Safe generation and direct use of diazoesters in flow chemistry

Article abstract of DOI:10.1055/s-0033-1340835

A safe and fast method for the production of β-hydroxy-α- diazoesters in continuous flow technology is described. The synthesis involves the formation of ethyl diazoacetate in situ and the addition to several aldehydes in a two-step continuous flow microreactor setup. Rhodium acetate catalyzes a subsequent 1,2-hydride shift to give access to β-keto esters in a three-step sequence. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340835

LETTER
▌871
lSetaterfe Generation and Direct Use of Diazoesters in Flow Chemistry
Safe Generation and Direct Use of Diazoesters in Flow Chemistry
Simon T. R. Müller,a Daniel Smith,a Paul Hellier,b Thomas Wirth*a
a
Cardiff University, School of Chemistry, Park Place, Cardiff CF10 3AT, UK
Fax +44(29)20876968; E-mail: wirth@cf.ac.uk
b
Institut de Recherche Pierre Fabre, 81603 Gaillac, France
Received: 13.12.2013; Accepted after revision: 27.01.2014
been successfully implemented on hazardous compounds
or intermediates such as azides,12 diethylaminosulfur tri-
fluoride as fluorination agent,13 hydrazine,14 diazonium
salts15 as well as diazo compounds.16 Herein, we describe
Abstract: A safe and fast method for the production of β-hydroxy-
α-diazoesters in continuous flow technology is described. The syn-
thesis involves the formation of ethyl diazoacetate in situ and the
addition to several aldehydes in a two-step continuous flow micro-
reactor setup. Rhodium acetate catalyzes a subsequent 1,2-hydride a two-step flow process giving access to β-hydroxy-α-di-
shift to give access to β-keto esters in a three-step sequence.
azoesters 4 as shown in Scheme 1.
Key words: addition, aldehydes, diazo compounds, flow chemis-
try, rhodium
N2
RCHO
NH2
CO2Et
N2
NaNO2
3
R
CO2Et
H2SO4
H2O
CO2Et
DBU
DMSO
OH
Over the past few decades diazo compounds have been
studied extensively in organic synthesis.1,2 An interesting
class of diazo compounds are β-hydroxy-α-diazoesters.
Although their major reactivity lies in a 1,2-hydride shift,
β-hydroxy-α-diazoesters have proven to be versatile
intermediates3 in the synthesis of asymmetric 1,2-diols4
and β-amino acids,5 vinyl diazo carbonyl compounds6 as
well as in fragmentations7 and for Pd-catalyzed arylation
reactions.8 β-Hydroxy-α-diazoester are usually obtained
via an aldol reaction of diazo esters with an aldehyde em-
ploying different bases. Unfortunately, the use of β-hy-
droxy-α-diazoesters as powerful building blocks remains
limited in industrial applications as diazo derivatives are
considered to be highly energetic compounds with associ-
ated hazardous properties.
1
2
4
Scheme 1 Synthesis of β-hydroxy-α-diazoesters 4 from glycine eth-
yl ester (1)
A variety of synthetic routes to ethyl diazoacetate (2) ex-
ist.17 The method of using glycine ethyl ester (1) with so-
dium nitrite in an acidic, aqueous solution still offers
cheap and fast access to 2. Also other synthetic routes
have already been investigated for the formation of ethyl
diazoacetate (2) in flow chemistry.16 In a recent report op-
timal reaction conditions for the synthesis of 2 from gly-
cine ethyl ester (1) were carefully evaluated.18 In our
hands the synthesis of ethyl diazoacetate (2) proceeded in
high yields in a flow system so that we initially investigat-
ed their use as nucleophiles after deprotonation. For these
experiments pure ethyl diazoacetate (2) was used.
There are safety concerns associated with handling diazo
compounds in batch chemistry. While diazomethane has
been reported to explode in contact with sharp glassware
and under certain reaction conditions (higher temperature,
irradiation, alkali metals),9 α-diazoesters are more stable.
