Furan-2,3-diones as masked dipoles: synthesis of isotetronic acids and mechanistic considerations

Article abstract of DOI:10.1016/j.tet.2016.07.072

The formal dipolar behaviour of furan-2,3-diones is illustrated by their reaction with ethyl glyoxylate under Lewis basic activation uniquely, giving access to isotetronic derivatives. The Janus-type nature of the activated species, both nucleophilic and

Full text of DOI:10.1016/j.tet.2016.07.072

Tetrahedron xxx (2016) 1e6
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Furan-2,3-diones as masked dipoles: synthesis of isotetronic acids
and mechanistic considerations
*
Vincent Barbier, Franc¸ ois Couty, Olivier R.P. David
ꢀ
ꢀ
Institut Lavoisier Versailles, UMR 8180, Universite de Versailles SQY, Universite Paris Saclay, 45 avenue des Etats-Unis, 78035 Versailles, France
a r t i c l e i n f o
a b s t r a c t
Article history:
The formal dipolar behaviour of furan-2,3-diones is illustrated by their reaction with ethyl glyoxylate
under Lewis basic activation uniquely, giving access to isotetronic derivatives. The Janus-type nature of
the activated species, both nucleophilic and electrophilic is revealed by ring-opening of the starting
ketolactone. An unexpected reversible side-reaction was identified by in situ monitoring.
Ó 2016 Elsevier Ltd. All rights reserved.
Received 8 June 2016
Received in revised form 28 July 2016
Accepted 29 July 2016
Available online xxx
Keywords:
Organocatalysis
Lewis base
Heterocyclic chemistry
Physical organic chemistry
Dipole
1. Introduction
Avery nice example of such a reaction was reported by the group
of Yanagisawa,7 moreover in an enantioselective manner, by using
The isotetronic moiety is well represented in the realm of sec-
ondary metabolites;1 a few examples are displayed on Fig. 1. Addi-
tionally, medicinal chemistry studies identified more than 70
compounds that exhibited interesting biological activities, mainly as
HIV-integrase inhibitors.2 It is therefore not surprising to find a fair
number of reports dealing with the synthesis of such molecules.
Most synthetic routes to these compounds rely on aldolisation
reactions,3 and several asymmetric versions have been developed.4
Less conventional methods were also explored.5
a chiral tin Lewis acid 13 in conjunction with a strong nucleophile,
here sodium methoxide (see Scheme 2). Our goal was to explore this
We recently initiated a series of studies directed towards the use
of particular substrates that could reveal a dipolar nature after
appropriate activation by a Lewis base (see Scheme 1), On this topic,
our group recently described the activation of b-lactams 7 by highly
nucleophilic pyridines, and their subsequent reaction with ethyl
glyoxylate to form oxazinanones 8.6 We next examined the feasi-
bility of a similar reaction employing a furanone 9 as a masked
dipole. Isotetronic derivatives seemed perfect examples to show-
case the potentialities of these particular substrates possessing an
ambivalent nature with masked nucleophilic and electrophilic sites
on the same compound. The present investigation reports the re-
action of furandiones with a highly activated aldehyde (ethyl
glyoxylate) forming functionalised isotetronic derivatives through
Lewis base catalysis.
* Corresponding author. E-mail address: olivier.david@uvsq.fr (O.R.P. David).
Fig. 1. Natural compounds with an embedded isotetronic moiety.
http://dx.doi.org/10.1016/j.tet.2016.07.072
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V. Barbier et al. / Tetrahedron xxx (2016) 1e6
Scheme 5. Oligomeric structures putatively formed from furandione 14 alone.
Scheme 1. Formal dipoles.
transformation of furandione 14a (used as model compound) with
ethyl glyoxylate 17 that showed its exceptional reactivity in pre-
vious investigations.10 Four solvents were tested to define the best
reaction medium, see Table 1. After 48 h the reaction reached
Table 1
Optimisation of the reaction medium
Solvent
Yield
Toluene-d8
55%
CDCl3
70%
THF-d8
47%
CD3CN
28%
Scheme 2. Enantioselective synthesis of lactone 12.
completion in all cases at room temperature, the slowest conver-
sion being observed in toluene. From this it was clear that chloro-
form was the solvent of choice. Attempts to accelerate the
conversion by increasing the temperature resulted in decreased
yields with extensive side-reactions. Lower catalyst loadings were
tested, resulting in impractically long reaction times. Optimal
conditions were defined as follows: 10 mol % of PPY at room-
transformation solelyusing Lewis bases as promoters, in a simplified
setting, and to explore the mechanistic details of such a process.
