Catalyst-free green synthesis of dihydropyrano[2,3-c]pyrazole scaffolds assisted by ethylene glycol (E-G) as a reusable and biodegradable solvent medium

Article abstract of DOI:10.1007/s12039-020-01775-4

Abstract: We revealed a catalyst-free, green and rapid one-pot four-component tandem strategy for the preparation of dihydropyrano[2,3-c]pyrazoles – a biologically significant scaffold – via Knoevenagel-Michael cyclocondensation based on green chemistry p

Full text of DOI:10.1007/s12039-020-01775-4

J. Chem. Sci.
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REGULAR ARTICLE
Catalyst-free green synthesis of dihydropyrano[2,3-c]pyrazole
scaffolds assisted by ethylene glycol (E-G) as a reusable
and biodegradable solvent medium
F ARZANE H M OHAM ADPOUR
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Keywords.
d i h y d r op yr ano [ 2, 3- c] py r az ol es
C
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-
f
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;
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(E
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;
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pr
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;
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m e di u m;
.
1
1
. Introduction
or ga ni c r ea c ti ons to pr e pa re som e imp or ta nt
c om poun ds.
Ov e r th e p re v io u s y ear s by i nc re as ed de man d f or
s u s ta i n a b le , e n v ir on men t al l y f ri en dl y , an d e ff e c tiv e
s y n th e s is a p p ro a c h es i n gr ee n ch em is tr y , ca t al yst -f r e e,
s o l ve n t- me d i a te d pr o to co ls f or p rep ar i ng t he or ga ni c
m i x tu re s h a s e me r ge d as a k ey ap pr oa ch co nsi de r ing
t h e i r lo w c o s t, s imp l e wo rk up , de cr ea se d p oll uti on,
a n d p re v e n ti n g th e i nfl uen ce o f t he ca t al ys t on se nsi -
t i v e s u b s tra te s . In t he or g ani c sy nt h es iz in g p ro ce du re ,
t h e re a c ti o n me d i um ha s a k ey r ol e i n en co ur agi ng th e
c o n ta c t wi th in th e r eac t ant s an d ev en al t er in g th e
re a c ti o n p ro g re s s . Hen ce , t he se ar ch f or gr ee n r ea c ti on
s o l ve n ts wi th e x cl u si ve f un ct io ns an d f eat u re s is st ill
s i g ni fi c an t in th e pr es en t g ree n o rg ani c syn the si s
i n v es ti g a tio n . Re c ent l y, ex t en si ve at t en t io n ha s be e n
d ri v en b y e th y l en e gl y co l ( E-G ) as a k in d of a gr e en
a n d fi n a n c ia lly v ia bl e al t er na t iv e t o t he co nv ent ion al
s o l ve n ts . It in c l u de s f avo r abl e f eat u re s l ik e non - cor -
ro s i v en e s s , s ta b i lit y, an d d ece nt so l ub il i ty i n or ga ni c
c o mp o u n d s. Al so , et h yl en e gl y co l ( E-G ) was al so use d
a s a g re e n re a c ti o n en vi r on men t i n so me co nve ni en t
B ioc he m ist s a nd syn the ti c or ga ni c c he mi sts ha ve
be e n f as ci na te d by th e st ru ct ur es c om pr ising the
pyr a nop yr az ol e de r iva ti ve s a s a r es ult of th e ir bio-
2
lo gi ca l a nd ph a rm a c eu ti ca l a c ti vit ie s ( Fi g ur e 1) .
The r e a re r ep or ts in th e li te r at ur e r eg ar di ng pyr a -
3
no pyr az ol e de r iva ti ve s, bi ode gr a da ble a gr oc he mic a ls ,
4
a n in hibi tor of th e hu ma n C hk1 ki na se, a nti ca nc er ,
5a
5
a na lge si c, m oll usc ic ida l a nd a nti mi cr ob ia l.
b
6
7
The r e a re num e r ous a ppr oa c he s f or syn the s iz ing
th es e c om poun ds usi ng va r iou s c at al yst s suc h a s Zr O
2
1 0
8
NP s, c hol ine c hlo ri de /Ur e a de e p, is onic oti nic ,
9
1
m ole c ula r si ev es, m eg lum ine , C APB , L- p ro line /
1
1 2
1 3
1
4
1 5
1 6
KF -a l umi na ,
C TACl ,
li pa se ,
bov ine s er um
1 9
m or phol ine tr ifl at e,
1
7
1 8
a lbu min ,
TP S PP TNM ,
na nop ar t ic le - suppo r te d I L,
b- cy cl ode xt r in,
2
0
2 1
[ Da bco - H][ Ac O] ,
F e O @ S iO
3 4 2
2
2
2 3
sod ium a sc or ba te ,
2 6
2
4
2
5
na no- S iO /DAB C O,
2
Na F,
ph ylli ne a nd [ HMI M ]C ( NO ) . I t wa s sho wn tha t
na no- S iO2 ,
2 8
t
h
e
o
-
2
7
2
3
th es e r ep or te d pr oc e dur e s le a d to num e r ous c a se s .
Tho ugh, som e of th e syn the ti c pol ic ie s c ont ain a ls o
*
F
o
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p
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Electronic supplementary material: The online version of this article (https://doi.org/10.1007/s12039-020-01775-4) contains supple-
mentary material, which is available to authorized users.