Ethyl diazoacetate is being used for many transformations
and its large-scale use has been investigated successful-
ly.10 Nevertheless, the use of ethyl diazoacetate requires
extensive safety considerations in batch chemistry.
α-Diazoesters have been described to undergo nucleophil-
ic addition to aldehydes 3 with bases such as LDA, n-BuLi,
KHMDS, NaH, NaOH19 as well as DBU,20 with the ad-
vantage of the latter being comparably easy to handle in
organic solvents.
Initially conditions for the condensation reaction of ethyl
diazoacetate with benzaldehyde were screened. In accor-
dance with literature precedents,20 DBU was selected as
the base and acetonitrile, dimethylsulfoxide, dichloro-
methane and water were compared as solvents in the reac-
tion using different temperatures. Water has been
successfully used as solvent for the condensation of ethyl
diazoacetate with various aldehydes,21 however, we ob-
served the highest conversions using dimethylsulfoxide
(Table 1, entries 5–7). Dichloromethane gave comparably
poor yields while acetonitrile gave only a moderate con-
version. The use of higher temperatures did not improve
conversions and the conditions described in Table 1, entry
5 with 6.8 minutes reaction time at room temperature de-
scribe the optimal reaction conditions for the addition
reaction leading to a conversion to 4a in 83%.
In contrast, continuous flow technology has shown great
potential in replacing batch techniques for handling reac-
tive intermediates.11 In a continuous flow setup highly re-
active species are not only generated in situ, but also in
small quantities at a specific time with methods such as
scaling-out and numbering-up for safe production of in-
dustrial quantities. Furthermore, due to the high surface-
to-volume ratio in microstructured devices typically used
for flow chemistry, heat and mass transfer occur very ef-
ficiently. Continuous flow in microreactors has already
SYNLETT 2014, 25, 0871–0875
Advanced online publication: 05.03.2014
DOI: 10.1055/s-0033-1340835; Art ID: ST-2013-D1138-L
© Georg Thieme Verlag Stuttgart · New York
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6

872
S. T. R. Müller et al.
LETTER
Table 1 Solvent Screening for the Synthesis of α-Hydroxy-β-keto
Ester 4a (R = Ph) in Continuous Flow
Table 2 Optimization of the Two-Step Flow Process to α-Hydroxy-
β-keto Ester 4a (R = Ph)
Entry
Reaction time Temperature Solvent
Conversion
(%)a,b
Entry Total flow ratea Temperature of
2/DBUb
Conversion
(%)c
(min)
(ºC)
(mL/min)
second reactor (°C) (equiv)
1
2
3
4
5
6
7
8
6.8
6.8
20
40
20
20
20
60
60
60
H2O
31
63
71
9
1
2
4
60
60
60
60
75
20
40
40
40
40
40
40
40
40
1:1.7
3:1
28
69
45
43
40
74
83
73
57
75
80
76
56
96
H2O
4
13.5
13.5
6.8
H2O
3
1.34
0.8
1:1.7
1:1.7
1:1.7
1:2.3
2:2.3
1.5:2
1.7:0.7
1.7:1
2:1
CH2Cl2
DMSO
DMSO
DMSO
MeCN
4
83
57
56
45
5
0.8
3.75
1.85
2.25
6
0.26
0.26
0.26
0.26
0.26
0.26
0.26
0.4
7
8
a Conversion determined by 1H NMR.
9
b Reaction conditions: DBU (1 equiv), ethyl diazoacetate (2; 1 equiv),
10
11
12
13
14d
reactor volume: 0.9 mL.
1.5:1
2:1
EtO2C
NH2
RCHO
3 (1.0 M) (1.15 M)
DMSO DMSO
DBU
1 (2.5 M)
N2
H2SO4 (0.2 M)
0.26
2:1
R
CO2Et
a Each pump had identical flow rate (Total flow rate/4).
b Amount of aldehyde 3 used was 1 equiv.
c Conversion determined by 1H NMR.