2. Results and discussion
temperature in chloroform at a concentration of 0.3 mol Lꢀ1
,
We started by attempting to reproduce the Yanagisawa trans-
formation using only highly nucleophilic and basic pyridines
(DMAP, super-DMAP.)8 It became rapidly apparent that furanones
of type 9 were not ring-opened even under forcing conditions. We
therefore turned our attention towards furandiones 14 as much
more electrophilic substrates, with success. The syntheses of the
starting materials9 are straightforward and high yielding, as pre-
sented in Scheme 3 (see Schemes 4 and 5).
which were employed in the next step for scope testing, see Table 2.
Scheme 3. Syntheses of furan-2,3-diones 14aeh.
When applied to furandiones 14, these conditions allowed
complete conversion in less than 24 h, see Table 2. All reactions
were also run in THF since, without a clear rationale, certain sub-
strates performed better in this solvent. Yields are between 42 and
73% when the right medium was chosen. In all cases the product
was isolated by simple evaporation of the solvent. Attempts of
purification by chromatography means on silica or alumina gels led
to ca. 10% decrease in yields and gave still impure compounds
contaminated with degradation products. The crude reaction
products could be engagement in further reactions without prob-
lem following procedures of silylation,4b,4f triflation,3e Williamson
Scheme 4. Oligomeric structures putatively formed under reaction conditions.
Optimisation studies were undertaken next, a 10% molar cata-
lytic charge of 4-pyrrolidinopyridine indeed triggered the
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V. Barbier et al. / Tetrahedron xxx (2016) 1e6
3
Table 2
ester quadruplet at 4.2 ppm also proves the incorporation of the
glyoxylate moiety into the isotetronic skeleton.
If at first glance this accumulation of spectra simply shows the
smooth conversion of 14a into 18a, a more informative phenome-
non was revealed after careful examination of the quantitative data
extracted from it.
By using 1,3,5-tris(isopropyl)benzene as an internal standard
the exact quantity of each compound could be measured at all
times. Inspection of these figures allowed two conclusions to be
drawn. First, the reaction is initially a fast process, since after half an
hour, two-thirds of the starting material was consumed, and, after
3 h it had nearly disappeared.
Formation of isotetronic acids 18
Substrate, R
Yield in CDCl3
Yield in THF-d8
14a: Ph
70%
65%
51%
33%
31%
43%
45%
47%
47%
73%
38%
42%
44%
39%
30%
46%
14b: 2-C6H4OMe
14c: 4-C6H4OMe
14d: 4-C6H4Me
14e: 4-C6H4Cl
14f: 4-C6H4F
14g: 4-C6H4NO2
14h: tert-Bu
Secondly, and most interestingly, when adding residual reactant
and product formed, one realises that a substantial amountof matter
is missing, which is not clearly visible in the proton NMR spectra.
Even more intriguing, this ‘missing material’ actually increases from
the onset of the reaction and for 2 h, then steeply decreases to finally
stabilise at around 30% of the mixture, as can be seen in Fig. 4.
Fig. 2. Other substrates tested.
100
90
80
70
60
50
40
30
20
10
0
alkylation,3h,11 or acylation.11 We next varied the electrophile op-
posed to the furandione, however, much as in our preceding studies
with b
-lactams,6 this met only with disappointment as none of the
substrates presented in Fig. 2 gave rise to the expected ring-
opening. Despite introduction of additives known to activate al-
dehydes (LiCl, Schreiner’s thiourea), screening of other Lewis bases
(DABCO, tributylphosphine, azide anion) no trace of the corre-
sponding condensation products could be observed. Intrigued by
these results, we gathered as much information as possible about
this transformation in order to gain some insight into this peculiar
reaction. Firstly, as only fair yields were observed, we were in-
trigued by the absence of observable side-products in the crude
reaction mixture that could explain the loss of material. After 24 h
of incubation, all starting furandione 14 was consumed and the
desired product 18 was the sole compound visible in the proton
NMR spectrum. We monitored the reaction against time by running
it in an NMR tube. Results are displayed in Fig. 3. The characteristic
H4 proton of the starting furandione 14a resonates at 6.5 ppm as
a singlet, while the product shows a new singlet at 5.9 ppm
denoting the resonance of H5 in the isotetronic structure 18a. The
0
200
400
600
800
1000
1200
1400
1600
1800
Time (min)
Fig. 4. Proportions in % of ) starting 14a, ) product 18a, and ) ‘missing material’
plotted against reaction time.
In fact, upon more careful examination of the proton NMR
spectra at intermediate times, one can see tiny signals that fade into
the background noise at longer reaction times.
