Expeditious synthesis of the marine natural products prepolycitrin a and polycitrins a and b through heck arylations

Article abstract of DOI:10.1002/ejoc.201301108

New, efficient protocols for the syntheses of the marine natural products prepolycitrin A as well as polycitrins A and B were developed by employing the Heck-Matsuda arylation of maleic anhydride or dimethyl fumarate with aryldiazonium tetrafluoroborates. Both symmetrical and unsymmetrical 3,4-diarylmaleic anhydrides were easily and effectively prepared. Efficient bromination reactions that employed tribromoisocyanuric acid provided access to the polycitrin family of compounds. Under microwave irradiation in the presence of tyramine, the corresponding maleimides were obtained in high yields from the brominated 3,4-diarylmaleic anhydrides. This methodology provided for the concise synthesis of prepolycitrin A and the total syntheses of the marine alkaloids polycitrins A and B in overall yields of 37 and 47 % from maleic anhydride and dimethyl fumarate, respectively. The efficient and concise syntheses of the marine natural products prepolycitrin A as well as polycitrins A and B were accomplished by using a Heck-Matsuda arylation of maleic anhydride with aryldiazonium tetrafluoroborates. Polycitrins A and B were synthesized in overall yields of 37 and 47 %, respectively. Copyright

Full text of DOI:10.1002/ejoc.201301108

FULL PAPER
DOI: 10.1002/ejoc.201301108
Expeditious Synthesis of the Marine Natural Products Prepolycitrin A and
Polycitrins A and B through Heck Arylations
Karen Canto,[a] Rodrigo da Silva Ribeiro,[a] André F. P. Biajoli,[a] and
Carlos Roque D. Correia*[a]
Keywords: Total synthesis / Heterocycles / Alkaloids / Heck reaction / Palladium
New, efficient protocols for the syntheses of the marine natu-
ral products prepolycitrin A as well as polycitrins A and B
were developed by employing the Heck–Matsuda arylation
of maleic anhydride or dimethyl fumarate with aryldiazon-
ium tetrafluoroborates. Both symmetrical and unsymmetrical
3,4-diarylmaleic anhydrides were easily and effectively pre-
pared. Efficient bromination reactions that employed tri-
bromoisocyanuric acid provided access to the polycitrin fam-
ily of compounds. Under microwave irradiation in the pres-
ence of tyramine, the corresponding maleimides were ob-
tained in high yields from the brominated 3,4-diarylmaleic
anhydrides. This methodology provided for the concise syn-
thesis of prepolycitrin A and the total syntheses of the marine
alkaloids polycitrins A and B in overall yields of 37 and 47%
from maleic anhydride and dimethyl fumarate, respectively.
diarylated maleimides and maleic anhydrides (see Fig-
ure 1),[10] no further strategies to expedite the synthesis of
this class of compounds have been reported.
We disclose our recent results regarding the efficient aryl-
ation of maleic anhydride and dimethyl fumarate through a
Heck–Matsuda arylation with arenediazonium tetrafluoro-
borates as well as the application of this methodology to
the concise and practical syntheses of prepolycitrin A (6),
polycitrin A (5), and polycitrin B (7), which occurred with
excellent overall yields.
Introduction
Maleimides constitute an important and diverse class of
bioactive compounds. Several relevant examples of these
compounds include purpurone (1), which is a potent ATP-
citrate lyase (ACL) inhibitor,[1] 1H-pyrrole-2,5-dione deriv-
ative 2, which was recently reported as a selective COX-2
inhibitor (similar to celecoxib),[2] 1H-pyrrole-2,5-dione de-
rivative 3, which is a nontoxic inhibitor of multidrug resis-
tance (MDR) in cancer cells,[3] and derivative 4, which is an
HIV integrase inhibitor.[4] Other maleimides include prepo-
lycitrin A (6) as well as polycitrins A and B (i.e., 5 and 7,
respectively, see Figure 1). This interesting group of bioac-
tive marine natural products was isolated from ascidians
of the genus Polycitor.[5] The structural elucidation of these
compounds was reported in 1994 by Kashman and co-
workers,[5] who confirmed the presence of the unusual di-
arylmaleic anhydride or diarylmaleimide unit. In 1995, Ste-
glich and co-workers[6] reported the biomimetic synthesis of
prepolycitrin A and polycitrin A. Several years later (in
2000), Beccalli and co-workers[7] reported the first synthesis
of the alkaloid polycitrin B, which was carried out in eight
steps. In 2006, two new approaches to the preparation of
polycitrin A were reported, that is, one by our group[8] and
the other by Steglich and co-workers.[9] Despite the impor-
tant biological and fluorescent properties displayed by these
Results and Discussion
Initial Studies
To achieve the efficient synthesis of the polycitrins, we
reevaluated our previous results with regard to the Heck
arylation of maleic anhydride using arenediazonium salts.[8]
Our earlier work described a method that worked reason-
ably well for the arylation of maleic anhydride, which em-
ployed electron-rich arenediazonium salts. For electron-
neutral and electron-deficient arenediazonium salts, the
method was either ineffective or provided low yields of the
desired diarylmaleic anhydrides. Because the Heck–Mat-
suda arylations potentially facilitate access to these key di-
arylmaleic anhydride frameworks,[11] we decided to rein-
vestigate our initial protocols and overcome the difficulties
faced by the method’s first iteration.
[a] Departmento de Química Orgânica, Instituto de Química,
Universidade Estadual de Campinas,
UNICAMP, Cx Postal 6154, CEP.13084-971, Campinas, São
Paulo, Brazil
Palladium catalysts play a crucial role in Heck arylations,
and, therefore, we decided to explore the new generation of
highly reactive, air-stable palladium–phosphinous acid
complexes, such as POPd and POPd1 (see Figure 2).[12]
E-mail: roque@iqm.unicamp.br
http://www.correia-group.com/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301108.
8004
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8004–8013

Synthesis of Prepolycitrin A and Polycitrins A and B
Figure 1. Bioactive diarylmaleimides and diarylmaleic anhydrides.
These catalysts have already demonstrated superior per- anion in the reaction medium might favor a neutral path-
formance when employed in many coupling reactions.[13]
way over the desired cationic mechanism, which would
drastically change the outcome of the reaction. At this
stage, we were focused on the synthesis of a monoarylated
Table 2. Heck arylation of maleic anhydride using POPd.
Figure 2. Palladium–phosphinous acid catalysts used in our studies.
We were initially reluctant to use these catalysts in Heck–
Matsuda arylations because the presence of the chloride
Table 1. Heck arylation of maleic anhydride using palladium–phos-
phinous acid catalysts.
Entry
Adduct
R1, R2
Compound
[% yield]
10/11[a]
1
2
3
4
5
6
7
8
9
Cl, H
Br, H
I, H
F, H
NO2, H
OCF3, H
CN, H
SCH3, H
OMe, OMe
10a (60)
10b (52)
10c (50)
10d (78)
10e (71)
10f (92)
10g (40)[b]
10h (55)
10i (95)
99:01
99:01
99:01
99:01
85:15
90:10
90:10
90:10
95:05
Entry
Catalyst
% Yield
8/9[a]
1
2
POPd (2 mol-%)
POPd1 (2 mol-%)
95
73
95:5
90:10
[a] Ratio determined by capillary gas chromatography. [b] During
isolation, the hydrolysis of an aryl anhydride with electron-with-
drawing groups may cause a significant decrease in yield.
[a] Ratio determined by capillary gas chromatography.
