Mechanochemical Oxidative Mannich Reaction: Evaluation of Chemical and Mechanical Parameters for the Mild and Chemoselective Coupling of N-tert-butoxycarbonyltetrahydroquinolines and Ketones

Article abstract of DOI:10.1002/ejoc.201600987

A mechanochemical oxidative Mannich reaction of N-tert-butoxycarbonyl (Boc) tetrahydroquinolines and ketones was successfully developed under solvent-free ball-milling conditions. The reaction afforded the desired coupling products in satisfactory yields under mild and tractable oxidative conditions. Side reactions such as deprotection of the Boc group were prevented by carefully adjusting the milling parameters, including milling frequency, time, milling-ball filling degree, milling-ball size, and grinding auxiliary. Further examination of the scope indicated that the reaction system could also be applied to the N-benzyloxycarbonyl and N-aryl substrates to afford the corresponding products in moderate to good yields.

Full text of DOI:10.1002/ejoc.201600987

A Journal of
Accepted Article
Title: Mechanochemical Oxidative Mannich Reaction: Evaluation of Chemical and
Mechanical Parameters for Mild and Chemo-Selective Coupling of N-Boc Te-
trahydroquinolines and Ketones
Authors: Jingbo Yu; Gang Peng; Zhijiang Jiang; Zikun Hong; Weike Su
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soon as possible and may be different to this Accepted Article as a result of editing.
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201600987
Link to VoR: http://dx.doi.org/10.1002/ejoc.201600987
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European Journal of Organic Chemistry
10.1002/ejoc.201600987
COMMUNICATION
Mechanochemical Oxidative Mannich Reaction: Evaluation of
Chemical and Mechanical Parameters for Mild and Chemo-
Selective Coupling of N-Boc Tetrahydroquinolines and Ketones
Jing-Bo Yu,[a] Gang Peng, [b] Zhi-Jiang Jiang, [a] Zi-Kun Hong, [b] and Wei-Ke Su*[a]
Abstract: A mechanochemical oxidative Mannich reaction of N-Boc
tetrahydroquinolines and ketones has been successfully developed
under solvent-free ball-milling conditions. The reaction affords
desired coupling products in satisfied yields under mild and tractable
oxidative system. Side reactions such as deprotection of Boc group
have been prevented by carefully adjustment of the milling
parameters, including milling frequency, time, milling ball filling
degree, milling ball size and grinding auxiliary. Further examination
of scope indicates the reaction system could also be applied to the
N-Cbz, and N-aryl substrates affording the corresponding products
in moderate to good yields.
participation of stronger oxidants.[9] Very recently, carboxybenzyl
(Cbz) protected THIQs have been coupled with series of pro-
nucleophiles under both solvent and solvent-free heating (SFH)
conditions.[10] Despite the excellent performance of N-Cbz
protected THIQs, t-butyloxycarbonyl (Boc) protected THIQs still
work poorly under similar conditions resulting large amount of
unexpected mixtures, which assumed to be brought by the harsh
reaction conditions. Thus, realizing this type of reaction under
mild conditions is still a challenge. As our continuously focusing
on functionalization of THIQs[11] the N-Boc THIQs were
subjected under HSBM conditions to improve their performance
by carefully examination of milling parameters. Thus, herein we
would like to unveil our latest efforts on mechanochemical
oxidative Mannich reaction of t-butyloxycarbonyl protected
THIQs and ketones under ball milling conditions.
High-speed ball-milling (HSBM) promoted mechanochemical
organic synthesis has been attracted considerable attention due
to its intriguing feature that such process could be carried out
under the solvent-free or solvent-less environment.[1] Comparing
with conventional solvent-based systems, where temperature is
the critical parameter for process control, the HSBM systems
control become more complicated and require delicate
adjustment towards series of parameters including milling
frequency (v), time (t), milling ball size (dMB) and milling ball
filling degree (ФMB), along with solid grinding auxiliary and
stock’s filling degree (ФST).[2] The combined evaluation of
reaction parameters may enhance the reactions proceeding in
chemo-selective, energy-saving and atom/substrate efficient
manners, resulting in an efficient and environmental friendly
synthesis.