OH
4
d Second reactor: 2 mL (0.8 mm i.d.).
0.9 mL
0.9 mL
NaNO2 (2.5 M)
H2O
alent of DBU and 40 ºC reaction temperature for the sec-
ond step with residence times of 6.8 minutes (first reactor)
and 7.5 minutes (second reactor), respectively.
sat. NaHCO3
Scheme 2 Continuous flow setup for the two-step process
Different aldehydes were investigated in the two-step
flow process under optimized reaction conditions. The re-
sults are shown in Table 3.
In a second stage, the DBU-mediated addition of ethyl di-
azoacetate (2) to aldehydes was combined with a protocol
for the synthesis of ethyl diazoacetate in situ as shown in
Scheme 2. Optimization studies for the production of α-
diazo-β-hydroxy esters 4 in a two-step flow system were
performed by altering temperature, reaction time, the
amount of base as well as the amount of ethyl diazoacetate
(2) generated in the first reactor. Some representative re-
sults are shown in Table 2.
The two-step flow system gives access to aliphatic (Table
3, entry 8) and aromatic α-diazo-β-hydroxy esters 4 in
good to excellent yields. A variety of aromatic aldehydes
can act as electrophiles with good yields, irrespective of
their electronic properties. Electron-withdrawing (Table
3, entries 2–4 and 7) and electron-donating functionalities
(Table 3, entry 6) work equally well. The reactions shown
in Table 3, entries 7 and 8 were performed before the de-
velopment of optimal reaction conditions. In our hands,
ortho-bromobenzaldehyde gave higher yields than the
meta or para derivatives (Table 3, entries 2–4). Ketones
or lactones are, however, not suitable substrates and there
is no conversion observed for acetophenone and γ-butyro-
lactone in the DBU-mediated addition to 2 under continu-
ous flow conditions. The reaction was scaled up to 38
mmol benzaldehyde giving access to 6 g of ethyl 2-diazo-
3-hydroxy-3-phenylpropanoate (4a) in 72% yield in less
than two hours. The slightly lower yields are due to diffi-
culties in the chromatography of the larger quantities of
reaction product.
The reaction time in the second reactor has an important
effect on the conversion of the condensation reaction. A
residence time of 7.5 minutes (Table 2, entry 14) is signif-
icantly lower than in the batch process.12 Temperatures of
60 °C and higher led to a significant drop in conversion
(Table 2, entries 1–5), while a temperature of 40 °C gave
a higher conversion than the reaction at room temperature
(Table 2, entries 5 and 6). Lowering the equivalents of the
in situ generated ethyl diazoacetate below two equivalents
(Table 2, entries 8 and 10) resulted in reduced conversions
as well as reducing the amount of base below one equiva-
lent (Table 2, entry 9). The best reaction conditions found
in this screening led to 96% conversion (Table 2, entry 14)
using two equivalents of ethyl diazoacetate (2), one equiv-
Synlett 2014, 25, 871–875
© Georg Thieme Verlag Stuttgart · New York

LETTER
Safe Generation and Direct Use of Diazoesters in Flow Chemistry
873
Table 3 Conversion of Various Aldehydes in the Two-Step Flow
Process under Optimized Reaction Conditions
Rh2(OAc)4
(2.5 mM)
DMSO–H2O (1:1)
Entry Aldehyde 3
Product 4
Yield (%)
Ph
N2
CO2Et
Ph
O
OH
CO2Et
5a
CHO
CO2Et
OH
1 mL
82
4a
1
2
72a
N2
two-step flow synthesis
(Scheme 2)
3a
4s
sat. NaHCO3
OH
CHO
Scheme 3 Flow set-up for the three-step process
CO2Et
74b
N2
Br
α-Diazo-β-hydroxy ester can undergo readily C–H migra-
tion reactions with metal catalysts under nitrogen expul-
sion.22 We therefore investigated the coupling of a third
step to the reaction setup using Rh2(OAc)4 as catalyst. The
1,2-hydride shift was first investigated as a single-step
flow reaction with 4a as starting material, addition of a so-
lution of Rh2(OAc)4 as catalyst and using a silica plug di-
rectly after the flow reaction as quench. No diazoalcohol
4a was left even with residence times of less than a min-
ute; the set-up described in Scheme 3 was used subse-
quently to enable a direct workup. Diazoalcohol 4a was
no longer detectable in the crude NMR after workup, con-
firming complete reaction to the β-keto ester 5a, which
was isolated in 73% yield.
