Continuous flow synthesis of diaryl ketones by coupling of aryl Grignard reagents with acyl chlorides under mild conditions in the ecofriendly solvent 2-methyltetrahydrofuran

Article abstract of DOI:10.1039/C8RA07447J

An efficient continuous flow sequential synthesis of diaryl ketones was achieved by coupling of aryl Grignard reagents with acyl chlorides in the bio-derived “green” solvent 2-methyltetrahydrofuran (2-MeTHF) under mild reaction conditions (ambient temperature, 1 hour), allowing a safe and on-demand generation of 2-(3-benzoylphenyl)propionitrile with a productivity of 3.16 g hour^?1

Full text of DOI:10.1039/C8RA07447J

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Continuous flow synthesis of diaryl ketones by
coupling of aryl Grignard reagents with acyl
chlorides under mild conditions in the ecofriendly
solvent 2-methyltetrahydrofuran†
Cite this: RSC Adv., 2019, 9, 2199
Chuan-Tao Zhang,a Rui Zhu,a Zheng Wang,a Bing Ma,b Adrian Zajac,c
a
Marcin Smiglak, c Chun-Nian Xia,d Steven L. Castle
e and Wen-Long Wang
*
*
Received 6th September 2018
Accepted 10th January 2019
An efficient continuous flow sequential synthesis of diaryl ketones was achieved by coupling of aryl Grignard
reagents with acyl chlorides in the bio-derived “green” solvent 2-methyltetrahydrofuran (2-MeTHF) under
mild reaction conditions (ambient temperature, 1 hour), allowing a safe and on-demand generation of 2-(3-
DOI: 10.1039/c8ra07447j
rsc.li/rsc-advances
benzoylphenyl)propionitrile with a productivity of 3.16 g hourꢀ1
.
limitations with regards to expensive catalysts, safety concerns,
and environmentally practical considerations.
Introduction
Compared to traditional batch processing, ow chemistry
represents a powerful technology with several advantages
including safety, cost, efficiency, robustness and quality. It is
considered an ideal partner with green chemistry,35 and is
a powerful tool for the pharmaceutical industry.36–38 Recently,
the Jamison group described an efficient continuous ow
synthesis of ketones from carbon dioxide and organolithium or
Grignard reagents at ambient temperature and pressure.39 The
Kim group developed an efficient method for the synthesis of
ketones using organolithium reagents and acid chlorides under
continuous ow conditions at ꢀ40 ꢁC.40 Unfortunately, most of
the solvents used in the synthesis of diaryl ketones are not
environmentally friendly. In recent years there has been a trend
towards the use of bio-derived, green solvents as replacements
for hazardous and/or environmentally-damaging solvents.35 In
fact, 2-methyltetrahydrofuran (2-MeTHF) is one such solvent
that has been developed as a greener alternative to classical
solvents.41,42 With our interest in developing green organic
reactions for the synthesis of diaryl ketones, herein we describe
an efficient continuous ow parallel synthesis of diaryl ketones
Diaryl ketones are frequently used as core motifs for developing
pharmaceutical agents.1–3 They exist in numerous bioactive
molecules (Fig. 1),1,4 such as the nonsteroidal anti-inammatory
drug (NSAID) ketoprofen,5 the broad-spectrum human anthel-
mintic mebendazole,6 the classical lipid regulating agent feno-
brate7 and the therapeutically useful uricosuric agent
benzbromarone (BBR)8 (Fig. 1). Therefore, development of
synthetic methods for diarylketones continues to be a highly
active area in synthetic chemistry (Scheme 1). The conventional
method is Friedel–Cras acylation of arenes, which has draw-
backs such as the requirement for superstoichiometric
amounts of Lewis acid and low regioselectivity.9,10 Alternative
synthetic approaches have been developed, including oxidation
of secondary alcohols,11,12 acylation of organometallic
reagents,13–16 transition-metal-catalyzed cross-coupling reac-
tions of carboxylic acid derivatives with organometallic
reagents,17–24 palladium-catalyzed carbonylative cross-coupling
reactions between aryl halides and related compounds with
carbon nucleophiles,25–30 acylation of (hetero)aryl halides with
aldehydes,31 decarboxylative cross-coupling reactions,32,33
decarboxylative addition reactions,33 and other uncommon
reactions.34 Unfortunately, there remain
a
number of
aSchool of Pharmaceutical Science, Jiangnan University, Wuxi, 214122, China. E-mail:
wwenlong2011@163.com
bHybrid-Chem Technologies, Shanghai, 201203, China
cPoznan Science and Technology Park, Adam Mickiewicz University Foundation, ul
Rubiez 46, 61-612, Poznan, Poland
dZhejiang University of Technology, Hangzhou, 310014, China
eDepartment of Chemistry and Biochemistry, Brigham Young University, Provo, Utah
84602, USA. E-mail: scastle@chem.byu.edu
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c8ra07447j
Fig. 1 Pharmaceutical with diary ketone motif.
