Catalyst-free aqueous multicomponent domino reactions from formaldehyde and 1,3-dicarbonyl derivatives

Article abstract of DOI:10.1039/b913846c

Here we report a catalyst-free aqueous multicomponent domino reaction (MCR) capable of affording a wide range of valuable dihydropyran derivatives from simple, cheap and readily available reactants such as formaldehyde, 1,3-dicarbonyl derivatives, styrene

Full text of DOI:10.1039/b913846c

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PAPER
www.rsc.org/greenchem | Green Chemistry
Catalyst-free aqueous multicomponent domino reactions from formaldehyde
and 1,3-dicarbonyl derivatives†
Yanlong Gu,b Rodolphe De Sousa,a Gilles Frapper,a Christian Bachmann,a Joe¨l Barraulta and
Franc¸ois Je´roˆme*a
Received 13th July 2009, Accepted 18th August 2009
First published as an Advance Article on the web 18th September 2009
DOI: 10.1039/b913846c
Here we report a catalyst-free aqueous multicomponent domino reaction (MCR) capable of
affording a wide range of valuable dihydropyran derivatives from simple, cheap and readily
available reactants such as formaldehyde, 1,3-dicarbonyl derivatives, styrene, indole and aniline
derivatives. Within the framework of green chemistry, these MCRs gather many advantages such
as (i) utilization of water as a solvent, (ii) creation of up to six bonds in one sequence, (iii) 100% of
carbon economy and (iv) water as a sole waste. These MCRs exhibit a broad substrate scope and
open access to valuable chemicals traditionally produced through multistep processes involving
catalysts or organic solvents. More generally, this work opens a new way for creating molecular
complexity with maximum simplicity.
reaction pathways are now strongly needed in order to increase
Introduction
the portfolio of environmentally benign organic reactions.3
Within the framework of green chemistry, the search of innova-
Development of new MCRs using water as a solvent is strongly
tive solutions for the reduction of chemical steps, wastes and
limited by (i) the low solubility of organic substrates in water
energy in organic processes has become a challenging task.
and (ii) the sensitivity of chemical groups towards hydrolytic
In this context, multicomponent domino reactions (MCRs)
degradations. One of the solution to circumvent this issue
represent a fascinating tool to achieve this goal.1 Indeed,
consists in the addition of a phase transfer agent.4 However, even
efficient MCRs lead to the creation of several bonds in one
if spectacular results have been reported in micellar conditions,
sequence without changing the reaction conditions, isolating the
this strategy still suffers from a complex purification work-up.
intermediates or adding reagents, thus allowing a minimization
Here, we wish to report an efficient aqueous and catalyst-free
of waste, cost and labor. To be efficient, MCRs have to be
MCR capable of affording, in water and without assistance of
highly selective in order to avoid an important production of
any catalyst or phase transfer agent, a wide range of substituted
waste which makes complex and costly the purification work-
and valuable dihydropyran derivatives with good yields. These
up. Toxicity of produced waste has also to be considered. On
MCRs involve cheap and readily available reactants such as
the other hand, MCRs have to be capable of affording highly
formaldehyde, 1,3-dicarbonyl compounds, styrene or indole
valuable substrates with good yields from cheap and readily
derivatives which represent a prerequisite for the viability of
available derivatives.
Generally, in MCRs, control of the selectivity is achieved by
a new MCR. On the other hand, from an environmental point
of view, these MCRs gather numerous advantages such as (i)
addition of a catalyst combined with the dilution of reactants
utilization of water as a solvent, (ii) creation of up to six bonds
in an organic solvent.2 With respect to green chemistry, the
in one sequence, (iii) 100% of carbon economy and (iv) water as
possibility of designing catalyst-free MCRs using water as a
a sole waste.