Br
3b
4b
OH
CHO
Br
CO2Et
3
4
5
6
7
96
82
77
85
82b
N2
Br
3c
4c
OH
Br
CHO
CHO
Br
CO2Et
N2
3d
4d
OH
CO2Et
In conclusion, we have described a quick and concise
method for the synthesis of α-diazo-β-hydroxy ester.23
The residence time for the addition reaction could be as
low as six minutes while still resulting in very good
yields. No isolation of the highly energetic ethyl diazoac-
etate was required. The method is reliable for scale up and
can be combined with the rhodium-catalyzed 1,2-hydride
shift.24
Me
N2
Me
3e
4e
OEt OH
CHO
OEt
CO2Et
N2
3f
4f
OH
Acknowledgment
CHO
CO2Et
Financial support by Pierre Fabre and the School of Chemistry, Car-
diff University, is gratefully acknowledged.
F
N2
F
3g
4g
References and Notes
OH
(1) For selected reviews on diazo compounds, see: (a) Ye, T.;
McKervey, A. Chem. Rev. 1994, 94, 1091. (b) Zhang, Z.;
Wang, J. Tetrahedron 2008, 64, 6577.
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Artamonov, O. S.; Komarov, I. V.; Mykhailiuk, P. K.
Tetrahedron 2011, 67, 803. (c) Honma, M.; Takeda, H.;
Takano, M.; Nakada, M. Synlett 2009, 1695.
CHO
4
CO2Et
4
8
9
66b
N2
3h
4h
OH
O
CHO
CO2Et
O
45
N2
3i
3j
(3) Gioiello, A.; Venturino, F.; Marinozzi, M.; Natalini, B.;
Pellicciari, R. J. Org. Chem. 2011, 76, 7431.
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J. Am. Chem. Soc. 2012, 134, 2075.
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(8) Shu, Z.; Zhang, J.; Zhang, Y.; Wang, J. Chem. Lett. 2011, 40,
1009.
4i
OH
CHO
CO2Et
10
75
N2
4j
a Reaction was performed on a 38-mmol scale.
b Conditions of Table 2, entry 7 were used.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 871–875

874
S. T. R. Müller et al.
LETTER
mL) and dried over anhyd MgSO4. After evaporating the
solvent in vacuo, the diazoalcohol was purified by column
chromatography (hexane–EtOAc gradient, 100% hexane to
85% hexane).
Ethyl 2-Diazo-3-hydroxy-3-phenylpropanoate (4a):
obtained as a yellow thick oil; 363 mg (30 min collection
time; 82% yield; 6.05 g, 115 min collection time, 72%). 1H
NMR (400 MHz, CDCl3): δ = 7.57 (m, 5 H, ArH), 6.11 (d,
J = 3.5 Hz, 1 H, CHOH), 4.47 (q, J = 7.5 Hz, 2 H, CH2CH3),
3.26 (br s, 1 H, OH), 1.50 (t, J = 7.5 Hz, 3 H, CH2CH3).
13C NMR (100 MHz, CDCl3): δ = 166.8, 139.2, 129.1,
128.6, 126.0, 69.2, 61.6, 15.0. MS (EI): m/z = 220.09 [M+].
