Microwave-assisted organocatalytic multicomponent Knoevenagel/hetero Diels-Alder reaction for the synthesis of 2,3-dihydropyran[2,3-c]pyrazoles

Article abstract of DOI:10.1016/j.tetlet.2009.09.047

A rapid protocol for the multicomponent microwave-assisted organocatalytic domino Knoevenagel/hetero Diels-Alder reaction (DKHDA) has been developed for the synthesis of 2,3-dihydropyran[2,3-c]pyrazoles. The reported procedure could be used for the fast g

Full text of DOI:10.1016/j.tetlet.2009.09.047

Tetrahedron Letters 50 (2009) 6572–6575
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Microwave-assisted organocatalytic multicomponent Knoevenagel/hetero
Diels–Alder reaction for the synthesis of 2,3-dihydropyran[2,3-c]pyrazoles
Marco Radi a, Vincenzo Bernardo a, Beatrice Bechi a, Daniele Castagnolo a, Mafalda Pagano a,
Maurizio Botta a,b,
*
a Dipartimento Farmaco Chimico Tecnologico, University of Siena, Via Alcide de Gasperi 2, I-53100 Siena, Italy
b Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, BioLife Science Bldg.,
Suite 333, 1900 N 12th Street, Philadelphia, PA 19122, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
A rapid protocol for the multicomponent microwave-assisted organocatalytic domino Knoevenagel/hetero
Diels–Alder reaction (DKHDA) has been developed for the synthesis of 2,3-dihydropyran[2,3-c]pyrazoles.
The reported procedure could be used for the fast generation of novel substituted 2,3-dihydropyran[2,3-
c]pyrazoles with potential anti-tuberculosis activity.
Received 3 August 2009
Revised 8 September 2009
Accepted 9 September 2009
Available online 12 September 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Keywords:
Multicomponent reaction
Organocatalysis
Microwave
Knoevenagel
Hetero Diels–Alder
During the course of a drug discovery program dedicated to the
identification of new molecular scaffolds as potential anti-tubercu-
losis agents, our research group identified compound 1 (Fig. 1) as a
promising hit for further optimization.1 In order to expand our
knowledge on the structure activity relationship (SAR) for this fam-
ily of compounds, we became interested in the development of rigid
analogues such as the 2,3-dihydropyran[2,3-c]pyrazole 2 (Fig. 1).
Furtherstudiesrevealedin factthebiologicalimportanceofa p-chlo-
rophenyl moiety fixed in a ‘syn’ relative position with respect to the
C3-methyl group.2 The synthesis of compounds closely related to 2
via inverse-electron-demand hetero Diels–Alder (HDA) reaction3
between 4-arylidene-5-pyrazolones (general structure I, Fig. 2)
and substituted vinyl ethers, has been thoroughly investigated by
Desimoni in the late seventies4 and more recently by Tietze and
co-workers.5 According to these studies, it has been hypothesized
that pyrazolones in the Z-configuration (I, characteristic for com-
pounds having R1 – H) do not give directly the 1,4-cycloaddition
product but are thermally converted into the E-isomers (II) in order
to allow the formation of the products (III) (Fig. 2).6 The latter com-
pounds were commonly obtained after long reaction times (2–7
days) as diastereoisomeric mixtures of cis and trans cycloadducts
in a 1:1 ratio (when R1 = Me, R2 = Et).6a Accordingly, we became
interested in the development of a time- and atom-efficient
"Syn" relative position
fundamental for
antimycobacterial
activity
Ar
Ar
Me
Me
O
OEt
N
N
O
OH
N
N
Ar
Ar
Ar = p-ClPh
1
2
Figure 1. Hit compound 1 and the rigid target analogue 2.
Ar
R1
R1
Ar
N
N
O
O
N
N
I
II
HDA
reaction
Ph
Ph
Ar
OR2
R1
N
OR2
O
N
III
Ph
* Corresponding author. Tel.: +39 0577 234306; fax: +39 0577 234333.
E-mail address: botta.maurizio@gmail.com (M. Botta).
Figure 2.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.09.047

