Microwave-assisted one-carbon chain extension in the preparation of terminal -hydroxy ketones

Article abstract of DOI:10.1080/00397910802632589

The microwave-assisted synthesis of terminal -hydroxy ketones from acid chlorides and tris(trimethylsiloxy)ethylene in the presence of triethylamine is reported. The use of triethylamine had several advantages in the reaction: it increased the reactivity

Full text of DOI:10.1080/00397910802632589

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Microwave-Assisted One-
Carbon Chain Extension in the
Preparation of Terminal α-
Hydroxy Ketones
Matti J. P. Vaismaa a , Mikko V. Leskinen a & Marja K.
Lajunen a
a Department of Chemistry , University of Oulu ,
Oulu, Finland
Published online: 27 Apr 2009.
To cite this article: Matti J. P. Vaismaa , Mikko V. Leskinen & Marja K. Lajunen
(2009) Microwave-Assisted One-Carbon Chain Extension in the Preparation of
Terminal α-Hydroxy Ketones, Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic Chemistry, 39:11, 2042-2052, DOI:
10.1080/00397910802632589
To link to this article: http://dx.doi.org/10.1080/00397910802632589
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Synthetic Communications1, 39: 2042–2052, 2009
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802632589
Microwave-Assisted One-Carbon Chain
Extension in the Preparation of Terminal
a-Hydroxy Ketones
Matti J. P. Vaismaa, Mikko V. Leskinen, and Marja K. Lajunen
Department of Chemistry, University of Oulu, Oulu, Finland
Abstract: The microwave-assisted synthesis of terminal a-hydroxy ketones from
acid chlorides and tris(trimethylsiloxy)ethylene in the presence of triethylamine
is reported. The use of triethylamine had several advantages in the reaction: it
increased the reactivity of the acid chloride, acted as a scavenger of the HCl that
was produced in the reaction, protected the silylated enol from decomposition,
and made the excess use of the silyl reagent unnecessary. Mechanistic effects of
triethylamine are discussed. Effects of various base additives, reaction tempera-
tures, reaction times, and solvents in the reaction are compared.
Keywords: a-Hydroxy ketone, hydroxymethyl ketone, microwave-assisted
synthesis, Wissner reaction
INTRODUCTION
Hydroxymethyl ketones are analogs of dihydroxyacetone, a compound
that widely occurs in natural products and participates in biological
processes.[1] a-Hydroxy substituted ketones are conventionally produced
by catalytic[2] or stoichiometric[3] oxidation of terminal olefins. 1,2-
Disubstituted diols[4–6] or a-halo substituted ketones[7] can also be selec-
tively converted to terminal a-hydroxy ketones. In some cases, the
oxidation of oxirane with dimethylsulfoxide[8] or kinetically controlled
Received October 17, 2008.
Address correspondence to Marja K. Lajunen, Department of Chemistry,
University of Oulu, P. O. Box 3000, FIN 90014, Oulu, Finland. E-mail: marja.
lajunen@oulu.fi
2042

Microwave-Assisted One-Carbon Chain Extension
2043
Scheme 1. Wissner hydroxy ketone synthesis, a modification of Mukaiyama’s
aldol reaction.[13]
a-hydroxylation of ketones[9] can be used to synthesize the a-hydroxy
ketone functionality.
Cross condensation is generally used to extend the carbon chain by
two or more carbon atoms, but in the reaction with diazomethane[10]
or paraformaldehyde[11] the one-carbon chain extension can also be
achieved. However, these reagents are hazardous and difficult to handle,
particularly in a large-scale reaction or a closed microwave reactor. The
Wissner modification of Mukaiyama’s[12] aldol reaction lengthens the
carbon chain by one carbon atom. The acid chloride 1 and the silylated
ketene acetal 2[13,14] were presented to generate a b-enol ester 3, which
decarboxylated to the product 4 (Scheme 1).[15]
Here we report our modification of this condensation reaction and its
application for the preparation of some substituted hydroxymethyl
ketones 4 using microwave heating. We show that the use of triethyl-
amine in this reaction increases the reactivity of the carboxyl compound
1 and protects tris(trimethylsiloxy)ethylene (2) from decomposition.
RESULTS AND DISCUSSION
The Wissner hydroxy ketone synthesis[16] is sensitive to moisture. It also
needs either heating or the assistance of a Lewis acid to be completed.[15]
The original reaction requires 2 equiv. of enol 2. One equiv. of 2 makes a
nucleophilic attack to acid chloride 1, and the second equiv. is consumed
by the HCl that evolved in the nucleophilic substitution. Finally, the
formed silyl enolate 3 was subsequently hydrolyzed to b-keto acid 5,
which after decarboxylation tautomerized to the desired a-hydroxy
ketone 4 (Scheme 1).[15]
During our studies, we observed that an increase in the reaction tem-
perature clearly greater than 100ꢀC significantly accelerated the conden-
sation. Our experiences related to the synthetic applications of microwave
activation[17] encouraged us to study the effect of microwaves on this
condensation reaction. In addition, the use of the closed microwave vessel
would also help avoid moisture.
The effects of reaction conditions on the condensation were studied
with 1 equiv. of octanoyl chloride (1a) and 2.2 equiv. of tris(trimethyl-
siloxy)ethylene (2).[15] For the comparison, the mixture of the reaction