Eur. J. Org. Chem. 2013, 8004–8013
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8005

K. Canto, R. da Silva Ribeiro, A. F. P. Biajoli, C. R. D. Correia
FULL PAPER
maleic anhydride, which would provide the opportunity to Heck–Matsuda arylation of maleic anhydride. The insensi-
prepare nonsymmetrical diarylmaleic anhydrides with a sec- tivity of the Heck reaction toward chloride anions in the
ond Heck–Matsuda arylation. After exhaustive experimen- reaction medium along with the fluorescence exhibited by
tation, we discovered that almost exclusive monoarylation many of the monoarylated maleic anhydrides were both
could be achieved by employing a large excess amount of surprising. With the exception of the product derived from
maleic anhydride. Good to excellent yields were obtained in benzenediazonium tetrafluoroborate, all other monoaryl-
refluxing acetonitrile with only 2 mol-% of POPd or POPd1 ated maleic anhydrides exhibited intense blue fluorescence.
as described in Table 1. Intriguingly, even a large excess
amount of maleic anhydride (50 equiv.) could not prevent
the formation of small amounts of the diarylated maleic
Table 3. Heck arylation of monoarylated maleic anhydride 8.
anhydride. POPd1 provided a lower overall yield and a
larger amount of the diarylated side product. Therefore,
POPd was chosen as the optimal Pd catalyst for the efficient
arylation of maleic anhydride.
With these results on hand, the evaluation of the Heck–
Matsuda reaction with a variety of aryldiazonium tetra-
fluoroborates, which included the previously low-per-
forming electron-deficient and -neutral structures (see
Entry
R1
Compound [% yield]
Table 2), could begin.
1
2
3
4
5
Cl
F
CF3
SCH3
OH
12a (65)
12b (30)
12c (40)
12d (55)
12e (69)[a]
It was encouraging that a variety of aryldiazonium tetra-
fluoroborates provided access to the respective monoaryl-
ated maleic anhydride as the major or exclusive product in
good to excellent yields. These results highlight the impor-
tance of choosing the correct Pd catalyst for the efficient [a] 2 equiv. of maleic anhydride 8 were used.
Figure 3. Proposed catalytic cycle.
8006
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8004–8013

Synthesis of Prepolycitrin A and Polycitrins A and B
POPd also effectively promoted the conversion of the the catalyst. As shown in Table 4, Pd(OAc)2 proved to be
monoarylated maleic anhydrides into the nonsymmetrical an effective Pd source, and the monoarylated (with 4-meth-
diarylated structures (see Table 3). A slight decrease in the oxyphenyl group) maleic anhydride was furnished in excel-
yield was observed for the second Heck–Matsuda arylation, lent yield (86%) by using only 4 mol-% of Pd(OAc)2 under
but this was most likely because of the steric interference CO, which acts as a reducing agent (see Table 4, Entry 3).
caused by the two aromatic rings interacting with the planar Even with 2 mol-% of Pd(OAc)2 (see Table 4, Entry 5), the
maleic anhydride structure. To achieve the yields displayed arylmaleic anhydride was produced in good 81% yield.
in Table 3, it was necessary to use an excess amount of the
Table 4. Heck monoarylation of maleic anhydride with Pd2(dba)3-
dba and Pd(OAc)2 combined with phosphinous acid.
diazonium salt (2 equiv.). An exception was in the case of
R1 = OH (see Table 3, Entry 5), in which 2 equiv. of maleic
anhydride 8 were employed to provide a moderate 69%
yield of diarylmaleic anhydride 12e.
The Heck arylation of maleic anhydrides is interesting
mechanistically, and a proposed reaction pathway is shown
in Figure 3. For the mono- and diarylation of maleic an-
hydride, the isomerization of the carbopalladation interme-
diate occurs through a palladium(II) enolate. This inversion
Entry
Pd source[a]
% Yield
of configuration is necessary to account for the facile syn
elimination, which occurs during the next stage.
1
Pd2(dba)3dba (2 mol-%)
Pd2(dba)3dba (2 mol-%)
Pd(OAc)2 (4 mol-%)
Pd(OAc)2 (4 mol-%)
Pd(OAc)2 (2 mol-%)
30
60
86
58
81
2[b]
3[b]
4
In spite of the superior performance displayed by the
POPd catalyst in the Heck–Matsuda arylations of maleic
anhydride, the cost of this reagent is a considerable draw-
back when considering a more general application of the
methodology. Therefore, we investigated the in situ forma-
tion of a similar palladium catalyst that could be as effective
as POPd.[12] The phosphinous acid was prepared and sub-
5[b]
[a] 4 equiv. of phosphinous acid with respect to palladium. [b] Re-
actions conducted under CO.
It is also worth mentioning that the performance of the
sequently combined with Pd2(dba)3 (dba = dibenzylidene- Heck–Matsuda arylation reactions can be carried out on a
acetone) or Pd(OAc)2 to attempt the in situ formation of gram scale. The arylation of maleic anhydride was con-
Scheme 1. Synthesis of Heck adduct 8 from maleic anhydride on a 5 mmol scale with 1 mol-% of POPd.
Scheme 2. Synthesis of the Heck adduct 3 from dimethyl fumarate.
Eur. J. Org. Chem. 2013, 8004–8013
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8007

K. Canto, R. da Silva Ribeiro, A. F. P. Biajoli, C. R. D. Correia
FULL PAPER
ducted with methoxyphenyldiazonium tetrafluoroborate on oxyphenyldiazonium tetrafluoroborate as described pre-
a 5 mmol scale with only 1 mol-% of POPd to provide the viously,[8] we decided to initiate the synthesis with 4-
monoarylated Heck adduct almost exclusively in 92% yield hydroxyphenyldiazonium tetrafluoroborate[15] to obtain
(see Scheme 1).
3,4-di(4-hydroxyphenyl)maleic anhydride (14) in a single
The need for an excess amount of the maleic anhydride step. The diarylation of maleic anhydride with POPd was
and the persistent occurrence of the diarylated products performed under different conditions, and the best pro-
were a potential problem for widespread synthetic applica- cedure to obtain the diarylated Heck product was achieved
tion. Therefore, new starting materials were investigated to by using an excess amount (3 equiv.) of maleic anhydride
obtain monoarylated maleic anhydride 8 exclusively. An al- (see Scheme 3), instead of the usual excess amount of the
ternative was found during the reaction of dimethyl fumar- aryldiazonium salt. Under these conditions, diarylated ma-
ate with 4-methoxyphenyldiazonium tetrafluoroborate, leic anhydride 14 was obtained in an isolated yield of 56%
which utilized Pd(OAc)2 (10 mol-%) in refluxing methanol (based on the aryldiazonium salt) along with some mono-
for 1 h.[14] These conditions provided the stereoselective arylated product, which was easily removed by flash
synthesis of monoarylated dimethyl maleate 13 in an iso- chromatography. When an excess amount of aryldiazonium
lated yield of 91% (see Scheme 2, route a). Further investi- salt (4 equiv.) was used, the diarylated Heck product was
gation allowed for the decrease of the palladium catalyst isolated in only 28% yield. Therefore, changing the maleic
loading to 4 mol-% when the reaction was carried out under anhydride/aryldiazonium salt ratio to favor the maleic an-
microwave irradiation (see Scheme 2, route b). This reaction hydride led to increased yields of the diarylated product
was completed in only 5 min and gave Heck adduct 13 in (56% yield). These results suggest that under the conditions
85% yield with a Z/E ratio of 85:15. Basic hydrolysis of established in our protocol, the second arylation of the
arylmaleate 13 with aqueous NaOH in methanol followed maleic anhydride is faster than the first and, additionally,
by the treatment of the crude mixture with acetic anhydride the maleic anhydride seems to stabilize the palladium inter-
provided monoarylated maleic anhydride 8 in a 89% yield mediates that are generated over the course of this reaction.
