Microwave-assisted synthesis of hydroxymethyl ketones using azolium-2-carboxylate zwitterions as catalyst precursors

Article abstract of DOI:10.1016/j.tet.2017.11.024

Following an initial screening of six common imidazolium, imidazolinium, and dithiolium salts in the presence of a base, 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IDip) and 1,3-dimesitylimidazolin-2-ylidene (SIMes) were identified as promising organocatalysts for the microwave-assisted synthesis of hydroxymethyl ketones from aldehydes and paraformaldehyde. The azolium-2-carboxylate zwitterions IDip·CO₂ and SIMes·CO₂ were then tested as single-component N-heterocyclic carbene (NHC) precursors in the hydroxymethylation of heptanal and benzaldehyde. The latter adduct was an efficient precatalyst for the two reactions. It was successfully applied to a broad range of aliphatic and aromatic substrates (14 examples, 10–97% yields).

Full text of DOI:10.1016/j.tet.2017.11.024

Accepted Manuscript
Microwave-assisted synthesis of hydroxymethyl ketones using azolium-2-carboxylate
zwitterions as catalyst precursors
Evanthia Papadaki, Lionel Delaude, Victoria Magrioti
PII:
S0040-4020(17)31172-9
10.1016/j.tet.2017.11.024
TET 29104
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 29 July 2017
Revised Date: 29 October 2017
Accepted Date: 9 November 2017
Please cite this article as: Papadaki E, Delaude L, Magrioti V, Microwave-assisted synthesis of
hydroxymethyl ketones using azolium-2-carboxylate zwitterions as catalyst precursors, Tetrahedron
(2017), doi: 10.1016/j.tet.2017.11.024.
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Microwave-assisted synthesis of hydroxy-
methyl ketones using azolium-2-carboxylate
zwitterions as catalyst precursors
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Evanthia Papadakia, Lionel Delaudeb and Victoria Magriotia,*
aLaboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece
b Laboratory of Organometallic Chemistry and Homogeneous Catalysis, Institut de Chimie Organique (B6a), Université de Liège, Allée du six Août 13,
Quartier Agora, 4000 Liège, Belgium

1
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Tetrahedron
journal homepage: www.elsevier.com
Microwave-assisted synthesis of hydroxymethyl ketones using azolium-2-carboxylate
zwitterions as catalyst precursors
Evanthia Papadakia, Lionel Delaudeb, Victoria Magriotia,*
a Laboratory of Organic Chemistry, Department of Chemistry, National and Kapodistrian University of Athens, Panepistimiopolis, Athens 15771, Greece
b Laboratory of Organometallic Chemistry and Homogeneous Catalysis, Institut de Chimie Organique (B6a), Université de Liège, Allée du six Août 13, Quartier
Agora, 4000 Liège, Belgium
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Following an initial screening of six common imidazolium, imidazolinium, and dithiolium salts
in the presence of a base, 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IDip) and 1,3-di-
mesitylimidazolin-2-ylidene (SIMes) were identified as promising organocatalysts for the
microwave-assisted synthesis of hydroxymethyl ketones from aldehydes and paraformaldehyde.
The azolium-2-carboxylate zwitterions IDip·CO2 and SIMes·CO2 were then tested as single-
component N-heterocyclic carbene (NHC) precursors in the hydroxymethylation of heptanal and
benzaldehyde. The latter adduct was an efficient precatalyst for the two reactions. It was
successfully applied to a broad range of aliphatic and aromatic substrates (14 examples, 10–97%
yields).
Available online
This paper is dedicated to the memory of Ronald
Brelow (1931–2017) by one of the authors (L.D.)
Keywords:
