Green Access to α-Haloalkyl and α-Halobenzyl Esters, Versatile Intermediates for the One-Pot Two-Step Synthesis of O, O ′-Diacyl Acetals Using Zinc-Based Ionic Liquid Catalyst

Article abstract of DOI:10.1055/s-0037-1612415

α-Haloalkyl and α-halobenzyl esters have been synthesized using a zinc-based ionic liquid catalyst, BMIZnCl ₃. These esters can then react with acids without intermediate purification to obtain mixed O, O ′-diacyl acetals in a one-pot process.

Full text of DOI:10.1055/s-0037-1612415

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2019, 51, A–E
paper
A
en
F. Fache et al.
Paper
Synthesis
Green Access to -Haloalkyl and -Halobenzyl Esters, Versatile
Intermediates for the One-Pot Two-Step Synthesis of O,O′-Diacyl
Acetals Using Zinc-Based Ionic Liquid Catalyst
Fabienne Fache*a
Ignasi de Azpiazua
Béatrice Pelotiera
O
O
O
O
O
R'
BMIZnCl3
(10 mol%)
O
R'
R
H
+
R"
OH
R
O
O
Olivier Pivaa
0
0
0
0-
0
0
0
2-2
5
5
5-7
6
4
4
R
Cl
O
R"
Christel Gozzib
R'
Cl
R, R' = alkyl, aryl
14 examples
up to 92% yield
a Univ Lyon, Université Claude Bernard Lyon 1, CNRS, INSA Lyon,
CPE Lyon, ICBMS, UMR 5246, 69622 Villeurbanne Cedex,
France
fabienne.fache@univ-lyon1.fr
b CPE-Lyon, Campus Lyon Tech-La Doua, 43 bd du 11 novembre
1918, 69616 Villeurbanne, France
Received: 28.01.2019
Accepted after revision: 16.02.2019
Published online: 14.03.2019
thesized according to the procedure described by Zhang et
al.12 It is air- and moisture-stable and turned out to be easy
to separate from the reaction mixture, recyclable, and po-
tentially suitable for one-pot two-step reactions (Scheme
1).
DOI: 10.1055/s-0037-1612415; Art ID: ss-2018-t1813-op
Abstract -Haloalkyl and -halobenzyl esters have been synthesized
using a zinc-based ionic liquid catalyst, BMIZnCl3. These esters can then
react with acids without intermediate purification to obtain mixed O,O′-
diacyl acetals in a one-pot process.
ZnCl3
N
N
O
Key words -haloalkyl esters, -halobenzyl esters, zinc, ionic liquids,
prodrugs, O,O′-diacyl acetals
O
O
BMIZnCl3
O
R'
+
R
H
R'
X
2
rt, 24 h
1
R
X
3
-Haloalkyl and -halobenzyl esters are bifunctional
derivatives bearing two different leaving groups and can
thus be considered as versatile intermediates in organic
synthesis. These compounds have been used for the prepa-
ration of vinyl monomers1 and fulvenes,2 but above all for
the synthesis of prodrugs.3
Scheme 1 Synthesis of -haloalkyl and -halobenzyl esters using IL
catalyst
We thus treated aldehyde 1 with 0.1 equivalent of
BMIZnCl3 and 2 equivalents of acyl halide 2 for 24 hours at
room temperature without additional solvent. At the end of
the reaction, as the IL was not soluble in diethyl ether, addi-
tion of this solvent in the reaction medium allowed the
clean separation of the different partners. In the diethyl
ether phase, products and reagents were obtained whereas
the IL catalyst remained in the lower phase. BMIZnCl3 was
thus easy to recover. The yields reported in Table 1 were de-
termined by 1H NMR analysis, after concentration of the up-
per diethyl ether phase once separated from the catalyst.
Both acyl bromides and acyl chlorides were tested, leading
to similar yields (Table 1, compounds 3a, 3b and 3n, 3o).
