Multicomponent reactions of 1,3-cyclohexanediones and formaldehyde in glycerol: Stabilization of paraformaldehyde in glycerol resulted from using dimedone as substrate

Article abstract of DOI:10.1002/adsc.200900770

Glycerol has proved to be an effective promoting medium for many multicomponent reactions of 1,3-cyclohexanediones and formaldehyde. Styrenes, amines, 2-naphthol, 4-hydroxy-6-methyl-2-pyrone and 4-hydroxy-1-methyl-2- quinolone could easily react with 1,3-cyclohexanediones and paraformaldehyde in glycerol under catalyst-free conditions to afford a variety of complex skeletons in fair to excellent yields. In these reactions, glycerol not only showed a significant promoting effect on the reaction yields but also endowed the reaction system with many typical properties of green chemistry, such as cheap, renewable, recyclable and biodegradable solvent, good safety and easy separation of product. The promoting effect of glycerol for the three-component reaction of styrene, dimedone and paraformaldehyde could be attributed to a restricted formation of the methylene intermediate in glycerol. During the reaction, a physical shell, which is mainly composed of a by-product generated in the beginning of the reaction, might be formed in the surface of paraformaldehyde and plays a key role in controlling the formation of the intermediate by means of restricting the decomposition of paraformaldehyde.

Full text of DOI:10.1002/adsc.200900770

FULL PAPERS
DOI: 10.1002/adsc.200900770
Multicomponent Reactions of 1,3-Cyclohexanediones and
Formaldehyde in Glycerol: Stabilization of Paraformaldehyde in
Glycerol Resulted from using Dimedone as Substrate
Minghao Li,a Chang Chen,a Fei He,a and Yanlong Gua,b,*
a
Institute of Physical Chemistry and Industrial Catalysis, School of Chemistry and Chemical Engineering, 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
Hubei Key Laboratory of Material Chemistry and Service Failure, Huazhong University of Science and Technology,
b
Wuhan 430074, Peopleꢀs Republic of China
Received: November 5, 2009; Published online: February 9, 2010
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.200900770.
Abstract: Glycerol has proved to be an effective pro- product. The promoting effect of glycerol for the
moting medium for many multicomponent reactions three-component reaction of styrene, dimedone and
of 1,3-cyclohexanediones and formaldehyde. Styr- paraformACTHNUGRTENUNGaldehyde could be attributed to a restricted
enes, amines, 2-naphthol, 4-hydroxy-6-methyl-2- formation of the methylene intermediate in glycerol.
pyrone and 4-hydroxy-1-methyl-2-quinolone could During the reaction, a physical shell, which is mainly
easily react with 1,3-cyclohexanediones and composed of a by-product generated in the begin-
paraformACHTUNGTRENNUNGaldehyde in glycerol under catalyst-free ning of the reaction, might be formed in the surface
conditions to afford a variety of complex skeletons of paraformaldehyde and plays a key role in control-
in fair to excellent yields. In these reactions, glycerol ling the formation of the intermediate by means of
not only showed a significant promoting effect on restricting the decomposition of paraformaldehyde.
the reaction yields but also endowed the reaction
system with many typical properties of green chemis- Keywords: 1,3-cyclohexandione derivatives; formal-
try, such as cheap, renewable, recyclable and biode- dehyde; glycerol; multicomponent reaction; tandem
gradable solvent, good safety and easy separation of Knoevenagel/hetero-Diels–Alder reaction
Introduction
as the starting material to prepare green and biomass-
based solvents, for example, new ionic liquids.[5a]
The biodiesel industry generates
amount of glycerol that has to be used in economical-
a
tremendous Some of glycerol-based solvents, for example, 1,3-di-
alkoxy-2-propanols and 1,2,3-trialkoxypropanes,[5b]
ACHTUNGTRENNUNG
ly feasible and environmentally benign processes. were proven, quite recently, to be applicable in oxida-
Today, most of the efforts in this area are focusing on tion reactions. More interestingly, pure glycerol has
value-added conversions of glycerol. Many successful also been proposed by Wolfson and his co-workers[6]
examples could be found in some comprehensive re- as a solvent for organic reactions. Taking the inherent
views.[1] The ever-increasing interest in the chemical properties of glycerol, such as long liquid range, poor
utilizations of glycerol has recently been summarized flammability and unique solubility for polar organic
as “glycerochemistry”.[2] Although a lot of methods to compounds, into consideration, the direct use of gly-
derivatize glycerol have been developed, today, only a
ACHTUNGTRENcNGNU erol as a solvent for organic reactions would perfect-
few processes have been commercialized. With the in- ly fit the requirements of green chemistry. It should
creasing demand for biodiesel, glycerochemistry has be noted that, as a solvent, data about the toxicity
to be extended urgently.[3]
and environmental compatibility have to be collected
Recently, the development of green solvents from before its utilizations on a large scale. In this respect,
renewable resources has gained much attention.[4] As a good understanding of the knowledge about glycer-
a by-product of biodiesel, glycerol has also been used ol, as well as the positive data, is helpful for the com-
Adv. Synth. Catal. 2010, 352, 519 – 530
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519

Minghao Li et al.
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mercialization of processes related to glycerol as sol- quinolone could assemble readily with 1,3-cyclohex-
vent. Inspired by these facts, during the past two
ACHTUNGTRENaNUNG nediones and formaldehyde to generate many com-
years, we and Jꢂrꢃme[7] have investigated many organ- plex cyclized or uncyclized products in fair to excel-
ic reactions using glycerol as a promising medium, lent yields. Particularly, in three-component reaction
such as the aza-Michael reaction, ring-opening of ep- of styrenes, 1,3-cyclohexanediones and formaldehyde,
oxides with amine and carboxylic acid, and electro- glycerol as solvent has proved to be a unique medium
philic activation of aldehydes. The results obtained in that can strategically stabilize paraformaldehyde.
these reactions verified that glycerol can indeed be
used as an effective solvent for the development of
new synthetic methodologies.
Results and Discussion
On the other hand, the ever-increasing demand for
novel medicinally active compounds and the laborious Initially, the three-component reaction between sty-
process of lead discovery and optimization have re- rene (1a), formaldehyde and dimedone, (2a) was in-
sulted in the continuous search for simple and effi- vestigated in different solvents. As shown in Table 1,
cient methods for the generation of libraries for bio- the combination of water and formalin, which has
logical screening. In this context, the development been proven to be the best system for the three-com-
and utilizations of multicomponent reactions (MCRs) ponent reaction between 1,3-dicarbonyl compounds,
are of prime importance.[8] In an MCR, a product is styrenes and formaldehyde,[11(a)] was found to be inef-
assembled according to a cascade of elementary fective for this reaction, and only a 14% yield was ob-
chemical reactions. The challenge is to conduct an tained after 12 h of stirring at 958C (entry 1). It
MCR in a suitable way that allows the pre-equilibrat- should be noted that a by-product, 2,2’-methylene-
ed elementary reactions to channel into the main bis[3-hydroxy-5,5-dimethyl-2-cyclohexen-1-one,
(II,
product and not to yield side products.[9] For this pur- Scheme 1), which was generated from reaction be-
pose, many efforts were devoted to optimization of tween 2a and formaldehyde, was formed under these
reaction conditions, and, among all the paramaters conditions (65% yield with respect to 2a). This im-
that might affect the selectivity of MCRs, the solvent plies that the methylene intermediate of 2a is so
is particularly important.
