Synthesis and chemistry of 4,5-dihydrothieno[3,2-b]pyrrol-6-ones - A heteroindoxyl

Article abstract of DOI:10.1021/jo900496u

(Chemical Equation Presented) Flash vacuum pyrolysis (FVP) of 2-acetyl-3-azidothiophene gives 3-methylthieno[3,2-c]isoxazole as the major product at a furnace temperature of 350°C whereas at temperatures above 550°C the new heteroindoxyl 4,5-dihydrothieno[3,2-b]pyrrol-6-one is exclusively formed. The heteroindoxyl exists predominantly as the keto tautomer. It is O-protonated by TFA, N-acetylated by acetic anhydride, N-nitrosated by nitrous acid, and provides an N-methylene Meldrum's acid derivative on treatment with methoxymethylene Meldrum's acid. Reactions of 4,5-dihydrothieno[3,2-b] pyrrol-6-one with diazonium salts, with isatin, and with dimethyl acetylenedicarboxylate take place at the methylene position to provide a hydrazone, an indirubin analogue, and a succinate derivative, respectively. Oxidation of 4,5-dihydrothieno[3,2-b]pyrrol-6-one gives a heteroindigotin, which shows a hypsochromic shift in the UV spectrum, relative to indigotin itself.

Full text of DOI:10.1021/jo900496u

Synthesis and Chemistry of 4,5-Dihydrothieno[3,2-b]pyrrol-6-onesA
Heteroindoxyl
Alexander P. Gaywood and Hamish McNab*
School of Chemistry, The UniVersity of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, United Kingdom
H.McNab@ed.ac.uk
ReceiVed March 6, 2009
Flash vacuum pyrolysis (FVP) of 2-acetyl-3-azidothiophene gives 3-methylthieno[3,2-c]isoxazole as the major
product at a furnace temperature of 350 °C whereas at temperatures above 550 °C the new heteroindoxyl
4,5-dihydrothieno[3,2-b]pyrrol-6-one is exclusively formed. The heteroindoxyl exists predominantly as the
keto tautomer. It is O-protonated by TFA, N-acetylated by acetic anhydride, N-nitrosated by nitrous acid, and
provides an N-methylene Meldrum’s acid derivative on treatment with methoxymethylene Meldrum’s acid.
Reactions of 4,5-dihydrothieno[3,2-b]pyrrol-6-one with diazonium salts, with isatin, and with dimethyl
acetylenedicarboxylate take place at the methylene position to provide a hydrazone, an indirubin analogue,
and a succinate derivative, respectively. Oxidation of 4,5-dihydrothieno[3,2-b]pyrrol-6-one gives a heteroin-
digotin, which shows a hypsochromic shift in the UV spectrum, relative to indigotin itself.
Introduction
In this paper, we report the first successful synthesis of a
parent heteroindoxyl, 4,5-dihydrothieno[3,2-b]pyrrol-6-one
3, which was made by a nitrene insertion strategy under flash
vacuum pyrolysis (FVP) conditions. The chemical properties
of the heteroindoxyl are also discussed, including its oxidative
dimerization to the new heteroindigotin 4, by analogy with
the known chemistry of indoxyl 2 and of monocylic 3-hy-
droxypyrroles [1H-pyrrol-3(2H)-ones].
Indigotin 1 is the major chemical constituent of indigo, which
has been used as a dyestuff for at least 4000 years.1,2 The
reduced monomeric unit of indigotin, 3-hydroxyindole 2E
[indol-3(2H)-one 2K] (or indoxyl), is much less studied owing
to its easy oxidative dimerization to indigotin 1. There are few
examples of indigotin structures in which the benzene ring has
been replaced by an aromatic heterocycle3 and none in which
that heterocycle is a thiophene unit. Equally, there are no simple
examples of corresponding heteroindoxyls, though some N-
functionalized derivatives have been claimed in a patent4 and
some related thieno-isatin analogues are known.5
(1) (a) Gordon, P. F.; Gregory, P. Organic Chemistry in Colour; Springer-
Verlag: Berlin, 1983. (b) Christie, R. M. Colour Chemistry; Royal Society of
Chemistry: Cambridge, 2001.
(2) Ferreira, E. S. B.; Hulme, A. N.; McNab, H.; Quye, A. Chem. Soc. ReV.
2004, 33, 329–336.
