Ni(ii)-Catalyzed vinylic C-H functionalization of 2-acetamido-3-arylacrylates to access isotetronic acids

Article abstract of DOI:10.1039/d0ob00557f

A ligand-free Ni(ii)-catalyzed cascade annulation reaction for the synthesis of 4-aryl-substituted isotetronic acids from 2-acetamido-3-arylacrylatesviavinylic C-H functionalization is reported. The reaction proceeds through heteroatom guided electrophilic insertion of nickel to the vinylic double bond followed by annulation with dibromomethane. This unconventional route features cascade steps, sole product formation, multiple functional group tolerance, low cost of catalysts and reagents, and readily available starting materials. Using this method, various aryl-substituted isotetronic acids have been synthesized which are biologically relevant. The annulation of 2-acetamido-3-arylacrylates has also been assessed with 1,2-dichloroethane, which resulted in the rearranged annulated products of 5-methyl substituted isotetronic acids.

Full text of DOI:10.1039/d0ob00557f

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OrPgleanaisce&dBoionmotoaledcjuulsatr mChaermgiinstsry
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DOI: 10.1039/D0OB00557F
ARTICLE
Ni(II)-catalyzed vinylic C-H functionalization of 2-acetamido-3-
arylacrylates to access isotetronic acids
Biswajit Roy, Eshani Das, Avijit Roy and Dipakranjan Mal*
Received 00th January 20xx,
Accepted 00th January 20xx
A ligand-free Ni(II)-catalyzed cascade annulation reaction for the synthesis of 4-aryl-substituted isotetronic acids from 2-
acetamido-3-arylacrylates via vinylic C-H functionalization is reported. The reaction proceeds through heteroatom guided
electrophilic insertion of nickel to the vinylic double bond followed by annulation with dibromomethane. This
unconventional route features cascade steps, sole product formation, multiple functional group tolerance, low cost of
catalysts and reagents, and readily available starting materials. Using this method, various aryl-substituted isotetronic acids
have been synthesized which are biologically relevant. The annulation of 2-acetamido-3-arylacrylates has also been assessed
with 1,2-dichloroethane, which resulted in the rearranged annulated products of 5-methyl substituted isotetronic acids.
DOI: 10.1039/x0xx00000x
Introduction
Isotetronic acids are an important scaffold of natural products1
exhibiting important activities (Fig. 1), such as antitumor, aldose
reductase inhibitory2 activities, etc. For example, butyrolactone
3a
I (1a
)
is a potent and selective inhibitor of CDK1 and CDK2,
important for regulating the cell cycle.3b Aspernolide A (1b
exhibits antiproliferative activity against colon and pancreatic
carcinoma.3c WF-3681 (
), a fungal metabolite, is an aldose
reductase inhibitor.2 Sotolon (
) is useful as a powerful
odorant.4a Compound
is a potent anti-oxidant and anti-
inflammatory agent.4b Xenofuranones A (5a) and B (5b) might
be involved directly in the nematode symbiosis.4c Serpenone (
and its synthetic analogs are used for the treatment of diabetic
neuropathy.4d Structure
represents a group of nonsteroidal
anti-inflammatory drugs (NSAID), which are selective COX-2
inhibitors.4e,f Compound is a fungicide.4g Compound
shows
)
2
3
4
6
)
7
8
9
potent 4-hydroxyphenylpyruvate dioxygenase (4-HPPD)
inhibitory activity. It also acts as a bleaching herbicide for the
control of grass and broadleaf weeds.5 Thus the wide range of
bioactivities of these compounds (Fig. 1) has drawn attention of
scientists from various fields. Many approaches were reported
for the synthesis of isotetronic acids and their derivatives.
Usually, base mediated homoaldol reaction of α-keto esters are
utilized for the synthesis of racemic mixture of isotetronic
acids3b or their O-protected derivatives6. High yielding
regioselective7a and enantioselective7b routes to isotetronic
acids are also reported from α-keto esters. Interestingly, Tius et
al. have reported an unusual oxidative cyclization pathway
using selenium dioxide on α,β-unsaturated methyl ketones to
access isotetronic acids.8
Fig. 1 Examples of some naturally occurring and bioactive isotetronic
acids (1-9).
The major limitations of these routes are (i) inaccessibility of
starting α-keto esters, very few of which are commercially
available and synthesis of substituted α-keto esters are not
easy.8 (ii) in a side reaction, homoaldolisation3b,6 of α keto ester
occurs.
Herein, we now report a ligand free Ni(II) catalyzed cascade
reaction for the synthesis of 3-hydroxy-4-arylfuran-2(5H)-ones
(9a-9t) from 2-acetamido-3-arylacrylates (10) via vinylic C-H
functionalization (Scheme 1). Acetamidoacrylates were
previously used for the synthesis of oxazoles via vinylic C-H
functionalization
by
hypervalent
iodine
mediated
intramolecular oxidative cyclization (Scheme 1) by Zhao and
coworkers.9 Koenig et al. reported a Pd(OAc)2 catalyzed ortho C-
H activation of 2-acetamido-3-arylacrylates for the synthesis of
a.Department of Chemistry, Indian Institute of Technology Kharagpur, Kharagpur-
721302, India.
Electronic Supplementary Information (ESI) available: See DOI: 10.1039/x0xx00000x
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Table 1 optimization of reaction
View Article Online
DOI: 10.1039/D0OB00557F
Entry
Base
Catalyst
Temp
°C
120
135
135
Time
(h)
72
48
48
Yieldb
9 (%)
10
22
21
1c,d
2
3
K2HPO4
KOAc
KOAc
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2 /
15 mol%
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Scheme 1 Intramolecular C−H functionalization reactions with 2-
acetamido-3-arylacrylates.
indole-2-carboxylate derivatives (Scheme 1) and used oxygen as
the terminal oxidant.10
4
5
6
NaOAc
CsOAc
KOAc
135
140
140
48
48
48
20
17
21
Hence, the reactivities of aryl amidoacrylates have drawn
considerable attention and inspired us to study its reactivity
towards vinylic C-H and ortho aryl C-H positions by employing
dibromomethane both as the solvent and alkylating agent and
palladium acetate as catalyst. We have found that no trace
amount of ortho-substituted product was formed, instead,
substitution at the vinylic position is achieved resulting in the
formation of cyclized isotetronic acid as the sole product with
the formation of one C-C bond and one C-O bond.
(5equiv.)
-
KOAc
7
8
Pd(OAc)2
-
135
135
135
140
140
140
140
150
150
150
48
48
48
48
48
48
48
48
36
15
0
0
9 e
10
11
12f
13
14
15
16g
KOAc
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Ni(PCy3)2 Cl2
Ni(PCy3)2 Cl2
Ni(PCy3)2 Cl2
26
41
49
0
62
69
58
81
Li(OAc).2H2O
Li(OAc).2H2O
Li(OAc).2H2O
Li(OAc).2H2O
Li(OAc).2H2O
Li(OAc).2H2O
Li(OAc).2H2O Ni(OAc)2.4H2O
(2 mol %)
Li(OAc).2H2O
Our newly developed methodology reports
a
[4+1]
annulation11a reaction leads to the formation of a heterocyclic
core,11b,c it has some advantages like (i) all reagents are of low
cost and the starting materials can be easily synthesized by one-
pot reaction from aromatic aldehydes.12 (ii) vinylic
functionalization of acetamidoacrylate directly leads to the sole
product i.e. iotetronic acid via cascade of steps. (iii) multiple
functional groups are tolerated.