2044
M. J. P. Vaismaa, M. V. Leskinen, and M. K. Lajunen
components was heated in an oil bath at 110ꢀC for 4 h under an N2 atmo-
sphere. After cooling, tetrahydrofuran (THF) and 2 M HCl were succes-
sively added into the solution, which was then heated at 85ꢀC for 30 min.
According to gas chromatographic (GC) analysis, the yield of the
product, 1-hydroxynonan-2-one (4a), was 73% (Table 1, entry 1), which
was less than originally reported for 4a.[13] In GC analysis decane was
used as the internal standard. The conversion was calculated by
Table 1. Effects of variable reaction conditions and components on the reaction
of octanoyl chloride (1a) with tris(trimethylsiloxy)ethylene (2)
2
Temp.
Conv. of
Time 4aa (%)
Entry Reaction conditions
(equiv.) (ꢀC)
1
2
Oil bath heating, no additives, no
solvent
MW activation, no additives, no
solvent
Et3N (1.0 equiv.), THF
Et3N (1.0 equiv.), THF
Et3N (1.0 equiv.), THF
MW, Et3N (1.0 equiv.), THF
MW, pyridine (1.0 equiv.), THF
MW, 1-methylimidazole (1.0 equiv.),
THF
MW, DIPEA (1.0 equiv.), THF
MW, DBU (1.0 equiv.), THF
MW, Et3N (1.0 equiv.), THF
MW, Et3N (1.0 equiv.), THF
MW, Et3N (1.0 equiv.), THF
MW, Et3N (1.0 equiv.), THF
MW, Et3N (1.0 equiv.), THF
MW, Et3N (1.0 equiv.), toluene
MW, Et3N (1.0 equiv.), CH2Cl2
MW, Et3N (1.0 equiv.), THF
MW, Et3N (2.0 equiv.), THF
MW, Et3N (1.0 equiv.), THF
MW, Et3N (1.0 equiv.), THF
2.2
2.2
110
4 h
73
98
180 10 min
3
4
5
6
7
8
1.1
1.1
1.1
1.1
1.1
1.1
ꢁ10 5 min
>24b
74
76
91
16
—
rt
rt
24 h
72 h
100 5 min
100 5 min
100 5 min
9
10
11
12
13
14
15
16
17
18
19
20
21
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.1
1.5
1.1
1.1
1.1d
100 5 min
100 5 min
80
120 5 min
100
90 sc
100 10 min
100 15 min
100 10 min
100 5 min
100 5 min
100 5 min
100 5 min
100 5 min
>50b
—
5 min
>79b
74
>54b
90
78
84
67
89
87
89
84
aConversion of 4a is based on the GC analysis of the reaction mixture after
decarboxylation using decane as an internal standard.
bA part of 4a further reacted with the octanoic acid derivative and formed
2-oxononyl octanoate as a side product (GC-MS). Look also at Ref. 25.
cIt took 90 s to achieve the temperature of 100ꢀC on absorption level ‘‘high’’
in the Biotage InitiatorTM microwave reactor in a 2-mL vial.
dEnolate 2 was added into the solution of 1a in THF before Et3N.