Green chemistry
2009 Elsevier Ltd. All rights reserved.
N-Heterocyclic carbenes
Hydroxymethyl ketones
Microwave irradiation
Organocatalysis
1. Introduction
stand-alone organocatalysts for various reactions has also under-
gone significant developments.25 The majority of these processes
are initiated by a nucleophilic attack of the carbene onto carbonyl
groups. According to the mechanism originally postulated by
Breslow for the condensation of aldehydes,26,27 the result is a
polarity reversal (“umpolung”) of these substrates and their
conversion into self-condensation products with the formation of
a new C–C bond.28,29
The α-hydroxymethyl ketone motif (also called acyloin) is
present in various important biologically active compounds, such
as antidepressant drugs, HIV-protease inhibitors,1 selective
inhibitors of amyloid-β protein production, agents for the
treatment of Alzheimer’s disease,2 antitumor,3,4 antibiotic,5,6 and
antifungal7 agents. Moreover, the CO–CH2OH unit is easily
converted into many other functional groups, which contribute to
further expand its synthetic potential. Hence, chemical or
enzymatic pathways leading to hydroxymethyl ketones have
found many applications in organic synthesis and pharmaceutical
chemistry.2 Currently, the most common strategies to access
these compounds involve oxidation,8–14 reduction,15,16 or hydro-
lysis17,18 of more complex substrates. Obviously, a simple and
efficient catalytic method that would allow the direct hydroxy-
methylation of aldehydes via C–C bond formation would provide
a highly valuable alternative to these stoichiometric functional
group interconversions in terms of atom economy and sustain-
ability.19
The NHC-catalyzed hydroxymethylation of several classes of
aldehydes with paraformaldehyde was first reported by Kuhl and
Glorius in 2011.30 A plausible catalytic cycle for this trans-
formation involves the nucleophilic attack of the carbene onto the
substrate (Scheme 1, step 1), followed by a proton transfer to
afford a Breslow intermediate (step 2), and its addition onto
formaldehyde (step 3). Another proton transfer and the release of
the final product regenerate the catalyst (steps 4 and 5).
Experimental protocols devised so far usually require heating for
extended periods of time (at least 24 h).30,31
In a recent report, we showed that microwave irradiation
promoted the fast and efficient conversion of aldehydes and
paraformaldehyde into α-hydroxymethyl ketones using NHC
organocatalysts derived from thiazolium salts under environ-
mentally friendly conditions.32 These results prompted us to
further investigate the influence of other types of NHC precursors
on the catalytic system. Herein, we disclose the results of these
endeavors.
Over the past 25 years, N-heterocyclic carbenes (NHCs) have
emerged as powerful tools for organometallic chemistry and
organic synthesis.20 At first, they served as ancillary ligands for a
wide range of transition metal complexes that found numerous
applications in homogeneous catalysis,21,22 with the best example
probably being Grubbs’ and Hoveyda-Grubbs’ second-generation
olefin metathesis catalysts.23,24 In the past decade, their use as

2
Table 1. Microwave-assisted hydroxymethylation of heptanal
and benzaldehyde using catalyst precursors 1–7
ACCEPTED MANUSCRIPT
Conversiona/yieldb of
1-hydroxy-2-octanone
(%)
Conversiona/yieldb of
2-hydroxyacetophenone
(%)
NHC precursor
1
2
3
4
5
6
7
17a
7b
65a (52)b
7b
0a
0a
7b
10b
Scheme 1. Plausible mechanism for the hydroxymethylation of aldehydes
15b
0a
29a (14)b,c
using NHCs as catalysts.
0a
2. Results and discussion
58b
45b
To begin our study, several common imidazolium (1–3),
imidazolinium (4, 5), or dithiolium salts (6) were screened in the
catalytic hydroxymethylation of aliphatic and aromatic aldehydes
with paraformaldehyde. The most efficient catalyst precursor
identified thus far, namely, thiazolium perchlorate 7 served as a
benchmark for these experiments (Chart 1). All these acidic salts
were deprotonated with a base to release the corresponding free
carbenes in situ. The reactions were carried out by using the
microwave-assisted procedure previously optimized in our
laboratory.32 Thus, one equivalent of an aldehyde was reacted
with three equivalents of paraformaldehyde in the presence of an
NHC precursor (10 mol%) and diisopropylethylamine (20 mol%)
in dry tetrahydrofuran for 1 h at 100 °C (Table 1).
a Conversion determined by NMR based on the relative integration of the two
protons next to the hydroxyl group of the product and the aldehyde proton of
the reactant.
b Isolated yield after flash column chromatography.
c Reaction performed in a round bottom flask with a reflux condenser under
argon using a thermostated oil bath at 70 °C for 24 h.
