51
(m, 2H), 5.91 (s, 1H), 7.20–7.26 (m, 6H), 7.40 (d, J=8.4 Hz,
2H), 10.08 (br, 1H); 13C NMR (DMSO-d6): d=19.4, 31.6,
39.0, 45.9, 113.6, 128.6, 129.1, 129.3, 131.6, 133.1, 133.2,
133.5, 137.8; IR: n=3079, 3022, 2959, 2872, 2570, 1895, 1562,
1475, 1383, 1336, 1252, 1212, 1150, 1093, 1013, 822, 603,
2680, 1604, 1488, 1373, 1257, 1147, 1089, 1015, 910, 731 cmÀ1
;
HR-MS (ESI): m/z=366.1233, calcd. for C20H2235ClNNaO2
[M+Na]+: 366.1237.
9-(4-Chlorophenyl)-3,3-dimethyl-3,4,5,6,7,9-hexahydro-
1H-xanthene-1,8(2H)-dione
(12c):
Colorless
liquid;
1H NMR (CDCl3): d=0.90 (s, 3H), 1.01 (s, 3H), 1.86–1.96
(m, 4H), 2.07 (d, J=16.4 Hz, 1H), 2.15 (d, J=16.4 Hz, 1H),
2.23–2.29 (m, 2H), 2.45–2.59 (m, 2H), 4.64 (s, 1H), 7.08 (d,
J=8.4 Hz, 2H), 7.16 (d, J=8.4 Hz, 2H); 13C NMR (CDCl3):
d=20.1, 27.0, 27.2, 29.0, 31.3, 32.1, 36.7, 40.6, 72.2, 115.0,
116.2, 128.0, 129.7, 131.8, 142.8, 162.6, 164.3, 196.6, 196.7;
IR: n=3382, 3305, 2958, 2873, 1659, 1484, 1362, 1203, 1177,
1133, 1048, 1013, 980, 836, 613, 560, 510 cmÀ1; HR-MS
(ESI): m/z=379.1073, calcd. for C21H2135ClNaO3 [M+Na]+:
379.1077.
531 cmÀ1
;
HR-MS (ESI): m/z=421.0791, calcd. for
C22H2335Cl2O2S [M+H]+: 421.0796.
2-[(2-Chlorophenyl)(phenylsulfonyl)methyl]-3-hydroxy-
5,5-dimethylcyclohex-2-enone (10a): White solid; mp 176–
1
1788C; H NMR (DMSO-d6): d=0.91 (s, 6H), 2.15–2.27 (m,
4H), 6.32 (s, 1H), 7.25–7.35 (m, 3H), 7.54 (t, J=7.6 Hz,
2H), 7.64–7.69 (m/, 3H), 8.47 (dd, Ja =1.2 Hz, Jb =8.0 Hz,
1H); 13C NMR (DMSO)-d6): d=28.0, 31.7, 61.9, 106.5,
126.5, 128.7, 129.3, 129.7, 132.2, 133.9, 134.0, 140.3; IR: n=
3082, 3021, 2965, 2862, 2556, 1685, 1560, 1455, 1323, 1258,
1150, 1093, 1013, 752, 508 cmÀ1; HR-MS (ESI): m/z=
405.0919. calcd. for C21H2235ClO4S [M+H]+: 405.0927.
4-(4-Chlorophenyl)-2-(4-ethoxyphenyl)-7,7-dimethyl-
3,4,7,8-tetrahydro-2H-chromen-5(6H)-one (13a): cis-Isomer:
1
colorless liquid; H NMR (CDCl3): d=1.12 (s, 3H), 1.18 (s,
3H), 1.43 (t, J=6.8 Hz, 3H), 1.96–2.05 (m, 1H), 2.19 (d, J=
16.4 Hz, 1H), 2.50 (d, J=16.4 Hz, 1H), 2.39–2.44 (m, 1H),
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Minghao Li et al.
