Bromide-assisted chemoselective Heck reaction of 3-bromoindazoles under high-speed ball-milling conditions: Synthesis of axitinib

Article abstract of DOI:10.3762/bjoc.14.66

A mechanically-activated chemoselective Heck coupling for the synthesis of 3-vinylindazoles has been developed with the aid of catalytic amounts of TBAB and NaBr as both dehalogenation restrainer and grinding auxiliary. After tuning of the chemical conditions and mechanical parameters, a series of non-activated 3-bromoindazoles and a broad scope of olefins worked well to give the corresponding coupling products in good to excellent yields. A further application of this protocol was performed in a two-step mechanochemical Heck/Migita cross coupling, which provided a highly efficient route for the synthesis of axitinib.

Full text of DOI:10.3762/bjoc.14.66

Bromide-assisted chemoselective Heck reaction of
3-bromoindazoles under high-speed ball-milling conditions:
synthesis of axitinib
Jingbo Yu1, Zikun Hong2, Xinjie Yang1, Yu Jiang1, Zhijiang Jiang1 and Weike Su*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2018, 14, 786–795.
1Collaborative Innovation Center of Yangtze River Delta Region
Green Pharmaceuticals, Zhejiang University of Technology,
Hangzhou 310014, PR China and 2College of Pharmaceutical
Sciences, Zhejiang University of Technology, Hangzhou 310014, PR
China
doi:10.3762/bjoc.14.66
Received: 07 February 2018
Accepted: 21 March 2018
Published: 06 April 2018
Email:
Associate Editor: L. Vaccaro
Weike Su* - pharmlab@zjut.edu.cn
© 2018 Yu et al.; licensee Beilstein-Institut.
License and terms: see end of document.
* Corresponding author
Keywords:
axitinib; ball-milling; dehalogenation; Heck reaction; indazoles
Abstract
A mechanically-activated chemoselective Heck coupling for the synthesis of 3-vinylindazoles has been developed with the aid of
catalytic amounts of TBAB and NaBr as both dehalogenation restrainer and grinding auxiliary. After tuning of the chemical condi-
tions and mechanical parameters, a series of non-activated 3-bromoindazoles and a broad scope of olefins worked well to give the
corresponding coupling products in good to excellent yields. A further application of this protocol was performed in a two-step
mechanochemical Heck/Migita cross coupling, which provided a highly efficient route for the synthesis of axitinib.
Introduction
The palladium-catalyzed vinylation of alkenes in the presence numbers of >1000 [9,10]. However, the couplings of bromo and
of a base, known as the Heck reaction (Mizoroki–Heck reac- chloro derivatives with unactivated alkenes still remain chal-
tion), is one of the most important transition-metal-catalyzed lenging. Though aryl bromides are always interesting sub-
reactions [1,2], which has shown itself as a powerful synthetic strates for industrial applications [11,12], possessing the charac-
tool in both academic and industrial practice [3-7]. The transfor- teristics of lower cost, easier to obtain and stable to store, they
mation has been enrolled as key steps for numerous synthetic face the problem of dehalogenations especially under metal-cat-
routes, including the recent President Green Chemistry Award alyzed reactions [8,13-18], affecting the reaction yield and
winner route of letermovir [8].
selectivity. Currently, the Heck reaction is usually carried out
by adding an excess of phase-transfer catalyst such as tetra-
Hitherto, highly effective systems had been developed for the butylammonium bromide (TBAB) or tetrabutylammonium
aryliodines that participated in Heck reactions with turn-over iodide (TBAI) to increase the reaction yield under both solvent-
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Results and Discussion
heating [19-23] and solvent-free conditions [24-27]. Despite
two proposals for the role of quaternary ammonium salts Optimisation of chemical conditons
NR4+X−, (1) Pd(0) stablizer and (2) phase transfer were sug- At the commencement of the investigation, the cross-coupling
gested [28-30], their effects and functions remain unrevealed. between 3-bromo-1-methyl-1H-indazole (1a) and n-butyl acry-
Hence, we want to get insight to the reaction pathway and the late (2a) was chosen as model reaction (Scheme 2). The initial
actual functions of NR4+X− for better inhibiting the dehalo- attempts using our previous established conditions [24,25], gave
genation of aryl bromides, wherever possible. Herein, only moderate conversion with a low yield of 53%. Noticeably,
3-bromoindazoles were chosen as model substrates not only for considerable amounts of 1-methyl-1H-indazole (4a) were ob-
their low activity and easy dehalogenation properties, but also tained, which implicated the existence of a significant debromi-
for their potential applications in the synthesis of natural prod- nation process. As expected, the situation was more badly when
ucts and pharmaceuticals, such as gamendazole [31,32], YC-1 the reaction was conducted under classic solvent-heating condi-
[33,34] and axitinib [35-38] (Scheme 1).