Next, we decided to probe the catalytic activity of azolium-2-
carboxylate zwitterions 8 and 9 (Chart 1). These betaines are the
inner salt analogues of IDip·HCl (1) and SIMes·HCl (5). They
behave as convenient surrogates for air- and moisture-sensitive
carbenes.33 Indeed, several research groups have already taken
advantage of these labile adducts for the stoichiometric
preparation of transition metal complexes bearing NHC ligands
with concomitant release of carbon dioxide.34–37 In organo-
catalysis, their use as NHC precursors is still underdeveloped
with only a few applications in organic synthesis38–40 and
polymer chemistry.41,42 It should be pointed out, however, that a
thiazolium-2-carboxylate zwitterion was found to induce the self-
condensation of aliphatic and aromatic aldehydes already in
1985.43
To our great satisfaction, IDip·CO2 (8) and SIMes·CO2 (9)
were efficient catalyst precursors for the hydroxymethylation of
the two model aliphatic and aromatic aldehydes (Table 2). The
latter betaine performed particularly well in the synthesis of
1-hydroxy-2-octanone from heptanal and paraformaldehyde. In
most cases, recourse to the azolium-2-carboxylate inner salts led
to higher yields than the combination of IDip·HCl (1) or
SIMes·HCl (5) and diisopropylethylamine. The zwitterions also
compared favorably with thiazolium salt 7 whose synthesis is
less straightforward.
Chart 1. NHC precursors used in this study.
Table 2. Microwave-assisted hydroxymethylation of heptanal and
benzaldehyde using catalyst precursors 8 and 9
Heptanal and benzaldehyde were chosen as representative
aliphatic and aromatic aldehydes and the experimental results are
listed in Table 1. Within the series of dinitrogen and disulfur
heterocycles under investigation (1–6), 1,3-bis(2,6-diisopropyl-
phenyl)imidazolium chloride (1) afforded the highest yields of
both target compounds. This bulky imidazolium salt that we shall
designate IDip·HCl also outperformed the mixed nitrogen/sulfur-
based thiazolium precatalyst 7 in the hydroxymethylation of
benzaldehyde, but not in the case of heptanal. With the aromatic
substrate, conversion reached 65% after 1 h and 2-hydroxyaceto-
phenone was isolated in 52% yield after purification by flash
column chromatography. It is noteworthy that the second best
catalyst precursor of our set was the ubiquitous mesityl-
substituted imidazolinium salt nicknamed SIMes·HCl (5).
Yield of 1-hydroxy-2-
octanone (%)a
Yield of 2-hydroxy-
acetophenone (%)a
NHC precursor
8
9
21
29
76 (9)b
44 (0)b
a Isolated yield after flash column chromatography.
b Reaction performed in a round bottom flask with a reflux condenser under
argon using a thermostated oil bath at 70 °C for 24 h.
Control experiments carried out under reflux conditions in an
oil bath at 70 °C revealed that the NHC·CO2 precatalysts were

3
almost inactive at this temperature (Table 2), whereas the
NHC·HCl salts mixed with iPr2NEt led to significant conversions
under similar conditions (cf. Table 1). This discrepancy might be
correlated with thermogravimetric analysis data, which showed
that IDip·CO2 (8) did not lose weight below ca. 120 °C in the
solid state, while SIMes·CO2 (9) resisted degradation up to ca.
160 °C.34 Thus, performing the reaction in a pressure vial at 100
°C under microwave irradiation was not only very convenient
from a practical point of view, it was also a requisite to induce a
thermal decarboxylation of the zwitterionic adducts.
quantitative yield of 1-hydroxy-2-undecanone (13) was
ACCEPTED MANUSCRIPT
obtained starting from decanal (entry 4), whereas butanal and
pentanal afforded the C5 and C6 linear hydroxymethyl ketones 10
and 11 in 15 and 37% yield, respectively (entries 1 and 2). The
progressive drop in yield observed when the alkyl chain was
shortened is probably due to the greater volatility of the reactants
and products, thereby leading to significant loss of materials
during experimental set-up and work-up. Additional syntheses
performed with various branched aldehydes afforded products
14–18 in moderate to satisfactory yields (entries 5–9). With these
bulkier substrates, it can be assumed that the activation of the
carbonyl group by nucleophilic attack of the NHC catalyst is
sterically hindered. It should be emphasized that only a few
successful hydroxymethylation reactions of aliphatic aldehydes
were reported in the literature so far.30,32 Moreover, to the best of
our knowledge, compound 18 had never been synthesized before.
Hence, despite the modest yields obtained in some cases, the
present study represents a significant advance in the field.
