First Total Synthesis of (±)-Rhodoconferimide

Article abstract of DOI:10.1055/s-0036-1590944

Starting from vanillin and dimethyl maleate, a concise and efficient racemic total synthesis of the potent antioxidant marine natural product (±)-rhodoconferimide has been carried out via the Wittig reaction, catalytic hydrogenation, selective brominations, and imide formation. An appropriate regioselective double bromination of the aromatic ring was a key step in the synthesis.

Full text of DOI:10.1055/s-0036-1590944

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–E
paper
A
en
K. R. Pandhade, N. P. Argade
Paper
Synthesis
First Total Synthesis of (±)-Rhodoconferimide
Br
O
O
Br
2
O
O
Kailas R. Pandhade
O
Wittig reaction
Catalytic hydrogenation
Basic hydrolysis
Anhydride formation
Br
Br
3
Narshinha P. Argade*
0
0
0
0
0-
0
0
3
4-
5
5
3
4-
0
7
6
H
O
O
O
O
1
6
NH
+
4
Imide formation
Demethylation
(4 steps, 59%)
Regioselective
brominations
(3 steps, 69%)
HO
HO
HO
5
O
Division of Organic Chemistry, National Chemical Laboratory
(CSIR), Pune 411 008, India
np.argade@ncl.res.in
OH
OMe
O
OMe
Vanillin
Dimethyl
Maleate
Dibromo-diester
(
)-Rhodoconferimide
Received: 24.08.2017
Accepted after revision: 05.10.2017
Published online: 06.11.2017
Br
O
Br
NH
O
DOI: 10.1055/s-0036-1590944; Art ID: ss-2017-z0547-op
Br
HO
OH
HO
Abstract Starting from vanillin and dimethyl maleate, a concise and
efficient racemic total synthesis of the potent antioxidant marine natu-
ral product (±)-rhodoconferimide has been carried out via the Wittig re-
action, catalytic hydrogenation, selective brominations, and imide for-
mation. An appropriate regioselective double bromination of the
aromatic ring was a key step in the synthesis.
(S)-3-(2,3-Dibromo-4,5-dihydroxybenzyl)
pyrrolidine-2,5-dione [(+)-Rhodoconferimide]
(Natural Antioxidant, IC50 = 5.22 μM)
Br
O
OH
HO
OH
OH
OH
Key words vanillin, bromination, (±)-rhodoconferimide, antioxidants,
natural products, total synthesis
Urceolatin
(Natural Antioxidant, IC50 = 7.90 μM)
2,6-Di-tert-butyl-4-methylphenol (BHT)
(Synthetic Antioxidant, IC50 = 82.10 μM)
In life processes free radicals are continuously generat-
ed from oxygen metabolism. However, their imbalance
causes damage to cells resulting in aging and diseases such
as atherosclerosis, cancer, cardiovascular disorder, diabetes,
inflammation, ischemia-reperfusion damage, Alzheimer’s
disease, and Parkinson’s disease.1–8 Antioxidants play a vital
role in protecting human beings from free-radical-induced
damage.9–11 The use of synthetic antioxidants has been lim-
ited due to their lipid profile alteration and carcinogenic ef-
fects.12,13 In this context the search for natural antioxidants
has received significant attention.14–20 The marine red alga
Rhodomela confervoides occurs along the northern coastline
of China and there it has been used as a food ingredient.21–25
In 2012, Wang and co-workers isolated 10 mg of the new
nitrogen-containing bromophenol (+)-rhodoconferimide
from a 33 kg air-dried sample of R. confervoides.26,27 (+)-
Rhodoconferimide exhibits a 15-fold more potent free radi-
cal scavenging activity compared to the well-known syn-
thetic antioxidant 2,6-di-tert-butyl-4-methylphenol (BHT)
(Figure 1).26 In continuation of our studies on the total syn-
thesis of recently isolated structurally interesting and bio-
logically important natural products;28–30 we herein report
Figure 1 Natural and synthetic antioxidants (+)-rhodoconferimide,
urceolatin, and BHT22,26
the first total synthesis of (±)-rhodoconferimide from the
readily available precursors vanillin and dimethyl maleate.