Oxidative Mannich reaction, as one of the most powerful
method for C-C bond construction, has been widely used in the
fields of organic synthesis and medicinal chemistry.[3] Inspired by
the pioneering work of Murahashi[4] and Li[5], the oxidative
coupling of amines have been mainly focused on N-aryl
protected tetrahydroquinolines (THIQs),[3e, 6] in which the in-situ
generated imine or iminium species could be well stabilized.
However, removal of those aromatic protecting groups (PGs)
usually requires harsh conditions.[7] Moreover, the N-acyl
derived THIQs perform inferior reactivity,[8] and require the
Scheme 1. Selection of model reaction.
At the beginning, the reaction of N-Boc THIQ (1a, 1 mmol)
and acetophenone (2a, 1.2 mmol) as substrates were
preliminary evaluated by using DDQ (1 equiv.) as oxidant,
milling with four stainless-steel balls (dMB = 14 mm) at 30 Hz
(Scheme 1). Similar as solvent-based system, a complex of
unexpected side products together with desired N-Boc 1-(2-oxo-
2-phenylethyl)-tetrahydroquinoline 3aa (21%) were obtained.
Also, deprotected THIQ was detected implicating the Boc group
had been removed during the milling process, which might
further lead to side reactions like oxidative polymerizations. In
order to suppress the side reaction, reaction optimizations were
started with the reagent system. As shown in Table 1, series of
oxidants were tested, where DDQ remain the optimal choice for
the reaction (Table 1, entry 1). Changing DDQ to its analogues
as TCQ and BQ resulted in obvious erosion of yields (Table 1,
entries 2, 3). Halide oxidants including NBS, NCS and Iodine
didn’t give desired product during the grinding process (Table 1,
entries 4-6). Persulfates, which was reported as a suitable
oxidant for the similar reactions of N-Cbz THIQ,[10] were also
tested which only gave low yield, even increasing the amount of
Na2S2O8 to 1.5 equiv. (Table 1, entries 7-9). Further testing on
the usage of DDQ showed 1.0 equiv. was the optimum, in which
adding DDQ in portions did not improve the performance (Table
1, entries 10-12). Considering the potential requirement
[a]
J.-B. Yu, Z.-J. Jiang, Prof. W.-K. 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
[b]
G. Peng, Z.-K. Hong
Key Laboratory for Green Pharmaceutical Technologies and
Related Equipment of Ministry of Education, College of
Pharmaceutical Sciences
Zhejiang University of Technology, Hangzhou 310014, (P. R. China)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201xxxxxx.
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COMMUNICATION
Table 1. Optimization of reagent system of oxidative Mannich reaction.[a]
Entry
1
Oxidant (equiv.)
DDQ (1.0)
TCQ (1.0)
BQ (1.0)
1a:2a
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.2
1:1.5
1:2
Yield (%)[b]
21
2
10
3
trace (< 5%)
4
NBS (1.0)
NCS (1.0)
I2 (1.0)
n.d.
5
n.d.
Figure 1. Influence of milling time and frequency on the oxidative Mannich
reaction: 1a (1.0 mmol), 2a (2.5 mmol), DDQ (1.0 mmol) and silica gel (0.45 g)
were placed in a 50 mL stainless steel vessel with four stainless-steel balls
(dMB = 14 mm, ФMB = 0.115).
6
n.d.