Moderate to excellent yields of esters were obtained.
With aromatic aldehydes, the nature of the substituent on
the aromatic ring seems to be crucial: an electron-with-
drawing group led to higher yield than an electron-donat-
ing one (compounds 3a, 3f and 3h). The nature of the acyl
halide, aromatic or not, was also important (compare for
example 3a/3c or 3g/3h). In the case of aliphatic aldehydes,
Several methods have been reported for the preparation
of these compounds,4 but the most useful is the reaction
between an acid halide and an aldehyde or ketone, most of
the time catalyzed by a Lewis acid such as ZnCl2,5
Zn(OTf)2·6H2O,6 or AlCl3.7 Ishino et al. also reported the effi-
cient use of metallic Zn with TMSCl in dichloromethane to
promote the reaction,8 but 6 equivalents of Zn are required.
Nevertheless, this carbonyl reaction, also known as Electro-
philic Carbonyl Addition (ECA)9 has been rarely reported so
far, because of the difficulties encountered in the product
isolation. In particular, -haloalkyl halides have to be puri-
fied by distillation, which sometimes results in product
degradation.10 Moreover, careful separation of the catalyst
before rectification and work at low temperature were
needed to avoid by-products formation and to increase the
overall yields.11 To overcome these problems, we have de-
veloped a method using a ZnCl2-based ionic liquid (IL) cata-
lyst BMIZnCl3 (1-butyl-3-methylimidazolium trichlorozin-
cate), acting both as solvent and catalyst. This IL was syn-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–E

B
F. Fache et al.
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Synthesis
Table 1 Synthesis of -Haloalkyl and -Halobenzyl Esters Using
BMIZnCl3
Aldehyde 1 and acyl chloride 2 were stirred for 24 hours
at room temperature with BMIZnCl3. Then nicotinic acid
was added without isolation of intermediate 3 and after 24
hours at 60 °C, the corresponding ester 4 was isolated by
flash chromatography in good to excellent overall yields
(Table 2). It was necessary to add a solvent in the second
step (DMF) to ensure a good contact between the reagents,
the nicotinic acid being a solid. Notably, the presence of IL
and especially of Zn did not interfere with the esterification
process as proved by the similarity of the yields of com-
pounds 3 and the isolated yields of compounds 4. Surpris-
ingly, compound 3e never led to the corresponding nicotin-
ic ester, but to the starting material p-nitrobenzaldehyde.
Comparison of our one-pot two-step sequential method
with procedures published in the literature is in favor of our
approach: for example, Nudelman et al.3a reported the syn-
thesis of product 4g starting from 3k in 48% and 74% isolat-
ed yield, respectively (overall yield 36%) whereas we ob-
tained 42% overall isolated yield for the same final product
4g. Even though the difference was not so significant, our
method turned out to be less solvent and time consuming,
and moreover, the catalyst could be recycled.
O
O
O
BMIZnCl3
rt, 24 h
O
R'
+
R'
X
R
H
R
X
1
2
3a–o
R
R′
Me
X
Yield (%)a of 3
Ph
Cl
Br
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Br
Cl
3a
3b
3c
3d
3e
3f
536
497
Ph
Me
Ph
Ph
906
Ph
t-Bu
Ph
7514
>9515
>956
707
p-O2NC6H4
p-O2NC6H4
Me
Ph
p-MeOC6H4
p-MeOC6H4
i-Pr
3g
3h
3i
Me
Ph
<5
808
i-Pr
Me
n-Pr
Ph
3j
>954a
>953a
33
Me
3k
3l
C5H11
Other acids were tested successfully in the same two-
step sequences, giving good to excellent overall isolated
C5H11
Me
Me
t-Bu
3m
3n
3o
>9516
8817
90
C5H11
C5H11
Table 2 One-Pot Two-Step Synthesis of Nicotinic Esters
a Based on the conversion of aldehyde, estimated by 1H NMR analysis. Con-
ditions: aldehyde (2 mmol), acyl halide (4 mmol), IL (0.2 mmol), rt, 24 h.
