A thermal cascade route to pyrroloisoindolone and pyrroloimidazolones

Article abstract of DOI:10.1021/jo0712502

(Chemical Equation Presented) Flash vacuum pyrolysis (FVP) of indol-1-ylacrylate derivatives 11 and 15 or the isomeric indol-3-ylacrylates 21, 22, and 24 at 925°C (0.05 Torr) provides pyrrolo[1,2-a]indol-3-ones 2, 18, 28, and 29 in 53-90% yield by a cascade mechanism that involves a sigmatropic migration, elimination, electrocyclization sequence. Pyrrolo[1,2-a]imidazol-5- ones 3 and pyrrolo[1,2-c]imidazol-5-ones 4 were similarly obtained by FVP of corresponding 2,5-unsubstituted imidazol-1-ylacrylates (e.g., 33), with the former isomer predominating in ca. 80:20 ratio. Migration to the 2-position is therefore favored in the initial sigmatropic shift. FVP of 2-substituted imidazol-1-ylacrylates 35, 37, and 51 (825-875°C) instead give pyrrolo[1,2-c]imidazol-5-ones 56-58 only (88-91%), and that of 4,5-disubstituted imidazol-1-ylacrylates 39 and 41 (825-850°C) provide pyrrolo[1,2-a] imidazol-5-ones 59 and 60 exclusively (93-95%), and thus the selectivity of the initial shift can be controlled by the presence of substituents on the imidazole 2- and 5-positions. FVP of the benzimidazole analogues 61 and 62 at 950°C gave the pyrrolo[1,2-a]benzimidazol-1-ones 6 (71%) and 63 (36%), respectively.

Full text of DOI:10.1021/jo0712502

A Thermal Cascade Route to Pyrroloisoindolone and
Pyrroloimidazolones
Hamish McNab* and Richard G. Tyas
School of Chemistry, The UniVersity of Edinburgh, West Mains Road, Edinburgh EH9 3JJ, U.K.
H.McNab@ed.ac.uk
ReceiVed June 27, 2007
Flash vacuum pyrolysis (FVP) of indol-1-ylacrylate derivatives 11 and 15 or the isomeric indol-3-
ylacrylates 21, 22, and 24 at 925 °C (0.05 Torr) provides pyrrolo[1,2-a]indol-3-ones 2, 18, 28, and 29 in
53-90% yield by a cascade mechanism that involves a sigmatropic migration, elimination, electrocy-
clization sequence. Pyrrolo[1,2-a]imidazol-5-ones 3 and pyrrolo[1,2-c]imidazol-5-ones 4 were similarly
obtained by FVP of corresponding 2,5-unsubstituted imidazol-1-ylacrylates (e.g., 33), with the former
isomer predominating in ca. 80:20 ratio. Migration to the 2-position is therefore favored in the initial
sigmatropic shift. FVP of 2-substituted imidazol-1-ylacrylates 35, 37, and 51 (825-875 °C) instead give
pyrrolo[1,2-c]imidazol-5-ones 56-58 only (88-91%), and that of 4,5-disubstituted imidazol-1-ylacrylates
39 and 41 (825-850 °C) provide pyrrolo[1,2-a]imidazol-5-ones 59 and 60 exclusively (93-95%), and
thus the selectivity of the initial shift can be controlled by the presence of substituents on the imidazole
2- and 5-positions. FVP of the benzimidazole analogues 61 and 62 at 950 °C gave the pyrrolo[1,2-a]-
benzimidazol-1-ones 6 (71%) and 63 (36%), respectively.
Introduction
ring systems can be conveniently made in the gas phase by flash
vacuum pyrolysis (FVP) of Meldrum’s acid derivatives6,7 (“the
Meldrum’s route”) and by FVP of pyrrol-2-ylacrylate derivatives
(“the C-acrylate route”).7 The Meldrum’s route has been
extended to give pyrrolo[1,2-a]indol-3-one8 2 (a benzopyrroliz-
inone), and both methods can be used to make pyrrolo[1,2-a]-
imidazol-5-one and pyrrolo[1,2-c]imidazol-5-one (azapyrroliz-
inone) systems9,10 (3 and 4, respectively). However, both these
routes can suffer from practical disadvantages. Certain substitu-
tion patterns are not available by the Meldrum’s route,6,7 or
require inconvenient precursor syntheses, or may be prone to
low yields as a consequence of poor precursor volatility. The
C-acrylate route7 is usually better in this latter regard but suffers
from the availability of specifically substituted starting materials.
The pyrrolizin-3-one ring system 11 and its analogues are of
interest because of their formally antiaromatic2 nature and
because of the biological activity of their derivatives. Thus,
reduced pyrrolizines (pyrrolizidines) form the carbon skeleton
of the necine bases of pyrrolizidine alkaloids,3 and the skeleton
of pyrrolo[1,2-a]indol-3-one 2 (a benzopyrrolizinone) is related
to that of the mitomycin series of antibiotics.4 Azapyrrolizinone
systems 3 and 4 are highly reactive cyclic N-acylimidazoles,
and the pyrrolo[1,2-c]imidazol-5-one system 4 is essentially a
dehydrated form of Z-urocanic acid which is implicated in
immunosuppressive activity in the skin.5
Conventional synthetic routes to these ring systems are scarce.
However, we have shown that pyrrolizin-3-ones 1 and related
(6) McNab, H. J. Org. Chem. 1981, 46, 2809.
(7) Campbell, S. E.; Comer, M. C.; Derbyshire, P. A.; Despinoy, X. L.
M.; McNab, H.; Morrison, R.; Sommerville, C. C.; Thornley, C. J. Chem.
Soc., Perkin Trans. 1 1997, 2195-2202.
(8) Benzies, D. W. M.; Fresneda, P. M.; Jones, R. A.; McNab, H. J.
Chem. Soc., Perkin Trans. 1 1986, 1651-1654.
(9) McNab, H. J. Chem. Soc., Perkin Trans. 1 1987, 653-656 and
references therein.
(1) McNab, H.; Thornley, C. Heterocycles 1994, 37, 1977-2008.
(2) Blockhuys, F.; Hinchley, S. L.; Robertson, H. E.; Blake, A. J.; McNab,
H.; Despinoy, X. L. M.; Harris, S. G.; Rankin, D. W. H. J. Chem. Soc.,
Perkin Trans. 2 2001, 2195-2201.
(3) For example: Mattocks, A. R. Chemistry and Toxicology of Pyr-
rolizidine Alkaloids; Academic Press: London, 1986.
(4) For example: Galm, U.; Hager, M. H.; Van Lanen, S. G.; Ju, J.;
Thorson, J. S.; Shen, B. Chem. ReV. 2005, 105, 739-758.
(5) For example: Simon, J. D. Acc. Chem. Res. 2000, 33, 307-313.
(10) McNab, H.; Thornley, C. J. Chem. Soc., Perkin Trans. 1 1997,
2203-2209.
10.1021/jo0712502 CCC: $37.00 © 2007 American Chemical Society
Published on Web 10/19/2007
8760
J. Org. Chem. 2007, 72, 8760-8769

Route to Pyrroloisoindolone and Pyrroloimidazolones
SCHEME 1
In work reported here, we have therefore extended our
sigmatropic shift-elimination-cyclization cascade (Scheme 1),
developed primarily11 for the isomeric benzopyrrolizinone 5,
to syntheses of the benzopyrrolizinone 2 and azapyrrolizinone
(3 and 4) systems. The key steps in the cascade are (i) a 1,5-
sigmatropic shift of the N-substituent in the azole system, well
recognized for alkyl and aryl groups12-14 but also known for
vinyl groups14 to provide the intermediate 7, (ii) elimination of
methanol to generate ketene11 8, and (iii) electrocyclization of
the ketene in a pseudopericyclic process.15 Steps (ii) and (iii)
are common to the C-acrylate route.7 The results of this study
have provided optimum synthetic routes to the benzopyrroliz-
inone 2 (in two steps from simple indoles), given regiocontrolled
routes to substituted azapyrrolizinones 3 and 4, and provided a
new route to the pyrrolo[1,2-a]benzimidazol-1-one (benzaza-
pyrrolizinone) system 6.
SCHEME 2 a
a Reagents: (a) TBAF, THF.
SCHEME 3
Results and Discussion
To explore the thermal cascade mechanism in the indole
series, we used the key precursor, indol-1-ylacrylate 11.
Compounds of this type are known,16 and the palladium-
catalyzed conjugate addition of indole 9 to methyl propynoate
10 in triethylamine was carried out using the reported method
to give 11 in 25-31% yield (see Supporting information).
Although this provided enough material to establish the viability
of the pyrolysis step (see below), it has proved to be too
inefficient for routine use. However, other heavily substituted
indol-1-ylacrylates have been made by reaction of the indole
with propynoic esters in THF at room temperature, in the
presence of 1 equiv of tetrabutylammonium fluoride (TBAF).17
This method proved to be general for our purposes and was
used to synthesize 11 and the 3-substituted precursors 13 and
15, in >80% yield (Scheme 2). Some limitations of the
procedure were identified. Thus, reduced yields were obtained
if less than 1 equiv of TBAF was employed. Reaction of the
alcohol 16 with methyl propynoate 10 gave a number of
products that were not identified. Finally, indole 9 did not react
with methyl phenylpropynoate in the presence of TBAF even
after extended reaction times at reflux temperatures, and thus
the method is best for the formation of indol-1-ylpropenoates
that are unsubstituted in the 2- and 3-positions of the acrylate
chain.
The parent compound 11 was obtained as a mixture of E-
and Z-isomers, whereas the 3-substituted compounds 13 and
15 were exclusively E-isomers. No attempt was made to separate
the isomers, which in any case would be subject to E/Z
equilibration under the pyrolysis conditions.18
FVP of the indol-1-ylacrylate 11 required a furnace temper-
ature of 925 °C for complete consumption of starting material,
and pyrrolo[1,2-a]indol-3-one 2, a yellow solid, was the sole
product in 78% yield after purification (Scheme 3). The furnace
temperature required for this transformation is significantly
higher than those required for the Meldrum’s route (typically
600-650 °C in our apparatus) or the C-acrylate route (typically
700 °C for Z-acrylate isomers and 800-850 °C for E-acrylate
isomers). This suggests that the rate-determining step of the
cascade route is the initial sigmatropic shift to 17 (R ) H).