17g
18g
Ni(Cl)2.6H2O
(2 mol %)
150
150
22
22
72
70
Li(OAc).2H2O Ni(NO3)2.4H2O
(2 mol %)
a = 100 wt % molecular sieve was used entries 11 to 18 except 15, b =
Yield was determined after column chromatographic purification; all
the compounds were added under: c = nitrogen atmosphere, d = air; In
all the cases 2 mL dibromomethane was used as solvent, except e = (1
mL / 1 mL) CH2Br2 / DMF, f = DCM (2 mL), g = (2 mL / 0.5 mL) CH2Br2 /
DMF was added as solvent.
Results and discussion
The use of dibromomethane as bridging methylene group has
been discussed previously by Yu et al.13 for phthalide synthesis
from benzoic acids. Following the similar reaction conditions as
reported by Yu et al.,13 we examined the reaction of 2-
acetamido-3-phenylacrylate (10a) with three equivalents of
K2HPO4 as base, dibromomethane as solvent and 10 mol%
Pd(OAc)2 as catalyst at 120 °C in nitrogen atmosphere (Table 1,
entry 1). No trace amount of ortho-substituted product was
formed. Instead, we noted the formation of C-4-aryl-substituted
isotetronic acid 9a with 10% yield and 60% recovery of starting
yield (Table 1, entry 6). No reaction occurred when the reaction
was carried out without base (Table 1, entry 7) and catalyst
(Table 1, entry 8). The reaction was carried out with different
solvent systems (Table S1, entries 12-14) but only a slight
improvement in yield was observed when DMF (normal) and
CH2Br2 were used (Table 1, entry 9). A significant improvement
of the yield was achieved in the presence of three equivalents
of LiOAc·2H2O as base (Table 1, entry 10). This may be explained
by the fact that Li+ interacts strongly with amide compared to
other alkali metals, such as Na+ and K+.15 Addition of 100 wt % 4
Å molecular sieve dust with respect to acetamidoacrylates
increased the yield to 49% (Table 1, entry 11).16 The reaction
does not proceed with dichloromethane (Table 1, entry 12).
Finally, we shifted to nickel(II) catalyst (Table 1, entry 13), which
resulted in significant improvement of yields. Both palladium
and nickel salts gave the same product, but nickel was found to
be more efficient catalyst in this reaction. Temperature
material after 72 h. The product 9a was characterized by 1H, 13
C
NMR14 and HRMS spectroscopic techniques. The structure of 9a
was further confirmed by using Single-crystal X-ray diffraction
(Table 2).
An attempt has also been made to optimize the reaction
conditions (Table 1 & Table S1). The reaction yield was negligibly
affected by the change of bases (Table S1, entries 1-4). A slight
improvement of the yield was observed when acetates of alkali
metals were used (Table 1, entries 2-6). Increased loading of the
palladium catalyst from 10 to 15 mol % resulted in the decrease
of reaction yield by 1 % (Table 1, entry 3). Increasing the amount
of KOAc from 3 to 5 equivalents did not result in any change in
optimization
was
carried
out
with
bis(tricyclohexylphosphine)nickel(II) dichloride as catalyst
(Table S1, entries 19-21), and the best result was obtained at
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Table 2 Substrate scope
Table 3 Acetamidoacrylates with different outcome of the
cascade reaction
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DOI: 10.1039/D0OB00557F
The positive outcome of nickel(II)-catalyzed isotetetronic acids
synthesis from acetamidoacrylates and dibromomethane
encouraged us to further investigate whether six-membered
cyclic product 3-hydroxy-4-phenyl-5,6-dihydro-2H-pyran-2-one
derivatives with 1,2-dibromoethane13 can be obtained.
Unfortunately, the reaction did not take place with 1,2-
dibromoethane. Interestingly, the similar reaction with 1,2-
dichloroethane successfully gave rearranged product, i.e., 5-
methyl-substituted isotetronic acids 11a and 11g with
moderate yields. Various reaction conditions (similar to Table 1)
were screened with nickel(II)-catalysts, but no improvement of
the yield was observed (Scheme 2).
Scheme 2 Synthesis of 5-methyl-substituted isotetronic acid via
Ni(II)-catalyzed cascade reaction of acetamidoacrylates.
150 °C. A yield of 69% was achieved along with 8% starting
material recovery (Table 1, entry 14). A significant drop in yield
was observed in the absence of molecular sieves (Table 1, entry
15). A number of nickel(II) catalyst of varying mol% were
screened (Table 1, entries 16-18 & Table S1, entries 24-30). Best
results were obtained by employing 2 mol% Ni(OAc)2·4H2O as
catalyst with 0.5 mL DMF along with 2 mL dibromomethane as
a mixed solvent, resulting in sole product formation with 81%
yield and complete consumption of starting material after 15 h
(Table 1, entry 16).
Our methodology merits greater significance due to its
applicability in the gram-scale synthesis of isotetronic acids with
reduced (half) solvent amount. A 10 mmol scale reaction was
undertaken with compound 10a which resulted in 72% isolated
yield of 9a after 48 h (Scheme 3). Compound 9a was also
methylated to obtain O- protected isotetronic acid 12a, using
DBU and methyl iodide in acetone18 (Scheme 3).
Under the above optimized conditions, we have successfully
synthesized twenty analogs of 9a (Table 2). All the compounds
were thoroughly characterized by 1H, 13C NMR and HRMS
techniques (sampling cone 10 eV). We obtained the single-
crystal structures for some of the synthesized isotetronic acids
(Table 2). Our methodology is found to be consistent with the
substrates containing both electron-donating and withdrawing
groups in aryl ring with good to excellent yield. Halogen-
containing compounds (10e-10i) were not only tolerated but
also obtained in good yields. A formyl group in 10o was well
tolerated under the reaction conditions.
However, hetero aryl-substituted substrate (10u) was found to
decompose (Table 3). The pyridine derivative (10u) might form
complex with nickel17 and get decomposed at high
temperature. No positive outcome was obtained with 10v to
10x due to decomposition and/or polymerization.
Scheme 3 Gram scale synthesis of 9a and synthesis of o-methy
ether (12a) of synthesized isotetronic acid.
Some different sets of reactions have also been carried out to
understand the mechanism of the reaction. At first, to
understand the carbon source at C-5 of isotetronic acid, we
carried out the reaction without dibromomethane (Scheme 4A).
As expected, no reaction took place and starting material
remained intact. We tried the reaction with excess
benzaldehyde instead of dibromomethane along with DMF as
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Scheme 5 A plausible mechanistic pathway for 9a.
oxidative addition with dibromomethane13 forming possible
nickel(IV)-intermediate B 20
Reductive elimination from Ni(IV)-
intermediate furnishes bromo derivative . which undergoes
hydrolysis to afford alcohol . Lactonization followed by
.
B
C
D
tautomerization gives isotetronic acid 9a
.