over two steps. For synthetic purposes, employing route a
Although the yield for the desired diarylmaleic anhydride
was optimal because of its higher yield and stereoselectivity. 14 was only moderate, the core structure of polycitrin A
was obtained in a single step. Bromination of anhydride 14
was achieved by using tribromoisocyanuric acid (TBCA)[16]
Synthesis of Prepolycitrin A and Polycitrin A
in a solution of acetic acid/trifluoroacetic acid (5:1) to com-
To perform a concise synthesis of these natural products, plete the synthesis of prepolycitrin A (6) in 90% yield. The
we decided to use the improved Heck–Matsuda arylation use of TBCA was advantageous because of its ease of hand-
procedure described above. Instead of starting with 4-meth- ling and high reactivity. However, the reactivity of the
Scheme 3. Synthesis of the alkaloids prepolycitrin A and polycitrin A.
8008
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8004–8013

Synthesis of Prepolycitrin A and Polycitrins A and B
Scheme 4. The total synthesis of polycitrin B.
TBCA was significantly affected by the acidity of the reac- scribed above for polycitrin A. We started as shown in
tion medium.[16b] In less acidic media (pH = 3–4), we ob- Scheme 2 from (4-methoxyphenyl)maleic anhydride 8,
served the formation of a mixture of prepolycitrin A and which was obtained from dimethyl fumarate. The Heck–
its tribrominated intermediate, which was very difficult to Matsuda arylation of 8 with (4-hydroxyphenyl)diazonium
separate by flash column chromatography. As we were able tetrafluoroborate, 2 mol-% of POPd, and NaOAc as the
to prepare prepolycitrin A in gram quantities, we noticed base in acetonitrile at approximately 80 °C afforded the
a curious relationship between the color of our synthetic nonsymmetrical 3,4-diarylmaleic anhydride 12e in an iso-
prepolycitrin A (an orange-red solid) and the actual color lated yield of 69% (see Scheme 4). The use of 2 equiv. of
of the marine animal Polycitor giganteus, from which pre- the arylmaleic anhydride 8 was necessary to decrease the
polycitrin A was first isolated (see picture in the Table of formation of side products (not identified). The bromin-
Contents).
ation of the phenol-anisole moiety of anhydride 12e by
To obtain polycitrin A, prepolycitrin A was initially treatment with TBCA was carried out under strictly con-
heated with tyramine, Hunig’s base, and phenol at 140 °C trolled conditions to avoid overoxidation. After several ex-
for 2 h. However, under these conditions the yields of the periments, we determined that the addition of 1.5 equiv. of
corresponding maleimide were always below 40%. We in- TBCA at 0 °C, a subsequent gradual temperature increase,
vestigated this reaction under microwave irradiation. After and then a 4 h period at 60 °C followed by a second ad-
examining several reaction conditions, it was possible to ob- dition of 0.08 equiv. of TBCA (see Exp. Section for details)
tain polycitrin A (5) in good yield by employing tyramine, provided the tetrabrominated diarylmaleic anhydride 15 in
Hünig’s base, and phenol at 90 °C under microwave irradia- 84% yield. Finally, conversion of the maleic anhydride into
tion (200 W, 4 min). The short irradiation time was critical the maleimide was carried out as described for the synthesis
to obtain good yields. This procedure allowed for the syn- of polycitrin A. The treatment of maleic anhydride 15 with
thesis of polycitrin A in 73% yield from prepolycitrin A and tyramine, HunigЈs base, and phenol under microwave irra-
in 37% overall yield from maleic anhydride, which is inex- diation (110 °C, 2 min) afforded polycitrin B (7) in an excel-
pensive.
lent 86% isolated yield. The total synthesis of polycitrin B
was accomplished in only five steps from dimethyl fumarate
with an overall yield of 47%.
Synthesis of Polycitrin B
The only reported total synthesis of polycitrin B was ac-
complished by Becalli et al.[7] These authors described a
sequence of eight steps to synthesize this natural product in
Conclusions
We developed a new and efficient protocol based on the
30% overall yield. For the preparation of polycitrin B, we Heck–Matsuda reaction for the synthesis of monoarylated
adopted a slightly different approach from the one de- maleic anhydrides as well as symmetrical and nonsymmetri-
Eur. J. Org. Chem. 2013, 8004–8013
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8009

K. Canto, R. da Silva Ribeiro, A. F. P. Biajoli, C. R. D. Correia
FULL PAPER
130.2, 139.2, 145.6, 163.2, 164.2 ppm. IR (KBr): ν = 3112, 1852,
˜
cal diarylated maleic anhydrides. The mono- and diaryl-
maleic anhydrides are interesting fluorophores for bio-
logical studies as well as valuable starting materials for total
syntheses. This method provided a new and straightforward
synthesis for prepolycitrin A, which upon treatment with ty-
ramine under microwave conditions, afforded polycitrin A.
A new total synthesis of polycitrin B was also accomplished
from monoaryl-substituted maleic anhydride 8. Both syn-
theses feature the carefully controlled bromination reac-
tions of the electron-rich aryl groups by employing TBCA
as well as the efficient conversion of the diarylmaleic an-
hydride into the corresponding maleimide, which occurred
under microwave conditions and with short reaction times.
The total syntheses of prepolycitrin A and polycitrins A
and B are simple and efficient compared to previously re-
ported approaches. The more complex polycitrins A and B
were synthesized through concise routes in overall yields of
37 and 47% from maleic anhydride and dimethyl fumarate,
respectively.
1754, 1222 cm–1. HRMS (ESI): calcd. for C10H5ClO3 207.9927;
found 207.9927.
3-(4-Bromophenyl)-2,5-dihydrofuran-2,5-dione (10b): Yellow solid
(52% yield); m.p. 167–168 °C. 1H NMR (300 MHz, CDCl3): δ =
7.02 (s, 1 H), 7.66 (d, 3J = 8.7 Hz, 2 H), 7.93 (d, 3J = 8.7 Hz, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 124.7, 125.7, 128.0,
130.4, 132.8, 145.9, 163.4, 164.4 ppm. IR (KBr): ν = 2958, 1822,
˜
1757, 1275 cm–1. HRMS (ESI): calcd. for C10H5BrO3 251.9422;
found 251.9420.
3-(4-Iodophenyl)-2,5-dihydrofuran-2,5-dione (10c): Yellow solid
1
(50% yield); m.p. 124 °C (decomp). H NMR (300 MHz, CDCl3):
3
3
δ = 7.04 (s, 1 H), 7.68 (d, J = 8.5 Hz, 2 H), 7.87 (d, J = 8.5 Hz,
2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 100.6, 124.9, 126.2,
130.3, 138.8, 146.0, 163.4 164.4 ppm. IR (KBr): ν = 3116, 1838,
˜
1765, 1750, 1237 cm–1. HRMS (ESI): calcd. for C10H5IO3
299.9283; found 299.9276.
