Solvent-free mechanochemical Buchwald-Hartwig amination of aryl chlorides without inert gas protection

Article abstract of DOI:10.1016/j.tetlet.2018.04.078

A solvent-free Buchwald-Hartwig amination had been developed under high-speed ball-milling conditions, which afforded the desired products with moderate to high yields. The addition of sodium sulfate was found to be crucial for improving both the performance and the reproducibility. Comparative solvent-free stirring experiments implicated the importance of mechanical interaction for the transformation, and the inert gas was proved to be unnecessary for this amination.

Full text of DOI:10.1016/j.tetlet.2018.04.078

Accepted Manuscript
Solvent-Free Mechanochemical Buchwald-Hartwig Amination of Aryl Chlor-
ides without Inert Gas Protection
Qiao-Ling Shao, Zhi-Jiang Jiang, Wei-Ke Su
PII:
S0040-4039(18)30564-1
https://doi.org/10.1016/j.tetlet.2018.04.078
TETL 49941
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 March 2018
20 April 2018
28 April 2018
Please cite this article as: Shao, Q-L., Jiang, Z-J., Su, W-K., Solvent-Free Mechanochemical Buchwald-Hartwig
Amination of Aryl Chlorides without Inert Gas Protection, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/
j.tetlet.2018.04.078
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Solvent-Free Mechanochemical Buchwald-Hartwig Amination of Aryl Chlorides
without Inert Gas Protection.
Authors: Qiao-Ling Shao, Zhi-Jiang Jiang, Wei-Ke Su*
Address: 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
Abstract
A solvent-free Buchwald-Hartwig amination had been developed under high-speed ball-milling
conditions, which afforded the desired products with moderate to high yields. The addition of sodium
sulfate was found to be crucial for improving both the performance and the reproducibility.
Comparative solvent-free stirring experiments implicated the importance of mechanical interaction
for the transformation, and the inert gas was proved to be unnecessary for this amination.
Keywords: Mechanochemistry, Aryl Chloride, Buchwald-Hartwig Amination, Inert Gas Protection
Free
High-speed ball milling (HSBM) has been emerged as a mechanochemical technique for green
synthesis by inputting mechanical force to the reaction system. During the past decade, HSBM
promoted mechanical reactions have been widely studied and its feature had been summarized
continuously,1 including high efficiency, special selectivity, and ignorance of substance solubility.
Hitherto, a panel of organic reactions have been investigated under HSBM conditions successfully,2
among which high-efficiency solvent-free cross-couplings have been achieved.3 Despite these
achievements, the aryl bromide still dominates the substrate of mechanical cross-couplings. The

more economic attracting aryl chlorides failed in the most cases, which may be due to its reluctance
toward oxidative addition.4 Although the elevation of temperature could be chosen to promote these
transformations as the conventional solvent-based reactions, the mechanical reactions are expected to
excite higher activity by mechanical interaction directly, which makes the mechanical cross-coupling
of aryl chlorides especially challenging.
During our continuous exploration of mechanochemistry,5 a mechanical Suzuki-Miyaura
reaction of aryl chlorides had been developed by our group recently,6 where the oxidative addition
was accounted by a drop of methanol hypothetically. Inspired by this exciting result, we started to
investigate the cross-coupling of aryl chlorides under HSBM conditions, and the Buchwald-Hartwig
amination, as one of the most powerful tools for C-N bond construction,7 was chosen to evaluate the
impacts from amines which may influence the catalytic system by ligation. Previously, this
amination had been studied in solvent-free manner successfully, providing excellent results.8
Interestingly, a HSBM-like process had been reported by Beletskaya et. al. using a vibrator.8c
However, this transformation of aryl bromides at 100 °C was suspected as a heat-promoted process,
and the mechanical Buchwald-Hartwig amination of aryl chlorides remain unexplored. Herein, we
wish to unveil our preliminary result on mechanical Buchwald-Hartwig amination of aryl chlorides,
which could be performed without deliberate inert gas protection. The grinding auxiliaries were
considered to be crucial for the transformation, where sodium sulfate was the optimal choice.
At the commencement, the coupling between p-chlorotoluene 1a and N-methylaniline 2a was
chosen as the model reaction for investigation. Unfortunately, the initial attempts using our previous
established liquid-assisted grinding (LAG) condition6 failed to furnish the catalytic cycle, which
gave approximately 5% yield after 60 minutes’ grinding. A fast survey of liquids indicated the
monophosphine/LAG system may be not suitable for the reaction (see Supporting Information for
more details). Subsequently, chemical conditions were tested and optimized for this transformation
under the HSBM conditions, and the selected results were presented in Table 1.9 Monophosphines
failed again to maintain the catalytic cycle (Table 1, entry 1), while bidentate bis(diphenylphosphine)
ligands examined didn't give any trace of product (Table 1, entry 2). Fortunately, ligands of
biphenylphosphine family10 could promote the model reaction (Table 1, entries 3-6), where XPhos
afforded the best result of 42%. Switching to other palladium source like PdCl2, Pd2(dba)3, and
Pd(TFA)2 didn’t give any improvement (Table 1, entries 7-9), while alternating base to NaOMe,
KOtBu, NaOH, and K3PO4 led to much worse outcomes (Table 1, entries 10-13), and the reaction
didn't work at all with K2CO3, NaOAc, DBU, NEt3, DMAP (not listed). Further attempt increasing
the usage of catalyst failed to provide significant improvement, while decreasing the loading resulted

