Synthetic routes to 3-alkylsulfanyl-6-aryl-diketopyrrolo[3,4-c]pyrroles - A class of efficient, visible light excitable fluorophores

Article abstract of DOI:10.1039/b707281c

Sulfide derivatives of diketopyrrolo[3,4-c]pyrrole (SDPPs) were prepared in a one-pot procedure from arylpyrrolinones, isothiocyanates and alkylating agents, and their properties as fluorophores were evaluated. The Royal Society of Chemistry.

Full text of DOI:10.1039/b707281c

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www.rsc.org/obc | Organic & Biomolecular Chemistry
Synthetic routes to 3-alkylsulfanyl-6-aryl-diketopyrrolo[3,4-c]pyrroles—a
class of efficient, visible light excitable fluorophores
Bert Metten, Karen Martinez, Joice Thomas, Wenwu Qin, Mario Smet, Noe¨l Boens and Wim Dehaen*
Received 15th May 2007, Accepted 19th June 2007
First published as an Advance Article on the web 4th July 2007
DOI: 10.1039/b707281c
Sulfide derivatives of diketopyrrolo[3,4-c]pyrrole (SDPPs) were prepared in a one-pot procedure from
arylpyrrolinones, isothiocyanates and alkylating agents, and their properties as fluorophores were
evaluated.
Introduction
In our research group we are interested in fluorophores that
combine high fluorescence quantum yields with absorption and
emission in the visible wavelength region.1–3 Such fluorophores
have the advantage to be useful in measurements using glass optics
and low energetic radiation. Moreover, they can be incorporated
in biosensors because they absorb and emit light outside the wave-
length region of autofluorescence of biological cell components.
Diketopyrrolo[3,4-c]pyrrole (DPP) 1 is a well known pigment
with a high colour strength and photostability.4 DPP is also a
fluorophore with fluorescence in the visible region and a high
fluorescence quantum yield.5 Besides the use of DPP in the
pigment industry, there is an increasing use of DPP for more
advanced (electronic) applications. Since the end of the 1980s,
many applications for DPP derivatives have been proposed, such as
their use as charge-generating materials for laser printers, erasable
optical information carriers or as electroluminescent elements.6–9
DPP has recently been derivatized for the incorporation of
different materials like conjugated polymers, liquid crystals and
metal complexes in view of processing DPP derivatives in OLEDs,
LCD applications, data carriers and NLO applications.10–15 In the
patent literature, the application of electroluminescent materials
like p-conjugated polymers with DPP in the backbone or some
Scheme 1 DPP synthesis under harsh conditions and one-pot synthesis
specific heteroaromatic DPP derivatives with a very efficient use
of SDPP 5, thioaminals 7 or S-alkylated thioaminals 8. * 6a Rꢀ = Me; 6b
of electrical energy and strong luminescence, can be found.16
Recently, we synthesized DPP derivatives which could be incor-
Rꢀ = Ph; 6c Rꢀ = 4-Me2NC6H4; 6d Rꢀ = 4-NO2C6H4.
porated into supramolecular systems. For instance, dendrimers
Recently, Morton et al. published the condensation of pyrroli-
were synthesized with DPP as a core.3,5 Furthermore, DPP was
nones 419 with nitriles 2, affording asymmetric DPP derivatives
used as a building block for rigid oligomers of well defined length.2
under similar conditions.20,21 In a subsequent paper,22 imidoyl
Several conjugates were prepared of a Ca2+-selective podand17
chlorides were also used in combination with pyrrolinones,
and DPP,18 which could be useful as intracellular fluorescent Ca2+
affording triaryl DPPs.
indicators.
DPP can be synthesized by condensation of 2 equivalents of
Results and discussion
an aromatic nitrile 2 with 1 equivalent of a dialkyl succinate 3
under harsh conditions involving the use of a strong base and high
reaction temperatures (Scheme 1). This is the most general method
used in industrial pigment production.4 However, only robust
substituents are tolerated such as halogens, aromatic, aliphatic
and alkoxy groups. Neither nitro groups nor electrophilic groups
are compatible with these conditions.
We are interested in extending the variety of substituents accessi-
ble, as well as breaking the symmetry of the DPP chromophore.
This can be achieved by using less drastic reaction conditions or
by synthesising asymmetric derivatives which can react selectively
at one position. For example, it is interesting to have only one free
amide NH group on the DPP, which could be used for selective
reactions.