7
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a
g
e
2
o
f
9
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2
OH
O
OH
O
CN
CN
N
N
N
N
O
ph
N
H
NH2
O
N
H
NH2
ph
Inhibitor of human chk1 kinase
Antimicrobial
Molluscicide
H C
3
O
OH
O
F3C
CN
OH
N
N
O
NH2
CN
N
N
H
NH2
F
Anticancer agent
Inhibitor of human chk1 kinase
Figure 1.
Bi
o
l
og
ic
al
ly
ac
ti
v
e
mo
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ec
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s
wi
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h
di
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3
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c
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p
y
r
a
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o
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s
c
a
f
f
o
l
d
.
R1
H
O
R1
O
3
CN
NH2
CN
4
Ethylene glycol
Catalyst-free, 100 °C
O
N
CN
N
O
R2
O
1
5
a-w
R2 NHNH2
2
Scheme 1.
S
yn
th
es
i
s
of
di
hy
d
ro
py
r
an
o
[2
,
3- c
]p
yr
az
o
l
e
s
ca
f
fo
l
ds
.
re s tr ic ti o n s re g a rdi n g t he ex pe ns iv e r eag en t s, m et al th e a bove - m en tio ne d di ffi c ult ie s a nd due to o ur c ur -
c at a ly s t , e n v ir o n me nt a l ha za rd , l on g r eac t io n ti me , r en t se ve r e a tte nt ion on e nvi ro nme nt all y be ni gn pr o-
2
9 –3 2
h a rs h re a c ti o n ci r cu mst an ce s, mo no to no u s wor ku p to co ls
th e se a rc h f or e co -s af e , si mp le a nd
p ro c e s s , u n a c c e p tab l e y ie ld , an d u si ng t he hom og e- e ff e c tiv e st ra te gi es c ap ab le of pr om oti ng or ga nic
n e o u s c a ta ly s t th a t i s se pa ra te d pr o bl ema t i cal ly f r om r ea c ti ons und er gr e en c ir c ums ta nc es ha s a ttr a c te d a
t h e re a c ti o n mi xt u re an d r eus ed . Nev ert he le ss, hug e de a l of in te re st in pr od uci ng di hydr op yr ano[ 2,3-
d e v e lo p in g g re e n , mi l d an d mo de st me asu r es is th e c] pyr a zo le sc a ff ol ds. He nc e, he r e th e c at aly st- f r e e
l e ad i ng o b je c ti v e of gr ee n ch em is tr y t o r em ove th e a nd e nvi ro nme nt a lly f r ie ndl y syn the si s of dihy -
u s a g e a n d c re a ti o n of ha za rd ou s ma te ri a ls . Owin g to dr op yr an o[ 2,3-c] pyr a zo le sc a ff ol ds a re r ep or te d via

