An efficient, one-pot regioselective synthesis of highly functionalized chromen-5-ones and pyrano[3,2-c]chromen-5-ones via a tandem knoevenagel-Michael- cyclization sequence

Article abstract of DOI:10.1055/s-0032-1317543

A facile, convenient, efficient, and high-yielding regioselective synthesis of a combinatorial library of hitherto unreported highly functionalized chromen-5-ones and pyrano[3,2-c]chromen-5-ones has been developed by one-pot three-component coupling of substituted aromatic aldehydes, dimedone/4- hydroxycoumarin with NMSM in the presence of catalytic amount of piperidine in ethanol medium. This transformation presumably proceeds via domino Knoevenagel condensation-Michael addition-intermolecular cyclization sequence creating three new bonds (two C-C and one C-O) and one stereocenter in a single operation. Georg Thieme Verlag KG · Stuttgart · New York.

Full text of DOI:10.1055/s-0032-1317543

2894▌
LETTER
lAettner Efficient, One-Pot Regioselective Synthesis of Highly Functionalized
Chromen-5-ones and Pyrano[3,2-c]chromen-5-ones via a Tandem
Knoevenagel–Michael–Cyclization Sequence
Chromen-5-ones and Pyrano[3,2-c]chromen-5-ones
Jayabal Kamalraja, Doraiswamy Muralidharan, Paramasivan Thirumalai Perumal*
Organic Chemistry Division, CSIR-Central Leather Research Institute, Adyar, Chennai 600020, Tamilnadu, India
Fax +91(44)24911589; E-mail: ptperumal@gmail.com
Received: 21.09.2012; Accepted after revision: 17.10.2012
Michael
donor site
Abstract: A facile, convenient, efficient, and high-yielding regio-
electron-
withdrawing group
selective synthesis of a combinatorial library of hitherto unreported
highly functionalized chromen-5-ones and pyrano[3,2-c]chromen-
5-ones has been developed by one-pot three-component coupling of
substituted aromatic aldehydes, dimedone/4-hydroxycoumarin with
NMSM in the presence of catalytic amount of piperidine in ethanol
medium. This transformation presumably proceeds via domino
Knoevenagel condensation–Michael addition–intermolecular cycli-
zation sequence creating three new bonds (two C–C and one C–O)
and one stereocenter in a single operation.
Michael
acceptor site
NO2
electron-donor
sites
good leaving
group
S
NH
Figure 1 The reaction profile of NMSM
Key words: NMSM, Michael addition, regioselectivity, chromenes
and pyranochromenes, one-pot synthesis
Due to their existence in a wide spectrum of synthetic and
natural products such as alkaloids, flavonoids, tocopher-
ols, and anthocyanins with varied biological properties,
chromenes are a class of privileged heterocycles11 signif-
icant for their spasmolytic, diuretic, anticoagulant, anti-
cancer, and antianaphylactic activities.12 Chromene
derivatives have latterly been applied in the treatment of
human inflammatory TNFα-mediated diseases such as
rheumatoid, psoriatic arthritis, as apoptosis inducers, and
as inhibitors of excitatory amino acid transport.13 They
have also found applications as pigments and as potential
biodegradable agrochemicals.14
Multicomponent reactions (MCRs)1–3 have gained emi-
nence as a synthetic tool for producing structurally com-
plex molecular entities with attractive biological features
through the establishment and cleavage of numerous
carbon–carbon and carbon–heteroatom bonds in one pot.4
It is becoming increasingly important both in academia
and in industry to design less toxic and more environmen-
tally friendly MCRs.5–7
Ambiphilic synthons which contain both nucleophilic and
electrophilic sites have great potential in developing novel
synthetic routes. (E)-N-Methyl-1-(methylthio)-2-nitro-
ethenamine (NMSM) is one such versatile intermediate.8
It contains four active sites with three functional groups
on an ethene motif (Figure 1). With a strongly electron-
withdrawing nitro group, the nitroethylene substructure is
a good Michael acceptor. The thiomethyl group is a good
leaving group and the methylamino group acts as electron
donor and hence a good Michael donor. The ethylene moi-
ety is a polarized push-pull alkene with the C1 showing
electrophilic character and C2 showing nucleophilic char-
acter. NMSM-type molecules are synthetic equivalents of
nitroacetic acid where the ester is masked as a ketene-N,S-
acetal and NMSM is also a synthetic equivalent of gly-
cine. It is used in the synthesis of antiulcer drugs such as
ranitidine9 and nizatidine10 on large scale. Herein we dem-
onstrate the use of the special reactivity of NMSM, for a
convenient combinatorial synthesis of 2-alkylamino-3-
nitro-4H-chromenes and pyrano[3,2-c]chromen-5-ones.
