Three-component coupling reaction of benzylic halides, carbon dioxide, and N,N-dimethylformamide by using paired electrolysis: Sacrificial anode-free efficient electrochemical carboxylation of benzylic halides

Article abstract of DOI:10.1016/j.tet.2015.04.020

Sacrificial anode-free efficient electrochemical carboxylation of benzylic halides was successfully performed by using a paired electrolysis protocol. Constant-current electrolysis of a DMF solution of benzylic halides in the presence of carbon dioxide using a one-compartment cell equipped with a Pt plate cathode and a Pt wire anode (quasi-divided cell) resulted in efficient three-component coupling reaction of benzylic halides, carbon dioxide and DMF to yield N-methyl-N-(phenylacetoxy)methylformamides, as carboxylated coupling products, in good yields.

Full text of DOI:10.1016/j.tet.2015.04.020

Accepted Manuscript
Three-component Coupling Reaction of Benzylic Halides, Carbon Dioxide, and N,N-
Dimethylformamide by Using Paired Electrolysis: Sacrificial Anode-free Efficient
Electrochemical Carboxylation of Benzylic Halides
Hisanori Senboku, Kotaro Nagakura, Tsuyoshi Fukuhara, Shoji Hara
PII:
S0040-4020(15)00510-4
10.1016/j.tet.2015.04.020
TET 26623
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 3 March 2015
Revised Date: 7 April 2015
Accepted Date: 8 April 2015
Please cite this article as: Senboku H, Nagakura K, Fukuhara T, Hara S, Three-component Coupling
Reaction of Benzylic Halides, Carbon Dioxide, and N,N-Dimethylformamide by Using Paired Electrolysis:
Sacrificial Anode-free Efficient Electrochemical Carboxylation of Benzylic Halides, Tetrahedron (2015),
doi: 10.1016/j.tet.2015.04.020.
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ACCEPTED MANUSCRIPT
Three-component Coupling Reaction of Benzylic Halides, Carbon Dioxide, and N,N-Dimethylformamide by
Using Paired Electrolysis: Sacrificial Anode-free Efficient Electrochemical Carboxylation of Benzylic
Halides
Hisanori Senboku,* Kotaro Nagakura, Tsuyoshi Fukuhara, Shoji Hara
Laboratory of Organic Reaction, Division of Chemical Process Engineering,
Graduate School of Engineering, Hokkaido University, Sapporo, Hokkaido 060-8628, Japan

ACCEPTED MANUSCRIPT
Three-component Coupling Reaction of Benzylic Halides, Carbon Dioxide, and
N,N-Dimethylformamide by Using Paired Electrolysis:
SacrificialAnode-free Efficient Electrochemical Carboxylation of Benzylic Halides
Hisanori Senboku,* Kotaro Nagakura, Tsuyoshi Fukuhara, Shoji Hara
Laboratory of Organic Reaction, Division of Chemical Process Engineering,
Graduate School of Engineering, Hokkaido University, 1) Sapporo, Hokkaido 060-8628, Japan
*Corresponding author. Tel&Fax: +81-11-706-6555; E-mail: senboku@eng.hokudai.ac.jp
Abstract
Sacrificial anode-free efficient electrochemical carboxylation of benzylic halides
was successfully performed by using
a paired electrolysis protocol.
Constant-current electrolysis of a DMF solution of benzylic halides in the
presence of carbon dioxide using a one-compartment cell equipped with a Pt
plate cathode and a Pt wire anode (quasi-divided cell) resulted in efficient
three-component coupling reaction of benzylic halides, carbon dioxide and DMF
to yield N-methyl-N-(phenylacetoxy)methylformamides, as carboxylated
coupling products, in good yields.