Microwave-Assisted One-Carbon Chain Extension
2045
comparing the calibrated integral values of GC-signals (flame ionization
detector) of decane and 1-hydroxynonan-2-one. However, when the same
reaction was carried out using microwave activation (MW) at 180ꢀC, an
almost complete conversion occurred in 10 min (Table 1, entry 2).
Earlier, triethylamine had been shown to successfully accelerate the
reaction of acid chloride with O-silyl ketene acetals.[18] Mechanistically,
it is commonly approved that a tertiary amine abstracts a-proton from
acid chlorides, leading to the cleavage of the chloride ion.[19] The formed
ketene 6 is very reactive toward nucleophiles. We believe that the rather
unstable ketene 6 in situ forms at the presence of triethylamine and
directly reacts with the nucleophilic enolate 2 (Scheme 2). Besides, the
Et3NHCl by-product would increase the absorption of the microwave
energy into the reaction mixture.
Our first experiments directly showed the benefits of triethylamine in
the reaction (Table 1, entries 3–5). The base was added into the cooled
mixture of octanoyl chloride (1a) and 2 in THF and then stirred at
ꢁ 10ꢀC for 5 min. After hydrolysis and decarboxylation, the formation
of 4a was detected (entry 3). The amount of 4a increased when the reac-
tion was carried out at room temperature for a prolonged time (entries 4
and 5). In these reactions, the silylated b-enol ester 3 was simultaneously
hydrolyzed and decarboxylated by the addition of 2 M hydrochloric acid
upon heating in open vessel (80–85ꢀC) for 30 min.[15] Later we noticed
that the heating in this step was not necessary (Table 2).
The microwave irradiation of the reaction mixture with triethylamine
substantially decreased the time of condensation (entry 6). In addition to
triethylamine, a set of liquid organic bases was tested at 100ꢀC (entries 7–
10). Triethylamine and diisopropylethylamine were most successful in
Scheme 2. Activating and protective effect of triethylamine in the condensation
of octanoyl chloride (1a) with tris(trimethylsiloxy)ethylene (2): the formation of
the ketene 6 and the capture of HCl, respectively.

2046
M. J. P. Vaismaa, M. V. Leskinen, and M. K. Lajunen
Table 2. Products, yields, and reaction conditions of the microwave-assisted
synthesis of terminal a-hydroxy ketones from acid chlorides 1a–i
Max. Time to
power reach
Max.
press. Continuation of
Yield
Yield in
lit. (%)
Entry Product
1
(W)a 100ꢀC (s)b (bar) power (W)c 4 (%)d
250
250
120
105
1.3
0.8
60
50
88
84[15]
[23]
—
2
75e
3
4
250
220
150
90
2.5
1.3
200!75
71
70
81[15]
[25]
—
100
5
6
250
250
150
1.3
0.4
145
250
6 (5 min)f
62[15]
15 (15 min)f
>300g
—
63
[26]
—
[27]
—
7
215
100
1.7
40
[28]
8
9
250
250
150
150
0.7
1.4
120
82
81
—
150!75
—
aThe maximum microwave power that was applied to the reaction to gain the
temperature of 100ꢀC.
bThe time needed to attain the set temperature (100ꢀC).
cThe microwave power required to maintain the temperature of 100ꢀC.
dThe yield of the isolated product. Reactions were performed on a 1-g scale in
20-mL vials.
eThe low yield was presumable due to the poor solubility of 4b to eluents used
in purification by flash chromatography.
fReaction was performed with normal procedure (5 min) and with extended
microwave radiation (15 min). Conversions were estimated from 1H NMR spectra
of the crude product mixture (isolated only by extraction).
gThe desired temperature was not reached during the reaction.

