Palladium-Catalyzed C-H/C-H Cross-Coupling by Mechanochemistry: Direct Alkenylation and Heteroarylation of N1-Protected 1 H-Indazoles

Article abstract of DOI:10.1021/acs.joc.9b02951

C3-alkenylated and C3-(hetero)arylated 1H-indazoles are privileged structural motifs in numerous pharmaceuticals. Direct C3-alkenylation and C3-(hetero)arylation of 1H-indazoles have been significantly challenging because of the inert nature of this carbon center. Herein, we present an efficient mechanochemical strategy for palladium-catalyzed C-H/C-H cross-coupling to construct C3-alkenylated and C3-heteroarylated 1H-indazoles using low-cost copper oxidants with satisfactory product yields and broad functional group tolerance. The robustness of the developed protocols was further demonstrated by the unprecedented total mechanosynthesis of the intermediate of PLK4 inhibitor CFI-400945 and HIF-1α inhibitor YC-1.

Full text of DOI:10.1021/acs.joc.9b02951

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Article
Palladium-Catalyzed C-H/C-H Cross Coupling by Mechanochemistry:
Direct Alkenylation and Heteroarylation of N1-Protected 1H-Indazoles
Jingbo Yu, Xinjie Yang, Chongyang Wu, and Wei-Ke Su
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02951 • Publication Date (Web): 10 Dec 2019
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Palladium-Catalyzed C−H/C−H Cross Coupling by Mechanochemistry: Direct
Alkenylation and Heteroarylation of N1-Protected 1H-Indazoles
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Jingbo Yu, Xinjie Yang, Chongyang Wu, Weike Su*
National Engineering Research Center for Process Development of Active Pharmaceutical
Ingredients, Collaborative Innovation Center of Yangtze River Delta Region Green
Pharmaceuticals, Zhejiang University of Technology. Hangzhou 310014, P.R. China.
E-mail: Pharmlab@zjut.edu.cn
H
H
R4
R3
R3
Het
R4
Het
Pd(OAc)2 (10 mol%)
1,10-phen (20 mol%)
H
Pd2(dba)3 (20 mol%)
Cu(OAc)2·H2O (2.0 equiv.)
Cu(OAc)2·H2O (1.5 equiv.)
R2
R2
R2
N
N
N
N
R1
N
R1
N
R1
Na2SO4 (8.5 g)
Ball-Milling
Na2SO4 (8.5 g)
Ball-Milling
9 examples
up to 45% yield
30 examples
up to 92% yield
900 rpm, 4×30 min
900 rpm, 4×30 min
• Inter C–H activation
• Mild conditions
• Pre-functionalization-free
• Low-cost [Cu] oxidant
• Broad substrate scope
• C(sp2)–H/C(sp2)–H coupling
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ABSTRACT: C3-alkenylated and C3-(hetero)arylated 1H-indazoles are privileged structural motifs
in numerous pharmaceuticals. Direct C3-alkenylation and C3-(hetero)arylation of 1H-indazoles have
been significant challenging due to the inert nature of this carbon center. Herein, we present an
efficient mechanochemical strategy for palladium-catalyzed C−H/C−H cross coupling to construct
C3-alkenylated and C3-heteroarylated 1H-indazoles using low-cost copper oxidants with satisfactory
products yields and broad functional groups tolerance. The robustness of the developed protocols
was further demonstrated by the unprecedented total mechanosynthesis of the intermediate of PLK4
inhibitor CFI-400945 and HIF-1α inhibitor YC-1.
INTRODUCTION
Indazoles, an efficient bio-isostere of indoles and benzimidazoles, are ubiquitous frameworks
found in various biologically active molecules.1 In particular, 3-alkenyl-1H-indazoles and
3-(hetero)aryl-1H-indazoles which embedded in numerous pharmaceuticals and drug candidates
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2
3
OH
4
O
5
O
N
6
7
N
N
NH
8
9
YC-1
Pyrazolanthrone
(Anti-cancer)
O
HIF-1 inhibitor)
a
(
N
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O
N
OH
OMe
N
N
Cl
N
S
N
F3C
H
HN
N
N
N
O
Cl
H
H
O
Axitinib
(Anti-cancer)
CFI-400945
(PLK4 inhibitor)
Gamendazole
(Anti-contraceptive)
Figure 1. Biologically Active 3-Substituted-1H-Indazoles
demonstrate therapeutic applications across a broad spectrum of human diseases,2 such as anti-cancer
drug (Pyrazolanthrone and Axitinib),2a-b anti-contraceptive drug (Gamendazole),2c PLK4 inhibitor
(CFI-400945)2d and HIF-1α inhibitor (YC-1)2e-f (Figure 1). The development of concise and efficient
synthetic methods for the preparation of these compounds is, therefore, a very attractive task.
Metal catalyzed direct C−H/C−H cross coupling has emerged as a valuable tool in organic
synthesis, allowing convenient access to the target molecules in high step- and atom-economy.3
Despite the remarkable efforts to the preparation of 3-substituted-2H-indazole derivatives,4 the
synthetic routes to C3-functionalization of 1H-indazoles are less prevalent due to the inherently poor
reactivity of this carbon center.5 Recently, Guillaumet’s group reported the first palladium-catalyzed
C3-alkenylation of 1H-indazoles using costly silver oxidant by long-time heating (Scheme 1a).4b
Later, Joo et al.6 taking an alternative copper oxidant but with only one example. For the
construction of 3-aryl-1H-indazoles, transition-metal-catalyzed C−H/C−X couplings were commonly
employed. Representative examples are Guillaumet’s,7a Itami’s7b and Yu’s5a independent works of
direct C3-arylation of 1H-indazoles with aryl halides (Scheme 1b). However, these protocols often
suffer from tedious multistep syntheses involving preactivation of substrates, which limit rapid
diversification toward indazole derivatives. In recent years, significant progress has been witnessed
on metal-catalyzed cross-couplings performed under mechanochemical activation.8 The most
thrilling is the showcase of miraculous potentials of mechanochemistry in the field of direct C−H
activations,8c,9 represented by Bolm’ s9b,10 and Xu’s11a works of directing groups assisted arenes C−H
functionalization. We also reported palladium and cobalt catalyzed C−H olefination11b and
allylation11c of indoles under ball milling conditions. Albeit the achieved advances, modification of
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Scheme 1. Direct C3-Alkenylation and (Hetero)arylation of 1H-Indazole
Previous works:
a. Direct C3-alkenylation of 1H-indazole
R
H
[Ag]
Pd(OAc)2,
, additive
H
+
N
N
R
120 C, 18 h

N
N
9
Me
Me
Guillaumet et al., 2015
b. Direct C3-arylation of 1H-indazole
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Ar
H
[Pd], base, additive
+
Ar
X = Br, I
X
N
N
160 C, 12 h-48 h

N
Guillaumet et al., 2012
Itami et al., 2012
Yu et al., 2013
N
PG
PG
This work:
H
R
Cu(OAc) ·H O
[Pd],
2
2
H
R
+
N
N
N
R'
R'
Ball-Milling, 900 rpm, 4×30 min
N
Alkenyl
R =
R =
, [Pd] = Pd(OAc)2
PG
PG
Heteroaryl
, [Pd] = Pd2(dba)3
• Mild conditions
• Low cost [Cu] oxidant
• Broad substrate scope
• Inert C–H activation
• Pre-functionalization-free
• C(sp2)–H/C(sp2)–H coupling
inert heterocycles through direct C−H activation by mechanochemistry continues to face great
challenges, since specific conditions are always required to functionalize each heterocyclic system.5b
In virtue of the unique chemical and pharmacological properties of 1H-indazoles and our successful
works on the functionalization of heteroarenes by mechanochemistry,11b-c,12 we wish to report herein
the first mechanochemical strategies for direct C3-alkenylation and C3-heteroarylation of
1H-indazoles through Pd-catalyzed C−H/C−H cross coupling (Scheme 1).
RESULTS AND DISCUSSION
On the basis of our previous protocols for mechanochemical C−H functionalization,11b-c we began
to screen conditions for the C3-alkenylation of 1-methyl-1H-indazole 1a. The treatment of 1a with
butyl acrylate 2a in the presence of Pd(OAc)2 (10 mol%), pyridine (10 mol%), Cu(OAc)2·H2O (2.0
equiv.) using silica gel as grinding auxiliary in a planetary mill gave the 3-olefination product 3aa in
only 9% yield (entry 1). Unexpected irreversible adsorption of the substrates by the silica gel was
observed with the material balance less than 40%. Further examination of the grinding auxiliary
showed that inorganic salts, particularly non-adsorptive Na2SO4, gave positive results and the
product yield was enhanced to 23% (entries 4-6). Most importantly, the material balance in Na2SO4
reached above 85%. Several nitrogen-based additives (see Figure S1 in the Supporting Information
for more details) were then examined to improve the reaction efficiency. All bidentate
nitrogen-containing reagents smoothly promoted the reaction, giving better results than pyridine
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Table 1. Optimization of the Reaction Conditionsa
CO2nBu
H
Pd(OAc)2 (10 mol%)
Oxidant, Additive
H
+
N
N
Me
CO2nBu
N
Grinding auxiliary (g)
Ball-Milling, 900 rpm
N
Me
1a
2a
3aa
10
11
12
13
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45
46
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58
59
60
no
oxidant
additive (mol%) auxiliary
yield
(%)
9
1
2
3
4
5
6
7
8
9
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
pyridine (10)
pyridine (10)
pyridine (10)
pyridine (10)
pyridine (10)
pyridine (10)
Silica gel
−
n.d.
n.d.
17
17
23
38
41
42
Al2O3
NaCl
KBr
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Cu(OAc)2·H2O bipyridine (10)
Cu(OAc)2·H2O
Cu(OAc)2·H2O
dtbpy (10)
1,10-phen (10)
10 Cu(OAc)2·H2O 1,10-phen (20)
Na2SO4 64, 58e, 48f
11
12
13
Cu(OAc)2
Ag2O
1,10-phen (20)
1,10-phen (20)
1,10-phen (20)
1,10-phen (16)
1,10-phen (10)
1,10-phen (20)
−
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
Na2SO4
−
60
n.d.