Key Words: electrochemical carboxylation; fixation of carbon dioxide; paired
electrolysis; three component coupling; quasi-divided cell
1. Introduction
Carbon dioxide (CO2) is an important carbon source in organic synthesis because of its abundance and
non-toxicity from the viewpoint of eco-friendly synthetic organic chemistry. The use of carbon dioxide as an
environmentally benign C1 carbon source for organic synthesis is an attractive subject of great interest and has
been widely investigated.2 Electroorganic synthesis3 is a powerful and effective tool for fixation of carbon dioxide
in organic molecules with carbon-carbon bond formation to afford carboxylic acids. Fixation of carbon dioxide
can be readily achieved in high yields under neutral and mild conditions even under atmospheric pressure of
carbon dioxide when a reactive metal, such as magnesium or aluminum, is used as an anode in the electrolysis.4,5
When the electrolysis is carried out in a one-compartment (undivided) cell, the use of a sacrificial anode is
essential for efficient electrochemical reduction and carboxylation. Reported examples of efficient electrochemical
carboxylation of benzyl halides in a one-compartment cell were all achieved by using sacrificial anodes,6 and, to
the best of our knowledge, there have been no reports on efficient electrochemical carboxylation of benzyl halides
in a one-compartment cell without the use of a sacrificial anode. However, the use of a sacrificial anode in
electrochemical carboxylation and reduction sometimes results in problems such as passivation of the cathode
caused by precipitation of insoluble salts of the dissolved anode metal on the cathode surface. The necessity of
exchanging a consumable sacrificial anode metal is also troublesome in continuous electrolysis. In the course of
our studies on electroorganic synthesis,6k-n,7 we found that a paired electrolysis system3a can be used for sacrificial
anode-free electrochemical carboxylation of benzyl halides. Efficient electrochemical carboxylation of benzyl
halides was successfully carried out in a one-compartment cell equipped with a Pt plate cathode and a Pt wire
anode (quasi-divided cell). It has been reported that a quasi-divided cell is the divided cell equipped with a much
smaller counter electrode than the working electrode, which can realize much higher current density at the counter
electrode. The major electrode reaction at the counter electrode in a quasi-divided cell focuses oxidation/reduction
of the solvent rather than of the substrate.8 Reductive cleavage of a C-halogen bond at the benzylic position
followed by fixation of carbon dioxide at the cathode and electrochemical oxidation of DMF yielding the

corresponding acyliminium ion at theAanCodCeEtoPoTk EplDaceMefAficNienUtlSyCinRthIePeTlectrolysis to provide three-component
coupling products of benzyl halides, carbon dioxide and DMF, N-methyl-N-(phenylacetoxy)methylformamides, in
good yields. N-Methyl-N-acyloxymethylformamides are known as useful electrophilic reagents9 and
pharmaceuticals,10 and have been synthesized by using hazardous organic peroxides.11 Electrolysis of carboxylic
acids in an undivided cell in the presence of DMF also gave N-methyl-N-acyloxymethylformamides.12-14 The
present reaction is, on the other hand, the first example of electrochemical three-component coupling including
carbon dioxide with carbon-carbon bond formation15 and synthesis of N-methyl-N-acyloxymethylformamides
from carbon dioxide. Moreover, to the best of our knowledge, efficient electrochemical carboxylation in a
one-compartment cell without the use of a sacrificial anode is achieved for the first time by the present reaction.
Herein we report sacrificial anode-free electrochemical carboxylation of benzyl halides by using paired
electrolysis to yield three-component coupling products of benzyl halides, carbon dioxide, and DMF in good
yields.
2. Results and discussion
2.1 Screening of reaction conditions
The results of reaction condition screening using benzyl chloride (1a-Cl) as a substrate are summarized
in Table 1. When constant-current electrolysis (20 mA/cm2) of 1a-Cl in DMF containing 0.1 M Bu4NBF4 was
carried out with 6 F/mol of electricity by using an undivided cell equipped with a Pt plate cathode (2×2 cm2) and a
Pt wire anode (1.0 mmφ, ca. 20 mm) (quasi-divided cell) in the presence of carbon dioxide at 0 °C, a
three-component coupling product, N-methyl-N-(phenylacetoxy)methylformamide (2a), was obtained in 47%
yield along with phenylacetic acid (3) in 30% yield (Entry 1 in Table 1). We next tested several amines (3 equiv)
as additives under the same conditions (Entries 2-4). Although 4-dimethylaminopyridine was not effective for the
present reaction (entry 2), triethylamine and diisopropylethylamine were found to be effective for providing three
component coupling product 2a in about 70% yields (Entries 3 and 4). Effects of current density and amount of
the additive were next investigated by using diisopropylethylamine as the additive (Entries 5-8). An increase and
decrease in current density resulted in a decrease in the yields of 2a (Entries 5 and 6). Even 1 equiv of the additive,
diisopropylethylamine, was sufficient for the reaction to give 2a in 69% yield. However, further decrease in the
amount (0.5 equiv) led to a decrease in the yield of 2a (Entry 8). The use of triethylamine (1 equiv), instead of
diisopropylethylamine, resulted in a slight decrease in the yield of 2a and increase in the yield of carboxylic acid 3
(Entry 9). When a Pt plate (2×2 cm2), instead of a Pt wire, was used as the anode in the electrolysis under the
same conditions as those in Entry 7, decrease in the yield of 2a and increase in the yield of carboxylic acid 3 were
observed (Entry 10). Finally, we selected the conditions used in Entry 7 as the best conditions for further
investigations at the present stage.