M. Radi et al. / Tetrahedron Letters 50 (2009) 6572–6575
6573
Table 1
Ar
Optimizing the Knoevenagel condensation multicomponent
Ar
ArCHO
4c (%)
5c (%)
N
N
Ar
Entry
Method
Solvent
Temp (°C)
Time (min)
N
N
N
O
O
N
Method
A or B
Aa
Bb
Bb
—
—
EtOH
130
110
110
40
3
3
87
32
41
5
38
50
N
N
OH
HO
1
2
3
Ar
Ar
Ar
3
4
5
a
b
c
Method
C or D
Conventional heating.
Microwave heating; reactions were conducted in a sealed tube.
Determined by chiral HPLC–MS using an (S,S)-Whelk-O1 column (methanol/
OEt
Ar
Ar = p-ClPh
Ar
formic acid (0.05%) 85:15, flow rate 1.0 mL/min, UV-254 nm).
5
OEt
OEt
N
N
O
O
2b
N
N
Initially, each step of the KHDA was studied independently. Die-
nophile 4 (the Z-configuration was confirmed by NOE experiments)
was synthesized in good yields by heating pyrazolone 3 (1.5 equiv)
with p-chlorobenzaldehyde (3 equiv) under neat conditions11 at
130 °C while the use of microwave irradiation always increased
the formation of the side-product 5 (resulting from the Michael
addition of compound 3 on the activated double bond of 4)12 (Table
1). The HDA reaction of compound 4 with EVE under different reac-
tion conditions (see Table 2) was then investigated in order to
identify the more efficient experimental procedure both in terms
of yields and diastereoisomeric excess. After an initial reaction con-
ducted according to the standard HDA protocol (Table 2, entry 1),
which led to the formation of pyranes 2a–b in 1/1 ratio, several dif-
ferent microwave-assisted protocols were investigated. Compound
4 and EVE were reacted in different solvents (Table 2, entries 2–7)
Ar
Ar
2a
Scheme 1. Two-step procedure for the synthesis of 2.
procedure for the preparation of rigid analogues such as the 2,3-
dihydropyran[2,3-c]pyrazole 2 that could allow us to quickly pro-
duce novel analogues to be screened as anti-tuberculosis agents
(Fig. 1). In this context, multicomponent reactions(MCRs) are partic-
ularly appealing, since they provide a practical access to complex
polycyclic products in a single step by simultaneous reactions of
three or more reagents, and allow to easily achieve substituent
diversity of the core structure by varying each component.7 We
decided to combine the advantage of MCRs with that of microwave
assisted technique and organocatalysis in order to speed up the
synthesis of 2,3-dihydropyran[2,3-c]pyrazoles such as 2.8 The latter
compound can in fact be seen as the product of a two step protocol
starting with a Knoevenagel condensation between a pyrazol-2-
one (3) and the opportune aldehyde, followed by a HDA reaction
with ethylvinyl ether (EVE). While the Knoevenagel condensation
is known to be catalyzed by both acids and bases, the Hetero
Diels–Alder reaction can be accelerated by Lewis acids or hydrogen
bond coordination with the heterodiene carbonyl group.9 Accord-
ingly, an organic compound bearing functional groups able to cata-
lyze both synthetic steps could be favorably employed in a MCR
for the synthesis of 2,3-dihydropyran[2,3-c]pyrazoles such as 2.
Moreover, considering that the thermal Z/E conversion of dieno-
philes I seems to be essential for the outcome of the HDA reaction,
microwave irradiation could be used to additionally boost the for-
mation of the desired product.10 Herein we report a straightforward
protocol for the microwave-assisted organocatalytic multicompo-
nent Knoevenagel/hetero Diels–Alder reaction (KHDA) applied to
the synthesis of 2,3-dihydropyran[2,3-c]pyrazoles (see Scheme 1).
N
H
(B)
N
H
(A)
N
H
(C)
OH
OH
MeO
COOH
N
H
N
N
H
H
OH
OTMS
(E)
(F)
(D)
OMe
InCl3
(G)
Figure 3. Catalysts.
Table 2
Optimizing the HDA reaction
Entry
Solvent
Method
Time (h)
2ac (%)
2bc (%)
4c (%)
5c (%)
Catd
1
2
3
4
5
6
7
8
9
10
11
12
13
—
Ca
48
38
20
6
41
4
31
13
2
12
3
7
—
8
19
10
11
26
21
—
—
—
—
—
—
—
—
—
—
A
B
E
A
B
MeOH
EtOH
tBuOH
CH3CN
DME
Toluene
tBuOH
tBuOH
tBuOH
DME
Db
Db
Db
Db
Db
Db
Db
Db
Db
Db
Db
Db
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
62
86
35
92
77
100
—
—
—
—
—
48
9
26
17
5
15
—
24
67
47
30
52
42
—
11
24
10
18
DME
DME
8
E
a
b
c
Conventional heating, 80 °C; reaction was conducted in a sealed tube.
Microwave heating, 110 °C; reactions were conducted in a sealed tube.
Determined by chiral HPLC–MS using an (S,S)-Whelk-O1 column (methanol/formic acid (0.05%) 85:15, flow rate 1.0 mL/min, UV-254 nm).
d
All the catalysts were used in 20 mol % amount.