Attempts to isolate this portion of the reaction mixture were in
vain, only product 18a could be recovered after chromatographic
separations. This experimental detail brought us to the trail of
polymeric materials. Mass spectrometry performed on reaction
mixtures showed several signals with high molecular masses (m/
e>300 Da, up to 899 Da!) suggesting the presence of oligomeric
compounds. From this we can hypothesize the occurrence of a fast
oligomerisation process resulting in a quick consumption of the
starting furandione. Partial depolymerisation then slowly takes
place, accounting for the final decrease in the amount of ‘missing
material.’ Additionally, the structure of 14a suggests a strong pro-
pensity to polymerise alone. To verify this, the evolution of a solu-
tion of 14a in the presence of 10 mol % of PPY was followed by
proton NMR, showing the rapid disappearance of the starting
compound. After 18 h, only unresolved signals, barely visible
against the background noise were observed. Mass-spectrometry
again showed a series of peaks with high molecular masses.
After having identified a plausible explanation for the limitation
in the yield of this reaction, we wanted to rationalise the limitation
in scope. Why is ethyl glyoxylate the sole successful substrate in
Fig. 3. Proton NMR monitoring of the reaction, disappearance of 14a and formation of
18a.
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4
V. Barbier et al. / Tetrahedron xxx (2016) 1e6
this transformation? From a fundamental viewpoint, the envi-
sioned mechanism at the base of this project is in concurrence with
a second, less intuitive, scenario. In Scheme 6, both sequences of
events are presented. The upper one, our working hypothesis, starts
Scheme 7. Two modes of interaction between the pyridine catalyst and ethyl
glyoxylate.
monomeric aldehyde 17. The shifts in ppm are reported for the three
solutions in Table 3. As can be seen, methanol exerts a notable but
small influence on DMAP, while ethyl glyoxylate has a more pro-
nounced effect on the chemical shifts, with large modifications of
the C2 and C4 resonances. These shifts are in agreement with the
formation of a pyridinium moiety as expected if PA2 is present in
notable amounts. Mass-spectrometry also indicated the formation
of such an adduct, as solutions of PPY and ethyl glyoxylate indeed
revealed the presence of the pyridinium-alcohol 19, depicted in
Fig. 5. Simply protonated PPY was not detected in these solutions.
Table 3
Chemical shifts in 13C,
d, ppm
DMAP
DMAPþMeOH
DMAPþEtG
C5
C4
C3
C2
38.15
38.22 (w)
154.73 (þ)
106.74 (w)
148.68 (ꢀ)
39.23 (þ)
154.09
106.56
149.64
156.89 (þþ)
106.64 (w)
139.08 (ꢀ ꢀ)
Scheme 6. Two plausible mechanisms for the formation of 18.
with the ring-opening of furandione 14 by the catalyst to form
a pyridinium-enolate PE1. The latter attacks, in an aldolisation step,
aldehyde 17 to form a pyridinium-alcoholate PA1, finally ring-
closing into product 18 with expulsion of PPY. An alternative
route is conceivable, depicted in the lower part of Scheme 6. PPY
starts by attacking aldehyde 17 giving pyridinium-alcoholate PA2,
the oxygen anion then serves as a nucleophile to ring-open fur-
andione 14 to lead to pyridinium-enolate PE2, which after an
intramolecular SN2 reaction gives 18. Although peculiar, this last
sequence of events could explain that only the extremely electro-
philic aldehyde 17 is reactive in the transformation as it is the sole
to give rise to a nucleophilic alcoholate of type PA2.
This scenario is furthermore substantiated by carbon-NMR ex-
periments on mixtures of ethyl glyoxylate and DMAP. We therefore
looked for putative interactions between the pyridine and ethyl
glyoxylate, proposed in Scheme 7; these studies had to circumvent
a practical difficulty.
Fig. 5. Addition adduct 19, observed by mass-spectrometry.
In a final part of our investigations, we wanted to determine the
rate-order of ethyl glyoxylate in this reaction. Precise kinetic studies
were hampered by the difficulty in following this fast reaction.
UVevis spectrometry was unable to detect the disappearance of the
furandione or the formation of isotetronic product in a clear man-
ner, and NMR spectroscopy gave only semi quantitative results as,
over time of an acquisition, most of the conversion had occurred.
No clear acceleration of the reaction rate could be measured by
increasing the number of equivalents of ethyl glyoxylate, but this
caused an increase in the extent of parasitic side-reactions,
resulting in lower formation of 18.
3. Conclusions
As shown in previous work,6 ethyl glyoxylate exists as partially
polymerized acetalic forms, which are in equilibrium with the mo-
nomeric aldehyde 17. Oligomers have hydroxyl end-groups which
could also interact with the pyridine nitrogen lone-pair. We there-
fore compared three solutions by 13C NMR with a constant con-
centration of DMAP as model catalyst: 1. the catalyst alone, 2. in the
presence of methanol, used as a model compound for the hemi-
acetalic end groups of ethyl glyoxylate oligomers, and 3. ethyl
glyoxylate itself, which under these conditions contains ca. 30% of
A novel route to highly functionalised isotetronic compounds was
optimised, exploiting the formal dipolar nature of the furandione
substrates after nucleophilic attack. In the course of this study, the
putative activation of ethyl glyoxylate by a highly nucleophilic pyri-
dine was substantiated by various techniques. An interesting ‘reser-
voir effect’ was brought to light, with initial polymerisation of the
substrate which then slowly converts into the expected product. We
are currently exploiting the knowledge gained in this study to em-
ploy other ‘masked dipoles’ in organocatalysis.