sole solvent is ideally the best choice owing to an easier work-
More generally, all these reported examples show that the
up procedure and the inherent environmental and economical
development of aqueous MCRs is not only attractive from
advantages of such process. To the best of our knowledge,
the viewpoint of environmentally benign reactions or atom
most of the successful aqueous and catalyst free MCRs involve
efficiency but also open a novel and straightforward way for
the Ugi or Passerini reactions (or derived reactions) and new
the creation of molecular complexity and diversity from simple,
cheap and readily accessible organic building blocks.
aLaboratoire de Catalyse en Chimie Organique, Universite´ de
Poitiers-CNRS, 40 Avenue du recteur Pineau, Poitiers Cedex, 86022,
France. E-mail: francois.jerome@univ-poitiers.fr; Fax: +33 5 49 45 33
Results and discussion
49; Tel: +33 5 49 45 40 52
bInstitute of Physical Chemistry and Industrial Catalysis, School of
Chemistry and Chemical Engineering, Huazhong University of Science
and Technology, 1037, Luoyu road, Hongshan District, Wuhan, 430074,
Hubei, China
In a first set of experiments, a-methylstyrene (1a) and 2,4-
pentanedione (2a) were heated at 80 ◦C with aqueous formalin
(HCHO, 37 wt% in water). Under these conditions, we were
pleased to see that an “ABC” three-component reaction selec-
tively took place. Indeed, after 3h of reaction, a highly pure
† Electronic supplementary information (ESI) available: Product char-
acterisation and 1H and 13C NMR spectra. See DOI: 10.1039/b913846c
1968 | Green Chem., 2009, 11, 1968–1972
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Table 1 MCR between 1a, formaldehyde and 1,3-dicarbonyl com-
Table 2 MCR between styrene derivatives, 2a and formaldehyde in/on
watera
pounds in/on watera
Entry
1,3-Dicarbonyl
Product
Time (h)
Isolated yield (%)
Entry
Olefin
Product
Time (h)
Isolated yield (%)
1b
2c
3d
4e
5
6
7
8
9
2a
2a
2a
2a
2b
2c
2d
2e
2f
3a
3a
3a
3a
3b
3c
3d
3e
3f
3
3
3
3
3
5
3
4
5
4
5
78
41
22
31
82
80
78
77
70
81
64
1
2
3
4
5
6
7
8
1b
1c
1d
1e
1f
1g
1h
1i
3i
6
3
6
4
3
3
3
6
54
84
28
81
93
91
71
67
72
40
79
3j
3k
3l
3m
3n
3o
3p
3p
3r
3s
9
1j
4
0.5
4
10
11
2g
2h
3g
3h
10b
11
1k
1l
a Formalin was used, 1a/1,3-dicarbonyl/formaldehyde: 1/1.5/2.5;
b 1a/2a/formaldehyde: 1/2/2.5; c 1a/2a/formaldehyde: 1/1/2.5;
d 1a/2a/formaldehyde: 1/2/1; e 1a/2a/formaldehyde: 1/2/4.
a Formalin was used, olefin/2a/formaldehyde: 1/2/2.5; b 60 ◦C.
the preparation of plant-protective agents and antiarrhythmic
drugs,5 but are also key intermediates for the synthesis of many
natural products.6 Synthetic methods previously reported for
the synthesis of analogous dihydropyran derivatives require
multistep processes with assistance of acid or transition metal
catalysts and organic solvents.7 In 2009, Botta et al. reported
an efficient MCR for the synthesis of 2,3-dihydropyran deriva-
tives. However, in this work, the MCR was carried out in
toluene, catalyzed by a Grubbs catalyst and with assistance of
microwaves.8 The most efficient synthetic method was recently
reported by Tietze and co-workers.9 However, utilization of
dichloromethane as a solvent, the low yield obtained (23-37%)
and the poor substrate scope represent the main limitation of
this work. Reactions summarized in Table 1 and Table 2 open a
direct and catalyst free access to a diverse array of substituted
dihydropyran derivatives (up to 93% yield) from simple and
easily available molecules, showing the economical effectiveness
of this methodology. On the other hand, within the framework
of green chemistry, this process gathers many advantages such
as (i) 100% of carbon economy (ii) creation of three bonds in
one sequence and (iii) water as a sole waste.