However, the yield and purity of the product are not compro-
mised by the high temperatures involved; this procedure gives
the benzopyrrolizinone 2 in two steps from indole, in 75%
(nonoptimized) overall yield. By comparison, the original
synthesis of 2 required a potentially capricious photooxygenation
step19 and our previous FVP route8 required the time-consuming
preparation of indole-2-carbaldehyde.
(11) McNab, H.; Parsons, S.; Stevenson, E. J. Chem. Soc., Perkin Trans.
1 1999, 2047-2048.
(12) Patterson, J. M. Synthesis 1976, 281-304.
(13) Gilchrist, T. L.; Rees, C. W.; Thomas, C. J. Chem. Soc., Perkin
Trans. 1 1975, 8-11.
The yield of the 1-methyl compound 18 was low (53%),
owing to the coformation of carbazol-3-ol 19 (47%), which was
not obtained by the Meldrum’s route8 (furnace temperature
600 °C) (Scheme 4). Repyrolysis of the benzopyrrolizinone 18
(14) Begg, C. G.; Grimmett, M. R.; Wethey, P. D. Aust. J. Chem. 1973,
26, 2435-2446.
(15) For example: Zhou, C.; Birney, D. M. J. Org. Chem. 2004, 69,
86-94.
(16) Reisch, J.; Dittmann, S. J. Heterocycl. Chem. 1993, 30, 379-380.
(17) Cross, P. E.; Dickenson, R. P.; Parry, M. J.; Randall, M. J. J. Med.
Chem. 1986, 29, 342-346.
(18) Hickson, C. L.; McNab, H. J. Chem. Res., Synop. 1989, 176-
177.
(19) Franck, R. W.; Auerbach, J. J. Org. Chem. 1971, 36, 31-36.
J. Org. Chem, Vol. 72, No. 23, 2007 8761

McNab and Tyas
SCHEME 4
SCHEME 5
at 925 °C also provided a 1:1 mixture of 18 and 19. These results
suggest that the benzopyrrolizinone 18 is the kinetic product
that can revert to the ketene 20 at high temperatures; the route
to the thermodynamic product 19 is then initiated by 1,5-
hydrogen shift from the methyl group (Scheme 4). This
mechanism is consistent with the known electrocyclization of
dienylketenes to phenol derivatives, first discovered by Brown
and McMullen.20
by a NOESY experiment. The known 2-methyl compound 25
was made26 to study whether multiple sigmatropic shifts leading
to cyclized products are possible in this series (cf. refs 11 and
12).
FVP of the aldehyde precursor 13 at 925 °C led only to the
parent pyrrolo[1,2-a]indol-3-one 2 (94%), and thus efficient
thermal deformylation21 takes place at such high tempera-
tures.
The feasibility of the route was established by the successful
formation of 2 (70%) by FVP of the indol-3-ylacrylate 21 at
925 °C. The mechanism therefore involves an initial sequence
of 1,5-hydrogen shifts to provide the intermediate 26 (R1 ) R2
) H) which can then undergo a (slower) 1,5-acrylate shift to
27, thus setting up the required connectivity (Scheme 5);
elimination and cyclization then follow (cf. Scheme 3). In
practice, this route proved more difficult to scale up than the
indol-1-ylacrylate method, because of the higher inlet temper-
atures required, and thus the latter precursor is preferred as a
synthetic route to pyrrolo[1,2-a]indol-3-one 2.
Because the sigmatropic migration of groups is likely to be
reversible between the 2- and 3-positions of indole,13 some
readily available indole-3-ylacrylate derivatives were also
synthesized as potential pyrrolo[1,2-a]indol-3-one precursors.
Compound 21 was made from indole-3-carbaldehyde by stan-
dard Wittig method (cf. ref 22), and Knoevenagel reaction
provided compounds 22 and 23.23,24 The phenylacrylate 24 was
made in 89% yield by application of a Pd(II)-catalyzed addition
process, originally developed for the pyrrole series,25 and here
applied to indole chemistry for the first time. The product 24
was obtained as a 90:10 mixture of E- and Z-isomers,
respectively; the regiochemistry of the reaction was established
The indol-3-ylacrylate route nevertheless provided a satisfac-
tory method for the synthesis of the 2-cyano compound 28 (65%
after chromatography), by FVP of 22 at 925 °C, but these
conditions proved too severe for the malonate 23 and only
decomposition products were obtained. The 1-phenyl compound
29 was also obtained in reasonable yield (57%) by FVP of 24,
but a second, isomeric product (6%) was isolated by chroma-
tography. This material was unstable in solution, and thus its
(20) Brown, R. F. C.; McMullen, G. L. Aust. J. Chem. 1974, 27, 2385-
2391.
(21) Schubert, W. M.; Kintner, R. R. The Chemistry of the Carbonyl
Group; Patai, S., Ed.; Wiley-Interscience: New York, 1966; p 695.
(22) Kusurkar, R. S.; Patil, U. G. Indian J. Chem., Sect. B 1986, 25,
1038-1041.
(23) Matsuoka, M.; Takao, M.; Kitao, T.; Fujiwara, T.; Nakatsu, K. Mol.
Cryst. Liq. Cryst. 1990, 182A, 71-79.
1
precise constitution could not be established. H NMR spec-
(24) Berestovitskaya, V. M.; Vasil’eva, O. S.; Aleksandrova, S. M.;
Kobzareva, V. N.; Usik, N. V.; Novikov, B. M. Russ. J. Gen. Chem. (Zh.
Obshch. Khim.) 2000, 70, 1154-1155.
troscopy showed that it had an NH and that the indole 2- and
(25) Oyamada, J.; Lu, W.; Jia, C.; Kitumara, T.; Fujiwara, Y. Chem.
Lett. 2002, 20-21.
(26) Inhoffen, H. H.; Nordsiek, K.-H.; Scha¨fer, H. Liebigs Ann. Chem.
1963, 668, 104-121.
8762 J. Org. Chem., Vol. 72, No. 23, 2007

Route to Pyrroloisoindolone and Pyrroloimidazolones
SCHEME 6 a
3-positions were both substituted. 13C NMR spectroscopy
showed the presence of a ketone carbonyl signal and that the
phenyl group was still intact, which suggests that a ketene is
able to cyclize onto carbon, in competition with the pseudo-
pericyclic formation of 29. The most likely structure is 3-phenyl-
4H-cyclopenta[b]indol-1-one 30, but the isomeric 1-phenyl-4H-
cyclopenta[b]indol-3-one 31 cannot be ruled out, in which the
sigmatropic shift step has been circumvented by prior cycliza-
tion. The influence of the phenyl substituent on this very minor
mode of cyclization is unclear at this stage.
FVP of the disubstituted indole 25 at 925 °C gave only very
small amounts of 9-methylpyrrolo[1,2-a]indol-3-one 18, which
could be identified by NMR spectroscopy of the crude pyroly-
sate.8 The thermal interchange of the 2- and 3-substituents of
25 has been shown to be feasible but not synthetically useful
in this case (cf. refs 27 and 28).
a Reagents: (a) Toluene, reflux. (b) Et3N, toluene, reflux.
Application of the cascade strategy in the imidazole series
introduces complications compared with the indole series. First,
the N-substituents must undergo highly selective sigmatropic
shifts for the method to be synthetically useful, and this is
exacerbated by the properties of azapyrrolizinone systems,
which are often unstable to crystallization and to chromatog-
raphy. The main questions therefore concern the regiochemistry
of the migration and whether any regioselectivity can be
controlled by substituents on the imidazole periphery. Literature
precedent is encouraging: Grimmett and co-workers have shown
that flow pyrolysis of 1-phenylimidazole provides 2- and
4-phenylimidazoles in 94:6 ratio,14 and, in preliminary work,
we observed some selectivity in migrations of substituted
acrylate and of aryl moieties en route to azapyrrolizinone
analogues.11
Imidazol-1-ylacrylates, unsubstituted in the propenoate
chain,29,30 were made by treatment of the appropriate imidazole
with methyl propynoate in refluxing toluene solution (Scheme
6) (cf. ref 30). Reactions of the diphenyl and dicyano compounds
40 and 42, respectively, were carried out in chloroform solution
for solubility reasons and required catalysis by triethylamine.
The yield in the latter case was vanishingly low with insufficient
material obtained for pyrolysis.
N-Alkenylimidazoles with substituents in the alkenyl chain
49-51 were made by treatment of an excess of the imidazole
with the dibromo compounds 47 or 48 in the presence of
triethylamine, as previously reported.29,30 Mixtures of E- and
Z-isomers were again obtained; these were not unambiguously
characterized, but as a general rule the R-methine signal of the
propenoate side chain (at δH 5.7-6.5) was found to resonate at
higher frequency for the E-isomer than that of the Z-isomer.
FVP of the parent compound 33, fortuitously available as
both E- and Z-isomers (Experimental Section), was chosen for
preliminary studies. Separate FVP of E-33 and Z-33 at 900 °C
(ca. 0.05 Torr) gave a crude pyrolysate that consisted of a 73:
27 mixture of the known9,10 pyrrolo[1,2-a]imidazol-5-one 3 as
the major product and pyrrolo[1,2-c]imidazol-5-one 4 as the
minor product, in ca. 80% overall yield. As expected, the
configuration of the acrylate isomer had no effect on the
cyclization, at the high temperatures involved. FVP of isomer
mixtures of 49 and 50 similarly gave 7-substituted isomers 52-
55 in excellent overall yield, with the pyrrolo[1,2-a]imidazol-
5-ones 52 and 53 again the major products (80:20 ratio in both
cases). Because of the poor stability of many azapyrrolizinones
in solution, the NMR spectra were recorded immediately after
the pyrolyses and analyses of the mixtures were made by
analogy with the well-characterized NMR spectra of the parent
azapyrrolizinones.31 The thermal sigmatropic shift of the 1-alk-
enyl group to the imidazole 2-position is therefore favored over
that to the 5-position before the cyclization. Unfortunately, the
level of regioselectivity is much less than that previously
observed for phenylimidazoles,14 and it is essentially indepen-
dent of substituents on the acrylate chain. Further work is
required to probe the reasons for these differences. Because of
the sensitivity of pyrroloimidazolones to chromatography and
other purification techniques, this cascade approach does not
supersede the C-acrylate route10 as the method of choice for 3
and 4, and it is not suitable for making pure 7-substituted
isomers of either ring system.