in an erosion of yield (Table 1, entries 14-15).
Table 1 Optimization of reaction conditions. a
entry
1
2
3
4
5
6
7
8
cat.
Ligand
Base
%yield b
< 5
Pd(OAc)2
monophosphines c
NaOtBu
Pd(OAc)2 bis(diphenylphosphines) d NaOtBu
n.d.
38
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd2(dba)3
Pd(TFA)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Davephos
XPhos
SPhos
NaOtBu
NaOtBu 42 (75)e
NaOtBu
NaOtBu
NaOtBu
NaOtBu
NaOtBu
17
12
37
25
40
JohnPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
XPhos
9
10
11
12
13
14f
15g
NaOMe 23 (60)e
KOtBu
NaOH
23
21
15
45
36
K3PO4
NaOtBu
NaOtBu
a Reaction conditions unless noted otherwise: 0.5 mmol N-methylaniline, 0.6 mmol p-chlorotoluene, 4 mol%
cat., 8 mol% Ligand, 2.0 equiv. base were added to the 25 mL stainless-steel vessel with two stainless-steel
b
balls (ø＝1.4 cm), which was then ground at 30 Hz for 60 min. Isolated yield based on 5 runs with valid data.
c
d
Monophosphines tested: PCy3, PtBu3, PPh3, and P(o-Tolyl)3. Bis(diphenylphosphines) tested: dppe, dppp,
dppb, dppf, and Xantphos. Irreproducible data. Pd(OAc)2 = 10 mol%, XPhos = 20 mol%. g Pd(OAc)2 = 2
e
f
mol%, XPhos = 4 mol%. n.d. = not detected.
During the reaction optimization, the annoying problem of irreproducibility was found, and was
proposed as the insufficient mixing of the slurry -like matter. Increasing the flowability of the
mixture had been proved useful,5c, 11 by screening grinding auxiliaries (G. A.) (Table 2). In this work
silica gel suppressed the cross-coupling as reported previously,6 while γ-Al2O3 still gave a declined
result (Table 2, entries 1-2). Commonly used NaCl inhibited the reaction (Table 2, entry 3),
meanwhile, KBr or NaBr didn't give any improvement (Table 2, entries 4-5). Fortunately, a yield of
92% was achieved when sodium sulfate was used (Table 2, entry 6), which gave a powder-like
mixture. Potassium sulfate also gave a fairly well outcome, however, magnesium or calcium sulfate
failed to give any trace of the product (Table 2, entries 7-9). Interestingly, the conventional bases
used in the cross-couplings failed to work as grinding auxiliaries (Table 2, entries 10-13). The
amount of Na2SO4 was also examined, where 2.0 g was the optimal choice for the current system
(Table 2, entries 14-16). Subsequently, mixing Na2SO4 with the aforementioned salts was surveyed
to evaluate the influence from anions (Table 2, entry 17-21). Interestingly, significant suppression
was found in all cases, where no reaction occurred with the presence of acetate and phosphate anion.