active under these conditions that it is difficult to be
1,3-Dicarbonyl derivatives have been widely used trapped by 1a. In order to solve this problem, two fac-
in MCRs.[10] Recently, we and Jꢂrꢃme have reported a tors were considered: (i) the source of formaldehyde,
three-component reaction of 1,3-dicarbonyl com-
pounds, formaldehyde and styrenes that generates
Table 1. Three-component reaction bewteen 1a, 2a and
HCHO.[a]
substituted dihydropyran derivatives in fair to excel-
lent yields using water as solvent.[11] Formation of a
methylene intermediate is the key to the success of
the MCR because it can act as an oxo-diene to react
with styrenes through hetero-Diels–Alder cycloaddi-
tion. Therefore, it is, in fact, a domino Knoevenagel/
hetero-Diels–Alder reaction, which has been well
documented by Tietze and others using different sub-
strates.[12] During our investigation, we found that
some active substrates, such as 1,3-cyclohexanediones,
cannot be used in these MCRs under aqueous condi-
tions owing to a lack of selectivity. In view of the fact
that derivatives of 1,3-cyclohexanediones are often
used in the total synthesis of natural products, such as
steroid hormones,[13] triterpenoid compounds,[14]
guaianolides[15] and other chemicals,[16] a three-compo-
nent reaction of 1,3-cyclohexanediones, formaldehyde
and alkenes would be, if realized, capable of signifi-
cantly maximizing the synthetic efficiency. In order to
realize this MCR, we thought that the solvent might
play a crucial role in controlling the selectivity. In this
paper, we report that glycerol can be used as a pro-
moting medium for developing MCRs of 1,3-cyclo-
hexanediones and formaldehyde. In glycerol, many
substrates, such as styrenes, amines, 2-naphthol, 4-hy-
droxy-6-methyl-2-pyrone and 4-hydroxy-1-methyl-2-
Entry
Solvent
Yield [%]
1[b]
2
3
4
5
H2O
14
33
<10
15
63
68
36
52
44
65
CH3NO2
toluene
no solvent
acetic acid
glycerol
glycerol
glycerol
glycerol
glycerol
6
7[c]
8[d]
9[e]
10[f]
[a]
1a: 0.5 mmol, 2 : 1.0 mmol, paraformaldehyde: 1.0 mmol.
Formaldehyde in aqueous slution was used, 958C.
1a/2a/HCHO=1/1/1, 1a: 0.5 mmol.
8 h.
[b]
[c]
[d]
[e]
[f]
908C.
Reused in the third run.
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Multicomponent Reactions of 1,3-Cyclohexanediones and Formaldehyde in Glycerol
Scheme 1. Plausible reaction pathway of three-component reaction of 2a, formaldehyde and 1a.
formalin (formaldehyde aqueous solution) is generally Alder reaction (see Scheme 1). It should be noted
much more reactive than paraformaldehyde in the re- that the previous method to access the skeleton 3a is
action between 1,3-dicarbonyl compounds and form- rather complicated (see Supporting Information,
aldehyde; (ii) the reaction solvent, both stability of Scheme S1).[17] Because it takes many synthetic steps
the reaction intermediate and reactivity of the follow- (in which rather low yields were, sometimes, reported
ing hetero-Diels–Alder reaction can be affected sig- in each individual step), the total yields are naturally
nificantly by the reaction solvent. In order to restrict poor. Our method, thus, offers an efficient and
the reaction between 2a and formaldehyde, parafor- straightforward way to prepare the skeleton of 3a.
maldehyde was used in the later experiments instead
The significant effect of glycerol on these MCRs
of formalin. It is well known that this kind of poly- led us to think about the exact reasons behind the
meric solid can release formaldehyde by simple heat- promising results. An interesting phenomenon might
ing. Thus, the reaction was then performed at 1108C be partially responsible for the obtained results.
in different solvents without use of any catalyst. As During the reaction, a large amount of white solid
shown in Table 1, only small amounts of product were was formed in glycerol, whereras nitromethane and
obtained in toluene, nitromethane and under solvent- toluene allowed the reaction to proceed in a homoge-
free conditions (entries 2 to 4). Acetic acid was then neous solution (Figure 1). Further investigation by
1
proved to be an effective solvent, and the desired means of H NMR revealed that the white solid is
product was obtained in 63% yield (entry 5). How- mainly composed of paraformaldehyde. Encouraged
ACHTUNGTRENNUNGever, in this case, a large amount of inorganic base by this fact, we first investigated the solubility and
has to be used in order to neutralize acetic acid and stability of paraformaldehye in three different sol-
to facilitate isolation of the product. To our delight, vents, glycerol, nitromethane and toluene. In order to
glycerol was found to be a suitable solvent for this re- explain our results, we expect, here, that paraformal-
action, and a 68% yield was obtained (entry 6). The dehyde can stay more steadily in glycerol than in tolu-
ratio of 1a/2a/HCHO was also crucial to achieve a ene and nitromethane. The experiments were done by
good yield as a low yield, 36%, was obtained with the mixing paraformaldehyde (60 mg) with the three sol-
ratio of 1/1/1 (entry 7). Further investigation revealed vents (1.2 mL) at 1108C. Disappointedly, the solid de-
that the reaction was also affected by temperature gradated quickly in glycerol, and a homogeneous so-
and reaction time, and the optimal conditions were lution was formed after 15 min of stirring. In nitrome-
1108C and 11 h (entries 8 and 9). It should be noted thane, a slightly longer time, 30 min, is necessary to
that because glycerol is insoluble in non-polar organic eliminate the solid paraformaldehyde. However,
solvents, the product could be easily extracted by under the identical conditions, a large amount of solid
ethyl acetate, and the recovered glycerol phase could is still remaining in toluene (see Figure 2). To com-
be reused in the next run after a simple treatment pletely eliminate the solid in toluene, 5 h of stirring at
under vacuum. The obtained results indicated that 1108C is necessary. There are two possibilities for the
glycerol kept its original activity for at least three solid to be soluble: (i) paraformaldehyde was dis-
runs, indicating the environmentally benign nature of solved into the solvent; (ii) it was decomposed to gen-
this system (entry 10).
erate formaldehyde that was soluble in the solvent.
As already proposed,[11] formation of methylene in- Because paraformaldehyde has a characteristic single
1
termediate (I) might be the first step of the reaction, peak in 4.77 ppm in its H NMR profile, probing the
thus the model three-component reaction might pro- solutions with H NMR should be able to answer the
1
ceed through a tandem Knoevenagel/hetero-Diels– question of whether or not the paraformaldehyde was
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Figure 1. Progress of the reaction between 1a, paraformaldehyde and 2a in glycerol without any catalyst: (a) the end of reac-
tion in nitromethane; (b) the end of reaction in toluene; (c) the beginning of reaction in glycerol; (d) the end of reaction in
glycerol.
Figure 3. Heating paraformaldehyde in glycerol in the pres-
Figure 2. Decomposition of paraformaldehyde at 1108C in
ence of dimedone or styrene (1108C, 30 min): (a) in the
different solvents: (a) after 15 min in glycerol; (b) after
presence of dimedone; (b) in the presence of styrene.
30 min in nitromethane; (c) after 30 min in toluene.
dissolved. It was found that no peak appeared around should be unable to stabilize paraformaldehyde at
4.77 ppm, indicating that no paraformaldehyde re- 1108C. In order to confirm our hypothesis, paraform-
mained in the solutions. These results ruled out the
ACHTUNGTRENaNGNU ldehyde was then heated in glycerol in the presence
possibility of dissolving paraformaldehyde by the sol- of dimedone or styrene. To our surprise, a large
vents. Therefore, we can conclude that (i) paraformal- amount of white solid was formed in a mixture of
1
dehyde was decomposed in the solvents; and (ii) glycerol and dimedone [Figure 3, (a)]. H NMR of the
while the decomposition proceeds sluggishly in non- slurry showed the existence of the characteristic peak
polar solvents, polar solvents, such as glycerol and ni- for paraformaldehyde,
a single sharp peak at
tromethane, can significantly enhance the decomposi- 4.77 ppm. In the case of styrene, no significant stabili-
tion rate. These results also, unfortunately ruled out zation effect was observed as paraformaldehyde dis-
the possibility of using glycerol as solvent to stabilize appeared very quickly [Figure 3, (b)].
paraformaldehyde.
