Rearrangement of 2-bromo-1-(bromomethyl)ethyl esters under basic conditions: Scope and mechanism

Article abstract of DOI:10.1055/s-0033-1339649

A novel rearrangement of 2-bromo-1-(bromomethyl)ethyl esters into the corresponding 2-oxopropyl derivatives is reported. The mechanism of this transformation was studied by means of ¹⁸O- and ²H- labeling experiments. The reaction pro

Full text of DOI:10.1055/s-0033-1339649

PAPER
▌2861
paper
Rearrangement of 2-Bromo-1-(bromomethyl)ethyl Esters Under Basic
Conditions: Scope and Mechanism
Rearrangement of 2-Bromo-1-(bromomethyl)ethyl Esters
Julien Alliot, Edmond Gravel, Eric Doris*
CEA, iBiTecS, Service de Chimie Bioorganique et de Marquage, 91191 Gif-sur-Yvette, France
Fax +33(0)169087991; E-mail: eric.doris@cea.fr
Received: 27.06.2013; Accepted after revision: 30.07.2013
Br
Abstract: A novel rearrangement of 2-bromo-1-(bromometh-
Br
yl)ethyl esters into the corresponding 2-oxopropyl derivatives is re-
ported. The mechanism of this transformation was studied by means
of 18O- and 2H-labeling experiments. The reaction proceeds through
a transient dioxolane intermediate that is hydrolyzed to form the
corresponding 2-oxopropyl acetate.
O
O
Br
HO
R
R
Br
X
O
X = OH, OMe, Cl
R = aryl, EWG, alkyl
2
Key words: esters, halogens, ketones, rearrangements
Scheme 2 Synthesis of halo ester 2
Before attempting to extend the scope of our novel rear-
rangement, we first optimized the reaction conditions for
ester 2a by changing the solvent, base, and reaction tem-
perature. Attempts to perform the reaction using 2.2
equivalents of sodium hydride in warm dimethyl sulfox-
ide (Table 1, entry 1) gave only a moderate yield of prod-
uct 3a (54%); this could be slightly improved by
performing the reaction in refluxing tetrahydrofuran, al-
though the yield (62%) was still less than satisfactory (en-
try 2). We nevertheless selected tetrahydrofuran as the
solvent and we examined the effects of other bases. The
use of lithium diisopropylamide in refluxing tetrahydrofu-
ran gave disappointing results, as no traces of the desired
keto ester 3a were detected (entry 3). The use of potassi-
um tert-butoxide in tetrahydrofuran at room temperature
gave the expected compound in a poor yield (21%; entry
4); the best results were obtained with this base in reflux-
ing tetrahydrofuran, which gave a 92% yield of keto ester
3a (entry 5).
As part of our ongoing interest in the synthesis of bioac-
tive compounds,1 we recently developed an original ap-
proach for the synthesis of milnacipran,2 an antidepressant
currently on the market for the treatment of major depres-
sive disorders. Our strategy involved the synthesis of a
halo lactone related to 1 (Scheme 1) as a key intermediate
that was subsequently transformed into the target drug.
The results obtained in the context of that study prompted
us to try to develop a general and alternative route to halo
lactone 1 by intramolecular cyclization of substituted 2-
bromo-1-(bromomethyl)ethyl phenylacetate (2a). How-
ever, various attempts to induce the formation of the lac-
tone ring by carbocyclization under basic conditions
systematically led to an unexpected rearrangement to the
keto ester 3a (Scheme 1), which contained an extra oxy-
gen atom and no bromine atoms. Intrigued by this peculiar
behavior of compound 2a, we decided to investigate the
scope and mechanism of this novel rearrangement.
O
O
Table 1 Optimization of the Reaction Conditions
O
Ph
Ph
base
base
Br
Ph
O
O
O
O
O
1) base (2.2 equiv)
2) H2O/H+
Ph
Br
Ph
O
Br
O
2a
O
Br
Br
1
2a
3a
O
3a
Scheme 1 Reaction of 2-bromo-1-(bromomethyl)ethyl phenylace-
tate (2a) on treatment with a base
Entry
Base
Solvent
Temp (°C)
Yield (%)
1
2
3
4
5
NaH
DMSO
THF
70
54
62
–
We synthesized a series of halo esters 2 from the corre-
sponding carboxylic acids by esterification with 1,3-di-
bromopropan-2-ol under dehydrating conditions, from the
corresponding methyl esters by transesterification under
acidic conditions, or from the corresponding acyl chlo-
rides (Scheme 2).