(3) (a) Ka¨gi, H. HelV. Chim. Acta 1942, 35, 1471–1480. (b) Sucharda, E.
Ber. Dtsch. Chem. Ges. 1925, 58, 1724–1727. (c) Lu¨ttke, W.; Hunsdiecker, D.
Chem. Ber. 1966, 99, 2146–2153.
4278 J. Org. Chem. 2009, 74, 4278–4282
10.1021/jo900496u CCC: $40.75 2009 American Chemical Society
Published on Web 04/29/2009

4,5-Dihydrothieno[3,2-b]pyrrol-6-onesA Heteroindoxyl
FIGURE 1. Temperature profile of the FVP of 2-acetyl-3-azidothiophene 6.
SCHEME 1
SCHEME 2
1
FIGURE 2. 13C NMR and H NMR (in parentheses) chemical shifts
of 3K and 7.
of 550 °C and above, the new heteroindoxyl 4,5-dihy-
drothieno[3,2-b]pyrrol-6-one 3 was formed exclusively (61%
isolated yield at 550 °C).
Two possible mechanisms can be drawn for the formation
of the thienoisoxazole 7 (Scheme 2). First, FVP of the azide 6
may give the nitrene 8 which is quenched by the adjacent keto
group to provide 7 as the kinetic product (route a). At higher
temperatures a CH insertion reaction of 8 would provide 3 as
the thermodynamic product. Alternatively, anchimeric assistance
of the N2 loss by the ketone function of 6 may provide 7 directly
without the involvement of free nitrene intermediates (route b).
Although the evidence is not unequivocal, we favor route b,
since there is some rate acceleration in the FVP of o-
azidoketones by comparison with non-ortho-substituted model
compounds.8 Formation of the heteroindoxyl 3 at higher
temperatures can then occur by reversible electrocyclic ring-
opening of 7 to the nitrene 8, which provides 3 by CH insertion
(Scheme 2).
Results and Discussion
The starting material, 2-acetyl-3-azidothiophene 6, was made
from 2-acetyl-3-aminothiophene6 5 by diazotization and reaction
with sodium azide (Scheme 1).7
Pyrolysis of 6 in solution has been previously reported, and
led to a 5% yield of a poorly characterized product which was
tentatively identified as 3-methylthieno[3,2-c]isoxazole 7.7 In
contrast, under FVP conditions, the temperature profile (Figure
1) shows the formation of two distinct products over different
temperature regimes. Onset of decomposition of the azide 6
began at 250 °C and was complete by 350 °C. At furnace
temperatures below ca. 400 °C, 3-methylthieno[3,2-c]isoxazole
7 was the major product (a 350 °C pyrolysis gave 7 in 51%
isolated yield after chromatography) whereas at temperatures
The mp and 1H NMR spectrum obtained for the thienoisox-
azole 7 correspond with data that had been tentatively assigned
7
1
to this compound (Figure 2). Although the H NMR spectra
of 6 and 7 show similar features, their 13C NMR and mass
spectra are very different; in particular 7 shows a dramatic
shielding of the methyl group [δC (7) 12.1 c.f. δC (6) 29.1].
Few other examples of 5,6-unsubstituted thieno[3,2-c]isoxazoles
are known.7,9
(4) Glenn, R. W.; Lim, M. U.S. Pat. Appl. Publ. US 2006042025, 2006.
(5) Shvedov, V. I.; Vasil’eva, V. K.; Kharizomenova, I. A.; Grinev, A. N.
Khim. Geterotsikl. Soedin 1975, 767–769; Chem. Abstr. 1975, 83, 193123.
(6) Huddleston, P. R.; Barker, J. M. Synth. Commun. 1979, 9, 731–734.
(7) Dyall, L. K.; Suffolk, P. M.; Dehaen, W.; L’abbe, G. J. Chem. Soc.,
Perkin Trans. 2 1994, 2115–2119.
(8) Gaywood, A. P. PhD. thesis, The University of Edinburgh, 2006.
J. Org. Chem. Vol. 74, No. 11, 2009 4279

Gaywood and McNab
The new heteroindoxyl 3K showed CH2 resonances at δH
(C[2H]Cl3) 4.22 and δC (C[2H]Cl3) 61.0 (c.f. corresponding
signals for indoxyl 2K at δH 3.89 and δC 54.1, respectively)
and the characteristic methyl signal of 7 was absent (Figure 2).