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ag
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72
e t hy l en e g ly c o l ( E-G ) as a gr ee n, r eus ab le a nd
b i o de g ra d a b l e p ro mot i ng me di a via t an de m Kno eve -
n a g e l-M ic h a e l c yc l oc on de nsat i on r eac t io n of e thy l
a cet o a c e ta te , h y d r azi n e hy d rat e /p he ny lh ydr az i ne , a ro -
m a t ic /a l ip h at i c a ld eh yd es an d ma lo no ni t r il e pr ov ide d
t h e a n ti c ip a te d p ro du ct s i n o ut st an di n g yi e ld s an d sho r t
re a c ti o n ti me s wh ic h mi gh t so l ve so me co st p r oble m s
i n th e in d u s t ry . S ub se qu en t l y, we st u di ed t he r ec yc l a-
b i l it y o f th e g ree n et h yl en e gl y co l f or t he a bove
re a c ti o n . Ho we v e r, t he E- G ca n b e r ecy cl ed at le a st si x
t i me s wi th n o c o ns i der ab l e r edu ct i on i n ac t iv i ty m ak -
i n g it g re a tl y a d v a nt ag eo us i n ad dr es si n g t he i ndu str ia l
re q u ire m e n ts a n d en vi r on men t al wo rr ie s.
a
n
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b
a
t
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(
1
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2.3 Comparing the spectroscopic information,
the products were categorized ( HNMR)
1
2
. Experimental
2.3 a 6-amino-3-methyl-4-phenyl-2,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5g):
2
.
1
G
e
n
e
r
a
l
i
n
f
o
r
m
a
t
i
o
n
U
t
i
l
i
z
i
n
g
a
n
E
l
e
c
t
r
o
t
h
e
r
m
a
l
9
1
0
0
d
e
v
i
c
e
,
a
l
l
c
o
m
g
p
o
u
n
d
s
’
r
m
m
e
a
l
t
i
n
g
p
o
i
n
t
s
w
e
r
e
f
o
u
n
d
.
M
o
r
e
o
v
e
r
,
r
e
c
o
r
d
i
n
n
u
c
l
e
a
1
g
n
e
t
i
c
r
e
s
o
n
4
a
n
c
e
a
,
H
N
M
R
s
p
e
c
t
r
a
w
e
r
e
c
a
r
r
i
e
d
o
u
t
o
n
a
B
r
u
k
e
r
D
R
X
-
0
0
n
d
B
r
u
k
e
r
D
R
X
-
3
0
0
A
v
a
n
c
a
e
t
o
o
l
w
i
t
h
D
M
S
O
-
d 6
a
s
a
s
o
l
v
e
n
t
.
A
l
l
s
o
l
v
e
n
k
l
t
s
a
n
d
r
e
g
e
n
t
s
w
e
r
e
CN
b
o
u
g
h
t
f
r
o
m
A
c
r
o
s
,
M
e
r
c
k
,
a
n
d
F
l
u
a
c
h
e
m
i
c
a
l
c
o
m
p
a
n
i
e
s
N
a
n
d
w
e
r
e
u
t
i
l
i
z
e
d
w
i
t
h
n
o
a
d
d
i
t
i
o
n
a
p
u
r
i
fi
c
a
t
i
o
n
.
N
H
O
NH2
2
.
2
O
v
e
r
a
l
l
p
r
o
c
e
s
s
o
f
p
r
e
p
a
r
i
n
g
(
5
a
-
w
)
5g
1
A
m
i
x
t
u
r
e
o
f
e
t
h
y
l
a
c
e
t
o
a
c
e
t
a
t
e
(
1
,
1
m
m
o
l
)
,
h
y
d
r
a
z
i
n
e
Y
i
e
l
d
:
9
4
%
;
M
.
p
.
2
4
3
–
2
4
5
°
C
;
H
N
M
R
,
(
3
0
0
M
H
z
,
h
y
d
r
a
t
e
/
p
h
e
n
y
l
h
y
d
r
a
z
i
n
e
(2
d
,
1
m
m
o
l
)
,
a
r
o
m
a
t
i
c
/
a
l
i
p
h
a
t
i
c
D
M
S
O
-
d 6
H 2
3
)
:
1
.
7
9
(
3
H
,
s
,
C
, J
H 3
=
)
,
4
.
6
1
(
1
H
,
s
C
H
A
r
)
,
6
.
8
9
a
l
d
e
h
y
d
e
s
(
3
,
1
m
m
o
l
)
a
t
n
m
a
l
o
n
o
n
i
t
r
i
l
e
(
4
,
1
m
s
m
o
l
)
w
d
a
s
(
2
H
,
s
,
N
)
,
7
.
1
8
(
2
H
,
d
,
9
.
2
H
z
,
A
r
H
)
,
7
.
2
1
-
7
.
2
6
(
1
H
,
a
d
d
e
d
E
-
G
(
3
m
L
)
,
a
n
d
h
e
o
b
t
a
i
n
e
d
m
i
x
t
u
r
e
w
a
h
e
a
t
e
i
n
m
,
A
r
H
)
,
7
.
1
-
7
.
3
6
(
2
H
m
,
A
r
H
)
,
1
2
.
1
1
(
1
H
,
s
,
N
H
)
.
Figure 2.
T
h
e
r
e
c
y
c
l
a
b
i
l
i
t
y
o
f
t
h
e
e
t
h
y
l
e
n
e
g
l
y
c
o
l
i
n
t
h
e
p
r
e
p
a
r
a
t
i
o
n
o
f
5
g
.