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V. Barbier et al. / Tetrahedron xxx (2016) 1e6
5
4. Experimental section
6.37 (s, 1H), 2.50 (s, 3H). 13C NMR (75 MHz, CDCl3):
d
179.30,
178.25, 155.26, 147.16, 130.33, 127.80, 123.27, 100.91, 22.15. HRMS
m/z (ESI, TOF) calcd. For C11H9O3 (MþH)þ 189.0552, found
189.0554.
1H NMR (300 MHz) and 13C (75 MHz) spectra were recorded
€
with Bruker Avance 300 MHz spectrometers using tetramethylsi-
lane as an internal standard. Chemical shifts (d) are given in parts
per million and coupling constants are given as absolute values
expressed in Hertz. Electrospray ionization (ESI) mass spectra were
collected using a Q-TOF instrument supplied by WATERS. Samples
(solubilized in CH3CN at 1 mg mLꢀ1 and then diluted by 1000) were
introduced into the MS via an UPLC system whilst a Leucine En-
kephalin solution was co-injected via a micro pump. Infrared
spectra were recorded with a Nicolet iS10 Infrared FT ATR spec-
trometer. Thin-layer chromatography (TLC) was carried out on al-
uminium sheets precoated with silica gel 60 F254 (Merck). Column
chromatography separations were performed using Merck Kie-
selgel 60 (0.040e0.060 mm). Tetrahydrofuran and dichloro-
methane were dried immediately before use by distillation from
standard drying agents.
4.1.5. 5-(4-Chlorophenyl)furan-2,3-dione
(14e). Yellow
y
solid,
384.2 mg (82% yield); mp¼149e151 ꢁC; IR
(cmꢀ1): 3082, 1820,
1712, 1592, 1492, 1420, 1109, 1087, 805, 758. 1H NMR (300 MHz,
CDCl3):
d
7.88 (d, J¼8.6 Hz, 2H), 7.58 (d, J¼8.6 Hz, 2H), 6.42 (s, 1H).
13C NMR (75 MHz, CDCl3):
d
178.20, 177.92, 154.56, 141.94, 130.04,
128.83, 124.49, 101.74. HRMS m/z (ESI, TOF) calcd. For C10H5O3N-
aCl (MþNa)þ 230.9825, found 230.9834.
4.1.6. 5-(4-Fluorophenyl)furan-2,3-dione (14f). Yellow solid, 587.3 mg
(64% yield); mp¼137e139 ꢁC; IR
y
(cmꢀ1): 3100, 1820, 1715, 1590,
1485, 1418, 1105, 1084. 1H NMR (200 MHz, CDCl3):
d 7.94e7.85 (m,
1H), 7.21 (d, J¼8.6 Hz, 1H), 6.31 (s, 1H). 13C NMR (75 MHz, CDCl3):
d
178.15,177.97, 165.21, 154.69,130.38 (d, J¼9.7 Hz), 122.36,117.20 (d,
J¼22.5 Hz), 101.32 (d, J¼1.6 Hz). HRMS m/z (ESI, TOF) calcd. For
4.1. General procedure for
b-ketolactones synthesis
C
10H6O3F (MþH)þ 193.0301, found 193.0304.
To a solution of diethyl oxalate (1 equiv) in EtOH, NaH (1 equiv,
60% in oil) and the methylketone were successively added portion-
wise at 0 ꢁC under inert atmosphere. After 16 h of stirring at room
temperature, the reaction mixture was concentrated in vacuo. The
resulting sodium salt was washed several times with diethylether.
This sodium salt was dissolved and stirred 2 day at room tempera-
ture in a solution of HCl (40 equiv, 6M) and acetonitrile. The reaction
mixture was concentrated in vacuo and dissolved in dichloro-
methane. The media was treated with an aqueous solution of
NaHCO3 (until basic pH) and extracted three times. Then aqueous
phase was treated with HCl 6M (until acidic pH), filtered and dried to
4.1.7. 5-(4-Nitrophenyl)furan-2,3-dione (14g). Yellow solid, 632.7 mg
(68% yield); mp¼150e152 ꢁC; IR
y
(cmꢀ1): 3100, 1820, 1715, 1590,
1579,1485,1418,1390,1210,1084.1HNMR(300MHz,CDCl3):
d8.37(d,
J¼8.9 Hz, 2H), 8.04 (d, J¼8.8 Hz, 2H), 6.49 (s, 1H). 13C NMR (75 MHz,
CDCl3):
d
178.15, 177.97, 165.21, 154.69, 130.38 (d, J¼9.7 Hz), 122.36,
117.20, 101.32. Note that the two carbonyl resonances could not be
detected even after modification of the relaxation parameters. HRMS
m/z (ESI, TOF) calcd. For C10H5NO5Na (MþNa)þ 242.0065, found
242.0066.