NaH
reflux
reflux
20
LDA
THF
t-BuOK
t-BuOK
THF
21
92
THF
reflux
Having optimized the reaction conditions, we next fo-
cused on the use of other substrates. Substitution of the
aryl moiety appeared to have little or no effect on the over-
SYNTHESIS 2013, 45, 2861–2866
Advanced online publication: 12.08.2013
DOI: 10.1055/s-0033-1339649; Art ID: SS-2013-T0443-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

2862
J. Alliot et al.
PAPER
all efficiency of the reaction; 4-bromo- and 4-methoxy- toxide were not clean, as many degradation products were
substituted esters (Table 2, entries 1 and 2) were convert- detected. In these specific cases, 1,8-diazabicyc-
ed into the corresponding keto esters in very high yields. lo[5.4.0]undec-7-ene was found to be a better choice of
The effects of substitution at the position between the car- base. Although the rearrangement reaction was highly ef-
bonyl group and the benzene ring were studied by intro- ficient in the case of substrates bearing an electron-
ducing either a second phenyl group (entry 3) or a withdrawing group in the position α to the ester, it failed
bromine atom (entry 4). Again, the rearrangement pro- in the case of an ester substituted with an aliphatic chain
ceeded smoothly to afford the expected compounds in (entry 8).
96% and 89% yield, respectively. Substitution of the halo
A proposed mechanism for this transformation is illustrat-
ester part of the molecule was then investigated by intro-
ed in Scheme 3 for the case of conversion of 2-bromo-1-
ducing two methyl groups onto the dibromoalkyl moiety
(bromomethyl)ethyl phenylacetate (2a) into 2-oxopropyl
phenylacetate (3a). The base deprotonates the position ad-
(entry 5). Rearrangement gave the expected product,
which incorporated a branched keto ester side chain. The
jacent to both the ester group and the aryl group. The re-
lower efficiency of this reaction (58% yield) might be due
sulting enolate is then O-alkylated by one of the vicinal
to greater steric hindrance in the substrate. Interestingly,
alkyl halide groups; this is followed by β-elimination of
the rearrangement also worked on malonate (entry 6) and
the second halogen atom, as already observed by Shimizu
cyano acetate (entry 7) substrates, although potassium
and Yoshioka3 (path B). Subsequently, the transient 2-
tert-butoxide was not the most appropriate base in these
benzylidene-4-methylene-1,3-dioxolane (5) is hydrolyzed
cases. In fact, 1H NMR spectroscopy of the crude mixtures
by quenching of the reaction with acidic water, which trig-
indicated that the reactions initiated by potassium tert-bu-
Table 2 Scope of the Reaction
Entry
Starting material
Base
Product
Yield (%)
93
Br
Br
Br
O
O
1
2b
t-BuOK
3b
3c
Br
O
O
O
MeO
O
MeO
Br
O
2
3
4
2c
t-BuOK
t-BuOK
t-BuOK
91
96
89
O
Br
O
O
Br
O
O
Br
O
O
2d
3d
O
Br
Br
Br
O
O
O
Br
Br
Br
2e
2f
3e
3f
O
O
O
O
Br
O
Br
O
O
5
6
t-BuOK
58
84
O
O
O
O
O
2g
DBU
3g
3h
MeO
NC
O
MeO
NC
O
O
Br
O
7
8
2h
2i
DBU
91
O
Br
O
O
Br
O
t-BuOK
–
NR
Br
O
Synthesis 2013, 45, 2861–2866
© Georg Thieme Verlag Stuttgart · New York

PAPER
Rearrangement of 2-Bromo-1-(bromomethyl)ethyl Esters
2863
gers opening of the dioxolane ring and rearrangement into copy (carbons bearing deuterium atoms appeared as trip-
the final product 3a. A similar transformation has previ- lets with a coupling constant of approximately 20 Hz) of
ously been reported for a fluorinated dioxolane system.4 compound 3a′′. This result is consistent with protonation
We believe that this reaction proceeds by a sequential of the benzylidene and methylene groups after addition of
two-step process (alkylation/elimination), as running the water at the 2-position of dioxolane 5. Finally, careful
reaction at room temperature and early quenching (for ex- quenching of the reaction with water permitted the isola-
ample, after 30 min) cleanly gave the hydroxy bromo ester tion of dioxolane 5 as a mixture of isomers in an 8:2 ratio.
6 (path A), in which only the primary O-alkylation had oc- On addition of acidic water, dioxolane 5 underwent
curred.
smooth ring cleavage to give keto ester 3a. Taken togeth-
er, these observations confirm our proposed pathway.