2.42 (d, J=17.6 Hz, 1H), 2.48 (d, J=17.6 Hz, 1H), 3.90 (tt,
Ja =2.0 Hz, Jb =8.8 Hz, 1H), 4.05 (t, J=2.8 Hz, 2H), 4.95
(dd, Ja =1.6 Hz, Jb =11.6 Hz, 1H), 6.90 (d, J=7.6 Hz, 2H),
7.12 (d, J=8.4 Hz, 2H), 7.23 (d, J=7.6 Hz, 2H), 7.29 (d, J=
8.4 Hz, 2H); 13C NMR (CDCl3): d=14.8, 27.2, 29.8, 31.4,
37.6, 41.2, 42.7, 50.7, 63.5, 78.8, 113.7, 114.5, 127.5, 128.0,
128.5, 131.1, 131.3, 143.8, 159.1, 171.7, 196.5; IR: n=3039,
2956, 2890, 1625, 1511, 1387, 1286, 1231, 1160, 1068, 1043,
919, 832, 722, 640, 531 cmÀ1; HR-MS (ESI): m/z=433.1542,
calcd. for C25H2735ClNaO3 [M+Na]+: 433.1546.
143.6, 143.7, 169.8, 196.2; IR: n=3060, 3029, 2958, 2929,
2886, 1655, 1619, 1491, 1447, 1373, 1230, 1126, 1087, 1070,
912, 825, 733, 700, 650, 523 cmÀ1; HR-MS (ESI): m/z=
403.1433, calcd. for C24H2535ClNaO2 [M+Na]+: 403.1441.
2-[4-(tert-Butyl)phenyl]-4-(4-chlorophenyl)-7,7-dimethyl-
3,4,7,8-tetrahydro-2H-chromen-5(6H)-one (13d): cis-Isomer:
1
colorless liquid; H NMR (CDCl3): d=1.13 (s, 3H), 1.19 (s,
3H), 1.34 (s, 9H), 1.99–2.08 (m, 1H), 2.20 (d, J=16.4 Hz,
1H), 2.26 (d, J=16.4 Hz, 1H), 2.24–2.53 (m, 3H), 3.92 (t,
J=8.8 Hz, 1H), 5.01 (dd, Ja =1.2 Hz, Jb =11.6 Hz, 1H), 7.11
(d, J=8.4 Hz, 2H), 7.21 (d, J=8.4 Hz, 2H), 7.30 (d, J=
8.4 Hz, 2H), 7.40 (d, J=8.4 Hz, 2H); 13C NMR (CDCl3):
d=27.3, 29.7, 31.3, 31.4, 34.5, 37.3, 41.0, 42.7, 50.8, 78.8,
113.7, 125.5, 125.8, 128.1, 128.4, 131.3, 136.2, 143.7, 151.4,
171.6, 196.4; IR: n=3030, 2959, 2870, 1656, 1617, 1488, 1383,
1331, 1287, 1230, 1158, 1082, 1056, 1013, 911, 826, 732,
1
trans-Isomer: colorless liquid; H NMR (CDCl3): d=1.11
(s, 3H), 1.17 (s, 3H), 1.39 (t, J=6.8 Hz, 3H), 2.03 (dt, Ja =
2.0 Hz, Jb =13.6 Hz, 1H), 2.15–2.23 (m, 1H), 2.26 (d, J=
16.0 Hz, 1H), 2.34 (d, J=16.0 Hz, 1H), 2.43 (d, J=17.2 Hz,
1H), 2.50 (d, J=17.2 Hz, 1H), 4.00 (q, J=7.2 Hz, 2H), 4.08
(t, J=2.8 Hz, 1H), 4.77 (dd, Ja =2.4 Hz, Jb =12.0 Hz, 1H),
6.85 (d, J=8.8 Hz, 2H), 7.12 (d, J=8.4 Hz, 2H), 7.16 (d, J=
8.8 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H); 13C NMR (CDCl3):
d=14.7, 28.0, 29.1, 32.2, 33.6, 37.3, 42.6, 50.8, 63.5, 74.6,
110.8, 114.5, 127.6, 128.5, 129.1, 131.3, 132.0, 143.4, 159.0,
171.1, 196.8; IR: n=3041, 2958, 2890, 1620, 1513, 1389, 1288,
1233, 1162, 1068, 1043, 919, 830, 732, 643, 533 cmÀ1; HR-MS
(ESI): m/z=433.1537, calcd. for C25H2735ClNaO3 [M+Na]+:
433.1546.