Pyranochromenes have been used for the treatment of nu-
merous neurodegenerative diseases, which include Al-
zheimer’s disease, Huntington’s disease, Parkinson’s
disease, amyotrophic lateral sclerosis, AIDS associated
dementia and Down’s syndrome and are also used in the
treatment of schizophrenia and myoclonus.15 Antihyper-
tensive and anti-ischemic behavior have been exhibited
by aminochromene derivatives16 and other substituted
chromenes encourage apoptosis in tumor cells by binding
to the Bcl-2 protein.17
Although many syntheses of chromens have been de-
scribed,18 many require long reaction times, harsh reac-
tion conditions, expensive catalysts/reagents, high
catalytic loading and multistep protocols. Therefore, a
search for more general, efficient, rapid, and feasible
routes remains a valid exercise.
Previous syntheses of 2-aminochromene and pyrano de-
rivatives have been established via a multicomponent re-
action approach.19 Herein, we disclose a chemo- and
regioselective synthesis of chromen-5-ones and 4H-pyra-
no [3,2-c]chromen-5-ones by one-pot three-component
coupling of NMSM, aromatic aldehydes, and 4-hydroxy-
coumarin/dimedone (Scheme 1). The reactions were com-
SYNLETT 2012, 23, 2894–2898
Advanced online publication: 16.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317543; Art ID: ST-2012-D0805-L
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chromen-5-ones and Pyrano[3,2-c]chromen-5-ones
2895
R2
R2
O
O
R1
R1
R2
O
NO2
NO2
Me
NO2
Me
O
piperidine (20 mol%)
EtOH, r.t., 2–5 h
O
R1
R1
or
+
+
1
S
NH
Me
or
O
N
O
N
CHO
H
Me
H
OH
5
6
3
4
O
O
2
Scheme 1 Synthesis of chromen-5-ones 5 and pyrano[3,2-c]chromen-5-ones 6
pleted within 2–5 hours and the pure products could be periments. While the product was obtained in 65% yield
isolated in high yields simply by filtration. The synthetic when the base was used in a catalytic amount, 0.2 equiva-
route is convergent, and allows easy placement of a vari- lent of piperidine provided the best results. Reducing the
ety of substituents around the periphery of the heterocy- amount of catalyst increased the reaction time and low-
clic ring system.
ered the yield drastically. Further an increase in the
amount of base showed no changes in the reaction time
and yield.
The synthesis of 2-(methylamino)-3-nitro-4,6,7,8-tetra-
hydrochromen-5-ones 5 was first undertaken. Dimedone
(1.0 mmol), 4-nitrobenzaldehyde (1.0 mmol), and NMSM With the optimized reaction conditions in hand, the scope
(1.0 mmol) were selected as test substrates to optimize the and generality of this protocol was next examined by em-
reaction conditions. Initially, the above three-component ploying various aromatic aldehydes. No obvious electron-
coupling was carried out in EtOH at room temperature in ic effects due to the substituent groups on the aldehyde
the absence of catalyst to establish the real effectiveness were observed, and the products were obtained in high
of the catalyst. No formation of the product was observed yields (Table 2).20 After successful coupling of NMSM,
even after 24 hours of stirring. Next, the test reaction was aromatic aldehydes and dimedone at room temperature, 4-
investigated in the presence of various bases and solvents hydroxycoumarin was also utilized in place of dimedone
(Table 1). The best results, in terms of yield and minimum in order to gain further insight about this transformation,
reaction time corresponded to the ethanol and piperidine and to show the versatility of the protocol. Thus, coupling
combination, which was employed in all subsequent ex- of 2, 3, and 4 provided easy access to pyrano[3,2-c]chro-
O
R
O
+
OH
CHO
R
R
H
R
2
3
O
O
O
base
Knoevenagel
condensation
NO2
NO2
NO2
solvent
path I
O
O
N
O
N
O
NH
Me
O
H
S
Me
8
Me
Me
– MeSH
6
R
9
O-attack
O
path II
R
NO2
H
O
R
R
S
N
O
Me
Me
O
4
7
O
O
H
H
NO2
NO2
NO2
O
Michael
addition
O
N
S
S
N
S
O
O
N
Me
Me
Me
– H2O
Me
Me
H
Me
8'
N-attack
9'
6'
Scheme 2 Plausible reaction scenario for the formation of 6
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2894–2898