Br
O
Br
Ph
Br
Br
O
O
Ph
Br
2a
O
B–
2a
Br
base
O–
18O
Ph
Ph
H318O
O
O
O
4
Ph
O
Ph
2
O
O
H2O/H+
path A
H
B–
O
5
3a'
Br
path B
D3O
O
Br
O
O
Ph
O
HO
Ph
Ph
O
D
O
O
5
H2O/H+
O
D
3a"
O
OH
Scheme 4 Isotopic labeling experiments
O
HO
Ph
H+
O
Ph
Br
In conclusion, we have identified a novel rearrangement
of 2-bromo-1-(bromomethyl)ethyl esters under basic con-
ditions. Mechanistic studies with 18O- or 2H-labeled water
showed that the reaction proceeds through a transient di-
oxolane intermediate that undergoes further hydrolysis to
give the corresponding 2-oxopropyl acetate, the classical
preparation of which involves alkylation5 or
esterification6 of a carboxylic acid with an α-halo or α-hy-
droxy ketone, respectively.
6
O
Ph
O
O
3a
Scheme 3 Proposed mechanism of the rearrangement reaction
Evidence for the formation of 2-benzylidene-4-methy-
lene-1,3-dioxolane (5) as an intermediate in the rearrange-
ment was provided by isotopic labeling techniques
(Scheme 4). When we replaced the water used to quench
the reaction with 18O-labelled water, we observed selec-
tive incorporation of 18O at the ester carbonyl position, as
confirmed by 13C NMR spectroscopy of compound 3a′,
which showed the presence of two signals at δ = 170.82
ppm and δ = 170.87 ppm. The observed difference in the
chemical shifts can be ascribed to the presence of labeled
and nonlabeled carbonyl groups. Isotope incorporation
was further confirmed by mass spectrometry, which indi-
cated 74% isotopic enrichment of the sample. Therefore,
the carbonyl group of the ester originated from water,
which confirmed the initial nucleophilic addition of the
latter at the 2-position of compound 5. Further evidence of
the occurrence of 5 as an intermediate was obtained by
quenching the reaction with water-d2/sulfuric acid-d2.
This experiment led to clean incorporation of deuterium in
the position α to the ester group and in the terminal methyl
group, as evidenced by 1H NMR (lower integration of the
methylene and methyl signals) and by 13C NMR spectros-
Chemicals were purchased from Aldrich except for 2,4-dibromo-
pentan-3-ol, which was prepared according to the procedures de-
scribed in the literature.7 Reactions were carried out with anhyd
solvents. THF and CH2Cl2 were distilled from Na/benzophenone
and CaH2, respectively. Flash chromatography was carried out on
Kieselgel 60 (230–240 mesh; Merck). Analytical TLC was per-
formed on plates precoated with silica gel (60 F254; Merck); visual-
ization was carried out by UV irradiation and/or by heating with a
5–7% soln of phosphomolybdic acid in EtOH. Mass spectra were
1
recorded on an ESI-TOF Mariner spectrometer. H and 13C NMR
spectra were recorded on a Bruker Avance DPX 400 spectrometer
at 400 and 100 MHz. IR spectra were recorded on a PerkinElmer
System 2000 FT-IR spectrometer.
2-Bromo-1-(bromomethyl)ethyl Phenylacetate (2a)8
HOCH(CH2Br)2 (5.4 mmol) and pyridine (6.9 mmol) were added to
a soln of BnCOCl (6.4 mmol) in anhyd THF (20 mL) under N2, and
the mixture was stirred overnight at r.t. The reaction was quenched
with 1 M aq HCl (20 mL), and the aqueous phase was extracted with
Et2O (3 × 20 mL). The organic layers were combined, washed with
brine (10 mL), dried (Na2SO4), filtered, and concentrated under vac-
uum. The crude mixture was purified by chromatography [silica gel,
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2861–2866

2864
J. Alliot et al.
PAPER
EtOAc–cyclohexane (5:95 to 30:70)] to give a colorless oil; yield:
1.7 g (95%).
13C NMR (CDCl3): δ = 170.5, 133.1, 129.3 (2 C), 128.6 (2 C),
127.9, 78.1, 49.7, 47.8, 41.2, 22.8, 21.5.
IR (neat): 2980, 1742, 1486 cm–1.
1H NMR (CDCl3): δ = 7.36–7.28 (m, 5 H), 5.14 (quin, J = 5.2 Hz,
1 H), 3.69 (s, 2 H), 3.60 (d, J = 5.2 Hz, 4 H).
13C NMR (CDCl3): δ = 170.4, 133.1, 129.2 (2 C), 128.6 (2 C),
127.3, 71.3, 41.0, 31.1 (2 C).