With the aim of proposing a plausible reaction mech-
anism, three counter experiments were undertaken. First,
a-methylstyrene was heated at 80 ◦C either with 2,4-
pentanedione and water or with aqueous formaldehyde. In these
cases, no reaction occurs and the reactants remained unaltered
(Scheme 1). These results are consistent with the literature.
Indeed, successful reactions between (i) styrene derivatives and
aqueous formaldehyde10 or (ii) styrene derivatives and 1,3-
dicarbonyl compounds11 normally require assistance of an acid
colorless liquid, identified as a 3-acyl-2,6-dimethyl-6-phenyl-
5,6-dihydropyran (3a), was obtained. After optimization of
the reaction conditions (molar ratio 1a/2a/formaldehyde =
1/2/2.5), 3a was isolated with 78% yield (Table 1, entries 1-4).
Having these first results in hand, various 1,3-dicarbonyl
compounds and styrene derivatives were subject to the optimized
conditions in order to determine the scope of this aqueous
MCR. The results are summarized in Table 1 and Table 2. All ex-
amined 1,3-dicarbonyl compounds including 1,3-diketones and
b-carbonyl esters reacted smoothly with a-methylstyrene and
formaldehyde affording the corresponding 5,6-dihydropyran
derivatives in good to high yields (64-82%, Table 1).
Styrenes with a methyl group in the a-position afforded
better yields than those without substituent (Table 2, entries
1-3). The presence of an electrondonating group on the aro-
matic ring of the styrenes led to an increase of the reaction
rate (Table 2, entries 2-9). A styrene type silyl enol ether,
1-phenyl-1-trimethylsiloxyethylene 1k, also reacted successfully
with formaldehyde and 2,4-pentanedione affording, after only
30 minutes of reaction at 60 ◦C, the corresponding dihydropyran
in 40% yield (Table 2, entry 10). It is noteworthy that the present
MCR was also proved to be tolerant to cyclic styrene since,
starting from indene, a 79% yield was obtained (Table 2, entry
11). Remarkably, in all experiments, dihydropyran derivatives
were always obtained as a single regioisomer.
Among heterocyles, substituted dihydropyran derivatives rep-
resent an important family of compounds and a lot of studies
are devoted to their synthesis. Dihydropyran derivatives are
not only used as odorous substances and intermediates for
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Table 3 MCR between indoles, formaldehyde and 1,3-dicarbonyl
compounds in/on watera
Entry Indole 1,3-Dicarbonyl Product Time (h) Yield (%)
1
4a
4a
4a
4b
4b
4b
4c
4d
2e
2d
2e
2e
2d
2f
5a
5b
5c
5d
5e
5f
6
6
20
9
15
15
17
17
70
64
54
71
70
51
50
52
Scheme 1 Plausible mechanism for the formation of 3a.
2
3b
4
catalyst. Interestingly, when 2,4-pentanedione was now heated
with aqueous formaldehyde at 80 ◦C, a messy mixture of
products was rapidly formed. This result indicates that the
MCR is initiated by a reaction involving 2,4-pentanedione and
formaldehyde. On the basis of these counter experiments, we
propose in Scheme 1 a plausible reaction mechanism. First,
we postulate for a Knoevenagel-type reaction between 2,4-
pentanedione and formaldehyde to produce a 2-methylene-1,3-
dicarbonyl compound (I). This species, known to be highly
unstable,9,12 would be rapidly trapped with a-methylstyrene by
means of a hetero Diels–Alder reaction yielding 3a.