Table 1 Screening of reaction conditions

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CH3
N
O
(plate)
Pt
Pt(wire)
Cl
CHO
CO2H
CO2
+
+
O
0.1 M Bu4NBF4-DMF
6 F/mol, 0 °C
1a-Cl
2a
3
Yield [%]a)
2a
Current Density
[mA/cm2]
Additive
[equiv]
Entry
3
1
2
20
none
47
50
71
72
52
65
69
59
64
57
30
13
20
20
20
10
30
20
20
20
20
DMAP (3)
Et3N (3)
3
13
4
i-Pr2NEt (3)
i-Pr2NEt (3)
i-Pr2NEt (3)
i-Pr2NEt (1)
i-Pr2NEt (0.5)
Et3N (1)
5
5
trace
trace
4
6
7
8
13
9
17
10b)
i-Pr2NEt (1)
18
a) Isolated yield. b) The reaction was carried out using a Pt plate anode (2 x 2 cm2).
2.2 Three-component coupling of benzylic halides
We next investigated the scope of the present three-component coupling using several benzylic halides,
and the results are summarized in Table 2. Benzyl bromides 1a-Br, 1b-e were also applicable to the present
electrochemical three-component coupling reaction to give 2a-e in good yields (Entries 1-5). Electrolysis of
benzyl bromide (1a-Br) under the same conditions as those in Entry 7 in Table 1 gave a slightly better yield, 74%,
than that of chloride 1a-Cl (Entry 1). When o- and p-bromobenzyl bromides (1b,c) were subjected to the present
reaction as substrates, selective carboxylation at the benzylic position occurred with retention of bromobenzene
moieties to give three-component coupling products 2b and 2c in 75% and 77% yields, respectively (Entries 2 and
3). Similar reaction of benzyl bromide 1d, having an ester group on the phenyl ring, afforded the coupling product
2d in 61% yield (Entry 4). We also investigated the three-component coupling of secondary benzyl bromide 1f
and found that the coupling product 2e was obtained in 78% yield (Entry 5). This result was successfully applied
to the synthesis of an ibuprofen derivative by using the present coupling reaction (vide infra). Electrolysis under
the conditions of a high concentration of the substrate was also investigated. When electrochemical carboxylation
was carried out by using a sacrificial anode such as magnesium, especially under the condition of a high
concentration of the substrate, insoluble salts, which were produced in situ from the formed carboxylate and
dissolving anode metal, were deposited on the cathode surface, sometimes resulting in passivation of the cathode.
Therefore, neither sufficient current nor electricity can be supplied for efficient electrolysis. The present reaction
system produces no salt, and no passivation of the cathode would occur during the electrolysis. For these reasons,
the present reaction system would be suitable for large-scale synthesis. As a result, an efficient current could
actually be obtained even at the end of the reaction, and 6 F/mol of electricity could easily be supplied even when
the electrolysis was performed using 5 mmol of 1a-Cl in the same volume of DMF (five times concentration).

After the usual work-up followed byAcoCluCmEnPcThrEomDatMogArapNhyU, SthCreRe-cIoPmTponent coupling product 2a could be
obtained in 69% yield. These results indicate that the present sacrificial anode-free electrochemical carboxylation
system is more suitable for large-scale carboxylation than conventional electrochemical carboxylation using a
sacrificial anode.
Table 2 Scope of benzylic halides in the three-component coupling
Y
Y
CH3
N
O
(plate)
Pt
Pt(wire)
X
CHO
CO2
R
R
+
O
0.1 M Bu4NBF4-DMF
20 mA/cm2, 6 F/mol, 0 °C
i-Pr2NEt (1 equiv)
1
2
Yield [%]b)
a)
Entry
1
Substrate and Ered
Product
CH3
N
Br
O
O
74
CHO
1a-Br: -2.6 V
2a
CH3
Br
O
O
N
2c,d)
3c)
4c,d)
5
75
77
61
78
69
CHO
Br
2b
2c
1b: -2.3 V
Br
CH3
N
Br
O
O
CHO
1c: -2.4 V
Br
O
Br
CH3
N
Br
O
CHO
CH3O2C
1d: -2.2 V
2d
CH3O2C
CH3
Br
CH3
O
CH3
N
O
CHO
1e: -2.6 V
2e
6 e)
Cl
2a
1a-Cl: -3.1 V
a) Reduction peak potential (Ered) was determined by cyclic voltammetry and was shown in V vs Ag/Ag+.
See 4.1 General in 4. Experimental section. b) Isolated yield. c) The electrolysis was carried out at a
current density of 10 mA/cm2. d) 4 F/mol of electricity was passed. e) The reaction was performed by
using 5 mmol of 1a-Cl.