Ethyl 3-(4-Bromophenyl)-2-diazo-3-hydroxypropanoate
(4b): obtained as a yellow oil; 295 mg (20 min collection
time; 74% yield). 1H NMR (400 MHz, CDCl3): δ = 7.79 (m,
2 H, ArH), 7.58 (m, 2 H, ArH), 6.15 (d, J = 3.5 Hz, 1 H,
CHOH), 4.55 (q, J = 7.0 Hz, 2 H, CH2CH3), 3.47 (br s, 1 H,
CHOH), 1.58 (t, J = 7.5 Hz, 3 H, CH2CH3). 13C NMR (100
MHz, CDCl3): δ = 166.8, 138.4, 132.5, 128.1, 122.8, 68.8,
61.8, 15.0. MS (EI): m/z = 297.98 [M+].
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Ethyl 3-(2-Bromophenyl)-2-diazo-3-hydroxypropanoate
(4c): obtained as a yellow oil; 421 mg (22 min collection
time; 96% yield). 1H NMR (500 MHz, CDCl3): δ = 7.71 (dd,
J = 8.0, 1.5 Hz, 1 H, ArH), 7.57 (dd, J = 8.0, 1.0 Hz, 1 H,
ArH), 7.39 (td, J = 7.5, 1.5 Hz, 1 H, ArH), 7.20 (td, J = 8.0,
1.5 Hz, 1 H, ArH), 6.09 (s, 1 H, CHOH), 4.29 (m, 2 H,
CH2CH3), 3.34 (br s, 1 H, CHOH), 1.30 (t, J = 7.0 Hz, 3 H,
CH2CH3). 13C NMR (125 MHz, CDCl3): δ = 166.3, 137.7,
132.9, 127.8, 127.6, 121.6, 68.8, 61.3, 14.8.
Ethyl 3-(3-Bromophenyl)-2-diazo-3-hydroxypropanoate
(4d): obtained as a yellow oil; 362 mg (22 min collection
time; 82% yield). 1H NMR (500 MHz, CDCl3): δ = 7.61 (m,
1 H, ArH), 7.46 (d, J = 8.0 Hz, 1 H, ArH), 7.35 (d, J = 8.0
Hz, 1 H, ArH), 7.26 (t, J = 7.5 Hz, 1 H, ArH), 5.87 (s, 1 H,
CHOH), 4.28 (q, J = 7.0 Hz, 2 H, CH2CH3), 3.09 (br s, 1 H,
CHOH), 1.30 (t, J = 7.0 Hz, 3 H, CH2CH3). 13C NMR (125
MHz, CDCl3): δ = 166.2, 141.1, 131.4, 130.5, 128.9, 124.5,
123.0, 68.1, 61.4, 14.5.
Ethyl 2-Diazo-3-hydroxy-3-(p-tolyl)propanoate (4e):
obtained as a yellow oil; 203 mg (17 min collection time;
77% yield). 1H NMR (500 MHz, CDCl3): δ = 7.31 (d, J = 8.0
Hz, 2 H, ArH), 7.19 (d, J = 8.0 Hz, 2 H, ArH), 5.88 (s, 1 H,
CHOH), 4.27 (q, J = 7.0 Hz, 2 H, CH2CH3), 3.12 (br s, 1 H,
CHOH), 2.35 (s, 3 H, ArMe), 1.29 (t, J = 7.0 Hz, 3 H,
CH2CH3). 13C NMR (125 MHz, CDCl3): δ = 166.5, 138.2,
135.6, 129.4, 125.7, 68.7, 61.1, 21.1, 14.5.
(23) General Procedure for the Two-Step Process: Glycine
ethyl ester hydrochloride (1.12 g, 8 mmol) was dissolved in
H2O (2.5 mL) and 5% sulfuric acid (0.76 mL, w/w) was
added and a 4-mL syringe was equipped with the mixture.