tions (see Scheme S1 in Supporting Information File 1). Subse-
quently, the optimization was carried out to improve the perfor-
Mechanochemistry as a burgeoning technique to promote sol- mance of the reaction. Palladium catalysts and ligands were
vent-free reactions has led to remarkable advances [39-42], par- firstly screened, which showed Pd(OAc)2/PPh3 as the most effi-
ticularly for cross-coupling reactions [43-45], involving Heck cient catalyst system (Table 1, entry 5). The catalyst loading
coupling with the aid of stoichiometric amounts of TBAB [24- could be reduced to 5 mol % without depriving of the product
27]. However, for inert and liable to dehalogenation bromo- yield (Table 1, entry 23). Other Pd catalysts and phosphorous
heteroarenes, no desired response had been obtained yet. Thus, ligands displayed little effects on the reaction selectivity and
this work was going to establish a mild and chemoselective product yield (Table 1, entries 1–4 and entries 6–9). As ex-
olefination of 3-bromoindazoles under ball-milling conditions pected, without any catalyst and ligand, the reaction cannot
(Scheme 2).
proceed (Table 1, entry 10). For the investigated bases, triethyl-
Scheme 1: Representative pharmaceutically useful indazoles.
Scheme 2: Model Heck reaction of 3-bromo-N-methyl-1H-indazole (1a) and n-butyl acrylate (2a). (173 stainless-steel balls (dMB = 6 mm,
ФMB = 0.245) were used. dMB = milling ball diameter. ФMB = milling ball filling degree.)
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Beilstein J. Org. Chem. 2018, 14, 786–795.
Table 1: Optimisation of the reaction conditions for the olefination of 3-bromoindazoles.a
Entry
Catalyst (mol %)
Ligand (mol %)
Base (equiv)
Yield (%) 3aa/4a
1
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
PdCl2 (10)
Xantphos (20)
dppf (20)
dppe (20)
P(o-tol)3 (20)
PPh3 (20)
PPh3 (20)
—
TEA (2)
43/24
44/21
45/19
32/22
53/18
47/18
47/20
37/17
48/18
0/30
2
TEA (2)
3
TEA (2)
4
TEA (2)
5
TEA (2)
6
TEA (2)
7
PdCl2(dppf) (10)
Pd2(dba)3 (10)
Pd(PPh3)4 (10)
—
TEA (2)
8
—
TEA (2)
9
—
TEA (2)
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
—
TEA (2)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (20)
Pd(OAc)2 (5)
Pd(OAc)2 (2.5)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (20)
PPh3 (40)
PPh3 (10)
PPh3 (5)
DABCO (2)
DIPEA (2)
DCHA (2)
DBU (2)
51/18
35/23
35/18
16/16
40/21
30/19
30/24
21/16
53/19
53/19
45/23
54/20
53/19
36/24
t-BuOK (2)
K2CO3 (2)
NaOH (2)
NaHCO3 (2)
TEA (1.5)
TEA (1.2)
TEA (1.0)
TEA (1.2)
TEA (1.2)
TEA (1.2)
aRaction conditions: 1a (1.5 mmol), 2a (2.25 mmol), Pd catalyst, ligand, base, TBAB (3 mmol), and silica gel (5.0 g) were placed in an 80 mL stain-
less steel vessel along with 173 stainless-steel balls (dMB = 6 mm, ФMB = 0.245), milling at 800 rpm for 90 min. TEA = triethylamine. DABCO = 1,4-
diazabicyclo[2.2.2]octane. DIPEA = N,N-diisopropylethylamine. DCHA = dicyclohexylamine. DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene.
amine (TEA) exhibited the best result though it was reported to dehalogenation counterpart 4a (Table S1, entry 2). However,
donate hydrides to arylpalladium species and lead to dehalo- TBAI or tetrabutylammonium chloride (TBAC) did not provide
genation [46]. While different from literature report [47], no a satisfactory result (Table S1, entries 3 and 4). It was interest-
improvement was found in the reaction selectivity when ing to find that using bromide salts (LiBr, NaBr, KBr and
replacing TEA by 1,4-diazabicyclo[2.2.2]octane (DABCO) TBAB) as additives, not only the conversion rate of 1a was in-
(Table 1, entry 11). Besides, other organic or inorganic bases creased, but also the side-product 4a was suppressed,
gave poor results (Table 1, entries 12–18).
suggesting the bromide ion plays an important role in amelio-
rating the reaction selectivity (Table S1, entries 9–11). Further
investigating the alkyl chain (R) of NR4+Br− showed that the
medium-length butyl was most efficient (Table S1, entries 5–7).