The carboxylated coupling product 2a could easily be transformed into the corresponding acid and
methyl ester, respectively. Thus, treatment of 2a with 1 M hydrochloric acid at rt for 12 h resulted in acidic
hydrolysis to give phenylacetic acid (3) in 94% yield. On the other hand, when 2a was treated with
p-toluenesulfonic acid in methanol at rt for 12 h, transesterification took place efficiently to give methyl

ACCEPTED MANUSCRIPT
phenylacetate (4) in 96% yield (Scheme 1). These results indicate that the obtained coupling product 2 is a useful
alternative and precursor of the corresponding acid and esters, respectively, as well as useful electrophilic
reagents13 and pharmaceuticals.14
Scheme 1 Hydrolysis and transesterification of three-component coupling product 2a
We successfully applied the present carboxylation to the synthesis of an ibuprofen derivative, well
known as a non-steroidal anti-inflammatory agent. A DMF solution of benzylic bromide 1f was electrolyzed in the
presence of carbon dioxide under similar conditions until 9 F/mol of electricity was passed. After the usual
work-up and purification by column chromatography on silica gel, ibuprofen derivative 2f was obtained as a
three-component coupling product in 66% yield (Scheme 2).
Scheme 2 Synthesis of ibuprofen derivative 2f by three-component coupling of benzylic bromide 1f
2.3 Three-component coupling of allylic bromides
It has been reported that electrochemical carboxylation of allylic bromides also proceeds efficiently as
well as benzyl halides by electrolysis in the presence of carbon dioxide in DMF using a sacrificial anode.16
Therefore, we also tried to apply the present three-component coupling reaction to allylic bromides, and the
results are summarized in Scheme 3. Electrolysis of (E)-1-bromo-2-dodecene (5a) was carried out in DMF by
using an undivided cell equipped with a Pt plate cathode and a Pt wire anode (quasi-divided cell) in the presence
of carbon dioxide and 1 equiv of i-Pr2NEt under conditions similar to those for the electrolysis of benzyl bromide.
It was found that both electrochemical reactions at the cathode and anode; electrochemical reduction of allylic
bromide followed by capture of carbon dioxide forming the corresponding carboxylate at the cathode and
electrochemical oxidation of DMF forming the corresponding N-acyliminium ion at the anode, took place
efficiently to give the expected three-component coupling products as a mixture of α-carboxylated and
γ-carboxylated isomers. It has been reported that electrochemical carboxylation of allylic bromides using a
magnesium anode gave the corresponding β,γ-unsaturated carboxylic acids as an inseparable mixture of two
regioisomers.16 Although a regioisomeric mixture of the products were also obtained in the present reaction, two
isomers of the coupling products were fortunately separable by column chromatography on silica gel with
hexane-ethyl acetate as an eluent. Finally, three-component coupling products of α-carboxylated 6a and
γ-carboxylated 7a were isolated in 48% and 12% yields, respectively. In a similar manner, three-component
coupling products 6b and 7b were also obtained as a separable mixture by similar electrolysis of cinnamyl
bromide (5b). After separation by column chromatography on silica gel, 6b and 7b were isolated in both 33%
yields. It should be noted that while electrochemical carboxylation of allylic bromides using magnesium as a
sacrificial anode only gives an inseparable mixture of α- and γ-carboxylated acids, the present paired
electrochemical carboxylation gives separable α- and γ-carboxylated three-component coupling products. These

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results indicate that the present electrochemical carboxylation system using a quasi-divided cell giving separable
three-component coupling products is superior to that using an undivided cell with a sacrificial anode giving
inseparable carboxylic acids.