4-(4-Chlorophenyl)-7,7-dimethyl-2,2-diphenyl-3,4,7,8-tet-
rahydro-2H-chromen-5(6H)-one (13b): Colorless liquid;
1H NMR (CDCl3): d=1.12 (s, 3H), 1.24 (s, 3H), 2.20 (d, J=
16.4 Hz, 1H), 2.24 (d, J=16.4 Hz, 1H), 2.43 (dd, Ja =6.4 Hz,
Jb =14.4 Hz, 1H), 2.60 (dd, Ja =2.0 Hz, Jb =17.2 Hz, 1H),
2.74 (d, J=17.2 Hz, 1H), 3.10 (dd, Ja =6.4 Hz, Jb =14.4 Hz,
1H), 3.63–3.67 (m, 1H), 7.08 (d, J=8.4 Hz, 2H), 7.21–7.30
(m, 5H), 7.33–7.35 (m, 3H), 7.39–7.43 (m, 2H), 7.47 (d, J=
8.4 Hz, 2H); 13C NMR (CDCl3): d=28.1, 29.0, 32.0, 34.9,
43.0, 43.1, 50.9, 84.0, 113.6, 125.4, 125.6, 127.6, 127.8, 128.3,
128.4, 128.8, 131.4, 142.4, 143.3, 143.9, 169.8, 196.3; IR: n=
3086, 3060, 3029, 2959, 2871, 1654, 1623, 1491, 1448, 1409,
1372, 1225, 1161, 1072, 1015, 909, 733, 699, 524 cmÀ1; HR-
MS (ESI): m/z=465.1592, calcd. for C29H2735ClNaO2 [M+
Na]+: 465.1597.
521 cmÀ1
;
HR-MS (ESI): m/z=445.1901, calcd. for
C27H3135ClNaO2 [M+Na]+: 445.1910.
1
trans-Isomer: colorless liquid; H NMR (CDCl3): d=1.15
(s, 3H), 1.20 (s, 3H), 1.33 (s, 9H), 2.10 (dt, Ja =2.0 Hz, Jb =
13.6 Hz, 1H), 2.19–2.28 (m, 1H), 2.31 (d, J=16.0 Hz, 1H),
2.38 (d, J=16.0 Hz, 1H), 2.48 (d, J=17.2 Hz, 1H), 2.54 (d,
J=17.2 Hz, 1H), 4.12–4.13 (m, 1H), 4.83 (dd, Ja =2.0 Hz,
Jb =12.0 Hz, 1H), 7.16 (d, J=8.4 Hz, 2H), 7.21 (d, J=
8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.39 (d, J=8.4 Hz,
2H); 13C NMR (CDCl3): d=28.0, 29.1, 31.3, 32.2, 33.5, 34.6,
37.3, 42.6, 50.8, 74.7, 110.9, 125.5, 126.0, 128.6, 129.1, 132.0,
136.4, 143.3, 151.5, 171.0, 196.8; IR: n=3030, 2959, 2870,
1653, 1622, 1487, 1387, 1288, 1231, 1210, 1163, 1069, 1015,
911, 829, 732, 621 cmÀ1; HR-MS (ESI): m/z=445.1904,
calcd. for C27H3135ClNaO2 [M+Na]+: 445.1910.