These results clearly indicated that the presence of
In order to shed light on the reason behind the dimedone in glycerol solvent is responsible for the
high stability of paraformaldehyde in the glycerol- stabilization of paraformaldehyde. As we have report-
mediated model reaction, the effects of other compo- ed quite recently, the electrophilic activity of alde-
nents on the stability of paraformaldehyde have to be hydes can be improved by using glycerol as solvent,
considered. Before setting up new investigations, the and 1,3-cyclohexanedione derivatives can react with
solubilities of the other two substrates, 1a and 2a, aldehydes in glycerol to form xanthene-1,8(2H)-dio-
were investigated, and it was found that both dime- nes.[7c] In the model reaction, an analogous product,
done and styrene were able to form a transparent so- (II), was also isolated at the end of the reaction
lution with glycerol under the reaction conditions. In (yield=46% with respect to dimedone). This com-
view of the fact that paraformaldehyde is more stable pound is a solid and has a melting point of 1928C.
in non-polar solvents, it would be reasonable to Further investigation revealed that compound (II) is
expect that the solutions resulted from large amount insoluble in glycerol at the reaction temperature. On
of glycerol and small amounts of dimedone or styrene the basis of these observations, we suspect here that a
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Multicomponent Reactions of 1,3-Cyclohexanediones and Formaldehyde in Glycerol
Figure 4. Imagined procedure of the model reaction in glycerol.
small amount of by-product (II) was quickly formed glycerol solvent cannot dissolve compound (II), this
in the beginning of the reaction. Because compound fact not only allows compound (II) to precipitate out
(II) is a solid and insoluble in glycerol, it tended to once it was generated, but also facilitates interaction
deposit on the surface of a suitable solid support once between solid paraformaldehyde and (II); and (ii)
it was formed. Here, the remaining solid paraformal- glycerol might be a favourable solvent for the second
dehyde in the reaction mixture might act as the solid step of the MCR, the hetero-Diels–Alder cycloaddi-
support to take over the generated (II). The deposi- tion, this property significantly enhances the selectivi-
tion might result in a thin layer of (II) on the surface ty of the model MCR. The importance of the later
of paraformaldehyde spheres, which blocks the way point can be demonstrated by the fact that although
for glycerol to contact the paraformaldehyde toluene has been proven to be a preferable solvent
(Figure 4). Because (II) is less polar than glycerol, it for stabilizing paraformaldehyde, only a trace amount
would not be unreasonable to expect that contact of of the desired product was obtained owing to the ex-
(II) to paraformaldehyde cannot significantly enhance tensive formation of by-product (II). With these facts,
the decomposition of paraformaldehyde. Therefore, a we can conclude that while glycerol strategically
large amount of white solid was observed in the makes the first reaction of the model MCR, the
model reaction using glycerol as solvent. In order to Knoevenagel condensation between dimedone and
verify our hypothesis, a glycerol-mediated reaction formaldehyde, to be the rate-determing step, toluene
between dimedone and paraformaldehyde at 1108C as solvent only favours the first step, and causes the
was quenched by adding ethyl acetate after 30 min. second step, the hetero-Diels–Alder reaction, to be
And as we expected, (II) was isolated with 39% of the rate-determing step. Therefore, the same sub-
yield in this case. strates in different solvents could produce different
Because the decomposition of paraformaldehyde products under identical conditions.
was restricted by the organic shell formed in the glyc-
Having these results in hand, various styrene deriv-
erol, the amount of the free-form of formaldehyde in atives were then examined in this MCR and results
the solution is inadequate. So, it is reasonable to are summarized in Table 2 and Table 3. All the exam-
expect that generation of the intermediate (I), from a ined styrenes readily reacted with 2a and formalde-
reaction between dimedone and formaldehyde, is not hyde in glycerol, and the desired 7,8-dihydro-2-
sufficient. Therefore, both the hetero-Diels–Alder cy- phenyl-5(6H)-chromanones were obtained in fair to
cloaddition in the “ABC” three-component reaction good yields. It should be noted that styrenes with a
pathway and the Michael reaction in the “ABB” side methyl group in the a-position (Table 2, entries 5 and
reaction pathway were restricted in glycerol. This is 7), which were found to be active alkenes in our pre-
particularly important for controlling the selectivity of vious work,[11] afforded relatively lower yields as com-
the model reaction because the hetero-Diels–Alder pared with styrene. But, for these styrenes, the ratio
reaction is reversible and might need a much longer of alkene/2a/HCHO seems not important because
time to reach an equilibrium than the Michael reac- nearly the same results were obtained with the condi-
tion. Restricted formation of (I) allows the intermedi- tion of alkene/2a/HCHO=1/1/1 (Table 2, entries 6
ate to be exposed to a large amount of styrene that and 8; Table 3, entries 5 and 6). Other 1,3-cyclohex-
can trap it. Furthermore, owing to the formation of
ACHTUNGTRENaNGNU nedione derivatives, such as 1,3-cyclohexanedione
(II), a part of dimedone in the reaction system was and 5-methyl-1,3-cyclohexanedione can also be used
consumed. This decreases the concentration of dime- in this reaction, and the desired products were ob-
done, and consequently, decreases the possibility of tained in fair to good yields. Interestingly, different
generating the by-product. This hypothesis not only from the reactions of dimedone, when 1,3-cyclohexa-
offers an explanation for the results, but also clearly nedione was used, substituted styrenes with electron-
indicates the key role of using glycerol as reaction sol- donating groups afforded higher yields than styrene
vent for the model reaction, It can be seen that: (i) and 4-chlorostyrene. This inconsistency regarding the
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Table 2. Three-component reactions between 1a, HCHO
general reactivities of alkenes might be mainly attrib-
uted to the following two factors: (i) controllability of
forming the methylene intermediate. As already de-
scribed in the model reaction, the methylene inter-
mediate (I) was generated slowly once paraformalde-
hyde was covered by the shell. This allows a smooth
trapping of the intermediate with styrenes. This is par-
ticularly important for some less reactive substrates,
such as styrene and 4-chlorostyrene, because these
styrenes have to take a much longer time to interact
with the intermediate than some active styrenes.
However, in the reaction of 1,3-cyclohexanedione, al-
though the analogous by-product was also formed,
owing to the fact that it is soluble in glycerol, no solid
shell could be formed in the surface of paraformalde-
hyde. As a result, paraformaldehyde was decomposed
quickly. This might result in an extensive formation of
the methylene intermediate in the beginning of the
reaction. In this case, active styrenes have to be used
in order to trap the intermediate as soon as possible
because, otherwise, the “ABB” type of by-product
will be formed. This can explain why styrene and 4-
chlorostyrene gave lower yields than a-methylstyrene
in the reaction of 1,3-cyclohexanedione. (ii) The effect
of the inherent thermal equilibrium on the reaction:
it is well known that the Diels–Alder reaction is re-
versible, there is an equilibrium between substrate
and product. Owing to the fact that the unreacted
styrenes still remain unchanged in all the reactions,
the equilibrium between styrenes and the desired
products might play a key role in determining the re-
action yield. The high yields obtained with less reac-
tive styrenes in the reactions of dimedone might
result from an equilibrium in favour of the desired
product.
and different styrenes.[a]
Entry
Alkene
Time [h]
Product
Yield [%]
1
2
3
4
1b
1c
1d
1e
1f
1f
1g
1g
11.0
6.0
6.0
11.0
6.0
4.0
3b
3c
3d
3e
3f
3f
3g
3g
82
56
49
33
51
50
57
57
5
6[b]
7
8.5
8.5
8[b]
[a]
Alkene: 0.5 mmol, 2a: 1.0 mmol; paraformaldehyde:
1.0 mmol.
Ratio of alkene/2a/HCHO=1/1/1.
[b]
Table 3. Substrate scope for 1,3-cyclohexanediones in the
three-component reactions of styrenes.[a]
As for the reasons to the insensitivity of the reac-
tion between 1f, 2a and formaldehyde to the ratio of
1f/2a/HCHO, it could be attributed to the high reac-
tivity of 1f, which allows trapping of the intermediate
(I) to proceed rapidly, and consequently, avoids for-
mation of the by-product. However, the trapping of
(I) with 1f is also under the control of an equilibrium
in which the desired product might only be slightly
favoured. Therefore, only moderate yields were ob-
tained when 1f and 1g were used as substrates.
Entry 1,3-Cyclohexane- Alkene Time Product Yield
dione
[h]
[%]
These promising results gave us impetus to examine
the possibility of assembling other substrates with 1,3-
cyclohexanediones and formaldehyde in glycerol. To
our delight, an “ABBC”-type multicomponent reac-
tion of aniline, dimedone and formaldehyde was then
proved to be applicable in our conditions (Table 4).