Conclusions
In summary, we have, for the first time, reported C-H
functionalization to access isotetronic acids. The reaction
proceeds via vinylic C-H functionalization of 2-acetamido-3-
arylacrylate derivatives with inexpensive nickel catalyst and
dibromomethane. The proposed methodology is compatible
with both electron-donating as well as electron-withdrawing
groups. The positive aspects of the reaction are sole product
formation, no requirement of external oxidants and
applicability in the gram-scale. We have successfully
synthesized twenty analogs of 9a and two C-5 methyl-
substituted isotetronic acids. Our future goals are to establish
the reaction conditions for the synthesis of C-5 methyl-
substituted isotetronic acids and apply them in the synthesis of
bioactive molecules.
Scheme 4 Supporting reactions.
solvent, keeping other conditions same (Scheme 4B). This has
been done to check whether our starting material
acetamidoacrylate in the reaction condition hydrolyzed to form
β-keto ester and follow
a normal aldol reaction with
benzaldehyde. But no product was formed and starting material
remained intact. Formation of compound 9o (Table 2) also
supports this assumption, where an existing formyl group was
present in the aromatic ring. From the result, we can assume
that hydrolysis of the amide group might occur after the new C-
C bond formation with dibromomethane (Scheme 5). When we
used benzoyl protection instead of acetyl (13a and 13b in
Scheme 4C) and N-methyl acetamidoacrylate 14 (Scheme 4D),
no reaction took place and starting material remained intact.
This may be explained by the fact that benzoyl protected and N-
methyl acetylacrylate unable to form complex with nickel
(Scheme 5). From the result, we conclude that both the electron
density and the presence of N-H bond is required for the
heteroatom directed metallation step. Next, we also think
about the possibility of ester hydrolysis at the beginning of the
reaction. To check this possibility, we have taken 2-acetamido-
3-phenylacrylic acid (Scheme 4E) instead of its methyl ester,
which results in poor yield. This might be due to its
decomposition at higher temperature via decarboxylation.
Experimental
General experimental details
Addition of all the reagents and solvents were performed under
air for GP-I and GP-II. Glassware used in the reactions was
thoroughly oven-dried. All commercial grade reagents were
used without further purification and solvents were dried prior
to use following standard protocol. Reactions were monitored
by thin layer chromatography (TLC) using Merck silica gel 60
F254 pre-coated plates (0.25 mm) and the spots were visualized
by exposure to UV light and/or by dipping into KMnO4 solution.
Silica gel of particle size 230–400 mesh and petroleum
ether/ethyl acetate as eluent were used for column
chromatographic purification. 1H and 13C NMR spectra for all the
compounds were recorded at 400/600 and 100/150 MHz
(BrukerUltrashieldTM 400, AscendTM 600), respectively. The
spectra were recorded in deuterochloroform (CDCl3) and
Based on these results and literature reports,13,19,20 a plausible
mechanistic pathway for the formation of isotetronic acid is
presented in Scheme 5. Initially, heteroatom-guided19a,b
electrophilic nickelation takes place with acetamidoacrylate
derivative 10a to form intermediate A, which then undergoes
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deuterated dimethyl sulfoxide (DMSO-d6) as solvent at room The titled compound 10l was synthesizeVdiew Afrrtoicmle Onli1ne-
temperature. Chemical shifts are reported in ppm from naphthaldehyde (1 g, 6.41 mmol) according to GP-1
DOI: 10.1039/.DT0hOeB0c0r5u5d7eF
tetramethylsilane with the solvent resonance as internal product was dissolved in acetone and triturated with hexane.
standard (CDCl3: δH = 7.26, δC = 77.16 ppm and DMSO-d6: δH = The mixture was filtered and dried in vacuo. The pure product
2.5, δC = 39.52 ppm). Data for 1H NMR are reported as follows: was obtained as a white solid (1.293 g, 4.79 mmol, yield = 75%);
1
chemical shift (δ ppm), multiplicity (s = singlet, d = doublet, t = m.p. = 157-159 °C; H NMR (400 MHz, CDCl3) δ 8.00–7.69 (m,
triplet, m = multiplet, dd = doublet of doublet q: quartet, dt: 4H), 7.61–7.39 (m, 4H), 6.91 (s, 1H), 3.90 (s, 3H), 1.93 (s, 3H);
doublet of triplets, br: broad.), coupling constant (Hz), 13C{1H} NMR (100 MHz, CDCl3) δ 168.9, 165.5, 133.7, 131.3,
integration. Data for 13C NMR are reported as chemical shift. 129.6, 128.84, 128.5, 127.7, 126.9, 126.4, 125.4, 124.4, 52.9,
HRMS spectra using ESI (+ ve) 70 eV for amidoacrylates and 23.2; FT-IR ν̃ 3229, 3046, 3007, 2953, 1720, 1656, 1637, 1517,
10eV for isotetronic acid were recorded on an ESI-FTMS mass 1429, 1249, 1124, 968, 770 cm-1; HRMS (ESI-TOF) calculated for
spectrometer.
C16H16NO3 [M+H]+ 270.1130, found 270.1126.
(Z)-methyl 2-acetamido-3-(anthracen-9-yl)acrylate (10m):
General procedure (GP-1) for the synthesis of The titled compound 10m was synthesized from anthracene-9-
acetamidoacrylates (10a-10x): carbaldehyde (300 mg, 1.456 mmol) according to GP-1. The
Acetamidoacrylate derivatives were synthesized from crude product was dissolved in acetone and triturated with
corresponding aromatic aldehydes and N-acetylglycine using hexane. The mixture was filtered and dried in vacuo. The pure
literature known procedure.12
product was obtained as a yellow solid (288 mg, 0.903 mmol,
1
To a suspension of N-acetylglycine (1 equiv) in dry benzene yield = 62%); m.p. = above 200 °C; H NMR (400 MHz, CDCl3) δ
(5mL/mmol) containing Et3N (1.5 equiv), ethyl chloroformate 8.45 (s, 1H), 8.08–7.92 (m, 4H), 7.82 (s, 1H), 7.57–7.42 (m, 4H),
(1.1 equiv) was added at 0 °C and the mixture was stirred at 6.56 (s, 1H), 3.96 (s, 3H), 1.65 (s, 3H). 13C{1H} NMR (100 MHz,
room temperature until the N-acetylglycine crystals CDCl3) δ 168.7, 165, 131.3, 130.9, 129.1, 129.1, 128.4, 126.7,
disappeared and triethylamine hydrochloride separated. The 126.6, 125.6, 125.3, 52.9, 22.8; FT-IR ν̃ 3292, 3050, 2960, 1705,
aldehyde (0.5 equiv) was added to the mixture and heated 1678, 1635, 1494, 1436, 1370, 1251, 1007, 745, 629 cm-1;HRMS
under reflux at 80 °C for 2h. After cooling to room temperature, (ESI-TOF) calculated for C20H18NO3 [M+H]+ 320.1284; found
triethylamine hydrochloride was removed by suction filtration 320.1281.
and washed twice with dry benzene. The combined solution (Z)-methyl 2-acetamido-3-(pyren-1-yl)acrylate (10n):
was concentrated and dried under reduced pressure. The The titled compound 10n was synthesized from pyrene-1-
residue was then dissolved in methanol (HPLC grade, carbaldehyde (500 mg, 2.174 mmol) according to GP-1. The
5mL/mmol), Et3N (1.5 equiv) was added and refluxed at 65 °C crude product was dissolved in acetone and triturated with
for 3h. The reaction mixture was allowed to cool to room hexane. The mixture was filtered and dried in vacuo. The pure
temperature and the solvent was evaporated under reduced product was obtained as a yellow solid ( 478 mg, 1.39 mmol,
pressure. Purification of the residue by silica gel flash column yield = 64%); m.p. = above 200 °C; 1H NMR (400 MHz, DMSO) δ
chromatography using EtOAc/Hexanes as eluent or trituration 9.67 (s, 1H), 8.40–8.06 (m, 9H), 7.93 (s, 1H), 3.82 (s, 3H), 1.89 (d,
afforded the desired acetamidoacrylates (10a-10x).