Department of Chemistry, Katholieke Universiteit Leuven, Celestijnenlaan
200F, Box 02404, B-3001, Leuven, Belgium. E-mail: Wim.Dehaen@
chem.kuleuven.be; Fax: +32 16 32 7990; Tel: +32 16 32 7439
A new synthetic strategy to functionalize asymmetric diaryl-
DPP analogues was devised based on mild cross-coupling
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reactions. In this way a large variety of groups or functions
could be attached to the chromophore, e.g., by the Liebeskind–
Srogl reaction.23 This reaction of arylboronic acids with thioesters,
thioalkynes and several thioethers affords arylated derivatives
under very mild (i.e., neutral) conditions. The synthesis of a
reactive thioether derivative of DPP 5 seemed possible starting
from pyrrolinones 4 and isothiocyanates 6.
The C-3 position of pyrrolinones 4a,b can easily be deproto-
nated, and in fact sodium hydride gives complete deprotonation.
Addition of isothiocyanates 6a–d to these deprotonated pyrroli-
nones 4a,b gave intermediate thioaminals 7 (Scheme 1, Table 1).
By subsequent addition of an equimolar quantity of base, isothio-
cyanate and an alkylating agent to pyrrolinone 4a,b, this sequence
yielded the selectively S-alkylated 8. When the amount of base
was doubled, the desired ring-closed alkylsulfanylpyrrolopyrroles
(SDPPs) 5a–f were obtained (Scheme 1, Table 1). The yields of
5 were fair (54–66%) except for compound 5d (derived from 4a
and 4-dimethylaminophenyl isothiocyanate 6c). In this case the
expected SDPP 5d was obtained in only 37% yield, and this was
at least in part the result of overalkylation, leading to the N,N-
dimethyl SDPP 5e (9% yield).
Scheme 2 N-Alkylation of SDPPs 5a,b and f.
Compound 5e could be prepared more effectively from 4d in
60% yield using an analogous procedure. We failed to obtain
cyclized products of type 5 when starting from 4-nitrophenyl
isothiocyanate 6d, probably due to the low nucleophilicity of the
nitrogen atom in this case. All reaction steps leading to compounds
5 could be performed at room temperature.
Also, N-substituted pyrrolinone 4c could be used for the
preparation of N,N-dialkylated SDPP 5g, albeit in somewhat
lower yield (31%).
Scheme 3 Transformation of SDPP 5 to monoalkylated DPP 12.
even after prolonged reaction time, which necessitated additional
purification by column chromatography. Electron-rich or electron-
poor arylboronic acids gave low yields or no reaction product.
Previously, the mono-N-alkyl-DPP 12 was difficult to prepare
because of the number of additional steps and purifications
required to prepare 12 starting from DPP 1. Indeed, Boc protection
of both amide functions and selective removal of one Boc group
was necessary. Direct monoalkylation of DPP is difficult because
the monoalkylated product is more soluble than the starting
material and hence more reactive towards further N-alkylation.24
To study the spectroscopic properties of the new SDPP com-
pounds, some representative UV/vis absorption and fluorescence
spectra were recorded in different solvents. As an example, Fig. 1
shows the absorption and steady-state fluorescence emission
spectra of 5b and 5g in toluene, and 9b in methanol. Typically, the
Most SDPPs 5 are only sparingly soluble in common organic
solvents such as dichloromethane, ethyl acetate or alcohols.
Replacement of the methyl group in 5b by the larger benzyl
substituent in 5c was found to increase the solubility. N-Alkylation
of the SDPPs 5a, b and f with a tert-butyl-protected acetate group
on the free amide function, providing 9a, b and c, respectively,
increased the solubility because in the latter compounds hydrogen
bond formation is impossible (Scheme 2). In order to prepare
water-soluble DPP derivatives, the easy deprotection of the acetate
group of 9a with trifluoroacetic acid (TFA) gave SDPP 10a in
quantitative yield. This compound was found to be soluble in
slightly basic aqueous media. From the SDPP derivative 9c the
acetate group and the phenol function could be deprotected
quantitatively using BBr3 affording the product 10b.
