A facile preparation of α-aryl carboxylic acid via one-flow arndt-eistert synthesis

Article abstract of DOI:10.1071/CH15342

An efficient, one-flow Arndt-Eistert synthesis was demonstrated. A sequence of acid chloride formation-nucleophilic acyl substitution-Wolff rearrangement-nucleophilic addition was performed in a microflow system without isolating any intermediates, which

Full text of DOI:10.1071/CH15342

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2015, 68, 1657–1661
Communication
http://dx.doi.org/10.1071/CH15342
A Facile Preparation of a-Aryl Carboxylic Acid via
One-Flow Arndt–Eistert Synthesis
A B C
, ,
A
A
A
Shinichiro Fuse,
Yuma Otake, Yuto Mifune, and Hiroshi Tanaka
A
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1, Ookayama,
Meguro-ku, Tokyo 152-8552, Japan.
B
Current address: Chemical Resources Laboratory, Tokyo Institute of Technology,
4259 Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan.
C
Corresponding author. Email: sfuse@res.titech.ac.jp
An efficient, one-flow Arndt–Eistert synthesis was demonstrated. A sequence of acid chloride formation–nucleophilic
acyl substitution–Wolff rearrangement–nucleophilic addition was performed in a microflow system without isolating any
intermediates, which included a potentially explosive compound. The microflow system was made from simple,
inexpensive, and readily available instruments and tubes. a-Aryl esters 2a and 2b were prepared in yields of 33 and
23 % (three steps) respectively.
Manuscript received: 10 June 2015.
Manuscript accepted: 14 July 2015.
Published online: 11 August 2015.
The Arndt–Eistert synthesis is a one-carbon homologation
of carboxylic compounds via a sequence of acid chloride for-
mation–nucleophilic acyl substitution–Wolff rearrangement–
nucleophilic addition.[1] This sequence is one of the most widely
used homologation methods in organic synthesis. However, the
Arndt–Eistert synthesis has several drawbacks. The homolo-
gation requires the treatment of potentially hazardous reagents
for the introduction of a diazo group, and the resultant a-diazo
carbonyl compounds are also potentially hazardous.[2] In addi-
tion, the key step of the Arndt–Eistert synthesis, the Wolff
rearrangement,[3] is usually carried out using a silver ion cata-
lyst. However, this procedure usually requires freshly prepared
catalyst, an extended period of reaction time, and high temper-
ature in order to obtain the desired products in high yields.[3a,4]
Further, another conventional procedure that includes a photo-
chemical process is attractive, because no catalysts are required.
However, photochemical reactors are usually expensive, and the
scale-up of photoreactions is not simple because they usually
require high-dilution conditions.
Microflow technology[5] offers solutions for these problems.
Light-penetration efficiency can be improved in microflow
photoreactions because the microflow photoreactor requires
only a thin reaction space.[5h,6] In addition, the risks associated
with the treatment of hazardous compounds are minimized
owing to the very small internal volume of the microflow
reactor. Moreover, one-flow, multistep syntheses enhance the
synthetic efficiency, because they require no intermediate
purification.[5g] Recently, Konopelski,[7] Danheiser,[8] Basso,[9]
and their coworkers demonstrated a Wolff rearrangement in a
microflow reactor for the synthesis of b-lactams,[7] aromatics,[8]
and acyloxyacrylamides.[9] More recently, Kappe and
coworkers reported microflow Arndt–Eistert homologation
using a tube-in-tube reactor in order to safely treat hazardous
diazomethane.[10] They also demonstrated an efficient one-flow
synthesis of b-amino acids.[11]
We have reported microflow syntheses including photo-
chemical reactions for the preparation of vitamin D3 and
its analogues.[12] Recently, we also reported the microflow
synthesis of a-aryl carboxylic acid from a-diazo ketone 5 via
photochemical Wolff rearrangement for the efficient prepara-
tion of N-allyloxycarbonyl-3,5-dihydroxyphenylglycine.[12f]
Herein, we wish to report a more efficient, one-flow Arndt–
Eistert homologation of substituted benzoic acid 1a to a-aryl
ester 2a (Scheme 1). In addition, we also report a one-flow
synthesis of a-aryl ester 2b, which is the precursor of a biologi-
cally active compound.[13]
The conversion of 3,5-bis(benzyloxy)benzoic acid (1a) to the
corresponding acid chloride in a microflow reactor was exam-
ined using a microflow system, as shown in Fig. 1. MeCN was
used to dissolve the activator in accordance with our previous
observations.[12e] We also attempted to use MeCN to dissolve
the carboxylic acid 1a, because MeCN was the best solvent for
the later photochemical Wolff rearrangement in our previous
examination.[12f] However, the carboxylic acid 1a was not
soluble in MeCN. Thus, we examined the use of 1,4-dioxane
and cyclopentyl methyl ether, which would not inhibit a later
photochemical Wolff rearrangement. The use of 1,4-dioxane for
dissolving 1a afforded the best result.
We connected a T-shape mixer with TeflonÒ tubing and
immersed them in a water bath (808C). A solution of carboxylic
acid 1a and DMF with or without N,N-diisopropylethylamine
(DIEA) in 1,4-dioxane was introduced into the T-shape mixer
with a syringe pump. A solution of triphosgene, thionyl chloride,
or oxalyl chloride in MeCN was also introduced into the T-shape
mixer with a syringe pump. We evaluated acid chloride forma-
tion by converting the generated acid chloride to the amide 3 in a
Journal compilation Ó CSIRO 2015
www.publish.csiro.au/journals/ajc