3-(4-Fluorophenyl)-2,5-dihydrofuran-2,5-dione (10d): Yellow solid
(78% yield); m.p. 127–129 °C (decomp). 1H NMR (300 MHz,
CDCl3): δ = 6.97 (s, 1 H), 7.18–7.24 (m, 2 H), 8.00–8.04 (m, 2
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 116.7, 117.0, 123.2,
124.0, 131.4, 131.6, 145.7, 163.3, 163.5, 164.5, 166.9 ppm. IR
(KBr): ν = 3116, 1765, 1750 cm–1. HRMS (ESI): calcd. for
˜
Experimental Section
C10H5FO3 192.0223; found 192.0224.
Typical Experimental Procedure for the Synthesis of Monoaryl-
maleic Anhydride: To a solution of POPd (5 mg, 2 mol-%) in
CH3CN (4 mL) were added maleic anhydride (0.98 g, 10 mmol),
NaOAc (123 mg, 1.5 mmol), and the appropriate aryldiazonium
tetrafluoroborate salt (0.5 mmol). The reaction mixture was heated
to reflux for 1 h. The mixture was then cooled, and EtOAc (20 mL)
was added. The organic phase was washed with saturated NaHCO3
(3ϫ 15 mL) and then separated. The combined organic extracts
were dried with Na2SO4. The solvent was removed under reduced
pressure, and the crude residue was purified by flash column
chromatography (silica gel, hexane/EtOAc) to give the correspond-
ing monoarylated maleic anhydride in yields ranging from 50 to
95%. Note: Monoarylated maleic anhydrides that contain strong
electron-withdrawing groups may undergo hydrolysis during isola-
tion (washing with saturated NaHCO3), which can cause a signifi-
cant decrease in the yields. In those cases (e.g., compounds 10e
and 10g), the crude product that was obtained after washing with
NaHCO3 and drying with Na2SO4 was dissolved in acetic anhy-
dride (approximately 1 mL), and the resulting solution was heated
at 100 °C for 90 min. After cooling to room temp., the acetic anhy-
dride was removed in vacuo to provide a crude mixture, which was
purified by flash chromatography as indicated above.
3-(4-Nitrophenyl)-2,5-dihydrofuran-2,5-dione (10e):[19] Yellow solid
(71% yield), m.p. 127–128 °C (decomp); ref.[19] m.p. 128–129 °C.
1H NMR (300 MHz, CDCl3): δ = 7.22 (s, 1 H), 8.17 (d, 3J = 8.9 Hz,
3
2 H), 8.37 (d, J = 8.9 Hz, 2 H) ppm.
3-(4-Trifluoromethoxyphenyl)-2,5-dihydrofuran-2,5-dione
(10f):
1
Orange solid (92% yield); m.p. 117–118 °C. H NMR (300 MHz,
3
3
CDCl3): δ = 7.03 (s, 1 H), 7.36 (d, J = 8.9 Hz, 2 H), 8.05 (d, J =
8.9 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 121.3, 125.1,
125.5, 131.0, 131.7, 145.5, 163.3, 164.4 ppm. IR (KBr): ν = 3111,
˜
1856, 1773, 1212 cm–1. HRMS (ESI): calcd. for C11H5F3O4
258.0140; found 258.0150.
3-(4-Cyanophenyl)-2,5-dihydrofuran-2,5-dione (10g): White solid
(70% yield); m.p. 142–143 °C. 1H NMR (300 MHz, CDCl3): δ =
7.15 (s, 1 H), 7.82 (d, 3J = 8.7 Hz, 2 H), 8.09 (d, 3J = 8.7 Hz, 2
H) ppm. 1H NMR {600 MHz, deuterated dimethyl sulfoxide ([D6]-
3
3
DMSO)}: δ = 6.54 (s, 1 H), 7.74 (d, J = 8.5 Hz, 2 H), 7.93 (d, J
= 8.5 Hz, 2 H) ppm. 13C NMR (150 MHz, [D6]DMSO): δ = 112.8,
118.8, 121.3, 128.1, 133.4, 138.6, 146.6, 166.2, 168.5 ppm. IR
(KBr): ν = 2958, 1773, 1712 cm–1. HRMS (ESI): calcd. for
˜
C11H5NO3 199.0269; found 199.0264.
3-(4-Methylthiophenyl)-2,5-dihydrofuran-2,5-dione (10h): Yellow so-
3-(4-Methoxyphenyl)-2,5-dihydrofuran-2,5-dione (8):[17] Orange so-
lid (95% yield), m.p. 142–143 °C; ref.[17a] m.p. 142–143 °C. 1H
NMR (300 MHz, CDCl3): δ = 3.90 (s, 3 H), 6.83 (s, 1 H), 7.00 (d,
3J = 8.9 Hz, 2 H), 7.99 (d, 3J = 8.9 Hz, 2 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 55.7, 115.0, 121.1, 131.2, 146.4, 163.4, 164.2,
165.2 ppm. 13C NMR (62.5 MHz, CD3CN): δ = 56.4, 115.8, 120.9,
123.4, 132.0, 147.2, 164.1, 165.7, 166.7 ppm.
1
lid (55% yield); m.p. 127–128 °C. H NMR (300 MHz, CDCl3): δ
3
= 2.54 (s, 3 H), 6.91 (s, 1 H), 7.30 (d, J = 8.6 Hz, 2 H), 7.90 (d,
3J = 8.6 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 121.3,
125.1, 125.5, 131.0, 131.7, 145.5, 163.3, 164 ppm. IR (KBr): ν =
˜
1818, 1761, 1218 cm–1. HRMS (ESI): calcd. for C11H8O3S
220.0194; found 220.0183.
3-(3,4-Dimethoxyphenyl)-2,5-dihydrofuran-2,5-dione (10i): Orange
3,4-Di(4-methoxyphenyl)-2,5-dihydrofuran-2,5-dione (9):[18] Orange
1
solid (95% yield); m.p. 164–166 °C. H NMR (300 MHz, CDCl3):
solid (56% yield), m.p. 169–171 °C; ref.[18] 170–171 °C. 1H NMR
3
δ = 3.95 (s, 3 H), 3.96 (s, 3 H), 6.85 (s, 1 H), 6.96 (d, J = 8.5 Hz,
3
1 H), 7.48 (d, 4J = 2.1 Hz, 1 H), 7.70 (dd, 3J = 8.5 Hz, 4J = 2.1 Hz,
1 H) ppm. 13C NMR (75 MHz, CDCl3): δ = 56.2, 111.2, 111.5,
119.9, 121.3, 123.9, 146.3, 149.6, 153.3, 164.1, 165.2 ppm. IR
(250 MHz, CDCl3): δ = 3.85 (s, 6 H), 6.91 (d, J = 9.0 Hz, 4 H),
3
7.57 (d, J = 9.0 Hz, 4 H) ppm. 13C NMR (CD3CN, 62.9 MHz): δ
= 55.4, 114.4, 119.9, 131.4, 135.7, 161.7, 165.4 ppm.
(KBr): ν = 2927, 1833, 1769, 1261 cm–1. HRMS (ESI): calcd. for
˜
3-(4-Chlorophenyl)-2,5-dihydrofuran-2,5-dione (10a): Pale yellow so-
C12H10O5 234.0528; found 234.0527.