4.1.8. 5-tert-Butylfuran-2,3-dione (14h). Prepared according to
get the resulting
b
-ketoacid as a solid. The
b
-ketoacid was dissolved
a reported procedure, see Ref. 9. 1H NMR (300 MHz, CDCl3): (62%)
in acetyl chloride at roomtemperature for 16 h. The reaction mixture
was concentrated under vacuum. The resulting power was washed
d 6.44 (s, 1H), 1.33 (s, 18H). HRMS m/z (ESI, TOF) calcd. For
C8H10O3Na (MþNa)þ 177.0528, found 177.0529.
with a small volume of cold ether to give
b
-ketolactones as a solid.
4.2. General procedure for isotetronic acid derivatives
synthesis
4.1.1. 5-Phenylfuran-2,3-dione (14a). Yellow solid, 0.24
g
(78%
yield) and perfectly fits analytic data described in Ref. 9.
mp¼133e135 ꢁC; IR
y
(cmꢀ1): 3062, 3026, 1785, 1712, 1592, 1492,
To a stirred solution of b-ketolatone (1 equiv), ethyl glyoxalate,
1450, 1411, 1366, 1310, 1291, 1277, 1165, 1129, 1109, 1087, 805, 758.
50% in toluene (Alfa Aesar) (1 equiv) in CDCl3 (1 mL), 1,3,5-
tris(isopropyl)benzene as an internal reference (1 equiv), is added
10 mol % of 4-PPY. After 24 h at RT, NMR analysis was performed
and yields were determined.
1H NMR (200 MHz, CDCl3):
d
7.65 (d, J¼8.3 Hz, 2H), 7.48e7.03 (m,
7H), 5.56 (dd, J¼5.7, 2.7 Hz, 1H), 3.38 (dd, J¼16.6, 5.7 Hz, 1H), 2.95
(dd, J¼16.6, 2.7 Hz, 1H), 2.43 (s, 3H).
4.1.2. 5-(2-Methoxyphenyl)furan-2,3-dione (14b). Orange solid,
4.2.1. Ethyl 3-benzoyl-4-hydroxy-5-oxo-2,5-dihydrofuran-2-
784.3 mg (85% yield); mp¼150e152 ꢁC; IR
y
(cmꢀ1): 3089, 1820,
carboxylate (18a). 70 % in CDCl3 and 47% in THF-d8 1H NMR
1715, 1592, 1583, 1487, 1421, 1080, 982. 1H NMR (300 MHz, CDCl3):
(300 MHz, CDCl3): d 7.67 (m, 2H), 7.55 (m, 3H), 5.87 (s, 1H), 4.24 (q,
d
7.98 (d, J¼7.9 Hz, 1H), 7.75e7.59 (m, 1H), 7.12 (dd, J¼16.9, 8.2 Hz,
J¼7.1 Hz, 2H), 1.23 (t, J¼7.1 Hz, 3H). 13C NMR (75 MHz, CDCl3):
2H), 6.72 (s, 1H), 4.03 (s, 3H). 13C NMR (75 MHz, CDCl3):
d
179.76,
d 189.82, 168.18, 166.66, 149.15, 137.92, 136.53, 129.14, 128.34,
175.30, 161.47, 155.07, 136.70, 128.64, 121.11, 111.74, 106.85, 55.94.
HRMS m/z (ESI, TOF) calcd. For C11H8O4Na (MþNa)þ 227.0320,
found 227.0324.
120.38, 77.02, 62.74, 13.85. HRMS m/z (ESI, TOF) calcd. For C14H13O6
(MþH)þ 277.0712, found 277.0716.