The obtained product, here, is 2-{[4,4-dimethyl-6-
oxo-2-(phenylamino)-1-cyclohexen-1-yl]methyl}-3-hy-
1
2
3
4
2b
2b
2b
2b
2b
2b
2b
2c
2c
1a
1b
1c
1d
1f
1f
1g
1a
1g
8.0
8.0
6.0
6.0
6.0
6.0
6.0
11.0
8.5
3h
3i
3j
3k
3l
3l
3m
3n
3o
26
32
58
49
44
43
55
64
58
5
6[b]
7
8
9
droxy-5,5-dimethyl-2-cyclohexen-1-one
(5a).
Al-
[a]
though this compound has been known, no detailed
information about the synthesis could be found in the
Alkene: 0.5 mmol, 1,3-cyclohexanedione: 1.0 mmol,
paraformaldehyde: 1.0 mmol.
[b]
The ratio of alkene/1,3-cyclohexanedione/HCHO=1/1/1. literature as it was obtained as a by-product of the
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Multicomponent Reactions of 1,3-Cyclohexanediones and Formaldehyde in Glycerol
Table 4. Hantzsch reactions of formaldehyde, 1,3-cyclohex-
ACHTUNGTRENNUNG
anediones and amine in different solvents.[a]
the other 1,3-cyclohexanediones, such as 2b, were
then applied in this reaction, and as shown in Table 4,
good to excellent yields were obtained in glycerol.
Particularly, the glycerol system precludes the use of
acid catalyst, and thus allows the use of acid-labile
substrates. For example, 2-(1-cyclohexenyl)ethylamine
could be smoothly converted to the desired product
without damage to the double bond in glycerol in the
presence of dimedone and paraformaldehyde
(entry 15), indicating the usefulness of glycerol as sol-
vent. It should be noted that although all the products
generated in Table 4 might be easily converted to the
corresponding Hantzsch adducts when an acid cata-
lyst was used, exclusive synthesis of these products
without the last step of the Hantzsch condensation,
dehydration, is not easy, because intramolecular cycli-
zation is generally favourable during the reaction.
Thus, the results in Table 4 indicate, again, the re-
markable effect of glycerol in organic synthesis.
Given the large number of commercially available
styrenes and the easy access to amines and 1,3-cyclo-
hexanediones, the present MCRs should be applicable
to the synthesis of libraries with high diversity. We
expect that glycerol as solvent could lead us to find
extensive applications in the field of developing new
MCRs. With this purpose, we finally extended our
strategy to more complex substrates in order to deter-
mine the scope of our methodology. Remarkably, as
shown in Scheme 2, 2-naphthol (6a), 4-hydroxy-6-
methyl-2-pyrone (6b) and 4-hydroxy-1-methyl-2-qui-
nolone (6c) were found to be able to react with form-
aldehyde and 2a or 2b in glycerol, affording three
complex skeletons in moderate to good yields. Al-
though the three-component reaction of 6a, formalde-
hyde and 2b has been reported, because the reaction
was conducted in acetic acid, in order to isolate the
product, an inorganic base has to be used.[19] The gly-
Entry Amine 1,3-Cyclohexanedione Product Yield [%]
derivative
1
4a
4a
4a
4a
4a
4a
4a
4a
4b
4c
4d
4e
4f
4e
4g
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2a
5a
5a
5a
5a
5a
5a
5a
5a
5b
5c
5d
5e
5f
5g
5h
80
57
45
50
72
40
<5
50
94
85
86
97
55
42
49
2[b]
3[c]
4[d]
5[e]
6[f]
7[g]
8[h]
9[i]
10
11[j]
12[h]
13
14
15
[a]
Amine: 0.5 mmol, 1,3-cyclohexanediones: 1.0 mmol,
paraformaldehyde: 0.5 mmol.
[b]
[c]
[d]
[e]
[f]
No solvent.
1
Solvent: DMSO, yield was determined by H NMR.
Solvent: toluene.
Solvent: water.
AHCTUNGTREGcNNUN erol system, here again, avoids the aqueous work-up
Solvent: CH3NO2.
Solvent: DMF, yield was determined by H NMR.
[g]
[h]
[i]
1
procedure, and thus, is more attractive for the synthe-
sis of 7a from the viewpoint of green chemistry. The
other two products, 7b and 7c, contain novel skeletons
that have never been accessed before, indicating the
great usefulness of our method for organic synthesis.
Furthermore, because 7c contains two hydroxy
908C, 3 h.
1.5 h.
908C, 2 h.
[j]
aminomethylation of dimedone enamines.[18] Interest- groups, it should not be difficult to eliminate water to
ingly, among different organic solvents tested in the generate a cyclized product. Particularly, in the pres-
reaction, glycerol clearly stood out, producing the ence of amine, it might be possible to generate a new
product with the highest yield (ca. 80%, entry 1), with class of Hantzsch adducts by using 7c as substrate.
toluene in a distant second place (entry 4). A moder- Therefore, our reactions have a good potential to be
ate yield, 57%, was achieved under solvent-free con- applied in organic synthesis. These results indicated
ditions (entry 2). In another protic solvent, water, the clearly that our method has a powerful ability to es-
reaction also proceeds well, but the yield obtained in tablish many new MCRs, which offer an efficient and
this case is inferior to that of glycerol (entry 5). After straightforward route to some valuable skeletons. In
a
brief optimization of the reaction condition all the cases, these MCRs involve a methylenation
(entry 8), some other amines, such as p-toluidine (4b), step of electron-rich carbons with formaldehyde,
p-anisidine (4c), benzylamine (4d), cyclohexylamine which generates active intermediates that were then
(4e) and 2-(3,4-dimethoxyphenyl)ethylamine (4f), and trapped by the next nucleophiles.
Adv. Synth. Catal. 2010, 352, 519 – 530
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
525

Minghao Li et al.
FULL PAPERS
Scheme 2. Other three-component reactions of 1,3-cyclohexanediones and formaldehyde in glycerol.
Conclusions
and plays a key role in controlling the formation of
the intermediate by means of restricting the decom-
In conclusion, glycerol was proved to be an effective position of paraformaldehyde.
medium to promote some MCRs of 1,3-cyclohexane-
diones and formalaldehyde. In glycerol and in the ab-
sence of any catalyst, many substrates, such as styr- Experimental Section
enes, amines, 2-naphthol, 4-hydroxy-6-methyl-2-
All reactions were conducted in a 10-mL V-type flask
pyrone and 4-hydroxy-1-methyl-2-quinolone reacted
readily with 1,3-cyclohexanediones and paraformalde-
hyde to afford the corresponding three-component
adducts in fair to excellent yields. These MCRs open
a straightforward way to synthesize the target com-
pounds, and thus maximize the synthetic efficiency
significantly. After the reaction, products could be
easily separated by means of extraction with ethyl
acetate. The recovered glycerol could be reused with-
out a significant loss of activity. Furthermore, the in-
herent properties of glycerol, such as low toxicity,
good biocompatibility, renewability, poor flammability
and comprehensive data about the safety endowd the
reaction system with many characteristic features of
green chemistry. These results also place a new impe-
tus upon the topic of solvent innovation using glycer-
ol, because glycerol was, here, demonstrated, for the
first time, to be an effective solvent for developing or-
ganic reactions that have never been realized before.
The promoting effect of glycerol for the three-compo-
nent reaction of styrene, dimedone and paraformalde-
hyde could be attributed to restricted formation of
the methylene intermediate. During the reaction, a
physical shell, which is mainly composed of a by-
product generated in the beginning of the reaction,
equipped with triangle magnetic stirring. In a typical reac-
tion, glycerol (1.2 g) was mixed with styrene (52 mg,
0.5 mmol), dimedone (140 mg, 1,0 mmol) and paraformalde-
hyde (30 mg, 1.0 mmol) under air. The mixture was stirred
for 11 h at 1108C. After reaction, the mixture was extracted
with ethyl acetate (2 mLꢄ3). The obtained ester phases
were then combined together and concentrated under re-
duced pressure. The product was obtained by preparative
TLC using a mixed solution of ethyl acetate and petroleum
ether as eluting solvent (normally, the ratio of ethyl acetate/
petroleum ether is 1/10). Procedures for the other reactions
and physicochemical data of the products are available in
the Supporting Information.