cis-2,4-Bis(4-chlorophenyl)-2,7,7-trimethyl-3,4,7,8-tetrahy-
dro-2H-chromen-5(6H)-one
(13e):
Colorless
liquid,
1H NMR (CDCl3): d=1.14 (s, 3H), 1.21 (s, 3H), 1.57 (s,
3H), 2.21–2.37 (m, 4H), 2.48 (dd, Ja =2.0 Hz, Jb =17.2 Hz,
1H), 2.60 (d, J=17.2 Hz, 1H), 3.85 (t, J=6.8 Hz, 1H), 6.80
(d, J=8.4 Hz, 2H), 7.05 (d, J=8.4 Hz, 2H), 7.09 (d, J=
8.4 Hz, 2H), 7.15 (d, J=8.4 Hz, 2H); 13C NMR (CDCl3):
d=27.4, 28.2, 28.8, 31.9, 33.7, 43.0, 43.1, 50.8, 80.0, 111.8,
125.7, 128.0, 128.2, 128.3, 131.1, 133.0, 142.4, 142.7, 169.4,
196.5; IR: n=3043, 2959, 2930, 2874, 1654, 1621, 1491, 1376,
4-(4-Chlorophenyl)-2,7,7-trimethyl-2-phenyl-3,4,7,8-tetra-
hydro-2H-chromen-5(6H)-one (13c): cis-Isomer: colorless
1
liquid; H NMR (CDCl3): d=1.16 (s, 3H), 1.23 (s, 3H), 1.61
1287, 1232, 1166, 1121, 1088, 1012, 911, 825, 733, 523 cmÀ1
;
(s, 3H), 2.24 (dd, Ja =8.0 Hz, Jb =14.0 Hz, 1H), 2.21 (d, J=
16.8 Hz, 1H), 2.31 (d, J=16.8 Hz, 1H), 2,38 (dd, Ja =2.8 Hz,
Jb =14.4 Hz, 1H)2.51 (dd, Ja =2.0 Hz, Jb =17.2 Hz, 1H), 2.63
(d, J=17.2 Hz, 1H), 3.87 (t, J=7.2 Hz, 1H), 6.84 (d, J=
8.4 Hz, 2H), 7.04 (d, J=8.4 Hz, 2H), 7.20 (s, 5H); 13C NMR
(CDCl3): d=27.3, 28.2, 28.9, 31.9, 33.9, 43.1, 43.3, 50.9, 80.4,
111.8, 124.2, 127.1, 128.0, 128.1, 128.3, 130.9, 142.7, 144.2,
169.8, 196.5; IR: n=3086, 3029, 2958, 2930, 2874, 1653, 1619,
1491, 1375, 1287, 1233, 1167, 1089, 1013, 912, 828, 762, 732,
699, 661, 522 cmÀ1; HR-MS (ESI): m/z=403.1438, calcd. for
C24H2535ClNaO2 [M+Na]+: 403.1441.
HR-MS (ESI): m/z=437.1045, calcd. for C24H2435Cl2NaO2
[M+Na]+: 437.1051.
4-(4-Chlorophenyl)-2-(4-methoxyphenyl)-7,7-dimethyl-
3,4,7,8-tetrahydro-2H-chromen-5(6H)-one (13f): cis-Isomer:
1
colorless liquid; H NMR (CDCl3): d=1.12 (s, 3H), 1.18 (s,
3H), 1.96–2.02 (m, 1H), 2.18 (d, J=16.0 Hz, 1H), 2.24 (d,
J=16.0 Hz, 1H), 2.39–2.50 (m, 3H), 3.80 (s, 3H), 3.81–3.93
(m, 1H), 4.95 (dd, Ja =1.6 Hz, Jb =11.6 Hz, 1H), 6.91 (d, J=
8.4 Hz, 2H), 7.11 (d, J=8.4 Hz, 2H), 7.23 (d, J=8.4 Hz,
2H), 7.30 (d, J=8.4 Hz, 2H); 13C NMR (CDCl3): d=27.2,
29.7, 31.4, 37.6, 41.2, 42.7, 50.5, 55.3, 78.8, 113.7, 114.0, 127.5,
128.0, 128.5, 131.3, 131.4, 143.8, 159.7, 171.7, 196.5; IR: n=
2999, 2957, 2887, 1655, 1613, 1514, 1463, 1381, 1250, 1157,
1083, 1055, 911, 828, 731, 628, 521 cmÀ1; HR-MS (ESI):
m/z=419.1386, calcd. for C24H2535ClNaO3 [M+Na]+:
419.1390.