2-Bromo-1-(bromomethyl)ethyl Cyanoacetate (2h)
Colorless oil; yield: 118 mg (83%).
IR (neat): 2967, 2264, 1755, 1178, 1024 cm–1.
1H NMR (CDCl3): δ = 5.25 (quin, J = 5.2 Hz, 1 H), 3.63 (d, J = 5.2
Hz, 4 H), 3.57 (s, 2 H).
13C NMR (CDCl3): δ = 161.9, 112.1, 73.6, 30.3 (2 C), 24.6.
Esters 2b–f, 2h, and 2i; General Procedure
The appropriate carboxylic acid (0.75 mmol), DMAP (0.05 mmol),
and DCC (0.75 mmol) were added to a soln of the dibromo alcohol
(0.5 mmol) in anhyd CH2Cl2 (5 mL) under N2, and the mixture was
stirred overnight. The precipitate was filtered off and the organic
phase was washed with 1 M aq HCl (10 mL). The aqueous layer was
extracted with CH2Cl2 (2 × 10 mL) and the organic layers were
combined, washed with brine (10 mL), dried (Na2SO4), filtered, and
concentrated under vacuum. The crude mixture was purified by
chromatography [silica gel, pentane–CH2Cl2 (8:2 to 0:1)].
2-Bromo-1-(bromomethyl)ethyl 4-Phenylbutanoate (2i)
Colorless oil; yield: 178 mg (98%).
IR (neat): 3027, 2933, 1740, 1139 cm–1.
1H NMR (CDCl3): δ = 7.31–7.28 (m, 2 H), 7.22–7.18 (m, 3 H), 5.14
(quin, J = 5.2 Hz, 1 H), 3.60 (d, J = 5.2 Hz, 4 H), 2.68 (t, J = 7.6 Hz,
2 H), 2.40 (t, J = 7.6 Hz, 2 H), 1.99 (quin, J = 7.6 Hz, 2 H).
13C NMR (CDCl3): δ = 172.2, 141.1, 128.5 (2 C), 128.3 (2 C),
126.0, 70.8, 34.9, 33.4, 31.4 (2 C), 26.8.
2-Bromo-1-(bromomethyl)ethyl 2-(4-Bromophenyl)acetate (2b)
Colorless oil; yield: 205 mg (99%).
IR (neat): 2923, 1743, 1488, 1146, 804 cm–1.
1H NMR (CDCl3): δ = 7.46 (d, J = 8.4 Hz, 2 H), 7.18 (d, J = 8.4 Hz,
2 H), 5.14 (quin, J = 5.2 Hz, 1 H), 3.64 (s, 2 H), 3.59 (d, J = 5.2 Hz,
4 H).
2-Bromo-1-(bromomethyl)ethyl Methyl Malonate (2g)
A soln of dimethyl malonate (1.35 mmol), HOCH(CH2Br)2 (0.5
mmol), and PTSA (0.05 mmol) in toluene (30 mL) was refluxed un-
der N2 while the toluene was slowly distilled off over 8 h. (More tol-
uene was added when the volume fell to ~10 mL.) H2O (10 mL) was
added and the mixture was extracted with Et2O (3 × 10 mL). The or-
ganic layers were combined, washed with brine (5 mL), dried
(Na2SO4), filtered, and concentrated under vacuum. The crude mix-
ture was purified by chromatography [silica gel, EtOAc–cyclohex-
ane (0:10 to 15:85)] to give a colorless oil; yield: 104 mg (63%).
13C NMR (CDCl3): δ = 169.8, 132.0, 131.7 (2 C), 131.0 (2 C),
121.4, 71.1, 40.4, 31.0 (2 C).
2-Bromo-1-(bromomethyl)ethyl 2-(4-Methoxyphenyl)acetate
(2c)
IR (neat): 2954, 1754, 1738, 1436, 1146, 732 cm–1.
1H NMR (CDCl3): δ = 5.19 (quin, J = 5.2 Hz, 1 H), 3.76 (s, 3 H),
3.63 (d, J = 5.2 Hz, 4 H), 3.49 (s, 2 H).
Colorless oil; yield: 181 mg (99%).
IR (neat): 3014, 2934, 1742, 1513, 1141, 821 cm–1.
1H NMR (CDCl3): δ = 7.22 (d, J = 8.4 Hz, 2 H), 6.87 (d, J = 8.4 Hz,
2 H), 5.14 (quin, J = 5.2 Hz, 1 H), 3.62 (s, 2 H), 3.80 (s, 3 H), 3.59
(d, J = 5.2 Hz, 4 H).