1
lid (60% yield); m.p. 160–162 °C. H NMR (300 MHz, CDCl3): δ
3
3
= 7.01 (s, 1 H), 7.49 (d, J = 8.6 Hz, 2 H), 7.93 (d, J = 8.6 Hz, 2
Typical Experimental Procedure for the Synthesis of Unsymmetrical
Diarylmaleic Anhydride: To a solution of POPd (2 mg, 2 mol-%) in
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 124.6, 125.1, 129.7,
8010
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8004–8013

Synthesis of Prepolycitrin A and Polycitrins A and B
CH3CN (3 mL) were added 3-(4-methoxyphenyl)-2,5-dihy-
drofuran-2,5-dione (8, 0.04 g, 0.2 mmol), NaOAc (0.024 g,
0.3 mmol), and the appropriate diazonium tetrafluoroborate salt
(0.4 mmol). The reaction mixture was heated to reflux for 1 h.
EtOAc (10 mL) was then added, and the organic phase was sub-
sequently washed with saturated NaHCO3 (3ϫ 7 mL) and sepa-
rated. The combined organic extracts were dried with Na2SO4. The
solvent was removed under reduced pressure, and the crude residue
was purified by flash column chromatography (silica gel, hexane/
EtOAc) to give the corresponding diarylated maleic anhydride in
yields ranging from 30 to 69%.
1745, 1623, 1605, 1589, 1508, 1437, 1350, 1273, 1236, 1175, 1122,
1095, 924, 841, 744, 575, 528 cm–1. HRMS (ESI): calcd. for
C17H12O5 296.0685; found 296.0672.
Preparation of Tribromoisocyanuric Acid:[16c] To a cold (ice bath,
0 °C) solution of cyanuric acid (1.61 g, 12.5 mmol), NaOH (1.50 g,
37.5 mmol), Na2CO3 (1.99 g, 18.75 mmol), and KBr (4.46 g,
37.5 mmol) in H2O (180 mL) was added dropwise a solution of
Oxone® (23.1 g, 37.5 mmol) in H2O (150 mL). During the addition
of the oxidant solution, a white solid precipitate appeared and
formed a dense suspension, which was stirred for 24 h. The product
was isolated by vacuum filtration, washed with cold H2O, and then
dried with P2O5 to give the product (86% yield). The m.p. was not
determined as the reagent decomposed upon heating. FTIR (KBr):
3-(4-Chlorophenyl)-4-(4-methoxyphenyl)furan-2,5-dione
(12a):
1
Orange solid (65% yield); m.p. 167–170 °C. H NMR (300 MHz,
3
3
CDCl3): δ = 3.85 (s, 3 H), 6.90 (d, J = 8.9 Hz, 2 H), 7.38 (d, J = ν = 1741, 1724, 1660, 1405, 1339, 1197, 1146, 1051, 737, 717 cm–1.
˜
8.6 Hz, 2 H), 7.50 (d, 3J = 8.6 Hz, 2 H), 7.54 (d, 3J = 8.9 Hz, 2
Dimethyl 2-(4-Methoxyphenyl)maleate (13)
H) ppm. 13C NMR (75 MHz, CDCl3): δ = 55.6, 114.7, 119.3, 126.2,
By Using Conventional Heating: To a 250 mL round-bottomed flask
129.5, 131.0, 131.8, 134.5, 137.2, 138.2, 162.3, 165.0, 165.1 ppm.
that contained Pd(OAc)2 (0.460 g, 2.05 mmol) in methanol
(180 mL) was added dimethyl fumarate (2.972 g, 20.0 mmol). 4-
Methoxyphenyldiazonium tetrafluoroborate (5.326 g, 24.0 mmol)
was added with stirring, and the reaction mixture was heated to
reflux (65 °C) for 1 h. The solution was cooled to room temp. and
concentrated under reduced pressure. The resulting residue was fil-
tered through a plug of silica gel (ethyl acetate). The solvent was
removed under reduced pressure, and the residue was purified by
flash column chromatography (silica gel, hexanes/EtOAc, 90:10) to
afford arylmaleate 13 (4.553 g, 18.19 mmol, 91%) as a colorless oil.
The spectroscopic data obtained for compound 13 are consistent
IR (KBr): ν = 2928, 1833, 1765, 1263 cm–1. HRMS (ESI): calcd.
˜
for C17H11ClO4 314.0346; found 314.0330.
3-(4-Fluorophenyl)-4-(4-methoxyphenyl)furan-2,5-dione (12b): Yel-
low solid (30% yield); m.p. 141–142 °C (decomp). 1H NMR
3
(300 MHz, CDCl3): δ = 3.86 (s, 3 H), 6.91 (d, J = 9.0 Hz, 2 H),
7.11 (t, 3J = 8.7 Hz, 2 H), 7.54–7.60 (m, 4 H) ppm. 13C NMR
(75 MHz, CDCl3): δ = 55.6, 114.6, 116.2, 116.5, 119.3, 123.8, 131.7,
134.6, 137.7, 162.1, 162.3, 165.0, 165.6 ppm. IR (KBr): ν = 2928,
˜
1826, 1761, 1261 cm–1. HRMS (ESI): calcd. for C17H11FO4
298.0641; found 298.0634.
3-(4-Trifluoromethoxyphenyl)-4-(4-methoxyphenyl)furan-2,5-dione with those reported.[14b]
(12c): Orange solid (40 % yield); m.p. 157–160 °C. 1H NMR
By Using Microwave Irradiation: To a microwave tube were added
3
(300 MHz, CDCl3): δ = 3.86 (s, 3 H), 6.92 (d, J = 9.0 Hz, 2 H),
methanol (3 mL), Pd(OAc)2 (0.003 g, 0.014 mmol), dimethyl fum-
arate (0.050 g, 0.35 mmol), the diazonium salt (0.093 g,
0.42 mmol), and a magnetic stir bar. The tube was then irradiated
(80 °C, 300 W) with stirring for 5 min. After this period of time,
the reaction mixture was submitted to the same procedure de-
scribed above, which furnished the desired product 13 (85% yield;
3
7.56 (d, J = 9.0 Hz, 2 H), 7.68 (s, 4 H) ppm. 13C NMR (75 MHz,
CDCl3): δ = 55.6, 114.8, 119.0, 126.0, 126.1, 130.0, 131.4, 132.0,
132.4, 133.9, 139.6, 162.6, 164.7, 164.8 ppm. HRMS (ESI): calcd.
for C18H11F3O4 348.0609; found 348.0609.
3-(4-Methylthiophenyl)-4-(4-methoxyphenyl)furan-2,5-dione
(12d):[2b] Orange solid (55% yield); m.p. 167–169 °C. 1H NMR
(300 MHz, CDCl3): δ = 2.40 (s, 3 H), 3.85 (s, 3 H, OMe), 6.90 (d,
1
Z/E ratio, 85:15). H NMR (250 MHz, CDCl3): δ = 3.77 (s, 3 H),
3.83 (s, 3 H), 3.95 (s, 3 H), 6.23 (s, 1 H), 6.90 (d, 3J = 8.9 Hz, 2 H),
3J = 8.8 Hz, 2 H), 7.22 (d, J = 8.4 Hz, 2 H), 7.46 (d, J = 8.2 Hz,
2 H), 7.57 (d, 3J = 8.8 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ = 14.9, 55.5, 114.6, 119.8, 123.9, 125.7, 130.0, 131.6, 135.3, 136.7,
143.4, 162.0, 165.3, 165.4 ppm.
7.42 (d, J = 8.9 Hz, 2 H) ppm. 13C NMR (62.9 MHz, CD3CN): δ
3
3
3
= 52.50, 53.15, 56.22, 115.1, 115.5, 126.2, 129.5, 149.4, 162.9, 166.6,
169.4 ppm. IR (KBr): ν = 3462, 1815, 1757, 1609, 1578, 1543, 1472,
˜
1398, 1342, 1329, 1310, 1267, 1253, 1244, 1159, 1148, 947, 893,
756, 621 cm–1.