1
trans-Isomer: colorless liquid, H NMR (CDCl3): d=1.09
(s, 3H), 1.19 (s, 3H), 1.57 (s, 3H), 2.00 (dd, Ja =11.6 Hz, Jb =
14.4 Hz, 1H), 2.09 (d, J=16.8 Hz, 1H), 2.17 (d, J=16.8 Hz,
1H), 2.50 (dd, Ja =2.4 Hz, Jb =17.6 Hz, 1H), 2.60 (d, J=
17.6 Hz, 1H), 2.71 (dd, Ja =6.4 Hz, Jb =14.4 Hz, 1H),
3.31(dd, Ja=6.4 Hz, Jb =11.6 Hz, 1H), 7.07 (d, J=8.4 Hz,
2H), 7.23 (d, J=8.4 Hz, 2H), 7.28–7.31 (m, 3H), 7.36–7.39
(m, 2H); 13C NMR (CDCl3): d=27.9, 29.0, 31.2, 31.8, 34.7,
43.0, 43.6, 81.2, 113.4, 124.1, 127.4, 128.2, 128.4, 128.7, 131.3,
1
trans-Isomer: colorless liquid, H NMR (CDCl3): d=1.14
(s, 3H), 1.20 (s, 3H), 2.06 (dt, Ja =2.0 Hz, Jb =14.0 Hz, 1H),
2.20–2.26 (m, 1H), 2.29 (d, J=16.0 Hz, 1H), 2.37 (d, J=
16.0 Hz, 1H), 2.46 (d, J=17.2 Hz, 1H), 2.53 (d, J=17.2 Hz,
554
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Three-Component Reactions of Aromatic Aldehydes and Two Different Nucleophiles
1H), 3.80 (s, 3H), 4.11–4.12 (m, 1H), 4.81 (dd, Ja =2.0 Hz,
Jb =12.0 Hz, 1H), 6.89 (d, J=8.4 Hz, 2H), 7.15 (d, J=
8.4 Hz, 2H), 7.20 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.4 Hz,
2H); 13C NMR (CDCl3): d=28.0, 29.1, 32.2, 33.6, 37.3, 42.6,
50.8, 55.3, 74.5, 110.8, 113.9, 127.6, 128.6, 129.1, 131.5, 132.0,
143.3, 159.6, 171.1, 196.9; IR: n=3039, 3000, 2957, 2929,
2837, 1651, 1619, 1514, 1388, 1289, 1232, 1164, 1068, 1035,
912, 885, 830, 732, 635, 535 cmÀ1; HR-MS (ESI): m/z=
419.1381, calcd. for C24H2535ClNaO3 [M+Na]+: 419.1390.
cis-4-(4-Chlorophenyl)-2-(4-fluorophenyl)-2,7,7-trimethyl-
3,4,7,8-tetrahydro-2H-chromen-5(6H)-one (13g): Colorless
Talents in the University of China (NCET-10-0383), Chutian
Scholar Program of the Hubei provincial government and
the Cooperative Innovation Center of Catalysts Materials of
Hubei Province are also acknowledged.