2896
J. Kamalraja et al.
LETTER
Table 2 Synthesis of Chromen-5-ones 5
Table 1 Effect of the Different Solvents and Bases on the Time and
Yield of Reactiona
R2
R2
O
Entry
Solvent
Base
Time (h) Yield (%)b
piperidine
+
O
R1
R1
c
(20 mol%)
1
2
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
EtOH
H2O
–
24
24
24
24
16
–
NO2
Me
O
EtOH, r.t., 2–5 h
CHO
R1
R1
K2CO3
10
1
3
O
N
NO2
c
H
3
NaOMe
NaOEt
–
+
5
c
S
NH
Me
4
–
Me
4
5
DABCO
piperidine
pyrrolidine
Et3N
55
86
65
60
40
28
55
30
69
25
Product R1
R2
Time(h) Yield (%)a
6
2.0
Entry
7
8
10
12
10
12
8
1
2
5a
5b
5c
5d
5e
5f
Me
4-O2N
2-F
2.0
2.5
3.5
2.2
4.0
2.5
5.0
2.3
3.2
3.5
86
78
79
76
80
76
78
80
85
84
8
Me
Me
Me
Me
Me
Me
Me
H
9
L-proline
DMAP
3
4-Me
2-O2N
2,4-Cl2
3-NO2
4-MeO
4-Br
10
11
12
13
14
15
16
4
DBU
5
piperidine
piperidine
piperidine
piperidine
piperidine
6
MeOH
MeCN
toluene
DMF
24
18
12
18
7
5g
5h
5i
8
c
–
9
4-Br
12
10
5j
H
4-Cl
a All reactions were performed at r.t.
b Yield after recrystallization from EtOH.
c Reaction failed to occur.
a Yield after recrystallization from ethanol.
Table 3 Synthesis of Pyrano[3,2-c]chromen-5-ones 6
men-5-ones 6 in good yields (Table 3).21 The utility of the
reaction was demonstrated for a wide range of functional
groups R. However, the reactions of NMSM with aliphat-
ic aldehydes as well as acyclic 1,3-dicarbonyl compounds
were unsuccessful.
R
R
piperidine
(20 mol%)
O
CHO
OH
O
NO2
Me
NO2
3
O
EtOH, r.t., 2–5 h
The main advantage of this procedure is the simple work-
up, isolating product in high purity simply by filtration.
The structure of 5 was deduced using NMR spectroscopic,
mass spectrometric, elemental analysis and single crystal
XRD analysis (Figure 2).22
+
O
N
S
NH
Me
H
O
Me
4
6
2
Entry
Product
R
Time (h)
Yield (%)a
Taking into consideration the entire outcome, a plausible
mechanistic pathway for the domino coupling is depicted
in Scheme 2. The first step is the Knoevenagel condensa-
tion between active methylene compound 2 and aldehyde
3 that leads to the adduct 7, which acts as a Michael accep-
tor. The adduct 7 immediately undergoes Michael-type
addition with NMSM 4 to generate the open-chain inter-
mediate 8. The intermediate 8 undergoes intramolecular
O-cyclization via path I to give compound 6 with elimina-
tion of MeSH. The intermediate 8 may exist in another ro-
tameric form 8′, which could undergo N-cyclization via
path II to give compound 6′. During our investigations,
we did not observe even traces of 6′ and only 6 was ob-
tained exclusively, suggesting O-cyclization through
route I, making the protocol highly chemo- and regio-
selective.
1
2
3
4
5
6
6a
6b
6c
6d
6e
6f
4-Me
3.0
2.5
2.2
2.7
3.5
2.5
86
81
76
80
79
83
4-Cl
3-O2N
2-F
4-MeO
4-Br
a Yield after recrystallization from ethanol.