The imidazol-1-ylacrylates were generally obtained as mix-
3
tures of E- and Z-isomers (E-isomer JHH ca. 14 Hz, Z-isomer
3JHH ca. 10 Hz). The nature of the isomer was expected to be
irrelevant for azapyrrolizinone formation (see below), and no
attempt was made to separate them. Reaction of 4-methylimi-
dazole 44 with methyl propynoate gave an inseparable 1:1
mixture of the acrylate isomers 45 and 46, and therefore this
route to methyl-substituted azapyrrolizinones was not pursued
further.
(27) Pinho e Melo, T. M. V. D.; Soares, M. I. L.; d’A. Rocha Gonsalves,
A. M.; McNab, H. Tetrahedron Lett. 2004, 45, 3889-3893.
(28) Pinho e Melo, T. M. V. D.; Soares, M. I. L.; d’A. Rocha Gonsalves,
A. M.; Paixao, J. A.; Beja, A. M.; Silva, M. R. J. Org. Chem. 2005, 70,
6629-6638.
(29) Kashima, C.; Tajima, T.; Omote, Y. J. Heterocycl. Chem. 1984,
21, 171-176.
(30) Kashima, C.; Tsuzuki, A.; Tajima, T. J. Heterocycl. Chem. 1984,
21, 201-203.
(31) McNab, H. J. Chem. Soc., Perkin Trans. 1 1987, 657-660.
J. Org. Chem, Vol. 72, No. 23, 2007 8763

McNab and Tyas
tively. Regiocontrolled routes to substituted azapyrrolizinones
56-60 have made these among the easiest azapyrrolizinones
to obtain. However, the very high furnace temperatures required
for the initial sigmatropic shift stage of the cascade limit the
available substituents, and often care is required in the workup.
The chemical properties of these new ring systems will be
reported in future articles.
Experimental Section
On the other hand, we have found that blocking one of the
possible migration sites of the N-propenoate by substituting
either the 2-position (precursors 35, 37, and 51) or the 4- and
5-positions of the imidazole ring (precursors 39 and 41) leads
to single azapyrrolizinone isomers. FVP of the 2-substituted
derivatives 35, 37, and 51 (825-875 °C) caused clean cycliza-
tion to the pyrrolo[1,2-c]imidazol-5-ones 56-58, respectively,
in 88-91% yield. This is the method of choice for the synthesis
of 3-substituted pyrrolo[1,2-c]imidazol-5-ones. In similar fash-
ion, FVP of the 4,5-disubstituted precursors 39 and 41 at 825-
850 °C gave the 2,3-disubstituted pyrrolo[1,2-a]imidazol-5-ones
59 and 60 in 93-95% yields. This is the method of choice for
the synthesis of 2,3-disubstituted pyrrolo[1,2-a]imidazol-5-ones.
In all of these cases, the migrating alkenyl group is forced in
the direction opposite to the substituent at the adjacent position.
This always overrides the “natural” direction of migration in
the unsubstituted ring system. The nature of the interaction that
causes this effect may be simply steric and is under investiga-
tion.
Finally, examples of the pyrrolo[1,2-a]benzimidazol-1-
one (benzazapyrrolizinone) system 6 are rare, and the parent
compound is known only in the patent literature.32 Precursors
61 (as a 44:56 E/Z mixture; 95%) and 62 (exclusively as the
E-isomer) were made by the methods of Scheme 6 (the latter
only in low yield; see Experimental Section). FVP of 61 and
62 at 950 °C gave the pyrrolo[1,2-a]benzimidazol-1-ones 6
(71%) and 63 (36%), respectively, after some optimization of
sublimation rate and trapping method. In both cases, rapid
chromatography (<5 min on the column) was essential to obtain
pure products.
Methyl 3-(Indol-1-yl)-acrylate Derivatives. General Method.17
A solution of TBAF (1 M in tetrahydrofuran, 1.0 cm3, 1.0 mmol)
was added dropwise to a solution of indole (1.0 mmol) and methyl
propynoate 10 (84 mg, 1.0 mmol) in tetrahydrofuran (6 cm3). The
reaction mixture was stirred at room temperature for 30 min. Water
(20 cm3) was added, the organic components were extracted into
ethyl acetate (3 × 40 cm3), and the organic extracts were washed
with water (10 cm3) and dried (MgSO4). Removal of the solvent
under reduced pressure afforded an E/Z isomer mixture of the
methyl 3-(indol-1-yl)-acrylate that was purified as described. The
following derivatives were made by this method:
Methyl 3-(Indol-1-yl)-acrylate 11. Application of the general
method using indole 9 (117 mg, 1.0 mmol) gave a 67:33 E/Z isomer
mixture of methyl 3-(indol-1-yl)-acrylate 11 that was purified by
distillation (192 mg, 96%); mp 81-83 °C, bp 170 °C (0.9 Torr);
(Found: M+ 201.0787. C12H11NO2 requires M 201.0790); δH (E-
3
isomer) 8.21 (1H, d, J ) 14.1), 7.59-7.47 (2H, m), 7.30 (1H, d,
3J ) 3.4), 7.29-7.11 (2H, m), 6.64 (1H, d, 3J ) 3.4), 5.88 (1H, d,
3J ) 14.1), and 3.74 (3H, s); δH (Z-isomer) 8.46 (1H, d, 3J ) 3.7),
3
3
6.58 (1H, d, J ) 3.7), 5.31 (1H, d, J ) 11.0), and 3.69 (3H, s)
(other signals indistinguishable); δC (E-isomer) 167.7 (quat), 137.2,
135.9 (quat), 129.7 (quat), 123.8, 123.4, 122.3, 121.4, 109.9, 108.7,
100.0, and 51.5; m/z 201 (M+, 100%), 171 (14), 170 (87), 143
(11), 142 (11), 117 (12), 115 (15), and 85 (10). (Data comparable
with reported values for the ethyl ester;16 see also Supporting
information.)
Methyl 3-(3-Formylindol-1-yl)-acrylate 13. Application of the
general method using indole 3-carbaldehyde 12 (145 mg, 1.0 mmol)
gave an immediate change from colorless to dark brown, and thus
the reaction was stirred at room temperature for only 10 min.
Tetrahydrofuran was removed in vacuo, and the crude product was
purified by dry flash chromatography on silica (8% DCM, 20%
ethyl acetate in hexane) to give methyl E-3-(3-formylindol-1-yl)-
acrylate 13 as a white solid (195 mg, 86%); mp 176-178 °C;
(Found: M+ 229.0737. C13H11N2O3 requires M 229.0739); δH 10.04
(1H, s), 8.21 (1H, d, 3J ) 7.8), 8.16 (1H, d, 3J ) 14.4), 8.00 (1H,
3
3
s), 7.54 (1H, d, J ) 7.8), 7.33 (2H, dq, J ) 14.4 and 7.3), 6.17
(1H, d, 3J ) 14.4), and 3.77 (3H, s); δC 184.5, 165.9 (quat), 136.1
(quat), 135.6, 132.7, 125.0, 123.8, 121.8, 121.5 (quat), 109.5, 104.2,
and 51.1 (CH3) (one quaternary overlapping); m/z 229 (M+, 100%),
228 (70), 198 (25), 185 (17), 170 (58), 140 (13), 116 (16), 115
(31), and 98 (14).
It is noteworthy that the furnace temperatures required for
the benzannelated examples (derived from indoles and benz-
imidazoles) are ca. 100 °C higher than those for the imidazole
analogues, owing to the quinonoid intermediates involved in
the former processes.
In conclusion, the work reported in this article has signifi-
cantly extended the synthetic versatility of the high-temperature
FVP cascade route (involving a sigmatropic migration, elimina-
tion, and cyclization) to a number of pyrrolizin-3-one analogues.
In the pyrrolo[1,2-a]indol-3-one and pyrrolo[1,2-a]benzimida-
zol-1-one series, we believe that the routes to the unsubstituted
compounds 2 and 6 are the best currently available, requiring
just two simple steps from indoles or benzimidazoles, respec-
Methyl 3-(3-Methylindol-1-yl)-acrylate 15. Application of the
general method using 3-methylindole 14 (131 mg, 1.0 mmol) gave
a crude product that was absorbed onto silica and purified by dry
flash chromatography (20% DCM, 2% ethyl acetate in hexane) to
give methyl 3-(3-methylindol-1-yl)-acrylate 15 as a white solid (186
mg, 87%); mp 81-82 °C (from hexane); bp 169 °C (1.2 Torr);
(Found: M+ 215.0946. C13H13NO2 requires M 215.0946); δH 8.14
3
3
(1H, d, J ) 13.9), 7.43 (1H, d, J ) 7.8), 7.26-7.10 (3H, m),
3
5
7.03 (1H, s), 5.73 (1H, dd, J ) 13.9 and J ) 0.9), 3.71 (3H, s),
and 2.22 (3H, s); δC 167.5 (quat), 136.4, 135.8 (quat), 130.0 (quat),
123.3, 121.5, 119.9, 118.8, 118.0 (quat), 109.2, 97.9, 50.8 (CH3),
and 9.1 (CH3); m/z 215 (M+, 57%), 184 (47), 154 (17), 131 (81),
130 (100), 103 (23), and 77 (34).
(32) (a) Minami, M.; Kitamura, K. JP 45032716; Chem. Abstr. 1971,
74, 43051. (b) Minami, M. JP 45032715; Chem. Abstr. 1971, 74, 43057.
(c) JP 59185349; Chem. Abstr. 1985, 102, 176456.