The heteroindoxyl 3 is relatively stable and can be handled at
the bench without special precautions. However, substantial
decomposition was evident after a few days in solution in
DMSO. Because of potential oxidative dimerization to the
heteroindigotin 4, it was normally used for reactivity studies
immediately after preparation.
Reaction of 3 with neat acetic anhydride gave a 98% yield
of the N-acyl product 12; the regiochemistry of the acylation
was confirmed by the continued presence of a CH2 group at δH
1
4.56 in the H NMR spectrum of the product. No acetoxy
compound 13 could be detected. Indoxyl 2 behaves similarly
under the same conditions.13 Treatment of 3 with aqueous
nitrous acid gave exclusively the N-nitroso-compound 14, (56%),
though nitrosation of indoxyl 2 itself is known to provide the
oxime 15.13 The presence of only small amounts of enol
tautomer 3E, coupled with the potential irreversibility of
N-nitrosation, may rationalize the change in regioselectivity.
Treatment of 3 with the weak electrophile, methoxymethylene
Meldrum’s acid (MMMA) 16 also takes place at N(4) to provide
the N-(2,2-dimethyl-4,6-dioxo-1,3-dioxan-5-ylidene)methylena-
ted product 17 (37%). The same regioselectivity is observed
for the corresponding reaction of indoxyl 2,8 though the reaction
of an N-unsubstituted pyrrolone with MMMA, took place instead
at the methylene group to give 18.14 The presence of the fused
rings in 2 and 3 clearly influence regioselectivity. Attempted
FVP of 17 was unsuccessful owing to its involatility.
Indoxyl 28,10 and simple 1H-pyrrol-3(2H)-ones11 (e.g., 9) are
known to exist preferentially as the enols 2E and 9E, respec-
tively, when dissolved in hydrogen-bond acceptor solvents such
as DMSO. Relative to these systems, the heteroindoxyl 3 shows
increased preference for the keto form 3K (Supporting Informa-
tion); the hydroxy tautomer 3E is detected at low level (20%)
only in DMSO solution [δH(3E) 10.30 (1H, br, s), 8.49 (1H, s),
7.13 (1H, d), 6.92 (1H, d) and 6.51 (1H, s)]. The fusion of two
electron-rich π-systems in 3E may contribute to its relative
destabilization.
Reactions of the heteroindoxyl 3 with mild electrophiles may
be expected to take place at the oxygen atom, at the nitrogen
atom or (Via the enol) at the CH2 group of the pyrrolone ring.
The regioselectivity of such reactions can depend on a number
of factors, including HSAB effects, the predominant tautomeric
form, rate of tautomer interconversions etc. In practice, although
reactions take place with high selectivity, examples of all three
modes have been observed in the specific cases described below.
The enaminone conjugated system of 1H-pyrrol-3(2H)-ones
is smoothly O-protonated in acid solution, supported experi-
mentally by the X-ray crystal structure of a picrate salt.12 Such
protonation results in well-defined shifts of signals in 13C NMR
spectra.12 Heteroindoxyl 3 is stable in TFA solution and the
key changes in the 13C NMR spectra in this medium are shown
in Table 1, by comparison with corresponding pyrrolone (9 and
Despite the relative lack of enol tautomer 3E, some electro-
philes react preferentially at the CH2 (5-position). Deuterium
exchange at this site takes place in neutral media, presumably
via traces of the enol form 3E. Competitive exchange of the
corresponding protons of 3 and indoxyl 2 was studied semi-
quantitatively in [2H4]methanol solution, by the method de-
scribed in the Supporting Information. In this way, any self-
catalysis of the exchange process would be experienced equally
by both compounds. In the event, both compounds reacted at a
similar rate with t1/2 ca. 3 h. Because the amount of enol
tautomer in 3 is significantly less than in 2, it follows that either
the rate of tautomerization or the rate of deuterium exchange
of the thiophene species 3 is likely to be faster than that of
indoxyl 2 itself.