Microwave-Assisted One-Carbon Chain Extension
2047
this reaction. Nucleophilic catalysts such as pyridine or 1-methylimida-
zole did not work in the reaction. When the reaction was carried out
without an additional base, GC-MS analysis of the thrice-silylated b-enol
a-hydroxy ester intermediate 3a nicely fit with structure presented in the
original article[15] (Table 1, entry 2). A careful study of the intermediate
7a formed at the presence of triethylamine resulted in the same molecular
mass ion as 3a but with a slightly different fragmentation pattern (entry
6). This supports the formation of the kinetic enolate 7 and the occur-
rence of the reaction via ketene intermediate (Scheme 2).[18]
It was also noted that neither a cooler (80ꢀC) nor a hotter (120ꢀC)
reaction temperature was profitable for this reaction, but the temperature
of 100ꢀC was optimal (entries 6, 11, 12). The increase of the reaction time
did not improve the yield (entries 14 and 15) and neither did the use of
other reaction solvents (entries 16 and 17). Toluene is a nonpolar solvent
that does not absorb the microwave energy as efficiently as THF, which
was seemed to slow the reaction (entry 16).[20,21] However, in toluene the
cleavage of the silyl group from the carboxyl of 3 occurred to a lesser
extent than in THF. The different molar ratios of the reagents or the
order of their addition did not show significant effect on the yield of the
product (entries 18–21).
The optimum reaction conditions found for octanoyl chloride (1a)
were applied to reactions of 2 with variable acid chlorides 1b–i
(Table 2). The compounds 1a–f were selected on the basis of the increas-
ing stereochemical hindrance at the a-position (Table 2, entries 1–6), and
the acid chlorides 1g–i contained functionalities useful in our further stu-
dies related to analogs of dihydroxyacetone phosphate (entries 7–9).[23]
Reactions were carried out with stoichiometric amounts of triethylamine,
1a, and tris(trimethylsiloxy)ethylene (2) in dry THF under microwave
heating followed by the addition of 2 M HCl solution. It was stirred
for 30 min at ambient temperature. Before the microwave heating,
triethylamine was added by a syringe into the reaction mixture, which
turned milky white, indicating the formation of a quaternary amine 6.
Acid chlorides with a primary or secondary carbon at the a-position were
also milky white mixtures after microwave irradiation and yielded a-
hydroxy substituted ketones 4 in good yields (Table 2, entries 1–4 and
7–9). The more dielectric[21] reaction mixtures heated faster and required
less power (entries 2, 4, and 7). The reaction mixtures were rather concen-
trated (1 M), and therefore their capability to absorb microwave energy
was dependent on the dielectric property of the substances. The pressure
in the reactor vessel followed the input power, and it was greatest when
the set temperature was reached and then decreased.
A further proof of the mechanism and the presence of ketene inter-
mediate 6 was derived from the acid chlorides 1e,f without a-protons.

2048
M. J. P. Vaismaa, M. V. Leskinen, and M. K. Lajunen
They did not produce white, milky mixtures as 1a–e or g–i at the begin-
ning of the reaction. Ketene did not form, and they only slightly reacted
within the given reaction time (Table 2, entries 5 and 6). The yield of 4e
hardly improved by a prolongation of the reaction time (entry 5).[14]
Instead, a minor amount of the product formed in the direct reaction
between acid chloride 1e and enolate 2. In addition, the Et3NHCl salt
formed poorly, which could be seen as the low absorption of microwave
energy, and therefore the direct condensation between 1f and 2 did not
take place (Table 2, entry 6). It was also detected that the cleavage and
decarboxylation of the silylated intermediate 7 g could be completed
without heating and even a sensitive ester group could stand the reaction
conditions (entry 7).
In summary, we have presented the improved and fast synthesis for
the preparation of hydroxymethyl ketones by the one-carbon chain
extension using microwave heating. The use of triethylamine had several
advantages: In the first step, the formation of ketene 6 from the acid
chloride 1 increased the reactivity of the carbonyl group toward tris-
(trimethylsiloxy)ethylene (2). Triethylamine protected the silyl compound
2 by neutralizing the HCl and made the excess use of 2 unnecessary.
Et3NHCl salt intensified the transfer of the microwave energy to the reac-
tion mixture by ionic conduction. The decarboxylation could be carried
out at room temperature or simply by leaving the reaction mixture to stay
out overnight, which enables syntheses of labile a-hydroxy ketones.
Microwave activation clearly made the condensation more effective
and enables the use of short reaction times.
EXPERIMENTAL
General
Commercial reagents (Aldrich, Fluka, TCI) were purchased as 95–99%
pure and used without further purification. THF was freshly distilled
over metallic sodium using benzophenone indicator; pyridine was dis-
tilled over CaHꢀand stored over molecular sieves. If necessary, petroleum
˚
ether (bp 40–65 C) was dried over 4-A molecular sieves. Reactions were
carried out in oven-dried (100ꢀC overnight) equipment under a protective
atmosphere (N2). Microwave-assisted synthesis were performed in
Biotage’s InitiatorTM microwave reactor with a single-mode cavity in
closed vials with a standard aluminum open-top seal with a septum and
a Teflon-coated stirring bar. Solvents were evaporated with Buchi rotary
¨
evaporator (water aspirator) followed by the removal of trace volatiles
using a vacuum oil pump. Flash chromatography was carried out using