1658
S. Fuse et al.
O
O
CI
DMF (0.1 equiv.)
1,4-dioxane
O
OH
O
OH
OMe
OBn
BnO
OBn
in situ IR
OBn
BnO
1a (1.0 equiv.)
4
150 µL minϪ1
OBn
BnO
BnO
1a
2a
80ЊC, 300 s
T-shape
mixer
One-flow Arndt–Eistert synthesis
Triphosgene (0.5 equiv.)
MeCN
1.50 mL
(i) triphosgene
(ii) TMSCHN2
(iii) hν, MeOH
O
150 µL minϪ1
OH
O
O
O
OMe
0.02
1b
2b
Reference acid
chloride 4
0.01
Scheme 1. One-flow Arndt–Eistert synthesis of a-aryl esters 2a and 2b
from substituted benzoic acids 1a and 1b. Bn, benzyl; Me, methyl; TMS,
trimethylsilyl.
0
Ϫ0.01
Reaction mixture
1,4-dioxane
1724 cmϪ1
CϭO str. of 4
H
DMF (0.1 equiv.)
DIEA (none or 0.1 equiv.)
1,4-dioxane
1768 cmϪ1
Ϫ0.02
N
O
OH
O
1820
1800 1780 1760 1740 1720
Wave number [cmϪ1
]
BnO
OBn
BnO
1a (1.0 equiv.)
OBn
150 µL minϪ1
3
Fig. 2. Confirmation of the formation of acid chloride 4 by in situ IR
80ЊC, 300 s
T-shape
mixer
measurement.
Activator (X equiv.)
MeCN
1.50 mL
In order to confirm the desired acid chloride formation, in
situ IR measurement was carried out using the optimal condi-
tions (Table 1, entry 2) shown in Fig. 2. We separately prepared
the reference acid chloride 4 (see Supplementary Material for
synthetic details for 4) and measured its IR spectrum. The
comparison between the observed in situ IR spectrum of the
obtained solution from the microflow system and the IR spec-
trum of the reference acid chloride 4 indicated that the desired
acid chloride was generated in the microflow system. It should
be noted that the desired acid chloride 4 was formed in only
5 min from unreactive, electron-rich carboxylic acid 1a using
the procedure we developed.[15]
150 µL minϪ1
i-PrNH2
Et2O
Fig. 1. Activation of 3,5-bis(benzyloxy)benzoic acid (1a) in a microflow
reactor. DMF, N,N-dimethyl formamide; DIEA, N,N-diisopropylethyla-
mine; Pr, propyl; Et, ethyl.
Table 1. Examination of the activation of 3,5-bis(benzyloxy)benzoic
acid (1a) in a microflow reactor
‘X’ refers to the amount of activator
Subsequent nucleophilic acyl substitution of the acid chloride
4 with trimethylsilyldiazomethane (TMSCHN2)[16] was exam-
ined using the microflow system shown in Fig. 3. We connected
two T-shape mixers with Teflon tubing. The temperature was
controlled by immersing the T-shape mixers and the Teflon
tubing in water baths. A solution of the acid chloride 4 that was
obtained from the first reaction was introduced to the second
T-shape mixer. Asolution ofTMSCHN2 and DIEAinMeCNwas
also introduced into the second T-shape mixer with a syringe
pump. The resultant solution was poured into a solution of acetic
acid (AcOH) in MeOH and H2O in a flask. The amount of
TMSCHN2 (3–5equiv.) was examined (Table 2, entries 1–3).
Increases in the amount of TMSCHN2 employed did not have
much influence on the yields, and neither did increases in the
amount of DIEA employed (entry 4). We used 3 equiv. of
TMSCHN2 and 4 equiv. of DIEA for the following examinations.
In accordance with our previous observation,[12f] photo-
chemical Wolff rearrangement and a subsequent nucleophilic
addition were examined, as shown in Fig. 4. We connected three
T-shape mixers using Teflon and fluorinated ethylene propylene
copolymer (FEP) tubing. The temperature was controlled by
immersing the T-shape mixers and the Teflon tubing into water
baths. A solution of the a-diazo ketone 5 that was obtained from
the second reaction was introduced into the third T-shape mixer.
A solution of AcOH in MeOH was also introduced into the third
Entry
Activator
X equiv.
DIEA
Yield of 3A [%]
1
2
3
4
5
6
7
Triphosgene
0.40
0.50
0.40
0.50
1.20
1.50
1.50
–
78
84
58
88
70
85
Triphosgene
–
Triphosgene
0.1 equiv.
Triphosgene
0.1 equiv.
Thionyl chloride
Thionyl chloride
Oxalyl chloride
–
–
–
B
–
AIsolated yield based on 1a.
BThe desired amide 3 was obtained as an inseparable mixture with N,N,N,N-
tetraisopropyl oxalamidine. The ratio of 3 to the oxalamidine was 2.7 : 1, as
determined by 1H NMR analysis.
flask that contained a solution of isopropylamine in Et2O. The
results obtained are shown in Table 1. The use of triphosgene
(entries 1 and 2) and thionyl chloride (entries 5 and 6) afforded
comparable results, whereas the use of oxalyl chloride afforded
an inseparable mixture of the desired amide 3 and N,N,N,N-
tetraisopropyl oxalamidine[14] (entry 7). The addition of DIEA
did not have much influence on the yields (entries 3 and 4). The
following examination was performed using 0.50 equiv. of
triphosgene without adding DIEA (entry 2).