O
O
O
BMIZnCl3
rt, 24 h
O
R'
+
R'
O
Cl
R
H
aliphatic acyl halides led to excellent results, better than
with aromatic acyl halides (compare 3i to 3j or 3k, 3m, 3n
and 3o to 3l). Nevertheless, it is difficult to draw a general
trend from our results. Bigler et al.13 have investigated in
details the mechanism of the reaction and proposed several
routes, depending strongly on the nature of the aldehyde
(aromatic or not). It should be noted that their reported re-
sults are not always in accordance with our experimental
results, probably because the reaction media were different
(IL in our case, organic solvent for Bigler et al.). The IL cata-
lyst could be recycled five times for the synthesis of com-
pound 3k without loss of activity and selectivity (yield:
95%, 97.3%, 97.4%, 93.7%, and 95.8%, respectively). These re-
sults highlight the robustness of our catalyst.
Results reported in Table 1 proved that our method was
suitable for the synthesis of -haloalkyl and -halobenzyl
esters. As cleaner products were obtained with chloro de-
rivatives, we thus decided to carry on our studies with acyl
chlorides. We tested the chloro derivatives without purifi-
cation and separation from the IL, in a one-pot two-step
procedure, thus developing a green methodology for the
synthesis of O,O′-diacyl acetals.
R
Cl
1
2
3
DMF, Et3N
60 °C, 24 h
OH
O
O
R'
O
N
R
O
4a–j
N
Nicotinic acid
R
R′
Yield (%)a of 4
Ph
Ph
Ph
Me
Ph
4a
4b
4c
4d
4e
4f
58
92
70
86
0
t-Bu
Ph
p-O2NC6H4
p-O2NC6H4
p-MeOC6H4
Me
Me
Ph
44
423a
15
68
58
n-Pr
Ph
4g
4h
4i
C5H11
C5H11
Me
t-Bu
C5H11
4j
a Overall isolated yield for the two steps. Conditions for the first step: alde-
hyde (2 mmol), acyl halide (4 mmol), IL (0.2 mmol), rt, 24 h. Conditions for
the second step: nicotinic acid (4 mmol), Et3N (0.6 mL), DMF (1 mL), 60 °C,
24 h.
We first studied the possibility to make the -chloroal-
kyl and -chlorobenzyl esters react with nicotinic acid,
leading to potential prodrugs3a (products 4a–j, Table 2).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–E

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F. Fache et al.
Paper
Synthesis
yields (Table 3). These mixed O,O′-diacyl acetals could be
used as O-acylating reagents for alcohols, to afford their
corresponding esters.18
1H NMR (300 MHz):  = 6.41 (t, J = 6 Hz, 1 H, CHCl), 2.06–1.98 (m, 2 H,
CH2CHCl), 1.48–1.42 (m, 2 H, CH2CH2CHCl), 1.33–1.31 (m, 4 H), 1.22
(s, 9 H, t-C4H9), 0.90 (t, J = 6.7 Hz, 3 H, CH3).
O,O′-Diacyl Acetals 4 and 6; General Procedure
Table 3 Synthesis of Mixed O,O′-Diacyl Acetals
Aldehyde 1 (2 mmol), BMIZnCl3 (62 mg, 0.2 mmol), and acid halide 2
(4 mmol) were stirred for 24 h at rt. To the -haloalkyl or -haloben-
zyl ester 3 thus obtained, without further purification, were added
DMF (1 mL), Et3N (0.6 mL), and nicotinic acid (492 mg, 4 mmol) or
acid 5 (4 mmol). The resulting mixture was left stirring at 60 °C for 24
h. After extraction with EtOAc, washing of the combined organic
phases with H2O and brine, drying (MgSO4), evaporation of the sol-
vent gave the crude product (4a–j, 6a–d), which was purified by flash
chromatography (PE/EtOAc 70:30 for compounds 4a–j, PE/Et2O 90:10
for compounds 6a–d).