Synthesis of 3-(4-Hydroxyphenyl)-4-(4-methoxyphenyl)2,5-furan-
2,5-dione (12e) on Gram Scale: To a stirred solution of POPd
(0.049 g, 0.097 mmol), sodium acetate (2.380 g, 29.0 mmol), and 8
(1.976 g, 9.68 mmol) in acetonitrile (50 mL) was added 4-hydroxy-
phenyldiazonium tetrafluoroborate (1.007 g, 4.840 mmol). The re-
sulting mixture was heated to reflux at 82 °C for 1 h and then sub-
sequently cooled to room temperature. The solution was concen-
trated under reduced pressure, and the residue was filtered through
silica gel (ethyl acetate). The solution was concentrated under re-
duced pressure, and the crude residue was purified by flash column
chromatography (silica gel, hexane/EtOAc, 95:5) to afford 12e
3-(4-Methoxyphenyl)-2,5-dihydrofuran-2,5-dione (8) from Dimethyl
2-(4-Methoxyphenyl)maleate (13): To a 125 mL round-bottomed
flask that contained 13 (1.110 g, 4.437 mmol) were added methanol
(50 mL) and NaOH (5 m solution, 10 mL). The reaction mixture
was heated at reflux for 2 h. After cooling, the solvent was evapo-
rated under reduced pressure to give a residue, which was sus-
pended in water (25 mL). As the mixture was stirred, concentrated
HCl (approximately 4.5 mL) was then added until the pH = 2. The
obtained precipitate was extracted with ethyl acetate (3ϫ 30 mL)
in a 250 mL separatory funnel. The organic phase was separated,
and the combined extracts were dried with anhydrous sodium sulf-
1
(0.920 g, 3.11 mmol, 69%) as a yellow solid; m.p. 152–153 °C. H
3
NMR (250 MHz, CD3CN): δ = 3.82 (s, 3 H), 6.85 (d, J = 8.7 Hz, ate and filtered. The solvent was evaporated under reduced pres-
3
3
2 H), 6.96 (d, J = 8.8 Hz, 2 H), 7.40 (d, J = 8.78 Hz, 2 H), 7.47
sure. To the residue was then added distilled acetic anhydride
(d, 3J = 8.8 Hz, 2 H), 7.48 (s, 1 H, OH) ppm. H NMR (300 MHz, (70 mL), and the mixture was heated at reflux for 12 h. The solvent
CDCl3): δ = 3.84 (s, 3 H), 6.84 (d, J = 8.9 Hz, 2 H), 6.90 (d, J = was then removed by using a rotary evaporator, and a yellow solid
1
3
3
9.0 Hz, 2 H), 7.48 (d, 3J = 8.9 Hz, 2 H), 7.54 (d, 3J = 9.0 Hz, 2
H) ppm. 13C NMR (50 MHz, CD3CN): δ = 56.2, 115.3, 116.6,
120.4, 121.2, 132.3, 132.6, 160.2, 162.5, 166.9 ppm. 13C NMR
(75 MHz, CDCl3): δ = 55.5, 114.6, 116.1, 119.9, 120.1, 131.5, 135.9,
precipitate formed. This solid could be purified either by
recrystallization or by silica gel chromatography. Recrystallization
was performed by dissolving the crude solid in hot ethyl acetate
(7 mL) followed by the slow addition of hexane until the solution
displayed a slight turbidity. The mixture was cooled to room tem-
158.2, 161.8, 165.6 ppm. IR (KBr): ν = 398, 3438, 1846, 1823, 1757,
˜
Eur. J. Org. Chem. 2013, 8004–8013
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8011

K. Canto, R. da Silva Ribeiro, A. F. P. Biajoli, C. R. D. Correia
FULL PAPER
perature, when a needle-shaped yellow solid started to precipitate.
The solid was filtered and washed with cold hexane and then was
allowed to dry to furnish product 8 (0.780 g, 3.82 mmol, 86%).
Alternatively, flash column chromatography [silica gel, 10% ethyl
acetate in hexane] furnished the desired product 8 (0.852 g,
4.171 mmol, 94%).
centrated under reduced pressure in the presence of silica gel
(2.2 g). The residue was placed on a short column of silica gel (ethyl
acetate). The solution that was obtained was concentrated under
vacuum. Purification of the residue by flash column chromatog-
raphy (silica gel, hexanes/EtOAc, 80:20) afforded 6 (1.498 g, 90%)
as an orange-red solid. The spectroscopic data obtained for this
compound are consistent with those reported.[5b,6] There was a sig-
nificant discrepancy between the reported melting points and the
one recorded by us. Steglich and co-workers[6] reported a m.p. of
148–149 °C, whereas Rudi and co-workers[5b] described prepolyci-
trin A as a yellow oil. Because of these discrepancies, we used
differential scanning calorimetry (DSC2910 TA Instrument, from
25 to 270 °C, at 10 °Cmin–1) to determine the precise melting point
of prepolycitrin A, m.p. 242.3 °C (DSC). 1H NMR (250 MHz, [D6]-
acetone): δ = 7.81 (s, 4 H), 9.31 (br. s, 2 H, OH) ppm. 13C NMR
(62.9 MHz, [D6]acetone): δ = 111.8, 122.6, 134.6, 136.2, 154.0,
3,4-Di(4-Hydroxyphenyl)-2,5-dihydrofuran-2,5-dione (14): To
a
stirred solution of POPd (0.050 g, 0.10 mmol), sodium acetate
(1.230 g, 15.0 mmol), and maleic anhydride (1.467 g, 14.97 mmol)
in acetonitrile (30 mL) was added 4-hydroxyphenyldiazonium tetra-
fluoroborate (1.038 g, 4.99 mmol). The resulting mixture was
heated to reflux at 82 °C for 1 h and then cooled to room tempera-
ture. The solution was concentrated under reduced pressure in pres-
ence of silica gel (6.3 g), and the resulting residue was placed on a
short silica gel column (ethyl acetate). The obtained solution was
concentrated, and the residual maleic anhydride was removed un-
der vacuum at 2 Torr (85 °C, 40 min). The crude residue was puri-
fied by flash column chromatography (silica gel, hexanes/EtOAc,
80:20) to afford 14 (0.395 g, 56% yield) as yellow solid and a small
amount of the monoarylated side product 3-(4-hydroxyphenyl)-
maleic anhydride (14a). The spectroscopic data for compound 14
are consistent with those reported.[6,20] M.p. 223 °C; ref.[20] m.p.
224 °C. 1H NMR (250 MHz, [D6]acetone): δ = 6.90 (d, 3J = 8.7 Hz,
4 H), 7.47 (d, 3J = 8.7 Hz, 4 H), 9.03 (s, 2 H, OH) ppm. 13C NMR
([D6]acetone, 62.9 MHz): δ = 116.6, 120.3, 132.5, 136.8, 160.6,
166.7 ppm.
165.6 ppm. IR (KBr): ν = 3462, 1815, 1757, 1608, 1578, 1543, 1483,
˜
1466, 1398, 1329, 1310, 1267, 1254, 1148, 1115, 947, 893, 879, 756,
748, 716, 621, 590 cm–1.