Microwave-Assisted One-Carbon Chain Extension
2049
Merck kieselgel 60 silica (230–400 mesh), and an elution was visualized
by thin-layer chromatography (ultraviolet and anisaldehyde colorizing).
Melting points were measured by differential scanning calorimetry on a
1
Mettler Tolero apparatus at a heating rate of 10ꢀC=min. H and 13C
NMR spectra were recorded on a Bruker DPX 200 spectrometer and
reported in parts per million (ppm) from internal tetramethylsilane
(TMS, dH 0.0 ppm) or CDCl3 solvent (dC 77.16 ppm). Data are reported
as follows: chemical shift [integration, multiplicity (s ¼ singlet, d ¼
doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet), coupling constants,
interpretation]. EI mass spectrum (GC-MS) were recorded at 70-eV
ionization energies using an HP 5973 mass spectrometer and HP 6890
series GC system with DB-624 column by the Oulu University mass
spectrometry laboratory. High-resolution mass spectra (HRMS) were
recorded positive (M þ Naþ) ESI by a Micromass LCT equipped with
time of flight (TOF) detector N-(N-butyl)benzene-sulfonamide as a lock
1
mass. All products were determined to be more than 95% pure by H
NMR.
General Synthetic Procedure
Acid chloride (1a–i, 1.0 equiv), tris(trimethylsiloxy)ethylene (2, 1.1
equiv),[15] and triethylamine (1.0 equiv) were successively added by a
syringe into THF (1M) in a closed reactor vessel atꢁ10ꢀC under an N2
atmosphere. The reaction mixture was stirred atꢁ10ꢀC for an additional
5 min after which microwave power was introduced (Biotage Initiator,
absorption level high, fixed hold time off, prestirring 10 s). The tempera-
ture and total irradiation time were controlled. Aqueous HCl (2 M) was
added, and the reaction mixture was stirred at ambient temperature for
30min. The water phase was saturated by NaCl and washed three times
with Et2O (4a,b,f,i) or EtOAc (4c–e and 4 g,h). The organic phases
were combined, washed with saturated NaHCO3 and brine, dried
(Na2SO4), filtered, and concentrated. The product was purified by column
chromatography.
1
The full analytical data with H and 13C NMR spectra and differen-
tial scanning calorimetry (DSC) graphs of all the compounds can be
obtained by e-mail to the corresponding author.
GC-MS (EI, 70 eV) spectra of trimethylsilyl 2,3-bis(trimethylsilyloxy)
dec-3-enoate (7a) (Table 1, entry 6); m=z (%) ¼ 418 (0.5%) [Mþ], 403 (3)
[Mþ ꢁMe], 375 (2), 328 (2), 313 (3), 301 (60) [Mþ ꢁCOOSiMe3], 257 (36),
217 (7), 199 (4), 147 (45), 133 (9), 103 (8), 73 (100) [SiMe3þ]. EI spectra of
trimethylsilyl 2,3-bis(trimethylsilyloxy)dec-2-enoate (3a) (Table 1, entry 2):
m=z (%) ¼ 418 (16) [Mþ], 403 (4) [Mþ ꢁMe], 375 (4), 333 (1), 301 (22)

2050
M. J. P. Vaismaa, M. V. Leskinen, and M. K. Lajunen
[Mþ ꢁCOOSiMe3], 285 (1), 244 (1), 217 (8), 147 (37), 129 (10), 103 (7), 73
(100) [SiMe3þ].
1-Hydroxy-3-(thiophen-2-yl)propan-2-one (4i)
1
Et2O–petroleum ether, 60:40; Rf 0.31; red oil; yield 81% (0.79 g); H
NMR (CDCl3, ppm) dH 7.24 (1H, dd, J ¼ 5.1, 1.3 Hz, CHS), 6.98 (1H,
dd, J ¼ 5.1, 3.5 Hz, CHC), 6.92 (1H, m, J ¼ 3.5, 1.3 Hz, SCHCHCHC),
4.34 (2H, s, CH2OH), 3.93 (2H, s, CH2CO), 3.09 (1H, br. s, OH); 13C
NMR dc 206.2 (CO), 133.5 (quaternary C), 127.4, 127.3, 125.7, 67.6
(CH2OH) 39.5 (CH2); HRMS (ESIþ): m=z 179.0159 (calcd. 179.0143
for C7H8O2SNa).
ACKNOWLEDGMENTS
The financial support from the Academy of Finland (project number
118227) as well as the Jenni and Antti Wihuri Foundation are gratefully
acknowledged. The authors thank Mrs. Pa¨ivi Joensuu for her assistance
with the MS measurements.
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