Noticeably, although the bromide and carbonate either suppressed the reaction, an improvement in
yield could be found compared with the data above (Table 2, entries 17 vs 4, and 19 vs 8). These
results implicated these anions may have an influence on the reactions, where the sulfate anion may
improve the performance of this reaction. To verify the hypothesis, another comparative experiment
had been carried out to add Na2SO4 to the conventional solvent-heating reaction. No acceleration or
improvement of the reaction was observed, which may be due to the poor solubility of Na2SO4 in
organic solvents. Thus, it's still hard to draw a conclusion whether the salt was an innocent bystander
to improve the flowability solely or participated in reaction mechanistically.
Table 2 Optimization of grinding auxiliary.a
entry
G.A.
Silica gel
γ-Al2O3
m/g
0.3
0.5
%yieldb
n.d.
21
1
2
3
4
NaCl
KBr
2.0
2.0
n.d.
16
5
6
KCl
Na2SO4
2.0
2.0
n.d.
92
7
K2SO4
2.0
75
8
9
MgSO4
CaSO4
K3PO4
K2CO3
Na2CO3
NaOAc
Na2SO4
Na2SO4
2.0
2.0
2.0
2.0
2.0
2.0
1.5
1.0
n.d.
n.d.
n.d.
n.d.
n.d.
n.d.
72
57
85
21
n.d.
16
10
11
12
13
14
15
16
17
18
19
20
21
22c
23d
Na2SO4
2.5
Na2SO4 + KBr
Na2SO4 + KBr
Na2SO4 + K2CO3
Na2SO4 + NaOAc
Na2SO4 + K3PO4
Na2SO4
1.5 + 0.5
1.0 + 1.0
1.5 + 0.5
1.5 + 0.5
1.5 + 0.5
2.0
n.d.
n.d.
91
Na2SO4
2.0
79
a Reaction conditions unless noted otherwise: 0.5 mmol N-methylaniline, 0.6 mmol p-chlorotoluene, 4 mol%
Pd(OAc)2, 8 mol% XPhos, 2.0 equiv. NaOtBu, and the grinding auxiliary were added to the 25 mL
b
stainless-steel vessel with two stainless-steel balls (ø＝1.4 cm), which was then ground at 30 Hz for 60 min.
Isolated yield based on 2 runs. Pd(OAc)2 = 2 mol%, XPhos = 4 mol%. Pd(OAc)2 = 1 mol%, XPhos = 2
mol%. n.d. = not detected.
c
d
Subsequent optimization showed the reaction could be performed with a catalyst loading of 2
mol% (Table 2, entry 22-23), while changing mechanical parameter didn’t provide any superior
results (see Table S2 in Supporting Information for more information). Noticeably, the reactions
above were conducted without inert gas protection. An experiment carried out in the glovebox
affording similar result, which implicated the sealed grinding vessel may provide a suitable

environment for air and moisture-sensitive reactions, as the previous mechanochemical Grignard
reaction result suggested.12 For further comparison, the condition was also conducted in
solvent-environment. A good yield of 91% was obtained after 4.5 hours’ heating under Ar
protection,13 while no reaction occurred without Ar.
During the optimization, a rapid heat accumulation was observed during the first 20 minutes’
grinding, by which the reaction was suspected to be driven by heating like Beletskaya’s work. Thus,
the optimized condition was exposed to solvent-free stirring, where the solid components were finely
ground before the reaction. However, only trace product was found after 24 hours vigorously stirring
under room temperature, 60 °C, and 90 °C (Table S4).14 These results showed the induced heat may
not sufficient to promoted the reaction solely, and the mechanical interaction played an important
role in the transformation.
With the optimal condition in hand, the scope of this amination reaction between aryl chlorides
and secondary amines was examined and summarized in Scheme 1. Firstly, different aryl chlorides
were exposed to the standard condition. Methyl substitutes at m- and p-position (3aa, 3da, 3ea) gave
excellent yields. While the steric hindrance was accounted for the slight drop in yield of o-methyl
phenyl chloride (3ca), and for the failure of o-isopropyl substituted one. The p-methoxyl substrate
(3fa) gave fairly well result within 60 minutes' grinding, which has been categorized as an inert
substrate in cross-couplings. Conversely, much active electron-deficient aryl chlorides (3ga-3ja)
failed to conduct the reaction, which was out of our expectation. Then another condition was
established for these substrates using Davephos and sodium methoxide affording satisfying results
(condition B). Besides, 2-naphthyl chloride (3ka) gave excellent yield under standard condition,
while 4-biphenyl chloride (3la) required a longer grinding time to afford good yield. Pyridyl and
thienyl also survived under the standard condition (3ma, 3na), where the erosion of yield may be
accounted by the coordination.