One-Flow Arndt–Eistert Synthesis
1659
DMF (0.1 equiv.)
1,4-dioxane
O
OH
O
CI
O
N2
BnO
OBn
BnO
OBn
BnO
OBn
4
5
150 µL minϪ1
1a (1.0 equiv.)
80ЊC, 300 s
0ЊC, 60 s
T-shape
mixer
Triphosgene (0.5 equiv.)
MeCN
1.50 mL
0.3 mL
80ЊC, 300 s
2.25 mL
TMSCHN2 (X equiv.)
DIEA (Y equiv.)
MeCN
150 µL minϪ1
BPR (276 kPa)
AcOH
MeOH
H2O
150 µL minϪ1
Fig. 3. Microflow synthesis of a-diazoketone 5. BPR, back-pressure regulator.
Table 2. Examination of the amount of TMSCHN2 and DIEA in the microflow nucleophilic acyl substitution reaction
X and Y refer to amounts of TMSCHN2 and DIEA, respectively.
Entry
X equiv.
Y equiv.
Yield of 5A [%]
1
2
3
4
3
4
5
3
4
4
4
6
63
59
67
58
AIsolated yield based on 1a (two steps).
DMF (0.1 equiv.)
1,4-dioxane
O
OH
O
CI
O
BnO
OBn
BnO
OBn
N2
4
150 µL minϪ1
1a (1.0 equiv.)
254 nm
X s
Y mM
80ЊC, 300 s
0ЊC, 60 s
0.3 mL
T-shape
mixer
BPR
(276 kPa)
BnO
OBn
Triphosgene (0.5 equiv.)
MeCN
1.50 mL
5
0ЊC, 60 s
80ЊC, 300 s
TMSCHN2 (3.0 equiv.)
DIEA (4.0 equiv.)
MeCN
0.45 mL
2.25 mL
150 µL minϪ1
O
150 µL minϪ1
AcOH, MeOH
OMe
OBn
NaHCO3
MeOH
BnO
Flow rate I
2a
Fig. 4. Microflow synthesis of a-aryl ester 2a.
T-shape mixer with a syringe pump. AcOH was used to decom-
pose unreacted TMSCHN2. The resultant solution flowed
through the FEP tube and was irradiated by a 6-W portable
UV lamp. The solution of the a-aryl ester 2a was poured into a
suspension of NaHCO3 in MeOH. To the reaction mixture
obtained, an excess amount of NaBH4 was added in order to
reduce the undesired substituted acetophenone that was proba-
bly generated from the triplet keto carbene species.[17] This
treatment facilitated the removal of the undesired acetophenone
derivative. The concentration and reaction time were examined
by changing the flow rate I and the volume of the FEP tube, as
shown in Table 3. The combination of 80 s and 14 mM afforded
the best results (entry 2).
We synthesized an a-aryl carboxylic acid 6, which retained
strong activity for the reduction of uric acid, as shown in
Fig. 5.[13] The desired a-aryl ester 2b was obtained using the
one-flow Arndt–Eistert synthesis we developed in a 23 % yield
(three steps). The obtained ester was converted to the desired
carboxylic acid 6 in a high yield using batch conditions.
In summary, we demonstrated a one-flow, Arndt–Eistert
synthesis. A sequence of acid chloride formation–nucleophilic
acyl substitution–Wolff rearrangement–nucleophilic addition
was performed to obtain a-aryl esters 2a and 2b in a micro-
flow system without isolating any intermediates, which includ-
ed a potentially explosive compound. The microflow system
was made from simple, inexpensive, and readily available