Spectroscopic Data of the Products
2,3,4,6,7,8-Hexahydro-2-phenyl-7,7-dimethyl-5H-1-benzopyr-
1
an-5-one (3a): Colourless liquid; H NMR (CDCl3): d=1.08
(s, 3H), 1.10 (s, 3H), 1.87 (dtd, Ja =4.8 Hz, Jb =8.4 Hz, Jc =
10.4 Hz, 1H), 2.16 (double quint, Ja =2.8 Hz, Jb =13.6 Hz,
1H), 2.25 (s, 1H), 2.28 (s, 1H), 2.20–2.30 (m, 1H), 2.34 (s,
2H), 2.40–2.49 (m, 1H), 4.95 (dd, Ja =2.4 Hz, Jb =10.0 Hz,
1H), 7.29–7.40 (m, 5H); 13C NMR: d=17.8, 27.7, 29.0, 29.2,
31.9, 32.1, 42.4, 50.6, 79.0, 110.3, 125.9, 128.1, 128.3, 128.4,
128.6, 140.3, 169.7, 197.9; IR: n=3033, 2956, 2870, 1652,
might be formed on the surface of paraformaldehyde 1626, 1496, 1452, 1394, 1368, 1306, 1287, 1233, 1210, 1163,
526
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Adv. Synth. Catal. 2010, 352, 519 – 530

Multicomponent Reactions of 1,3-Cyclohexanediones and Formaldehyde in Glycerol
1148, 1123, 1067, 962, 758, 700, 658, 531 cmÀ1; HR-MS:
m/z=256.1427, calcd. for C17H20O2 [M+]: 256.1463.
1654, 1627, 1495, 1448, 1388, 1309, 1291, 1268, 1231, 1164,
1119, 1189, 1070, 1032, 1005, 965, 935, 854, 764, 701,
658 cmÀ1; HR-MS: m/z=270.1648, calcd. for C18H22O2 [M+]:
270.1620.
2,3,4,6,7,8-Hexahydro-2-(4-chlorophenyl)-7,7-dimethyl-
5H-1-benzopyran-5-one (3b): White solid, mp 132–1338C;
1H NMR (CDCl3): d=1.09 (s, 3H), 1.11 (s, 3H), 1.84 (dtd,
Ja =4.8 Hz, Jb =8.4 Hz, Jc =10.4 Hz, 1H), 2.15 (double quint,
Ja =2.8 Hz, Jb =13.6 Hz, 1H), 2.26 (s, 1H), 2.28 (s, 1H),
2.20–2.30 (m, 1H), 2.34 (s, 2H), 2.40–2.49 (m, 1H), 4.94 (dd,
Ja =2.4 Hz, Jb =6.4 Hz, 1H), 7.7 (d, J=8.4 Hz,2H), 7.35
(d, J=8.4 Hz, 2H); 13C NMR: d=17.7, 27.7, 29.0, 29.1, 32.1,
42.4, 50.6, 78.3, 110.3, 127.3, 127.4, 128.8, 133.9, 138.8, 169.5,
197.9. IR: n=2944, 2870, 1649, 1626, 1491, 1394, 1345, 1286,
1234, 1213, 1164, 1144, 1124, 1070, 1010, 991, 965, 900, 867,
843, 818, 617, 539 cmÀ1; HR-MS: m/z=290.1097, calcd. for
C17H19ClO2 [M+]: 290.1074.
2,3,4,6,7,8-Hexahydro-2-(4-fluorophenyl)-2,7,7-trimethyl-
5H-1-benzopyran-5-one (3g): Colourless liquid; 1H NMR
(CDCl3): d=1.56 (s, 3H), 1.85–1.94 (m, 2H), 1.94–2.04 (m,
2H), 2.17–2.23 (m, 1H), 2.25–2.32 (m, 1H), 2.32–2.38 (m,
2H), 2.48–2.55 (m, 2H), 7.02 (dt, Ja =2.4 Hz, Jb =6.8 Hz,
2H), 7.23–7.28 (m, 2H); 13C NMR: d=15.7, 21.0, 28.9, 29.0,
32.5, 36.7, 80.2, 111.4, 115.2, 115.4, 126.0, 126.1, 140.4, 140.4,
160.6, 163.1, 170.0, 198.0; IR: n=2957, 2932, 2870, 1654,
1628, 1511, 1452, 1389, 1309, 1292, 1266, 1230, 1163, 1119,
1077, 837, 651 cmÀ1; HR-MS: m/z=288.1560, calcd. for
C18H21FO2 [M+]: 288.1526.
2,3,4,6,7,8-Hexahydro-2-(4-methylphenyl)-7,7-dimethyl-
5H-1-benzopyran-5-one (3c): White solid, mp 76–778C;
1H NMR (CDCl3): d=1.08 (s, 3H), 1.10 (s, 3H), 1.89 (dtd,
Ja =5.6 Hz, Jb =10.8 Hz, Jc =16.0 Hz, 1H), 2.15 (double
quint, Ja =2.8 Hz, Jb =13.6 Hz, 1H), 2.25 (s, 1H), 2.28 (s,
1H), 2.20–2.30 (m, 1H), 2.33 (s, 2H), 2.36 (s, 3H), 2.41–2.49
(m, 1H), 4.93 (dd, Ja =2.4 Hz, Jb =10.4 Hz, 1H), 7.18 (d, J=
8.0 Hz, 2), 7.23 (d, J=8.0 Hz, 2H); 13C NMR: d=17.8, 21.2,
27.7, 28.9, 29.2, 32.1, 42.5, 50.6, 79.0, 110.2, 125.9, 129.3,
137.3, 138.0, 169.9, 189.5, 198.0; IR: n=2957, 2928, 2870,
1656, 1627, 1517, 1393, 1368, 1306, 1287, 1233, 1210, 1164,
1123, 1071, 1054, 962, 815, 772, 632 cmÀ1; HR-MS: m/z=
270.1656, calcd. for C18H22O2 [M+]: 270.1620.
2,3,4,6,7,8-Hexahydro-2-(4-methoxylphenyl)-7,7-dimethyl-
5H-1-benzopyran-5-one (3d): White solid, mp 122–1248C;
1H NMR (CDCl3): d=1.08 (s, 3H), 1.09 (s, 3H), 1.89 (dtd,
Ja =5.6 Hz, Jb =10.8 Hz, Jc =14.0 Hz, 1H), 2.13 (double
quint, Ja =2.8 Hz, Jb =14.0 Hz, 1H), 2.25 (s, 1H), 2.28 (s,
1H), 2.20–2.30 (m, 1H), 2.32 (s, 2H), 2.43–2.52 (m, 1H),
3.81 (s, 3H), 4.90 (dd, Ja =2.4 Hz, Jb =10.4 Hz, 1H), 6.91 (d,
J=8.8 Hz, 2H), 7.27 (d, J=8.8 Hz, 2H); 13C NMR: d=18.0,
27.7, 28.8, 29.2, 32.1, 42.5, 50.6, 55.3, 78.9, 110.2, 114.0, 127.4,
132.3, 159.5, 170.0, 198.0; IR: n=2950, 2914, 1624, 1516,
1468, 1444, 1396, 1360, 1307, 1291, 1249, 1231, 1209, 1177,
1164, 1126, 1069, 1054, 1028, 838, 812, 642, 628, 568,
530 cmÀ1; HR-MS: m/z=286.1583, calcd. for C18H22O3 [M+]:
286.1569.
2,3,4,6,7,8-Hexahydro-2-(4-tert-butylphenyl)-7,7-dimethyl-
5H-1-benzopyran-5-one (3e): White solid, mp 64–658C;
1H NMR (CDCl3): d=1.08 (d, J=4.4 Hz, 6H), 1.33 (s, 9H),
1.89 (dtd, Ja =6.0 Hz, Jb =10.4 Hz, Jc =13.6 Hz, 1H), 2.16
(double quint, Ja =2.8 Hz, Jb =14.0 Hz, 1H), 2.20–2.30 (m,
3H), 2.33 (s, 2H), 2.42–2.50 (m, 1H), 4.94 (dd, Ja =2.4 Hz,
Jb =10.4 Hz, 1H), 7.27 (d, J=8.8 Hz, 2H), 7.41 (d, J=
6.8 Hz, 2H); 13C NMR: d=17.8, 27.7, 28.8, 29.2, 31.3, 32.1,
34.6, 42.5, 50.6, 79.0, 110.3, 125.5, 125.7, 137.2, 151.2, 169.9,
198.0; IR: n=2959, 2870, 1657, 1628, 1515, 1466, 1392, 1367,
1286, 1233, 1210, 1164, 1123, 1071, 1054, 1016, 962, 835, 702,
624, 572 cmÀ1; HR-MS: m/z=312.2123, calcd. for C21H28O2
[M+]: 312.2089.