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Scheme 1 (a) Friedel–Crafts acylation, (b) oxidation of the corresponding secondary alcohols, (c) acylation of organometallic reagents, (d)
transition-metal-catalyzed cross-coupling reactions of carboxylic acid derivatives with organometallic reagents, (e) palladium-catalyzed car-
bonylative cross-coupling reactions between aryl halides and related compounds with carbon nucleophiles, (f) acylation of (hetero)aryl halides
with aldehydes, (g) decarboxylative cross-coupling reactions, (h) decarboxylative addition reactions.
by the direct coupling of aryl Grignard reagents with acyl chlo- a productivity of 3.16 g hourꢀ1 in the synthesis of 2-(3-ben-
rides without additives at ambient temperature using the bio- zoylphenyl)propionitrile, an important intermediate in the
derived “green” solvent 2-methyltetrahydrofuran (2-MeTHF). synthesis of ketoprofen.
We demonstrated the scalability of our method by achieving
Table 1 Optimization of the coupling between phenylmagnesium bromide and benzoyl chloride in continuous flow
c (mol Lꢀ1
)
Q (mL minꢀ1
)
Entry
Solvent
1a
2a
1
2
Rt (min)
T (ꢁC)
Yielda (%)
b
1
2
3
4
5
6
7
8
THF
THF
THF
THF
1.2
0.9
0.6
0.3
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.6
0.4
0.4
0.6
0.8
0.6
0.4
0.2
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
1
1
1
1
1
1
1
1
1
1
2
0.5
1
1
1
1
1
1
1
1
1
1
1
2
0.5
1
—
rt
rt
rt
rt
rt
rt
rt
rt
0
50
rt
rt
rt
—
60
60
60
—
—
—
60
60
60
30
120
60
120
60
71
72
56
b
Ether
Dioxane
DME
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
THF
—
b
—
b
—
85
64
70
61
54
61
33c
34d
9
10
11
12
13
14
15
—
—
—
—
ꢀ78
2-MeTHF
rt
a
b
Isolated yield from 4 mmol of 2a by ash column chromatography. System clogged. c Yield in ref. 44. d Batch reaction.
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Results and discussion
To optimize the parameters (concentration, solvent, ow rate,
residence time and temperature) (Table 1), our initial studies
focused on the coupling between phenylmagnesium bromide
and benzoyl chloride using a simple continuous system
comprised of two standard-pressure HPLC pumps, a T-shaped
mixer (Peek 1/3200 inner diameter) and a standard PTFE
reactor (poly tetrauoroethylene, 1/1600 inner diameter,
120.0 mL internal volume). Upon exiting the reactor, the reac-
tion stream was immediately quenched with 1 N HCl. The
Scheme 2 Possible mechanism for low yield of 3a from the batch
process.