Next, NaNO2 (664 mg, 10 mmol) was dissolved in H2O (3.9
mL) and another 4-mL syringe was equipped with this
solution. The two syringes were connected to a flow setup
with a T-piece mixer and a 0.9-mL coil (PTFE, i.d. = 0.5
mm). 1,8-Diazabicycloundec-7-ene (596 μL, 4 mmol) was
dissolved in dimethylsulfoxide (3.4 mL) and charged into a
4-mL syringe. Aldehyde (4 mmol) was dissolved in the
required amount of DMSO to have a solution of exactly 4
mL volume. This mixture was charged into another 4-mL
syringe. Both syringes were put to another syringe pump and
connected with two T-pieces to the outlet of the first coil as
well as to the inlet of the second coil. The second coil
consisted of a 2-mL coil (PTFE, i.d. = 0.8 mm). The pumps
were set to 4 mL/h and the entire setup ran for 28 min to
reach the steady state. Afterwards, the product was collected
for 20–30 min in NaHCO3 as quenching agent. Extraction
was performed with CH2Cl2 (3 × 10 mL), the combined
organic layers were washed with H2O thoroughly (3 × 10
Ethyl 2-Diazo-3-(2-ethoxyphenyl)-3-hydroxypropanoate
(4f): obtained as a yellow solid; 328 mg (22 min collection
time; 85% yield). 1H NMR (500 MHz, CDCl3): δ = 7.44 (d,
J = 7.5 Hz, 1 H, ArH), 7.28 (td, J = 8.0, 1.5 Hz, 1 H, ArH),
6.98 (dt, J = 7.5, 1 Hz, 1 H, ArH), 6.90 (d, J = 8.0 Hz, 1 H,
ArH), 5.90 (d, J = 6.5 Hz, 1 H, CHOH), 4.25 (q, J = 7.0 Hz,
2 H, CO2CH2CH3), 4.08 (m, 2 H, OCH2CH3), 3.62 (br s, 1 H,
CHOH), 1.42 (t, J = 7.0 Hz, 3 H, OCH2CH3), 1.29 (t, J = 7.0
Hz, 3 H, CO2CH2CH3). 13C NMR (125 MHz, CDCl3): δ =
166.5, 155.4, 129.3, 127.2, 127.2, 120.8, 111.2, 66.4, 63.7,
60.9, 14.8, 14.5.
Ethyl 2-Diazo-3-(4-fluorophenyl)-3-hydroxypropanoate
(4g): obtained as a yellow oil; 259.8 mg (20 min collection
time; 1.09 mmol, 82%). 1H NMR (400 MHz, CDCl3): δ =
7.68 (m, 2 H, ArH), 7.35 (m, 2 H, ArH), 6.17 (d, J = 3.5 Hz,
1 H, CHOH), 4.55 (q, J = 7.0 Hz, 2 H, CH2CH3), 3.36 (br s,
1 H, CHOH), 1.57 (t, J = 7.0 Hz, 3 H, CH2CH3). 13C NMR
(100 MHz, CDCl3): δ = 167.0, 163.5 (d, J = 234 Hz), 135.4,
128.2 (d, J = 9 Hz), 116.3 (d, J = 20 Hz), 68.8, 61.9, 15.1.
MS (EI): m/z = 238.07 [M+].
Ethyl 2-Diazo-3-hydroxyoctanoate (4h): obtained as pale
Synlett 2014, 25, 871–875
© Georg Thieme Verlag Stuttgart · New York

LETTER
Safe Generation and Direct Use of Diazoesters in Flow Chemistry
875
yellow oil; 188 mg (20 min collection time; 66% yield). 1H
reactor (i.d. 0.8 mm, 1 mL). After the first two reactors had
reached steady state, the third pump was started and
collection commenced after another 4 min after the last
reactor has reached steady state. The product was collected
for 20–30 min in sat. NaHCO3 solution. Extraction was
performed with CH2Cl2 (3 × 10 mL), the combined organic
layers were washed with H2O (3 × 10 mL) and dried over
anhyd MgSO4. After evaporating the solvent in vacuo, the β-
keto ester was purified by column chromatography (hexane–
EtOAc, 98:2).