Encouraged by these results, we then explored a novel three-
component reaction involving, this time, aqueous formaldehyde,
indole and ethyl acetoacetate. The targeted C3-substituted
indole derivatives are potent tryptophan precursors. In the
literature, three methods were developed to synthesize such
derivatives: i) coupling of ethyl acetoacetate to gramine deriva-
tives in the presence of bases; ii) oxidative Michael reaction
of Baylis–Hillman adducts with indole derivatives promoted
by iodoxybenzoic acid (IBA); iii) condensation between 2-(2-
nitrophenyl)propenal and ethyl acetoacetate.13 Unfortunately,
these methods suffer either from a lack of commercially available
starting materials or environmental problems due to the use of
toxic chemicals and the important generation of waste.
As observed above for the synthesis of 3a-u, we found that
indole derivative 5a can be directly prepared from aqueous
formaldehyde, indole and ethyl acetoacetate without assistance
of any catalyst. Indeed, after 6 hours of reaction at 45 ◦C, indole
and ethyl acetoacetate were selectively assembled with aqueous
formaldehyde to generate the desired C3-substituted indole with
70% yield. Here again, water was the sole by-product (Table 3,
entry 1). Note that the 30% remaining are unaltered starting
materials, further indicating the high selectivity of this process.
Investigation of the substrate scope revealed that many
indoles and b-ketone esters can be successfully used and all
the desired C3-substituted indole derivatives were obtained with
good yields (Table 3). On the basis of the above-described
mechanism, we assume that the reaction proceeds here according
to a tandem procedure involving a Knoevenagel-type reaction
between formaldehyde and 2e followed by a Michael addition
of indole to the generated 2-methylene-b-ketone ester (ESI,
Scheme S1).†14 From indole derivatives, Knoevenagel/Michael
5
6c
7d
8d
2e
2e
5g
5h
a Formalin was used as source of formaldehyde, 4a/1,3-
dicarbonyl/formaldehyde: 1/1.5/2; b 3,3¢-diindolylmethane was
also isolated in 11% yield, 60 ◦C; c 3,3¢-di(N-methylindolyl)methane
was also isolated in 17% yield; d 50 ◦C.
tandem reactions are usually difficult to achieve mainly because
it normally requires the concomitant presence of acid and base
catalysts in the same reaction pot, thus showing the convenience
of the presented MCRs.15
Remarkably, when indole derivatives were now replaced
by N-ethylaniline (6a), we observed that a novel “ABBCC”-
type five-component reaction selectively took place. Indeed,
when a mixture of N-ethylaniline and acetylacetone (molar
ratio is 1/2.5/2.5) was heated with aqueous formaldehyde at
45 ◦C for only 2 hours, a complex tricyclic skeleton, iden-
tified as a 3,4a-diacetyl-2,10a-dimethyl-10-ethyl-4,4a,5,10,10a-
pentahydropyrano[2,3-b]quinoline 7a, was obtained (Scheme 2).
To our great delight, 7a was isolated with 77% yield, which is a
very impressive yield considering the fact that five molecules are
involved in its construction.
From the viewpoint of green chemistry, this water-based
MCR is nearly perfect, since only three molecules of water are
released during the reaction and 100% of carbon economy is
still achieved. On the other hand, during the synthesis of 7a, six
bonds were created in one sequence. Note that the use of aniline
derivatives in MCRs normally requires not only the assistance
of Brønsted acid, transition metals or bromoalkylsulfonium
bromide salt as catalyst but also the use of organic solvents,
showing here again the versatility of this procedure.16
Inspired by the observations made above, we assume that
the tricyclic 7a derivative might be formed through a cascade
of elementary reactions involving i) Friedel-Craft addition of
N-ethylaniline to (I);17 ii) dehydrative cyclization of the adduct
(II)18 and iii) a hetero Diels Alder reaction between the cyclized
product (III) and (I) (Scheme 2). Interestingly, as observed above
for the “ABC” three-component reaction, the hetero Diels–
Alder step was also regioselective and 7a was obtained as a single
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products were extracted from water with a solution of ethyl
acetate and heptane (1:4 v/v, 6 mL ¥ 2). After concentration of
the organic phases, the crude compounds were purified by flash
chromatography over silica gel.