O
O
DMF, Et3N
O
O
O
Ph
R"
60 °C, 24 h
Ph
Ph
H
BMIZnCl3
rt, 24 h
O
Ph
OH
Ph
O
O
Ph
Cl
O
R"
3c
5
Cl
6a–d
R′′
Ph
Yield (%)a of 6
6a18
6b
90
(RS)-Acetoxy(phenyl)methyl Nicotinate (4a)
(E)-styryl
Me
50
72
22
Following the general procedure using benzaldehyde and acetyl chlo-
ride; yellow oil; yield: 314 mg (1.16 mmol, 58%); Rf = 0.35.
1H NMR (300 MHz):  = 9.27 (dd, J = 2.0, 0.9 Hz, 1 H, Py-H2), 8.80 (dd,
J = 4.8, 2.0 Hz, 1 H, Py-H6), 8.34 (dt, J = 8, 2.0 Hz, 1 H, Py-H4), 7.96 (s, 1
H, OCHO), 7.64–7.61 (m, 2 H, ArH), 7.47–7.42 (m, 4 H, 3 ArH + Py-H5),
2.18 (s, 3 H, CH3CO).
6c
C5H11
6d
a Overall isolated yield for the two steps; conditions for the first step: alde-
hyde (2 mmol), acyl halide (4 mmol), IL (0.2 mmol), rt, 24 h; conditions for
the second step: acid 5 (4 mmol), Et3N (0.6 mL), DMF (1 mL), 60 °C, 24 h.
13C{1H} NMR (75 MHz):  = 168.9 (CH3CO), 163.3 (PyCO), 153.9 (Py-
C2), 151.1 (Py-C6), 137.6 (Py-C4), 135.2 (Cq, Ar), 130.2 (1 C, Ar), 128.8
(2 C, Ar), 126.8 (2 C, Ar), 125.4 (Py-C3), 123.6 (Py-C5), 90.5 (OCHO),
20.9 (CH3CO).
HRMS (ESI): m/z [M + H]+ calcd for C15H14NO4: 272.0917; found:
272.0919.
In conclusion, we have shown that the use of Zn-based
ionic liquid catalyst BMIZnCl3 for the synthesis of -haloal-
kyl and -halobenzyl esters was a particularly relevant
method. These esters could react without intermediate pu-
rification in a one-pot two-step procedure leading to mixed
O,O′-diacyl acetals in moderate to very good overall isolated
yields. Moreover, BMIZnCl3 turned out to be recyclable.
Thanks to this green approach, further studies are in prog-
ress in our laboratory to develop the use of -haloalkyl and
-halobenzyl esters as versatile intermediates in organic
synthesis.
(RS)-(Benzoyloxy)(phenyl)methyl Nicotinate (4b)
Following the general procedure using benzaldehyde and benzoyl
chloride; yellow oil; yield: 615 mg (1.84 mmol, 92%); Rf = 0.33.
1H NMR (300 MHz):  = 9.30 (dd, J = 2.0, 0.9 Hz, 1 H, Py-H2), 8.81 (dd,
J = 4.8, 2.0 Hz, 1 H, Py-H6), 8.36 (dt, J = 8.0, 2.0 Hz, 1 H, Py-H4), 8.23 (s,
1 H, OCHO), 8.13–8.10 (m, 2 H, ArH), 7.74–7.71 (m, 2 H, ArH), 7.63–
7.57 (m, 2 H, ArH), 7.50–7.41 (m, 5 H, 4 × ArH + Py-H5).
13C{1H} NMR (75 MHz):  = 164.5 (CH3CO), 163.3 (Py-CO), 153.9 (Py-
C2), 151.1 (Py-C6), 137.9 (Py-C4), 135.5 (Cq, Ar), 133.9 (1 C, Ar), 130.2
(2 C, Ar), 129.0 (Cq, Ar), 128.9 (2 C, Ar), 128.7 (2 C, Ar), 128.5 (1 C, Ar),
126.9 (2 C, Ar), 125.4 (Py-C3), 123.6 (Py-C5), 91.0 (OCHO).