Synthesis of an appropriately pentasubstituted aromatic
ring bearing compounds is a challenging task for both elec-
tronic and steric reasons. A careful scrutiny of the rhodo-
conferimide structure revealed that 3,4-methylenedioxy-
benzaldehyde (piperonal), dimethyl maleate, elemental
bromine, and urea would be suitable chemical constituents
to accomplish the practical total synthesis of the target
compound. Appropriate sequencing of the reactions, regi-
oselective electrophilic introduction of two bromine atoms
on the properly activated aromatic ring, and overall stabili-
ty of the catechol moiety were the synthetic concerns. A
Wittig reaction of the in situ generated ylide from dimethyl
maleate (2) and tributylphosphine with piperonal (1) ex-
clusively supplied the (E)-olefin 3 in 79% yield (Scheme 1).
The catalytic hydrogenation of (E)-olefin 3 to saturated di-
ester 4, followed by the bromination of 4 in methanol solely
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

B
K. R. Pandhade, N. P. Argade
Paper
Synthesis
O
O
O
Br
O
O
O
O
H
O
O
H2, Pd/C, MeOH
25 °C, 5 h (98%)
O
O
O
O
O
O
Br2, MeOH
PBu3, THF
+
25 °C, 36 h (79%)
O
25 °C, 8 h (98%)
O
O
O
O
O
O
O
O
O
Piperonal (1)
Dimethyl
3
(
)-4
( )-5
Maleate (2)
Scheme 1 Synthesis of monobrominated model compound
formed the monobrominated product 5 in 96% yield over
two steps. The position of the bromine atom in compound 5
was confirmed on the basis of two sharp singlets of the aro-
matic protons in the 1H NMR spectrum. Treatment of 4 with
an excess of bromine (4.00 equiv) in acetic acid at 25 °C for
24 hours resulted in an inseparable mixture of the corre-
sponding mono- and dibrominated products in very good
yield in a 1:3 ratio (by 1H NMR). Unfortunately, the aromatic
ring system in compound 4 was not sufficiently activated
for facile electrophilic introduction of the desired second
bromine atom. Therefore, at this stage it was decided to
commence the synthesis from vanillin instead of piperonal.
A Wittig reaction of vanillin (6) with the in situ generat-
ed ylide from dimethyl maleate (2) and tributylphosphine
furnished the required product 7 in 76% yield; catalytic re-
duction of the carbon–carbon double bond provided diester
8 in 99% yield (Scheme 2). Treatment of 8 with an excess of
bromine (4.00 equiv) in acetic acid resulted in smooth step-
wise regioselective electrophilic aromatic substitutions and
directly provided the desired dibromo compound 9 in 91%
yield. In compound 9, position 2 is para to the directing me-
thoxy group, while position 3 is ortho to the relatively more
electron-rich hydroxy group and therefore the introduction
of the two bromine atoms selectively took place at those
positions. The introduction of a third bromine atom at posi-
tion 6 in compound 9 does not take place, probably due to
less activation and/or steric hindrance reasons (presence of
methoxy instead of hydroxy group at position 5). Base-pro-
moted hydrolysis of diester 9 yielded dicarboxylic acid 10 in
87% yield. One-pot acetic anhydride induced transforma-
tion of dicarboxylic acid 10 to the corresponding anhydride
11, followed by its neat fusion with urea directly provided
the in situ deacylated benzylsuccinimide 12 in 83% yield
over two steps. Anhydride 11 was used for the next step
without any purification and characterization, due to its
propensity towards hydrolytic cleavage. Boron tribromide
(BBr3) induced demethylation of 12 at –78 °C delivered the
final product (±)-rhodoconferimide (13) in 82% yield.
Rhodoconferimide (13) was obtained in seven steps in an
overall yield of 41%, and its analytical and spectral data
were in complete agreement with the reported data.26,31
In the present synthesis of (±)-rhodoconferimide, appli-
cation of vanillin as a starting material was strategically
planned for the desired regioselective introduction of two
bromine atoms. Thus on the basis of the results described
in Schemes 1 and 2, we propose that when the correspond-
ing veratraldehyde, isovanillin, and protocatechuic alde-
hyde are used, the undesired monobrominated, dibromi-
nated, and tribrominated products would result, respec-
tively.