Under Liebeskind–Srogl conditions,23 SDPP 5a could be cou-
pled with phenylboronic acid 11 to provide DPPD 12 in good
yield (Scheme 3). Unfortunately, the reaction was not complete
Table 1 One-pot synthesis of SDPP 5
SDPP
Ar
R
Rꢀ
Rꢀꢀ
Yield (%)a
5a
5b
5c
5d
5e
5f
Ph
Ph
Ph
Ph
H
H
H
H
CH3
H
Allyl
CH3
Ph
Ph
4-Me2NC6H4
4-Me2NC6H4
CH3
CH3
CH3
Bn
CH3
CH3
CH3
CH3
58
66
54
37
60
62
31
Ph
4-MeOC6H4
2-Thienyl
5g
CH3
Fig. 1 Normalized absorption (A) and fluorescence emission (F) spectra
(excitation at 470 nm) of 5b (black) and 5g (red) in toluene and 9b (green)
in methanol.
a Isolated yield.
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compounds have absorption spectra with an intense absorption
band ranging from 452 nm for 9b in methanol, to 497 nm for 5g
in toluene. An additional (more or less pronounced) shoulder is
observed on the short-wavelength side. The emission spectra show
a Stokes-shifted fluorescence emission band of mirror image shape.
The fluorescence quantum yields are for most compounds higher
than 0.8 and often reach 1.0. The excitation maxima coincide
exactly with the absorption maxima.
ing 1.0) that are excitable with visible light (above 450 nm).
They possess several synthetic advantages compared to diaryl-
DPP 1. SDPPs can easily be prepared starting from pyrrolinones
4, isothiocyanates 6 and alkylating agents in a one-pot three-
component reaction at room temperature. A moderate number
of functional groups can be introduced via the substituents on the
aryl group of 4 or via the N-substituents of 4 or 6. Through N-
alkylation of the remaining unsubstituted nitrogen atom, a variety
of functional groups can be incorporated. Using the very mild
Liebeskind–Srogl conditions it is possible to convert the SDPP
into the corresponding monoalkylated diaryl-DPP.
Compound 5b was studied in some more detail. The absorption
spectra of 5b are only slightly affected by solvent polarity: the
maximum being slightly shifted hypsochromically (ca. 7 nm) when
the solvent is changed from toluene (477 nm) to acetonitrile and
methanol (470 nm). They all show two absorption maxima: (1) a
strong S0–S1 transition with a maximum between 470 and 477 nm,
(2) the second maximum, or shoulder, at the high-energy side, is
centered at about 445 nm, which is attributed to the 0–1 vibrational
transition. The molar absorption coefficients emax at the maximum
for the new SDPP analogues are relatively high. For example, for
compound 5b, emax equals (19 2) × 103 M−1 cm−1 in ethyl acetate
and (20.7 0.8) × 103 M−1 cm−1 in chloroform.
Experimental
Spectroscopic measurements
The absorption measurements were performed on a Perkin-
Elmer Lambda 40 UV/Vis spectrophotometer. Corrected steady-
state excitation and emission spectra were recorded on a SPEX
Fluorolog. For the determination of the relative fluorescence
quantum yields (φf), only dilute solutions with an absorbance
below 0.1 at the excitation wavelength (470 nm for all measured
compounds) were used. Rhodamine 6G in water (φf = 0.76) was
used as a fluorescence standard.25 The φf values reported in this
work are the averages of multiple (generally 3), fully independent
measurements. All measurements were done at 20 ◦C using non-
degassed samples. The absorption spectra match the excitation
spectra in all cases.
The rather low fluorescence quantum yield φf for 5d in methanol
and toluene may be rationalized by an efficient quenching via an
intramolecular charge transfer process in the excited state from the
tertiary amino group to the DPP moiety. Protonation drastically
alters the electron-donating properties of the tertiary amino group
and consequently “switches off” any charge-transfer process,
resulting in a large fluorescence enhancement (φf rises from 0.001
to 0.69). Simultaneously, the full width at half maximum (fwhmabs
)
of the absorption band slightly decreases upon addition of HClO4
(from 3513 cm−1 for 5d in methanol, to 3322 cm−1 for 5d-H+ in
acidified methanol). Table 2 summarizes the photophysical data
of several new SDPP derivatives.