HRMS (ESI): m/z [M + H]+ calcd for C20H16NO4: 334.1034; found:
334.1028.
All commercially available compounds were used without further pu-
rification. Petroleum ether (PE) refers to a hydrocarbon mixture with
a boiling range of 40–60 °C. Column chromatography was performed
with silica gel (0.040–0.063 mm, Macherey-Nagel). NMR spectra were
recorded on a 300 or 400 MHz NMR spectrometer (Bruker, DRX 300
or AMX 400). Spectra were referenced to solvent lines (CDCl3:  = 7.26
(1H), 77.16 (13C{1H}). High-resolution mass spectra were recorded on
a MicrOTOF-Q II Bruker spectrometer.
(RS)-Phenyl(pivaloyloxy)methyl Nicotinate (4c)
Following the general procedure using benzaldehyde and pivaloyl
chloride; yellow oil; yield: 438 mg (1.4 mmol, 70%); Rf = 0.35.
-Haloalkyl and -Halobenzyl Esters 3a–o: General Procedure
1H NMR (300 MHz):  = 9.24 (dd, J = 2.0, 0.9 Hz, 1 H, Py-H2), 8.80 (dd,
J = 4.8, 2.0 Hz, 1 H, Py-H6), 8.32 (dt, J = 8.0, 2.0 Hz, 1 H, Py-H4), 7.93 (s,
1 H, OCHO), 7.58–7.62 (m, 2 H, ArH), 7.47–7.38 (m, 4 H, 3 × ArH + Py-
H5), 1.26 (s, 9 H, t-C4H9).
13C{1H} NMR (75 MHz):  = 171.1 (CH3CO), 163.3 (Py-CO), 153.9 (Py-
C2), 151.1 (Py-C6), 137.4 (Py-C4), 135.4 (Cq, Ar), 129.9 (1 C, Ar), 128.7
(2 C, Ar), 126.6 (2 C, Ar), 125.3 (Py-C3), 123.4 (Py-C5), 90.5 (OCHO),
38.9 (Cq, t-C4H9), 26.9 (3 × CH3, t-C4H9).
Aldehyde 1 (2 mmol), BMIZnCl3 (62 mg, 0.2 mmol), and acid halide 2
(4 mmol) were stirred for 24 h at rt. After the addition of Et2O (5 mL),
stirring, and decantation (3 ×), the desired ester was recovered in the
upper phase while the ionic liquid remained in the lower phase and
could be used in another run. After evaporation of Et2O, the crude -
haloalkyl and -halobenzyl esters 3a–o were obtained in the propor-
tions reported in Table 1. NMR data are in agreement with reported
spectra (see references in Table 1).
HRMS (ESI): m/z [M + H]+ calcd for C18H20NO4: 314.1386; found:
314.1383.
(RS)-1-Chlorohexyl Pivalate (3o)
Following the general procedure using hexanal and pivaloyl chloride;
1H NMR estimated yield: 90%.
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Synthesis
(RS)-(Benzoyloxy)(4-nitrophenyl)methyl Nicotinate (4d)
(RS)-1-(Pivaloyloxy)hexyl Nicotinate (4j)
Following the general procedure using 4-nitrobenzaldehyde and ben-
Following the general procedure using hexanal and pivaloyl chloride;
zoyl chloride; yellow oil; 650 mg (1.72 mmol, 86%); Rf = 0.33.
yellow oil; yield: 357 mg (1.16 mmol, 58%); Rf = 0.55.