In summary, the total synthesis of (±)-rhodoconferim-
ide was carried out without involving any separate protec-
tion step. We believe that the bromophenol moiety in (+)-
rhodoconferimide is responsible for the antioxidant activity
and the source of the bromine atoms could be marine wa-
ter. It is noteworthy that the structurally simple (+)-rhodo-
conferimide is a more potent antioxidant than the multi-
functional urceolatin from Figure 1. (+)-Rhodoconferimide
O
O
Br
O
O
O
2
Br
3
H
O
O
O
O
O
O
O
O
PBu3, THF
H2, Pd/C, MeOH
25 °C, 5 h (99%)
Br2, AcOH
1
6
+
4
HO
HO
25 °C, 36 h (76%)
25 °C, 10 h (91%)
HO
HO
5
OMe
Vanillin (6)
O
OMe
O
OMe
O
OMe
O
Dimethyl
Maleate (2)
(
)-8
7
(
)-9
Br
O
Br
Br
Br
O
O
O
Br
Br
Br
Br
BBr3, CH2Cl2
Ac2O, reflux
4 h
Urea, 150 °C
5 h (83%)
(i) Aq KOH, MeOH
OH
OH
O
NH
NH
reflux, 12 h
(ii) 2 N HCl (87%)
–78 °C to 25 °C
3 h (82%)
HO
AcO
HO
HO
O
O
O
OMe
(
O
OMe
[( )-11]
OMe
OH
)-10
(
)-Rhodoconferimide (13)
(
)-12
Scheme 2 First total synthesis of (±)-rhodoconferimide via one-pot regioselective brominations
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

C
K. R. Pandhade, N. P. Argade
Paper
Synthesis
is important from an activity and utility point of view and
this constituent from edible seaweed may find application
as a food additive and/or drug candidate.32 The presented
synthetic strategy is flexible and would be useful for de-
signing a focused mini library of rhodoconferimide deriva-
tives and congeners for tailored antioxidant property stud-
ies. Moreover, conceptually, custom-made polymers de-
rived from bromine-containing compounds such as
rhodoconferimide would be useful to fabricate marine-
water-friendly durable fishing nets.
13C NMR (50 MHz, CDCl3): δ = 34.8, 37.4, 43.2, 51.8, 51.9, 100.9, 108.2,
109.2, 122.0, 131.8, 146.3, 147.7, 172.3, 174.6.
HRMS (ESI): m/z calcd for C14H16O6Na: 303.0839; found: 303.0834.
Dimethyl 2-{[6-Bromobenzo(d)(1,3)dioxol-5-yl]methyl}succinate
(5)
Br2 (0.15 mL, 2.85 mmol) was added to a stirred solution of 4 (200 mg,
0.71 mmol) in MeOH (10 mL) at 0 °C and the reaction mixture was
stirred at 25 °C for 8 h. The mixture was concentrated in vacuo and
the obtained residue was dissolved in EtOAc (15 mL). The organic lay-
er was washed with sat. aq Na2S2O3 (10 mL) and brine (15 mL), dried
over Na2SO4, and concentrated in vacuo. The obtained bromo com-
pound was purified by column chromatography (silica gel, 60–120
mesh, EtOAc–PE, 2:8) to furnish product 5.
Melting points are uncorrected. The 1H NMR spectra were recorded
on 200 MHz NMR, 400 MHz NMR, and 500 MHz NMR spectrometers
using residue solvent signals as an internal standard. The 13C NMR
spectra were recorded on 200 NMR (50 MHz) and 500 NMR (125
MHz) spectrometers. High-resolution MS (HRMS) [electrospray ion-
ization (ESI)] were obtained on Orbitrap (quadrupole plus ion trap)
and TOF mass analyzers. The IR spectra were recorded on an FTIR
spectrophotometer. Column chromatographic separations were car-
ried out on silica gel (60–120 and 230–400 mesh). Commercially
available starting materials and reagents were used.
Yield: 250 mg (98%); thick oil.
IR (CHCl3): 1734, 1600 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 2.46 (dd, J = 16.6, 4.5 Hz, 1 H), 2.60–
2.90 (m, 2 H), 2.95–3.60 (m, 2 H), 3.65 (s, 3 H), 3.68 (s, 3 H), 5.95 (s, 2
H), 6.66 (s, 1 H), 6.98 (s, 1 H).
13C NMR (50 MHz, CDCl3): δ = 35.0, 37.5, 41.6, 51.7, 52.0, 101.7, 110.5,
112.8, 114.9, 130.6, 147.29, 147.34, 172.0, 174.4.
HRMS (ESI): m/z calcd for C14H15O6BrNa: 380.9944; found: 380.9941.