NMR (400 MHz, CDCl3): δ = 4.90 (dt, J = 4.5, 9.5 Hz, 1 H,
CHOH), 4.47 (q, J = 7.0 Hz, 2 H, OCH2CH3), 2.80 (br s, 1
H, CHOH), 1.86 (m, 2 H, CH2CHOH), 1.53 (m, 9 H,
CH2CH2CH2CH3), 1.12 (t, J = 7.0 Hz, 3 H, OCH2CH3). 13
C
NMR (100 MHz, CDCl3): δ = 167.3, 67.3, 61.6, 34.5, 32.0,
25.8, 23.1, 15.1, 14.6. MS (EI): m/z = 214.14 [M+].
Ethyl 2-Diazo-3-(furan-2-yl)-3-hydroxypropanoate (4i):
obtained as a yellow oil; 94 mg (15 min collection time; 45%
yield). 1H NMR (400 MHz, CDCl3): δ = 7.49 (t, J = 0.8 Hz,
1 H, OCH=C), 6.46 (m, 2 H, CH=CH), 5.91 (d, J = 4.5 Hz,
1 H), 5.64 (d, J = 5.0 Hz, 1 H), 4.35 (q, J = 7.0 Hz, 2 H), 1.38
(t, J = 7.5 Hz, 3 H). 13C NMR (125 MHz, CDCl3): δ = 166.1,
143.4, 143.1, 110.7, 107.8, 63.9, 61.5, 14.7. MS (EI): m/z =
208.11 [M+].
Ethyl 3-(Bicyclo[2.2.1]hept-5-en-2-yl)-2-diazo-3-
hydroxypropanoate (4j): obtained as a yellow oil; 238 mg
(20 min collection time; 75% yield). MS (EI): m/z = 236.12
[M+].
General Procedure for the Three-Step Process: Syringes,
pumps, reagents and flow setup were built the way as
described for the two-step procedure. Rhodium acetate
dimer (0.025 mmol, 11 mg) was dissolved in a H2O–DMSO
(1:1; 10 mL) mixture. The solution was charged onto a 10-
mL syringe and put on a third syringe pump which was
calibrated on a flow rate of 16 mL/h to run through the third
Ethyl 3-Oxo-3-phenylpropanoate (5a): obtained as a
colourless oil; 187 mg (20 min collection time; 73% yield).
Keto form: 1H NMR (400 MHz, CDCl3): δ = 7.88 (m, 2 H,
ArH), 7.39 (m, 3 H, ArH), 4.14 (q, J = 7.0 Hz, 2 H, CH2CH3),
3.92 (s, 2 H, OCCH2CO), 1.18 (t, J = 7.0 Hz, 3 H, CH3CH2).
13C NMR (125 MHz, CDCl3): δ = 193.2, 168.1, 134.4, 129.4,
60.9, 40.6, 14.6. Enol form: 1H NMR (400 MHz, CDCl3): δ
= 12.78 (s, 1 H, OH), 7.70 (m, 2 H, ArH), 7.53 (m, 2 H,
ArH), 7.34 (m, 1 H, ArH), 5.60 (s, 1 H, C=CH), 4.19 (q, J =
7.0 Hz, 2 H, OCH2CH3), 1.26 (t, J = 7.0 Hz, 3 H, OCH2CH3).
13C NMR (100 MHz, CDCl3): δ = 173.8, 172.0, 134.0, 131.8,
126.6, 88.0, 60.9, 14.9. MS (EI): m/z = 192.07 [M+].
(24) During the finalization of this manuscript, a similar report
has been published: Maurya, R. A.; Min, K.-I.; Kim, D.-P.
Green Chem. 2014, 16, 116.
© Georg Thieme Verlag Stuttgart · New York
Synlett 2014, 25, 871–875

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