2,3,4,6,7,8-Hexahydro-2-phenyl-2,7,7-trimethyl-5H-1-ben-
zopyran-5-one (3f): Colourless liquid; 1H NMR (CDCl3):
d=1.07 (s, 3H), 1.09 (s, 3H), 1.57 (s, 3H), 1.80–1.95 (m,
2H), 2.22 (s, 2H), 2.23–2.32 (m, 2H), 2.41 (d, J=1.2 Hz,
2H), 7.21–7.29 (m, 3H), 7.29–7.37 (m, 2H); 13C NMR: d=
15.6, 28.4, 28.5, 29.3, 32.3, 32.5, 42.7, 50.6, 80.8, 110.1, 124.3,
127.2, 128.5, 144.6, 168.6, 197.8; IR: n=2956, 2932, 2870,
2,3,4,6,7,8-Hexahydro-2-phenyl-5H-1-benzopyran-5-one
(3h): Colourless liquid; H NMR (CDCl3): d=1.83–1.92 (m,
1
2H), 1.93–2.05 (m, 2H), 2.12–2.20 (m, 1H), 2.22–2.33 (m,
1H), 2.37–2.52 (m, 4H), 4.94 (dd, Ja =2.4 Hz, Jb =10.4 Hz,
1H), 7.31–7.41 (m, 5H); 13C NMR: d=18.2, 20.9, 28.7, 29.2,
36.7, 79.1, 111.7, 125.9, 128.2, 128.6, 140.3, 171.5, 198.3; IR:
n=2944, 2893, 1650, 1622, 1497, 1453, 1394, 1294, 1248,
1231, 1214, 1181, 1131, 1075, 1033, 1005, 984, 920, 862, 759,
701, 661, 588, 531 cmÀ1; HR-MS: m/z=228.1129, calcd. for
C15H16O2 [M+]: 228.1150.
2,3,4,6,7,8-Hexahydro-2-(4-chlorophenyl)-5H-1-benzopyr-
1
an-5-one (3i): White solid, mp 76–788C; H NMR (CDCl3):
d=1.78–1.90 (m, 2H), 1.93–2.06 (m, 2H), 2.14 (double
quint, Ja =3.2 Hz, Jb =14.0 Hz, 1H), 2.21–2.33 (m, 1H),
2.37–2.51 (m, 4H), 4.91 (dd, Ja =2.0 Hz, Jb =10.4 Hz, 1H),
7.28 (d, J=8.8 Hz, 2H), 7.35 (d, J=6.8 Hz, 2H); 13C NMR:
d=18.2, 20.9, 28.7, 29.2, 36.7, 79.1, 111.7, 125.9, 128.2, 128.6,
140.3, 171.5, 198.3; IR: n=2936, 1653, 1620, 1492, 1391,
1293, 1247, 1230, 1213, 1179, 1128, 1090, 1075, 1033, 922,
829, 605 cmÀ1
;
HR-MS: m/z=262.0739, calcd. for
C15H15ClO2 [M+]: 262.0761.
2,3,4,6,7,8-Hexahydro-2-(4-methylphenyl)-5H-1-benzopyr-
1
an-5-one (3j): White solid, mp 70–728C; H NMR (CDCl3):
d=1.85–1.95 (m, 1H), 1.96–2.02 (m, 2H), 2.13 (double
quint, Ja =2.4 Hz, Jb =10.4 Hz, 1H), 2.22–2.32 (m, 1H), 2.36
(s, 3H), 2.37–2.42 (m, 2H), 2.42–2.50 (m, 3H), 4.90 (dd, Ja =
2.0 Hz, Jb =10.4 Hz, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.23 (d,
J=8.0 Hz, 2H); 13C NMR: d=18.2, 20.9, 21.1, 28.7, 29.0,
36.7, 79.1, 111.6, 126.0, 129.3, 137.3, 138.0, 171.6, 198.2; IR:
n=2946, 2930, 1642, 1615, 1516, 1452, 1427, 1398, 1368,
1294, 1250, 1235, 1185, 1130, 1077, 1034, 1004, 816, 622,
553 cmÀ1; HR-MS: m/z=242.1339, calcd. for C16H18O2 [M+]:
242.1307.
2,3,4,6,7,8-Hexahydro-2-(4-methoxylphenyl)-5H-1-benzo-
pyran-5-one (3k): Yellow solid, mp 102–1048C; 1H NMR:
d=1.85–1.92 (m, 1H), 1.93–2.02 (m, 2H), 2.08–2.17 (m,
1H), 2.20–2.31 (m, 1H), 2.34–2.52 (m, 5H), 3.80 (s, 3H),
4.87 (dd, Ja =2.0 Hz, Jb =10.4 Hz, 1H), 6.90 (d, J=8.4 Hz,
2H), 7.27 (d, J=8.8 Hz, 2H); 13C NMR: d=18.3, 20.9, 28.7,
28.9, 36.7, 55.3, 78.9, 111.5, 114.0, 127.4, 132.3, 159.6, 171.6,
198.2; IR: n=2947, 2916, 2834, 1651, 1626, 1515, 1390, 1290,
1251, 1180, 1131, 1075, 1031, 1001, 985, 837, 807, 616,
570 cmÀ1; HR-MS: m/z=258.1228, calcd. for C16H18O3 [M+]:
258.1256.
2,3,4,6,7,8-Hexahydro-2-methyl-2-phenyl-5H-1-benzopyr-
1
an-5-one (3l): Colourless liquid; H NMR (CDCl3): d=1.57
(s, 3H), 1.83–1.95 (m, 2H), 1.99 (quint, J=6.4 Hz, 2H),
Adv. Synth. Catal. 2010, 352, 519 – 530
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Minghao Li et al.
FULL PAPERS
2.20–2.31 (m, 2H), 2.34 (td, Ja =4.4 Hz, Jb =6.4 Hz, 2H),
2.41 (dd, Ja =6.8 Hz, Jb =13.2 Hz, 2H), 7.21–7.29 (m, 3H),
7.29–7.37 (m, 2H); 13C NMR: d=15.8, 21.0, 28.9, 29.0, 32.3,
32.5, 36.7, 80.6, 111.4, 124.2, 127.2, 128.5, 144.6, 170.3, 198.1;
IR: n=2976, 2936, 1652, 1623, 1495, 1449, 1389, 1298, 1251,
1226, 1191, 1161, 1124, 1091, 1073, 1029, 993, 930, 847, 765,
701, 656 cmÀ1; HR-MS: m/z=242.1318, calcd. for C16H18O2
[M+]: 242.1307.
50.1, 109.8, 113.3, 124.4, 129.8, 135.5, 136.1, 163.3, 177.1,
196.7, 200.7; IR: n=2956, 2921, 1636, 1589, 1515, 1488, 1447,
1406, 1393, 1364, 1329, 1288, 1270, 1218, 1158, 1082, 947,
809, 499 cmÀ1; HR-MS: m/z=410.2731, calcd. for C26H36NO3
[M+H+]: 410.2695.