In order to see whether the quaternary ammonium salt had the
function of phase-transfer, other kinds of phase-transfer cata-
lysts (SDS = sodium dodecyl sulfate) were also examined, how-
ever, this gave rise to a negative effect (Table S1, entry 8). To
Next, the additives were investigated in the coupling reactions
(Figure 1, see detailed results in Supporting Information File 1,
Table S1). Consistent to previous reports [3,24-27,48-52],
TBAB helped to improve the product yield in this reaction,
since without additive under the standard conditions, only 14%
of target product 3aa was obtained along with 38% of the
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Beilstein J. Org. Chem. 2018, 14, 786–795.
Figure 1: Investigation of additives in the Heck reaction: 1a (1.5 mmol), 2a (2.25 mmol), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), TEA (1.8 mmol), addi-
tive (3.0 mmol), and silica gel (5.0 g) were placed in an 80 mL stainless steel vessel along with 173 stainless-steel balls (dMB = 6 mm, ФMB = 0.245),
milling at 800 rpm for 90 min.
our delight, when we replaced the grinding auxiliary by sodium genation was depressed (Table 2, entry 1), which showed silica
bromide, a moderate product yield (69%) and an excellent gel played an important role of promoting the dehalogenations.
selectivity (trace of 4a) were achieved (Table S1, entry 12). In When using a halogen salt (NaBr, KBr, NaCl) as grinding auxil-
this way, the amount of TBAB could even be reduced to 5 mol iary, NaBr displayed the most efficiency (Table 2, entries 3–6),
% (Table S1, entry 14).
and lowering the amount of NaBr did not significantly influ-
ence the product yield (Table 2, entry 4). Other solid auxiliaries
such as γ-Al2O3 and sand afforded a low yield of 3aa with poor
Influence of grinding auxiliary
In the process of ball milling, the grinding auxiliary was always selectivity (Table 2, entries 7 and 8).
found to be an efficient transfer medium between energy and
reactant [53-55]. Thus, the effect of the grinding auxiliaries was Reaction pathway investigation
also investigated. The results were shown in Table 2. Com- The control experiments were further conducted to disclose the
pared to using silica gel as grinding auxiliary, the reaction under reaction pathway (Scheme 3). In the case of taking TEA as sole
neat conditions gave only 10% yield of 3aa, but the dehalo- reagent in the reaction, the substrate 1a was converted to 4a in
27% yield (conditions a), while the dehalogenation was exacer-
bated in the presence of Pd(OAc)2/PPh3 (conditions b). This
Table 2: Examination of the influence of the grinding auxiliary on the
reaction outcomea.
Entry
Grinding auxiliary Weight (g)
Yield (%)
3aa/4a
1
2
3
4
5
6
7
8
—
—
10/trace
53/19
silica gel
NaBr
5.0
10.0
5.0
5.0
5.0
5.0
5.0
69/trace
65/trace
63/trace
27/5
NaBr
KBr
NaCl
γ-Al2O3 (neutral)
sand
20/6
30/10
aInfluence of the grinding auxiliary on the Heck reaction: 1a
(1.5 mmol), 2a (2.25 mmol), Pd(OAc)2 (5 mol %), PPh3 (10 mol %),
TEA (1.8 mmol), TBAB (5 mol %), and grinding auxiliary were placed
in an 80 mL stainless steel vessel along with 173 stainless-steel balls
(dMB = 6 mm, ФMB = 0.245), milling at 800 rpm for 90 min.
Scheme 3: The control experiments. aTEA (1.8 mmol), silica gel
(5.0 g), bPd(OAc)2 (5 mol %), PPh3 (10 mol %), TEA (1.8 mmol), silica
gel (5.0 g), cPd(OAc)2 (5 mol %), PPh3 (10 mol %), TEA (1.8 mmol),
NaBr (10.0 g).