Methyl 3-(1H-Indol-3-yl)-acrylate 21 (cf. ref 22). Methyl-
(triphenylphosphoranylidene)acetate (0.67 g, 2 mmol) was added
8764 J. Org. Chem., Vol. 72, No. 23, 2007

Route to Pyrroloisoindolone and Pyrroloimidazolones
to a solution of indole 3-carboxaldehyde 12 (0.29 g, 2 mmol) in
toluene (25 cm3) and stirred overnight. The crude product was
purified by dry flash chromatography on silica using a 15-50%
ethyl acetate in hexane eluent gradient and afforded E- and
Z-isomers of methyl 3-(1H-indol-3-yl)-acrylate 21 (0.35 g, 88%,
0.31 g of E-isomer, 0.04 g of Z-isomer); mp (E-isomer) 152-
153 °C (lit.,26 153-154 °C); mp (Z-isomer) 162-164 °C (lit.,26
163-164 °C); δH (E-isomer) 8.46 (1H broad, NH), 7.89-7.79 (2H,
were not separated, and neither isomer was assigned specific
geometry; mp 159-161 °C; (Found: M+ 277.1099. C18H15NO2
requires M 277.1103); δH (major isomer) 8.58 (1H, broad, NH),
7.73 (1H, m), 7.31-7.24 (6H, m), 7.19-7.14 (2H, m), 6.70 (1H,
3
d, J ) 2.9), 6.52 (1H, s), and 3.57 (3H, s); δH (minor isomer)
8.52 (1H, broad, NH), 7.07 (1H, m), 6.92-6.89 (2H, m), 6.19 (1H,
s), and 3.65 (3H, s) (other signals indistinguishable); δC (major
isomer) 167.6 (quat), 153.3 (quat), 140.2 (quat), 137.3 (quat), 129.8,
128.9 (2CH), 128.0, 127.8 (2CH), 125.1 (quat), 123.1, 121.4, 120.8,
118.6 (quat), 112.0, 111.4, and 51.1 (CH3); m/z 277 (M+, 100%),
246 (80), 219 (25), 218 (27), 217 (42), 216 (23), 204 (13), 191
(18), 189 (21), 165 (5), 144 (18), and 109 (20).
Methyl 3-(2-Methyl-1H-indol-3-yl)-acrylate 25. 2-Methyl-1H-
indole-3-carboxaldehyde33 (0.5 g, 3 mmol) and methyl(triph-
enylphosphoranylidene)acetate (1.05 g, 3 mmol) were dissolved in
toluene (15 cm3) and heated under reflux for 24 h. The solvent
was removed in vacuo, and the product was purified by dry flash
chromatography on silica (20% ethyl acetate in hexane) to give
methyl E-3-(2-methyl-1H-indol-3-yl)-acrylate 25 (0.62 g, 93%); mp
153-154 °C (lit.,26 154-155 °C); δH 8.64 (1H, broad, NH), 8.05
(1H, d, 3J ) 15.8), 7.93 (1H, m), 7.42-7.26 (3H, m), 6.52 (1H, d,
3J ) 15.8), 3.92 (3H, s), and 2.60 (3H, s); δC 169.1 (quat), 140.2
(quat), 137.8, 135.6 (quat), 126.2 (quat), 122.3, 121.3, 119.8, 111.3,
110.8, 109.4 (quat), 51.3 (CH3), and 12.2 (CH3); m/z 215 (M+,
100%), 184 (80), 183 (22), 156 (44), 155 (33), 154 (37), 128 (18),
129 (18), 78 (30), and 77 (41).
Flash Vacuum Pyrolysis Reactions. FVP reactions were carried
out by sublimation of the precursor under reduced pressure through
an empty silica tube (35 × 2.5 cm) heated by an electrical tube
furnace. The products were usually collected in a U-tube cooled
by liquid nitrogen situated at the exit point of the furnace, but in
some cases a dry ice acetone cooled “cold finger” trap was used to
minimize product degradation (see specific examples later in this
section). Upon completion of the pyrolysis, the U-tube trap was
allowed to warm to room temperature under an atmosphere of dry
nitrogen. The product was dissolved in chloroform and removed
from the trap. Evaporation of the solvent under reduced pressure
gave the product. Products that were collected on the cold finger
were washed from the cold surface with acetone under a dry
nitrogen atmosphere, and the solution was worked up in the usual
way. Pyrolysis conditions are reported in the form: precursor
(quantity), furnace temperature (Tf), inlet temperature (Ti), pressure
(Prange), and pyrolysis time (t).
3
m), 7.39 (1H, m), 7.32 (1H, d, J ) 15.7), 7.17-7.10 (2H, m),
6.34 (1H, d, 3J ) 15.7), and 3.81 (3H, s); δH (Z-isomer) 8.82 (1H,
3
d, J ) 2.9), 8.57 (1H broad, NH), 7.67 (1H, m), 7.37-7.12 (3H,
m), 7.23 (1H, d, 3J ) 12.4), 5.77 (1H, d, 3J ) 12.4), and 3.71 (3H,
s); δC (E-isomer) 168.4 (quat), 138.6, 137.2 (quat), 129.6, 124.9
(quat), 122.4, 120.7, 119.8, 112.3 (quat), 111.8, 111.4, and 50.9
(CH3); δC (Z-isomer) 168.8 (quat), 138.6, 137.0 (quat), 129.0, 125.1
(quat), 123.2, 121.4, 120.3, 113.3 (quat), 112.6, 111.7, and 51.4
(CH3); m/z (E-isomer) 201 (M+, 97%), 171 (32), 170 (100), 143
(40), 142 (24), 141 (39), 115 (71), and 114 (30); m/z (Z-isomer)
201 (M+, 96%), 171 (34), 170 (100), 143 (37), 142 (28), 141 (43),
115 (66), and 114 (32).
Methyl 2-Cyano-3-(1H-indol-3-yl)-acrylate 22. A solution of
indole 3-carboxaldehyde 12 (0.72 g, 5 mmol) and methyl cyanoac-
etate (0.495 g, 5 mmol) in toluene (15 cm3) was treated with glacial
acetic acid (15 drops) and piperidine (15 drops). The reaction was
stirred for 2 h, after which a yellow precipitate formed. Toluene
was removed in vacuo, and the crude solid was dissolved in DCM.
Water (75 cm3) was added, and the organic layer was separated.
The aqueous layer was then extracted with DCM (3 × 25 cm3),
and the combined organic extracts were washed with water
(50 cm3) and then dried (MgSO4). The solvent was removed to
give methyl 2-cyano-3-(1H-indol-3-yl)-acrylate 22 (1.10 g, 97%);
mp 183-185 °C (lit.,23 187-188 °C); δH 9.34 (1H, broad, NH),
8.57 (1H, m) 8.55 (1H, s), 7.77 (1H, m), 7.42 (1H, m), 7.31-7.12
(2H, m), and 3.86 (3H, s); δC 164.9 (quat), 147.2, 136.7 (quat),
132.4, 127.9 (quat), 124.0, 122.6, 118.7 (quat), 118.3, 113.1, 110.9
(quat), 92.9 (quat), and 53.0 (CH3); m/z 226 (M+, 38%), 195 (25),
145 (90), 144 (100), 116 (40), and 89 (45).
Dimethyl 2-(1H-Indol-3-ylmethylene)malonate 23. A solution
of indole 3-carboxaldehyde 12 (0.72 g, 5 mmol) and dimethyl
malonate (0.66 g, 5 mmol) in toluene (15 cm3) with glacial acetic
acid (15 drops) and piperidine (15 drops) was stirred for 45 min,
after which the reaction was fitted with a Dean/Stark trap and briefly
heated under reflux until red in color. Upon cooling, water (50 cm3)
was added to the mixture, and the organic layer was separated.
The aqueous phase was then extracted with ether (3 × 25 cm3),
and the combined extracts were washed with water (50 cm3) and
dried (MgSO4), after which the solvents were removed to give
dimethyl 2-(1H-indol-3-ylmethylene)malonate 23 (0.62 g, 48%);
mp 195-197 °C (from methanol) (lit.,24 117-119 °C). This
compound was characterized as follows in view of the mp
discrepancy with the literature: (Found: C, 64.8; H, 5.0; N, 4.9.
C14H13NO4 requires C, 64.85; H, 5.0; N, 5.4); (Found: M+
259.0841. C14H13NO4 requires M 259.0845); δH 8.85 (1H, broad,
NH), 8.16 (1H, s), 7.79-7.76 (2H, m), 7.35 (1H, m), 7.29-7.21
(2H, m), and 3.86 (6H, s); δC 168.8 (quat), 166.2 (quat), 136.3,
136.1 (quat), 128.3, 127.9 (quat), 123.8, 122.0, 119.2 (quat), 118.9,
112.1, 110.9 (quat), 53.0, and 52.8; m/z 259 (M+, 100%), 228 (38),
199 (38), 196 (29), 170 (26), 145 (30), 144 (40), 141 (50), and
114 (27).
3H-Pyrrolo[1,2-a]indol-3-one 2 [from Methyl 3-(Indol-1-yl)-
acrylate 11]. FVP of 11 (300 mg, 1.5 mmol, Ti ) 90 °C, Tf )
925 °C, P ) 0.01-0.08 Torr, t ) 40 min) afforded a solid yellow
pyrolysate (230 mg, 90%), and subsequent purification by dry flash
chromatography on silica (40% DCM in hexane) gave 3H-pyrrolo-
[1,2-a]indol-3-one 2 (200 mg, 78%); mp 86-88 °C (lit.,19 86-
3
4
89 °C); δH 7.58 (1H, ddd, J ) 7.7, 1.7 and J ) 0.9), 7.27 (1H,
3
4
3
4
dt, J ) 7.7 and J ) 0.9), 7.15 (1H, td, J ) 7.7 and J ) 1.1),
3
3
4
7.02 (1H, d, J ) 5.8), 6.96 (1H, td, J ) 7.7 and J ) 1.1), 6.27
3
(1H, s), and 5.86 (1H, d, J ) 5.8); δC 164.8 (quat), 141.2 (quat),
134.9, 134.4 (quat), 133.7 (quat), 127.3 (2CH), 123.1, 122.7, 112.1,
and 108.2; m/z 169 (M+, 100%), 141 (47), 140 (37), 114 (26), 113
(16), 88 (12), 70 (13), and 63 (20).