Selected
product:
3-Acyl-2,6-dimethyl-6-phenyl-5,6-
dihydropyran (3a): Colorless liquid, 78% yield (Heptane/ethyl
1
acetate: 2/1), H NMR (300 MHz, CDCl3): d = 1.55 (s, 3H),
1.85-2.08 (m, 2H), 2.11 (s, 3H), 2.15-2.33 (m, 2H), 2.37 (s, 3H),
7.19-7.27 (m, 3H), 7.32-7.36 (m, 2H); 13C NMR (75 MHz,
CDCl3): d = 20.8, 21.3, 29.4, 29.5, 32.6, 79.3, 109.6, 124.2,
127.0, 128.5, 144.7, 163.2, 198.8. IR (cm-1): 2980, 2929, 2966,
1668, 1567, 1446, 1375, 1284, 1095, 1073, 945, 766, 699. HRMS
(ESI): calcd for C15H18O2, [M] 230.3022; found: 230.3109.
Characterizations of all other products (3b-u) as well as copies
of NMR spectra are provided in the ESI.†
Typical procedure for three component reaction of indole,
formaldehyde and ethyl acetoacetate
All reactions were conducted in a 10 mL V-type flask equipped
with triangle magnetic stirring. In a typical procedure, aqueous
formaldehyde (160 mg, 2.0 mmol, 37 wt% in H2O) was mixed
with indole (117 mg, 1.0 mmol), ethyl acetoacetate (195 mg,
1.5 mmol) and water (850 mg) under air. The mixture was then
◦
Scheme 2 “ABBCC”-type five component reaction in/on water.
stirred for 6 hours at 45 C. After completion of reaction, the
products were extracted from water with a solution of ethyl
acetate and heptane (1:1 v/v, 6 mL ¥ 2). After concentration of
the organic phases, the crude compounds were purified by flash
chromatography over silica gel.
regioisomer. Note that this “ABBCC”-type five-component
reaction is not diastereoselective and diastereoisomers of 7a
were equally produced. An analogous five-component reaction
involving methyl acetoacetate, N-ethylaniline and formaldehyde
also proceeded well and 7b was obtained in a 47% yield.
Selected product: Ethyl a-benzoyl-1H-indole-3-propanoate
1
(5c): Red liquid, yield: 54% (Heptane/ethyl acetate: 4/1), H
NMR (300 MHz, CDCl3): d = 1.02 (t, J = 7.1 Hz, 3H), 3.42
(dd, Ja = 7.8 Hz, Jb = 2.2 Hz, 2H), 4.02 (ddd, Ja = 14.3 Hz,
Jb = 7.2 Hz, Jc = 1.8 Hz, 2H), 4.68 (t, J = 7.2 Hz, 1H), 6.92 (d,
J = 2.2 Hz, 1H), 7.07 (quint/double, Ja =7.0 Hz, Jb = 1.2 Hz,
2H), 7.24 (dd, Ja = 7.4 Hz, Jb = 1.2 Hz, 1H), 7.33 (t, J = 7.7 Hz,
2H), 7.46 (t, J = 7.2 Hz, 1H), 7.56 (d, J = 0.5 Hz, 1H), 7.87 (dd,
Ja = 7.5 Hz, Jb = 1.4 Hz, 2H), 8.0 (bs, 1H); 13C NMR (75 MHz,
CDCl3): d = 12.9, 23.6, 54.0, 60.4, 110.2, 111.4, 117.4, 118.4,
121.0, 121.9, 126.1, 127.6, 132.4, 135.1, 135.2, 168.7, 194.2. IR
(cm-1): 3403, 3056, 2948, 2871, 1730, 1688, 1671, 1458, 1448,
1393, 1368, 1323, 1303, 1227, 1182, 1148, 1096, 1044, 967, 928,
911, 781, 740. HRMS (ESI): calcd for C20H19NO3, [M + H+] =
322.3777; found: 322.3794.