41
Ag2CO3
14b Cu(OAc)2·H2O
15c Cu(OAc)2·H2O
54
44
16
−
n.d.
n.d.
n.d.
17 Cu(OAc)2·H2O
18d Cu(OAc)2·H2O
1,10-phen (20)
a
Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), Pd(OAc)2 (10 mol%), oxidant (2.0 equiv.), additive and grinding
auxiliary (8.5 g) at 900 rpm in a planetary mill [3(30 min + 2 min break)], using 138 stainless-steel balls (dMB = 6 mm,
b
c
d
ФMB = 0.228) in a 80 mL stainless steel vial. Pd(OAc)2 (8 mol%) was used. Pd(OAc)2 (5 mol%) was used. The
reaction was performed in dry 1,4-dioxane (0.5 mL) at 120 °C under argon for 12 h (see Scheme S1 in the Supporting
Information for more details). e 2a (1.5 equiv.). f 2a (1.0 equiv.). dtbpy = 4,4'-di-tert-butyl-2,2'-bipyridine.
which has weak coordination ability (entries 6-9). Among which, 1,10-phen (20 mol%) showed the
best performance, and two equivalent coupling partners were necessary for the desired yields (entry
10). Exhilarating, low-cost Cu(OAc)2·H2O was superior to silver-based oxidants in our
mechanochemical reactions (Table 1, entries 10-13). Control experiments showed that the
Cu(OAc)2·H2O and 1,10-phen are essential for the observed reactivity (entries 16 and 17) while
reducing of Pd loading led to an obvious reduction in the yield (entries 14 and 15). Surprisingly,
when the reaction was performed in dry 1,4-dioxane at 120 °C for 12 h,4b no desired product was
found (entry 18), demonstrating the advantages of the solvent-free mechanochemical protocol over
the liquid-phase reaction.
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Table 2. Indazole Substrate Scopea
4
5
6
7
8
CO2nBu
H
Pd(OAc)2
Cu(OAc)2·H2O, 1,10-phen
H
R
N
N
R1
+
CO2nBu
R
N
Na2SO4 (8.5 g)
Ball-Milling, 900 rpm
[4(30 min + 2 min break)]
N
R1
1
2a
3
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CO2nBu
CO2nBu
CO2nBu
Cl
OMe
N
N
N
N
N
N
Me
3ca
, 25% (60%)
Me
3aa
Me
b
3ba
, 78%
, 57%
CO2nBu
CO2nBu
CO2nBu
MeO
O2N
N
N
N
N
N
N
Me
Me
Me
Me
3da
3ea
3fa
, 75%
, 58%
, 81%
CO2nBu
CO2nBu
CO2nBu
N
N
N
N
N
N
NC
Me
Cl
Me
Bn
3ia
b
3ga
3ha
, 67%
, 25% (58%)
, 45%
a
Reaction conditions: 1 (1.0 mmol), 2a (2.0 mmol), Pd(OAc)2 (10 mol%), Cu(OAc)2·H2O (2.0 equiv.), 1,10-phen (20
mol%) and Na2SO4 (8.5 g) at 900 rpm in a planetary mill [4(30 min + 2 min break)], using 448 stainless-steel balls (dMB
= 4 mm, ΦMB = 0.228) in a 80 mL stainless steel vial. b NaCl (8.5 g) was used instead of Na2SO4 (8.5 g).
As far as we know, mechanical parameters usually have a strong influence on the reaction
outcomes, which were shown by us12a and others13 previously. Not surprisingly, after careful
adjustment of the synergistic effects of the grinding time (t), the milling-ball filling degree (ФMB) and
the milling-ball size (dMB), 3aa was obtained in the best yield of 78% (see Figure S2 in the
Supporting Information for more details).
With optimal conditions in hand, we varied indazoles with various substituents (Table 2).
Substrates bearing electron-donating groups at either the 4-, 5- or 6-position gave the desired
3-olefination products (3ba, 3da and 3fa) in satisfactory yields (57-81%). In contrast, indazoles with
electron-withdrawing groups provided inferior results (3ca, 3ea, 3ga-3ha). Of note, those substrates
with a chloro at either the 4- or the 7-position gave poor yields with dehalogenation taking place as a
significant competing pathway. On the basis of our previous work12b that halogen salts were
beneficial to reduce the dehalogenation rendered by palladium catalysis or by high energy impact,
NaCl was consequently taken as an alternative grinding auxiliary and the product yields of 3ca and
3ha were dramatically improved to 60% and 58%, respectively. Besides, indazole with N-Bn group
(1i) was also amenable to this C3-alkenylation protocol and afforded moderate yield of 45%.
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Table 3. Alkene Substrate Scopea
5
6
7
8
R2
H
Pd(OAc)2
Cu(OAc)2·H2O, 1,10-phen
H
N
R2
+
N
N
N
Na2SO4 (8.5 g)
Ball-Milling, 900 rpm
[4(30 min + 2 min break)]
Me
Me
1a
2
3
9
O
O
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
R2
, R2 = CO2Me, 78%
, R2 = CO2Et, 82%
, R2 = CO2Cy, 78%
3ab
3ac
3ad
N
N
N
N
Me
Me
3ae
, 79%
O
O
O
O
O
O
O
N
N
N
N
N
N
Me
Me
Me
3af
3ag
3ah
, 65%
O
, 67%
O
, 78%
O
O
N
O
N
OAc
O
N
N
N
N
N
Me
Me
Me
3ak
, 53%
b
3ai
3aj
, 79%
O
, 62%
O
P
R2
O
, R2 = C6H5, 92%
,
R2 = m-MeC6H4, 69%
R2 = m-ClC6H4, 65%
R2 = o-MeC6H4, 52%
R2 = o-ClC6H4, 51%
,
R2 = pyridine, 54%
3am
3ar
,
R2 = p-MeC6H4, 90%
R2 = p-OMeC6H4, 68%
R2 = p-ClC6H4, 81%
R2 = p-CNC6H4, 65%
,
3an
3as
3at
N
3ao
,
,
3au
3av
N
N
3ap
,
,
N
Me
3aq
,
Me
3al
, 45%
a
Reaction conditions: 1a (1.0 mmol), 2 (2.0 mmol), Pd(OAc)2 (10 mol%), Cu(OAc)2·H2O (2.0 equiv.), 1,10-phen (20
mol%) and Na2SO4 (8.5 g) at 900 rpm in a planetary mill [4(30 min + 2 min break)], using 448 stainless-steel balls (dMB
= 4 mm, ΦMB = 0.228) in a 80 mL stainless steel vial. b Ac2O (1.0 equiv.) was used as an additive.
Next, the 1-methyl-1H-indazole 1a was chosen to examine reaction scope with respect to the
olefins (Table 3). Various α,β-unsaturated olefins from readily available methyl to cyclohexyl
acrylates reacted with 1a to give the desired products 3ab-3ad in good yields (78-82%). Fortunately,
other functionalized olefins, for instance, dicyclopentanyl acrylate 2e, isobornyl acrylate 2f,
(tetrahydrofuran-2-yl)methyl acrylate 2g, benzyl acrylate 2h, phenoxyethyl acrylate 2i, hydroxyethyl
acrylate 2j and acrylamide 2k were all effective coupling partners under the standard conditions
affording satisfactory yields (3ae-3ak). In addition, diethyl vinylphosphonate 2l was also compatible
with this reaction to give the coupling product in yield of 45%. It is worth noting that styrenes were
excellent coupling partners providing the 3-olefination products 3am-3au in moderate to excellent
yields (up to 92%), wherein steric hindrance exerted obvious influences on the reaction
transformations (3an vs 3ar and 3at, 3ap vs 3as and 3au).
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Table 4. Heteroarylation of 1H-Indazoles with Heteroarenesa
R3
H
Pd2(dba)3
Cu(OAc)2·H2O
Het
H
R2
N
N
R1
+
R3
Het
Na2SO4 (8.5 g)
Ball-Milling, 900 rpm
[4(30 min + 2 min break)]
R2
N
N
R1
1
4
5
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
CHO
CHO
S
CHO
S
S
MeO
N
N
N
N
N
N
NC
Me
Me
Me
5ga,
25%
5aa
5da
, 42%
, 45%
Ac
CHO
CHO
S
S
N
O
Me
N
N
N
N
N
Me
Me
Me
Cl
5ha
b
5ac
, 41% (9%)
5jb
, 36%
, 35%
Ac
O
CHO
CHO
S
N
O
N
N
N
N
N
Me
Bn
Bn
5ia
5ic
, 34%
5ad
, 30%
, 35%
a Reaction conditions: 1 (1.0 mmol), 4 (2.0 mmol), Pd2(dba)3 (20 mol%), Cu(OAc)2·H2O (1.5 equiv.) and Na2SO4 (8.5 g)
at 900 rpm in a planetary mill [4(30 min + 2 min break)], using 448 stainless-steel balls (dMB = 4 mm, ΦMB = 0.228) in a
80 mL stainless steel vial. b NaCl (8.5 g) was used instead of Na2SO4 (8.5 g).