General procedure for the compounds 5
6-Phenyl-2-methyl-3-(methylsulfanyl)-1,4-(2H,5H)-dioxopyr-
rolo[3,4-c]pyrrole (5a). To a solution of pyrrolinone 4a (Ar =
Ph, R = H, 924 mg, 4.00 mmol), in DMSO (10 mL) under argon
atmosphere was added NaH (264 mg, 8.00 mmol, 80% in oil),
and after 15 min methyl isothiocyanate (297 mg, 4.40 mmol). The
mixture was stirred at room temperature for 6 h. After cooling the
Conclusion
The novel alkylthiopyrrolopyrroles (SDPP) 5 are valuable fluo-
rophores with high fluorescence quantum yields (often approach-
◦
mixture to 0 C, methyl iodide (624 mg, 4.40 mmol) was added
Table 2 Absorption and fluorescence data for some of the SDPP compounds in different solvents
c
d
e
Compound
Solvent
kabs /nm a
kem/nm b
Dm¯/cm−1
fwhmabs /cm−1
φf
5b
MeOH
470
470
474
475
474
477
459
458
469
487
497
476
482
455
464
452
459
499
493
492
494
494
497
513
501
505
539
526
506
497
498
500
497
499
1237
993
772
810
854
2672
3092
2868
2898
2680
2561
3513
3322
3630
3439
2979
2508
2675
3323
3147
3233
3118
0.84
0.94
0.87
0.87
1.00
1.00
0.001
0.69
0.002
0.40
0.71
0.78
0.91
0.87
1.00
0.88
1.00
CH3CN
Ethyl acetate
THF
CHCl3
Toluene
MeOH
MeOH + HClO4
Toluene
MeOH
Toluene
MeOH
Toluene
MeOH
Toluene
MeOH
844
5d
2293
1874
1520
1981
1109
1246
626
1898
1552
2003
1746
5g
5f
9a
9b
Toluene
a The position of the absorption maximum. The absorption spectra match the excitation spectra in all cases. b The position of the fluorescence emission
maximum. All samples were excited at 470 nm. c Stokes shift (in cm−1). d Full width at half maximum of the absorption band (in cm−1). e Fluorescence
quantum yield (all samples were excited at 470 nm).
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and the mixture was stirred for 12 h at room temperature. The
mixture was then added to an ice/water mixture (150 mL) and
1 mL of acetic acid, and stirred for 15 min. The finely divided
precipitate was filtered and washed with water and cold methanol
until colorless, furnishing pure 5a (640 mg, 58%) as a bright
orange powder. dH (300 MHz, CDCl3–CF3COOD): 3.17 (s, 3H),
3.24 (s, 3H), 7.48–7.51 (m, 3H), 8.21–8.23 (m, 2H), 8.97 (s, 1H);
dC (75 MHz, CDCl3–CF3COOD): 16.5, 28.6, 108.2, 113.0, 116.8,
127.0, 127.7, 129.8, 132.7, 141.3, 160.4, 162.4; LR-MS (CI): 273
MH+; UV (CH2Cl2): kmax (log emax) = 476 nm (4.292), 450 nm
(4.213); mp 284 ◦C.
CDCl3); 15.5, 27.62, 55.04, 107.4, 109.2, 114.6, 120.3, 129.7, 142.5,
149.0, 159.8, 161.5, 162.0; MS (EI, 70 eV) m/z 302 (M+, 100),
287 (19), 269 (19), 256 (11), 255 (56). HRMS (EI+): calcd for
C15H14O3N2S (M+) 302.0725; found 302.0722. UV (CH2Cl2): kmax
(log emax) = 480 nm (4.331), 451 nm (4.243); mp 280 ◦C.
2-Allyl-5-methyl-6-(methylsulfanyl)-3-(2-thienyl)-1,4-(2H,5H)-
dioxopyrrolo[3,4-c]pyrrole (5g). Prepared following the general
procedure, starting from 4c (Ar = 2-thienyl, R = allyl), in 31%
yield after purification by column chromatography. dH (300 MHz,
CDCl3) 3.13 (s, 3H), 3.20 (s, 3H), 4.59 (t, 2H, J = 1.8 Hz), 5.11–
5.22 (m, 2H), 5.90–6.01 (m, 1H), 7.19 (t, 1H, J = 4.5 Hz), 7.55 (d,
1H, J = 6.4 Hz), 8.54 (m, 2H); dC (75 MHz, CDCl3) 16.2, 27.9,
44.1, 107.6, 108.4, 116.7, 128.5, 129.6, 130.5, 133.1, 133.9, 137.9,
152.6, 160.5, 160.7; LR-MS (CI): 319 MH+; UV (CH2Cl2): kmax
(log emax) = 492 nm (4.321), 308 nm (4.188); mp 143 ◦C.