TABLE 1. Change in 13C Chemical Shifts between Neutral and
Protonated Forms of 4,5-Dihydrothieno[3,2-b]pyrrol-6-one 3 and
Pyrrolones 9 and 1012
Azo-coupling reactions take place at C(5) to provide hydra-
zones (e.g., 19K) (25%). In the 1H-pyrrol-3(2H)-one series, in
which analogous azo-coupling products have been shown by
X-ray crystallography to adopt the hydrazone tautomer, the 13
C
NMR chemical shift of the CdO function is in the range δC
912
1012
178-18015 and similar values are found for corresponding
position
3
C(R′)
C(ꢀ)
C(ꢀ′)
+7.3
-12.7
-0.5
+7.5
-11.9
+1.7
+10.6
-10.2
-1.5
(9) (a) Paulmier, C. C.R. Acad. Sci. Ser. IIc: Chim. 1975, 319–321. (b)
Gronowitz, S.; Westerlund, C.; Hornfeldt, A. B. Chem. Scripta 1976, 10, 165–
72.
(10) Capon, B.; Kwok, F. J. Am. Chem. Soc. 1989, 111, 5346–5356.
(11) Blake, A. J.; McNab, H.; Monahan, L. C. J. Chem. Soc., Perkin Trans.
2 1988, 1455–1458.
10) species. The labeling schemes shown are used for ease of
comparison. The pattern of shielding and deshielding observed
on protonation of 3 [significant deshielding at C(R′), significant
shielding at C(ꢀ) and little change at C(ꢀ′)] mirrors the situation
in both pyrrolone models 9 and 10, which suggests that the
O-protonated species 11 contributes significantly to the equil-
brium.12
(12) Blake, A. J.; McNab, H.; Monahan, L. C. J. Chem. Soc., Perkin Trans.
2 1988, 1463–1468.
´
(13) Etienne, A. Bull. Soc. Chim. Fr. 1948, 651–658.
(14) Derbyshire, P. A.; Hunter, G. A.; McNab, H.; Monahan, L. C. J. Chem.
Soc., Perkin Trans. 1 1993, 2017–2025.
(15) Blake, A. J.; McNab, H.; Monahan, L. C. J. Chem. Soc., Perkin Trans.
2 1991, 701–704.
4280 J. Org. Chem. Vol. 74, No. 11, 2009

4,5-Dihydrothieno[3,2-b]pyrrol-6-onesA Heteroindoxyl
derivatives of indoxyl 2.8 The corresponding signal for 19 occurs
at δC 171.40; the observed shielding of 8-10 ppm relative to
its structural analogues may suggest that, although the hydrazone
19K predominates, the azo-tautomer 19E may contribute to the
equilibrium.
The methylene group of 3 can participate in aldol reactions;
condensation takes place spontaneously in [2H6]acetone in the
absence of any added catalysts to give the alkene 20. In the
presence of Hu¨nig’s base, condensation of 3 with isatin 21
provides an indirubin analogue (20%) as a single isomer, thought
to be the Z-isomer 22 by analogy with the indirubin structure
23. Compound 22 shows λmax 521 nm (ε 7200 L mol-1 cm-1),
(methanol), displaying a hypsochromic shift of 19 nm compared
with the spectrum of indirubin 23 itself.16
The effect of substituents on the colors of indigoids has been
the subject of much theoretical analysis,20 with hypsochromic
shifts observed for electron-donating substituents located at the
6(6′)-positions. Bathochromic shifts are observed for corre-
sponding substituents at the 5(5′)-positions. With respect to
electronic absorption spectra, it therefore follows that the
electron-rich fused thiophene rings in 4 are behaving as 6(6′)-
indigotin substituents.
In conclusion, we have synthesized the first heteroindoxyl 3,
by a pyrolytic strategy in which the final step is a nitrene
insertion. The heteroindoxyl 3 reacts readily with a number of
electrophilic reagents, but in some cases these reactions show
different regiochemistry from that of analogues such as indoxyl
and 3-hydroxypyrroles. The indigotin analogue 4 can be made
from 3 under radical-coupling conditions. The thermal behavior
of azidoacetyl compounds, providing fused isoxazoles at low
temperatures and indoxyl analogues at high temperatures, has
some generality, and further examples will be reported in future
publications.
Experimental Section
Flash Vacuum Pyrolysis (FVP) Experiments. The precursor
was volatilized under rotary pump vacuum (pumping speed 100
dm3 min-1) through an empty, electrically heated silica tube (35 ×
2.5 cm) and the products were collected in a U-tube, cooled with
liquid nitrogen, situated at the exit point of the furnace. For the
azide precursor described below, a metal sublimation oven was used
and the scale was limited to a maximum of a few hundred mg. We
experienced no problems with pyrolyses of the azide reported here
but clearly every precaution must be taken in handing such
potentially explosive materials. The pressure was measured by a
Pirani gauge situated between the product trap and the pump. Upon
completion of the pyrolysis, the trap was allowed to warm to room
temperature under a nitrogen atmosphere. The entire pyrolysate was
dissolved in solvent and removed from the trap. The precursor,
pyrolysis conditions [quantity of precursor, furnace temperature (Tf),
inlet temperature (Ti), initial pressure (Pi) and pyrolysis time (t)]
and products are quoted.