1660
S. Fuse et al.
Table 3. Examination of the effect of times and concentrations in the photochemical Wolff
rearrangement and subsequent nucleophilic addition of methanol
X and Y refer to reaction times and concentrations of 5, respectively.
Entry
X [s]
Y [mM]
Yield of 2aA [%]
1B
2C
3D
4E
5F
53
80
22
14
22
33
22
27
33
28
15
26
80
80
128
AIsolated yield based on 1a (three steps).
BFlow rate: 450 mL minÀ1, volume of FEP (fluorinated ethylene propylene) tube: 800 mL.
CFlow rate: 1000 mL minÀ1, volume of FEP tube: 1930 mL.
DFlow rate: 450 mL minÀ1, volume of FEP tube: 1200 mL.
EFlow rate: 150 mL minÀ1, volume of FEP tube: 800 mL.
FFlow rate: 450 mL minÀ1, volume of FEP tube: 1930 mL.
DMF (0.1 equiv.)
1,4-dioxane
OH
O
O
150 µL minϪ1
1b (1.0 equiv.)
80ЊC, 300 s
0ЊC, 60 s
T-shape
mixer
BPR
(276 kPa)
254 nm, 80 s
14 mM, 1.93 mL
Triphosgene (0.5 equiv.)
MeCN
1.50 mL
0.3 mL
80ЊC, 300 s
2.25 mL
0ЊC, 60 s
TMSCHN2 (3.0 equiv.)
DIEA (4.0 equiv.)
MeCN
0.45 mL
150 µL minϪ1
O
150 µL minϪ1
MeOH, AcOH
O
OR
NaHCO3
MeOH
KOH, MeOH,
H2O, 96 %, (batch)
2b: R ϭ Me (23 %)
6: R ϭ H
1000 µL minϪ1
Fig. 5. Microflow synthesis of a-aryl carboxylic acid 6.
instruments and tubes. It should be possible to scale up the
developed process by either continuous running using high-
pressure pumps such as plunger pumps or by increasing the
number of microreactors. The developed procedure would be a
valuable aid for the efficient preparation of a-aryl carbonyl
compounds.
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