To demonstrate the versatility of the developed template approach for diverse C3−H
functionalization of indazoles, a number of indazole substrates 1 and heteroarenes 4 were subjected
to the above-mentioned conditions with slight modification (see Table S1 in the Supporting
Information for more details). As anticipated, indazoles substituted with different functional groups
underwent C−H arylation smoothly with thiophenes and furans containing electron-withdrawing
substituents, requiring no ligands or additives (Table 4). Pleasingly, the substituent position and the
electrical effects of indazoles did not show significant influences on the product yields (5aa, 5da,
5ga, 5ha). It is worth mentioning that there were also dehalogenated byproducts (1a 22%, 5aa 8%)
in the reaction of 1h and 5a, wherein using sodium chloride as an alternative grinding auxiliary gave
very low yield of 5ha, which probably due to its poor dispersibility for 4a. In addition, the
removable Bn protecting group was compatible with both 2-thenaldehyde 5ia and furfural 5ic but
gave lower yields than Me group (5aa and 5ac). Unfortunately, furans and thiophenes containing
electron-donating groups, such as 2-methylfuran, 2-phenylthiophene or benzo[b]thiophene, could
hardly obtain the target products under the standard conditions. In any case, to the best of our
knowledge, it was the first time to achieve C3-heteroarylated 1H-indazoles by C−H/C−H
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Scheme 2. Mechanistic Studies of Heteroarylation
a. H/D exchange experiment
H/D
Pd2(dba)3 (20 mol%)
w/o Cu(OAc)2·H2O (1.5 equiv.)
N
N
N
N
Na2SO4 (8.5 g), Ball-Milling, 900 rpm, 30 min
Me
1a
Me
D2O
[D1]-
1a
with Cu(OAc)2·H2O: 0% D
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without Cu(OAc)2·H2O: 0% D
D/H
Pd2(dba)3 (20 mol%)
w/o Cu(OAc)2·H2O (1.5 equiv.)
S
S
CHO
CHO
Na2SO4 (8.5 g), Ball-Milling, 900 rpm, 30 min
4a
[D1]-
4a
D2O
with Cu(OAc)2·H2O: 22% D
without Cu(OAc)2·H2O: < 1% D
b. Intermolecular kinetic isotopic effect study
H/D
Pd2(dba)3 (20 mol%)
S
Cu(OAc)2·H2O (1.5 equiv.)
+
+
N
N
Me
5aa
5aa
CHO
Na2SO4 (8.5 g), Ball-Milling, 900 rpm
kH/kD = 3.2
1a 1a
4a
or -[D1]
Pd2(dba)3 (20 mol%)
Cu(OAc)2·H2O (1.5 equiv.)
D/H
N
N
S
CHO
-[D1]
Na2SO4 (8.5 g), Ball-Milling, 900 rpm
kH/kD = 1.5
Me
1a
4a or 4a
cross-coupling way.
Several experiments were conducted to elucidate the mechanism of the heteroarylation (Scheme
2). The H/D exchange tests were performed (Scheme 2a) using NMR spectroscopy to clarify the
competitiveness for palladation of the reactive partners. A totally different outcome was obtained
when the coupling partners were exposed to the same reaction conditions in the absence of the other
component (1a (0% D), 4a (22% D)). The results suggested that the coupling partner 4a undergo a
substitution reaction in the presence of the Pd-catalyst to generate a palladium intermediate. Notably,
the reactions without the Cu(OAc)2·H2O oxidant did not result in deuterium incorporation in 1a or
4a, implying that a Pd(0)/Cu(II)-mediated C−H activation mechanism is operating. In addition,
initial rate measurements revealed kinetic isotope effects (KIEs) of 3.2 and 1.5 for 1a and 4a,
respectively. These factors indicated that the C−H bond breaking of 1a might be related to the
rate-limiting step.
Based on our mechanistic studies and previous literatures,14 a tentative mechanism has been
proposed (Scheme 3). The catalytic cycle is initiated with the oxidant reaction of palladium(0),
followed by the C−H insertion of Pd(II) to thiophene-2-carbaldehyde 4a to form the key intermediate
A. Then, intermediate A reacts with 1-methyl-1H-indazole 1a to give heteroaryl-Pd complex B
through an electrophilic C−H substitution or a concerted metalation deprotonation. Finally, reductive
elimination of B affords product 5aa and Pd(0), which is oxidized by Cu(OAc)2·H2O, thus
completing the catalytic cycle.
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Scheme 3. Proposed Mechanism
4
5
6
Pd2(dba)3
7
Cu(OAc)2·H2O
8
9
H
Cu(0)
S
Cu(0)
CHO
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II
Pd( )Ln
4a
Cu(OAc)2·H2O
OHC
S
Pd(0)
II
Pd( )Ln
CHO
S
A
N
N
CHO
H
S
Me
5aa
Ln
Pd
N
N
N
Me
1a
N
B
Me
Scheme 4. Mechanosynthesis of CFI-400945 Intermediate and YC-1
O
a. Intermediate of CFI-400945
O
N
N
N
O
TBAF (5.5 equiv.)
Silica gel (0.5 g)
2w
N
N
NC
Ball-Milling, 25 Hz, 2 h
Pd(OAc)2 (10 mol%)
1, 10-phen (20 mol%)
Cu(OAc)2·H2O (2 equiv.)
Na2SO4 (8.5 g)
Ball-Milling, 900 rpm
[4(30 min + 2 min break)]
SEM
1k
N
N
N
NC
N
NC
SEM
H
3kw, 69%
3lw, 89%
O
O
N
N
MeO
O
Raney-Nickel
Na2PO2H2 (5.4 equiv.)
N
H
OMe
Ball-Milling, 600 rpm, 2 h
piperidine (10 mol%)
Silica gel (0.5 g)
Ball-Milling, 30 Hz, 1 h
N
HN
N
N
N
OHC
H
H
O
3mw, 46%
CFI-400945
3nw, 72%
Intermediate of
b. YC-1
O
CHO
OH
NaBH4 (1.1 equiv.)
CeCl3·7H2O (20 mol%)
Silica gel (0.5 g)
CHO
O
O
4c
N
N
Ball-milling, 20 Hz, 30 min
N
Pd2(dba)3 (10 mol%)
Cu(OAc)2·H2O (1.5 equiv.)
Na2SO4 (8.5 g)
N
Bn
N
N
1i
Bn
Bn
Ball-Milling, 900 rpm
[4(30 min + 2 min break)]
YC-1, 85%
5ic, 34%
The use of mechanochemical milling or grinding for multi-component and multi-step reactions, is
emerging as a faster, cleaner alternative to traditional synthesis, providing new routes to known
active pharmaceutical ingredients or complex organometallic species.8h,15 A remarkable aspect of the
present methods is the application in the multi-step synthesis of biologically active compounds as
shown in Scheme 4. The intermediate of potential anticancer compound CFI-400945 (3nw) could be
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easily synthesized by a practical four-step mechano-synthesis under mild conditions (Scheme 4, a).
The reaction started from the regioselective C3-alkenylation of
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1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbaldehyde 1k with olefin 2w under the
established milling conditions and gave compound 3kw in 69% yield. Deprotection of the SEM
group was effected by TBAF under ball milling to offer the desired compound 3lw in 89% yield.
Next, mechanochemical reduction of the nitrile by Ra-Ni to give 3mw, which was later subjected to
Knoevenagel condensation with indolinone, giving the key intermediate of CFI-400945 in a total
yield of 20%. Another anticancer drug candidate YC-1 was also constructed with acceptable results
(Scheme 4, b). The treatment of the indazole 1i by furfural 4c under heteroarylation milling
conditions led to intermediate 5ic in 34% yield. Finally, mechanochemical reduction of 5ic
completed the synthesis of YC-1 in a total yield of 29%.
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CONCLUSION
In summary, we have developed a highly efficient mechanochemical method for
palladium-catalyzed direct C3-alkenylation and C3-heteroarylation of 1H-indazoles for the first time.
This protocol features low oxidant cost, mild reaction conditions and compatibility with diverse
functional groups in short reaction times. The utility of this methodology has been demonstrated in
the concise mechano-syntheses of anticancer drug candidates CFI-400945 intermediate and YC-1.
With these systems, we hope to expand the synthetic pharmaceutical toolbox in mechanochemistry.
EXPERIMENT SECTION
General Information
Materials were obtained from commercial suppliers and purified by standard procedures unless
otherwise
noted.
1-Methyl-1H-indazole
1a,16
1-benzyl-1H-indazole
1i,17
1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbonitrile 1k,18 4-(4-vinylbenzyl)morpholine
2w,19 thiophene-5-d-2-carbaldehyde 4a-[D1]20 were prepared by following literature reports. All of
the ball‐milling reactions were conducted in a Planetary Mill or Mixer Mill with 80 or 50 mL
stainless-steel grinding vessels and stainless-steel balls, if not mentioned otherwise. TLC
(Thin-Layer Chromatography) analysis was performed using precoated glass plates. Melting points
(mp) were obtained on a digital melting point apparatus and uncorrected. Mass spectra were recorded
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with a HRMS-ESI-Q-TOF. NMR spectra were recorded with 400, 500 or 600 MHz spectrometer for
1H NMR, 100, 125 or 150 MHz for 13C NMR, and 162 MHz for 31P NMR.
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Typical Procedure for the Synthesis of Butyl (E)-3-(1-methyl-1H-indazol-3-yl)acrylate
(3aa12b). A mixture of 1-methyl-1H-indazole 1a (132 mg, 1.0 mmol), butyl acrylate 2a (256 mg, 2.0
mmol), Pd(OAc)2 (23 mg, 0.1 mmol), 1,10-phen (36 mg, 0.02 mmol), Cu(OAc)2·H2O (400 mg, 2.0
mmol), and Na2SO4 (8.5 g) was placed in a stainless-steel vessel, along with 448 stainless-steel balls
(dMB = 4 mm, ФMB = 0.228). Then the ball milling vessel was placed in the planetary mill (milling
cycle: 30 min milling at 900 rpm, followed by 2 min break, 4 repetitions). The crude product was
collected by washing the vessel and the balls with EtOAc (3 × 20 mL). The mixture was
concentrated in vacuum and purified by column chromatography on silica gel (Hexane/EtOAc = 20:1
to 8:1) to give the desired product 3aa as a white solid (201 mg, 78% yield), mp: 43–45 °C (lit.,12b
42–44 °C); 1H NMR (600 MHz, Chloroform-d) δ 7.98 (d, J = 16.2 Hz, 1H), 7.94 (d, J = 8.4 Hz, 1H),
7.47–7.40 (m, 2H), 7.29–7.24 (m, 1H), 6.76 (d, J = 16.2 Hz, 1H), 4.24 (t, J = 6.6 Hz, 2H), 4.11 (s,
3H), 1.74–1.68 (m, 2H), 1.50–1.42 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz,
Chloroform-d) δ 167.4, 141.4, 139.8, 135.9, 126.9, 122.7, 122.2, 120.9, 119.1, 109.7, 64.6, 36.0,
30.9, 19.4, 13.9.