Dimethyl (E)-2-[Benzo(d)(1,3)dioxol-5-ylmethylene]succinate (3)
Dimethyl (E)-2-(4-Hydroxy-3-methoxybenzylidene)succinate (7)
n-Bu3P (0.85 mL, 3.46 mmol) was added dropwise to a stirred solu-
tion of dimethyl maleate (2; 0.33 mL, 2.66 mmol) and piperonal (1;
0.40 mL, 2.66 mmol) in THF (10 mL) at 25 °C under argon. The mix-
ture was stirred for 36 h and then concentrated in vacuo. The ob-
tained residue was dissolved in EtOAc (20 mL) and the resultant solu-
tion was washed with H2O (20 mL) and brine (20 mL) and dried over
Na2SO4. Concentration of the organic layer in vacuo followed by col-
umn chromatographic purification of the obtained residue (silica gel,
60–120 mesh, EtOAc–PE, 2:8) furnished product 3.
n-Bu3P (8.73 mL, 35.45 mmol) was dropwise added to a stirred solu-
tion of dimethyl maleate (2; 3.42 mL, 27.30 mmol) and vanillin (6;
4.15 g, 27.30 mmol) in THF (40 mL) at 25 °C under argon. The reaction
mixture was stirred for 36 h and then concentrated in vacuo. The ob-
tained residue was dissolved in EtOAc (100 mL) and the resultant
solution was washed with H2O (50 mL) and brine (50 mL) and dried
over Na2SO4. Concentration of the organic layer in vacuo followed by
column chromatographic purification of the obtained residue (silica
gel, 60–120 mesh, EtOAc–PE, 2:8) furnished product 7.
Yield: 586 mg (79%); white solid; mp 78–80 °C.
Yield: 5.81 g (76%); white solid; mp 89–91 °C.
IR (CHCl3): 1711, 1691 cm–1
.
IR (CHCl3): 3417, 1710, 1632 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 3.56 (s, 2 H), 3.74 (s, 3 H), 3.82 (s, 3 H),
6.00 (s, 2 H), 6.80–6.92 (m, 3 H), 7.81 (s, 1 H).
13C NMR (50 MHz, CDCl3): δ = 33.5, 52.18, 52.22, 101.4, 108.6, 109.1,
124.0, 124.3, 128.8, 141.9, 147.9, 148.3, 167.9, 171.6.
1H NMR (400 MHz, CDCl3): δ = 3.57 (s, 2 H), 3.69 (s, 3 H), 3.78 (s, 3 H),
3.82 (s, 3 H), 6.27 (br s, 1 H), 6.85–6.90 (m, 3 H), 7.80 (s, 1 H).
13C NMR (50 MHz, CDCl3): δ = 33.5, 52.0, 52.1, 55.7, 111.7, 114.6,
123.2, 123.3, 126.9, 142.2, 146.5, 146.7, 168.0, 171.8.
HRMS (ESI): m/z calcd for C14H14O6Na: 301.0683; found: 301.0678.
HRMS (ESI): m/z calcd for C14H16O6Na: 303.0839; found: 303.0833.
Dimethyl 2-[Benzo(d)(1,3)dioxol-5-ylmethyl]succinate (4)
Dimethyl 2-(4-Hydroxy-3-methoxybenzyl)succinate (8)
Activated Pd/C (50 mg, 10 wt%) was added to a stirred solution of 3
(500 mg, 1.79 mmol) in MeOH (10 mL) and the reaction mixture was
stirred under a balloon pressure H2 atmosphere at 25 °C for 5 h. The
reaction mixture was filtered to remove the Pd/C, and the filtrate was
concentrated in vacuo. The obtained compound was dissolved in
EtOAc (20 mL) and the formed solution was washed with H2O (20 mL)
and brine (20 mL) and dried over Na2SO4. The resultant solution was
concentrated in vacuo and then dried by using a vacuum pump to
provide pure product 4.
Activated Pd/C (400 mg, 10 wt%) was added to a stirred solution of 7
(4.00 g, 14.28 mmol) in MeOH (40 mL) and the reaction mixture was
stirred under a balloon pressure H2 atmosphere at 25 °C for 5 h. The
reaction mixture was filtered to remove the Pd/C and the filtrate was
concentrated in vacuo. The obtained compound was dissolved in
EtOAc (100 mL) and the formed solution was washed with H2O (50
mL) and brine (50 mL) and dried over Na2SO4. The resultant solution
was concentrated in vacuo and then dried by using a vacuum pump to
provide pure product 8.
Yield: 493 mg (98%); thick oil.
Yield: 3.98 g (99%); thick oil.