7
2
P
a
g
e
4
o
f
9
J. Chem. Sci.
(
2
0
2
0
)
1
3
2
:
7
2
Table 1.
O
p
t
i
m
i
z
i
n
g
t
h
e
r
e
a
c
t
i
o
n
c
i
r
c
u
m
s
t
a
n
c
e
i
n
t
h
e
e
x
i
s
t
e
n
c
e
o
f
v
a
r
i
o
u
s
s
o
l
v
e
n
t
s
a
n
d
t
e
m
p
e
r
a
t
u
r
e
s
o
n
t
h
e
y
i
e
l
d
o
f
5
g
.
Ph
Me
Me
Ph
CN
CN
CN
NH2
O
NH H O
N
2
.
2
H
O
N
H
O
NH2
O
O
En
t
r
y
S
ol
ve
n
t
(
3
m
L)
Te
m
p
er
a
tu
re
(°
C
)
Ti
m
e
(m
i
n)
Is o lat ed Yi el ds ( %)
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
E
E
E
E
E
E
E
H2
H2
EtO H
-
-
-
-
-
-
-
G
G
G
G
G
G
G
r
t
4
3
1
1
2
0
31
4
6
8
9
0 °
0 °
0 °
0 °
C
C
C
C
6
8
0
8
0
0
0
0
47
58
73
8 5
100 °C
0 °
80
94
1
1
C
8
6
6
2
2
8
8
8
8
8
8
8
0
0
0
0
0
0
0
0
0
0
0
0
9 5
67
62
58
43
O
O
R
R
R
R
1
1
R
1
R
R
R
e
e
e
e
fl
fl
fl
fl
ux
ux
ux
ux
3
3
4
4
4
4
4
4
4
4
4
/
E
t
O
H
( 1: 1)
1
1
1
1
1
1
1
1
1
M
e
O
H
e
S
o
l
v
n
O
t
-
f
r
e
e
0
0
0 °
0 °
C
C
x
Tra
Tra
Tra
Tra
Tra
Tra
Tra
ce
ce
ce
ce
ce
ce
ce
D
M
S
F
F
TH
efl
u
D
C
CH Cl 3
D CM
M
H 3
0
0 °
C
C
N
efl
efl
efl
u
u
u
x
x
x
2 . 3 b 6-amino-4-(3-chlorophenyl)-3-methyl-2,4-
dihydropyrano[2,3-c]pyrazole-5-carbonitrile (5q):
f our - e le me nt r ea c ti on be twe e n a c om bina t ion of e thyl
a ce to ac e ta te ( 1 m mol ) , hyd r az in e hyd r at e ( 1 mm ol) ,
be nz a lde hy de ( 1 m mol ) a nd m al onon itr ile ( 1 mm ol) .
S om e sol ve nts li ke DMS O, THF , DMF , C H C N, C HC l
3
Cl
3
a nd DC M we r e a lso e xa mi ne d a nd on ly a sm a ll q ua ntity
of pr od uct s wa s f oun d in th es e sol ve nts a nd sol ve nt- f r e e
c ondi tio ns ( Ta ble 1, e ntr i es 12 –18) . W he r e a s, the
r ea c ti on c ont inue d sl owly in H O, H O/E tOH ( 1:1) ,
CN
2
2
N
Et OH a nd Me OH, th e yi el d a nd r ea c ti on r at e inc r e a se d
( Ta ble 1, e ntr i es 8– 11) . Ac co rd ing to th e d et e ct ed
de te r mi nin g in flu enc e of a lc oho lic sol ve nts on the
r ea c ti on, we th en st udie d th e e ff e c tiv en ess of e thyle ne
gl yc ol a s a sol ve nt f or th is r ea c ti on. An out sta ndi ng
yi el d of 94% wa s c re a te d by usi ng gr e en E- G ( 3 mL)
a s a sol ve nt wit h no f ur the r c at al yst a t 100 °C f or
N
H
O
NH2
5q
1
Y
i
e
l
d
:
8
7
%
;
M
.
p
.
2
2
9
–
2
3
1 °
C
;
H
N
M
R
(
4
0
,
0
M
Hz
,
,
D
M
S
O
-
d 6
)
:
1
.7
7
(
3H
,
s
,
C
H 3
)
,
5
.
0
8
(
1
H
,
s
C HA r)
7
.
1
9–
7
.
4
5
(6
H
,
m
,
Ar
H
an
d
N
H 2
) , 12 .1 5 ( 1H , s , N H).
80 m in ( Ta ble 1 , e ntr y 6) . As obs er ve d in T ab le 2
a nd S ch em e 1 , it wa s in dic a te d th at th is te c hniqu e
c an wor k wit h va r iou s sub str a te s. I t sho uld be note d
th at f or pu ri fy ing th e pr od uct s (5a-w) , a mod es t
3
. Results and Discussion
In th e b e g in n in g , we t oo k i nt o ac co un t sy nt h es izi ng th e fi ltr a ti on a nd r ec r yst a lli ze d wit h e tha no l is ne e de d.
-a m i n o -3 -m e th y l - 4 - p he n y l -2 , 4 - d i h y d r o p y r an o [2 ,3 - c] Als o, th e r ec om m en de d m ec ha ni sm f or syn the s iz ing
6
p y ra z o le -5 -c a rb o n i tr il e (5g) i n t he was st u di ed in va r i- 6 - a m i n o - 3 - m e t h y l - 4 - p h e n y l - 2 , 4 - d i h y d r o p y r a n o [ 2 , 3 -
o u s s o lv e n ts u n de r ca t al ys t- fr e e ci r cu mst an c es a t c] p y r a z o l e - 5 - c a r b o n i t r i l e ( 5g) i s d e m o n s t r a t e d i n
d i f fe re n t te m p e rat u re s i n a mo de l sy st e m in th e S c h e m e 2 .