FVP of 2-Acetyl-3-azidothiophene 6. CAUTION Azides are
potentially explosivessee precautions outlined in the previous
paragraph. FVP of 2-acetyl-3-azidothiophene 6 (135 mg, 0.81
mmol; Tf 350 °C; Ti 55 °C; Pi 2.8 × 10-2 Torr; t 7 min) gave a
product which was dissolved in dichloromethane and purified by
dry flash chromatography on silica (eluted with 25% hexane in ethyl
acetate) to yield 3-methylthieno[3,2-c]isoxazole 7 (57 mg, 51%);
mp 50-52 °C (lit.,7 56-57 °C); δH (360 MHz) 2.61 (3H, s, CH3),
6.92 [1H, d, J6,5 5.1, H(6)], 7.49 [1H, d, J5,6 5.1, H(5)]; δC (90
MHz) 12.1 (CH3), 111.6 [C(6)], 115.7 [quat, C(3a)], 140.6 [C(5)],
160.1 [quat, C(3)] and 170.3 [quat, C(6a)]; m/z 139 (M+, 100%),
126 (62), 111 (50), 110 (28), 97 (17) and 70 (40).
FVP of 2-acetyl-3-azidothiophene 6 (115 mg, 0.68 mmol; Tf 550
°C; Ti 55 °C; Pi 3.8 × 10-2 Torr; t 9 min) yielded 4,5-
dihydrothieno[3,2-b]pyrrol-6-one 3K (58 mg, 61%); mp 120-123
°C; (Found: M+ 139.0092. C6H5NOS requires M 139.0092); δH
(360 MHz) 4.22 (2H, s, CH2), 4.89 (1H, br s, NH), 6.68 [1H, d,
J3,2 5.1, H(3)] and 7.85 [1H, d, J2,3 5.1, H(2)]; δC (90 MHz) 61.0
[CH2, C(5)], 113.7 [C(3)], 116.3 [quat, C(6a)], 143.9 [C(2)], 175.0
[quat, C(3a)] and 190.2 [quat, C(6)]; m/z 139 (M+, 100%), 111
(68), 110 (79), 84 (61), 70 (31) and 67 (48). In [2H6]DMSO solution
the enol form 3E made up ca. 20% of the tautomeric mixture δH(3E,
[2H6]DMSO) 6.51 (1H, s), 6.92 (1H, d), 7.13 (1H, d), 8.49 (1H, s)
and 10.30 (1H, br, s) and δH(3K, [2H6]DMSO) 4.20 (2H, s), 6.86
(1H, d), 7.38 (1H, br. s) and 8.25 (1H, d).
4,5-Dihydrothieno[3,2-b]pyrrol-6-one 3 undergoes a Michael
reaction with DMAD, to give dimethyl 2-[6-oxo-4,6-dihy-
drothieno[3,2-b]pyrrol-(5Z)-ylidene]-succinate 24 (30%) as a
single isomer. Reactions of 1-substituted pyrrol-3(2H)ones with
DMAD can also take place at the corresponding (2-)position,
though the tautomeric nature of the product is different.17 The
structure of 24 was confirmed by X-ray crystallography (Sup-
porting Information) which defines the Z-nature of the geometry
around the alkene function, presumably assisted by hydrogen-
bonding from the N-H to the carbonyl of the ester function
O(9) [e.g., O9A · · ·H8, 2.14 Å; O9A · · ·N8, 2.691(3) Å]. This
structure also shows the geometry of a heteroindoxyl unit for
the first time; it is planar about the core fused ring system (e.g.,
mean deviation from planarity 0.0211 Å; maximum deviation
0.035 Å at C5) and the bond angles between the two fused
5-membered rings [135.3(3)° and 139.3(2)°] are characteristi-
cally .120°.