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phenomenon was in agreement with previous reports [14-16], screened systematically (Figure 2). The results show a sharp
that Pd-catalyzed homocoupling of aryl halides under alkaline increase of the product yield when elevating the rotation speed
heating conditions was often accompanied by dehalogenation as from 600 to 800 rpm, and a progressive increase of the yield by
side reaction. When using NaBr as a grinding auxiliary instead prolonging the reaction time from 60 to 90 min. Further increas-
of silica gel, the dehalogenation of 1a was greatly inhibited ing the rotation speed or prolonging the reaction time did not
(conditions c), but still gave 4a in 30% without the presence of help to improve the product yield but promoted the occurrence
olefins.
of 4a (see Table S2 in Supporting Information File 1), which
mainly due to the redundant energy input spurred the dehalo-
Based on the above research, the reaction pathway for this Heck genation.
reaction under mechanical ball milling conditions was pro-
posed. As shown in path a, (Scheme 4). The reaction proceeded Next, the combination of filling degree (ФMB) and size of the
through Heck cross coupling, where a catalytic amount of milling balls (dMB) was investigated for further improving the
TBAB was enough to stabilize the Pd(0). However, the oxida- product yield. As seen in Figure 3, the yield of 3aa elevated
tive addition intermediate I was unstable so that it was prone to sharply as the filling degree increased to around 0.3–0.35 for all
produce 4a, as depicted in path b, particularly in the absence of types of the milling balls, and then decreased gradually due to
the coupling counterpart 2. Besides, alkaline and high energy milling vessel space limitations [24,61,62]. A maximum prod-
input conditions promoted the dehalogenation as shown in path uct yield (93%) was obtained by using 6 mm diameter milling
c, while the addition of bromine salts helped diminishing this balls (ФMB = 0.293), indicating small-size milling balls more
effect dramatically [56].
beneficial for the reaction, which was in accordance with the
previous studies reported by us [24] and others [57,63,64].
Adjusting of mechanical parameters
Having identified the optimal chemical conditions for the reac- Substrate scopes
tion selectivity on the basis of the reaction pathway, we then After a comprehensive study of the reaction pathway and the
focussed on the milling parameters such as rotation speed (νrot), reaction conditions, an excellent product yield (93%) and selec-
ball milling time (t), milling ball filling degree (ФMB), and tivity (trace of 4a) can be achieved. We then turned our efforts
milling ball diameter (dMB), which usually play important roles toward the investigation of the scope and limitations of the de-
in mechanochemistry processes [57-60]. First, the combined veloped method with respect to a broad range of indazoles and
effect between ball-milling time and rotation speed was olefins (Scheme 5). Pleasingly, neutral, electron-rich and elec-
Scheme 4: Plausible reaction pathway.
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Beilstein J. Org. Chem. 2018, 14, 786–795.
Figure 2: Influence of milling time and rotation speed on the Heck reaction: 1a (1.5 mmol), 2a (2.25 mmol), Pd(OAc)2 (5 mol %), PPh3 (10 mol %),
TEA (1.8 mmol), TBAB (5 mol %), and NaBr (10.0 g) were placed in 80 mL stainless steel vessel with stainless-steel balls (dMB = 6 mm,
ФMB = 0.245).
Figure 3: Influence of the milling ball filling degree with different size on the Heck reaction: 1a (1.5 mmol), 2a (2.25 mmol), Pd(OAc)2 (5 mol %), PPh3
(10 mol %), TEA (1.8 mmol), TBAB (5 mol %), and NaBr (10.0 g) were placed in 80 mL stainless steel vessel milling, milling at 800 rpm for 90 min.
tron-poor indazoles were perfectly tolerated in this reaction, went removal of the protecting group [65], and resulted in the
affording the corresponding target product 3ba–ka in high coupling product 3oa (70%). Besides, N-unsubstituted indazole
yields (88–96%) and excellent selectivity (the dehalogenated 1n could also be tolerated in this reaction giving 3na (52%) and
side-product 4 was not detected in most cases). Among which, 3nf (49%) in moderate yield by using 1,8-bis(dimethyl-
strong electron-withdrawing substrates required long reaction amino)naphthalene as a base. To our delight, 3-chloroindazole
times to achieve the desired results (3ca, 3ga, 3pn). It was could also be activated in this reaction, giving the correspond-
suprising to find that substrate 1d showed excellent site-selec- ing coupling products 3aa and 3af in considerable yields. The
tivity under 700 rpm, giving 6-bromo-substituted product 3da scope of the reaction with respect to the olefins was also exten-
in 94% yield. Indazoles with N-Me, THP and Bn groups sively investigated and encompasses acrylates 2a, acrylamides
afforded good to excellent yields in the coupling reaction with 2b and 2c, styrenes 2f–m and 2-vinylpyridine (2n). In addition,
n-butyl acrylate. However, the N-Boc substrate readily under- even non-activated allylbenzene 2o and disubstituted olefins 2d
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Beilstein J. Org. Chem. 2018, 14, 786–795.