J. Chem. Sci.
Table 2.
(
2
0
2
0
)
1
3
2
:
7
2
P
ag
e
5
of
9
72
Sy
n
t
h
es
i
s
o
f
d
i
h
y
d
r
o
p
y
r
an
o
[
2,
3- c]
py
r
az
ol
e
s
ca
f
fo
l
ds
.
Cl
NO2
OMe
CN
CN
N
CN
NH2
N
N
H
O
NH2
N
H
N
O
NH2
N
H
O
5
a (90 min, 83%)
5b (80 min, 91%)
Mp. 250-252 °C
5c (75 min, 90%)
Mp. 191-193 °C
Mp. 234-236 °C
Lit. 234-235 °C [12]
Lit. 249-250 °C [12]
Lit. 190-193 °C [13]
Br
F
Cl
CN
NH
Cl
CN
CN
NH2
N
N
H
N
O
2
N
N
H
N
H
O
O
NH2
5
d (90 min, 85%)
5e (70 min, 96%)
Mp. 240-242 °C
5f (90 min, 81%)
Mp. 228-230 °C
Mp. 180-182 °C
Lit. 180-181 °C [8]
Lit. 242-243 °C [12]
Lit. 229-230 °C [12]
OH
F
CN
CN
N
N
CN
NH2
N
H
O
NH2
N
H
O
NH2
N
N
H
O
5
h (85 min, 83%)
5
g (80 min, 94%)
5i (70 min, 94%)
Mp. 245-247 °C
Mp. 227-229 °C
Mp. 243-245 °C
Lit. 225-228 °C [13]
Lit. 244-246 °C [13]
Lit. 244-245 °C [12]
Br
NO2
S
CN
NH2
CN
NH2
N
N
CN
NH2
N
H
O
N
H
O
N
N
H
O
5
j (85 min, 82%)
5k (75 min, 93%)
Mp. 249-251 °C
5l (95 min, 81%)
Mp. 226-228 °C
Mp. 222-224 °C
Lit. 223-224 °C [13]
Lit. 248-249 °C [12]
Lit. 224-226 °C [18]