Having identified 1,3-dimesitylimidazolinium-2-carboxylate
(9) as a valuable, single-component catalyst precursor for the
hydroxymethylation of heptanal and benzaldehyde, we decided to
probe the scope of the reaction by testing additional aliphatic and
aromatic substrates. These reactants and the hydroxymethyl
ketones obtained are depicted in Table 3, along with the yields
recorded after purification of the products by flash column
chromatography.
In a final series of experiments, we investigated the reactivity
of various para-substituted benzaldehydes with paraformalde-
hyde in the presence of SIMes·CO2 (9) in a microwave reactor at
100 °C. As already evidenced using thiazolium salt 7 as a catalyst
precursor,30,32 electron-withdrawing groups led to higher yields of
2-hydroxyacetophenones than electron-donating ones. Indeed,
almost quantitative yields of products 21 and 22 bearing para-
chloro and para-methoxycarbonyl substituents, respectively,
were attained within 1 h (Table 3, entries 12 and 13), whereas
unsubstituted benzaldehyde led to a 44% yield under the same
conditions (entry 10). The activating effect of a fluorine atom in
para-position was less pronounced and derivative 23 was isolated
in 53% yield (entry 14). Conversely, the introduction of a para-
methoxy group significantly decreased the yield of product 20
that stagnated below 10% (entry 11). Last but not least, we were
pleased to note that SIMes·CO2 (9) afforded higher yields of
aromatic hydroxymethyl ketones 21 and 22 than thiazolium salt 7
and diisopropylethylamine whether these catalyst precursors
were heated at 60 °C for 24 h in a Schlenk flask or at 100 °C for
1 h in a microwave reactor.30,32
Table 3. Microwave-assisted hydroxymethylation of various
aliphatic and aromatic aldehydes catalyzed by SIMes·CO2 (9)
Yield
Entry
Reactant
Product
(%)a
15
1
2
3
37
77
4
5
6
97
52
25
7
8
49
20
26
44
3. Conclusion
The catalytic activity of six common NHCs generated in situ
by deprotonation of imidazolium, imidazolinium, and dithiolium
salts (1–6) with a base was probed in the hydroxymethylation of
two representative aliphatic and aromatic aldehydes using a
microwave-assisted procedure previously optimized for thiazo-
lium salt 7 in our laboratory. This screening allowed us to
identify 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IDip)
and 1,3-dimesitylimidazolin-2-ylidene (SIMes) as promising
nucleophilic catalysts for the synthesis of hydroxymethyl ketones
via C–C bond formation.
9
10
11
12
<10
94
We then investigated the use of azolium-2-carboxylates 8 and
9 as a convenient alternative to the association of azolium
chlorides and a base. Indeed, IDip·CO2 and SIMes·CO2 are stable
zwitterionic adducts that can be easily prepared on a multigram
scale and kept for extended periods of time before being handled
in the air to ultimately release free carbenes without the need for
a base or any other additive. To our great satisfaction,
SIMes·CO2 (9) proved to be an efficient catalyst precursor for the
two test-reactions under consideration. It was also successfully
applied to the hydroxymethylation of a broad range of aliphatic
and aromatic substrates. Hence, recourse to an NHC·CO2 betaine
under microwave irradiation is a catalytic method of choice for
accessing the important class of α-hydroxymethyl ketones, espe-
13
14
96
53
a Isolated yield after flash column chromatography.
First, we repeated the synthesis of 1-hydroxy-2-octanone (12),
which was isolated in 77% yield after 1 h of reaction under
microwave irradiation at 100 °C (Table 3, entry 3). An almost

4
4.2.4. 1-Hydroxy-2-undecanone (13)5 0
cially those derived from aliphatic aldehydes, which are notori-
ACCEPTED MANUSCRIPT
ously difficult to obtain.
4. Experimental section
4.1. Materials and methods
Yellowish solid (97% yield); m.p. 44–46 °C (lit. m.p. 47
°C);50 flash column chromatography eluent: PE/AcOEt 8/2 to 7/3
v/v; δH (200 MHz, CDCl3) 4.18 (2H, s, CH2OH), 3.50 (1H, s,
OH), 2.34 (2H, t, J 8.0 Hz, CH2) 1.59–1.49 (2H, m, CH2), 1.27–
1.10 (12H, m, CH2), 0.85 (3H, t, J 8.0 Hz, CH3); δC (50 MHz,
CDCl3) 210.3, 68.3, 38.6, 32.0, 29.6, 29.5, 29.4, 29.3, 23.9, 22.8,
14.3; m/z (ESI) 190.2 ([M+H]+, 100%).