1H NMR (300 MHz):  = 9.28 (m, 1 H, Py-H2), 8.83 (dt, J = 4.8, 1.3 Hz, 1
H, Py-H6), 8.38–8.31 (m, 3 H, 2 ArH + Py-H4), 8.28 (s, 1 H, OCHO),
8.90 (d, J = 8.4 Hz, 2 H, ArH), 7.90 (d, J = 8.7 Hz, 2 H, ArH), 7.62 (td, J =
6.7, 1.4 Hz, 2 H, ArH), 7.50–7.41 (m, 2 H, ArH + Py-H5).
13C{1H} NMR (75 MHz):  = 164.3 (CH3CO), 163.2 (Py-CO), 154.2 (Py-
C2), 151.1 (Py-C6), 149.0 (CNO2), 141.8 (Cq, ArNO2), 137.9 (Py-C4),
134.3 (Cq, Ar), 130.2 (2 C, Ar), 128.8 (2 C, Ar), 128.4 (1 C, Ar), 128.1 (2
C, Ar), 126.8 (2 C, Ar), 124.9 (Py-C3), 123.7 (Py-C5), 89.6 (OCHO).
1H NMR (300 MHz):  = 9.13 (d, J = 2.0 Hz, 1 H, Py-H2), 8.71 (dt, J = 4.8,
2.0 Hz, 1 H, Py-H6), 8.22 (dt, J = 8.0, 2.0 Hz, 1 H, Py-H4), 7.35 (dd, J =
8.0, 4.8 Hz, 1 H, Py-H5), 6.96 (t, J = 5.6 Hz, 1 H, OCHO), 1.88–1.82 (m, 2
H, CH2CO), 1.45–1.26 (m, 6 H, 3 × CH2), 1.14 (s, 9 H, t-C4H9), 0.81 (t, J =
7.4 Hz, 3 H, CH3).
13C{1H} NMR (75 MHz):  = 176.6 (t-BuCO), 163.5 (Py-CO), 153.8 (Py-
C2), 151.1 (Py-C6), 137.5 (Py-C4), 125.7 (Py-C3), 123.5 (Py-C5), 91.5
(OCHO), 38.9 (Cq, t-C4H9), 33.3, 31.4, 23.2, 22.5 (4 × CH2 alkyl), 27.0 (3
× CH3, t-C4H9), 14.0 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C20H14N2O6Na: 401.0744; found:
401.0741.
HRMS (ESI): m/z [M + Na]+ calcd for C23H18O4Na: 381.1097; found:
381.1092.
(RS)-(Benzoyloxy)(4-methoxyphenyl)methyl Nicotinate (4f)
(RS)-(Cinnamoyloxy)(phenyl)methyl Benzoate (6b)
Following the general procedure using 4-methoxybenzaldehyde and
benzoyl chloride; yellow oil; 318 mg (0.88 mmol, 44%); Rf = 0.34.
Following the general procedure using cinnamic acid; white oil; yield:
358 mg (1.0 mmol, 50%); Rf = 0.35.
1H NMR (400 MHz):  = 9.30 (dd, J = 2.0, 0.9 Hz, 1 H, Py-H2), 8.79 (dd,
J = 4.8, 2.0 Hz, 1 H, Py-H6), 8.35 (dt, J = 8.0, 2.0 Hz, 1 H, Py-H4), 8.20 (s,
1 H, OCHO), 8.11–8.08 (m, 2 H, ArH), 7.68–7.65 (d, J = 8.7 Hz, 2 H,
ArH), 7.56–7.48 (m, 2 H, ArH), 7.42–7.36 (m, 2 H, ArH + Py-H5), 6.97
(d, J = 8.7 Hz, 2 H, ArH), 3.78 (s, 3 H, OCH3).
13C{1H} NMR (100 MHz):  = 164.3 (CH3CO), 163.0 (Py-CO), 160.8
(COMe),153.3 (Py-C2), 150.5 (Py-C6), 137.8 (Py-C4), 133.6 (1 C, Ar),
129.9 (2 C, Ar), 128.8 (1 C, Ar), 128.4 (2 C, Ar), 128.2 (2 C, Ar), 127.3
(Cq, Ar), 125.4 (Py-C3), 123.6 (Py-C5), 114.1 (2 C, Ar), 90.9 (OCHO),
55.2 (OCH3).