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Butyl (E)-3-(4-methoxy-1-methyl-1H-indazol-3-yl)acrylate (3ba). Yellow oil (164 mg, 57%
1
yield); H NMR (400 MHz, Chloroform-d) δ 8.20 (d, J = 16.0 Hz, 1H), 7.30–7.25 (m, 1H), 6.95–
6.86 (m, 2H, including d, J = 16.0 Hz, 1H), 6.51 (d, J = 7.6 Hz, 1H), 4.21 (t, J = 6.6 Hz, 2H), 4.03 (s,
13
3H), 3.97 (s, 3H), 1.73–1.65 (m, 2H), 1.50–1.40 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H); C{1H} NMR
(100 MHz, Chloroform-d) δ 167.7, 154.7, 143.1, 139.6, 136.0, 128.0, 118.9, 114.4, 102.1, 100.8,
64.3, 55.4, 36.1, 30.9, 19.3, 13.9; HRMS (ESI) m/z calcd for C16H21N2O3 [M+H]+: 289.1547, found:
289.1554.
Butyl (E)-3-(4-chloro-1-methyl-1H-indazol-3-yl)acrylate (3ca12b). White solid (176 mg, 60%
yield), mp: 65–68 °C (lit.,12b 63–66 °C); 1H NMR (600 MHz, Chloroform-d) δ 7.92 (d, J = 16.2 Hz,
1H), 7.80 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 7.2 Hz, 1H), 7.16–7.11 (m, 1H), 6.74 (d, J = 16.2 Hz, 1H),
4.43 (s, 3H), 4.24 (t, J = 6.6 Hz, 2H), 1.73–1.67 (m, 2H), 1.49–1.42 (m, 2H), 0.97 (t, J = 7.2 Hz, 3H);
13C{1H} NMR (125 MHz, Chloroform-d) δ 167.1, 139.7, 137.6, 134.7, 127.8, 125.5, 122.8, 119.8,
119.4, 116.8, 64.6, 39.7, 30.9, 19.4, 13.9.
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Butyl (E)-3-(5-methoxy-1-methyl-1H-indazol-3-yl)acrylate (3da12b). Yellow oil (216 mg, 75%
yield); 1H NMR (400 MHz, Chloroform-d) δ 7.95 (d, J = 16.2 Hz, 1H), 7.30 (d, J = 9.1 Hz, 1H), 7.19
(s, 1H), 7.09 (d, J = 9.1, 1H), 6.66 (d, J = 16.2 Hz, 1H), 4.23 (t, J = 6.6 Hz, 2H), 4.06 (s, 3H), 3.89 (s,
3H), 1.75–1.66 (m, 2H), 1.51–1.40 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz,
Chloroform-d) δ 167.6, 155.9, 138.9, 137.3, 135.9, 123.3, 119.1, 118.0, 110.7, 100.0, 64.5, 56.0,
36.2, 30.9, 19.4, 13.9.
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Butyl (E)-3-(1-methyl-5-nitro-1H-indazol-3-yl)acrylate (3ea12b). Yellow solid (176 mg, 58%
yield), mp: 113–115 °C (lit.,12b 117–119 °C); 1H NMR (400 MHz, Chloroform-d) δ 8.87 (s, 1H), 8.31
(dd, J = 9.2, 2.0 Hz, 1H), 7.91 (d, J = 16.3 Hz, 1H), 7.49 (d, J = 9.2 Hz, 1H), 6.81 (d, J = 16.3 Hz,
1H), 4.25 (t, J = 6.6 Hz, 2H), 4.16 (s, 3H), 1.76–1.68 (m, 2H), 1.52–1.41 (m, 2H), 0.98 (t, J = 7.4 Hz,
3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 166.7, 143.2, 143.0, 142.5, 133.8, 122.0, 121.8,
121.5, 118.4, 110.1, 64.9, 36.5, 30.9, 19.3, 13.9.
1
Butyl (E)-3-(1,6-dimethyl-1H-indazol-3-yl)acrylate (3fa12b). Yellow oil (221 mg, 81% yield); H
NMR (600 MHz, Chloroform-d) δ 7.95 (d, J = 16.2 Hz, 1H), 7.80 (d, J = 8.4 Hz, 1H), 7.19 (s, 1H),
7.09 (d, J = 8.4 Hz, 1H), 6.72 (d, J = 16.2 Hz, 1H), 4.23 (t, J = 6.6 Hz, 2H), 4.06 (s, 3H), 2.52 (s, 3H),
1.73–1.67 (m, 2H), 1.49–1.42 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (150 MHz,
Chloroform-d) δ 167.4, 142.0, 139.6, 137.3, 136.1, 124.4, 120.8, 120.4, 118.9, 109.1, 64.5, 35.8,
30.9, 22.0, 19.3, 13.9.
Butyl (E)-3-(6-cyano-1-methyl-1H-indazol-3-yl)acrylate (3ga12b). White solid (190 mg, 67%
1
yield), mp: 112–113 ℃ (lit.,12b 115–117 °C); H NMR (400 MHz, Chloroform-d) δ 8.00 (d, J = 8.4
Hz, 1H), 7.92 (d, J = 16.4 Hz, 1H), 7.80 (s, 1H), 7.45 (d, J = 8.4 Hz, 1H), 6.75 (d, J = 16.4 Hz, 1H),
4.23 (t, J = 6.6 Hz, 2H), 4.15 (s, 3H), 1.74–1.66 (m, 2H), 1.50–1.39 (m, 2H), 0.96 (t, J = 7.4 Hz, 3H);
13C{1H} NMR (100 MHz, Chloroform-d) δ 166.9, 140.3, 140.1, 134.2, 124.6, 124.1, 122.0, 120.5,
119.0, 115.0, 110.1, 64.8, 36.4, 30.8, 19.3, 13.9.
Butyl (E)-3-(7-chloro-1-methyl-1H-indazol-3-yl)acrylate (3ha12b). White solid (170 mg, 58%
yield), mp: 60–64 °C (lit.,12b 59–61 °C); 1H NMR (400 MHz, Chloroform-d) δ 7.90 (d, J = 16.4 Hz,
1H), 7.78 (d, J = 8.4 Hz, 1H), 7.36 (d, J = 7.6 Hz, 1H), 7.12 (t, J = 7.8 Hz, 1H), 6.73 (d, J = 16.4 Hz,
1H), 4.41 (s, 3H), 4.23 (t, J = 6.6 Hz, 2H), 1.74–1.66 (m, 2H), 1.50–1.40 (m, 2H), 0.97 (t, J = 7.4 Hz,
3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 167.2, 139.6, 137.6, 134.8, 127.8, 125.5, 122.8,
119.8, 119.4, 116.8, 64.6, 39.7, 30.9, 19.3, 13.9.
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Butyl (E)-3-(1-benzyl-1H-indazol-3-yl)acrylate (3ia12b). Yellow oil (150 mg, 45% yield); H
NMR (400 MHz, Chloroform-d) δ 8.03 (d, J = 16.2 Hz, 1H), 7.96 (d, J = 8.0 Hz, 1H), 7.40–7.35 (m,
2H), 7.33–7.19 (m, 6H, subtracting CDCl3), 6.79 (d, J = 16.2 Hz, 1H), 5.62 (s, 2H), 4.25 (t, J = 6.8
Hz, 2H), 1.74–1.70 (m, 2H), 1.52–1.41 (m, 2H), 0.98 (t, J = 7.4 Hz, 3H); 13C{1H} NMR (100 MHz,
Chloroform-d) δ 167.3, 141.0, 140.3, 136.2, 136.0, 128.9 (2C), 128.1, 127.3 (2C), 127.0, 123.1,
122.3, 121.0, 119.5, 110.1, 64.6, 53.5, 30.9, 19.4, 13.9.
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Methyl (E)-3-(1-methyl-1H-indazol-3-yl)acrylate (3ab4b). Yellow solid (169 mg, 78% yield), mp:
75–78 ℃ (lit.,4b 74–76 °C); 1H NMR (400 MHz, Chloroform-d) δ 7.98 (d, J = 16.4 Hz, 1H), 7.90 (d,
J = 8.0 Hz, 1H), 7.45–7.38 (m, 2H), 7.27–7.22 (m, 1H), 6.75 (d, J = 16.4 Hz, 1H), 4.08 (s, 3H), 3.83
(s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 167.7, 141.4, 139.6, 136.1, 126.8, 122.7, 122.2,
120.7, 118.4, 109.6, 51.8, 36.0.
Ethyl (E)-3-(1-methyl-1H-indazol-3-yl)acrylate (3ac4b). White solid (189 mg, 82% yield), mp:
65–67 ℃ (lit.,4b 48–50 °C); 1H NMR (500 MHz, Chloroform-d) δ 7.99 (d, J = 16.2 Hz, 1H), 7.94 (d,
J = 8.0 Hz, 1H), 7.47–7.39 (m, 2H), 7.29–7.24 (m, 1H, subtracting CDCl3), 6.75 (d, J = 16.2 Hz, 1H),
4.29 (q, J = 7.1 Hz, 2H), 4.10 (s, 3H), 1.36 (t, J = 7.1 Hz, 3H); 13C{1H} NMR (125 MHz,
Chloroform-d) δ 167.3, 141.4, 139.8, 135.9, 126.8, 122.7, 122.2, 120.8, 119.0, 109.6, 60.6, 36.0,
14.5.