2,6-Diphenyl-3-(methylsulfanyl)-1,4-(2H,5H)-dioxopyrrolo[3,4-
c]pyrrole (5b). Prepared in the same way from phenyl
isothiocyanate and 4a in 66% yield. dH (300 MHz, CDCl3)
3.09 (s, 3H), 7.31–7.36 (m, 3H), 7.46–7.53 (m, 5H), 8.19–8.23 (m,
2H), 8.48 (s, 1H); dC (75 MHz, CDCl3) 16.6, 109.4, 111.5, 128.5,
128.6, 129.6, 130.0, 130.2, 132.6, 135.2, 143.7, 151.8, 160.5, 162.8;
LR-MS (CI): 335 MH+; UV (CH2Cl2): kmax (log emax) = 472 nm
(4.485), 444 nm (4.327); mp 283–285 ◦C.
General procedure for compounds 9
tert-Butyl-2-(6-(methylsulfanyl)-1,4-dioxo-3,5-diphenyl-4,5-di-
hydropyrrolo[3,4-c]pyrrol-2(1H)-yl)acetate (9b). A suspension of
5b (100 mg, 0.30 mmol), K2CO3 (103 mg, 0.75 mmol) and NaI
(100 mg) in DMF (20 mL) was heated for 15 min until 5b was
dissolved. At room temperature tert-butyl bromoacetate (98 mg,
73 mL, 0.50 mmol) was added in a drop-wise manner. The reaction
mixture was stirred for 12 h at 80 ◦C. After cooling to room
temperature, the mixture was diluted with ethyl acetate (50 mL)
and water (50 mL). The organic phase was washed with water
(2 × 50 mL) and the aqueous phase was extracted with ethyl
acetate (3 × 40 mL). The combined organic phases were dried
over MgSO4. The solvent was evaporated under reduced pressure
and the residue was purified by column chromatography (silica gel,
CH2Cl2–ethyl acetate), furnishing 9b (46 mg, 34%) as an orange-
red powder. dH (300 MHz, CDCl3): 1.39 (s, 9H), 3.08 (s, 3H), 4.41
(s, 2H), 7.28–7.31 (m, 2H), 7.42–7.49 (m, 6H), 7.70–7.72 (m, 2H);
dC (75 MHz, CDCl3): 16.6, 28.3, 44.7, 83.0, 128.1, 128.7, 129.0,
129.3, 129.4, 129.6, 131.2, 134.4, 144.3, 155.1, 160.8, 161.8, 168.1;
UV (CH2Cl2): kmax (log emax) = 455 nm (4.159), 288 nm (4.006);
LR-MS (CI): 449 MH+; mp 127 ◦C.
2,6-Diphenyl-3-(benzylsulfanyl)-1,4-(2H,5H)-dioxopyrrolo[3,4-
c]pyrrole (5c). Prepared in the same way, using benzyl bromide
instead of methyl iodide, from phenyl isothiocyanate and 4a in
54% yield. dH (300 MHz, CDCl3) 5.00 (s, 2H), 7.25–7.31 (m, 7H),
7.44–7.56 (m, 6H), 8.43 (m, 2H), 11.32 (s, 1H); dC (75 MHz,
CDCl3) 65.7, 86.0, 125.7, 127.7, 127.8, 128.1, 128.2, 128.3, 129.4,
129.5, 129.8, 130.3, 135.1, 135.7, 144.1, 169.9, 173.8, 208.7;
LR-MS (CI): 411 MH+; UV (CH2Cl2): kmax (log emax) = 475 nm
(4.347), 448 nm (4.267); mp 264 ◦C.