2-[(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-
methyl]-3-[(4-methoxyphenyl)amino]-5,5-dimethyl-2-cyclo-
hexen-1-one (5c): White solid, mp 121–1228C; 1H NMR
(CDCl3): d=0.95 (s, 3H), 1.05 (s, 9H), 2.25 (s, 4H), 2.34 (s,
4H), 3.33 (d, J=11.6 Hz, 2H), 3.79 (s, 3H), 6.91 (d, J=
6.8 Hz, 2H), 7.06 (d, J=6.8 Hz, 2H), 10.33 (s, 1H), 13.08
(bs, 1H); 13C NMR: d=17.2, 28.2, 31.8, 32.6, 40.2, 43.4, 48.7,
50.1, 55.4, 109.3, 113.3, 114.4, 126.2, 131.5, 157.7, 163.8,
177.1, 196.3, 200.6; IR: 2962, 2933, 1586, 1513, 1471, 1422,
1405, 1366, 1327, 1300, 1271, 1237, 1173, 1159, 1108, 1080,
2,3,4,6,7,8-Hexahydro-2-methyl-2-(4-fluorophenyl)-5H-1-
1
benzopyran-5-one (3m): White solid, mp 92–948C; H NMR
(CDCl3): d=1.56 (s, 3H), 1.84–1.94 (m, 2H), 1.99 (quint, J=
6.0 Hz, 2H), 2.16–2.23 (m, 1H), 2.25–2.32 (m, 1H), 2.35 (dt,
Ja =4.4 Hz, Jb =6.4 Hz, 2H), 2.48–2.55 (m, 2H), 7.02 (dt, Ja =
2.4 Hz, Jb =6.8 Hz, 2H), 7.21–7.29 (m, 2H); 13C NMR: d=
15.7, 21.0, 28.9, 29.0, 32.5, 36.7, 80.2, 111.4, 115.2, 115.4,
126.0, 126.1, 140.4, 140.4, 160.6, 163.1, 170.0, 198.0; IR: n=
2977, 2933, 2898, 1652, 1624, 1509, 1457, 1431, 1382, 1301,
1222, 1196, 1162, 1121, 1089, 1076, 992, 930, 857, 832, 642,
555 cmÀ1; HR-MS: m/z=260.1188, calcd. for C16H17FO2
[M+]: 260.1213.
1033, 925, 822, 785, 755, 656, 628, 594, 573, 545, 493 cmÀ1
;
HR-MS: m/z=426.2670, calcd. for C26H36NO4 [M+H+]:
426.2644.
2-[(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-
methyl]-3-benzylamino-5,5-dimethyl-2-cyclohexen-1-one
1
2,3,4,6,7,8-Hexahydro-2-phenyl-7-methyl-5H-1-benzopyr-
(5d): Gum-like liquid; H NMR (CDCl3): d=0.95 (s, 6H),
1
an-5-one (3n): White solid, mp 67–688C; H NMR (CDCl3):
1.04 (s, 6H), 2.20 (s, 5H), 2.28 (s, 3H), 3.29 (d, J=25.2 Hz,
2H), 4.52 (s, 2H), 7.20–7.35 (m, 5H), 9.12 (t, J=6.0 Hz,
1H), 13.30 (bs, 1H); 13C NMR: d=16.9, 31.8, 38.7, 43.5,
46.8, 48.2, 50.1, 77.4, 108.2, 113.2, 126.6, 127.4, 128.8, 130.9,
138.1, 166.1, 177.4, 194.8, 200.4; IR: n=3270, 3170, 3058,
3031, 2956, 2870, 2508, 1732, 1594, 1534, 1465, 1409, 1363,
1328, 1296, 1270, 1248, 1161, 1122, 1103, 924, 890, 734, 698,
581, 491 cmÀ1; HR-MS: m/z=410.2733, calcd. for C26H36NO3
[M+H+]: 410.2695.
d=1.08 (d, J=5.0 Hz, 3H), 1.80–1.95 (m, 1H), 2.04–2.35 (m,
5H), 2.35–2.55 (m, 3H), 4.88 (dd, Ja =2.0 Hz, Jb =10.8 Hz,
.037H), 5.01 (dd, Ja =2.4 Hz, Jb =9.6 Hz, 0.63 Hz), 7.24–7.43
(m, 5H); 13C NMR: d=17.5, 18.4, 21.0, 21.1, 28.4, 28.6, 28.8,
29.3, 36.7, 36.9, 44.9, 45.2, 78.9, 79.2, 110.9, 111.3, 125.8,
126.0, 128.1, 128.2, 128.6, 140.3, 170.7, 171.0, 198.0, 198.2;
IR: n=2954, 2927, 1654, 1624, 1496, 1454, 1395, 1297, 1231,
1203, 1134, 1067, 980, 898, 758, 700, 659 cmÀ1; HR-MS:
m/z=242.1332, calcd. for C16H18O2 [M+]: 242.1307.
2-[(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-
2,3,4,6,7,8-Hexahydro-2-(4-fluorophenyl)-2,7-dimethyl-
5H-1-benzopyran-5-one (3o): Colourless liquid; 1H NMR
(CDCl3): d=1.03–1.12 (m, 3H), 1.55 (d, J=9.6 Hz, 3H),
1.75–2.14 (m, 4H), 2.19–2.32 (m, 3H), 2.43(dt, Ja=3.6 Hz,
Jb =12.8 Hz, 1H), 2.49–2.58 (m, 1H), 7.01 (q, J=8.4 Hz,
2H), 7.19–7.25 (m, 1H), 7.25–7.32 (m, 1H); 13C NMR: d=
15.7, 15.7, 21.0, 21.0, 27.8, 28.5, 28.6, 30.0, 32.2, 32.8, 37.0,
37.1, 45.0, 80.2, 80.3, 110.6, 111.0, 115.5, 126.0, 126.1, 140.1,
140.1, 140.7, 140.8, 160.6, 160.6, 163.0, 163.1, 169.4, 169.5,
198.0; IR: n=2955, 2931, 2873, 1653, 1626, 1510, 1453, 1391,
1305, 1267, 1222, 1161, 1127, 1090, 1078, 1013, 909, 838, 810,
methyl]-3-cyclohexylamino-5,5-dimethyl-2-cyclohexen-1-one
(5e): White solid, mp 116–1178C; 1H NMR (CDCl3): d=
1.02 (s, 9H), 1.05 (s, 3H), 1.15–1.45 (m, 4H), 1.48–1.60 (m,
1H), 1.61–1.70 (m, 1H), 1.72–1.90 (m, 3H), 1.90–2.00 (m,
1H), 2.21 (d, J=7.6 Hz, 4H), 2.24–2.40 (m, 4H), 3.13 (d, J=
15.2 Hz, 1H), 3.24–3.48 (m, 2H), 8.49 (d, J=7.6 Hz, 1H),
13.60 (bs, 1H); 13C NMR: d=16.8, 25.0, 27.3, 27.4, 29.2,
29.5, 31.7, 31.7, 33.3, 34.2, 38.9, 43.6, 48.0, 50.1, 52.6, 107.2,
113.0, 164.8, 177.4, 193.5, 199.9; IR: n=3258, 2932, 2857,
1588, 1470, 1435, 1407, 1367, 1334, 1295, 1271, 1150, 1117,
966, 890, 829, 791, 766, 584, 505 cmÀ1; HR-MS: m/z=
424.2866, calcd. for C25H39NNaO3 [M+Na+]: 424.2828.
2-[(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-
655, 632, 554 cmÀ1
; HR-MS: m/z=274.1401, calcd. for
C17H19FO2 [M+]: 274.1369.
2-[(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-
methyl]-3-phenylamino-5,5-dimethyl-2-cyclohexen-1-one
(5a): White solid, mp 148–1508C; 1H NMR (CDCl3): d=
0.93 (s, 3H), 1.11 (s, 9H), 2.28 (s, 4H), 2.36 (s, 4H), 3.35 (d,
J=12.8 Hz, 2H), 7.14–7.31 (m, 3H), 7.32–7.42 (m, 2H),
10.52 (s, 1H), 12.95 (bs, 1H); 13C NMR: d=17.4, 31.8, 32.9,
40.4, 43.5, 48.9, 50.1, 110.2, 113.3, 124.3, 125.4, 129.3, 138.8,
162.9, 177.2, 197.1, 200.8; IR: n=2959, 2928, 1591, 1533,
1487, 1444, 1405, 1366, 1326, 1300, 1270, 1224, 1160, 1109,
1081, 917, 840, 788, 761, 697, 597, 485 cmÀ1; HR-MS: m/z=
369.2577, calcd. for C25H34NO3 [M+H+]: 369.2539.