Melting points were determined on a Büchi 530 apparatus and
are uncorrected. NMR spectra were recorded in CDCl3 at 298 K
on a Varian Mercury spectrometer using the CHCl3 residual peak
as an internal reference for 1H (7.27 ppm) and the central peak of
CDCl3 at 77.0 ppm for 13C. A CEM Discover apparatus was used
for microwave irradiation. TLC plates (silica gel 60 F254) and
silica gel 60 (230–400 mesh) for flash column chromatography
were purchased from Merck. Spots were detected with UV light
and/or phosphomolybdic acid and/or ninhydrin in EtOH stain.
THF was dried by standard procedures and stored over molecular
sieves. Aldehydes were purified by extraction with 10% aqueous
NaHCO3 or distillation and employed within a day. 1,3-Benzo-
dithiolium tetrafluoroborate (6) was purchased from TCI.
Imidazol(in)ium salts 1–5,44 thiazolium salt 7,45 and imidazol(in)-
ium-2-carboxylates 8 and 934 were prepared according to
literature. All the other solvents and chemicals were reagent
grade and used without any further purification. Petroleum ether
(PE) refers to the fraction of b.p. 40–60 °C. All the products gave
satisfactory elemental analysis. The microwave-assisted synthesis
of hydroxymethyl ketones using NHC·HX precursors 1–7 was
carried out according to literature.32 The two protected aldehydes
4.2.5. 1-Cyclohexyl-2-hydroxyethan-1-one (14)3 0
Yellow oil (52% yield); flash column chromatography eluent:
PE/AcOEt 8/2 to 7/3 v/v; δH (200 MHz, CDCl3) 4.26 (2H, s,
CH2OH), 3.35 (1H, s, OH), 2.50–2.20 (1H, m, CH), 2.00–1.50
(4H, m, CH2), 1.50–1.10 (6H, m, CH2); δC (200 MHz, CDCl3)
212.0, 66.4, 46.3, 28.8, 25.8, 25.4; m/z (ESI) 143.3 ([M+H]+,
52%).
4.2.6. 1-Hydroxy-3-phenylbutan-2-one (15)3 0
Yellowish oil (25% yield); flash column chromatography
eluent: PE/AcOEt 9/1 to 7/3 v/v; δH (200 MHz, CDCl3) 7.50–
7.00 (5H, m, arom), 4.20 (2H, s, CH2OH), 3.77 (1H, q, J 4.0 Hz,
CH), 2.88 (1H, s, OH), 1.48 (3H, d, J 4.0 Hz, CH3); δC (50 MHz,
CDCl3) 210.0, 139.3, 129.1, 127.7, 127.6, 66.8, 49.1, 17.1; m/z
(ESI) 135.0 ([M+H]+, 48%).
4.2.7. 1-Hydroxy-4-phenylbutan-2-one (16)5 1
Yellow oil (49% yield); flash column chromatography eluent:
PE/AcOEt 8/2 to 7/3 v/v; δH (200 MHz, CDCl3) 7.30–7.13 (5H,
m, arom), 4.16 (2H, s, CH2OH), 2.98 (2H, t, J 8.0 Hz, CH2), 2.70
(2H, t, J 8.0 Hz, CH2); δC (200 MHz, CDCl3) 209.6, 141.8, 126.3,
125.8, 125.6, 68.7, 38.0, 35.5.
that derived from
L-aspartic acid were prepared according to the
literature.46,47
4.2. Typical procedure for the synthesis of hydroxymethyl-
ketones using catalyst 9
4.2.8. Methyl (S)-2-((bis-tert-butoxycarbonyl)amino)-
5-hydroxy-4-oxopentanoate (17)3 2
A solution of an aldehyde (1.0 mmol) in dry THF (0.29 mL),
SIMes·CO2 (0.1 mmol, 35 mg), and paraformaldehyde (3 mmol,
90 mg) were introduced into a 10 mL glass vial. The vial was
flushed with argon and the reaction mixture was stirred and
heated to 100 °C for 1 h in a microwave reactor (50 W maximum
power). After cooling to room temperature, the solvent was
evaporated under reduced pressure. The residue was taken up
with CH2Cl2 (15 mL) and H2O (15 mL). The aqueous layer was
extracted twice with CH2Cl2 (15 mL each). The combined
organic layers were dried over anhydrous Na2SO4 and the solvent
was removed under reduced pressure. The product was purified
by flash column chromatography using the eluents described
below.