J = 11.3 Hz, 3H). 13C{1H} NMR (100 MHz, DMSO) δ 169.5, 165.5,
131.1, 130.7, 130.3, 129.1, 128.6, 128, 127.4, 127.2, 126.6,
Experimental details and characterization data for 126.5, 125.8, 125.7, 124.8, 123.9, 123.7, 123.6, 52.3, 22.3; FT-IR
acetamidoacrylates (10a-10x): Yields and characterization data
ν̃ 3229, 3038, 3003, 2952, 1730, 1657, 1517, 1429, 1240, 1124,
are given below for each product. Most of the synthesized 838, 714 cm-1; HRMS (ESI-TOF): calculated for C22H18NO3 [M+H]+
acetamidoacrylates are literature known (see S.I. pages, S4 – 344.1285; found 344.1281.
S7). Characterization data for the unknown acetamidoacrylates (Z)-methyl 2-acetamido-3-(4-formylphenyl)acrylate (10o):
are given below.
The titled compound 10o was synthesized from
terephthalaldehyde (2.2 g, 16.418 mmol) according to GP-1
Purification was done by flash column chromatography using
.
(Z)-methyl 2-acetamido-3-(2,6-dichlorophenyl)acrylate (10i):
The titled compound 10i was synthesized from 2,6- 25% ethyl acetate in hexane as eluent to afford white solid
dichlorobenzaldehyde (500 mg, 2.857 mmol) according to GP-1 product (2.93 g, 11.82 mmol, yield = 72%); m.p. = 148-150 °C;
.
Purification was done by flash column chromatography using 1H NMR (400 MHz, DMSO) δ 10.01 (s, 1H), 9.83 (s, 1H), 7.93 (d,
25% ethyl acetate in hexane as eluent to afford white solid J = 8.0 Hz, 2H), 7.81 (d, J = 8.0 Hz, 2H), 7.17 (s, 1H), 3.72 (s, 3H),
product (567 mg, 1.97 mmol, yield = 69%); m.p. = 120-122 °C; 2.01 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 192.5, 169.4,
1H NMR (400 MHz, CDCl3) δ 7.51–7.23 (m, 3H), 7.19–7.15 (m, 165.3, 139.3, 135.8, 130.1, 129.5, 128.8, 128.5, 52.3, 22.4; FT-IR
2H), 3.88 (s, 3H), 1.97 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ
167.8, 165, 147.2, 133.3, 131.3, 129.6, 129.1, 127.6, 125.6, 1246, 1211, 1131, 1013, 744 cm-1; HRMS (ESI): calculated for
ν̃ 3227, 2999, 2951, 2851, 2742, 1723, 1697, 1661, 1643, 1513,
124.8, 53.1, 23.4; FT-IR ν̃
3310, 3085, 2954, 1717, 1694, 1652, C13H14NO4 [M+H]+ 248.0920; found 248.0917.
1496, 1425, 1365, 1284, 1136, 782 cm-1; HRMS (ESI-TOF) (Z)-methyl 2-acetamido-3-(2-nitrophenyl)acrylate (10p):
calculated for C10H12Cl2NO3 [M+H]+ 288.0194; found 288.0192. The titled compound 10p was synthesized from 2-
(Z)-methyl 2-acetamido-3-(naphthalen-1-yl)acrylate (10l):
nitrobenzaldehyde (500 mg, 3.31 mmol) according to GP-1.
Purification was done by flash column chromatography using
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Organic & Biomolecular Chemistry
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30% ethyl acetate in hexane as eluent to afford white solid The titled compound 9a was synthesized from compound 10a,
View Article Online
DOI: 10.1039/D0OB00557F
product (526 mg, 1.986 mmol, yield = 60%); m.p. = 158-160 °C; according to GP-2. Purification was done by flash column
1H NMR (400 MHz, CDCl3) δ 8.14 (d, J = 8.3 Hz, 1H), 7.73 (s, 1H), chromatography using 15% ethyl acetate in hexane as eluent to
7.59 (t, J = 7.5 Hz, 1H), 7.47 (t, J = 7.7 Hz, 1H), 7.41 (d, J = 7.5 Hz, afford white solid product (71 mg, 81%). m.p. = above 200 °C;
1H), 7.12 (s, 1H), 3.90 (s, 3H), 1.97 (s, 3H); 13C{1H} NMR (100 1H NMR (600 MHz, DMSO) δ 10.72 (s, 1H), 7.71-7.69 (m, 2H),
MHz, DMSO) δ 167.8, 165, 147.2, 133.3, 131.3, 129.6, 129.1, 7.46-7.44 (m, 2H), 7.37-7.36 (m, 1H), 5.18 (s, 2H). 13C{1H} NMR
127.6, 125.6, 124.8, 53.1, 23.4; FT-IR ν
2949, 1726, 1652, 1638, 1518, 1357, 1249, 1130, 985 cm-1; FT-IR ν
HRMS (ESI): calculated for C12H13N2O5 [M+H]+ 265.0820; found 1027, 757, 685 cm-1; HRMS (ESI): calculated for C10H9O3 [M+H]+
265.0819. 177.0552; found 177.0546.
(Z)-methyl 2-acetamido-3-(4-(trifluoromethyl)phenyl)acrylate Gram scale synthesis of 3-hydroxy-4-phenylfuran-2(5H)-one
̃
3024, 3149, 3077, 3001, (150 MHz, DMSO) δ 170.1, 137.5, 130.8, 128.8, 126.3, 126, 67.6;
̃
3298, 3053, 2939, 1719, 1683, 1451, 1399, 1322, 1163,
(10s):
(9a): In a 100 ml pressure tube, acetamidoacrylate 10a (2.190 g,
The titled compound 10s was synthesized from 4- 10 mmol), Ni(OAc)2 4H2O (50 mg, 2 mol%) Li(OAc).2H2O (3.06 g,
(trifluoromethyl)benzaldehyde (500 mg, 2.873 mmol) according 3 equiv.), 4 Å Molecular Sieve (2.2 g, 100 wt%), were taken.
to GP-1. The crude product was dissolved in acetone and Then CH2Br2 (20 mL) and DMF (5 mL) were added and heated at
triturated with hexane. The mixture was filtered and dried in 150 °C. After completion of reaction (48 h, checked by TLC), add
vacuo. The pure product was obtained as a white solid (660 mg, EtOAc into the reaction mixture and filtered through a short pad
.