Cyclohexyl (E)-3-(1-methyl-1H-indazol-3-yl)acrylate (3ad4b). White solid (222 mg, 78% yield),
mp: 99–102 ℃ (lit.,4b 88–90 °C); 1H NMR (400 MHz, Chloroform-d) δ 8.00–7.90 (m, 2H, including
d, J = 16.4 Hz, 1H), 7.46–7.37 (m, 2H), 7.27–7.21 (m, 1H, subtracting CDCl3), 6.73 (d, J = 16.4 Hz,
1H), 4.97–4.87 (m, 1H), 4.08 (s, 3H), 1.97–1.89 (m, 2H), 1.81–1.73 (m, 2H), 1.58–1.27 (m, 6H);
13C{1H} NMR (100 MHz, Chloroform-d) δ 166.7, 141.4, 139.8, 135.6, 126.8, 122.6, 122.1, 120.9,
119.7, 109.6, 72.8, 36.0, 31.8 (2C), 25.6, 23.9 (2C).
Octahydro-1H-4,7-methanoinden-2-yl (E)-3-(1-methyl-1H-indazol-3-yl)acrylate (3ae). Colorless
1
oil (266 mg, 79% yield); H NMR (400 MHz, Chloroform-d) δ 7.97–7.91 (m, 2H, including d, J =
16.0 Hz, 1H), 7.46–7.39 (m, 2H), 7.28–7.23 (m, 1H, subtracting CDCl3), 6.72 (d, J = 16.0 Hz, 1H),
4.72 (dd, J = 7.0, 2.1 Hz, 1H), 4.09 (s, 3H), 2.06 (d, J = 4.4 Hz, 1H), 1.95–1.60 (m, 7H), 1.55–1.48
(m, 1H), 1.31–1.16 (m, 1H), 1.05–0.89 (m, 2H); C{1H} NMR (100 MHz, Chloroform-d) δ 167.1,
13
141.4, 139.9, 135.6, 126.8, 122.7, 122.2, 120.9, 119.7, 109.7, 77.4, 47.5, 46.4, 43.2, 39.8, 39.3, 36.0,
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32.2, 31.8, 29.6, 27.9; HRMS (ESI) m/z calcd for C21H24N2NaO2 [M+Na]+: 359.1730, found:
359.1720.
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(1S,2S,4S)-1,7,7-Trimethylbicyclo[2.2.1]heptan-2-yl (E)-3-(1-methyl-1H-indazol-3-yl)acrylate
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(3af). Colorless oil (220 mg, 65% yield); H NMR (400 MHz, Chloroform-d) δ 7.97–7.91 (m, 2H,
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including d, J = 16.2 Hz, 1H), 7.47–7.41 (m, 2H), 7.30–7.25 (m, 1H, subtracting CDCl3), 6.76 (d, J =
16.2 Hz, 1H), 4.89–4.83 (m, 1H), 4.12 (s, 3H), 1.92–1.86 (m, 2H), 1.81–1.72 (m, 2H), 1.65–1.57 (m,
1H), 1.28–1.15 (m, 2H), 1.11 (s, 3H), 0.94 (s, 3H), 0.89 (s, 3H); 13C{1H} NMR (100 MHz,
Chloroform-d) δ 166.8, 141.4, 139.8, 135.2, 126.8, 122.7, 122.1, 120.8, 119.7, 109.6, 81.3, 49.0,
47.1, 45.2, 39.0, 36.0, 33.9, 27.2, 20.3, 20.2, 11.7; HRMS (ESI) m/z calcd for C21H26N2NaO2
[M+Na]+: 361.1886, found: 361.1883.
(Tetrahydrofuran-2-yl)methyl (E)-3-(1-methyl-1H-indazol-3-yl)acrylate (3ag). Yellow solid (192
mg, 67% yield), mp: 52–54 ℃; 1H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 16.4 Hz, 1H), 7.92
(d, J = 8.4 Hz, 1H), 7.45–7.39 (m, 2H), 7.28–7.23 (m, 1H, subtracting CDCl3), 6.79 (d, J = 16.4 Hz,
1H), 4.32 (dd, J = 10.4, 2.4 Hz, 1H), 4.25–4.14 (m, 2H), 4.09 (s, 3H), 3.97–3.90 (m, 1H), 3.86–3.79
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(m, 1H), 2.09–1.87 (m, 3H), 1.74–1.64 (m, 1H); C{1H} NMR (100 MHz, Chloroform-d) δ 167.2,
141.3, 139.6, 136.4, 126.8, 122.6, 122.2, 120.8, 118.5, 109.6, 76.7, 68.6, 66.6, 36.0, 28.1, 25.8;
HRMS (ESI) m/z calcd for C16H18N2NaO3 [M+Na]+: 309.1210, found: 309.1197.
Benzyl (E)-3-(1-methyl-1H-indazol-3-yl)acrylate (3ah). White solid (228 mg, 78% yield), mp:
77–80 ℃; 1H NMR (400 MHz, Chloroform-d) δ 8.03 (d, J = 16.2 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H),
7.46–7.30 (m, 7H), 7.27–7.21 (m, 1H, subtracting CDCl3), 6.79 (d, J = 16.2 Hz, 1H), 5.28 (s, 2H),
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4.07 (s, 3H); C{1H} NMR (100 MHz, Chloroform-d) δ 167.1, 141.4, 139.7, 136.5, 136.2, 128.7
(2C), 128.32 (2C), 128.29, 126.8, 122.7, 122.2, 120.8, 118.6, 109.7, 66.4, 36.0; HRMS (ESI) m/z
calcd for C18H16N2NaO2 [M+Na]+: 315.1104, found: 315.1090.
2-Phenoxyethyl (E)-3-(1-methyl-1H-indazol-3-yl)acrylate (3ai). Yellow solid (255 mg, 79%
1
yield), mp: 79–82 ℃; H NMR (400 MHz, Chloroform-d) δ 8.04 (d, J = 16.2 Hz, 1H), 7.93 (d, J =
8.4 Hz, 1H), 7.47–7.40 (m, 2H), 7.32–7.25 (m, 3H, subtracting CDCl3), 6.98–6.93 (m, 3H), 6.80 (d,
J = 16.2 Hz, 1H), 4.60 (t, J = 4.8 Hz, 2H), 4.27 (t, J = 4.8 Hz, 2H), 4.10 (s, 3H); 13C{1H} NMR (100
MHz, Chloroform-d) δ 167.2, 158.6, 141.4, 139.7, 136.7, 129.6 (2C), 126.9, 122.7, 122.3, 121.3,
120.8, 118.3, 114.8 (2C), 109.7, 66.1, 63.1, 36.1; HRMS (ESI) m/z calcd for C19H18N2NaO3
[M+Na]+: 345.1210, found: 345.1205.
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2-Acetoxyethyl (E)-3-(1-methyl-1H-indazol-3-yl)acrylate (3aj). Colorless oil (179 mg, 62%
1
yield); H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 16.2 Hz, 1H), 7.93 (d, J = 8.0 Hz, 1H),
7.47–7.40 (m, 2H), 7.29–7.24 (m, 1H, subtracting CDCl3), 6.76 (d, J = 16.2 Hz, 1H), 4.46–4.33 (m,
4H), 4.10 (s, 3H), 2.10 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 171.0, 167.0, 141.4,
139.6, 136.7, 126.9, 122.7, 122.3, 120.8, 118.1, 109.7, 62.5, 62.4, 36.1, 21.0; HRMS (ESI) m/z calcd
for C15H16N2NaO4 [M+Na]+: 311.1002, found: 311.0996.
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(E)-3-(1-methyl-1H-indazol-3-yl)-1-(piperidin-1-yl)prop-2-en-1-one (3ak12b). Yellow solid (143
mg, 53% yield), mp: 106–108 ℃ (lit.,12b 107–110 °C); 1H NMR (600 MHz, Chloroform-d) δ 7.96 (d,
J = 15.4 Hz, 1H), 7.88 (d, J = 7.8 Hz, 1H), 7.44–7.38 (m, 2H), 7.32 (d, J = 15.4 Hz, 1H), 7.25–7.21
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(m, 1H), 4.12–4.08 (m, 3H), 3.67 (s, 4H), 1.71–1.66 (m, 2H), 1.65–1.60 (m, 4H); C{1H} NMR
(150 MHz, Chloroform-d) δ 165.4, 141.2, 140.4, 132.2, 126.7, 123.0, 121.6, 120.4, 118.1, 109.4,
47.1, 43.4, 35.9, 26.9, 25.7, 24.8.
Diethyl (E)-(2-(1-methyl-1H-indazol-3-yl)vinyl)phosphonate (3al). Colorless oil (132 mg, 45%);
1H NMR (400 MHz, Chloroform-d) δ 7.89 (d, J = 8.0 Hz, 1H), 7.76 (dd, J1= J2 = 18.0 Hz, 1H),
7.46–7.36 (m, 2H), 7.27–7.20 (m, 1H), 6.58 (dd, J1= J2 = 18.0 Hz, 1H), 4.19–4.11 (m, 4H), 4.08 (s,
3H), 1.35 (t, J = 7.0 Hz, 6H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 141.3, 140.1, 139.8, 139.5
(d, J = 7 Hz), 126.8, 122.5, 122.1, 120.5, 115.7, 113.7, 109.6, 62.0 (d, J = 6 Hz), 36.0, 16.5 (d, J = 6
Hz); 31P NMR (162 MHz, Chloroform-d) δ 19.37; HRMS (ESI) m/z calcd for C14H20N2O3P [M+H]+:
295.1206, found: 295.1208.
(E)-1-Methyl-3-styryl-1H-indazole (3am12b). Yellow solid (216 mg, 92% yield), mp: 73–76 °C
(lit.,12b 72–75 °C); 1H NMR (500 MHz, Chloroform-d) δ 8.03 (d, J = 8.5 Hz, 1H), 7.62 (d, J = 7.5 Hz,
2H), 7.53 (d, J = 16.5 Hz, 1H), 7.49–7.36 (m, 5H, including d, J = 16.5 Hz, 1H), 7.33–7.28 (m, 1H),
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7.27–7.22 (m, 1H), 4.08 (s, 3H); C{1H} NMR (125 MHz, Chloroform-d) δ 142.2, 141.4, 137.5,
130.4, 128.8 (2C), 127.8, 126.6, 126.5 (2C), 122.1, 121.1, 121.0, 120.1, 109.3, 35.6.