1H NMR (300 MHz):  = 8.17–8.13 (m, 2 H, ArH), 8.16 (s, 1 H, O,O′–
CH), 7.83 (d, J = 16 Hz, 1 H, PhCH=CH), 7.74–7.40 (m, 13 H, ArH), 6.53
(d, J = 16 Hz, 1 H, Ph-CH=CH).
13C{1H} NMR (75 MHz):  =164.8 (CO–C=C), 164.6 (CO), 146.8 (CO–
C=C), 135.9, 134.2, 129.3 (3 Cq, Ar), 133.7, 130.8 (2 C, Ar), 130.2 (2 C,
Ar), 129.9 (1 C, Ar), 129.1 (2 C, Ar), 128.8 (2 C, Ar), 128.6 (2 C, Ar),
128.4 (2 C, Ar), 126.9 (2 C, Ar), 117.0 (CO–C=C), 90.4 (OCHO).
HRMS (ESI): m/z [M + Na]+ calcd for C17H25NO4Na: 330.1676; found:
330.1668.
HRMS (ESI): m/z [M + Na]+ calcd for C21H17NO5Na: 386.0999; found:
386.0991.
(RS)-Acetoxy(phenyl)methyl Benzoate (6c)
Following the general procedure using AcOH; white oil; yield: 388 mg
(1.44 mmol, 72%); Rf = 0.4.
(RS)-1-(Benzoyloxy)hexyl Nicotinate (4h)
Following the general procedure using hexanal and benzoyl chloride;
yellow oil; yield: 98 mg (0.3 mmol, 15%); Rf = 0.51.
1H NMR (300 MHz):  = 9.24 (s, 1 H, Py-H2), 8.77 (m, 1 H, Py-H6), 8.31
(dq, J = 8.0, 2.0 Hz, Py-H4), 8.05 (d, J = 8.4 Hz, 2 H, ArH), 7.56–7.30 (m,
5 H, 3 × ArH + Py-H5 + OCHO), 2.09–2.01 (m, 2 H, CH2CH), 1.57–1.24
(m, 6 H, CH2), 0.89 (t, J = 7.4 Hz, 3 H, CH3).
1H NMR (300 MHz):  = 8.11 (d, J = 8.5 Hz, 2 H, ArH), 8.00 (s, 1 H, O,O′–
CH), 7.67–7.56 (m, 3 H, ArH), 7.49–7.43 (m, 5 H, ArH), 2.17 (s, 3 H,
CH3).
13C{1H} NMR (75 MHz):  = 168.8, 164.5 (2 × CO),135.7, 129.2 (2 Cq,
Ar), 133.7 (C, Ar), 130.0 (2 C, Ar), 129.9 (C, Ar), 128.7 (2 C, Ar), 128.5 (2
C, Ar), 126.8 (2 C, Ar), 90.2 (OCHO), 20.9 (CH3).
13C{1H} NMR (75 MHz):  = 164.7 (CH3CO), 163.4 (Py-CO), 153.7 (Py-
C2), 151.0 (Py-C6), 137.6 (Py-C4), 133.6 (1 C, Ar), 130.6 (Cq, Ar), 129.9
(2 C, Ar), 128.5 (2 C, Ar), 125.5 (Py-C3), 123.5 (Py-C5), 91.8 (OCHO),
33.4, 31.4, 23.2, 22.5 (4 × CH2 alkyl), 14.0 (CH3).
HRMS (ESI): m/z [M + H]+ calcd for C19H22NO4: 328.1543; found:
328.1539.
HRMS (ESI): m/z [M + Na]+ calcd for C16H14O4Na: 293.0784; found:
293.0790.