Scheme 3 Three-component coupling of allylic bromides 5
CH3
O
N
R
CHO
6a: R = C9H19, 48%
6b: R = C6H5, 33%
O
(plate) Pt
Pt (wire)
+
Br
CO2
+
R
0.1 M Bu4NBF4-DMF
10 mA/cm2, 6 F/mol, 0 °C
i-Pr2NEt (1 equiv)
R
CH3
N
5a: R = C9H19
5b: R = C6H5
O
CHO 7a: R = C9H19, 12%
7b: R = C6H5, 33%
O
2.4 Reaction mechanism
A probable reaction mechanism in the present three-component coupling of benzyl halides, carbon
dioxide and DMF by paired electrolysis using an undivided cell equipped with a platinum plate cathode and
platinum wire anode (quasi-divided cell) is shown in Scheme 4. At the cathode, two-electron reduction of the
benzyl halide 1 results in C-halogen bond cleavage at the benzylic position to generate benzylic anion A as an
intermediate. The generated anion A attacks carbon dioxide to give the corresponding carboxylate ion B. On the
other hand, at the anode, electrochemical oxidation of DMF takes place through one-electron oxidation followed
by deprotonation and further one-electron oxidation to generate N-acyliminium ion intermediate C.17,18 In an
undivided cell equipped with a platinum plate cathode and platinum wire anode (quasi-divided cell), high current
density at the anode favors oxidation of the solvent, DMF, and avoids oxidation of the starting material,
diisopropylethylamine and other intermediates.8 Addition of diisopropylethylamine would accelerate the
deprotonation step and capture proton to prevent the formation of carboxylic acid and a protonated product,
toluene. Competitive reduction of generated proton with the substrate at the cathode would takes place in the
electrolysis resulting in an excess amount of electricity for a high yield. Coupling of carboxylate ion B with
N-acyliminium ion C gives coupling product 2.
Scheme 4 Probable reaction mechanism of the present three-component coupling reaction

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3. Conclusion
In conclusion, we have successfully carried out sacrificial anode-free electrochemical carboxylation of
benzyl halides in an undivided cell equipped with a Pt plate cathode and a Pt wire anode (quasi-divided cell) to
afford three-component coupling products of benzyl halides, carbon dioxide and DMF in good yields. Allylic
bromides can also be applied to the present carboxylation system. Although the electrochemical carboxylation of
allylic bromides gave an inseparable isomeric mixture of β,γ-unsaturated carboxylic acids, three-component
coupling products obtained in the present system could readily be separated by column chromatography on silica
gel to provide each isomer as a pure form. These results indicate that the present system is promising as a
powerful alternative to conventional electrochemical carboxylation of benzylic and allylic halides using an
undivided cell equipped with a sacrificial anode to give phenylacetic acids and β,γ-unsaturated carboxylic acids.
4 Experimental section
4.1 General
Melting points were measured on a Yanagimoto micro melting point apparatus and are uncorrected. IR
1
spectra were determined with a JASCO FT/IR-410 spectrometer in neat form unless otherwise stated. H (400
MHz) and 13C (100 MHz) NMR spectra were recorded in CDCl3 with a JEOL A400II FT NMR spectrometer. The
chemical shifts, δ, are given in ppm with tetramethylsilane as a reference. J values are in Hz. Peak multiplicities
were given as follows: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet. MS spectra were determined using a
JEOL JMS-FABmate, JEOL JMS-HX110 or JEOL JMS-700TZ at Instrumental Analysis Division, Equipment
Management Center, Creative Research Institution Sousei in Hokkaido University. Electrochemical reactions
were carried out using a Constant Current Power Supply (model 5944), Metronix Corp., Tokyo. Cyclic
voltammetry was performed by a Hokuto Denko HSV-100 in a DMF solution (substrate concentration: 10 mM)
containing 0.1 M Bu4NBF4 using a Pt disk electrode (φ 1.6 mm) as a working electrode, a Pt wire (φ 0.5 mm) as a
counter electrode, and Ag/Ag+/CH3CN/Bu4NClO4 (0.01 M AgNO3 in 0.1 M Bu4NClO4 in CH3CN), purchased
from BAS (product code; RE-7), as a reference electrode, respectively, with a scan rate 0.1 V/sec. Column
chromatography was carried out using Kanto Kagaku Silica gel 60N with hexane/EtOAc as an eluent. Reagents
1a-d, 5b and solvents were commercially available and were used as received without further purification except

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for 1b and 1c, which were recrystallized before use. 1-Bromo-1-phenylethane (1e) was prepared from
1-phenylethanol by reaction with 48% aqueous HBr in 77% yield by the standard procedure.
1-Bromo-1-(4-isobutyl)phenylethane (1f) was prepared according to the reported procedure.19
(E)-1-Bromo-2-dodecene (5a) was prepared from (E)-dodec-2-en-1-ol with PBr3 in 63% yield by the standard
procedure.
4.1.1 1-Bromo-1-phenylethane (1e).20 oil. 1H NMR: δ 2.05 (3H, d, J = 7.0 Hz), 5.22 (1H, q, J = 7.0 Hz), 7.2–7.5
(5H, m).