(E)-1-Methyl-3-(4-methylstyryl)-1H-indazole (3an12b). White solid (223 mg, 90% yield), mp: 90–
1
93 °C (lit.,12b 92–93 °C); H NMR (400 MHz, Chloroform-d) δ 8.02 (d, J = 8.4 Hz, 1H), 7.54–7.46
(m, 3H, including d, J = 16.8, 1H), 7.46–7.36 (m, 3H, including d, J = 16.8, 1H), 7.27–7.18 (m, 3H,
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subtracting CDCl3), 4.08 (s, 3H), 2.39 (s, 3H); C{1H} NMR (100 MHz, Chloroform-d) δ 142.4,
141.4, 137.7, 134.7, 130.4, 129.6 (2C), 126.5, 126.5 (2C), 122.1, 121.1, 120.9, 119.1, 109.3, 35.6,
21.4.
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(E)-3-(4-Methoxystyryl)-1-methyl-1H-indazole (3ao4b). Brown solid (180 mg, 68% yield), mp:
63–65 °C (lit.,4b 56–58 °C); 1H NMR (400 MHz, Chloroform-d) δ 8.01 (d, J = 8.0 Hz, 1H), 7.53 (d, J
= 8.4 Hz, 2H), 7.49–7.35 (m, 3H, including d, J = 16.8, 1H), 7.30 (d, J = 16.8 Hz, 1H), 7.25–7.18 (m,
1H), 6.93 (d, J = 8.4 Hz, 2H), 4.07 (s, 3H), 3.84 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ
159.5, 142.5, 141.3, 130.3, 130.0, 127.8 (2C), 126.5, 122.0, 121.1, 120.9, 117.9, 114.3 (2C), 109.3,
55.4, 35.6.
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(E)-3-(4-Chlorostyryl)-1-methyl-1H-indazole (3ap12b). Yellow solid (218 mg, 81% yield), mp:
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104–107 °C (lit.,12b 102–103 °C); H NMR (400 MHz, Chloroform-d) δ 7.99 (d, J = 8.4 Hz, 1H),
7.50 (d, J = 8.0 Hz, 2H), 7.46–7.37 (m, 4H, including d, J = 16.4 Hz, 2H), 7.34 (d, J = 8.0 Hz, 2H),
13
7.23–7.20 (m, 1H), 4.08 (s, 3H); C{1H} NMR (150 MHz, Chloroform-d) δ 141.8, 141.3, 136.0,
133.3, 129.0 (2C), 128.9, 127.7 (2C), 126.6, 122.1, 121.1, 120.9, 120.6, 109.4, 35.7.
(E)-4-(2-(1-Methyl-1H-indazol-3-yl)vinyl)benzonitrile (3aq12b). White solid (169 mg, 65% yield),
mp: 158–161 °C (lit.,12b 157–159 °C); 1H NMR (400 MHz, Chloroform-d) δ 7.97 (d, J = 8.4 Hz, 1H),
8.00–7.95 (m, 4H), 7.51 (d, J = 16.4 Hz, 1H), 7.47–7.39 (m, 3H, including d, J = 16.4 Hz, 1H), 7.29–
13
7.23 (m, 1H, subtracting CDCl3), 4.09 (s, 3H); C{1H} NMR (100 MHz, Chloroform-d) δ 142.0,
141.4, 141.2, 132.6 (2C), 127.9, 126.80 (2C), 126.78, 123.7, 122.2, 121.5, 120.8, 119.2, 110.6, 109.6,
35.8.
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(E)-1-Methyl-3-(3-methylstyryl)-1H-indazole (3ar). Yellow oil (171 mg, 69% yield); H NMR
(400 MHz, Chloroform-d) δ 8.03 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 16.8 Hz, 1H), 7.45 (s, 1H), 7.44–
7.36 (m, 4H, including d, J = 16.8 Hz, 1H), 7.13–7.27 (m, 1H), 7.26–7.21 (m, 1H, subtracting
CDCl3), 7.11 (d, J = 7.6 Hz, 1H), 4.08 (s, 3H), 2.41 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d)
δ 142.3, 141.4, 138.4, 137.5, 130.5, 128.73, 128.66, 127.3, 126.6, 123.7, 122.1, 121.1, 121.0, 119.9,
109.3, 35.6, 21.6; HRMS (ESI) m/z calcd for C17H17N2 [M+H]+: 249.1386, found: 249.1391.
(E)-3-(3-Chlorostyryl)-1-methyl-1H-indazole (3as12b). White solid (175 mg, 65% yield), mp: 95–
97 °C (lit.,12b 98–99 °C); 1H NMR (400 MHz, Chloroform-d) δ 7.94 (d, J = 8.0 Hz, 1H), 7.53 (s, 1H),
7.45–7.35 (m, 4H), 7.31 (d, J = 8.0 Hz, 1H), 7.29–7.18 (m, 3H, subtracting CDCl3), 4.01 (s, 3H);
13C{1H} NMR (100 MHz, Chloroform-d) δ 141.3, 141.0, 139.2, 134.4, 129.7, 128.2, 127.3, 126.3,
126.1, 124.4, 121.8, 121.3, 120.9, 120.6, 109.1, 35.3.
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(E)-1-Methyl-3-(2-methylstyryl)-1H-indazole (3at). Yellow oil (129 mg, 52% yield); H NMR
(400 MHz, Chloroform-d) δ 8.00 (d, J = 8.0 Hz, 1H), 7.75–7.68 (m, 2H, including d, J = 16.4 Hz,
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1H), 7.46–7.38 (m, 2H), 7.35 (d, J = 16.4 Hz, 1H), 7.27–7.20 (m, 4H, subtracting CDCl3), 4.10 (s,
3H), 2.51 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 142.6, 141.4, 136.5, 135.9, 130.6,
128.3, 127.8, 126.6, 126.4, 125.2, 122.1, 121.3, 121.09, 121.08, 109.4, 35.7, 20.2; HRMS (ESI) m/z
calcd for C17H17N2 [M+H]+: 249.1386, found: 249.1389.
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(E)-3-(2-Chlorostyryl)-1-methyl-1H-indazole (3au12b). Yellow solid (137 mg, 51% yield), mp:
90–92 °C (lit.,12b 87–89 °C); 1H NMR (600 MHz, Chloroform-d) δ 8.08 (d, J = 8.4 Hz, 1H), 7.89 (d,
J = 16.6 Hz, 1H), 7.77 (d, J = 7.8 Hz, 1H), 7.47–7.39 (m, 4H, including d, J = 16.6 Hz, 1H), 7.32–
7.24 (m, 2H, subtracting CDCl3), 7.24–7.19 (m, 1H), 4.10 (s, 3H); 13C{1H} NMR (150 MHz,
Chloroform-d) δ 142.1, 141.4, 135.6, 133.5, 129.9, 128.7, 127.1, 126.7, 126.4, 126.2, 123.0, 122.0,
121.4, 121.3, 109.4, 35.7.
(E)-1-Methyl-3-(2-(pyridin-2-yl)vinyl)-1H-indazole (3av12b). Yellow soild (127 mg, 54% yield).
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mp: 89–91 °C (lit.,12b 86–89 °C); H NMR (600 MHz, Chloroform-d) δ 8.63 (d, J = 4.8 Hz, 1H),
8.07 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 16.4 Hz, 1H), 7.71–7.67 (m, 1H), 7.57 (d, J = 16.4 Hz, 1H),
7.48 (d, J = 7.8 Hz, 1H), 7.45–7.39 (m, 2H), 7.26–7.22 (m, 1H), 7.19–7.15 (m, 1H), 4.10 (s, 3H);
13C{1H} NMR (150 MHz, Chloroform-d) δ 155.9, 149.8, 141.7, 141.4, 136.7, 129.4, 126.6, 123.8,
122.6, 122.2, 121.9, 121.3, 121.1, 109.4, 35.8.
Typical
Procedure
for
the
(5aa).
Synthesis
mixture
of
5-(1-methyl-1H-indazol-3-yl)thiophene-2-carbaldehyde
A
of
1-methyl-1H-indazole 1a (132 mg, 1.0 mmol), thiophene-2-carbaldehyde 4a (224 mg, 2.0 mmol),
Pd2(dba)3 (183 mg, 0.2 mmol), Cu(OAc)2·H2O (299 mg, 1.5 mmol), and Na2SO4 (8.5 g) was placed
in a stainless-steel vessel, along with 448 stainless-steel balls (dMB = 4 mm, ФMB = 0.228). Then the
ball milling vessel was placed in the planetary mill (milling cycle: 30 min milling at 900 rpm,
followed by 2 min break, 4 repetitions). The crude product was collected by washing the vessel and
the balls with EtOAc (3 × 20 mL). The mixture was concentrated in vacuum and purified by column
chromatography on silica gel (Hexane/EtOAc = 20:1 to 8:1) to give the desired product 5aa as a
yellow solid (109 mg, 45%), mp: 87–89 ℃; 1H NMR (400 MHz, Chloroform-d) δ 9.94 (s, 1H), 8.03
(d, J = 8.0 Hz, 1H), 7.81 (d, J = 4.0 Hz, 1H), 7.71 (d, J = 4.0 Hz, 1H), 7.50–7.43 (m, 2H), 7.32–7.28
(m, 1H), 4.14 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 183.0, 146.2, 142.2, 141.6, 137.6,
137.3, 127.0, 124.8, 122.3, 121.5, 120.9, 109.8, 36.0; HRMS (ESI) m/z calcd for C13H10N2NaOS
[M+Na]+: 265.0406, found: 265.0396.