White solid (20% yield); m.p. 103–105 °C (lit. m.p. 108–110
20
°C);32 [α]D –69 (c 1.12, CHCl3); flash column chromatography
eluent: PE/AcOEt 8/2 to 7/3 v/v; δH (200 MHz, CDCl3) 5.56–
5.49 (1H, m, CH), 5.09 (1H, br, OH), 4.40–4.20 (2H, m,
CH2OH), 3.67 (3H, s, OCH3), 3.47–3.34 (1H, m, CHH), 2.69–
2.54 (1H, m, CHH), 1.46 (18H, s, Boc); δC (200 MHz, CDCl3)
206.7, 170.3, 151.6, 83.7, 68.2, 54.1, 52.6, 39.3, 27.8; m/z (ESI)
216.3 ([M–(Boc–COOMe)]–, 100%).
4.2.9. tert-Butyl
(S)-2-((bis-tert-butoxycarbonyl)-
amino)-5-hydroxy-4-oxopentanoate (18)
Yellow oil (57% yield); [α]D20 –27 (c 1, CHCl3); flash column
chromatography eluent: PE/AcOEt 8/2 to 7/3 v/v; Rf (30%
AcOEt/PE) 0.40; δH (200 MHz, CDCl3) 5.50–5.45 (1H, m, CH),
4.36 (1H, d, J 6 Hz, CHHOH), 4.28 (1H, d, J 6 Hz, CHHOH),
3.46–3.33 (1H, m, CHH), 3.15–3.00 (1H, br, OH), 2.65–2.54
(1H, m, CHH), 1.49 (18H, s, Boc), 1.40 (9H, s, C(CH3)3); δC (200
MHz, CDCl3) 206.5, 168.7, 152.1, 83.4, 82.2, 68.4, 55.0, 39.1,
29.6, 28.0; Anal. Calcd for C19H33NO8: C, 56.56; H, 8.24; N,
3.47; found C, 56.50; H, 8.27; N, 3.50.
4.2.1. 1-Hydroxy-2-pentanone (10)4 8
Yellowish oil (15% yield); flash column chromatography
eluent: PE/AcOEt 8/2 to 7/3 v/v; δH (200 MHz, CDCl3) 4.24 (2H,
s, CH2OH), 3.50 (1H, s, OH), 2.33 (2H, t, J 8.0 Hz, CH2), 1.72–
1.59 (2H, m, CH2), 0.85 (3H, t, J 8.0 Hz, CH3); δC (50 MHz,
CDCl3) 210.7, 67.4, 31.5, 17.0, 13.6.
4.2.2. 1-Hydroxy-2-hexanone (11)4 8
4.2.10. 2-Hydroxyacetophenone (19)5 2
Yellow oil (32% yield); flash column chromatography eluent:
PE/AcOEt 8/2 to 7/3 v/v; δH (200 MHz, CDCl3) 4.21 (2H, s,
CH2OH), 2.39 (2H, t, J 8.0 Hz, CH2), 2.20–2.16 (2H, m, CH2),
1.73–1.62 (2H, m, CH2), 0.88 (3H, t, J 8.0 Hz, CH3); δC (200
MHz, CDCl3) 180.9, 70.2, 34.5, 25.0, 23.0, 14.4.
White solid (44% yield); m.p. 82–84 °C (lit. m.p. 84–85 °C);52
flash column chromatography eluent: PE/AcOEt 8/2 to 7/3 v/v;
δH (200 MHz, CDCl3) 7.91 (2H, d, J 8.0 Hz, arom), 7.80–7.20
(3H, m, arom), 4.87 (2H, s, CH2OH), 3.52 (1H, br, OH); δC (50
MHz, CDCl3) 198.4, 134.3, 133.3, 128.9, 127.6, 65.4; m/z (ESI)
135.0 ([M–H]–, 45%).