In summary, we have developed a convenient, efficient,
chemoselective, and regioselective synthesis of tetrahy-
drochromen-5-one and pyrano[3,2-c]chromen-5-one
Synlett 2012, 23, 2894–2898
© Georg Thieme Verlag Stuttgart · New York

LETTER
Chromen-5-ones and Pyrano[3,2-c]chromen-5-ones
2897
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Acknowledgment
The author J. Kamalraja thanks the Council of Scientific and Indu-
strial Research (CSIR), New Delhi, India for the research fellow-
ship.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.SnoIufproig
m
iotSrat
ungIifoop
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deposit@ccdc.cam.ac.uk].
7,7-Dimethyl-2-(methylamino)-3-nitro-4-(4-
nitrophenyl)-7,8-dihydro-4H-chromen-5(6H)-one (5a):
white solid; yield: 86%; mp 220–222 °C. IR (KBr): 3203,
2598, 1682, 1637, 1515, 1469, 1357, 1263, 1137, 1056, 825,
694, 632, 544 cm–1. 1H NMR (500 MHz, DMSO-d6): δ =
0.91 (s, 3 H, Me), 1.06 (s, 3 H, Me), 2.13 (d, J = 16 Hz, 1 H,
CH), 2.28 (d, J = 16.5 Hz, 1 H, CH), 2.64 (dd, J = 18 Hz, 2
H, CH2), 3.12 (d, J = 5.5 Hz, 3 H, NMe), 5.0 (s, 1 H, CH),
7.53 (d, J = 9.0 Hz, 2 H, ArH), 8.11 (d, J = 8.5 Hz, 2 H, ArH),
10.28 (q, J = 5.0 Hz, 1 H, D2O exchangeable, NH). 13C NMR
(125 MHz, DMSO-d6): δ = 27.2, 28.8, 28.9, 32.4, 36.6, 39.6,
50.1, 108.1, 114.6, 123.5, 130.1, 146.7, 150.6, 157.6, 162.0,
195.9. ESI–MS: 374 [M+ + 1]. Anal. Calcd for C18H19N3O6:
C, 57.90; H, 5.13; N, 11.25. Found: C, 57.96; H, 5.07; N,
11.31.
2-(Methylamino)-3-nitro-4-para-tolylpyrano[3,2-
c]chromen-5(4H)-one (6a): white solid; yield: 86%; mp
258–260 °C. IR (KBr): 3211, 2923, 2369, 1728, 1674, 1628,
1359, 1264, 1153, 1110, 948, 807, 771, 689, 530, 438 cm–1.
1H NMR (500 MHz, DMSO-d6): δ = 2.22 (s, 3 H, Me), 3.22
(d, J = 5.0 Hz, 3 H, NMe), 5.03 (s, 1 H, CH), 7.06 (d, J = 8.0
Hz, 2 H, ArH), 7.21 (d, J = 7.5 Hz, 2 H, ArH), 7.47–7.52 (m,
2 H, ArH), 7.72 (t, J = 7.5 Hz, 1 H, ArH), 8.00 (d, J = 7.5 Hz,
1 H, ArH), 10.39 (d, J = 5.5 Hz, 1 H, D2O exchangeable,
NH). 13C NMR (125 MHz, DMSO-d6): δ = 21.1, 29.2, 37.5,
107.3, 108.3, 113.1, 117.1, 123.3, 125.5, 128.8, 129.1,
133.6, 136.8, 138.8, 152.2, 152.4, 157.2, 159.7. ESI–MS:
365 [M+ + 1]. Anal. Calcd for C20H16N2O5: C, 65.93; H,
4.43; N, 7.69. Found: C, 65.87; H, 4.49; N, 7.74.
(20) General Procedure for the Synthesis of
Tetrahydrochromen-5-one 5a–j: A solution of the
requisite aldehyde (1.0 mmol), cyclic 1,3-dicarbonyl
compound (1.0 mmol), NMSM (1.0 mmol), and piperidine
(0.2 equiv) in EtOH (2 mL) was stirred for the appropriate
time (Table 2). After reaction was complete as indicated by
TLC, the product was filtered and washed with EtOH (2 mL)
to remove the excess base and other impurities. Finally, the
products were recrystallized from EtOH.
Synlett 2012, 23, 2894–2898
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