7
Oxone (1.0)
Na2S2O8 (1.0)
Na2S2O8 (1.5)
DDQ (1.3)
DDQ (0.8)
DDQ (1.0)
DDQ (1.0)
DDQ (1.0)
DDQ (1.0)
DDQ (1.0)
DDQ (1.0)
DDQ (1.0)
trace (< 5%)
8
10
which regulates the energy input and therefore influences the
heat generation during the grinding. Considering the interruption
of the grinding process will lead to irreproducible results, the
examination of frequency was performed with specified time,
and was summarized in Figure 1. Obviously, changing
frequency led to dramatically fluctuation of yields, and the best
result came up at 20 Hz with 45 minutes’ grinding. A stepwise
increasing of the yield was found at 15 Hz with prolonging of the
time. Similar trends were also observed at 20 Hz, where over
long reaction time led to undesired deprotection of the substrate.
However, compared with 20Hz, grinding at 25 Hz for 45 minutes
resulted in obvious drop of product yield, which probably due to
the heat accumulation. Further energy input led to a significant
and unpredictable deprotection of both substrate and product, in
which the inflection point appeared at 35 minutes.
9
11
10
11
12[c]
13
14
15
16
17[d]
18[e]
12
13
20
25
34
1:2.5
1:3
42
43
1:3
trace (< 5%)
< 10%
1:5
Afterwards, our investigation was focus on the combined
effects of the milling ball filling degree (ФMB) and the size of the
milling balls, which has strong influences not only on the
occurrence of the collision and friction event, but also the
trajectories of the balls affecting the yield and the amount of heat
dissipation.[2a, 12] The experiments were then carried out at 20 Hz,
to test whether further improvement of yield could achieve or not.
The grinding balls ranging from 6 mm to 14 mm were tested with
different filling degrees. As shown in Figure 2, large ball systems
(dMB > 10 mm) and small ball system (dMB < 10 mm) showed
different trends, while larger ball system gave better yields than
the smaller ones at the same filling degree when ФMB < 0.15. A
maximum product yield was observed at 20 Hz grinding with four
balls of 1.4 cm diameter (ФMB = 0.115). Besides, two grinding
balls also gave the similar result (57.9%) as the reaction grinding
at 30 Hz (ФMB = 0.057).[13] Further increasing of ФMB led to sharp
decrease of product yield for both large size and small size balls
after the inflection point of ФMB ≈ 0.10 and 0.20 respectively,
implicating the energy input and heat accumulation was
overabundant. This observation was in accord with the results
found by Stolle[14] and Takacs.[15] On the other hand, the reaction
with small ball system required relative higher ФMB to get a
maximum product yield, which may due to the inner friction of
ball-ball interaction for energy transfer. Nevertheless, overfull
milling balls were also detrimental to the product yield since ball
movement would be hindered and therefore the energy input
[a] Reaction conditions: 1a (1.0 mmol), 2a, oxidant and Silica gel (0.45 g)
were placed in a 50 mL stainless steel vessel with four stainless-steel ball
(dMB = 14 mm, ФMB = 0.115). Ball milling conditions: 35 min at 30 Hz. [b]
Isolated yields based on 1a. [c] DDQ was added in 3 portions. [d] The
reaction was proceeded in 4.0 mL CH3CN at 80 °C for 24 h. [e] The reaction
was proceeded without solvent by heating at 80 °C for 24 h.
of excessive usage of pro-nucleophiles in similar reactions,[3d, 3e,
6] the usage of 2a was then increased for further improvement
(Table 1, entries 13-16). The results showed that the ratio of
1:2.5 was essential for a better transformation and further
increasing of 2a did not lead to a significant improvement.
Comparative experiments indicated that the reaction carried out
under solvent-based conditions and/or solvent-free heating
conditions merely gave the product in very poor yields (Table 1,
entries 17 and 18). Noteworthy, although the reaction may be
catalyzed by iron, shifting the stainless-steel vessel and milling
balls to the zirconium dioxide ones still gave similar results.