13C NMR (CDCl3): δ = 166.3, 165.2, 72.0, 52.6, 41.1, 30.7 (2 C).
Oxoalkyl Esters 3a–h; General Procedure
13C NMR (CDCl3): δ = 170.6, 158.7, 130.2 (2 C), 125.1, 114.0 (2
C), 71.2, 55.2, 40.1, 31.1 (2 C).
t-BuOK or DBU (see Table 2; 0.44 mmol) was added to a soln of
dibromo ester 2 (0.2 mmol) in anhyd THF (2 mL) under N2. The
mixture was stirred under reflux for 3 h then cooled to r.t. The reac-
tion was then quenched with 1 M aq HCl (2 mL), and the aqueous
layer was extracted with Et2O (3 × 2 mL). The organic layers were
combined, washed with brine (2 mL), dried (Na2SO4), filtered, and
concentrated under vacuum. The crude mixture was purified by
chromatography [silica gel, pentane–CH2Cl2 (8:2 to 5:1)].
2-Bromo-1-(bromomethyl)ethyl Diphenylacetate (2d)
Colorless oil; yield: 354 mg (86%).
IR (neat): 3029, 2991, 1740, 1599, 1494, 1138, 698 cm–1.
1H NMR (CDCl3): δ = 7.33–7.7.41 (m, 8 H), 7.28–7.31 (m, 2 H),
5.21 (quin, J = 5.2 Hz, 1 H), 5.09 (s, 1 H), 3.58 (d, J = 5.2 Hz, 4 H).
2-Oxopropyl 2-Phenylacetate (3a)9
Colorless oil; yield: 35 mg (92%).
IR (neat): 2935, 1744, 1732, 1451, 1148 cm–1.
1H NMR (CDCl3): δ = 7.35–7.27 (m, 5 H), 4.66 (s, 2 H), 3.75 (s, 2
H), 2.11 (s, 3 H).
13C NMR (CDCl3): δ = 201.4, 170.8, 133.4, 129.3 (2 C), 128.6 (2
C), 127.2, 68.5, 40.8, 25.9.
13C NMR (CDCl3): δ = 171.3, 137.8 (2 C), 128.6 (8 C), 127.4 (2 C),
71.7, 56.8, 31.0 (2 C).
2-Bromo-1-(bromomethyl)ethyl Bromo(phenyl)acetate (2e)
IR (neat): 3031, 2967, 1750, 1134, 694 cm–1.
Colorless oil; yield: 201 mg (97%).
1H NMR (CDCl3): δ = 7.58–7.55 (m, 2 H), 7.40–7.37 (m, 3 H), 5.39
(s, 1 H), 5.18 (quin, J = 5.4 Hz, 1 H), 3.64 (d, J = 5.2 Hz, 2 H), 3.58
(d, J = 5.2 Hz, 2 H).
13C NMR (CDCl3): δ = 167.1, 134.9, 129.5, 128.8 (2 C), 128.6 (2
C), 72.7, 45.9, 30.4 (2 C).
2-Oxopropyl 2-(4-Bromophenyl)acetate (3b)
Colorless oil; yield: 50 mg (93%).
IR (neat): 2928, 1749, 1732, 1489, 1148, 800 cm–1.
1H NMR (CDCl3): δ = 7.46 (d, J = 8.3 Hz, 2 H), 7.19 (d, J = 8.3 Hz,
2 H), 4.67 (s, 2 H), 3.71 (s, 2 H), 2.13 (s, 3 H).
13C NMR (CDCl3): δ = 201.0, 170.2, 132.2, 131.6 (2 C), 131.0 (2
C), 121.3, 68.6, 40.1, 25.9.
MS (ESI+): m/z = 271/273 [M + H]+.
HRMS: m/z [M + H]+ calcd for C11H12BrO3: 270.9970; found:
2-Bromo-1-(1-bromoethyl)propyl Phenylacetate (2f)
Colorless oil; yield: 84 mg (46%).
IR (neat): 3031, 2981, 1744, 1135 cm–1.
1H NMR (CDCl3): δ = 7.34–7.28 (m, 5 H), 4.94 (dd, J = 9.6, 2.0 Hz,
1 H), 4.74 (qd, J = 6.8, 2.0 Hz, 1 H), 4.23–4.19 (m, 1 H), 3.74 (d,
J = 1.8 Hz, 2 H), 1.55 (d, J = 2.0 Hz, 3 H), 1.53 (d, J = 2.0 Hz, 3 H),
270.9959.