4.1.2 1-Bromo-1-(4-isobutyl)phenylethane (1f).19 oil. 1H NMR: δ 0.90 (6H, d, J = 6.5 Hz), 1.80-1.90 (1H, m), 2.05
(3H, d, J = 6.8 Hz), 2.46 (2H, d, J = 7.2 Hz), 5.33 (1H, q, J = 6.8 Hz), 7.11 (2H, d, J = 8.0 Hz), 7.34 (2H, d, J =
8.0 Hz).
4.1.3 (E)-1-Bromo-2-dodecene (5a).21 oil. 1H NMR: δ 0.88 (3H, t, J = 7.1 Hz), 1.2–1.4 (14H, m), 2.05 (2H, q, J =
7.3 Hz), 3.95 (2H, d, J = 7.3 Hz), 5.46–5.81 (2H, m). 13C NMR: δ 14.1, 22.7, 28.0, 29.1, 29.3, 29.4, 29.5, 31.9,
32.1, 33.4, 126.2, 136.8; IR: 2925, 2854, 1654, 1558, 1457, 1203, 965 cm-1. MS (EI): 248 ([M+2]+, 2), 246 ([M]+,
2), 167 (4), 125 (11), 111 (54), 97 (95), 83 (100), 69 (83), 55 (74), 43 (36), 41 (35); HRMS (EI): m/z [M]+ calcd
for C12H2379Br 246.0983. Found 246.0979.
4.2 Three-component coupling reaction of benzylic halides 1 or allylic bromides 5, carbon dioxide and DMF:
general procedure.
A solution of halide 1 or 5 (1 mmol) in anhyd DMF (16 mL) containing Bu4NBF4 (0.1 M) was
electrolyzed at 0 °C with a constant current (20 mA/cm2, 10 mA/cm2 for 1b-1d) under atmospheric pressure of
bubbling carbon dioxide. A test tube-like (ca. 26 mmφ) undivided cell equipped with a Pt plate cathode (2×2 cm2)
and a Pt wire anode (1.0 mmφ, ca. 20 mm) was used for the electrolysis. After an appropriate amount of electricity
had been passed (shown in the tables and schemes), the electrolyzed solution was poured into 30 mL of Et2O and
then 50 mL of satd brine was added. The organic layer was separated and the resulting aqueous solution was
extracted with Et2O (30 mL×2). The combined ethereal solution was washed with satd NaHCO3 (30 mL) and
dried over MgSO4. Evaporation of the solvent gave a crude product, which was purified by column
chromatography on silica gel (hexane/ethyl acetate = 1/1, hexane/ethyl acetate = 2/3 for 2d) to give coupling
products 2, 6, and 7. In 1H and 13C NMR data, chemical shifts of the observed peaks of a minor rotamer are shown
in parentheses.
1
4.2.1 N-(Phenylacetoxymethyl)-N-methylformamide (2a). Oil. H NMR: δ 2.89 (2.99) (3H, s), 3.647 (3.654) (2H,
s), 5.30 (5.41) (2H, s), 7.25–7.36 (m, 5H), 8.29 (8.09) (1H, s). 13C NMR: δ 29.5 (34.0), 41.1 (40.9), 73.8 (68.1),
127.3 (127.2), 128.6 (128.5), 129.06 (129.13), 133.1 (133.3), 163.8 (163.4), 171.1 (171.3). HRMS (EI): Calcd for
[M+H]+ C11H14NO3: m/z 208.0974. Found: m/z 208.0970. IR: 1740, 1691, 1497, 1396, 1271, 1237, 1140, 1070,
963 cm-1.
4.2.2 N-{(2-Bromophenyl)acetoxymethyl}-N-methylformamide (2b). Solid, mp: 54–55 °C. 1H-NMR: δ 2.92 (3.03)
(3H, s), 3.81 (3.82) (2H, s), 5.33 (5.44) (2H, s), 7.15–7.19 (1H, m), 7.27-7.32 (2H, m), 7.58 (1H, d, J = 7.9 Hz),
8.30 (8.10) (1H, s). 13C-NMR: δ 29.7 (34.1), 41.5 (41.4), 74.0 (68.3), 124.9, 127.7 (127.6), 129.2 (129.16), 131.4
(131.5), 132.83 (132.76), 133.4 (133.6), 163.9 (163.5), 170.2 (170.4). HRMS (FAB): m/z [M+H]+ calcd for
C11H13BrNO3 286.0079. Found: 286.0088. IR (KBr): 1733, 1697, 1474, 567 cm-1.
1
4.2.3 N-{(4-Bromophenyl)acetoxymethyl}-N-methylformamide (2c). Solid, mp: 54–55 °C. H-NMR: δ 2.90 (3.00)

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(3H, s), 3.60 (2H, s), 5.30 (5.41) (2H, s), 7.14 (2H, d, J = 8.3 Hz), 7.46 (2H, d, J = 8.3 Hz), 8.29 (8.10) (1H, s).