7
2
Pa
g
e
c
6
o
f
9
J. Chem. Sci.
(
2
0
2
0
)
1
3
2
:
7
2
Table 2.
o nt i n u e d
OMe
Me
O
OH
CN
N
CN
CN
NH2
N
H
O
NH2
N
N
N
H
N
H
O
NH2
5
m (90 min, 84%)
5n (80 min, 86%)
Mp. 206-208 °C
5o (75 min, 95%)
Mp. 209-211 °C
Mp. 207-209 °C
Lit. 210-212 °C [12]
Lit. 208-210 °C [18]
Lit. 205-208 °C [13]
OH
Cl
NO2
CN
CN
N
CN
NH2
N
N
N
H
O
NH
2
N
O
NH
2
H
N
H
O
5
p (85 min, 79%)
5q (80 min, 87%)
Mp. 229-231 °C
5r (70 min, 94%)
Mp. 245-247 °C
Mp. 222-224 °C
Lit. 220-223 °C [11]
Lit. 230-231 °C [12]
Lit. 243-244 °C [12]
O
CN
Cl
CN
CN
N
N
N
H
O
NH2
N
N
H
O
NH2
N
H
O
NH2
5
s (80 min, 85%)
5t (90 min, 83%)
Mp. 228-230 °C
5u (105 min, 76%)
Mp. 143-145 °C
Mp. 242-244 °C
Lit. 245-246 °C [12]
Lit. 230-231 °C [12]
Lit. 144-145 °C [23]
NO2
Me
CN
N
CN
NH2
N
O
NH2
N
Ph
N
O
Ph
5
v (80 min, 94%)
5
w (75 min, 91%)
Mp. 208-210 °C
Mp. 177-179 °C
Lit. 207-209 °C [28]
Lit. 179-181 °C [28]

J. Chem. Sci.
(
2
0
2
0
)
1
3
2:
72
P
ag
e
7
of
9
72
CN
N
N
H
H
O
O
H
O
NH2
O
5
g
H
N
H
C
O
O
H
C
Tautomerization
Ethylene glycol
N
3
4
Knoevenagel
condensation
H
O
CN
O
N
O
H
N
CN
H
H
N
H
O
N
N
NC
O
H
H
OH
H
C
C
NH
O
Phenylidenemalononitrile (A)
Pyrazolone (B)
N
D
Cyclization
_
H N NH
Dehydration
2
2
H
O
2
O
H
H
N
N
N
H
O
O
O
O
O
H
N
C
HO
OEt
1
NC
NC
Michael addition
NH
N
N
NH
C
O
B
Scheme 2.
l
R
e
r
c
o
e
m
m
( 5g
e
)
n
.
de
d
m
ec han is t ic pa th f or s ynt hes i zi ng 6 -am i no -3- m et hyl -4 - phe nyl -2, 4- di hydr opy ra no[ 2, 3- c] py r a-
z
o
e
-
5
-
c
a
r
bo
n
i
t
i
l
4
. Conclusions
c yc loc on de nsa tio n r ea c ti on. C omp le tin g th e r e a ct ions
ta ke s th or ough ly le ss ti me whi le ob ta ini ng the pr od-
uc ts in out sta nd ing yi el ds. Thi s gr e en m et hod i nc lude s
not ic e ab le pr op er ti es suc h a s c at al yst -f r e e, r e usa bl e
a nd bi ode gr a da ble pr om oti ng m ed ia , di re c t w or k- up
wit hout c olu mn c hr om at ogr a phic se pa r at ion , c os t- e f-
f ec t ive , m ild a nd si mpl e syn the si s, one - pot pr o ce du re ,
a nd hi gh a tom - ec on om y.
In c o n c lu s io n , in t he pr es en t wo rk , i t was de m on-
s t rat e d th a t a reu sa bl e an d bi o de gr ad ab le sol ve nt
m e di u m, g re e n E -G, ca n be us ed as a g rea t ly e ffi c ie nt
a n d a v a il a b ili ty me di a f or ca t al ys t- fr e e on e- pot m ild
4 -c o mp o n e n t s y nt h es iz in g di h yd ro py r ano[ 2 ,3- c] pyr a -
z o l e s c a ffo ld s via t an de m Kn oev en ag el - Mic ha e l

7
2
Pa
g
e
8
o
f
9
J. Chem. Sci.
(2 020) 1 32: 72
Supplementary Information (SI)
2
0
i
1
d
3
a
S
s
y
a
n
d
t
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