Synthesis 2013, 45, 2861–2866
© Georg Thieme Verlag Stuttgart · New York

PAPER
Rearrangement of 2-Bromo-1-(bromomethyl)ethyl Esters
2865
2-Oxopropyl 2-(4-Methoxyphenyl)acetate (3c)
Colorless oil; yield: 40 mg (91%).
HRMS: m/z [M – H]+ calcd for C6H6NO3: 140.0348; found:
140.0349.
IR (neat): 2936, 1741, 1732, 1513, 1146, 815 cm–1.
1H NMR (CDCl3): δ = 7.23 (d, J = 8.8 Hz, 2 H), 6.87 (d, J = 8.8 Hz,
2 H), 4.65 (s, 2 H), 3.79, (s, 3 H), 3.69 (s, 2 H), 2.11 (s, 3 H).
13C NMR (CDCl3): δ = 201.5, 171.1, 158.7, 130.4 (2 C), 125.4,
113.9 (2 C), 68.5, 55.2, 39.8, 26.0.
MS (ESI+): m/z = 245 [M + H]+.
HRMS: m/z [M+] calcd for C12H15O4: 223.0966; found: 223.0961.
2-Oxopropyl 2-Phenylacetate-d2 (3a′′)
t-BuOK (0.75 mmol) was added to a soln of BnCO2CH(CH2Br)2
(0.29 mmol) in anhyd THF (3 mL) under N2, and the mixture was
stirred under reflux for 3 h then cooled to r.t. The reaction was
quenched with 1 M D2SO4 in D2O (0.5 mL), and the aqueous layer
was extracted with Et2O (3 × 3 mL). The organic layers were com-
bined, washed with brine (2 mL), dried (Na2SO4), filtered, and con-
centrated under vacuum. The crude mixture was purified by
chromatography [silica gel, pentane–CH2Cl2 (8:2 to 5:5)].
2-Oxopropyl Diphenylacetate (3d)
Colorless oil; yield: 51 mg (96%).
IR (neat): 3029, 2929, 1743, 1732, 1600, 1495, 1143, 700 cm–1.
1H NMR (CDCl3): δ = 7.38–7.27 (m, 10 H), 5.17 (s, 1 H), 4.70 (s, 2
H), 2.10 (s, 3 H).
13C NMR (CDCl3): δ = 201.3, 171.8, 138.1 (2 C), 128.7 (4 C), 128.6
(4 C), 127.4 (2 C), 68.7, 56.7, 26.0.
MS (ESI+): m/z = 291 [M + Na]+.
Colorless oil; yield: 49 mg (89%).
IR (neat): 1744, 1732 cm–1.
1H NMR (CDCl3): δ = 7.35–7.27 (m, 5 H), 4.66 (s, 2 H), 3.77–3.74
(s, 1 H), 2.14–2.10 (s, 2 H).
13C NMR (CDCl3): δ = 201.4, 170.8, 133.4, 129.3 (2 C), 128.6 (2
C), 127.2, 68.5, 40.6 (t, JC–D = 19.9 Hz), 25.8 (t, JC–D = 19.9 Hz).
MS (ESI+): m/z = 193 [MH + H]+, 195 [MD + H]+ (relative intensity:
1:2).
HRMS: m/z [M + H]+ calcd for C17H17O3: 269.1178; found:
269.1168.
2-Oxopropyl Phenylacetate-18O (3a′)
t-BuOK (0.36 mmol) was added to a soln of BnCO2CH(CH2Br)2
(0.16 mmol) in anhyd THF (1.5 mL) under N2, and the mixture was
stirred under reflux for 3 h. The reaction was then quenched by the
addition of H218O (50 µL) and one drop of concd H2SO4. The mix-
ture was stirred for 2 h and then diluted with H2O (2 mL). The aque-
ous layer was extracted with Et2O (3 × 2 mL), and the organic layers
were combined, washed with brine (2 mL), dried (Na2SO4), filtered,
and concentrated under vacuum. The crude mixture was purified by
chromatography [silica gel, pentane–CH2Cl2 (8:2 to 5:5)] to give a
colorless oil; yield: 12 mg (41%).
IR (neat): 1743, 1732 cm–1.
1H NMR (CDCl3): δ = 7.35–7.27 (m, 5 H), 4.67 (s, 2 H), 3.77 (s, 2
H), 2.12 (s, 3 H).
13C NMR (CDCl3): δ = 201.4, 170.87/170.82, 133.4, 129.3 (2 C),
2-Oxopropyl Bromo(phenyl)acetate (3e)
Colorless oil; yield: 48 mg (89%).