1
2.3 mmol, yield = 80%); m.p. = 153-154 °C; H NMR (400 MHz, of cellite, solvent was evaporated under reduced pressure.
CDCl3) δ 7.52 - 7.43 (m, 5H), 7.26 (s, 1H), 3.77 (s, 3H), 1.99 (s, Purification was done by flash column chromatography using
3H); 13C{1H} NMR (100 MHz, CDCl3) δ 168.7, 165.4, 137.5, 131.1, 15% ethyl acetate in hexane as eluent to afford white solid
130.8, 130.5, 130.1, 129.7, 129.6, 127.9, 125.7, 125.3, 125.2, product (1.27 g, 72%).
122.5, 119.8, 77.4, 77.1, 76.8, 52.9, 23.3; FT-IR ν̃ 3216, 2957, 3-hydroxy-4-(2-methoxyphenyl)furan-2(5H)-one (9b):
2853, 1730, 1664, 1649, 1523, 1321, 1244, 1164, 1124, 1066, The titled compound 9b was synthesized from compound 10b,
1015, 836, 745 cm-1; HRMS (ESI): calculated for C13H13F3NO3 according to GP-2. Purification was done by flash column
[M+H]+ 288.0841; found 288.0842.
(2Z,2'Z)-dimethyl
acetamidoacrylate) (10x):
chromatography using 15% ethyl acetate in hexane as eluent to
3,3'-(1,4-phenylene)bis(2- afford white solid product (80 mg, 78%). m.p. = 153-155 °C; 1H
NMR (400 MHz, CDCl3) δ 7.76 – 7.74 (m, 1H), 7.41 – 7.37 (m,
The titled compound 10x was synthesized from compound 10o 1H), 7.12 – 7.08 (m, 2H), 7.01 (d, J = 8.4 Hz, 1H), 5.18 (s, 2H),
(700 mg, 2.822 mmol) according to GP-1. The crude product was 3.95 (s, 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.2, 156.3,
dissolved in acetone and triturated with hexane. The mixture 136.8, 130.8, 129.1, 124.4, 121.9, 119.6, 111.9, 69.4, 56.1; FT-IR
was filtered and dried in vacuo. The pure product was obtained
ν̃ 3265, 2922, 2851, 1727, 1493, 1463, 1394, 1314, 1251, 1163,
as a white solid (437 mg, 1.213 mmol, yield = 43%). m.p. = 160- 1020, 763 cm-1; HRMS (ESI): calculated for C11H11O4 [M+H]+
1
162 °C; H NMR (600 MHz, DMSO) δ 9.71 (s, 1H), 7.68 (s, 2H), 207.0657; found 207.0652.
7.17 (s, 1H), 3.72 (s, 3H), 2.02 (s, 3H). 13C{1H} NMR (100 MHz, 3-hydroxy-4-(3-methoxyphenyl)furan-2(5H)-one (9c):
CDCl3) δ 168.5, 165.6, 137.7, 129.7, 125.5, 122.6, 53.1, 23.6; FT- The titled compound 9c was synthesized according to GP-2
.
IR ν̃ 3233, 2920, 2851, 2750, 1713, 1664, 1640, 1428, 1362, Purification was done by flash column chromatography using
1245, 1126, 966, 733 cm-1; HRMS (ESI): calculated for 15% ethyl acetate in hexane as eluent to afford white solid
C18H21N2O6 [M+H]+ 361.1396; found 361.1394.
product (78 mg, 76%); m.p. = above 200 °C; H NMR (600 MHz,
1
CDCl3) δ 7.38 (t, J = 8.0 Hz, 1H), 7.30 (s, 1H), 7.20 (d, J = 7.6 Hz,
General procedure (GP-2) for the synthesis of isotetronic acids 1H), 6.97 (dd, J = 8.2, 2.2 Hz, 1H), 6.58 (s, 1H), 5.13 (s, 2H), 3.88
(9a-9t):
(s, 3H). 13C{1H} NMR (150 MHz, CDCl3) δ 171, 159.9, 136.5,
In a 15 ml pressure tube, acetamidoacrylate 10 (0.5 mmol), 131.1, 130, 126, 118.8, 115.25, 112.3, 68.3, 55.4; FT-IR ν 3266,
̃
Ni(OAc)2 4H2O (2 mol%), Li(OAc).2H2O (3 equiv.), 4 Å Molecular 2919, 2852, 1719, 1678, 1461, 1394, 1322, 1163, 1034, 770 cm-
Sieve dust (100 wt% with respect to acetamidoacrylate), were 1; HRMS (ESI): calculated for C11H11O4 [M+H]+ 207.0657; found
taken. Then CH2Br2 (2 mL) and DMF (0.5 mL) were added in open 207.0654.
.
atmosphere and heated at 150 °C (Caution: Keep the reaction 3-hydroxy-4-(4-methoxyphenyl)furan-2(5H)-one (9d):
inside the hood and bring it to room temperature for The titled compound 9d was synthesized from compound 10d,
monitoring the reaction). After completion of reaction (10-20 h, according to GP-2. Purification was done by flash column
checked by TLC), add EtOAc into the reaction mixture and chromatography using 15% ethyl acetate in hexane as eluent to
filtered through a short pad of cellite, solvent was evaporated afford white solid product (81 mg, 79% ); m.p. = above 200 °C;
under reduced pressure. Purification was done by silica gel flash 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J = 8.8 Hz, 2H), 6.97 (d, J =
column chromatography using EtOAc/Hexanes as eluent to 8.8 Hz, 2H), 6.36 (s, 1H), 5.09 (s, 2H), 3.85 (s, 3H). 13C{1H} NMR
afford the desired isotetronic acid.
(150 MHz, CDCl3) δ 171.4, 160.6, 134.9, 128.4, 126.7, 122.8,
114.6, 68.3, 55.5; FT-IR ν̃ 3266, 2923, 2852, 1717, 1688, 1603,
Experimental details and characterization data:
3-hydroxy-4-phenylfuran-2(5H)-one (9a):
1457, 1689, 1310, 1216, 1163, 1127, 825, 771 cm-1; HRMS (ESI):
calculated for C11H11O4 [M+H]+ 207.0657; found 207.0657.
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
4-(2-bromophenyl)-3-hydroxyfuran-2(5H)-one (9e):
The titled compound 9e was synthesized according to GP-2
15% ethyl acetate in hexane as eluent to afford white solid
View Article Online
1
.
product (74 mg, 78%); m.p. = 157-158 °DCO; I:H10N.10M39R/D(04O00B0M05H57zF,
Purification was done by flash column chromatography using CDCl3) δ 7.45 – 7.34 (m, 4H), 6.57 (s, 1H), 5.13 (s, 2H), 2.50 (s,
15% ethyl acetate in hexane as eluent to afford white solid 3H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.8, 137.2, 136.8, 131.2,
1
product (116 mg, 91%); m.p. = 145-146 °C; H NMR (400 MHz, 129.5, 129.2, 128.7, 128.2, 126.1, 70, 20.7; FT-IR ν
̃
3256, 3065,
CDCl3) δ 7.66 (d, J = 7.9 Hz, 1H), 7.61 (d, J = 7.5 Hz, 1H), 7.40 (t, 3025, 1719, 1491, 1449, 1390, 1304, 1168, 1031, 893, 759, 721
J = 7.3 Hz, 1H), 7.26 (t, J = 6.8 Hz, 1H), 5.24 (s, 2H). 13C{1H} NMR cm-1; HRMS (ESI): calculated for C11H11O3 [M+H]+ 191.0708;
(100 MHz, CDCl3) δ 170.5, 138.1, 134, 131.4, 131.1, 130.8, 127.8, found 191.0703.