13C-NMR: δ 29.7 (34.2), 40.5 (40.3), 74.1 (68.4), 121.5, 130.9 (131.0), 131.8 (131.7), 132.0 (132.3), 163.8 (163.5),
170.7 (170.9). HRMS (EI): m/z [M]+ calcd for C11H12BrNO3 285.0000. Found: 284.9981. IR (KBr): 1736, 1666,
1404, 1347, 1274, 1217, 1145, 1068, 962 cm-1.
1
4.2.4 N-{(4-Methoxycarbonylphenyl)acetoxymethyl}-N-methylformamide (2d). Solid, mp: 64–65 °C. H-NMR: δ
2.89 (3.00) (3H, s), 3.71 (2H, s), 3.92 (3H, s), 5.31 (5.42) (2H, s), 7.34 (2H, d, J = 8.2 Hz), 8.01 (2H, d, J = 8.2
Hz), 8.29 (8.09) (1H, s). 13C-NMR: δ 29.7 (34.1), 41.0 (40.9), 52.11 (52.09), 74.1 (68.4), 129.25, 129.31, 129.93
(129.85), 138.1 (138.4), 163.8 (163.5), 166.65 (166.72), 170.5 (170.7). HRMS (FAB): m/z [M+H]+ calcd for
C13H16NO5 266.1028. Found: 266.1031. IR (KBr): 1734, 1717, 1684, 1558, 1457, 1282, 1127, 1065, 970 cm-1.
1
4.2.5 N-(2-Phenylpropanoyloxymethyl)-N-methylformamide (2e). Oil. H-NMR: δ 1.502 (1.508) (3H, d, J = 7.0
Hz), 2.78 (2.88) (3H, s), 3.73 (1H, q, J = 7.0 Hz), 5.22 (5.35) (1H, d, J = 11.0 (10.1) Hz), 5.28 (5.42) (1H, d, J =
11.0 (10.1) Hz), 7.25–7.35 (5H, m), 8.27 (8.04) (1H, s). 13C-NMR: δ 18.7 (18.2), 29.4 (33.8), 45.4 (45.3), 73.7
(67.9), 127.3, 127.4, 128.7 (128.6), 139.7 (139.9), 163.8 (163.3), 174.1 (174.30). HRMS (FAB): m/z [M+H]+
calcd for C12H16NO3 222.1130. Found: 222.1135. IR: 1739, 1694, 1456, 1396, 1271, 1154, 1063, 934 cm-1.
4.2.6 N-{2-(4-Isobutylphenyl)propanoyloxymethyl}-N-methylformamide (2f). Solid, mp: 41–42 °C. 1H NMR: δ
0.89 (6H, d, J = 6.6 Hz), 1.487 (1.495) (3H, d, J = 7.3 (7.0) Hz), 1.84 (m, 1H), 2.44 (2H, d, J = 7.2 Hz), 2.77
(2.87) (3H, s), 3.70 (1H, q, J = 7.3 Hz), 5.21 (5.35) (1H, d, J = 11.0 (10.1) Hz), 5.28 (5.42) (1H, d, J = 11.0 (10.1)
Hz), 7.10 (2H, d, J = 8.1 Hz), 7.16 (7.19) (2H, d, J = 8.1 Hz), 8.27 (8.04) (1H, s). 13C NMR: δ 18.0 (18.2), 22.3,
29.3 (33.8), 30.1, 44.9, 45.0 (44.9), 73.7 (67.8), 127.0 (127.1), 129.4 (129.3), 136.9 (137.1), 140.9 (140.7), 163.8
(163.3), 174.3 (174.5). HRMS (EI): m/z [M]+ calcd for C16H23NO3 277.1678. Found: 277.1686. IR (KBr): 1735,
1684, 1558, 1540, 1507, 1457, 1271, 1160, 1070, 940 cm-1.
4.2.7 N-{(E)-4-Phenylbut-3-enoyloxymethyl}-N-methylformamide (6a). Oil. 1H NMR: δ 2.95 (3.05) (3H, s), 3.28
(2H, dd, J = 7.0 and 1.4 Hz), 5.23 (5.43) (2H, s), 6.25 (1H, dt, J = 15.8 and 7.0 Hz), 6.51 (1H, d, J = 15.8 Hz),
7.22–7.38 (5H, m), 8.32 (8.11) (1H, s). 13C NMR: δ 29.7 (34.2), 38.1 (38.0), 73.9 (68.2), 120.5 (120.9), 126.2,
127.7 (127.6), 128.53 (128.50), 134.1 (133.9), 136.5 (136.6), 163.9 (163.6), 171.2 (171.4). HRMS (EI): m/z [M]+
calcd for C13H15NO3 233.1052. Found: 233.1047. IR: 1740, 1686, 1654, 1457, 1397, 1272, 1146, 1071, 965 cm-1.