FVP of Methyl 3-(3-Formylindol-1-yl)-acrylate 13. FVP of
13 (40 mg, 0.17 mmol, Tf ) 925 °C, Ti ) 205 °C, P ) 0.02-0.12
Torr, t ) 10 min) using a dry ice/acetone cold finger trap gave a
solid yellow pyrolysate that was removed from the cold finger by
dissolving in acetone. The solvent was removed in vacuo to provide
exclusively 3H-pyrrolo[1,2-a]indol-3-one 2 (32 mg, 94%) after
decarbonylation of the formyl group; mp 86-88 °C (lit.,19 86-
Methyl 3-(1H-Indol-3-yl)-3-phenylacrylate 24 (cf. ref 25). A
solution of indole 9 (0.234 g, 2 mmol) and methyl phenylpropynoate
(0.320 g, 2 mmol) in glacial acetic acid (25 cm3) containing
palladium(II) acetate (9 mg, 2% cat) was stirred at room temperature
for 30 h. The crude product was absorbed onto silica and purified
by dry flash chromatography (10-40% ethyl acetate in hexane
eluent gradient) and then crystallized by evaporation of DCM at
atmospheric pressure to give a 15:85 isomer mixture of methyl
3-(1H-indol-3-yl)-3-phenylacrylate 24 (0.477 g, 89%). The isomers
3
4
89 °C); δH 7.59 (1H, ddd, J ) 7.7, 1.7 and J ) 0.9), 7.29 (1H,
3
4
3
4
dt, J ) 7.7 and J ) 0.9), 7.15 (1H, td, J ) 7.7 and J ) 1.2),
(33) Downie, I. M.; Earle, M. J.; Heaney, H.; Shuhaiber, K. F.
Tetrahedron 1993, 49, 71-79.
J. Org. Chem, Vol. 72, No. 23, 2007 8765

McNab and Tyas
3
3
4
7.01 (1H, d, J ) 5.8), 6.96 (1H, td, J ) 7.7 and J ) 1.2), 6.28
(1H, s); δC 164.8 (quat), 149.2 (quat), 140.3 (quat), 134.3 (quat),
130.8, 129.0 (2CH), 127.4, 127.0 (2CH), 123.1, 122.7, 119.9, 112.4,
and 108.8 (two pairs of quaternary signals overlapping); m/z 245
(M+, 100%), 217 (85), 216 (31), 204 (15), 189 (16), 149 (16), 123
(16), 109 (24), 95 (32), and 87 (94); and a product thought to be
either 3-phenyl-4H-cyclopenta[b]indol-1-one 30 or 1-phenyl-4H-
cyclopenta[b]indol-3-one 31 (6 mg, 6%) (decomposes in chloroform
solution); mp 253-255 °C (dec); (Found: M+ 245.0837. C17H11-
NO requires M 245.0841); δH 11.44 (1H, br, s, NH), 8.02 (1H, dd,
3
(1H, s), and 5.86 (1H, d, J ) 5.8).
FVP of Methyl 3-(3-Methylindol-1-yl)-acrylate 15. FVP of 15
(95 mg, 4.4 mmol, Tf ) 925 °C, Ti ) 160 °C, P ) 0.02-0.10
Torr, t ) 13 min) using a dry ice/acetone cold finger trap gave a
solid yellow pyrolysate (74 mg) that contained two major products.
Separation by dry flash chromatography (5-30% ethyl acetate in
hexane gradient) gave, in order of elution: 9-methyl-3H-pyrrolo-
[1,2-a]indol-3-one 18 (36 mg, 53%); mp 92-93 °C (lit.,8 94-
4
3J ) 7.6 and J ) 0.6), 7.70-7.64 (4H, m), 7.47-7.41 (4H, m),
3
95 °C); δH 7.58 (1H, d, J ) 7.8), 7.24-7.20 (2H, m), 7.08 (1H,
3
3
3
and 6.59 (1H, s); δC 185.3 (quat), 147.9 (quat), 136.8 (quat), 135.4
(quat), 126.2 (quat), 111.0 (quat), 130.3, 128.8, 128.6 (2CH), 127.7
(2CH), 125.0, 124.2, 120.3, and 116.6 (one quaternary signal
overlapping); m/z 245 (M+, 100%), 244 (26), 217 (32), 216 (16),
189 (20), 169 (6), and 123 (9).
d, J ) 5.9), 7.02 (1H, d, J ) 7.8), 5.81 (1H, d, J ) 5.9), and
2.19 (3H, s) (compatible with literature data8); and 9H-carbazol-
3-ol 19 (32 mg, 47%); mp 260-261 °C (lit.,34 259-260 °C); δH
3
10.80 (1H, br, s), 8.85 (1H, br, s), 7.90 (1H, d, J ) 7.8), 7.36-
3
4
3
7.31 (2H, m), 7.24 (1H, dt, J ) 7.4, J ) 1.1), 7.22 (1H, d, J )
8.4), 6.99 (1H, dt, 3J ) 7.4, 4J ) 1.1), and 6.83 (1H, dd, 3J ) 8.6
and 2.4); m/z 183 (M+, 14%), 170 (7), 154 (8), 143 (28), 130 (14),
129 (100), 128 (21), 115 (8), and 102 (24).
Methyl 3-(2H-Imidazol-1-yl)-acrylate 33. A solution of methyl
propynoate 10 (4.20 g, 0.05 mol) and imidazole 32 (3.63 g, 0.05
mol) in toluene (15 cm3) was heated under reflux for 2 h. The
E-isomer of methyl 3-(2H-imidazol-1-yl)-acrylate 33 crystallized
on cooling the solution. The product was filtered and recrystallized
from the minimum volume of toluene. The filtrate from the original
reaction was concentrated under reduced pressure. The product that
crystallized was filtered and dissolved in ethyl acetate, and hexane
was added to precipitate unreacted imidazole that was removed by
filtration. This filtrate was then concentrated under reduced pressure
to give Z-isomer 33, which was recrystallized from toluene (6.42
g, 82%; 3.11 g, E-isomer, 3.31 g, Z-isomer); mp (E-isomer) 117-
119 °C (lit.,29 121-122 °C); mp (Z-isomer) 46-48 °C; δH
(E-isomer) 7.86 (1H, d, 3J ) 14.3), 7.74 (1H, s), 7.19 (1H, s), 7.10
Repyrolysis of 9-methyl-3H-pyrrolo[1,2-a]indol-3-one 18 at
925 °C (20 mg, 0.11 mmol, Tf ) 925 °C, Ti ) 160 °C, P ) 0.02-
0.05 Torr, t ) 9 min) gave a 50:50 mixture of 9-methyl-3H-pyrrolo-
[1,2-a]indol-3-one 18 and 9H-carbazol-3-ol 19 shown by 1H NMR
spectroscopy.
3H-Pyrrolo[1,2-a]indol-3-one 2 (from Methyl 3-(Indol-3-yl)-
acrylate 21). FVP of methyl 3-(3H-indol-3-yl)-acrylate 21
(100 mg, 0.5 mmol, Ti ) 210 °C, Tf ) 925 °C, P ) 0.01-0.09
Torr, t ) 25 min) afforded a solid yellow pyrolysate (71 mg, 85%),
and subsequent purification by dry flash chromatography on silica
(40% DCM in hexane) gave 3H-pyrrolo[1,2-a]indol-3-one 2 (59
3
(1H, s), 6.01 (1H, d, J ) 14.3), and 3.74 (3H, s); δH (Z-isomer)
mg, 70%); mp 86-88 °C (lit.,19 86-89 °C); δH 7.60 (1H, ddd, J
3
3
8.02 (1H, s), 7.79 (1H, s), 7.02 (1H, s), 6.85 (1H, d, J ) 10.6),
) 7.7, 1.7 and 4J ) 0.9), 7.26 (1H, dt, 3J ) 7.7 and 4J ) 0.9), 7.15
3
5.44 (1H, d, J ) 10.6), and 3.69 (3H, s); δC (E-isomer) 166.1
3
4
3
(1H, td, J ) 7.7 and J ) 1.1), 7.02 (1H, d, J ) 5.8), 6.94 (1H,
td, 3J ) 7.7 and 4J ) 1.1), 6.27 (1H, s), and 5.88 (1H, d, 3J ) 5.8).
However, larger-scale pyrolysis (ca. 500 mg) was impractical
because of the relative involatility of the precursor. Variation of
inlet temperature (210-270 °C), throughput rate, and the use of a
“cold finger” trap did not significantly increase yields. In practice,
methyl 3-(3H-indol-1-yl)-acrylate 11 is a better precursor for 3H-
pyrrolo[1,2-a]indol-3-one 2 on a preparative scale.
(quat), 137.7, 136.4, 131.6, 115.9, 106.2, and 51.7 (CH3); δC (Z-
isomer) 166.9 (quat), 136.1 (2CH), 130.2, 115.5, 106.2, and 52.1
(CH3).
Methyl 3-(2-Methylimidazol-1-yl)-acrylate 35. 2-Methylimi-
dazole 34 (1.23 g, 15 mmol) and methyl propynoate 10 (1.26 g, 15
mmol) were added to toluene (15 cm3) and heated under reflux for
2 h during which time the reaction darkened to deep yellow. Methyl
3-(2-methylimidazol-1-yl)-acrylate 35 crystallized upon removal of
the solvent as the E-isomer exclusively (1.36 g, 55%); mp 92-
93 °C (from toluene) (lit.,30 91-92 °C); δH 7.84 (1H, d, 3J ) 14.1),
2-Cyano-3H-pyrrolo[1,2-a]indol-3-one 28. FVP of methyl
2-cyano-3-(1H-indol-3-yl)-acrylate 22 (302 mg, 1.3 mmol, Tf )
925 °C, Ti ) 240 °C, P ) 0.02-0.10 Torr, t ) 20 min) using a
dry ice/acetone cold finger trap gave a solid orange pyrolysate of
2-cyano-3H-pyrrolo[1,2-a]indol-3-one 28 (170 mg, 65%) that was
purified by dry flash chromatography on silica (45% DCM and
1% ethyl acetate in hexane); mp 165-167 °C; (Found: M+
194.0478. C12H6N2O requires M 194.0480); δH 7.71 (1H, dt, 3J )
3
7.15 (1H, s), 6.97 (1H, s), 5.93 (1H, d, J ) 14.1), 3.88 (3H, s),
and 2.50 (3H, s); m/z 166 (M+, 100%), 135 (82), 107 (81), 81 (28),
and 67 (38).