Finally, oxidative dimerization of 3 using potassium ferri-
cyanide in a pH 7 phosphate buffer18 gave the heteroindigotin
4 (53%), assumed to be the E-isomer shown. Due to its very
low solubility, this compound could be characterized only by
mass spectrometry and UV spectroscopy. It had λmax 577 nm
(DMSO) and 570 nm (DMF) showing a hypsochromic shift of
44 nm relative to indigotin 1 itself [λmax 621 nm (DMSO)19].
(16) Guengerich, F. P.; Sorrells, J. L.; Schmitt, S.; Krauser, J. A.; Aryal, P.;
Meijer, L. J. Med. Chem. 2004, 47, 3236–3241.
(17) Hunter, G. A. PhD thesis, The University of Edinburgh, 1990.
(18) Pfeiffer, G.; Bauer, H. Liebigs Ann. Chem. 1980, 564–589.
(19) Gompper, R.; Hartmann, K.; Kellner, R.; Polborn, K. Angew. Chem.,
Int. Ed. Engl. 1995, 34, 464–467.
(20) Reference 1a, pp 211-219.
J. Org. Chem. Vol. 74, No. 11, 2009 4281

Gaywood and McNab
4-Acetyl-4,5-dihydrothieno[3,2-b]pyrrol-6-one 12. Acetic an-
hydride (2 cm3) was added to 4,5-dihydrothieno[3,2-b]pyrrol-6-
one 3 (35 mg, 0.25 mmol) and the mixture was gently heated using
a hot air blower for 5 min. The solvent was removed under reduced
pressure to yield 4-acetyl-4,5-dihydrothieno[3,2-b]pyrrol-6-one 12
(44 mg, 98%); mp 126-128 °C; (Found: M+ 181.0196, C8H7NO2S
requires M 181.0198); δH 2.25 (3H, s, CH3), 4.56 (2H, s, CH2),
7.69 (1H, d, J 5.0, thiophene-H) and 7.94 (1H, d, J 5.0, thiophene-
H); δC 22.3 (CH3), 61.1 (CH2), 118.2, 123.0 (quat), 143.1, 164.9
(quat), 165.3 (quat) and 184.5 (quat); m/z 181 (M+, 41%), 135 (100),
138 (39), 111 (70), 110 (52) and 69 (21).
4-Nitroso-4,5-dihydrothieno[3,2-b]pyrrol-6-one 14. A solution
of sodium nitrite (135 mg, 1.73 mmol) in water (0.6 cm3) was added
to a solution of 4,5-dihydrothieno[3,2-b]pyrrol-6-one 3 (143 mg,
1.04 mmol) in water (40 cm3) containing acetic acid (0.2 cm3).
The mixture was stirred at room temperature for 1 h. The resulting
precipitate was collected, added to dichloromethane (5 cm3) and
filtered. The filtrate was concentrated to provide 4-nitroso-4,5-
dihydrothieno[3,2-b]pyrrol-6-one 14 (74 mg, 43%). Another crop
of almost pure product (23 mg) was obtained by extraction of the
initial aqueous filtrate with dichloromethane (3 × 75 cm3 portions).
These combined organic extracts were dried (MgSO4) and the
solvent was removed under reduced pressure (overall yield 56%);
mp 135-138 °C; (Found: M+ 167.9991, C6H4N2O2S requires M
167.9994); δH 4.79 (2H, s, CH2), 7.83 (1H, d, J 5.1, thiophene-H)
and 8.58 (1H, d, J 5.1, thiophene-H); δC 58.4 (CH2), 113.7, 123.9
(quat), 145.5, 161.2 (quat) and 182.0 (quat); m/z 168 (M+, 8%),
139 (34), 138 (100), 111 (12), 110 (41) and 83 (14).
2,2-Dimethyl-5-(6-oxo-5,6-dihydrothieno[3,2-b]pyrrol-4-ylm-
ethylene)-1,3-dioxane-4,6-dione 17. 5-Methoxymethylene Mel-
drum’s acid 16 (144 mg, 0.81 mmol) was added to a suspension of
4,5-dihydrothieno[3,2-b]pyrrol-6-one 3 (120 mg, 0.86 mmol) in
acetonitrile (7 cm3) and the mixture was stirred at room temperature
for 24 h. The solution was then filtered through Celite, the solvent
concentrated to 0.5 cm3 under vacuum and the precipitate was
collected to yield 2,2-dimethyl-5-(6-oxo-5,6-dihydrothieno[3,2-
b]pyrrol-4-ylmethylene)-1,3-dioxane-4,6-dione 17 (87 mg, 37%);
mp 204-206 °C (from acetone); (Found: C; 52.9; H 4.0; N 4.85.