IR (CHCl3): 3539, 1733, 1611 cm–1
1H NMR (200 MHz, CDCl3): δ = 2.41 (dd, J = 16.7, 5.0 Hz, 1 H), 2.60–
2.68 (m, 1 H), 2.72 (d, J = 8.2 Hz, 1 H), 2.92–3.18 (m, 2 H), 3.65 (s, 3 H),
3.68 (s, 3 H), 3.87 (s, 3 H), 5.56 (s, 1 H), 6.60–6.68 (m, 2 H), 6.85 (d, J =
7.2 Hz, 1 H).
IR (CHCl3): 1733, 1601 cm–1
.
.
1H NMR (400 MHz, CDCl3): δ = 2.41 (dd, J = 16.5, 4.9 Hz, 1 H), 2.66 (t,
J = 9.8 Hz, 1 H), 2.69 (t, J = 7.3 Hz, 1 H), 2.96 (dd, J = 13.4, 6.1 Hz, 1 H),
3.02–3.13 (m, 1 H), 3.65 (s, 3 H), 3.68 (s, 3 H), 5.93 (s, 2 H), 6.59 (d, J =
7.3 Hz, 1 H), 6.65 (s, 1 H), 6.73 (d, J = 7.3 Hz, 1 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E

D
K. R. Pandhade, N. P. Argade
Paper
Synthesis
13C NMR (50 MHz, CDCl3): δ = 34.9, 37.5, 43.3, 51.7, 51.9, 55.9, 111.3,
114.3, 121.8, 129.9, 144.4, 146.5, 172.4, 174.7.
over Na2SO4, and concentrated in vacuo. The obtained product was
purified by column chromatography (silica gel, 230–400 mesh,
MeOH–CH2Cl2, 1:9) to provide in situ deacylated imide 12.
HRMS (ESI): m/z calcd for C14H18O6Na: 305.0996; found: 305.0991.
Yield: 415 mg (83%); white solid; mp 204–206 °C.
IR (CHCl3): 3621, 3451, 1703 cm–1
.
Dimethyl 2-(2,3-Dibromo-4-hydroxy-5-methoxybenzyl)succinate
(9)
1H NMR (400 MHz, DMSO-d6): δ = 2.42–2.60 (m, 2 H), 2.81 (t, J = 13.4
Hz, 1 H), 3.11–3.28 (m, 2 H), 3.83 (s, 3 H), 7.08 (s, 1 H), 9.81 (s, 1 H),
11.18 (br s, 1 H).
13C NMR (50 MHz, DMSO-d6): δ = 34.4, 37.5, 40.8, 56.4, 113.0, 113.4,
116.7, 129.9, 144.1, 147.3, 178.0, 180.6.
Br2 (2.18 mL, 42.55 mmol) was added to a stirred solution of 8 (3.00 g,
10.63 mmol) in AcOH (30 mL) at 0 °C and the reaction mixture was
stirred at 25 °C for 10 h. The mixture was then concentrated in vacuo
and the obtained residue was dissolved in EtOAc (40 mL). The organic
layer was washed with sat. aq Na2S2O3 (20 mL), 5% aq NaHCO3 (20
mL), and brine (20 mL), dried over Na2SO4, and concentrated in vacuo.
The obtained dibromo product was purified by column chromatogra-
phy (silica gel, 60–120 mesh, EtOAc–PE, 2:8) to furnish pure product
9.
HRMS (ESI): m/z calcd for C12H11O4NBr81BrNa: 415.8927; found:
415.8919.
3-(2,3-Dibromo-4,5-dihydroxybenzyl)pyrrolidine-2,5-dione
(Rhodoconferimide, 13)
Yield: 4.20 g (91%); brown solid; mp 106–108 °C.
A solution of BBr3 in CH2Cl2 (0.61 mL, 0.65 mmol) was added to a
stirred solution of 12 (170 mg, 0.43 mmol) in anhyd CH2Cl2 (10 mL) at
–78 °C over a period of 5 min under argon. The reaction mixture was
stirred for 3 h and allowed to reach 25 °C. The reaction mixture was
concentrated in vacuo and the obtained residue was diluted with
H2O. The reaction mixture was extracted with EtOAc (3 × 10 mL) and
the combined organic layer was washed with brine (25 mL) and dried
over Na2SO4. Concentration of the organic layer in vacuo followed by
column chromatographic purification of the obtained compound (sil-
ica gel, 230–400 mesh, MeOH–CH2Cl2, 1:9) furnished pure product
13.
IR (CHCl3): 3426, 1733, 1638 cm–1
.