Scheme 1 Substrate scope of mechanochemical Buchwald-Hartwig amination. Reaction conditions unless
noted otherwise: 0.5 mmol amine, 0.6 mmol aryl chloride, 2 mol% Pd(OAc)2, 4 mol% XPhos, 2.0 equiv.
NaOtBu, and 2.0 g Na2SO4 were added to the 25 mL stainless-steel vessel with two stainless-steel balls (ø＝
a
1.4 cm), which was then ground at 30 Hz for 60 min. Isolated yield based on 3 runs. Reaction at 10 mmol
scale. b 2 mol% Davephos, 2.0 equiv. NaOMe. c 99 mins. d 120 mins. n.r. = not reacted. e Without Na2SO4.
Amines were examined subsequently. For secondary amines bearing methyl and methoxyl on
phenyl group (3bb, 3bc), the standard condition worked fairly well. However, much lower yields
were observed again with electro-withdrawing groups (3bd, 3be), while these problems were solved
by employing the condition B. N-ethyl aniline (3bf) could also afford good yield, while N-Boc
aniline (3bh) failed in the transformation. Indole (3bi) required 2 hours to afford an acceptable yield.
Interestingly, the cyclic secondary amines as tetrahydroisoquinoline and morpholine (3bj, 3bk, 3ol)
provide excellent yield. However, no corresponding reaction occurred using dibenzylamine (3bm).
Primary amines could also be coupled with aryl chlorides under standard condition, where lower
yields were found. Interestingly, the reaction of 2-butylamine gave desired secondary amine (3bp) in
the yield of 89%.
The potential application of this mechanical Buchwald-Hartwig amination was then investigated
in the synthesis of biologically active compounds (Scheme 2). The Phase II anti-HIV compound
ABX46415 could be synthesized under standard condition with moderate yield, which reacted at
2-position selectively. The intermediate of anti-depression reagent Vilazodone16 (4) and

anti-Schizophrenia reagent Brexpiprazole17 (5) were then furnished with acceptable results, and
benzofuran and benzothiophene motifs were both tolerated under grinding conditions.
Scheme 2 Synthetic application in biological active compounds.
In summary, a highly efficient solvent-free mechanical Buchwald-Hartwig amination of aryl
chlorides had been developed. The protocol could afford desired products with moderate to high
yields. The addition of sodium sulfate was found to be crucial for the reaction, while its role
remained unclear. The reaction could be conducted without inert gas protection, which indicated the
potential application of mechanosynthesis in air and moisture sensitive reactions. The reaction is still
under investigation in our lab, including substrate scope, potential application, and the influence of
additives in mechanical cross-coupling of aryl chlorides.
Acknowledgement
This work was supported by the Special Program for Key Basic Research of the Ministry of Science
and Technology of China (No. 2014CB460608) and the National Natural Science Foundation of
China (Nos. 21376221, 21406201). J. Z.-J. also thank the financial support from The Prominent
Ph.D. Thesis Supporting Project of Zhejiang University of Technology.
Supplementary Material
Supplementary data associated with this article can be found, in the online version, at:
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- Solvent-free mechanochemical Buchwald-Hartwig amination of aryl chlorides
- Significant yield promotion by grinding auxiliary addition
- No inert gas protection required