Scheme 5: Examination of the substrate scope. Reaction conditions: 1 (1.5 mmol), 2 (2.25 mmol), Pd(OAc)2 (5 mol %), PPh3 (10 mol %), TEA
(1.8 mmol), TBAB (5 mol %), and NaBr (10.0 g) were placed in an 80 mL stainless steel vessel along with 207 stainless-steel balls (dMB = 6 mm,
ФMB = 0.293), milling at 800 rpm for 90 min. aN-Boc-3-bromoindazole was used as substrate. b150 min. c700 rpm. d3-chloro-1-methyl-1H-indazole
was used as substrate, νrot = 900 rpm. e1,8-Bis(dimethylamino)naphthalene was used as base.
and 2e could participate in the reaction to deliver 3ao (67%), Application in API synthesis
3ad (26%) and 3ae (27%). Finally, the steric hindrance of To demonstrate the broad utility of this method, a concise syn-
styrene was examined. Larger steric hindrance (2m) led to thesis of axitinib, eutherapeutic drug for the treatment of renal
lower yield (58%) as compared with 2k (89%) and 2l (88%). cell carcinoma, was undertaken (Scheme 6). The reaction
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Beilstein J. Org. Chem. 2018, 14, 786–795.
Scheme 6: Synthesis of axitinib by mechanochemical Heck–Migita coupling. Reagents and conditions: (i) NBS, NaOH, silica gel (4.0 g), 173 stain-
less-steel balls (dMB = 6 mm, ФMB = 0.245), 200 rpm, 30 min; (ii) CH3SO3H, dihydropyran, silica gel (4.0 g), 173 stainless-steel balls (dMB = 6 mm,
ФMB = 0.245), 200 rpm, 45 min; (iii) compound 2n, Pd(OAc)2, PPh3, TBAB, TEA, NaBr (10.0 g), 207 stainless-steel balls (dMB = 6 mm, ФMB = 0.293),
700 rpm, 90 min; (iv) compound 6, Pd2(dba)3, Xantphos, Cs2CO3, silica gel (4.0 g), 207 stainless-steel balls (dMB = 6 mm, ФMB = 0.293), 750 rpm,
50 min; (v) p-TsOH, silica gel (4.0 g), 207 stainless-steel balls (dMB = 6 mm, ФMB = 0.293), 500 rpm, 45 min.
started from commercially available 6-bromo-1H-indazole (5),
Supporting Information
bromination of the 3-position and N-protection gave 3,6-
dibromo-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (3q) in
Supporting Information File 1
90% yield. Next, sequential two-step Heck coupling and Migita
coupling under ball milling conditions selectively afforded
THP-axitinib 7. Finally, deprotection of 7 with p-TsOH gave
axitinib in a total yield of 44% (41% [66]). Comparing to
previous synthetic procedures [35,36], this mechanochemical
protocol provided a solvent-free, highly efficient and tractable
alternative, and the residual Pd content in the axitinib was deter-
mined to be no more than 2 ppm by ICP analysis.
Reaction optimization studies, details of experimental
procedures, characterization and copies of 1H and
13C NMR spectra of prepared compounds.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-14-66-S1.pdf]
Acknowledgements
We gratefully acknowledge the National Natural Science Foun-
dation of China (No. 21406201) and Zhejiang Province Science
and Technology Plan Project (No. LGF18B060004) for finan-
cial support.
Conclusion
In conclusion, a solvent-free, chemoselective Heck cross-cou-
pling for the synthesis of 3-vinylindazoles has been developed
by sophisticated tuning of the chemical and mechanical parame-
ters under ball-milling conditions. The reaction pathway was
comprehensively studied, revealing the bromide salts to play a
dual role by not only suppressing the dehalogenation of
3-bromoindazoles but also assisting grinding, while a catalytic
amount of TBAB was sufficient to stabilize Pd(0) and to
promote the cross coupling. A series of non-activated indazoles
and a broad scope of olefins were tolerated in the reaction
giving high yields and excellent selectivity. Further application
of this protocol was conducted in a total mechanosynthesis of
axitinib in short reaction time and high efficiency. With this
system, we hope to expand the pharmaceutical synthetic
toolbox in mechanochemistry.
ORCID® iDs
Jingbo Yu - https://orcid.org/0000-0002-7296-3493
Zikun Hong - https://orcid.org/0000-0003-4527-7698
Weike Su - https://orcid.org/0000-0003-2544-1948
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795