2-(4-(N,N-Dimethylamino)phenyl)-6-phenyl-3-(methylsulfanyl)-
1,4-(2H,5H)-dioxopyrrolo[3,4-c]pyrrole (5d). Prepared in the
same way, from the corresponding isothiocyanate and 4a in
37% yield. dH(300 MHz, CDCl3) 2.52 (s, 6H), 2.93 (s, 3H), 6.82
(d, 2H, J = 8.8 Hz), 7.10 (d, 2H, J = 9.5 Hz), 7.49–7.53 (m,
3H), 8.28–8.32 (m, 2H), 11.16 (s, 1H); dC (75 MHz, CDCl3) a
sufficiently high concentration could not be reached; MS (EI,
70 eV) m/z 378 (MH+, 32), 377 (M+, 100), 331 (14), 330 (74),
302 (18), 134 (17); HRMS (EI+): calcd for C21H19O2N3S (M+)
377.11980; found 377.12029; UV (CH2Cl2): kmax (log emax) =
474 nm (4.45), 449 nm (4.262); mp >300 ◦C.
tert-Butyl-2-(3-phenyl-5-methyl-6-(methylsulfanyl)-1,4-dioxo-4,
5-dihydropyrrolo[3,4-c]pyrrol-2(1H)-yl)acetate (9a). Prepared
from 5a according to the general procedure in 86% yield, dH
(300 MHz, CDCl3): 1.38 (s, 9H), 3.15 (s, 3H), 3.17 (s, 3H), 4.34 (s,
2H), 7.46–7.53 (m, 3H), 7.65–7.70 (m, 2H); dC (75 MHz, CDCl3):
16.31, 27.9, 29.4, 44.5, 82.5, 107.3, 110.7, 128.3, 128.7, 129.0,
143.9, 155.1, 161.1, 161.3, 168.1, 169.9; UV (CH2Cl2): kmax (log
emax) = 456 nm (4.153), 287 nm (4.120); LR-MS (CI): 386 MH+;
mp 79 ◦C.
2-(4-(N,N-Dimethylamino)phenyl)-5-methyl-6-phenyl-3-(methyl-
sulfanyl)-1,4-(2H,5H)-dioxopyrrolo[3,4-c]pyrrole (5e). Prepared
following the general procedure, from the corresponding
isothiocyanate and 4d (Ar = Ph, R = Me), in 60% yield. dH
(300 MHz, CDCl3) 2.90 (s, 6H), 3.04 (s, 3H), 3.36 (s, 3H), 6.75
(d, 2H, J = 8.9 Hz), 7.13 (d, 2H, J = 9.1 Hz), 7.43–7.49 (m,
3H), 7.79–7.82 (m, 2H), 11.12 (s, 1H); dC (75 MHz, CDCl3) 16.4,
30.0, 40.7, 108.5, 109.6, 112.4, 122.7, 128.3, 129.1, 129.3, 131.0,
144.5, 151.0, 156.0, 156.1, 161.3, 162; MS (EI, 70 eV) m/z 391
(M+, 100), 345 (19), 344 (95), 172 (11): calcd for C22H21O2N3S
(M+) 391.13545; found 391.13545; UV (CH2Cl2): kmax (log emax) =
464 nm (4.277), 441 nm (4.219); mp 229 ◦C.
tert-Butyl-2-(3-(4-methoxyphenyl)-5-methyl-6-(methylsulfanyl)-
1,4-dioxo-4,5-dihydropyrrolo[3,4-c]pyrrol-2(1H)-yl)acetate (9c).
Prepared from 5f according to the general procedure in 70%
yield, dH (300 MHz, CDCl3): 1.39 (s, 9H), 3.13 (s, 3H), 3.16 (s,
3H), 3.80 (s, 3H), 4.34 (s, 2H), 6.95 (d, 2H, J = 8.8 Hz), 7.57
(d, 2H, J = 8.8 Hz); dC (75 MHz, CDCl3): 16.2, 28.8, 44.6, 55.7,
82.7, 109.8, 114.7, 120.5, 130.6, 144.2, 153.5, 161.1, 161.8, 168.1;
UV (CH2Cl2): kmax (log emax) = 462 nm (4.308), 298 nm (4.145);
LR-MS (CI): 417 MH+; mp 123 ◦C.