IR (neat): 3064, 2927, 1743, 1732, 1138, 708 cm–1.
1H NMR (CDCl3): δ = 7.60–7.57 (m, 2 H), 7.40–7.36 (m, 3 H), 5.48
(s, 1 H), 4.72 (s, 2 H), 2.14 (s, 3 H).
13C NMR (CDCl3): δ = 200.6, 167.6, 135.2, 129.4, 128.8 (2 C),
128.6 (2 C), 69.4, 45.9, 26.1.
HRMS: m/z [M + Na]+ calcd for C11H11BrNaO3: 292.9789; found:
292.9781.
1-Methyl-2-oxobutyl Phenylacetate (3f)
Colorless oil; yield: 25 mg (58%).
IR (neat): 3015, 1742, 1733, 1454, 1145 cm–1.
128.6 (2 C), 127.3, 68.6, 40.9, 26.1.
1H NMR (CDCl3): δ = 7.38–7.30 (m, 5 H), 5.13 (q, J = 7.0 Hz, 1 H),
3.73 (s, 2 H), 3.50–3.34 (m, 2 H), 1.41 (d, J = 7.0 Hz, 3 H), 1.04 (t,
J = 7.3 Hz, 3 H).
MS (ESI+): m/z = 215 [M16O + Na]+, 217 [M18O + Na]+ (relative in-
tensity 1:3).
13C NMR (CDCl3): δ = 208.2, 170.9, 133.5, 129.3 (2 C), 128.5 (2
2-Benzylidene-4-methylene-1,3-dioxolane (5)
t-BuOK (0.44 mmol) was added to a soln of BnCO2CH(CH2Br)2
(0.2 mmol) in anhyd THF (2 mL) under N2, and the mixture was
stirred under reflux for 3 h then cooled to r.t. The reaction was
quenched with H2O (2 mL), and the aqueous layer was extracted
with Et2O (3 × 2 mL). The organic layers were combined, washed
with brine (2 mL), dried (Na2SO4), filtered, and concentrated under
vacuum to give the product as a yellow oil; yield: 33 mg (95%; 8:2
mixture of two isomers A and B).
C), 127.2, 74.8, 41.0, 31.4, 16.2, 7.1.
HRMS: m/z [M + H]+ calcd for C13H17O3: 221.1178; found:
221.1167.
2-Oxopropyl Methyl Malonate (3g)
Colorless oil; yield: 32 mg (84%).
IR (neat): 2998, 1757, 1734, 1438, 1149 cm–1.
IR (neat): 2935, 1135 cm–1.
1H NMR (CDCl3): δ = 4.72 (s, 2 H), 3.77 (s, 3 H), 3.52 (s, 2 H), 2.18
(s, 3 H).
1H NMR (CDCl3): δ (isomers A + B) = 7.43–7.40 (m, 2 HAB), 7.30–
7.26 (m, 2 HAB), 7.10–7.07 (m, 1 HAB), 5.01–4.99 (m, 3 HA), 4.97
(s, 1 HB), 4.86 (m, 1 HB), 4.81 (m, 2 HB), 4.71 (m, 1 HA), 4.32 (m, 1
HB), 4.25 (m, 1 HA).
13C NMR (CDCl3): δ (isomer A) = 158.9, 151.2, 135.1, 128.3 (2 C),
126.4 (2 C), 124.2, 82.3, 76.6, 68.7.
13C NMR (CDCl3): δ = 200.9, 166.3, 165.2, 72.0, 52.6, 41.1, 30.7
(2 C).
HRMS: m/z [M + Na]+ calcd for C7H10O5Na: 197.0426; found:
197.0425.
HRMS: m/z [M+] calcd for C11H10O2: 174.0681; found: 174.0687.
2-Oxopropyl Cyanoacetate (3h)
Colorless oil; yield: 26 mg (91%).
IR (neat): 2932, 2261, 1758, 1733, 1652, 1167 cm–1.
2-Bromo-1-(hydroxymethyl)ethyl Phenylacetate (6)
t-BuOK (0.44 mmol) was added to a soln of BnCO2CH(CH2Br)2
(0.2 mmol) in anhyd THF (2 mL) under N2, and the mixture was
stirred at r.t. for 30 min. The reaction was then quenched with 1 M
aq HCl (2 mL) and the aqueous layer was extracted with Et2O (3 ×
2 mL). The organic layers were combined, washed with brine (2
1H NMR (CDCl3): δ = 4.78 (s, 2 H), 3.61 (s, 2 H), 2.19 (s, 3 H).