With optimal reagent system combination in hand, we then
turned our focus on the evaluation of mechanical process for the
reaction, wishing to restrain the process of deprotection during
the milling. According to previous study,[2] the milling frequency
(v) usually plays an important role in mechanochemical process,
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Table 3. Substrate scope of oxidative Mannich reaction.[a,b]
Figure 2. Influence of the milling ball filling degree with different size of the
milling balls on the oxidative Mannich reaction: 1a (1.0 mmol), 2a (2.5 mmol),
DDQ (1.0 mmol) and silica gel (0.45 g) were placed in a 50 mL stainless steel
vessel milling for 45 min at 20 Hz. Isolated yield based on 1a, average of three
times. (rhombuses: d = 14 mm, squares: d = 12 mm, triangles: d= 10 mm,
skew crossings: d = 6 mm)
Table 2. Influence of grinding auxiliary on the oxidative Mannich reaction.[a]
Entry
1
Grinding auxiliary
Silica gel
Weight (g)
0.25
0.45
1.50
1.00
1.65
0.80
1.30
0.60
1.00
1.00
－
Yield (%)[b]
29
58
37
18
25
27
35
13
24
35
10
2[c]
3
Silica gel
Silica gel
4
quartz sand
quartz sand
NaCl
5[c]
6
7[c]
8
NaCl
[a] Reaction conditions unless specified otherwise: 1 (1.0 mmol), 2 (2.5
mmol), DDQ (1.0 mmol) and Silica gel (0.45 g) were placed in a 50 mL
γ-Al2O3 (neutral)
γ-Al2O3 (neutral)
α-Al2O3 (base)
－
stainless steel vessel with four stainless-steel balls (dMB = 14 mm, ФMB
=
9[c]
10[c]
11
0.115). Ball milling conditions: 45 min at 20 Hz. [b] Yield based on 1a. [c]
Two stainless-steel balls (dMB = 14 mm, ФMB = 0.057) were used. Ball milling
conditions: 60 min at 30 Hz. [d] Milling vessels were placed under the
atmosphere of N2 gas when adding the substrates.
[a] Reaction conditions: 1a (1.0 mmol), 2a (2.5 mmol), DDQ (1.0 equiv.) and
grinding auxiliary were placed in a 50 mL stainless steel vessel with four
stainless-steel ball (dMB = 14 mm, ФMB = 0.115). Ball milling conditions: 45
min at 20 Hz. [b] Isolated yields based on 1a. [c] Bulk volume of the grinding
auxiliaries was kept as constant.
Accordingly, 450 mg of silica gel remained the optimal choice for
the screening (Table 2, entry 2). Decreasing the amount of silica
gel resulted in flake form of the mixture, which could not give
sufficient mixing of the reactants (Table 2, entry 1). While, the
drop of yield using excessive silica gel (1.5 g) may be explained
for the low dispersion concentration of 2a (Table 2, entry 3). Low
loading of quartz sand, NaCl, and γ-Al2O3 led to a slurry mixture
with low product yields, which could be improved by increasing
their usage until the mixture became powdery (Table 2 entries 4-
9). Besides, it seemed the reaction favored basic α-Al2O3 than γ-
Al2O3 due to its possible assistance for the enolation of 2a.
Noteworthy, different degrees of THIQ was recovered from all
was reduced,[16] while the heat accumulation increased
dramatically through inner frictions.
Further optimization of the mechanochemistry system was
paid to the solid grinding auxiliaries, which provided micro-
environment for the transformation. Different kinds of solid
auxiliaries were examined and the results were shown in Table 2.
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the cases tested implicating the acidity of silica gel may not be
the main cause for the deprotection of Boc group.
the chemo-selective process without significant losing of N-Boc
group. During the optimization, the deprotection was found to
have correlation with the energy input and system temperature,
which may due to overheat accumulation. Thus, through the
optimization of HSBM system, the reaction could proceed
successfully under mild oxidative conditions. Further
examination showed the established reaction system could also
be applied to the substrates as N-Cbz, and -aryl THIQs,
affording moderate to high yields in short reaction time (no more
than 60 minutes). The investigations of selective removing of
Boc groups and cascade coupling-deprotection reaction by
parameter controlling are under investigation in our lab.