Polycitrin A (5): A mixture of the diarylmaleic anhydride 6 (0.036 g,
0.060 mmol), phenol (0.160 g), tyramine (0.019 g, 0.14 mmol), N,N-
diisopropylethylamine (DIPEA, 0.096 mL, 0.55 mmol), and acti-
vated powdered molecular sieves (4 Å, 0.134 g) under nitrogen were
placed in the microwave tube. The tube was heated to 90 °C over
1 min at 200 W and then maintained under these conditions for an
additional 4 min. After the irradiation process, the reaction mixture
was transferred to a 50 mL separatory funnel by using ethyl acetate
(9 mL). The organic phase was washed with HCl (2 n solution,
5 mL), separated, and dried with anhydrous MgSO4. After fil-
tration, the organic solvent was removed under reduced pressure.
The crude residue was then purified by flash chromatography (chlo-
roform/hexanes, 1:1; pure chloroform; and then 1% methanol in
chloroform). The fractions were collected, and the solvents were
evaporated under vacuum to provide polycitrin A (0.031 g,
0.043 mmol, 72%) as a yellow solid. The spectroscopic data ob-
tained for compound 5 are consistent with those reported for poly-
citrin A.[5,6] M.p. 180–181 °C; ref.[6,9] m.p. 180–182 °C. 1H NMR
3-(4-Hydroxyphenyl)-2,5-dihydrofuran-2,5-dione (14a): M.p. 199–
1
200 °C (decomp). H NMR (250 MHz, [D6]acetone): δ = 7.00 (d,
3
3J = 8.8 Hz, 2 H), 7.24 (s, 1 H), 8.03 (d, J = 8.8 Hz, 2 H), 9.31 (s,
1 H, OH) ppm. 13C NMR (62.9 MHz, CD3CN): δ = 117.1, 120.2,
122.7, 132.2, 147.2, 161.9, 165.7, 166.7 ppm. IR (KBr): ν = 3395,
˜
1841, 1740, 1594, 1573, 1504, 1242, 1174, 907, 837 cm–1. HRMS
(ESI): calcd. for C10H7O4 191.0344; found 191.0343.
3-(3,5-Dibromo-4-hydroxyphenyl)-4-(3,5-dibromo-4-methoxyphen-
yl)-2,5-furan-2,5-dione (15): To a 50 mL round bottomed flask that
contained 12e (0.253 g, 0.854 mmol) in trifluoroacetic acid (TFA,
20 mL) at 0 °C was added TBCA (0.468 g, 1.28 mmol), and the
reaction mixture was stirred at this temperature for 1 h. The cool-
ing bath was removed, and the reaction mixture was warmed to
room temp. and then stirred for 3 h. Next, the mixture was heated
to 60 °C and then stirred for 4 h. After this period of time, another
portion of TBCA (0.024 g; 0.066 mmol) was added, and the reac-
tion mixture was stirred for an additional hour. The reaction mix-
ture was cooled, and the solvent was evaporated under vacuum.
The crude reaction mixture was filtered through a plug of silica
gel and then purified by flash column chromatography (10% ethyl
acetate in hexane) to yield the desired product 15 (0.439 g,
0.717 mmol, 84%). The spectroscopic data that was obtained for
compound 15 are consistent with those reported.[7] 1H NMR
(250 MHz, CD3CN): δ = 3.91 (s, 3 H), 7.66 (s, 2 H), 7.70 (s, 2
H) ppm. 13C NMR (62.9 MHz, CD3CN): δ = 61.7, 111.2, 119.5,
122.1, 126.9, 134.6, 134.8, 136.0, 137.8, 154.1, 157.2, 165.4,
3
3
(250 MHz, CD3CN): δ = 2.86 (t, J = 7.6 Hz, 2 H), 3.77 (t, J =
3
7.6 Hz, 2 H), 6.77 (d, J = 8.4 Hz, 2 H), 7.08 (d, J = 8.4 Hz, 2 H),
7.72 (s, 4 H) ppm. 13C NMR (62.9 MHz, [D6]acetone): δ = 34.7,
41.2, 112.0, 116.7, 124.1, 130.4, 131.2, 134.2, 135.2, 153.8, 157.4,
171.1 ppm. 13C NMR (62.9 MHz, CD3CN): δ = 34.3, 40.9, 111.4,
116.3, 124.0, 130.6, 131.0, 134.2, 134.6, 152.7, 156.7, 170.8 ppm.
IR (KBr): ν = 3433, 1762, 1694, 1625, 1618, 1473, 1438, 1406, 1362,
˜
1319, 1242, 1155, 1137, 1081, 1041, 995, 825, 800, 756, 730, 713,
621 cm–1.
Polycitrin B (7): A mixture of diarylmaleic anhydride 15 (0.040 g,
0.065 mmol), phenol (0.160 g), tyramine (0.019 g, 0.14 mmol), N,N-
diisopropylethylamine (0.096 mL, 0.55 mmol), and powdered mo-
lecular sieves (4 Å, 0.134 g) was placed in the microwave tube under
nitrogen. The tube was heated to 110 °C over 1 min at 300 W and
then maintained under these conditions for another 2 min. After
the irradiation process, the reaction mixture was transferred to a
50 mL separatory funnel by using ethyl acetate (9 mL). The organic
phase was washed with 4% HCl (9 mL), separated, and dried with
anhydrous MgSO4. After filtration, the organic solvent was re-
moved under reduced pressure. The crude residue was then purified
by flash column chromatography (chloroform/pentane, 1:2; pure
chloroform; and then Et2O/chloroform, 1:20). The fractions were
collected and evaporated under reduced pressure to provide polyci-
trin B (0.041 g, 0.056 mmol, 86% yield) as a yellow solid. The spec-
troscopic data obtained for compound 7 are consistent with those
reported for polycitrin B.[5a,7] 1H NMR (250 MHz, [D6]acetone): δ
165.5 ppm. IR (KBr): ν = 3433, 1825, 1761, 1583, 1544, 1481, 1467,
˜
1421, 1394, 1343, 1321, 1253, 1188, 1151, 1119, 1068, 993, 941,
878, 802, 756, 748, 727, 629, 613, 594 cm–1.
Prepolycitrin A
hydrofuran-2,5-dione (6): To
hydroxyphenyl)-2,5-dihydrofuran-2,5-dione
–
3,4-Di(3,5-dibromo-4-hydroxyphenyl)-2,5-di-
stirred solution of 3,4-di(4-
(14, 0.790 g,
a
2.80 mmol) in AcOH/trifluoroacetic acid (5:1, 22 mL) was slowly
added TBCA (1.613 g, 4.41 mmol) at room temp. over a period of
2 h. After the complete addition of TBCA, the reaction mixture
was stirred for an additional 30 min. Next, the solution was con-
8012
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 8004–8013

Synthesis of Prepolycitrin A and Polycitrins A and B
3
3
[8] A. C. B. Burtoloso, A. L. L. Garcia, K. C. Miranda, C. R. D.
= 2.86 (t, J = 7.5 Hz, 2 H), 3.78 (t, J = 7.5 Hz, 2 H), 3.92 (s, 3
H, OMe), 6.77 (d, 3J = 8.2 Hz, 2 H), 7.08 (d, 3J = 8.2 Hz, 2 H), 7.71
(s, 2 H), 7.76 (s, 2 H) ppm. 13C NMR (62.9 MHz, [D6]acetone): δ
= 33.3, 39.9, 60.3, 110.6, 115.3, 117.8, 122.5, 127.6, 128.9, 129.7,
132.6, 133.8, 134.1, 134.3, 152.4, 155.2, 156.1, 169.4, 169.5 ppm.