Conclusions
We showed here that the combination of formaldehyde and 1,3
dicarbonyl derivatives was a powerful tool to create molecular
complexity while perfectly fitting with the concept of green
chemistry. In this context, two new aqueous “ABC”-type three
component reactions involving formaldehyde, 1,3-dicarbonyl
compounds and styrenes or indoles derivatives were successfully
developed yielding dihydropyran and C3-substituted indole
derivatives in fair to good yields. The presented MCRs exhibit
a broad substrate scope and afford a direct access to a wide
range of complex organic skeletons, usually synthesized through
multistep processes. Note that this MCR is also tolerant to the
use of aniline derivatives which normally require assistance of
a catalyst further demonstrating the usefulness of this aqueous
MCR.
Characterizations of all other products (5a-h) as well as copies
of NMR spectra are provided in the ESI.†
Typical procedure for the “ABBCC”-type five component
reaction of N-ethylaniline, formaldehyde and acetylacetone
Experimental
All reactions were conducted in a 10 mL V-type flask equipped
with triangle magnetic stirring. In a typical procedure, aqueous
formaldehyde (203 mg, 2.5 mmol, 37 wt% in H2O) was mixed
with N-ethylaniline (123 mg, 1.0 mmol), acetylacetone (250 mg,
2.5 mmol) and water (850 mg) under air. The mixture was then
Typical procedure for three component reaction of
a-methylstyrene, formaldehyde and 2,4-pentanedione
All reactions were conducted in a 10 mL V-type flask equipped
with triangle magnetic stirring. In a typical procedure, aqueous
formaldehyde (203 mg, 2.5 mmol, 37 wt% in H2O) was mixed
with a-methylstyrene (118 mg, 1.0 mmol) and 2,4-pentanedione
(200 mg, 2.0 mmol) under air. The mixture was then stirred
for 3 hours at 80 ◦C. After completion of the reaction, the
◦
stirred for 2 hours at 45 C. After completion of the reaction,
the products were extracted from water with a solution of ethyl
acetate and heptane (1:1 v/v, 6 mL ¥ 2). After concentration of
the organic phases, the crude compounds were purified by flash
chromatography over silica gel.
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Selected product: 3,4a-diacetyl-2,10a-dimethyl-10-ethyl-
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4,4a,5,10,10a-pentahydropyrano[2, 3-b]quinoline (7a): Yellow
1
pale liquid, yield: 77% (Heptane/ethyl acetate: 4/1), H NMR
(300 MHz, CDCl3): d = 1.15 (t, J = 7.4 Hz, 3H), 1.89 (s,
3H), 2.09 (s, 3H), 2.11 (s, 3H), 2.44 (dd, Ja = 15.1 Hz, Jb
=
7.5 Hz, 2H), 2.81 (d, J = 15.8 Hz, 1H), 3.20 (d, J = 15.8 Hz,
1H), 3.54 (d, J = 12.5 Hz, 1H), 3.87 (dd, Ja = 12.5 Hz, Jb =
2.3 Hz, 1H), 7.01 (d, J = 7.3 Hz, 1H), 7.12-7.29 (m, 3H); 13C
NMR (75 MHz, CDCl3) d = 13.3, 18.3, 22.1, 25.0, 25.5, 28.5,
29.3, 53.0, 64.4, 101.4, 126.4, 127.3, 128.3, 140.6, 141.9, 153.8,
194.6, 202.6, 202.7. IR (cm-1): 2977, 2876, 1698, 1636, 1516,
1489, 1357, 1233, 1146, 1119, 1046, 968, 943, 911, 775, 728,
683. HRMS (ESI): calcd for C20H25NO3, [M + H+] = 328.4253;
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Acknowledgements
Authors are grateful to the CNRS and the French Ministry of
research for their financial supports. YG also thanks the CNRS
for the funding of his temporary research associate position.
DDS is grateful to the Agence Nationale de la Recherche (action
CP2D) for his PhD grant.
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