4.2.8 N-(2-Phenylbut-3-enoyloxymethyl)-N-methylformamide (7a). Oil. 1H NMR: δ 2.82 (2.93) (3H, s), 4.32 (2H,
d, J = 7.8 Hz), 5.16 (1H, d, J = 17.1 Hz), 5.25 (d, J = 10.0 Hz, 1H), 5.28 (5.40) (1H, d, J = 10.1 Hz), 5.31 (5.44)
(1H, d, J = 10.1 Hz), 6.19 (1H, ddd, J = 17.1, 10.0, and 7.8 Hz), 7.25–7.36 (5H, m), 8.28 (8.06) (1H, s).
13C-NMR: δ 29.5 (33.9), 55.43 (55.37), 74.0 (68.2), 118.2 (117.9), 127.6 (127.5), 127.8 (127.9), 128.8 (128.7),
134.7 (135.0), 137.2, 163.8 (163.4), 172.0 (172.1). HRMS (FAB): m/z [M+H]+ calcd for C13H16NO3 234.1130.
Found: 234.1112. IR: 1736, 1687, 1654, 1456, 1397, 1274, 1148, 1070, 985, 929 cm-1.
1
4.2.9 N-{(E)-Tridec-3-enoyloxymethyl}-N-methylformamide (6b). Oil. H NMR: δ 0.88 (3H, t, J = 7.0 Hz), 1.26–
1.4 (14H, m), 2.02 (2H, q, J = 6.9 Hz), 2.95 (3.05) (3H, s), 3.05 (2H, dd, J = 6.8 and 0.8 Hz), 5.30 (5.40) (2H, s),
5.43–5.62 (2H, m), 8.31 (8.11) (1H, s). 13C NMR: 14.1, 22.6, 29.0, 29.1, 29.3, 29.4, 29.5, 29.7 (34.1), 31.8, 32.4,
37.8 (37.7), 73.6 (67.9), 120.3 (120.6), 135.8 (135.5), 163.9 (163.5), 171.8 (172.0). HRMS (EI): m/z [M]+ calcd
for C16H29NO3 283.2147. Found: 283.2139. IR: 2925, 2854, 1739, 1699, 1654, 1457, 1397, 1272, 1146, 1070, 964
cm-1
1
4.2.10 N-(2-Vinylundecanoyloxymethyl)-N-methylformamide (7b). Oil. H NMR: δ 0.88 (3H, t, J = 7.1 Hz), 1.25
(14H, m), 1.49–1.58 (1H, m), 1.69–1.78 (1H, m), 2.94 (3.04) (3H, s), 3.01 (1H, m), 5.12–5.16 (2H, m), 5.30
(5.41) (2H, s), 5.77 (1H, m), 8.31 (8.11) (1H, s). 13C NMR: δ 14.1, 22.6, 27.0, 29.2, 29.38, 29.40, 29.5, 29.6 (34.1),
31.8, 31.9, 50.1 (50.1), 73.8(67.8), 117.7 (117.5), 135.3 (135.6), 163.9 (163.4), 173.8 (174.0). HRMS (FAB): m/z
[M+H]+calcd for C16H30NO3 284.2226. Found: 284.2224. IR: 2925, 2854, 1740, 1696, 1457, 1396, 1271, 1139,
1069 cm-1.

4.3 Hydrolysis of coupling product 2a AproCvCidiEngPT3.ED MANUSCRIPT
A solution of 2a (204 mg, 0.99 mmol) in 5 mL of 1 M hydrochloric acid was stirred at rt for 12 h. After
addition of water (10 mL) and Et2O (10 mL), the ethereal solution was separated and the resulting aqueous
solution was extracted with Et2O (10 mL). The combined ethereal solution was washed with water (20 mL×2) and
then dried over MgSO4. Evaporation of the solvent gave 126 mg (0.93 mmol, 94%) of phenylacetic acid 3.7h,22
4.4 Transesterification of coupling product 2a providing 4.
To a solution of 2a (205 mg, 0.990 mmol) in 3 mL of methanol was added p-toluenesulfonic acid (190
mg, 1.1 mmol) and then the solution was stirred at rt for 12 h. After addition of water (10 mL), the mixture was
extracted with Et2O (10 mL×2) and the combined ethereal solution was washed with water (20 mL×2). Drying
over MgSO4 followed by evaporation of the solvent gave 143 mg (0.95 mmol, 96%) of methyl phenylacetate 4.23
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