Methyl 3-(2-Phenylimidazol-1-yl)-acrylate 37. A solution of
2-phenylimidazole 36 (0.43 g, 3 mmol) and methyl propynoate 10
(0.25 g, 3 mmol) in toluene was heated under reflux for 4 h. The
solvent was then removed under reduced pressure, and the crude
product was purified by Kugelrohr distillation to give methyl 3-(2-
phenylimidazol-1-yl)-acrylate 37 (0.42 g, 61%) as a 34:66 mixture
of Z- and E-isomers, respectively; bp 179 °C (3.8 Torr); (Found:
C, 68.4; H, 5.4; N, 12.05. C13H12N2O2 requires C, 68.4; H, 5.25;
N, 12.3); (Found: M+ 228.0891. C13H12N2O2 requires M 228.0898);
4
3
4
7.9 and J ) 0.9), 7.70 (1H, s), 7.46 (1H, dt, J ) 7.9 and J )
3
4
3
0.9), 7.39 (1H, td, J ) 7.8 and J ) 1.1), 7.16 (1H, td, J ) 7.8
and 4J ) 1.1), and 6.79 (1H, s); δC 158.7 (quat), 142.9, 137.4 (quat),
135.3 (quat), 133.5 (quat), 130.0, 124.5, 124.1, 115.3, 113.0, 111.6
(quat), and 111.2 (quat); m/z 194 (M+, 100%), 166 (21), 165 (11),
140 (8), and 139 (26).
FVP of Methyl 3-(1H-Indol-3-yl)-3-phenylacrylate 24. FVP
of 24 (120 mg, 0.14 mmol, Tf ) 925 °C, Ti ) 210 °C, P ) 0.02-
0.10 Torr, t ) 8 min) using a dry ice/acetone cold finger trap gave
a solid yellow pyrolysate that was washed into acetone and analyzed
by TLC, indicating two products (99 mg, 94%). Separation by dry
flash chromatography (30% DCM and 1% ethyl acetate in hexane
for the first band and 80% ethyl acetate for the second band) gave,
in order of elution: 1-phenyl-3H-pyrrolo[1,2-a]indol-3one 29 (60
mg, 57%); mp 111-113 °C; (Found: M+ 245.0841. C17H11NO
requires M 245.0847); δH 7.68-7.62 (3H, m), 7.43-7.41 (3H, m),
7.37 (1H, dt, 3J ) 7.8 and 4J ) 0.8), 7.22 (1H, td, 3J ) 7.6 and 4J
) 1.1), 7.03 (1H, td, 3J ) 7.6 and 4J ) 1.1), 6.64 (1H, s), and 6.08
3
δH (E-isomer) 8.02 (1H, d, J ) 14.1), 7.59-7.52 (5H, m), 7.40
(1H, s), 7.18 (1H, s), 6.09 (1H, d, 3J ) 14.1), and 3.81 (3H, s); δH
(Z-isomer) 7.99 (1H, s), 7.59-7.39 (5H, m), 7.20 (1H, s), 6.93
3
3
(1H, d, J ) 10.3), 5.61 (1H, d, J ) 10.3), and 3.82 (3H, s); δC
(E-isomer) 166.9 (quat), 150.0 (quat), 137.8, 131.4, 130.3, 130.03
(2CH), 129.37 (2CH), 117.0, 107.5, and 52.4 (CH3) (one quaternary
overlapping); δC (Z-isomer) 165.1 (quat), 134.9, 129.96 (2CH),
129.44 (2CH), 129.1 (2CH), 122.4, 107.8, and 52.3 (CH3) (two
quaternaries overlapping); m/z 228 (M+, 85%), 197 (48), 169 (100),
157 (49), and 128 (36).
Methyl 3-(4,5-Dimethylimidazol-1-yl)-acrylate 39. Methyl pro-
pynoate 10 (0.27 g, 3.2 mmol) was added to a solution of 4,5-
dimethylimidazole 38 (0.26 g, 2.7 mmol) in toluene (25 cm3), and
the solution was heated under reflux, with stirring, for 30 min.
Removal of the solvent under reduced pressure gave the crude
(34) Bisagni, E.; Ducrocq, C.; Hung, N. C. Tetrahedron 1980, 36, 1327-
1330.
8766 J. Org. Chem., Vol. 72, No. 23, 2007

Route to Pyrroloisoindolone and Pyrroloimidazolones
product, which was filtered and recrystallized from toluene (8 cm3)
to give methyl 3-(4,5-dimethylimidazol-1-yl)-acrylate 39 (0.39 g,
79%) as a 67:33 E/Z isomer mixture; mp 172-174 °C; (Found:
M+ 180.0890. C9H12N2O2 requires M 180.0899); δH (E-isomer) 7.70
(1H, s), 7.68 (1H, d, 3J ) 14.3), 6.00 (1H, d, 3J ) 14.3), 3.73 (3H,
s), 2.16 (3H, s), and 2.10 (3H, s); δH (Z-isomer) 8.53 (1H, s), 6.79
(1H, d, 3J ) 10.5), 5.67 (1H, d, 3J ) 10.5), 3.66 (3H, s), 2.16 (3H,
s), and 2.10 (3H, s); δC (E-isomer) 167.1 (quat), 136.3 (quat), 136.0,
133.8, 122.6 (quat), 105.8, 52.16 (CH3), 12.7 (CH3), and 9.1 (CH3);
δC (Z-isomer) 165.2 (quat), 137.8, 134.4 (quat), 131.9, 122.3, 106.8,
52.10 (CH3), 12.7 (CH3), and 9.1 (CH3); m/z 180 (M+, 100%), 179
(17), 165 (14), 164 (15), 149 (27), 121 (38), 93 (22), 80 (23), and
70 (45).
(5.00 g, 50 mmol) in toluene (100 cm3) and heated under reflux
overnight. Water (60 cm3) was added to the cooled reaction to
dissolve the solids present. The solution was extracted with
dichloromethane (3 × 50 cm3), and the organic extracts were
washed with water (60 cm3) and dried (MgSO4). The crude product
was purified by dry flash chromatography on silica (50% ethyl
acetate in hexane) to give a 17:83 isomer mixture of methyl 3-(2H-
imidazol-1-yl)-3-phenylacrylate 50 (1.74 g, 78%); mp 102-103 °C
(lit.,29 102-103 °C), which was not further analyzed; δH (major
4
isomer) 7.51 (1H, s), 7.46-7.14 (5H, m), 7.06 (1H, d, J ) 1.1),
4
6.84 (1H, d, J ) 1.1), 6.16 (1H, s), and 3.59 (3H, s); δH (minor
3
4
isomer) 7.00 (2H, dd, J ) 6.6, J ) 1.1), 6.06 (1H, s), and 3.52
(3H, s), other signals overlapping.
Methyl 3-(4,5-Diphenylimidazol-1-yl)-acrylate 41. Methyl pro-
pynoate 10 (0.21 g, 2.5 mmol) was added to a solution of 4,5-
diphenylimidazole 40 (0.55 g, 2.5 mmol) in chloroform (25 cm3)
in the presence of triethylamine (1 cm3), and the solution was heated
under reflux, with stirring, for 72 h. The solvent was removed under
reduced pressure, and the crude product was purified by dry flash
chromatography (10-40% ethyl acetate in hexane as eluent) to give
methyl 3-(4,5-diphenylimidazol-1-yl)-acrylate 41 (0.45 g, 59%) as
a 88:12 E/Z isomer mixture; mp 208-210 °C (from toluene);
(Found: C, 74.9; H, 5.25; N, 8.95. C19H16N2O2 requires C, 75.0;
H, 5.25; N, 9.2); (Found: M+ 304.1211. C19H16N2O2 requires M
Methyl 3-(2-Methylimidazol-1-yl)-3-phenylacrylate 51. A
solution of 2-methylimidazole 34 (0.68 g, 8.2 mmol) and methyl
2,3-dibromo-3-phenylpropanoate 48 (1.34 g, 4.1 mmol) in a mixture
of toluene (35 cm3) and triethylamine (5 cm3) was heated under
reflux overnight. The solvent was removed under reduced pressure,
and the crude product was purified by dry flash chromatography
(40% ethyl acetate in hexane as eluent) followed by Kugelrohr
distillation to give methyl 3-(2-methylimidazol-1-yl)-3-phenylacry-
late 51 as a 86:14 isomer mixture (0.70 g, 70%); bp 168 °C (3.0
Torr); (Found: M+ 242.1052. C14H14N2O2 requires M 242.1053);
δH (major isomer) 7.42-7.27 (3H, m), 7.17-7.13 (2H, m), 6.98
3
3
3
304.1211); δH (E-isomer) 8.06 (1H, s), 7.54 (1H, d, J ) 14.5),
(1H, d, J ) 1.5), 6.73 (1H, d, J ) 1.5), 6.47 (1H, s), 3.58 (3H,
3
7.51-7.42 (5H, m), 7.43-7.29 (2H, m), 7.24-7.16 (3H, m), 6.07
s), and 2.09 (3H, s); δH (minor isomer) 6.86 (1H, d, J ) 1.5),
3
(1H, d, J ) 14.5), and 3.70 (3H, s); δH (Z-isomer) 8.73 (1H, s),
6.77 (1H, d, 3J ) 1.5), 5.95 (1H, s), and 2.04 (3H, s) (other signals
indistinguishable); δC (major isomer) 163.7 (quat), 146.9 (quat),
145.1 (quat), 134.7 (quat), 131.1, 129.0 (2CH), 127.6, 126.4 (2CH),
120.0, 114.7, 51.6 (CH3), and 12.7 (CH3); δC (minor isomer) 165.1
(quat), 149.1 (quat), 145.4 (quat), 133.4 (quat), 130.5, 128.0, 120.6,
113.8, 51.5 (CH3), and 14.3 (CH3) (other signals indistinguishable);
m/z 242 (M+, 90%), 211 (59), 183 (88), 161 (47), 129 (36), 115
(60), 102 (76), and 56 (100).