1H NMR (200 MHz, CDCl3): δ = 2.49 (dd, J = 16.6, 4.5 Hz, 1 H), 2.64–
2.82 (m, 1 H), 2.87–3.04 (m, 1 H), 3.10–3.32 (m, 2 H), 3.66 (s, 3 H),
3.67 (s, 3 H), 3.89 (s, 3 H), 6.07 (br s, 1 H), 6.71 (s, 1 H).
13C NMR (50 MHz, CDCl3): δ = 35.2, 39.2, 41.5, 51.8, 52.0, 56.4, 112.1,
112.4, 118.1, 130.5, 143.3, 145.9, 172.0, 174.4.
HRMS (ESI): m/z calcd for
C
14H16O6Br81BrNa: 462.9185; found:
462.9172.
2-(2,3-Dibromo-4-hydroxy-5-methoxybenzyl)succinic Acid (10)
Yield: 135 mg (82%); colorless thick oil.
A solution of KOH (1.30 g, 22.83 mmol) in H2O (5 mL) was added to a
stirred solution of ester 9 (1.00 g, 2.28 mmol) in MeOH (15 mL) at 25
°C and the reaction mixture was refluxed for 12 h. The mixture was
allowed to reach 25 °C and then concentrated in vacuo. The obtained
residue was diluted with EtOAc (25 mL) and acidified with 2 N HCl
(15 mL). The organic layer was separated and the aqueous layer was
further extracted with EtOAc (3 × 10 mL). The combined organic layer
was washed with brine (30 mL), dried over Na2SO4, and concentrated
in vacuo. The obtained product was purified by column chromatogra-
phy (silica gel, 60–120 mesh, EtOAc–PE, 3:7) to provide diacid 10.
IR (CHCl3): 3600–3000, 1679, 1758 cm–1
.
1H NMR (400 MHz, DMSO-d6): δ = 2.35 (dd, J = 17.7, 4.3 Hz, 1 H), 2.58
(dd, J = 18.0, 9.2 Hz, 1 H), 2.79 (dd, J = 12.2, 10.4 Hz, 1 H), 3.00–3.25
(m, 2 H), 6.81 (s, 1 H), 9.46 (s, 1 H), 9.99 (s, 1 H), 11.15 (s, 1 H).
13C NMR (50 MHz, DMSO-d6): δ = 34.6, 37.1, 40.9, 113.5, 114.9, 116.5,
129.8, 143.5, 145.2, 178.0, 180.7.
HRMS (ESI): m/z calcd for
C
11H8O4NBr81Br: 377.8794; found:
377.8809 [M – H]–.
Yield: 813 mg (87%); white solid; mp 159–161 °C.
IR (CHCl3): 3450, 1728, 1600 cm–1
.
Acknowledgment
1H NMR (500 MHz, CD3OD): δ = 2.44 (dd, J = 16.8, 4.2 Hz, 1 H), 2.64
(dd, J = 17.0, 8.8 Hz, 1 H), 2.98 (td, J = 11.1, 4.3 Hz, 1 H), 3.12–3.21 (m,
2 H), 3.87 (s, 3 H), 6.88 (s, 1 H).
K.R.P. thanks CSIR, New Delhi, for the award of research fellowship.
N.P.A. thanks the Science and Engineering Research Board (SERB),
New Delhi for financial support.
13C NMR (125 MHz, CD3OD): δ = 36.4, 40.4, 43.1, 57.0, 114.1 (2 C),
118.8, 131.4, 145.9, 148.5, 175.5, 177.9.
HRMS (ESI): m/z calcd for
434.8861.
C
12H12O6Br81BrNa: 434.8872; found:
Supporting Information
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1590944. NMR spectra of all the syn-
3-(2,3-Dibromo-4-hydroxy-5-methoxybenzyl)pyrrolidine-2,5-di-
one (12)
thesized compounds are included.
S
u
p
p
ortiInfogrmoaitn
S
u
p
p
o
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f
rmoaitn
A solution of diacid 10 (500 mg, 1.27 mmol) in Ac2O (10 mL) was gen-
tly refluxed for 4 h under an argon atmosphere. The reaction mixture
was allowed to reach 25 °C and concentrated in vacuo. The obtained
residue was dried by using a vacuum pump and mixed with urea (229
mg, 3.80 mmol). The neat reaction mixture was heated at 150 °C for 5
h and then it was allowed to cool down to 25 °C. The reaction mixture
was diluted with H2O (20 mL) and extracted with EtOAc (3 × 10 mL).
The combined organic layer was washed with brine (20 mL), dried
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–E