4.2.2. Ethyl 4-hydroxy-3-(2-methoxybenzoyl)-5-oxo-2,5-
4.1.3. 5-(4-Methoxyphenyl)furan-2,3-dione (14c). Orange solid,
dihydrofuran-2-carboxylate (18b). 65 % in CDCl3 and 73% in THF-d8
855 mg (93% yield); mp¼140e142 ꢁC IR
y
(cmꢀ1): 3089, 1820, 1715,
1H NMR (300 MHz, CDCl3):
d
7.58 (t, J¼7.9 Hz, 1H), 7.51 (d, J¼6.6 Hz,
1592, 1583, 1487, 1421, 1080, 982. 1H NMR (200 MHz, CDCl3):
d
7.91
1H), 7.10 (t, J¼7.5 Hz, 1H), 7.04 (d, J¼8.5 Hz, 1H), 5.88 (s, 1H),
4.08e3.85 (m, 2H), 3.96 (s, 3H), 1.02 (t, J¼7.1 Hz, 3H). 13C NMR
(75MHz, CDCl3): 191.87,166.23,166.04,157.37,154.98,134.36,130.16,
127.09, 125.36, 121.21, 111.35, 76.28, 62.41, 55.63, 13.64. HRMS m/z
(ESI, TOF) calcd. For C15H15O7 (MþH)þ 307.0818, found 307.0826.
(d, J¼8.9 Hz, 1H), 7.07 (d, J¼8.9 Hz, 1H), 6.30 (s, 1H), 3.95 (s, 3H).).
13C NMR (75 MHz, CDCl3):
d
178.81, 177.77, 165.72, 155.78, 130.25,
118.16, 115.20, 99.92, 55.89. HRMS m/z (ESI, TOF) calcd. For C11H9O4
(MþH)þ 205.0501, found 205.0501.
4.1.4. 5-(4-Methylphenyl)furan-2,3-dione
(14d). Yellow solid,
(cmꢀ1): 3092, 1825,
4.2.3. Ethyl 4-hydroxy-3-(4-methoxybenzoyl)-5-oxo-2,5-
670.3 mg (74% yield); mp¼139e141 ꢁC; IR
y
dihydrofuran-2-carboxylate (18c). 51 % in CDCl3 and 38% in THF-d8
1710, 1593, 1584, 1485, 1418, 1320, 1268, 1005, 989. 1H NMR
1H NMR (300 MHz, CDCl3):
d
7.95 (d, J¼8.7 Hz, 1H), 7.02 (d, J¼8.7 Hz,
(200 MHz, CDCl3):
d
7.84 (d, J¼8.3 Hz, 2H), 7.40 (d, J¼8.0 Hz, 2H),
1H), 5.87 (s,1H), 4.22 (q, J¼7.2 Hz, 1H),1.21 (t, J¼7.1 Hz, 2H). 13C NMR
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6
V. Barbier et al. / Tetrahedron xxx (2016) 1e6
(75 MHz, CDCl3): 187.90, 167.72, 166.49, 164.42, 149.67, 137.90,
131.71,120.48,114.07, 77.04, 62.68, 55.62,13.84. HRMS m/z (ESI, TOF)
calcd. For C15H15O7 (MþH)þ 307.0818, found 307.0824.
References and notes
1. Natural isotetronic derivatives: (a) sotolone, first identified in aged sake: Ta-
kahashi, K.; Tadenuma, M.; Sato, S. Agric. Biol. Chem. 1976, 40, 325e330; (b)
Xenofuranone B: Brachmann, A. O.; Forst, S.; Furgani, G. M.; Fodor, A.; Bode, H.
B. J. Nat. Prod. 2006, 69, 1830e1832; (c) Aspernolide A: Parvatkar, R. R.; D’Souza,
C.; Tripathi, A.; Naik, C. G. Phytochemistry 2009, 70, 128e132; (d) Pityriarubin C:
4.2.4. Ethyl 4-hydroxy-3-(4-methylbenzoyl)-5-oxo-2,5-
dihydrofuran-2-carboxylate (18d). 33 % in CDCl3 and 42% in THF-
€
Irlinger, B.; Kramer, H.-J.; Mayser, P.; Steglich, W. Angew. Chem., Int. Ed. 2004, 43
d8 1H NMR (300 MHz, CDCl3):
d
7.94 (d, J¼8.1 Hz, 2H), 7.35 (d,
1098e1098 (e) 2-hydroxyluzofuranone: Sua, H.; Yuana, Z.-H.; Lia, J.; Guoa, S.-J.;
Denga, L.-P.; Hana, L.-J.; Zhu, X.-B.; Shi, D.-Y. Helv. Chim. Acta 2009, 92,
1291e1297; (f) Isochlorotiorin: Chong, R.; King, R. R.; Whalley, W. B. J. Chem.
Soc., Chem. Commun. 1969, 1512e1513.
J¼8.1 Hz, 2H), 5.89 (s, 1H), 4.21 (q, J¼7.2 Hz, 2H), 1.20 (t, J¼7.1 Hz,
3H). 13C NMR (75 MHz, CDCl3): 189.45, 167.29, 166.29, 145.16,
137.90, 133.67, 129.51, 120.25, 76.94, 62.71, 21.69, 13.79. HRMS m/z
(ESI, TOF) calcd. For C15H15O6 (MþH)þ 291.0869, found 291.0872.