Correia, Synlett 2006, 3145–3149.
C. Winklhofer, A. Terpin, C. Peschko, W. Steglich, Synthesis
2006, 3043–3047.
[9]
[10]
a) H. Yeb, W. Wu, C. Chen, Chem. Commun. 2003, 404–405;
b) E. K. Fields, S. J. Behrend, S. Meyerson, M. L. Winzenburg,
B. R. Ortega, H. K. Hall, J. Org. Chem. 1990, 55, 5165–5170;
c) C. Peschko, W. Steglich, Tetrahedron Lett. 2000, 41, 9477–
9481; d) C. Peifer, A. Krasowski, N. Hämmerle, O. Kohlbacher,
G. Dannhardt, F. Totzke, C. Schächtele, S. Laufer, J. Med.
Chem. 2006, 49, 7549–7553; e) M. Nakazono, S. Nanbu, A.
Uesaki, R. Kuwano, M. Kashiwabara, K. Zaitsu, Org. Lett.
2007, 9, 3583–3586; f) S. J. Manning, W. Bogen, L. A. Kelly, J.
Org. Chem. 2011, 76, 6007–6013.
IR (KBr): ν = 3437, 1767, 1699, 1612, 1589, 1515, 1467, 1406, 1353,
˜
1342, 1319, 1259, 1244, 1138, 1113, 1080, 993, 918, 879, 825, 756,
731, 631, 615, 594, 553 cm–1.
Supporting Information (see footnote on the first page of this arti-
cle): Copies of 1H and 13C NMR spectra for compounds 7 (polyci-
trin B), 8, 9, 10a–10i, 12a–12e, 13, 14 and 15, as well as IR spectra
for compounds 12e and 17.
[11]
[12]
a) A. Roglans, A. Pla-Quintana, M. Moreno-Manas, Chem.
Rev. 2006, 106, 4622–4643; b) J. G. Taylor, A. V. Moro, C. R. D.
Correia, Eur. J. Org. Chem. 2011, 1403–1428; c) F.-X. Felpin,
L. Nassar-Hardy, F. L. Callonnec, E. Fouquet, Tetrahedron
2011, 67, 2815–2831; for the first examples of an enantioselec-
tive Heck–Matsuda reaction, see: C. R. D. Correia, C. C. Ol-
iveira, A. G. Salles Jr., E. A. F. Santos, Tetrahedron Lett. 2012,
53, 3325–3328.
a) G. Y. Li, Angew. Chem. 2001, 113, 1561; Angew. Chem. Int.
Ed. 2001, 40, 1513–1516; b) G. Y. Li, G. Zheng, A. F. Noonan,
J. Org. Chem. 2001, 66, 8677–8681; c) G. Y. Li, J. Org. Chem.
2002, 67, 3643–3650.
a) C. Wolf, R. Lerebours, J. Org. Chem. 2003, 68, 7551–7554;
b) C. Wolf, R. Lerebours, Org. Lett. 2004, 6, 1147–1150; c) L.
Ackermann, Synthesis 2006, 10, 1557–1571.
a) A similar Heck–Matsuda arylation using fumaric acid was
reported recently; for details, see: A. I. Roshchin, Tetrahedron
Lett. 2010, 51, 3633–3635; b) J. R. Cook, B. Chamberlin, R. J.
Mawby, J. Chem. Soc., Dalton Trans. 1989, 465–470.
Acknowledgments
The authors thank the São Paulo Research Foundation (FAPESP)
(grant number 2011/23832-6), the Brazilian Research Council
(CNPq), and the Coordination for the Improvement of Higher
Education Level Personnel (CAPES) for financial support of this
work. The authors also would like to thank Dr. Roberta L. Drek-
ener (Unicamp) for some spectroscopic analyses as well as Ms.
Becca Saunders for providing us with a high-resolution photo of
Policitor giganteus and giving the authorization to use it as the
background illustration for Table of Contents.
[13]
[14]
[1] a) G. W. Chan, T. Francis, D. R. Thureen, P. H. Offen, N. J.
Pierce, J. W. Westley, R. K. Johnson, D. J. Faulkner, J. Org.
Chem. 1993, 58, 2544–2546; b) T. A. Berkhout, L. M. Havekes,
N. J. Pearce, P. H. E. Groot, Biochem. J. 1990, 272, 181–186; c)
Q. Li, A. Fan, Z. Lu, Y. Cui, W. Lin, Y. Jia, Org. Lett. 2010,
12, 4066–4069.
[2] a) W. C. Pham, J.-S. Shin, M. J. Choi, T. W. Kim, K. Lee, K. J.
Kim, G. Huh, J. Kim, D. J. Choo, K.-T. Lee, J. Y. Lee, Bull.
Korean Chem. Soc. 2012, 33, 721–724; b) J. T. Moon, J. Y. Jeon,
H. A. Park, Y. Noh, K. Lee, J. Kim, D. J. Choo, J. Y. Lee, Bi-
oorg. Med. Chem. Lett. 2010, 20, 734–737.
[15] a) O. Danek, D. Snobl, I. Knizek, S. Nouzová, Collect. Czech.
Chem. Commun. 1967, 32, 1642; b) B. Schmidt, R. Berger, A.
Kelling, U. Schilde, Chem. Eur. J. 2011, 17, 7032–7040.
[16] a) L. S. de Almeida, P. M. Esteves, M. C. S. de Mattos, Synthe-
sis 2006, 221–223; b) L. S. de Almeida, P. M. Esteves, M. C. S.
de Mattos, Tetrahedron Lett. 2009, 50, 3001–3004; c) L. S.
de Almeida, P. M. Esteves, M. C. S. de Mattos, Synlett 2006,
1515–1518.
[17] a) B. Gabriele, L. Veltri, G. Salerno, M. Costa, G. P. Chiusoli,
Eur. J. Org. Chem. 2003, 1722–1728; b) A. I. Roshchin, Y. V.
Kuznetsov, E. V. Polunin, Russ. Chem. Bull. Int. Ed. 2007, 56,
509–512.
[3] P. Y. Zhang, I. L. K. Wong, C. S. W. Yan, X. Y. Zhang, T. Ji-
ang, L. M. C. Chow, S. B. Wan, J. Med. Chem. 2010, 53, 5108–
5120.
[4] J. Y. Lee, K. J. Yoon, Y. S. Lee, Bioorg. Med. Chem. Lett. 2003,
13, 4331–4334.
[5] a) A. Rudi, I. Goldberg, Z. Stein, F. Frolow, Y. Benayahu, M.
Schleyer, Y. Kashman, J. Org. Chem. 1994, 59, 999–1003; b) A.
Rudi, T. Evan, M. Aknin, Y. Kashman, J. Nat. Prod. 2000, 63,
832–833.
[18] C. S. Rondestvedt Jr., O. Vogl, J. Am. Chem. Soc. 1955, 77,
2313–2315.
[19] L. E. Miller, C. J. Strickler, J. Am. Chem. Soc. 1954, 76, 698–
702.
[6] A. Terpin, K. Polborn, W. Steglich, Tetrahedron 1995, 51,
[20] M. J. Hoch, M. M. Delépine, Compt. Rend. 1950, 231, 625–
9941–9946.
626.
[7] E. M. Beccalli, F. Clerici, A. Marchesini, Tetrahedron 2000, 56,
2699–2702.
Received: July 24, 2013
Published Online: October 9, 2013
Eur. J. Org. Chem. 2013, 8004–8013
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
8013