6574
M. Radi et al. / Tetrahedron Letters 50 (2009) 6572–6575
Cl
Cl
Cl
OEt
Cl
MW
110 oC
N
N
N
N
OEt
O
OEt
N
N
OH
HO
N
N
O
O
30min
cat
N
N
CHO
2a
5
2b
4
3
Cl
Cl
Cl
Cl
Cl
Scheme 2. Microwave-assisted organocatalytic multicomponent Knoevenagel/hetero Diels–Alder reaction (KHDA).
due to the loss of a hydrogen-donor moiety. The pyrrolidine cata-
lyst A probably catalyzed a retro-Knoevenagel reaction,14 which
resulted in an increase of the side-product 5. Once the usefulness
of diaryl-prolinol derivatives in the catalysis of the microwave-as-
sisted HDA reaction was verified, we applied the same reaction
conditions to the multicomponent KHDA reaction. In a classical
Table 3
Optimizing the DKHDA reaction
Entry
Solvent
Catalysta
2ab (%)
2bb (%)
5b (%)
Ratio 2a:2b
1
2
3
4
5
6
7
8
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
tBuOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
DME
DME
DME
DME
DME
DME
DME
—
—
B
C
D
E
—
—
Trace
18
23
42
54
41
—
Trace
27
4
51
43
38
78
Trace
4
34
49
36
60
—
—
4:1
4:1
4:1
4:1
4:1
1.5:1
—
1.5:1
1.5:1
1.5:1
1.5:1
1.5:1
—
56c
56
20
32
27
11
—
12c
15
6
procedure,
a mixture of pyrazolone 3 (1 equiv), aldehyde 4
8
8
7
—
27
33c
19
20
18
—
(1 equiv), and EVE (10 equiv) was irradiated at 110 °C for 30 min
in the presence of the opportune catalyst (Scheme 2, Table 3).
Apart from pyrrolidine, which showed the increase in the forma-
tion of the side-product 5, a series of catalysts (B–G, Fig. 3) were
used in the multicomponent KHDA reaction: diaryl-prolinols C
and F were used in order to analyze how the functionalization of
the aryl moiety could influence the yields and diastereomeric ex-
F
G
—
B
C
D
E
9
42
50c
27
33
32
—
10
11
12
13
14
15
16
17
18
19
20
21
22
F
cess. The commonly used L-proline (D) and the lewis acid in-
G
—
B
C
D
E
F
G
B
—
—
—
dium-chloride (G) were also introduced in order to have a wider
picture of the catalyst’s effect. The results reported in Table 3 high-
light the importance of the catalyst both for the Knoevenagel reac-
tion between 3 and 4 and the next HDA reaction with EVE: as
shown in entries 1, 8, and 15. In the absence of the catalyst the
reaction did not start at all, while the best results were obtained.
in the presence of diaryl-prolinols B and C. Neat reaction condi-
tions (Table 3, entry 22) were not appropriate for this multicompo-
nent KHDA protocol, giving high yields of the side-product 5. Once
more, the importance of the double hydrogen bond coordination
for the carbonyl activation was also proved by the lower yields ob-
tained with the O-TMS protected catalyst E and the deactivated
catalyst F bearing electron releasing m-OMe groups on the aryl
45c
38
30
18
24
10
21
15c
19
14
6
2.3:1
2.3:1
2.3:1
3:1
2.3:1
1.2:1
2.3:1
10
12
9
52
a
All the catalysts were used in 20 mol % amount.
Determined by chiral HPLC–MS using an (S,S)-Whelk-O1 column (methanol/
b
formic acid (0.05%) 85:15, flow rate 1.0 mL/min, UV-254 nm).
c
Isolated yield.
at 110 °C under microwave irradiation for 30 min thus allowing us
to select the best protic and aprotic solvents (tBuOH and DME, en-
tries 4 and 6) to be used next in combination with different organ-
ocatalysts (Table 2, entries 8–13). All the reactions were analyzed
via HPLC–MS in order to quickly select the best reaction parame-
ters for further optimizations. The organocatalyst to be used in
the HDA reaction should possess one or two hydrogen donor moi-
eties13 (to activate the carbonyl group of the heterodiene) and a
secondary amine moiety for iminium catalysis of the Knoevenagel
reaction in the final multicomponent KHDA procedure. Accord-
ingly, we combined the two solvents selected above with the
organocatalysts A, B, and E reported in Figure 3 (Table 2, entries
8–13). The use of these catalysts demonstrated the important role
played by the hydrogen bond coordination of the catalyst in accel-
erating the HDA reaction. In fact, while the HDA reactions in tBuOH
(Table 2, entries 8–10) always gave the desired products 2a and 2b
in high yields (probably due to additional coordination with the
solvents), the reactions in DME (Table 2, entries 11–13) led to 2a
and 2b in lower yield but allowed us to prove the importance of
the sole catalyst in accelerating the HDA reaction (compare entry
6 with entries 11–13). In addition, while the carbonyl activation
by double hydrogen bond (catalyst B) gave the best results both
in terms of yields and diastereomeric excess (Table 2, entries 9
and 12), the O-TMS-protected catalyst E showed minor efficiency
moieties. L-Proline, gave high yields of the side-product 5 while
InCl3 gave unsatisfactory results, even if outcome was different,
regardless of the solvent used.
In summary, an efficient multicomponent microwave-assisted
KHDA protocol for the synthesis of 2,3-dihydropyran[2,3-c]pyra-
zoles has been developed. Using the diaryl-prolinol catalyst B
t
and BuOH as the solvents, it was possible to obtain the desired
compounds 2a and 2b in good yields (56% and 12%, respectively)
and improved diastereoisomeric ratio (4:1) compared to the re-
sults previously obtained for similar compounds. The exploitation
of this procedure will allow us to quickly synthesize novel rigid
analogues of compound 1 as potential antitubercular agents.
Acknowledgments
We gratefully acknowledge financial support provided by the
Fondazione Monte dei Paschi di Siena and the University of Siena.
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