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5-(5-Methoxy-1-methyl-1H-indazol-3-yl)thiophene-2-carbaldehyde (5da). Brown solid (114 mg,
42%), mp: 135–137 ℃; 1H NMR (400 MHz, Chloroform-d) δ 9.92 (s, 1H), 7.79 (d, J = 4.0 Hz, 1H),
7.64 (d, J = 4.0 Hz, 1H), 7.31 (d, J = 9.2 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 7.11 (dd, J = 9.2, 2.2 Hz,
1H), 4.08 (s, 3H), 3.90 (s, 3H); 13C{1H} NMR (100 MHz, Chloroform-d) δ 182.9, 156.0, 146.5,
141.7, 137.43, 137.41, 136.6, 124.3, 121.7, 119.3, 110.8, 99.9, 55.9, 36.2; HRMS (ESI) m/z calcd for
C14H12N2NaO2S [M+Na]+: 295.0512, found: 295.0506.
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3-(5-Formylthiophen-2-yl)-1-methyl-1H-indazole-6-carbonitrile (5ga). Yellow solid (67 mg,
25%), mp: 203–205 ℃; 1H NMR (400 MHz, Chloroform-d) δ 9.96 (s, 1H), 8.13 (d, J = 8.4 Hz, 1H),
7.85–7.81 (m, 2H, including d, J = 3.9 Hz, 1H), 7.71 (d, J = 3.9 Hz, 1H), 7.50 (d, J = 8.4 Hz, 1H),
13
4.19 (s, 3H); C{1H} NMR (100 MHz, Chloroform-d) δ 182.9, 144.3, 143.1, 140.3, 138.4, 137.0,
125.6, 124.2, 123.3, 122.3, 118.9, 115.2, 110.5, 36.4; HRMS (ESI) m/z calcd for C14H10N3OS
[M+H]+: 268.0539, found: 268.0539.
5-(7-Chloro-1-methyl-1H-indazol-3-yl)thiophene-2-carbaldehyde (5ha). Yellow solid (113 mg,
41%), mp: 126–128 ℃; 1H NMR (500 MHz, Chloroform-d) δ 9.94 (s, 1H), 7.90 (dd, J = 8.5, 0.5 Hz,
1H), 7.80 (d, J = 3.9 Hz, 1H), 7.67 (d, J = 3.9 Hz, 1H), 7.40 (dd, J = 7.5, 0.5 Hz, 1H), 7.19–7.14 (m,
1H), 4.45 (s, 3H); 13C{1H} NMR (125 MHz, Chloroform-d) δ 182.9, 145.1, 142.6, 137.8, 137.6,
137.0, 128.0, 125.2, 124.1, 122.9, 119.6, 116.9, 39.7; HRMS (ESI) m/z calcd for C13H9ClN2NaOS
[M+Na]+: 299.0016, found: 299.0007.
1-(5-(1,5-Dimethyl-1H-indazol-3-yl)thiophen-2-yl)ethan-1-one (5jb). Yellow solid (95 mg, 35%),
mp: 125–127 ℃; 1H NMR (400 MHz, Chloroform-d) δ 7.80 (s, 1H), 7.73 (d, J = 4.0 Hz, 1H), 7.62 (d,
13
J = 4.0 Hz, 1H), 7.33–7.27 (m, 2H), 4.09 (s, 3H), 2.60 (s, 3H), 2.51 (s, 3H); C{1H} NMR (100
MHz, Chloroform-d) δ 190.8, 144.9, 142.4, 140.2, 137.1, 133.3, 131.8, 129.0, 124.5, 121.7, 120.0,
109.4, 36.0, 26.9, 21.6; HRMS (ESI) m/z calcd for C15H15N2OS [M+H]+: 271.0900, found:
271.0902.
1
5-(1-Methyl-1H-indazol-3-yl)furan-2-carbaldehyde (5ac21). Brown oil (82 mg, 36%); H NMR
(400 MHz, Chloroform-d) δ 9.74 (s, 1H), 8.25 (d, J = 6.4 Hz, 1H), 7.50–7.42 (m, 2H), 7.40 (d, J =
13
3.2 Hz, 1H), 7.34–7.29 (m, 1H), 7.08 (d, J = 3.2 Hz, 1H), 4.15 (s, 3H); C{1H} NMR (125 MHz,
Chloroform-d) δ 177.3, 155.1, 152.2, 141.1, 134.6, 127.3, 122.5, 122.0, 121.5, 109.5, 108.7, 36.2;
HRMS (ESI) m/z calcd for C13H10N2NaO2 [M+Na]+: 249.0634, found: 249.0630.
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1-(5-(1-Methyl-1H-indazol-3-yl)furan-2-yl)ethan-1-one (5ad). Yellow solid (84 mg, 35%), mp:
95–97 ℃; 1H NMR (400 MHz, Chloroform-d) δ 8.24 (d, J = 8.4 Hz, 1H), 7.52–7.43 (m, 2H), 7.38–
7.30 (m, 2H), 7.04 (d, J = 3.6 Hz, 1H), 4.16 (s, 3H), 2.62 (s, 3H); 13C{1H} NMR (100 MHz,
Chloroform-d) δ 186.4, 153.3, 152.1, 141.1, 134.9, 127.2, 122.3, 121.9, 119.2, 110.3, 109.5, 108.5,
36.1, 26.3; HRMS (ESI) m/z calcd for C14H12N2NaO2 [M+Na]+: 263.0791, found: 263.0780.
5-(1-Benzyl-1H-indazol-3-yl)thiophene-2-carbaldehyde (5ia21). Yellow solid (96 mg, 30%), mp:
124–126 ℃; 1H NMR (400 MHz, Chloroform-d) δ 9.95 (s, 1H), 8.05 (d, J = 8.0 Hz, 1H), 7.81 (d, J =
4.0 Hz, 1H), 7.74 (d, J = 4.0 Hz, 1H), 7.42–7.36 (m, 2H), 7.34–7.24 (m, 6H, subtracting CDCl3),
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5.65 (s, 2H); C{1H} NMR (100 MHz, Chloroform-d) δ 183.0, 146.1, 142.3, 141.1, 138.0, 137.2,
136.2, 128.9 (2C), 128.1, 127.4 (2C), 127.1, 125.1, 122.4, 121.9, 120.9, 110.2, 53.6.
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5-(1-Benzyl-1H-indazol-3-yl)furan-2-carbaldehyde (5ic2f). Yellow oil (103 mg, 34%); H NMR
(400 MHz, Chloroform-d) δ 9.74 (s, 1H), 8.27 (d, J = 8.0 Hz, 1H), 7.43–7.34 (m, 3H), 7.34–7.26 (m,
4H), 7.25–7.20 (m, 2H), 7.11 (d, J = 3.6 Hz, 1H), 5.67 (s, 2H); 13C{1H} NMR (100 MHz,
Chloroform-d) δ 177.3, 155.1, 152.2, 140.7, 136.2, 135.0, 129.0 (2C), 128.1, 127.4, 127.3 (2C),
122.6, 122.0, 121.9, 109.9, 109.0, 53.7.
Synthesis of Intermediate of CFI-400945: (E)-5-methoxy-3-((3-((E)-4-(morpholinomethyl)
styryl)-1H-indazol-6-yl)methylene)indolin-2-one (3nw2d).
(E)-3-(4-(Morpholinomethyl)styryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbonit
rile
(3kw).
According
to
the
method
for
compound
3aa,
using
1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbonitrile (273 mg, 1.0 mmol) and
4-(4-vinylbenzyl)morpholine (406 mg, 2.0 mmol), the title compound 3kw was obtained as an
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Yellow oil (327 mg, 69%); H NMR (400 MHz, Chloroform-d) δ 8.09 (d, J = 8.4 Hz, 1H), 7.95 (s,
1H), 7.56–7.45 (m, 4H, including d, J = 17.6 Hz, 1H), 7.39–7.34 (m, 3H), 5.75 (s, 2H), 3.75–3.71 (m,
4H), 3.58 (t, J = 8.2 Hz, 2H), 3.53 (s, 2H), 2.51–2.44 (m, 4H), 0.91 (t, J = 8.2 Hz, 2H), -0.05 (s, 9H);
13C{1H} NMR (100 MHz, Chloroform-d) δ 143.7, 139.9, 135.8, 132.4, 129.8 (2C), 126.7 (2C), 125.0,
123.9, 122.4, 119.2, 118.4, 115.4, 110.3, 78.3, 67.1, 67.0 (2C), 63.2, 53.8 (2C), 17.8, -1.3 (3C);
HRMS (ESI) m/z calcd for C27H35N4O2Si [M+H]+: 475.2524, found: 475.2528.
(E)-3-(4-(Morpholinomethyl)styryl)-1H-indazole-6-carbonitrile
(3lw).
A
mixture
of
(E)-3-(4-(morpholinomethyl)styryl)-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-indazole-6-carbonitrile
3kw (237 mg, 0.5 mmol), TBAF (tetra-n-butylammonium fluoride) (719 mg, 2.75 mmol) and silica
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gel (0.5 g) was placed in a 50 mL screw-capped stainless-steel vessel, along with two stainless-steel
balls (dMB = 1.2 cm, ΦMB= 0.036). Then, the vessel was placed in the mixer mill, and the contents
were milled at 25 Hz for 2 h. At the end of the experiment, the crude product was scratched off from
the vessel and directly purified by column chromatography on silica gel (Dichloromethane/MeOH =
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40:1) to give the desired product 3lw as a white solid (153 mg, 89%), mp: 211–213 °C; H NMR
(400 MHz, DMSO-d6) δ 13.72 (s, 1H), 8.38 (d, J = 8.4 Hz, 1H), 8.16 (s, 1H), 7.67 (d, J = 8.0 Hz,
2H), 7.57–7.50 (m, 3H), 7.33 (d, J = 8.0 Hz, 2H), 3.59–3.55 (m, 4H), 3.46 (s, 2H), 2.38–2.32 (m,
4H); C{1H} NMR (100 MHz, DMSO-d6) δ 142.8, 140.0, 137.7, 135.6, 130.3, 129.3 (2C), 126.5
13
(2C), 122.7, 122.6, 122.3, 119.4, 118.8, 116.3, 108.4, 66.2 (2C), 62.2, 53.2 (2C); HRMS (ESI) m/z
calcd for C21H21N4O [M+H]+: 345.1710, found: 345.1727.