4.2.3. 1-Hydroxy-2-octanone (12)4 9
Yellow oil (77% yield); flash column chromatography eluent:
PE/AcOEt 8/2 to 7/3 v/v; δH (200 MHz, CDCl3) 4.22 (2H, s,
CH2OH), 3.36 (1H, s, OH), 2.38 (2H, t, J 8.0 Hz, CH2), 1.60–
1.40 (2H, m, CH2), 1.40–1.10 (6H, m, CH2), 0.85 (3H, t, J 8.0
Hz, CH3); δC (50 MHz, CDCl3) 210.2, 68.3, 38.6, 31.7, 29.1,
23.9, 22.6, 14.2; m/z (ESI) 145.3 ([M+H]+, 52%).
4.2.11. 2-Hydroxy-1-(4-methoxyphenyl)ethan-1-one
(20)5 3
Yellow solid (6% yield); m.p. 98–100 °C (lit. m.p. 99–101
°C);53 flash column chromatography eluent: PE/AcOEt 9/1 to 7/3
v/v; δH (200 MHz, CDCl3) 7.89 (2H, d, J 8.0 Hz, arom), 6.96

5
18. McLaughlin, M.; Belyk, K. M.; Qian, G.; Reamer, R. A.; Chen,
(2H, d, J 8.0 Hz, arom), 4.81 (2H, s, CH2OH), 3.87 (3H, s,
OCH3), 3.51 (1H, s, OH); δC (50 MHz, CDCl3) 196.7, 164.3,
132.2, 130.0, 114.1, 64.9, 55.5.
ACCEPTED MANUSCRIPT
C.-y. J. Org. Chem. 2012, 77, 5144–5148.
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4.2.12. 1-(4-Chlorophenyl)-2-hydroxyethan-1-one
(21)5 1
Yellowish solid (94% yield); m.p. 117–119 °C (lit. m.p. 116–
118 °C);51 flash column chromatography eluent: PE/AcOEt 8/2 to
7/3 v/v; δH (200 MHz, CDCl3) 7.86 (2H, d, J 6.0 Hz , arom), 7.48
(2H, d, J 6.0 Hz, arom), 4.84 (2H, s, CH2OH), 3.47 (1H, br, OH);
δC (50 MHz, CDCl3) 197.9, 164.3, 132.2, 130.0, 129.7, 65.8.
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4.2.13. Methyl 4-(2-hydroxyacetyl)benzoate (22)3 0
Yellowish solid (96% yield); m.p. 154–156 °C (lit. m.p. 154–
156 °C);32 flash column chromatography eluent: PE/AcOEt 9/1 to
7/3 v/v; δH (200 MHz, CDCl3) 8.16 (2H, d, J 8.0 Hz, arom), 7.97
(2H, d, J 8.0 Hz, arom), 4.86 (2H, s, CH2OH), 3.91 (3H, s,
OCH3), 3.16 (1H, s, OH); δC (50 MHz, CDCl3) 214.5, 139.3,
130.4, 130.1, 127.2, 127.6, 65.8, 52.6; m/z (ESI) 195.1 ([M+H]+,
55%).
4.2.14. 1-(4-Fluorophenyl)-2-hydroxyethan-1-one
(23)1 4
White solid (53% yield); m.p. 108–110 °C (lit. m.p. 109–111
°C);14 flash column chromatography eluent: PE/AcOEt 8/2 to 7/3
v/v; δH (200 MHz, CDCl3) 7.93–7.86 (2H, m, arom), 7.20–7.08
(2H, m, arom) 4.79 (2H, s, CH2OH), 3.47 (1H, br, OH); δC (50
MHz, CDCl3) 196.8, 166.4 (d, JCF 255 Hz), 130.4 (d, JCF 9.5 Hz),
129.8 (d, JCF 3.0 Hz), 116.2 (d, JCF 22 Hz), 65.3.
Acknowledgments
37. Olszewski, T. K.; Jaskólska, D. E. Heteroat. Chem. 2012, 23, 605–
609.
38. Naik, P. U.; Petitjean, L.; Refes, K.; Picquet, M.; Plasseraud, L.
Adv. Synth. Catal. 2009, 351, 1753–1756.
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40. Hans, M.; Delaude, L.; Rodriguez, J.; Coquerel, Y. J. Org. Chem.
2014, 79, 2758–2764.
We would like to thank the support of COST action CM0905
“Organocatalysis” and Dr Morgan Hans (University of Liege) for
his help with the synthesis of the precatalysts.
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