127.4, 121.8, 69.8; FT-IR ν̃ 3251, 2923, 2853, 1741, 1472, 1396, 3-hydroxy-4-(p-tolyl)furan-2(5H)-one (9k):
1307, 1264, 1162, 1029, 767, 654 cm-1; HRMS (ESI): calculated The titled compound 9k was synthesized according to GP-2
.
for C10H8BrO3 [M+H]+ 254.9657; found 254.9662.
Purification was done by flash column chromatography using
4-(4-bromophenyl)-3-hydroxyfuran-2(5H)-one (9f):
The titled compound 9f was synthesized according to GP-2
15% ethyl acetate in hexane as eluent to afford white solid
product (78 mg, 82%); m.p. = above 200 °C; 1H NMR (400 MHz,
.
Purification was done by flash column chromatography using DMSO) δ 10.57 (s, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.26 (d, J = 8.0
15% ethyl acetate in hexane as eluent to afford white solid Hz, 2H), 5.14 (s, 2H), 2.33 (s, 3H). 13C{1H} NMR (100 MHz, DMSO)
product (115 mg, 90%); m.p. = above 200 °C; 1H NMR (400 MHz, δ 170.1, 138.4, 136.8, 129.3, 127.9, 126.3, 126.2, 67.5, 21; FT-IR
DMSO) δ 10.97 (s, 1H), 7.72 – 7.56 (m, 4H), 5.16 (s, 2H). 13C{1H}
NMR (100 MHz, DMSO) δ 169.8, 138.1, 131.7, 129.9, 128.2, cm-1; HRMS (ESI): calculated for C11H11O3 [M+H]+ 191.0708;
124.7, 121.8, 67.4; FT-IR ν 304, 2971, 1726, 1451, 1388, 1230, found 191.0713.
ν̃ 3293, 2920, 2852, 1723, 1452, 1312, 1231, 1155, 1024, 768
̃
1166, 1025, 993, 827, 771, 678 cm-1; HRMS (ESI): calculated for 3-hydroxy-4-(naphthalen-2-yl)furan-2(5H)-one (9l):
C10H8BrO3 [M+H]+ 254.9657; found 254.9679.
The titled compound 9l was synthesized according to GP-2.
4-(4-fluorophenyl)-3-hydroxyfuran-2(5H)-one (9g):
The titled compound 9g was synthesized according to GP-2
Purification was done by flash column chromatography using product (96 mg, 85%); m.p. = above 200 °C; H NMR (400 MHz,
Purification was done by flash column chromatography using
.
15% ethyl acetate in hexane as eluent to afford white solid
1
15% ethyl acetate in hexane as eluent to afford white solid CDCl3) δ 7.94 -7.89 (m, 3H), 7.59 – 7.43 (m, 4H), 6.15 (s, 1H),
1
product (89 mg, 92%); m.p. = above 200 °C; H NMR (400 MHz, 5.14 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.5, 137.5, 134,
DMSO) δ 10.76 (s, 1H), 7.75 (s, 2H), 7.30 (t, J = 8.2 Hz, 2H), 5.16 130.4, 130.3, 128.9, 127.5, 127.1, 126.7, 126.3, 125.6, 125.3,
(s, 2H). 13C{1H} NMR (100 MHz, DMSO) δ 169.9, 163.1, 160.6, 70.3; FT-IR ν
̃
3195, 2923, 2854, 1726, 1436, 1351, 1253, 1150,
137.1, 128.5, 128.5, 127.3, 125.1, 115.8, 115.6, 67.4; FT-IR ν
̃
1116, 1020, 772, 627 cm-1; HRMS (ESI): calculated for C14H11O3
3310, 2922, 2852, 1739, 1514, 1458, 1398, 1231, 1166, 1830, [M+H]+ 227.0708; found 227.0693.
841, 771 cm-1; HRMS (ESI): calculated for C10H8FO3 [M+H]+ 4-(anthracen-9-yl)-3-hydroxyfuran-2(5H)-one (9m):
195.0457; found 195.0439.
The titled compound 9m was synthesized according to GP-2.
4-(4-chlorophenyl)-3-hydroxyfuran-2(5H)-one (9h):
The titled compound 9h was synthesized according to GP-2
Purification was done by flash column chromatography using product (93 mg, 68%); m.p. = 171-173 °C; H NMR (600 MHz,
Purification was done by flash column chromatography using
.
25% ethyl acetate in hexane as eluent to afford white solid
1
15% ethyl acetate in hexane as eluent to afford white solid CDCl3) δ 8.56 (s, 1H), 8.07 (d, J = 8.1 Hz, 2H), 7.89 (d, J = 8.3 Hz,
1
product (92 mg, 87%); m.p. = above 200 °C; H NMR (400 MHz, 2H), 7.59 – 7.50 (m, 4H), 5.16 (s, 2H). 13C{1H} NMR (150 MHz,
CDCl3) δ 7.59 (d, J = 8.3 Hz, 2H), 7.42 (d, J = 8.3 Hz, 2H), 6.33 (s, CDCl3) δ 139.6, 131.5, 129.7, 129.2, 129.1, 127.1, 125.8, 124.9,
1H), 5.10 (s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 169.8, 137.9, 70.7; FT-IR ν
̃ 3290, 3056, 2926, 2854, 1753, 1444, 1335, 1286,
133.1, 129.6, 128.8, 128, 124.7, 67.4; FT-IR ν̃
3280, 2919, 2851, 1156, 1123, 1030, 737 cm-1; HRMS (ESI): calculated for C18H13O3
1718, 1679, 1494, 1450, 1387, 1162, 1032, 770, 722, 651 cm-1; [M+H]+ 277.0865; found 277.0859.
HRMS (ESI): calculated for C10H8ClO3 [M+H]+ 211.0162; found 3-hydroxy-4-(pyren-1-yl)furan-2(5H)-one (9n):
211.0157.
The titled compound 9n was synthesized according to GP-2
.