After the mechanochemical parameter optimization, we were
pleased to obtain the desired coupling product of satisfied yield
without significant deprotection under the optimal condition of 20
Hz in 45 minutes (dMB = 14 mm, ФMB = 0.115). Encouraged by
the result, continuous efforts were applied to extend the utility of
this reaction system, especially the substrates with different
protecting groups (Table 3). Firstly, the oxidative Mannich
reaction of different aryl ketones 2a-e was examined. To our
delight, N-Cbz, N-Ph and N-PMP protected THIQs also
proceeded smoothly under this standard condition giving good to
high yields, in which N-Cbz protected substrate performed better
than N-aryl ones. Further expansion of aryl ketones showed the
N-Boc THIQs could afford moderate yield in most cases, where
propiophenone 2d and 3,4-dihydronaphthalen-1(2H)-one 2e
gave higher yield of 60% within 45 minutes’ grinding. Then,
THIQ derivatives were subjected with acetone 2f. In this case,
N-Boc THIQ could also give moderate yield after the milling
process though the best yield was obtained by using N-phenyl
substrate. Besides, when coupling with propanone 2g, N-Boc
THIQ afforded inseparable mixtures, which probably due to the
multiple-reaction site of the substrate as well as the steric factors,
while N-Ph THIQ 1c could selectively give the coupling product
at methyl position. Cyclic ketones 2h-j were also examined to
give satisfied results, where N-Cbz and N-Ph substrates
affording comparative yields to their solvent-free heating/stirring
counterpart.[3e, 10] Further attempt using 7-member ring substrate
of tetrahydro-1H-benzo[c]azepine 1g failed in coupling, but
afforded an oxidative ring-opening product as our previous
reported (Scheme 2).[11c] Furthermore, it is delight to find that
under the above optimal condition, propionaldehyde could be
tolerated in the coupling reaction, which give the desired amino
aldehyde product in 56% yield (Scheme 3 ).
Experimental Section
A mixture of the substrate N-acyl/aryl THIQs 1 (1.0 mmol, 1.0 equiv),
ketone/aldehyde 2 (2.5 mmol, 2.5 equiv), DDQ (1.0 mmol, 227 mg, 1.0
equiv), and silica gel (0.45 g) was placed in a 50 mL screw-capped
stainless-steel vessel, along with four stainless-steel balls (14 mm, ФMB
=
0.115) or two stainless-steel balls (14 mm, ФMB = 0.057). Then, the
vessel was placed in the mixer mill, and the contents were milled at 20
Hz or 30 Hz for 45 or 60 min. At the end of the experiment, all of the
reaction mixtures were scratched of from the vessel and dissolved in
ethyl acetate followed by concentrating in vacuo to give a residue, which
was purified by column chromatography on silica gel (eluents: petroleum
ether/ethyl acetate 20/1~6/1) to give the desired product.
Acknowledgements
We gratefully acknowledge 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. 21406201, 21506190 and 21376221)
for financial support. We also thank Dr. Bin Mao and Miss Qiao-
Ling Shao at Zhejiang Uni-versity of Technology for technical
assistance.
Keywords: oxidative mannich reaction• ball mill • mechanical
parameters • cross coupling • chemoselectivity •
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Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
High-speed
promoted
ball-milling
mechanochemical
Jing-Bo Yu, Gang Peng, Zhi-Jiang
Jiang, Zi-Kun Hong, and Wei-Ke
Su*
oxidative Mannich reaction of N-
Boc tetrahydroquinolines and
ketones is developed to give
desired products in satisfied
yields under mild oxidative
Page No. – Page No.
Mechanochemical Oxidative
Mannich Reaction: Evaluation
of Chemical and Mechanical
Parameters for Mild and
Chemo-selective Oxidative
Coulping of N-Boc
conditions,
where
chemo-
selective coupling can be
realized by avoiding the side
reactions through fine tuning of
the milling parameters. The
reaction is further applied to N-
Cbz, and N–aryl substrates to
afford good results.
Tetrahydroquinolines and
Ketones
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