13C NMR (CDCl3): δ = 199.1, 162.3, 112.5, 69.6, 25.8, 24.3.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2861–2866

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J. Alliot et al.
PAPER
mL), dried (Na2SO4), filtered, and concentrated under vacuum. The
crude mixture was purified by chromatography [silica gel, CH2Cl2–
EtOAc (10:0 to 9:1)] to give a colorless oil; yield: 33 mg (62%).
IR (neat): 3400, 1744, 1135 cm–1.
1H NMR (CDCl3): δ = 7.38–7.35 (m, 2 H), 7.32–7.29 (m, 3 H),
4.28–4.24 (m, 2 H), 4.05 (m, 1 H), 3.70 (s, 2 H), 3.46 (dd, J = 10.6,
5.4 Hz, 1 H), 3.40 (dd, J = 10.6, 5.4 Hz, 1 H).
(h) Leroux, S.; Larquetoux, L.; Nicolas, M.; Doris, E. Org.
Lett. 2011, 13, 3549. (i) Giovanelli, E.; Leroux, S.; Moisan,
L.; Carreyre, H.; Thuéry, P.; Buisson, D. A.; Meddour, A.;
Coustard, J. M.; Thibaudeau, S.; Rousseau, B.; Nicolas, M.;
Hellier, P.; Doris, E. Org. Lett. 2011, 13, 4116.
(j) Giovanelli, E.; Moisan, L.; Leroux, S.; Comesse, S.;
Rousseau, B.; Hellier, P.; Nicolas, M.; Doris, E. Chem. Eur.
J. 2013, 19, 1170. (k) Giovanelli, E.; Moisan, L.; Comesse,
S.; Leroux, S.; Rousseau, B.; Hellier, P.; Nicolas, M.; Doris,
E. Org. Biomol. Chem. 2013, 11, 5885.
13C NMR (CDCl3): δ = 171.5, 133.5, 129.2 (2 C), 128.7 (2 C),
127.3, 69.2, 66.1, 41.2, 34.8.
(2) Alliot, J.; Gravel, E.; Pillon, F.; Buisson, D. A.; Nicolas, M.;
Doris, E. Chem. Commun. 2012, 48, 8111.
MS (ESI+): m/z = 295/297 [M + Na]+.
(3) Shimizu, M.; Yoshioka, H. J. Chem. Soc., Chem. Commun.
1987, 689.
(4) Ter-Gabriélyan, E. G.; Avetisyan, E. A.; Gambaryan, N. P.
Russ. Chem. Bull. 1973, 22, 2496.
Acknowledgment
J.A. thanks the CEA and Les Laboratoires Pierre Fabre for a CTCI
PhD grant. We thank Dr. François Fenaille (CEA/SPI) for helpful
discussions. The Service de Chimie Bioorganique et de Marquage
belongs to the Laboratory of Excellence in Research on Medication
and Innovative Therapeutics (LabEx LERMIT).
(5) For an example, see: (a) Jung, M. E.; Chu, H. V.
Tetrahedron Lett. 2011, 52, 4512. (b) Fichna, J.; Lewellyn,
K.; Yan, F.; Roth, B. L.; Zjawiony, J. K. Bioorg. Med. Chem.
Lett. 2011, 21, 160. (c) Yajima, A.; Kagohara, Y.; Shikai,
K.; Katsuta, R.; Nukada, T. Tetrahedron 2012, 68, 1729.
(6) For examples, see: (a) Trukhin, D. V.; Bagryanskaya, I. Y.;
Gatilov, Y. V.; Mikhalina, T. V.; Rogozhnikova, O. Y.;
Troitskaya, T. I.; Tormyshev, V. M. Synlett 2005, 2072.
(b) Su, S.; Seiple, I. B.; Young, I. S.; Baran, P. S. J. Am.
Chem. Soc. 2008, 130, 16490. (c) Altuna-Urquijo, M.;
Gehre, A.; Stanforth, S. P.; Tarbit, B. Tetrahedron 2009, 65,
975.
(7) (a) Nikishin, G.; Sokova, L.; Kapustina, N. Russ. Chem.
Bull. 2010, 391. (b) Parvez, M.; Kabir, S. M. H.; Sorensen,
T. S.; Sun, F.; Watson, B. Can. J. Chem. 2002, 413.
(c) Föhlisch, B.; Gottstein, W. Liebigs Ann. Chem. 1979,
1768.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnuIomprifgtooatrinSugpIoi
nnfomartit
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Synthesis 2013, 45, 2861–2866
© Georg Thieme Verlag Stuttgart · New York