(RS)-(Hexanoyloxy)(phenyl)methyl Benzoate (6d)
Following the general procedure using hexanoic acid; white oil; yield:
144 mg (0.44 mmol, 22%); Rf = 0.57.
1H NMR (300 MHz):  = 8.11 (d, J = 8.5 Hz, 2 H, ArH), 8.01 (s, 1 H, O,O′–
CH), 7.67–7.56 (m, 3 H, ArH), 7.48–7.42 (m, 5 H, ArH), 2.45–2.39 (m, 2
H, CH2CO), 1.71–1.66 (m, 2 H, CH2), 1.35–1.30 (m, 4 H, CH2), 0.92–0.86
(m, 3 H, CH3).
13C{1H} NMR (75 MHz):  = 171.7 (CO–CH2), 164.5 (CO–Ar), 135.8 (Cq,
Ar), 133.6 (C, Ar), 129.7 (2 C, Ar), 129.2 (Cq, Ar),128.7 (2 C, Ar), 128.5
(2 C, Ar), 126.7 (2 C, Ar), 90.1 (OCHO), 34.1, 31.1, 24.4, 22.3 (4 × CH2),
13.9 (CH3).
(RS)-1-(Acetoxy)hexyl Nicotinate (4i)
Following the general procedure using hexanal and acetyl chloride;
yellow oil; yield: 360 mg (1.36 mmol, 68%); Rf = 0.55.
1H NMR (300 MHz):  = 9.20 (d, J = 2.0 Hz, 1 H, Py-H2), 8.77 (dd, J =
4.8, 2.0 Hz, 1 H, Py-H6), 8.29 (dt, J = 8.0, 2.0 Hz, 1 H, Py-H4), 7.40 (dd,
J = 8.0, 4.8 Hz, 1 H, Py-H5), 7.03 (t, J = 5.6 Hz, 1 H, OCHO), 2.09 (s, 3 H,
CH3CO), 1.93–1.86 (m, 2 H, CH2CO), 1.47–1.23 (m, 6 H, CH2), 0.87 (t,
J = 7.4 Hz, 3 H, CH3).
13C{1H} NMR (75 MHz):  = 169.1 (CH3CO), 163.5 (Py-CO), 153.8 (Py-
C2), 151.1 (Py-C6), 137.5 (Py-C4), 125.5 (Py-C3), 123.5 (Py-C5), 91.3
(OCHO), 33.3, 31.4, 23.2, 22.5 (4 × CH2 alkyl), 20.9 (CH3CO), 14.0 (CH3).
HRMS (ESI): m/z [M + Na]+ calcd for C20H22O4Na: 349.1410; found:
349.1410.
HRMS (ESI): m/z [M + Na]+ calcd for C14H19NO4Na: 288.1206; found:
288.1197.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–E

E
F. Fache et al.
Paper
Synthesis
Funding Information
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1966, 20, 1273; and references cited therein. (b) Benneche, T.;
Strande, P.; Wiggen, U. Acta Chem. Scand. 1989, 43, 74. (c) For a
review, see: Luk’yanov, S. M.; Koblik, A. V. Russ. Chem. Rev.
1996, 65, 1.
Financial support from Université Lyon 1 and CNRS are warmly ac-
knowledged.()
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593. (b) Bigler, P.; Neuenschwander, M. Helv. Chim. Acta 1978,
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Mühle, H. Helv. Chim. Acta 1978, 61, 2047.
Acknowledgment
The authors thank the CCRMN, Centre Commun de RMN-Lyon 1 and
the CCSM, Centre Commun de Spectrométrie de Masse-Lyon 1 for
spectroscopic analyses.
(8) Ishino, Y.; Mihara, M.; Takeuchi, T.; Takemoto, M. Tetrahedron
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Meeting of the American Chemical Society, Chicago, IL, March 25–
29, 2007; American Chemical Society: Washington DC, 2007,
ORGN CAPLUS 2007: 291142.
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1612415.
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2019, 51, A–E