Table 2 Reaction of phenylmagnesium bromides 1a with acyl chloride 2b–o under continuous flow parallel system
Entry
1
Product
Yielda (%)
79
Entry
8
Product
Yielda (%)
77
2
3
4
5
6
57
64
85
65
55
9
83
60
61
43
42
10
11
12
13
7
82
14
56
a
Isolated yield from 4 mmol of 2b–2o by ash column chromatography.
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Table 3 Reaction of aryl Grignard reagents 1b–h with 2-fluorobenzoyl chloride 2e under continuous flow parallel system
Entry
1
Product
Yielda (%)
43
Entry
5
Product
Yielda (%)
73
2
3
95
81
6
7
35
81
4
74
—
—
—
a
Isolated yield from 4 mmol of 2e by ash column chromatography.
results indicated that concentration obviously impacted the purposes the reaction was run as a standard batch process,
yield, as high concentrations clogged the reactor (entry 1) and applying the same concentration of reagents, temperature, and
low concentrations decreased the yield (entry 4). The optimal reaction time as optimized in the ow protocol (entry 8). We
concentrations of 2a and 3a were 0.6 M and 0.4 M respectively. found that the yield of the batch process to produce compound
Some common solvents such as ether, dioxane, and 1,2-dime- 3a was 34%, which is similar to the reported yield at ꢀ78 C,43
ꢁ
thoxyethane, were investigated, and the results demonstrated and, signicantly lower than the yield of the optimized ow
that none were suitable due to clogging the reactor (entries 5–7). protocol. Based on the GC-MS of 3a from batch process, the
The substitution of 2-MeTHF (entry 8) for THF (entry 3) proved major byproduct 7 was identied (ESI†). We proposed the
to be benign to the reaction, and room temperature led to the possible mechanism that Grignard reagent 1a discomposed to
highest yield of 85% (entry 8). These results clearly show that radical 5 when the internal temperature increased by addition
this procedure ts the 5th and 6th principles of Green Chemistry of a solution of benzoyl chloride 2b, followed by oxidation to
very well, which demand biomass-derived solvents that meet phenol (Scheme 2).44–47
the 3R requirements (reduce, recycle, and reuse) and energy
Over the past several years, high-throughput chemical
efficiency by employing synthetic methods conducted at mild synthesis has become increasingly important due to its poten-
temperatures and atmospheric pressure.35 Aer prolonging the tial to positively impact the drug discovery process.48–51 With the
residence time from 30 min to 120 min by lowering the ow rate proof of concept, we explored the sequential ow synthesis of
(entries 8, 11, and 12), we determined that a 60 min residence a library of diaryl ketones using the optimized reaction condi-
time afforded the best yield (85%). Decreasing the stoichio- tions. Firstly, we evaluated the substrate scope for various aryl
metric ratio of 1a to 2a from 3 : 2 to 1 : 1 had a detrimental acid chlorides with phenylmagnesium bromide using a contin-
effect on the formation of 3a (entry 13). For comparative uous ow parallel system adjusted by a ve-way valve. The data
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in Table 2 clearly demonstrate that the formation of diaryl
ketones from acyl chlorides was quite general and occurred
smoothly in the continuous ow system, with moderate to good
yields. Among the acid chlorides with meta substituents, yields
of uoride 3f (65%), chloride 3h (82%), and triuoromethylated
compound 3i (77%) were higher than those of methylated
compound 3c (57%), methoxylated compound 3k (60%), and 1-
cyanoethylated compound 3o (56%). These results indicate that
presence of electron-withdrawing groups on the acyl chlorides
has a positive inuence on the reaction with phenylmagnesium
bromide. Interestingly, among the compounds 3b–3d and 3e–
3g, the yields of ortho-substituted ketones (3b and 3e) were
clearly better than those of the corresponding meta-substituted
(3c and 3f) or para-substituted ketones (3d and 3g).
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This work was supported by National Natural Science Founda-
tion of China (21772068), the Department of Science and
Technology of Jiangsu Province (BY2016022-37), and National
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