6-(4-Methoxyphenyl)-2-methyl-3-methylsulfanyl-1,4-(2H,5H)-
dioxopyrrolo[3,4-c]pyrrole (5f). Prepared following the general
procedure, starting from 4b (Ar = 4-anisyl, R = H), in 62% yield.
dH (300 MHz, CDCl3) 3.06 (s, 3H), 3.07 (s, 3H), 4.14 (s, 3H), 6.86 (d,
2H, J = 9.2 Hz), 7.57 (d, 2H, J = 9.1 Hz), 9.00 (s, 1H); dC (75 MHz,
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2-(3-Phenyl-5-methyl-6-(methylsulfanyl)-1,4-dioxo-4,5-dihydro-
pyrrolo[3,4-c]pyrrol-2(1H)-yl)acetic acid (10a). A solution of 9a
(110 mg, 0.28 mmol) in trifluoroacetic acid (3ml) was stirred
overnight at room temperature. After addition of water, the
aqueous layer was extracted with diethyl ether. The collected
organic layers were washed with brine and water, and the solvent
evaporated under reduced pressure to afford 10a in 87% yield, dH
(300 MHz, DMSO-d6): 3.08 (s, 3H), 3.10 (s, 3H), 4.34 (s, 2H),
7.52–7.55 (m, 3H), 7.66–7.70 (m, 2H), 10.27 (s(br), 1H), 13.03
(s(br), 1H); dC (75 MHz, DMSO-d6): 18.5, 30.0, 45.8, 108.9, 111.9,
130.2, 131.0, 131.6, 133.5, 145.7, 157.3, 160.8, 161.3, 162.6, 162.8,
172.6; MS (EI, 70 eV) m/z 330 (M+, 100), 297 (15), 284 (19), 283
(81); HRMS (EI+): calcd for C16H14N2O4S (M+) 330.06734; found
330.06734; UV (H2O): kmax = 455 nm; mp 192 ◦C.
2-(3-(4-Hydroxyphenyl)-5-methyl-6-(methylsulfanyl)-1,4-dioxo-
4,5-dihydropyrrolo[3,4-c]pyrrol-2(1H)-yl)acetate (10b). Prepared
from 9c in a similar way as for 10a, in quantitative yield. dH
(300 MHz, DMSO-d6): 3.07 (s, 3H), 3.09 (s, 3H), 4.37 (s, 2H),
6.90 (d, 2H, J = 8.8 Hz), 7.59 (d, 2H, J = 8.8 Hz), 10.27 (s(br),
1H), 13.03 (s(br), 1H); dC (75 MHz, DMSO-d6): 15.7, 27.7, 43.6,
106.6, 108.2, 116.0, 118.3, 130.7, 144.4, 152.2, 160.3, 160.7, 170.4;
MS (EI, 70 eV) m/z 346 (M+, 100), 313 (25), 302 (15), 300 (12),
299 (63), 255 (14); HRMS (EI+): calcd for C16H14N2O5S (M+)
346.06234; found 346.06257; UV (H2O, NaHCO3 3 mM); kmax
(log emax) = 466 nm (4.328), 293 (4.064); mp 242 ◦C.
2-Methyl-3,6-diphenyl-1,4(2H,5H)-dioxopyrrolo[3,4-c]pyrrole
(12). A solution of 5a (136 mg, 0.50 mmol), phenylboronic acid
(67 mg, 0.55 mmol), Cu(I) thiophene-2-carboxylic acid (114 mg,
0.60 mmol) and Pd(PPh3)4 (5 mg, 10 mol%) in THF (30 mL)
under argon atmosphere was stirred for 18 h at 50 ◦C. The
mixture was cooled and then diluted with ether (50 mL). The
organic phase was washed with a saturated NaHCO3 solution
(50 mL), brine (50 mL) and water (50 mL), dried over MgSO4
and the solvent evaporated under reduced pressure. Purification
with column chromatography (silica gel, CH2Cl2) furnished pure
12 (170 mg, 70%) as a red powder. dH (300 MHz, DMSO): 3.30
(s, 3H), 7.57–7.60 (m, 6H), 7.92–7.95 (m, 2H), 8.46–8.49 (m, 2H),
11.22 (s(br), 1H); dC (75 MHz, DMSO): 29.6, 108.9, 110.4, 127.7,
127.9, 128.1, 129.0, 129.3, 129.7, 131.1, 132.4, 146.1, 146.4, 161.8,
162.7; LR-MS (CI): 303 MH+.
Acknowledgements
We thank the K. U. Leuven, the Fonds voor Wetenschappelijk
Onderzoek-Vlaanderen (F.W.O.) and the IAP-V-3 programme for
financial support.
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