2. Biological activities: (a) Dayam, R.; Deng, J.; Neamati, N. Med. Res. Rev. 2006, 26,
271e309; (b) Ferro, S.; Barreca, M. L.; De Luca, L.; Rao, A.; Monforte, A. M.;
Debyser, Z.; Witvrouw, M.; Chimirri, A. Arch. Pharmacol. 2007, 340, 292e298;
(c) Xu, H.; Lv, M. Curr. Pharm. Des. 2009, 15, 2120e2148; (d) De Luca, L.; Ferro, S.;
Gitto, R.; Barreca, M. L.; Agnello, S.; Christ, F.; Debyser, Z.; Chimirri, A. Bioorg.
Med. Chem. 2010, 18, 7515e7521; (e) De Luca, L.; Ferro, S.; Morreale, F.; Chimirri,
A. Mini-Reviews Med. Chem 2011, 11, 714e727; (f) DeLuca, L.; Ferro, S.; Morreale,
F.; DeGrazia, S.; Chimirri, A. Chem. Med. Chem. 2011, 6, 1184e1191; (g) Ferro, S.;
De Luca, L.; Lo Surdo, G.; Morreale, F.; Christ, F.; Debyser, Z.; Gitto, R.; Chimirri,
A. Bioorg. Med. Chem. 2014, 22, 2269e2279; (h) Ferro, S.; De Luca, L.; Morreale,
F.; Christ, F.; Debyser, Z.; Gitto, R.; Chimirri, A. J. Enz. Inhib. Med. Chem. 2014, 29,
237e242.
3. Via aldolisation: (a) Bonadies, F.; Scarpati, M. L. Gazz. Chim. Ital. 1983, 113,
421e426; (b) Amer, A.; Ventura, M.; Zimmer, H. J. Heterocycl. Chem. 1983, 20,
359e364; (c) Gein, V. L.; Gein, L. F.; Bezmaternykh, E. N.; Voronina, E. V. Pharm.
Chem. J. 2000, 34, 254e256; (d) Weber, V.; Coudert, P.; Rubat, C.; Duroux, E.;
Leal, F.; Couquelet, J. J. Pharm. Pharmacol. 2000, 52, 523e530; (e) Dede, R.;
Michaelis, L.; Langer, P. Tetrahedron Lett. 2005, 46, 8129e8131; (f) Dede, R.;
Michaelis, L.; Fuentes, D.; Yawer, M. A.; Hussain, I.; Fischer, C.; Langer, P. Tet-
rahedron 2007, 63, 12547e12561; (g) Lee, D.; Newman, S. G.; Taylor, M. S. Org.
Lett. 2009, 11, 5486e5489; (h) Lu, P.; Herdtweck, E.; Bach, T. Chem.dAsian. J.
2012, 7, 1947e1958; (i) Kuhajda, F. P., Townsend, C. A., Medghalchi, S. M.,
McFadden, J. M. Johns Hopkins University and Fasgen Inc. US2006/028979, 26
July 2005.
4. Enantioselective aldolisations: (a) Enders, D.; Dycker, H.; Leusink, F. R. Chem.
dEur. J. 1998, 4, 311e320; (b) Gathergood, N.; Juhl, K.; Poulsen, T. B.;
Thordrup, K.; Jorgensen, K. A. Org. Biomol. Chem. 2004, 2, 1077e1085; (c)
Dambruoso, P.; Massi, A.; Dondoni, A. Org. Lett. 2005, 7, 4657e4660; (d)
Vincent, J.-M.; Margottin, C.; Berlande, M.; Cavagnat, D.; Buffeteau, T.;
Landais, Y. Chem. Commun. 2007, 4782e4784; (e) Zhang, B.; Jiang, Z.; Zhou, X.;
Lu, S.; Li, J.; Liu, Y.; Li, C. Angew. Chem., Int. Ed. 2012, 51, 13159e13162; (f) Guo,
W.; Wang, X.; Zhang, B.; Shen, S.; Zhou, X.; Wang, P.; Liu, Y.; Li, C. Chem.dEur.
J. 2014, 20, 8545e8550.
5. (a) Nozaki, K.; Sato, N.; Ikeda, K.; Takaya, H. J. Org. Chem. 1996, 61, 4516e4519;
(b) Nair, V.; Nair, J. S.; Vinod, A. U.; Rath, N. P. J. Chem. Soc., Perkin Trans. 1 1997,
3129e3130; (c) Tejedor, D.; Santos-Exposito, A.; Garcia-Tellado, F. Chem. Com-
mun. 2006, 2667e2669; (d) Zhou, Z.; Walleser, P. M.; Tius, M. A. Chem. Commun.
2015, 10858e10860.