(E)-3-(4-(Morpholinomethyl)styryl)-1H-indazole-6-carbaldehyde (3mw2d).
A
mixture of
(E)-3-(4-(morpholinomethyl)styryl)-1H-indazole-6-carbonitrile 3lw (172 mg, 1.0 mmol), sodium
hypophosphite (476 mg, 5.4 mmol), Raney-Nickel (slurry in H2O, 1.0 mL), and silica gel (3.0 g) was
placed in a stainless-steel vessel, along with 166 stainless-steel balls (dMB = 6 mm, ФMB = 0.234).
Then the ball milling vessel was placed in the planetary mill (milling cycle: 30 min milling at 600
rpm, followed by 2 min break, 4 repetitions). The crude product was collected by washing the vessel
and the balls with EtOAc (3 × 20 mL). The mixture was concentrated in vacuum and purified by
column chromatography on silica gel (Dichloromethane/MeOH = 40:1) to give the desired product
1
3mw as a white solid (80 mg, 46%), mp: 171–174 °C; H NMR (400 MHz, DMSO-d6) δ 13.71 (s,
1H), 10.14 (s, 1H), 8.34 (d, J = 8.4 Hz, 1H), 8.17 (s, 1H), 7.70–7.51 (m, 5H), 7.33 (d, J = 8.0 Hz,
2H), 3.60–3.54 (m, 4H), 3.46 (s, 2H), 2.38–2.31 (m, 4H); C{1H} NMR (100 MHz, DMSO-d6) δ
13
193.3, 142.8, 140.9, 137.6, 135.7, 134.3, 123.0, 129.3 (2C), 126.4 (2C), 123.7, 121.5, 119.3, 119.0,
115.3, 66.2 (2C), 62.2, 53.2 (2C); HRMS (ESI) m/z calcd for C21H22N3O2 [M+H]+: 348.1707, found:
348.1696.
(E)-5-Methoxy-3-((3-((E)-4-(morpholinomethyl)styryl)-1H-indazol-6-yl)methylene)indolin-2-on
e (3nw). A mixture of (E)-3-(4-(morpholinomethyl)styryl)-1H-indazole-6-carbaldehyde 3mw (174
mg, 0.5 mmol), 5-methoxyindolin-2-one (245 mg, 1.5 mmol), piperidine (4.3 mg, 0.05 mmol) and
silica gel (0.5 g) was placed in a 50 mL screw-capped stainless-steel vessel, along with two
stainless-steel balls (dMB = 1.2 cm, ΦMB= 0.036). Then, the vessel was placed in the mixer mill, and
the contents were milled at 30 Hz for 1 h. At the end of the experiment, the crude product was
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scratched off from the vessel and directly purified by column chromatography on silica gel
(Dichloromethane/MeOH = 40:1) to give the desired product 3nw as a yellow solid (177 mg, 72%),
mp: 235–238 °C; 1H NMR (400 MHz, DMSO-d6) δ 13.38 (s, 1H), 10.44 (s, 1H), 8.32 (d, J = 8.4 Hz,
1H), 7.91 (s, 1H), 7.80 (s, 1H), 7.72–7.50 (m, 5H), 7.33 (d, J = 7.6 Hz, 2H), 7.20 (s, 1H), 6.88–6.79
(m, 2H), 3.62–3.55 (m, 7H), 3.47 (s, 2H), 2.36 (s, 4H); 13C{1H} NMR (100 MHz, DMSO-d6) δ 168.7,
154.0, 142.6, 141.1, 137.5, 136.8, 136.5, 135.9, 132.3, 129.6, 129.3 (2C), 128.2, 126.3 (2C), 122.0,
121.7, 121.1, 121.0, 119.8, 115.2, 111.4, 110.5, 109.0, 66.2 (2C), 62.2, 55.3, 53.2 (2C); HRMS (ESI)
m/z calcd for C30H29N4O3 [M+H]+: 493.2234, found: 493.2249.
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Synthesis of (5-(1-benzyl-1H-indazol-3-yl)furan-2-yl)methanol (YC-12e). A mixture of
5-(1-benzyl-1H-indazol-3-yl)furan-2-carbaldehyde 5ic (151 mg, 0.5 mmol), NaBH4 (21 mg, 0.55
mmol), CeCl3·7H2O (37 mg, 0.1 mmol), and silica gel (0.5 g) was placed in a 50 mL screw-capped
stainless-steel vessel, along with two stainless-steel balls (dMB = 1.2 cm, ΦMB= 0.036). Then, the
vessel was placed in the mixer mill, and the contents were milled at 20 Hz for 30 min. At the end of
the experiment, the reaction mixture was scratched off from the vessel and directly purified by
column chromatography on silica gel (Hexane/EtOAc = 20:1 to 8:1) to give the desired product
1
YC-1 as a white solid (129 mg, 85%), mp: 108–110 °C, (lit.,2e 110–112 °C); H NMR (400 MHz,
Chloroform-d) δ 8.08 (d, J = 8.0 Hz, 1H), 7.42–7.35 (m, 2H), 7.34–7.25 (m, 3H, subtracting CDCl3),
7.23–7.18 (m, 3H), 6.89 (d, J = 3.2 Hz, 1H), 6.49 (d, J = 3.2 Hz, 1H), 5.67 (s, 2H), 4.76 (s, 2H);
13C{1H} NMR (100 MHz, Chloroform-d) δ 154.1, 148.7, 140.7, 136.7, 136.3, 128.9 (2C), 127.9,
127.2 (2C), 127.0, 121.7, 121.6, 121.5, 109.8 (2C), 108.1, 57.7, 53.3.
General Procedure for the H/D Exchange Control Experiments. The deuteration reactions of
either 1-methyl-1H-indazole 1a or thiophene-2-carbaldehyde 4a separately carried out using the
conditions noted in Scheme 2. Heavy water D2O (15.0 equiv.) was used as a deuterium source. The
crude product was isolated by washing the vessel and the balls with EtOAc (3 × 20 mL). The mixture
was concentrated in vacuum and purified by column chromatography on silica gel (Hexane/EtOAc =
20:1 to 8:1). The obtained residues were individually analyzed by means of 1H NMR spectroscopy.
Synthesis of 1-methyl-1H-indazole-3-d (1a-[D1]). The synthesis of 1a-[D1] were carried out
according to the characters of ball milling that Pd-catalyzed Heck reaction of aryl halides was often
accompanied by dehalogenation as side reaction which was proposed by our group.12b A mixture of
3-bromo-1-methyl-1H-indazole (211 mg, 1.0 mmol), Pd(OAc)2 (112 mg, 0.5 mmol), D2O (272 μL,
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15 equiv.) and dry NaCl (3.0 g) was placed in a stainless-steel vessel, along with 207 stainless-steel
balls (dMB = 6 mm, ФMB = 0.293). Then the ball milling vessel was placed in the planetary mill
milling at 800 rpm for 30 min. The crude product was collected by washing the vessel and the balls
with EtOAc (3 × 20 mL). The mixture was concentrated in vacuum and purified by column
chromatography on silica gel (Hexane/EtOAc = 8:1) to give the desired product 1a-[D1] as a white
solid (66 mg, 50% yield, deuterated ratio > 98%).
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Intermolecular KIE Experiments by Independent Reactions between 1a or 1a-[D1] and 4a.
1-methyl-1H-indazole 1a (132 mg, 1.0 mmol) or 1a-[D1] (133 mg, 1.0 mmol),
thiophene-2-carbaldehyde 4a (224 mg, 2.0 mmol), Pd2(dba)3 (183 mg, 0.2 mmol), Cu(OAc)2·H2O
(299 mg, 1.5 mmol), and Na2SO4 (8.5 g) was placed in a stainless-steel vessel, along with 448
stainless-steel balls (dMB = 4 mm, ФMB = 0.228). Then the ball milling vessel was placed in the
planetary mill, and the contents were milled at 900 rpm for designated times (0.5 h, 1 h and 1.5 h).
The crude product was collected by washing the vessel and the balls with EtOAc (3 × 20 mL). The
mixture was concentrated in vacuum and purified by column chromatography on silica gel
(Hexane/EtOAc = 20:1 to 8:1) to give the desired product 5aa (KIE = 27.7/8.7 = 3.2).
Intermolecular KIE Experiments by Independent Reactions between 1a and 4a or 4a-[D1].
1-methyl-1H-indazole 1a (132 mg, 1.0 mmol), thiophene-2-carbaldehyde 4a (224 mg, 2.0 mmol) or
4a-[D1] (226 mg, 2.0 mmol), Pd2(dba)3 (183 mg, 0.2 mmol), Cu(OAc)2·H2O (299 mg, 1.5 mmol),
and Na2SO4 (8.5 g) was placed in a stainless-steel vessel, along with 448 stainless-steel balls (dMB
=
4 mm, ФMB = 0.228). Then the ball milling vessel was placed in the planetary mill, and the contents
were milled at 900 rpm for designated times (0.5 h, 1 h and 1.5 h). The crude product was collected
by washing the vessel and the balls with EtOAc (3 × 20 mL). The mixture was concentrated in
vacuum and purified by column chromatography on silica gel (Hexane/EtOAc = 20:1 to 8:1) to give
the desired product 5aa (KIE = 27.7/18.4 = 1.5).
ASSOCIATED CONTENT
Supporting Information
Chemical Conditions Optimization; Mechanical Parameters Screening; NMR Spectra of Organic
Compounds; NMR Spectra of Mechanistic Studies; KIE Measurement by Independent Reaction
(PDF)
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AUTHOR INFORMATION
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Corresponding Author
*E-mail: pharmlab@zjut.edu.cn.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the National Natural Science Foundation of China (No. 21978270 and
21406201) for financial support.
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