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1
liquid; H NMR (CDCl3): d=1.14 (s, 3H), 1.21 (s, 3H), 1.58
(s, 3H), 2.18–2.24 (m, 1H), 2.24 (d, J=16.4 Hz, 1H), 2.29
(d, J=16.4 Hz, 1H), 2.33–2.38 (m, 1H), 2.48 (dd, Ja =2.0 Hz,
Jb =17.2 Hz, 1H), 2.60 (d, J=17.2 Hz, 1H), 3.85 (t, J=
7.2 Hz, 1H), 6.82 (d, J=8.4 Hz, 2H), 6.87 (t, J=8.8 Hz,
2H), 7.05 (d, J=8.4 Hz, 2H), 7.14 (dd, Ja =5.3 Hz, Jb =
8.8 Hz, 2H); 13C NMR (CDCl3): d=27.3, 28.2, 28.8, 31.9,
33.9, 43.0, 43.4, 50.8, 80.0, 111.8, 114.9 (d, JC,F
21.3 Hz),126.0 (d, JC,F =8.0 Hz), 128.0, 128.3, 131.0, 140.1 (d,
C,F =3.2 Hz), 142.6, 161.8 (d, JC,F =244.6 Hz), 169.5, 196.5;
=
J
IR: n=3047, 2958, 2930, 2874, 1654, 1619, 1508, 1376, 1287,
1230, 1162, 1087, 1013, 911, 833, 731, 631, 526 cmÀ1; HR-MS
(ESI): m/z=421.1342, calcd. for C24H2435ClFNaO2 [M+
Na]+: 421.1347.
cis-4-(4-Chlorophenyl)-7,7-dimethyl-2-phenyl-3,4,7,8-tetra-
hydro-2H-chromen-5(6H)-one (13h): Colorless liquid;
1H NMR (CDCl3): d=1.11 (s, 3H), 1.17 (s, 3H), 1.87–2.02
(m, 1H), 2.17 (d, J=16.4 Hz, 1H), 2.15 (d, J=16.4 Hz, 1H),
2.39–2.51 (m, 3H), 3.90 (t, J=8.8 Hz, 1H), 5.00 (dd, Ja =
1.6 Hz, Jb =11.6 Hz, 1H), 7.09 (d, J=8.4 Hz, 2H), 7.20 (d,
J=8.4 Hz, 2H), 7.31–7.37 (m, 5H); 13C NMR (CDCl3): d=
27.2, 29.7, 31.4, 37.5, 41.4, 42.6, 50.7, 79.0, 113.8, 126.0, 128.0,
128.3, 128.4, 128.6, 131.3, 139.2, 143.6, 171.1, 196.6; IR: n=
3033, 2956, 2927, 2874, 1654, 1616, 1489, 1385, 1287, 1230,
1157, 1124, 1083, 1056, 826, 759, 700, 654 cmÀ1; HR-MS
(ESI): m/z=389.1281, calcd. for C23H2335ClNaO2 [M+Na]+:
389.1284.
cis-4-(4-Chlorophenyl)-7,7-dimethyl-2-(para-tolyl)-3,4,7,8-
tetrahydro-2H-chromen-5(6H)-one (13i): Colorless liquid;
1H NMR (CDCl3): d=1.13 (s, 3H), 1.19 (s, 3H), 1.96–2.05
(m, 1H), 2.19 (d, J=16.8 Hz, 1H), 2.25 (d, J=16.8 Hz, 1H),
2.37 (s, 3H), 2.38–2.52 (m, 3H), 3.92 (t, J=8.8 Hz, 1H), 4.97
(dd, Ja =1.2 Hz, Jb =11.6 Hz, 1H), 7.12 (d, J=8.0 Hz, 2H),
7.20 (d, 8.0 Hz, 2H), 7.23 (d, 8.0 Hz, 2H), 7.28 (d, J=
8.0 Hz, 2H); 13C NMR (CDCl3): d=21.1, 27.3, 29.7, 31.4,
37.6, 41.3, 42.7, 50.7, 79.0, 113.8, 126.0, 128.1, 128.5, 129.3,
131.4, 136.2, 138.3, 143.8, 171.7, 196.5; IR: n=3026, 2957,
2925, 2884, 1654, 1618, 1489, 1384, 1330, 1287, 1230, 1157,
1083, 1057, 1013, 912, 817, 732, 629, 518 cmÀ1; HR-MS
(ESI): m/z=403.1435, calcd. for C24H2535ClNaO2 [M+Na]+:
403.1441.
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China for the financial support (21173089 and 21373093).
The authors are also grateful for all the staff members in the
Analytical and Testing Center of HUST, for their contribu-
tions to our works. The Program for new Century Excellent
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