C13H11NO5S requires C 53.25; H 3.75; N 4.75); δH 1.77 (6H, s, 2
× CH3), 5.10 (2H, s, CH2), 7.28 [1H, d, J3,2 5.2, H(3)], 8.09 [1H,
d, J2,3 5.2, H(2)] and 8.47 (1H, s, alkene); δC 26.9 (2 × CH3), 65.6
(CH2), 90.2 (quat), 104.0 (quat), 112.8, 124.8 (quat), 143.9, 147.5,
159.5 (quat), 164.5 (quat), 165.8 (quat) and 183.7 (quat); m/z 293
(M+, 17%), 235 (100), 191 (25), 167 (68) and 135 (47).
5-[(4-Methoxyphenyl)hydrazono]-4,5-dihydrothieno[3,2-b]pyr-
rol-6-one 19. A saturated solution of sodium nitrite (125 mg, 1.58
mmol) in water was added dropwise to a solution of p-anisidine (123
mg, 1 mmol) in conc. hydrochloric acid (5 cm3) at 0 °C. The mixture
was stirred for 15 min. A solution of 4,5-dihydrothieno[3,2-b]pyrrol-
6-one 3 (139 mg, 1 mmol) in methanol (20 cm3) was added dropwise,
and the solution was stirred for a further 30 min. The resulting
precipitate was collected and washed with water to yield 5-[(4-
methoxyphenyl)-hydrazono]-4,5-dihydrothieno[3,2-b]pyrrol-6-one 19
(69 mg, 25%); mp 173-175 °C; (Found: M+ 273.0572, C13H11N3O2S
requires M 273.0572); δH ([2H6]DMSO) 3.73 (3H, s, MeO), 6.92 (2H,
d, J 8.9, 2 × Ar-H), 7.00 (1H, d, J 5.0, thiophene-H), 7.19 (2H, d, J
8.9, 2 × Ar-H), 8.16 (1H, d, J 5.0, thiophene-H) and 10.49 (1H, br
s); δC ([2H6]DMSO) 55.1 (CH3), 113.8, 114.2 (2 × CH), 114.5 (2 ×
CH), 137.1 (quat), 137.6 (quat), 141.5, 154.0 (quat), 160.3 (quat) and
171.7 (quat) (one quat overlapping); m/z 273 (M+, 66%), 123 (57),
122 (87), 108 (78), 91 (100) and 84 (60).
mass spectrum showed a dominant ion at m/z 185, corresponding
to 5-([2H6]isopropylidene)-4,5-dihydrothieno[3,2-b]pyrrol-6-one 20.
3-[6-Oxo-4,6-dihydrothieno[3,2-b]pyrrol-(5Z)-ylidene]-1,3-di-
hydro-indol-2-one 22. Solid 4,5-dihydrothieno[3,2-b]pyrrol-6-one 3
(83 mg, 0.60 mmol) followed by N,N-disopropylethylamine (ca. 0.1
cm3) was added to a solution of isatin 21 (87 mg, 0.59 mmol) in
methanol and the solution was stirred at room temperature for 5 h.
The solution was concentrated to 5 cm3 under vacuum, and the resulting
precipitate was collected and washed with methanol to provide 3-[6-
oxo-4,6-dihydrothieno[3,2-b]pyrrol-(5Z)-ylidene]-1,3-dihydro-indol-2-
one 22 (32 mg, 20%); mp >330 °C; (Found: M+ 268.0305,
C14H8N2O2S requires 268.0306); λmax (Methanol) 521 nm (ε 7200
mol-1 cm-1); δH ([2H6]-DMSO) 6.92 (1H, m, Ar-H), 7.00-7.06 (2H,
m, 1 × Ar-H and 1 × thiophene-H), 7.29 (1H, m, Ar-H), 8.28 (1H,
d, J 7.2), 8.84 (1H, m, Ar-H), 10.89 (1H, s, NH) and 10.93 (1H, s,
NH); δC ([2H6]DMSO) 110.0, 110.3 (quat), 113.0 (quat), 115.6, 121.3
(quat), 121.8, 126.0, 130.3, 141.8 (quat), 144.0 (quat), 144.9, 166.5
(quat), 171.0 (quat) and 179.0 (quat); m/z 268 (M+, 100%), 240 (50),
191 (46), 147 (32), 119 (39) and 92 (36).