4-(2,6-dichlorophenyl)-3-hydroxyfuran-2(5H)-one (9i):
Purification was done by flash column chromatography using
The titled compound 9i was synthesized according to GP-2. 25% ethyl acetate in hexane as eluent to afford white solid
1
Purification was done by flash column chromatography using product (94 mg, 63%); m.p. = above 200 °C; H NMR (600 MHz,
15% ethyl acetate in hexane as eluent to afford white solid DMSO) δ 10.45 (s, 1H), 8.371- 8.352 (m, 3H), 8.29 – 8.21 (m, 3H),
1
product (103 mg, 84%); m.p. = 134-136 °C; H NMR (400 MHz, 8.17 – 8.09 (m, 3H), 5.36 (s, 2H). 13C{1H} NMR (150 MHz, DMSO)
CDCl3) δ 7.40 (d, J = 7.9 Hz, 2H), 7.29 (m, 1H), 6.69 (s, 1H), 5.02 δ 170.2, 138.8, 131.6, 131.2, 130.9, 128.5, 128.4, 128.4, 128.1,
(s, 2H). 13C{1H} NMR (100 MHz, CDCl3) δ 170.2, 139.1, 135.2, 127.7, 127, 126.6, 126.4, 126.1, 126.1, 126, 125.2, 124.5, 124.2,
131.1, 128.4, 128, 124.3, 68.6; FT-IR ν̃ 3252, 3084, 1750, 1737, 69.8; FT-IR ν̃ 3334, 3258, 3040, 2921, 2851, 1755, 1391, 1329,
1557, 1429, 1391, 1317, 1158, 1025, 893, 775, 725 cm-1; HRMS 1297, 1150, 845, 720 cm-1; HRMS (ESI): calculated for C20H13O3
(ESI): calculated for C10H7Cl2O3 [M+Na]+ 244.9772; found [M+H]+ 301.0865; found 301.0878.
244.9767.
4-(4-hydroxy-5-oxo-2,5-dihydrofuran-3-yl)benzaldehyde (9o):
3-hydroxy-4-(o-tolyl)furan-2(5H)-one (9j):
The titled compound 9j was synthesized according to GP-2
The titled compound 9o was synthesized according to GP-2.
Purification was done by flash column chromatography using
.
Purification was done by flash column chromatography using 20% ethyl acetate in hexane as eluent to afford white solid
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1
product (81 mg, 79%); m.p. = above 200 °C; H NMR (400 MHz, Hz, 2H), 5.20 (s, 2H). 13C{1H} NMR (150 MHz, DMSO) δ 169.5,
View Article Online
DMSO) δ 11.34 (s, 1H), 10.01 (s, 1H), 7.98 (d, J = 8.3 Hz, 2H), 7.89 140, 135.2, 132.6, 126.7, 123.4, 118.7, 11D0O.4I,: 6107.1.403;9F/TD-0IROBν00557F
̃ 3273,
(d, J = 8.3 Hz, 2H), 5.23 (s, 2H); 13C{1H} NMR (100 MHz, DMSO) δ 2923, 2853, 2229, 1727, 1462, 1397, 1317, 1171, 1029, 841, 771
192.6, 169.7, 139.8, 136.4, 135.4, 129.8, 126.7, 124.1, 67.6; FT- cm-1; HRMS (ESI): calculated for C11H8NO3 [M+H]+ 202.0504;
IR ν̃ 3288, 2923, 2853, 1731, 1697, 1606, 1393, 1320, 1219, found 202.0509.
1170, 1027, 830, 772 cm-1; HRMS (ESI): calculated for C11H9O4
[M+H]+ 205.0501; found 205.0482.
3-hydroxy-4-(2-nitrophenyl)furan-2(5H)-one (9p):
General procedure (GP-3) for synthesis of 5-methyl-
substituted isotetronic acid:
The titled compound 9p was synthesized according to GP-2
.
In a 15 ml pressure tube, acetamidoacrylate 10 (0.5 mmol),
.
Purification was done by flash column chromatography using Ni(OAc)2 4H2O (2 mol %) Li(OAc).2H2O (3 equiv.), 4 Å Molecular
20% ethyl acetate in hexane as eluent to afford white solid Sieve (100 wt% with respect to acetamidoacrylate), were taken.
1
product (66 mg, 60%); m.p. = 140-142 °C; H NMR (600 MHz, Then DCE (2 mL) was added in open atmosphere and heated at
DMSO) δ 10.75 (s, 1H), 8.04 (dd, J = 8.1, 0.7 Hz, 1H), 7.79 (td, J = 150 °C (Caution: Keep the reaction inside the hood and bring it
7.7, 1.1 Hz, 1H), 7.71 – 7.60 (m, 2H), 5.14 (s, 2H). 13C{1H} NMR to room temperature for monitoring the reaction). After
(150 MHz, DMSO) δ 168.7, 148.5, 139, 133.4, 130.1, 129.9, completion of reaction (12-15 h, checked by TLC). Add EtOAc
124.9, 124.7, 124, 68; FT-IR ν̃ 2923, 2853, 1763, 1528, 1352, into the reaction mixture and filtered through a short pad of
1156, 1028, 749 cm-1; HRMS (ESI): calculated for C10H8NO5 cellite, solvent was evaporated under reduced pressure.
[M+H]+ 222.0402; found 222.0399.
3-hydroxy-4-(3-nitrophenyl)furan-2(5H)-one (9q):
Purification of the residue by silica gel chromatography using
EtOAc/Hexanes as eluent afforded the desired isotetronic acid.
The titled compound 9q was synthesized according to GP-2. Yields and characterization data are given below for each
Purification was done by flash column chromatography using product.
20% ethyl acetate in hexane as eluent to afford white solid
1
product (74 mg, 67%); m.p. = above 200 °C; H NMR (600 MHz, Experimental details and characterization data:
DMSO) δ 11.40 (s, 1H), 8.58 (s, 1H), 8.20 (dd, J = 8.1, 1.6 Hz, 1H), Methyl (Z)-2-acetamido-3-phenylacrylate (11a):
8.01 (d, J = 7.8 Hz, 1H), 7.75 (t, J = 8.0 Hz, 1H), 5.26 (s, 2H); The titled compound 11a was synthesized according to GP-3
.
13C{1H} NMR (150 MHz, DMSO) δ 169.5, 148.1, 139.4, 132.3, Purification was done by flash column chromatography using
132, 130.3, 123.3, 122.9, 120.7, 67.5 (s); FT-IR ν
̃
3267, 2933, 15% ethyl acetate in hexane as eluent to afford white solid
1
2854, 1730, 1529, 1352, 1156, 957, 751 cm-1; HRMS (ESI): product (22 mg, 23%); m.p. = 104-108 °C; H NMR (400 MHz,
calculated for C10H8NO5 [M+H]+ 222.0402; found 222.0409.
3-hydroxy-4-(4-nitrophenyl)furan-2(5H)-one (9r):
The titled compound 9r was synthesized according to GP-2
CDCl3) δ 7.64 – 7.62 (m, 2H), 7.47 – 7.40 (m, 2H), 7.40 - 7.36 (m,
1H), 6.40 (s, 1H), 5.47 (q, J = 6.5 Hz, 1H), 1.58 (d, J = 6.5 Hz, 3H).
13C{1H} NMR (100 MHz, CDCl3) δ 170.2, 136.4, 131.4, 129.9,
.
Purification was done by flash column chromatography using 129.3, 129, 127.7, 76.5, 20.4; FT-IR ν̃ 3289, 3061, 2924, 2854,
20% ethyl acetate in hexane as eluent to afford white solid 1724, 1450, 1393, 107, 1157, 1057, 881, 764, 694 cm-1; HRMS
1
product (70 mg, 63%); m.p. = above 200 °C; H NMR (400 MHz, (ESI): calculated for C11H11O3 [M+H]+ 191.0708; found 191.0702.