3
3
6.53 (1H, d, J ) 10.3), 5.54 (1H, d, J ) 10.3), and 3.75 (3H, s)
(with other signals overlapping); δC (E-isomer) 166.8 (quat), 140.3
(quat), 136.2, 135.0, 133.6 (quat), 131.5 (2CH), 130.0, 129.9 (2CH),
129.1 (quat), 128.7 (2CH), 128.3 (quat), 127.7, 127.4 (2CH), 107.6,
and 52.4 (CH3); δC (Z-isomer) 139.4, 132.5, and 108.2 (all other
signals were indistinguishable); m/z 304 (M+, 93%), 273 (14), 245
(100), 219 (97), 190 (32), 165 (85), 142 (30), 115 (49), and 89
(54).
FVP of Methyl 3-(2H-Imidazol-1-yl)-acrylate 33. Separate
pyrolysis of E- and Z-isomers of methyl 3-(2H-imidazol-1-yl)-
acrylate 33 under the same conditions (130 mg, Tf ) 900 °C, Ti )
120 °C, P ) 0.017-0.065 Torr, t ) 15 min) gave solid yellow
pyrolysates containing pyrrolo[1,2-a]imidazol-5-one 3 as the major
product and pyrrolo[1,2-c]imidazol-5-one 4 as the minor product
in a 73:27 ratio in each case (80 mg, 78%). Products were identified
by comparison of their 1H NMR spectra with those previously
Methyl 3-(4,5-Dicyanoimidazol-1-yl)-acrylate 43. Methyl pro-
pynoate 10 (0.29 g, 3.5 mmol) was added to a solution of 4,5-
dicyanoimidazole 42 (0.41 g, 3.5 mmol) in chloroform (25 cm3) in
the presence of triethylamine (1 cm3), and the solution was heated
under reflux, with stirring, for 72 h. The crude product was purified
by dry flash chromatography (10-20% ethyl acetate in hexane as
eluent) to give methyl 3-(4,5-dicyanoimidazol-1-yl)-acrylate 43 as
a 90:10 E/Z isomer mixture (0.04 g total, 6%); mp 140-142 °C;
(Found: M+ 202.0494. C9H6N4O2 requires M 202.0491); δH (E-
3
reported.31 Z-Isomer pyrolysis δH (3) 7.17 (1H, d, J ) 6.2), 6.95
(1H, s), 6.90 (1H, s), and 5.96 (1H, d, 3J ) 6.2); δH (4) 7.70 (1H,
s), 7.26 (1H, d, 3J ) 5.9), 6.74 (1H, s), and 5.79 (1H, d, 3J ) 5.9);
E-isomer pyrolysis δH (3) 7.18 (1H, d, 3J ) 6.2), 6.97 (1H, d, J )
1.8), 6.92 (1H, s), and 5.96 (1H, d, 3J ) 6.2); δH (4) 7.69 (1H, s),
7.25 (1H, d, 3J ) 5.9), 6.75 (1H, s), and 5.79 (1H, d, 3J )
5.9).
3
isomer) ([2H6]acetone) 8.76 (1H, s), 8.08 (1H, d, J ) 14.4), 6.83
(1H, d, 3J ) 14.4), and 3.83 (3H, s); δH (Z-isomer) 7.90 (1H, d, 3J
) 12.1), 5.67 (1H, d, 3J ) 12.1), and 3.69 (3H, s) (imidazole singlet
indistinguishable); δC (E-isomer) ([2H6]acetone) 163.8 (quat), 140.9,
133.1, 123.0 (quat), 112.8, 110.9 (CN), 110.6 (CN), 107.1 (quat),
and 50.9; m/z 202 (M+, 8%), 171 (17), 156 (53), 155 (98), 154
(100), 153 (99), 152 (76), 146 (36), 118 (53), and 113 (72).
FVP of Methyl 3-(2H-Imidazol-1-yl)but-2-enoate 49. Pyrolysis
of the isomer mixture of 4929 (see Supporting Information) (41 mg,
Tf ) 850 °C, Ti ) 110 °C, P ) 0.020-0.038 Torr, t ) 10 min)
gave a solid yellow pyrolysate of 7-methylpyrrolo[1,2-a]imidazol-
5-one 52 as the major product and 7-methylpyrrolo[1,2-c]imidazol-
5-one 54 as the minor product in a 80:20 ratio (with products
identified by comparison with the 1H NMR spectra of pyrrolo[1,2-
a]imidazol-5-one and pyrrolo[1,2-c]imidazol-5-one31 (25 mg, 76%);
Reaction of 4(5)-Methylimidazole with Methyl Propynoate.
4-Methylimidazole 44 (0.41 g, 5 mmol) and methyl propynoate 10
(0.42 g, 5 mmol) were heated under reflux in toluene (15 cm3) for
2 h, during which time the reaction darkened to deep yellow. The
solvent was removed under reduced pressure to afford a deep yellow
crude liquid that was distilled [136 °C (5.0 Torr)], yielding a yellow
oil (0.67 g, 80%). A 1H NMR spectrum showed four characteristic
doublets due to the R-methine proton of a propenoate carbon-
carbon double bond in each case and hence indicating that the oil
contained E- and Z-isomers of both methyl 3-(4-methylimidazol-
1-yl)-acrylate 45 and methyl 3-(5-methylimidazol-1-yl)-acrylate 46.
Separation of the 4-methyl and 5-methyl isomers could not be
achieved by distillation or by dry flash chromatography (very similar
Rf values for all eluents).
n
δH (52) 6.97 (1H, d, J ) 1.5), 6.89 (1H, s), 5.67 (1H, m), and
2.16 (3H, s); δH (54) 7.67 (1H, s), 6.76 (1H, s), 5.53 (1H, m), and
2.13 (3H, s).
FVP of Methyl 3-(2H-Imidazol-1-yl)-3-phenylacrylate 50.
Pyrolysis of the isomer mixture of 50 (43 mg, Tf ) 850 °C, Ti )
140 °C, P ) 0.012-0.026 Torr, t ) 15 min) gave a solid dark
yellow pyrolysate of 7-phenylpyrrolo[1,2-a]imidazol-5-one 53 and
7-phenylpyrrolo[1,2-c]imidazol-5-one 55 in a 80:20 ratio, respec-
tively (33 mg, 90%); (Found: M+ 196.0621. C12H8N2O requires
M 196.0636); δH (53) 8.11-8.05 (2H, m), 7.47-7.38 (3H, m), 7.07
(1H, m), 7.02 (1H, m), and 6.15 (1H, s); δC 162.7 (quat), 154.8 (quat),
Methyl 3-(2H-Imidazol-1-yl)-3-phenylacrylate 50. Methyl 2,3-
dibromo-3-phenylpropanoate 48 (3.19 g, 10 mmol) was added to a
solution of imidazole 32 (1.00 g, 15 mmol) and triethylamine
J. Org. Chem, Vol. 72, No. 23, 2007 8767

McNab and Tyas
149.0 (quat), 134.1, 134.0 (quat), 131.9, 128.8 (2CH), 128.4 (2CH),
116.6, and 113.8; δH (55) 7.80 (1H, s), 7.65-7.61 (2H, m), and
6.01 (1H, s), other signals overlapping.
(quat), 144.2 (quat), 143.9, 142.6 (quat), 141.3, 135.3, 133.1 (quat),
131.8 (quat), 130.3, 124.7, 124.02, 123.97, 123.6, 120.8, 120.4,
110.8, 109.2, 105.8, 105.0, 51.69 (CH3), and 51.58 (CH3); m/z 202
(M+, 82%), 187 (35), 172 (43), 171 (100), 170 (40), 159 (37), 145
(73), 144 (57), 143 (60), 142 (67), 129 (48), and 118 (51).
3-Methylpyrrolo[1,2-c]imidazol-5-one 56. FVP of methyl 3-(2-
methylimidazol-1-yl)-acrylate 35 (65 mg, Tf ) 875 °C, Ti )
120 °C, P ) 0.020-0.065 Torr, t ) 7 min) gave a solid yellow
pyrolysate of 3-methylpyrrolo[1,2-c]imidazol-5-one 56 (47 mg,
88%), mp > 195 °C (dec); (Found: M+ 134.0479. C7H6N2O
requires M 134.0480); δH 7.21 (1H, d, 3J ) 5.7), 6.60 (1H, s), 5.75
Methyl 3-(Benzimidazol-1-yl)-3-phenylacrylate 62. Methyl 2,3-
dibromo-3-phenylpropanoate 48 (3.19 g, 10 mmol) was added to a
solution of benzimidazole (1.24 g 10 mmol) and triethylamine (5.0
g) in toluene (100 cm3) and heated under reflux for 1.5 h. The
solution was concentrated to afford a crude reaction mixture that
was added to ether. Unreacted benzimidazole was filtered, and the
filtrate was washed with water (2 × 40 cm3), dried (MgSO4), and
concentrated under reduced pressure to give methyl R-bromocin-
namate (2.13 g, quantitative); δH 8.22 (1H, s), 7.87-7.83 (2H, m),
7.44-7.40 (3H, m), and 3.90 (3H, s); m/z 242 and 240 (M+, 36
and 38%), 211 (22), 209 (22), 183 (20), 181 (21), 162 (40), 161
(100) 129 (71), and 102 (98) (cf ref 36). This product was dissolved
in toluene (100 cm3), benzimidazole (1.24 g, 10 mmol) was added,
and the solution was heated under reflux for 24 h. The solvent was
removed, water (50 cm3) was added, and the mixture was extracted
with dichloromethane (3 × 30 cm3). The organic extracts were
washed with water (50 cm3) and dried (MgSO4). Removal of the
magnesium sulfate and concentration of the filtrate under reduced
pressure gave the crude product, which was recrystallized from
toluene (20 cm3) to give methyl 3-(benzimidazol-1-yl)-3-phenyl-
acrylate 62 (0.49 g, 21%); mp 127-129 °C; (Found: M+ 278.1051.
C17H14N2O2 requires M 278.1055); δH 8.00 (1H, s), 7.83 (1H, dt,
3J ) 8.0, 4J ) 0.9), 7.51-7.41 (2H, m), 7.40-7.34 (2H, m), 7.31-
7.22 (2H, m), 7.13 (1H, td, 3J ) 7.7, 4J ) 1.2), 6.80 (1H, dt, 3J )
3
(1H, d, J ) 5.7), and 2.44 (3H, s); δC 163.5 (quat), 148.0 (quat),
137.1, 134.9 (quat), 126.2, 122.6, and 13.9; m/z 134 (M+, 100%),
105 (19), 79 (38), and 42 (100).