Dimethyl 2-[6-Oxo-4,6-dihydrothieno[3,2-b]pyrrol-(5Z)-ylide-
ne]succinate 24. A solution of DMAD (60 mg, 0.42 mmol) in DMSO
(0.5 cm3) was added to a solution of 4,5-dihydrothieno[3,2-b]pyrrol-
6-one 3 (66 mg, 0.42 mmol) in DMSO (1.5 cm3) and the mixture was
stirred at room temperature for 1 h. Water (3 cm3) was added and the
mixture was stored overnight at -20 °C. The resulting precipitate was
collected and washed with water to yield dimethyl 2-[6-oxo-4,6-
dihydrothieno[3,2-b]pyrrol-(5Z)-ylidene]succinate 24 (35 mg, 30%);
mp 194-196 °C; (Found: M+ 281.0361, C12H11NO5S requires M
281.0358); δH 3.71 (3H, s, CO2Me), 3.82 (3H, s, CO2Me), 4.11 (2H,
s, CH2), 6.67 [1H, d, J3,2 5.0, H(3)], 7.83 [1H, d, J2,3 5.0, H(2)] and
9.33 (1H, br s, NH); δC 29.4 (CH2), 51.9 (CH3), 52.3 (CH3), 107.3
(quat), 112.6, 114.7 (quat), 143.4, 146.8 (quat), 164.4 (quat), 168.8
(quat), 171.6 (quat) and 178.3 (quat); m/z 281 (M+, 22%), 249 (30),
217 (20), 136 (18), 101 (39) and 78 (100).
4H,4′H-[5,5′]Bi[thieno[3,2-b]pyrrolylidene]-6,6′-dione 4. 4,5-
Dihydrothieno[3,2-b]pyrrol-6-one 3 (40 mg, 0.3 mmol) was dis-
solved in a mixture of phosphate buffer (pH 7, 11 cm3) and
methanol (2 cm3), and heated to 50 °C, under a nitrogen atmosphere.
A solution of potassium ferricyanide (292 mg, 0.96 mmol) in water
(2 cm3) was added dropwise over 10 min, and the mixture was
stirred for a further 30 min, keeping the temperature at 50 °C. The
mixture was allowed to cool, stored overnight at -20 °C, and the
resulting precipitate was collected and washed with water to
give 4H,4′H-[5,5′]bi[thieno[3,2-b]pyrrolylidene]-6,6′-dione 4 as a
purple solid (21 mg, 53%); (Found: M+ 273.9871, C12H6N2O2S2
requires M 273.9871); λmax (DMSO) 577 nm; m/z 274 (M+, 17%),
191 (51), 139 (60), 126 (54), 112 (55), 110 (57), 69 (36) and 54
(100). No NMR or extinction coefficient data could be obtained
due to the extreme insolubility of the compound.
Acknowledgment. We are most grateful to the EPSRC (UK)
and The University of Edinburgh for a Research Studentship (for
A.P.G.), to Ms Kirsty Stefaniuk for preliminary experiments and to
Dr. S. A. Moggach and Professor S. Parsons for the X-ray crystal
structure.
Supporting Information Available: Full experimental details
for synthesis and FVP of 6, solvent dependence of keto:enol
tautomer ratio for 3, 2 and 9, conditions for attempted FVP of 17,
competitive deuterium exchange of methylene signals of 2 and 3,
1
effect of O-protonation on NMR spectra of 3, H and 13C NMR
5-[2H6]Isopropylidene-4,5-dihydrothieno[3,2-b]pyrrol-6-one 20.
A solution of 4,5-dihydrothieno[3,2-b]pyrrol-6-one 3 in [2H6]acetone
was allowed to stand at room temperature for 24 h. New peaks
were observed at δH ([2H6]acetone) 6.76 (1H, d, J 5.3) and 7.90
(1H, d, J 5.3). Removal of solvent provided a compound whose
spectra of 3, 7, 12, 14, 17, 19, 22 and 24, ORTEP plot and selected
bond lengths [Å] and angles [deg] for 24. This material is available
free of charge via the Internet at http://pubs.acs.org.
JO900496U
4282 J. Org. Chem. Vol. 74, No. 11, 2009