2-[(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-
methyl]-3-[(4-methylphenyl)amino]-5,5-dimethyl-2-cyclo-
hexen-1-one (5b): White solid, mp 170–1718C; 1H NMR
(CDCl3): d=0.94 (s, 3H), 1.05 (s, 9H), 2.20–2.40 (m, 10H),
2.45–2.62 (m, 1H), 3.33 (d, J=15.6 Hz, 2H), 7.03 (d, J=
8.0 Hz, 2H), 7.17 (d, J=8.0 Hz, 2H), 10.42 (s, 1H), 13.03
(bs, 1H); 13C NMR: d=17.3, 21.0, 31.8, 43.5, 40.3, 43.5, 48.9,
methyl]-3-[2-(3,4-dimethoxyphenyl)ethylamino]-5,5-dimeth-
yl-2-cyclohexen-1-one (5f): Gum-like liquid; 1H NMR
(CDCl3): d=0.95 (d, J=12.4 Hz, 6H), 1.04 (s, 6H), 2.06 (s,
1H), 2.16 (d, J=2.8 Hz, 2H), 2.21 (s, 3H), 2.30 (s, 2H), 2.93
(t, J=6.0 Hz, 2H), 3.14 (d, J=12.4 Hz, 1H), 3.28 (d, J=
12.4 Hz, 1H), 3.50 (q, J=6.0 Hz, 2H), 3.85 (s, 6H), 6.75–
6.82 (m, 3H), 8.73 (t, J=5.2 Hz, 1H), 13.60 (bs, 1H);
13C NMR: d=17.0, 27.2, 27.4, 29.5, 31.5, 31.7, 35.9, 38.9,
43.6, 45.4, 47.9, 50.1, 55.8, 55.9, 107.4, 111.4, 112.2, 113.1,
120.8, 130.9, 147.8, 148.9, 165.8, 177.7, 194.0, 200.3; IR: n=
3268, 3166, 2956, 2870, 1735, 1591, 1516, 1470, 1432, 1366,
1329, 1265, 1239, 1158, 1142, 1104, 1029, 940, 920, 806, 763,
733, 582, 488 cmÀ1
; HR-MS: m/z=506.2910, calcd. for
C29H41NNaO5 [M+Na+]: 506.2882.
2-[(2-Hydroxy-6-oxo-1-cyclohexen-1-yl)methyl]-3-cyclo-
hexylamino-2-cyclohexen-1-one (5g): Colourless liquid;
1H NMR (CDCl3): d=1.20–1.49 (m, 5H), 1.50–1.70 (m,
2H), 1.75–2.10 (m, 7H), 2.18–2.55 (m, 6H), 2.55–2.77 (m,
528
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Adv. Synth. Catal. 2010, 352, 519 – 530

Multicomponent Reactions of 1,3-Cyclohexanediones and Formaldehyde in Glycerol
1H), 3.05–3.20 (m, 1H), 3.20–3.45 (m, 2H), 8.76 (d, J=
7.6 Hz, 1H), 14.03 (bs, 1H); 13C NMR: d=17.5, 20.9, 21.0,
25.0, 25.1, 25.4, 30.1, 34.4, 36.2, 52.9, 108.5, 114.2, 166.6,
179.8, 194.4, 200.5; IR: n=3256, 3148, 2935, 2856, 2510,
1736, 1589, 1436, 1413, 1370, 1341, 1307, 1264, 1245, 1199,
bers in the Analytical and Testing Center of HUST, for their
supportive and constant contributions to our work. The Pro-
gram for new Centzry Excellent Talents in the University of
China and Chutian Scholar Program of Hubei Provincial
Government are also acknowledged.
1145, 1113, 1028, 982, 933, 889, 861, 785, 732, 595, 488 cmÀ1
;
HR-MS: m/z=346.2397, calcd. for C21H32NO3 [M+H+]:
346.2382.
References
2-[(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-
methyl]-3-[2-(1-cyclohexene-1-ethyl)amino]-5,5-dimethyl-2-
1
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cyclohexen-1-one (5h): Colourless liquid; H NMR (CDCl3):
d=1.03 (s, 9H), 1.05 (s, 3H), 1.51–1.60 (m, 2H), 1.60–1.68
(m, 2H), 1.98 (s, 2H), 2.18–2.26 (m, 5H), 2.26–2.38 (m, 5H),
3.06–3.20 (m, 1H), 3.22–4.20 (m, 3H), 5.49 (s, 1H), 8.58 (s,
1H), 13.56 (bs, 1H); 13C NMR: d=16.9, 22.3, 22.9, 25.2,
28.4, 31.7, 31.7, 38.3, 39.0, 42.3, 43.6, 48.0, 50.1, 107.4, 113.1,
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2942, 2871, 2832, 1587, 1474, 1435, 1408, 1366, 1333, 1299,
1270, 1158, 1124, 1105, 1052, 977, 831, 797, 770, 584,
504 cmÀ1; HR-MS: m/z=428.3191, calcd. for C27H42NO3
[M+H+]: 428.3165.
8,9,10,12-Tetrahydro-11H-benzo[a]xanthen-11-one (7a):
White solid, mp: 154–1568C; 1H NMR (CDCl3): d=2.02
(quint, J=6.4 Hz, 2H), 2.45 (t, J=6.4 Hz, 2H), 2.50 (t, J=
6.0 Hz, 2H), 3.64 (s, 2H), 7.06 (d, J=8.8 Hz, 1H), 7.41 (dt,
Ja =0.8 Hz, Jb =6.8 Hz, 1H), 7.51 (dt, Ja =1.2 Hz, Jb =6.8 Hz,
1H), 7.61 (d, J=9.2 Hz, 1H), 7.74 (d, J=8.0 Hz, 1H), 7.81
(d, J=8.4 Hz, 1H); 13C NMR: d=19.0, 20.6, 27.5, 36.7,
109.9, 113.5, 117.0, 123.1, 124.9, 126.3, 126.9, 128.2, 128.2,
130.7, 132.0, 146.7, 166.3, 198.3; IR: n=2942, 1646, 1595,
1512, 1455, 1435, 1391, 1377, 1227, 1191, 1128, 1000, 952,
811, 774, 760, 709, 664, 524 cmÀ1; HR-MS: m/z=250.1029,
calcd. for C17H14O2 [M+]: 250.0994.
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7,9,10,11-Tetrahydro-4,10,10-trimethyl-6H,8H-pyranoACTHNUTRGNEU[GN 4,3-
b][1]benzopyran-6,8-dione (7b): White solid, mp 118–
1
1198C; H NMR (CDCl3): d=1.06 (s, 3H), 1.07 (s, 3H), 2.24
(s, 3H), 2.27 (s, 2H), 2.36 (s, 2H), 3.32 (bs, 2H), 5.96 (s,
1H); 13C NMR: d=17.2, 19.7, 31.8, 42.8, 49.1, 102.0, 102.7,
113.0, 160.9, 168.3, 170.0, 177.1; IR: n=2958, 1673, 1588,
1373, 1296, 1243, 1165, 1149, 1088, 1038, 996, 868, 826, 742,
514 cmÀ1; HR-MS: m/z=260.1085, calcd. for C15H16O4 [M+]:
260.1049.
3-[(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-
methyl]-4-hydroxy-1-methyl-2(1H)-quinolinone (7c): White
solid, mp 156–1588C; 1H NMR (CDCl3): d=1.04 (s, 3H),
1.08 (s, 3H), 2.10–2.47 (m, 4H), 3.52 (d, J=14.0 Hz, 1H),
3.61 (d, J=14.0 Hz, 1H), 3.72 (s, 1H), 7.20–7.40 (m, 2H),
7.55 (t, J=7.6 Hz, 1H), 8.10 (d, J=3.6 Hz, 1H), 11.3 (bs,
1H), 12.8 (bs, 1H); 13C NMR: d=18.5, 27.1, 29.6, 30.0, 31.7,
43.2, 49.2, 109.3, 113.2, 114.2, 117.4, 122.6, 124.2, 130.8,
138.1, 159.7, 165.9, 177.9, 202.0; IR: n=2967, 2929, 2880,
1633, 1612, 1576, 1526, 1464, 1375, 1329, 1295, 1248, 1149,
1117, 914, 756, 492 cmÀ1; HR-MS: m/z=356.1897, calcd. for
C21H26NO4 [M+H+]: 356.1862.
Acknowledgements
The authors thank for National Natural Science Fundation of
China for the financial support (20903042). The authors are
also grateful to Ms. Ping Liang and all the other staff mem-
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Adv. Synth. Catal. 2010, 352, 519 – 530