3-Phenylpyrrolo[1,2-c]imidazol-5-one 57. FVP of methyl 3-(2-
phenylimidazol-1-yl)-acrylate 37 (48 mg, Tf ) 850 °C, Ti )
180 °C, P ) 0.019-0.085 Torr, t ) 9 min) gave 3-phenylpyrrolo-
[1,2-c]imidazol-5-one 57 (36 mg, 88%) as a yellow oil; (Found:
M+ 196.0635. C12H8N2O requires M 196.0636); δH 8.37-8.30 (2H,
3
m), 7.49-7.41 (3H, m), 7.31 (1H, d, J ) 5.9), 6.88 (1H, s), and
5.87 (1H, d, 3J ) 5.9); δC 163.3 (quat), 150.3 (quat), 136.8, 131.2,
128.3 (2CH), 128.2 (2CH), 127.6 (quat), 127.1, and 122.6 (one
quaternary overlapping); m/z 196 (M+, 65%), 168 (100), 141 (35),
and 114 (39).
2,3-Dimethylpyrrolo[1,2-a]imidazol-5-one 59. FVP of methyl
3-(4,5-dimethylimidazol-1-yl)-acrylate 39 (40 mg, Tf ) 850 °C, Ti
) 80 °C, P ) 0.020-0.075 Torr, t ) 9 min) gave 2,3-
dimethylpyrrolo[1,2-a]imidazol-5-one 59 (38 mg, 95%) as a red
solid; mp > 205 °C (dec); (Found: M+ 148.0634. C8H8N2O requires
3
3
M 148.0636); δH 7.08 (1H, d, J ) 6.0), 5.88 (1H, d, J ) 6.0),
2.21 (3H, s), and 2.06 (3H, s); δC 164.1 (quat), 153.3 (quat), 139.9
(quat), 136.4, 126.6, 123.1 (quat), 12.0 (CH3), and 8.5 (CH3); m/z
180 (M+, 78%), 133 (18), 107 (13), and 79 (49).
4
8.0, J ) 0.9), 6.43 (1H, s), and 3.59 (3H, s); δC 164.1 (quat),
146.0 (quat), 143.9, 143.5 (quat), 134.6 (quat), 133.5 (quat), 131.4,
129.0 (2CH), 127.5 (2CH), 123.5, 122.7, 120.4, 113.1, 111.3, and
51.7 (CH3); m/z 278 (M+, 51%), 263 (24), 247 (23), 219 (31), 161
(21), 118 (27), and 91 (100).
2,3-Diphenylpyrrolo[1,2-a]imidazol-5-one 60. FVP of methyl
3-(4,5-diphenylimidazol-1-yl)-acrylate 41 (76 mg, Tf ) 825 °C, Ti
) 230 °C, P ) 0.010-0.100 Torr, t ) 14 min) gave 2,3-
diphenylpyrrolo[1,2-a]imidazol-5-one 60 (63 mg, 93%) as a red
oil; (Found: M+ 272.0944. C18H12N2O requires M 272.0949); δH
7.55-7.46 (5H, m), 7.40-7.36 (2H, m), 7.29-7.23 (4H, m), and
6.02 (1H, d, 3J ) 6.1); δC 163.3 (quat), 154.6 (quat), 143.6 (quat),
132.9 (quat), 129.2 (2CH), 128.6 (quat), 128.40, 128.35 (2CH), 128.2
(2CH), 127.9, 127.7, 127.6, 127.4 (2CH), and 127.2 (quat); m/z
272 (M+, 15%), 244 (15), 165 (6), 121 (10), and 84 (100).
3-Methyl-7-phenylpyrrolo[1,2-c]imidazol-5-one 58. FVP of
methyl 3-(2-methylimidazol-1-yl)-3-phenylacrylate 51 (42 mg, Tf
) 875 °C, Ti ) 160 °C, P ) 0.010-0.060 Torr, t ) 10 min) gave
3-methyl-7-phenylpyrrolo[1,2-c]imidazol-5-one 58 (33 mg, 91%)
as a yellow solid; mp > 200 °C (dec); (Found: M+ 210.0793.
C13H10N2O requires M 210.0793); δH 7.72-7.67 (2H, m), 7.57-
7.48 (3H, m), 7.02 (1H, s), 6.06 (1H, s), and 2.59 (3H, s); δC 163.4
(quat), 151.3 (quat), 147.6 (quat), 133.9 (quat), 131.7, 130.0 (quat),
129.1 (2CH), 127.3 (2CH), 126.6, 114.3, and 13.9 (CH3); m/z 210
(M+, 21%), 182 (14), 169 (29), 154 (10), 140 (49), 128 (28), 114
(62), 102 (78), and 42 (100).
Pyrrolo[1,2-a]benzimidazol-1-one 6. Pyrolysis conditions for
methyl 3-(benzimidazol-1-yl)-acrylate 61 required optimization of
sublimation temperature by small-scale reactions (50 mg, Tf )
950 °C, Ti ) 50-200 °C, Prange ) 0.01-0.05 Torr, t ) 12 min)
leading to pyrrolo[1,2-a]benzimidazol-1-one 6. However, pyrolysis
on a larger scale was complicated by poor volatility (resulting in
degradation of substrate) and degradation of products at the furnace
exit/trap due to the high furnace temperature. Optimum conditions
utilized a dry ice/acetone cold finger trap and slow sublimation of
the substrate at an inlet temperature of 115 °C (0.50 g, 2.5 mmol,
Ti ) 115 °C, Prange ) 0.01-0.10 Torr, t ) 105 min) after which
the pyrolysate was rinsed with dry ether from the cold trap surface
under a dry nitrogen atmosphere. The crude product was absorbed
onto silica and rapidly purified by dry flash chromatography (70%
ethyl acetate in hexane) to give pyrrolo[1,2-a]benzimidazol-1-one
632 (0.30 g, 71%); mp 106-108 °C (from cyclohexane); (Found:
M+ 170.0481. C10H6N2O requires M 170.0480); δH 7.62 (2H, dd,
3J ) 7.8 and 4.2), 7.35-7.12 (2H, m), 7.24 (1H, d, 3J ) 6.1), and
6.27 (1H, d, 3J ) 6.1); δC 162.4 (quat), 159.2 (quat), 148.9 (quat),
135.0, 132.6, 129.9 (quat), 127.2, 124.4, 121.8, and 111.7; m/z 170
(M+, 31%), 143 (15), 142 (100), 118 (25), 115 (32), 114 (13), 102
(15), 91 (11), and 88 (11).
3-Phenylpyrrolo[1,2-a]benzimidazol-1-one 63. Pyrolyses of
methyl 3-(benzimidazol-1-yl)-3-phenylacrylate 62 (92 mg, 0.33
mmol, Tf ) 950 °C, Ti ) 50-180 °C, Prange ) 0.03-0.12 Torr, t
) 23 min) using a dry ice/acetone cold finger trap were also
complicated by thermal degradation of the product at the exit point
of the furnace. The pyrolysate was rinsed from the trap in dry ether,
absorbed onto silica, and purified by dry flash chromatography (50%
ethyl acetate in hexane) to give 3-phenylpyrrolo[1,2-a]benzimidazol-
1-one 63 (29 mg, 36%); mp 120-122 °C; (Found: M+ 246.0790.
Methyl 3-(Benzimidazol-1-yl)-acrylate 61. Methyl propynoate
10 (4.20 g, 50 mmol) was added dropwise to a stirred solution of
benzimidazole (5.90 g, 50 mmol) in tetrahydrofuran (40 cm3) and
heated under reflux for 4 h. The solution was stirred overnight.
The solvent was removed under reduced pressure, and the crude
product was recrystallized from toluene (15 cm3) to afford methyl
3-(benzimidazol-1-yl)-acrylate 61 as a 44:56 E/Z isomer mixture
(9.58 g, 95%); mp 102-104 °C (lit.,35 Z-isomer 95.5-96.5 °C,
E-isomer 111.0-112.0 °C); δH (E-isomer) 8.06 (1H, s), 7.96 (1H,
d, 3J ) 14.5), 7.72 (1H, m), 7.31-7.21 (3H, m), 6.14 (1H, d, 3J )
14.5), and 3.70 (3H, s); δH (Z-isomer) 9.09 (1H, s), 7.72 (1H, m),
3
3
7.31-7.21 (3H, m), 6.94 (1H, d, J ) 10.4), 5.52 (1H, d, J )
10.4), and 3.67 (3H, s); δC (E- and Z-isomers) 166.5 (quat), 164.9
(35) Kashima, C.; Tajima, T.; Omote, Y. J. Heterocycl. Chem. 1984,
21, 133-138.
(36) Klein, J.; Zitrin, S. J. Org. Chem. 1970, 35, 666-669.
8768 J. Org. Chem., Vol. 72, No. 23, 2007

Route to Pyrroloisoindolone and Pyrroloimidazolones
C16H10N2O requires M 246.0793); δH 8.20-8.15 (2H, m), 7.73 (1H,
ddd, 3J ) 7.9, 4J ) 1.1, and nJ ) 0.7), 7.66 (1H, ddd, 3J ) 7.9, 4J
Acknowledgment. We are grateful to The University of
Edinburgh for financial support and to Dr. Elizabeth Stevenson
for some preliminary experiments.
n
3
) 1.1, and J ) 0.7), 7.55-7.46 (3H, m), 7.34 (1H, td, J ) 7.6
and 4J ) 1.2), 7.24 (1H, td, 3J ) 7.6 and 4J ) 1.2), and 6.44 (1H,
s); δC 162.6 (quat), 148.7 (quat), 147.2 (quat), 131.8, 129.8 (quat),
129.0 (2CH), 128.6 (quat), 128.2 (2CH), 127.1, 125.4 (quat), 124.2,
121.8, 121.7, and 111.8; m/z 246 (M+, 34%), 219 (23), 218 (62),
194 (9), 147 (10), 109 (23), and 86 (100).
Supporting Information Available: Full experimental details
for the synthesis of 9, 47, 48, and 49 and FVP of 23 and 25; NOESY
spectrum of 24. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO0712502
J. Org. Chem, Vol. 72, No. 23, 2007 8769