4.2.5. Ethyl 4-hydroxy-3-(4-chlorobenzoyl)-5-oxo-2,5-dihydrofuran-
2-carboxylate (18e). 31 % in CDCl3 and 44% in THF-d8 1H NMR
(300 MHz, CDCl3):
d
8.00 (d, J¼8.6 Hz, 2H), 7.89 (d, J¼8.5 Hz, 2H),
5.84 (s, 1H), 4.33e4.21 (m, 2H), 1.26 (t, J¼7.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3): 188.26, 167.88, 166.42, 140.30, 137.90, 134.72,
130.52, 129.53, 120.18, 76.79, 62.76, 13.67. HRMS m/z (ESI, TOF)
calcd. For C14H12O6Cl (MþH)þ 311.0322, found 311.0328.
4.2.6. Ethyl 4-hydroxy-3-(4-fluorobenzoyl)-5-oxo-2,5-dihydrofuran-
2-carboxylate (18f). 43 % in CDCl3 and 39% in THF-d8 1H NMR
(300 MHz, CDCl3):
d
7.97 (d, J¼8.7 Hz, 2H), 7.25 (d, J¼8.7 Hz, 2H),
5.96 (s, 1H), 4.32e4.24 (m, 2H), 1.21 (t, J¼7.1 Hz, 3H). 13C NMR
(75 MHz, CDCl3): 188.30, 168.36 (d, J¼6.8 Hz), 166.63, 164.90,
147.49, 137.93, 132.09 (d, J¼8.5 Hz), 121.26, 116.24 (d, J¼22.3 Hz),
77.31, 63.69, 13.63. HRMS m/z (ESI, TOF) calcd. For C14H12O6F
(MþH)þ 295.0618, found 295.0625.
4.2.7. Ethyl 4-hydroxy-3-(4-nitrobenzoyl)-5-oxo-2,5-dihydrofuran-
2-carboxylate (18g). 45 % in CDCl3 and 30% in THF-d8 1H NMR
(300 MHz, CDCl3):
d
7.95 (d, J¼8.7 Hz, 1H), 7.02 (d, J¼8.7 Hz, 1H),
5.87 (s, 1H), 4.31 (q, J¼7.2 Hz, 2H), 1.31 (t, J¼7.1 Hz, 2H). 13C NMR
(75 MHz, CDCl3): 187.71, 168.27, 166.52, 150.39, 148.39, 141.40,
137.91, 130.13, 123.72, 76.91, 63.06, 13.93. HRMS m/z (ESI, TOF)
calcd. For C14H11NO8Na (MþNa)þ 344.0382, found 344.0378.
4.2.8. Ethyl 4-hydroxy-5-oxo-3-pivaloyl-2,5-dihydrofuran-2-
carboxylate (18h). 47 % in CDCl3 and 46% in THF-d8 1H NMR
6. Barbier, V.; Marrot, J.; Couty, F.; David, O. R. P. Eur. J. Org. Chem. 2015, 17,
3679e3688.
(300 MHz, CDCl3):
d 5.58 (s, 1H), 4.42e4.25 (m, 2H), 1.35 (m, 3H)
1.25 (s, 9H). 13C NMR (75 MHz, CDCl3): 202.57, 169.39, 166.90,
144.99, 120.56, 77.99, 62.56, 43.58, 24.92, 13.97. HRMS m/z (ESI,
TOF) calcd. For C12H17O6 (MþH)þ 257.1025, found 257.1032. Ex-
perimental details.
7. Yanagisawa, A.; Kushihara, N.; Yoshida, K. Org. Lett. 2011, 13, 1576e1578 A
precedent of this reaction was reported earlier using boron trifluoride as pro-
moter: see Ref. 3d.
8. (a) De Rycke, N.; Berionni, G.; Couty, F.; Mayr, H.; Goumont, R.; David, O. R. P.
Org. Lett. 2011, 13, 530e533; (b) De Rycke, N.; Couty, F.; David, O. R. P. Chem.
dEur. J. 2011, 17, 12852e12871.
9. Kappe, O. C.; Kollenz, G.; Wentrup, C. Heterocycles 1994, 779.
10. Barbier, V.; Marrot, J.; Couty, F.; David, O. R. P. Eur. J. Org. Chem. 2016, 3,
549e555.
Acknowledgements
11. Chen, H.; Ma, X.; Li, Z.; Wang, Q.; Tao, F. Arkivoc 2009, X, 87e105.
VB wishes to thanks the French Ministry of Education for
a Doctoral contract. Estelle Galmich is warmly acknowledged for
performing mass-spectrometry measurements.
Please cite this article in press as: Barbier, V.; et al., Tetrahedron (2016), http://dx.doi.org/10.1016/j.tet.2016.07.072