DMSO) δ 11.63 (s, 1H), 8.30 (d, J = 8.7 Hz, 2H), 7.92 (d, J = 8.7 4-(4-fluorophenyl)-3-hydroxy-5-methylfuran-2(5H)-one (11g).
Hz, 2H), 5.24 (s, 2H). 13C{1H} NMR (100 MHz, DMSO) δ 169.5, The titled compound 11g was synthesized according to GP-3
.
146.4, 140.6, 137.2, 127.1, 124, 122.9, 67.5; FT-IR ν̃ 3273, 2924, Purification was done by flash column chromatography using
2854, 1760, 1525, 1351, 1170, 751 cm-1; HRMS (ESI): calculated 15% ethyl acetate in hexane as eluent to afford white solid
for C10H8NO5 [M+H]+ 222.0402; found 222.0412.
3-hydroxy-4-(4-(trifluoromethyl)phenyl)furan-2(5H)-one (9s):
The titled compound 9s was synthesized according to GP-2
product (29 mg, 28%); m.p. = 117-120 °C; H NMR (400 MHz,
CDCl3) δ 7.71 – 7.56 (m, 4H), 7.15 (t, J = 8.6 Hz, 4H), 6.66 (s, 2H),
5.43 (q, J = 6.4 Hz, 2H), 1.57 (d, J = 6.5 Hz, 6H). 13C{1H} NMR (100
1
.
Purification was done by flash column chromatography using MHz, CDCl3) δ 170.2, 164.2, 161.7, 136.3, 130.6, 129.7, 129.6,
15% ethyl acetate in hexane as eluent to afford white solid 126.3, 126.2, 116.4, 116.1, 76.3, 20.4; FT-IR ν 3302, 2922, 2867,
̃
product (87 mg, 71%); m.p. = above 200 °C; H NMR (400 MHz, 1740, 1566, 1459, 1401, 1166, 1026, 771 cm-1; HRMS (ESI):
DMSO) δ 11.26 (s, 1H), 7.88 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 8.1 calculated for C11H10FO3 [M+H]+ 209.0614; found 209.0618.
Hz, 1H), 5.20 (s, 2H). 13C{1H} NMR (100 MHz, DMSO) δ 169.7,
1
139.4, 134.7, 128.8, 128.5, 128.2, 127.9, 126.8, 125.6, 125.6, General procedure (GP-4) for synthesis of o-methyl ether of
125.6, 125.5, 125.5, 123.8, 122.8, 120.1, 67.5; FT-IR ν̃ 3284, isotetronic acid:
2964, 1742, 1396, 1327, 1153, 1102, 1060, 1016, 844, 771, 641 DBU (1.3 equiv.) was added to a stirred solution of isotetronic
cm-1; HRMS (ESI): calculated for C11H8F3O3 [M+H]+ 245.0426; acid derivative (1 equiv.) in acetone (5 mL) and the reaction was
found 245.0419.
4-(4-hydroxy-5-oxo-2,5-dihydrofuran-3-yl)benzonitrile (9t):
The titled compound 9t was synthesized according to GP-2
stirred for 15 min. at 0 °C. Iodomethane (2 equiv.) was added
dropwise. Ice bath was removed after 10 min. and stirring was
continued for 4 h at room temperature. After completion of
.
Purification was done by flash column chromatography using reaction the solvent was removed, and the residue was diluted
15% ethyl acetate in hexane as eluent to afford white solid with EtOAc. The resulting solution was washed successively
1
product (75 mg, 75%); m.p. = above 200 °C; H NMR (600 MHz, with HCl (5 mL, 1 N), water (3 x 20 ml), saturated aqueous
DMSO) δ 11.43 (s, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 8.2 solution of Na2S2O3 (2 mL), and brine. The combined organic
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
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H. Chen, X. Ma, Z. Li, Q. Wang, F. Tao, ARKIVOC, 2009, x, 87-
layers were dried using Na2SO4, concentrated in vacuo, and
purified on silica gel column using EtOAc/Hexanes eluent.
View Article Online
105.
(a) D. Lee, S. G. Newman, M. S. TayloDr,OOI: r1g0..10Le39tt/.D,02O0B0090,51571F
,
5486-5489; (b) B. Zhang, Z. Jiang, X. Zhou, S. Lu, J. Li, Y. Liu, C.
Li, Angew. Chem. Int. Ed., 2012, 51, 13159 –13162.
Z. Zhou, P. M. Wallesera, M. A. Tius, Chem. Commun., 2015,
51, 10858-10860.
Experimental details and characterization data:
Methyl (Z)-2-acetamido-3-phenylacrylate (12a):
8
9
The titled compound 12a was synthesized from 0.2 mmol 9a
according to GP-4. Purification was done by flash column
chromatography using 5% ethyl acetate in hexane as eluent to
Y. Zheng, X. Li, C. Ren, D. Zhang-Negrerie, Y. Du, K. Zhao, J.
Org. Chem., 2012, 77, 10353−10361.
10 K. Clagg, H. Hou, A. B. Weinstein, D. Russell, S. S. Stahl, S. G.
Koenig, Org. Lett., 2016, 18, 3586−3589.
1
afford white solid product (35 mg, 92%); m.p. = 87-88 °C; H
NMR (400 MHz, CDCl3) δ 7.66 - 7.65 (m, 2H), 7.45 – 7.38 (m, 3H),
5.08 (s, 2H), 4.15 (s, 3H). 13C{1H} (100 MHz, CDCl3) δ 169.1,
140.1, 134, 130, 130, 129, 126.8, 67.4, 58.6; FT-IR ν̃ 2924, 2852,
1732, 1650, 1457, 1354, 1148, 1076, 1021, 978, 758, 683 cm-1;
HRMS (ESI): calculated for C11H11O3 [M+H]+ 191.0708; found
191.0708.
11 (a) D. Mal, Anionic Annulations in Organic Synthesis: A
Versatile and Prolific Class of Ring-Forming Reactions,
Elsevier, Amsterdam, 2018; (b) Q.-W. Gui, X. He, W. Wang, H.
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Zhang, G.-K. Jia, Z. Cao, Z. Tang, X. Yu, X. Xu and W.-M. He,
Org. Biomol. Chem., 2018, 16, 5050–5054.
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Mishra, A. K. Mukerjee, Synthesis, 1980, 10, 836-839.
Conflicts of interest
There are no conflicts to declare.
13 Y. H. Zhang, B. F. Shi, J. Q. Yu, Angew. Chem. Int. Ed., 2009, 48
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We gratefully acknowledge the Council of Scientific and
Industrial Research (CSIR) for financial support and the
Department of Science and Technology for instrumental
facilities. B.R. thanks CSIR for his research fellowship
[09/081(1220)/2014-EMR-I]. We are thankful to Prof. N. D.
Pradeep Singh for providing lab facilities, Dr. Santanu Chand for
solving X-ray crystal structure, Dr. Debanjana Biswal, Dr. Siba
Prasad Midya and Mr. Sabuj Kanti Das for their kind help.
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