Parham-type cycliacylation with Weinreb amides. Application to the synthesis of fused indolizinone systems

Article abstract of DOI:10.1021/ol034194+

(Matrix presented) Weinreb amides behave as efficient internal electrophiles in Parham-type cycliacylation reactions. Thus, aryl- and heteroaryllithiums generated by lithium-halogen exchange undergo intramolecular cyclization to give fused indolizinone systems as pyrrolo[1,2-b]isoquinolines, thieno[2,3-f]indolizinones, and pyrrolo[1,2-b]acridinones in high yields.

Full text of DOI:10.1021/ol034194+

ORGANIC
LETTERS
2003
Vol. 5, No. 7
1115-1117
Parham-Type Cycliacylation with
Weinreb Amides. Application to the
Synthesis of Fused Indolizinone
Systems
Javier Ruiz, Nuria Sotomayor, and Esther Lete*
Departamento de Qu´ımica Orga´nica II, Facultad de Ciencias, UniVersidad del Pa´ıs
Vasco, Apdo. 644, 48080 Bilbao, Spain
qopleexe@lg.ehu.es
Received February 4, 2003
ABSTRACT
Weinreb amides behave as efficient internal electrophiles in Parham-type cycliacylation reactions. Thus, aryl- and heteroaryllithiums generated
by lithium−halogen exchange undergo intramolecular cyclization to give fused indolizinone systems as pyrrolo[1,2-b]isoquinolines, thieno-
[2,3-f]indolizinones, and pyrrolo[1,2-b]acridinones in high yields.
Aryl- and heteroaryllithium compounds1 are interesting
building blocks in synthetic organic chemistry because by
reaction with carbon electrophiles they produce, together with
the formation of a carbon-carbon bond, the transference of
functionality to the electrophilic reagent, so polyfunctional-
ized molecules are prepared in one step. Lithium-halogen
exchange, though mechanistically controversial,2 is a par-
ticularly useful tactic for the metalation of aromatic substrates
because metal-halogen exchange can effectively compete
with the organolithium reaction with internal electrophiles.
Thus, many carbocyclic and heterocyclic ring systems have
been accessed using Parham-type cyclizations, using various
types of internal electrophiles.3 In this context, we had
previously shown4 that iodine-lithium exchange could be
performed on N-(o-iodobenzyl)pyrrole-2-carboxamides, ac-
cessing pyrrolo[1,2-b]isoquinolones by a Parham-type cy-
clization using the N,N-diethylcarbamoyl group as an internal
electrophile. However, moderate yields were obtained, and
the procedure was limited to aromatic rings activated with
donor groups.
With these precedents, we decided to reinvestigate this
protocol using Weinreb amide as an internal electrophile.
This type of amides has been widely used in synthesis,5
although their use in Parham cyclizations is scarce. Thus,
aryl- and heteroaryllithium compounds have been generated
in the presence of this group to give access to benzocy-
clobutenones,6 thieno[2,3-b]thiophenes,7 or methylidenein-
danones.8 Weinreb amides have also been successfully used
as internal electrophiles in cyclization reactions of organo-
(3) For reviews, see: (a) Parham, W. E.; Bradsher, C. K. Acc. Chem.
Res. 1982, 15, 300 (b) Gray, M.; Tinkl, M.; Snieckus, V. In ComprehensiVe
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G.,
Eds.; Pergamon: Exeter, 1995; Vol. 11; p 66. (c) Ardeo, A.; Collado, M.
I.; Osante, I.; Ruiz, J.; Sotomayor, N.; Lete, E. In Targets in Heterocyclic
Systems Vol. 5; Atanassi, O., Spinelli, D., Eds.; Italian Society of
Chemistry: Rome, 2001; p 393. (d) Mealy, M. M.; Bailey, W. F. J.
Organomet. Chem. 2002, 649, 59. (e) Sotomayor, N.; Lete, E. Curr. Org.
Chem. 2003, 7, 275. See also ref 1
(1) (a) Wakefield, B. J. The Chemistry of Organolithium Compounds,
2nd ed.; Pergamon Pres: New York, 1990. (b) Clayden, J. Organolithi-
ums: SelectiVity for Synthesis; Pergamon Press: New York, 2002.
(2) (a) Bailey, W. F.; Patricia, J. I. J. Organomet. Chem. 1988, 352, 1.
(b) Beak, P.; Allen, D. J.; Lee, W. K. J. Am. Chem. Soc. 1990, 112, 1629.
(c) Beak, P.; Allen, D. J. J. Am. Chem. Soc. 1992, 114, 3420. (d) Reich, H.
J.; Green, D. P.; Phillips, N. H. J. Am. Chem. Soc. 1991, 113, 1414. (e)
Bailey, W. F. In AdVances in Detailed Reaction Mechanisms; Coxon, J.
M., Ed.; JAI Press: Greenwich, 1994; Vol 3. p 251. See also ref 1b.
(4) Ardeo, A.; Lete, E.; Sotomayor, N. Tetrahedron Lett. 2000, 41, 5211.
10.1021/ol034194+ CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/14/2003

lithiums derived from alkyliodides, accesing cyclic ketones,9
or vinyliodides, in the synthesis of (-)-brunsvigine10 or the
hexahydrobenzofuran subunit of avermeticin.11
Table 1. Synthesis of Pyrrolo[1,2-b]isoquinolines
N-(o-Iodobenzyl) pyrroles 2 were prepared by alkylation
of N-methoxy-N-methylpyrrole-2-carboxamide with benzyl
bromides 1a-g12 under standard conditions (Scheme 1).
Scheme 1
a Method A: t-BuLi (2.2 equiv), -78 °C, 3 h. b Method B: t-BuLi (2.2
equiv), -78 °C, 3 h; f rt, 4 h. c Yields in parentheses correspond to
products obtained using N,N-diethylamides (see ref 4). d 3 equiv of t-BuLi
was used. e No cyclization product was obtained. 81% of deiodinated
benzylpyrrole was isolated.
These benzylpyrroles 2 were submitted to metalation-
cyclization conditions using 2.2 equiv of t-BuLi at -78 °C
(Scheme 2) As shown in Table 1, good yields of pyrrolo-
obtained except when the aromatic ring bears methoxy
groups on C-6 or C-3 (entries 5 and 7). In these cases,
significantly lower yields of cycled products were obtained
probably due to an equilibration of the intermediate orga-
nolithium prior to cyclization. Besides, a larger excess of
t-BuLi (3 equiv) was necessary to achieve complete cycliza-
tion of benzylpyrrole 2b (entry 2).
Scheme 2a
As shown in Table 1, in all cases, the use of Weinreb
amides as internal electrophiles improved our previous results
in the synthesis of pyrrolo[1,2-b]isoquinolones (yields in
parentheses). Amides are generally useful electrophiles in
Parham cyclizations due to a complex induced proximity
effect (CIPE).13 Thus, lithium-iodine exchange could be
favored first by coordination of the organolithium to the
amide group and second by stabilization of the resulting
aryllithium. The better behavior of Weinreb amides as
internal electrophiles in these cyclizations compared to N,N-
diethylamides could be attributed to the extra stabilization
a (a) t-BuLi (2.2 equiv), -78 °C.
isoquinolones 3a-g were obtained when the reaction mixture
was quenched at low temperature after 3 h (method A). If
the reaction mixture was allowed to warm to room temper-
ature before quenching (method B), good yields were also
(5) For a review, see: (a) Sibi, M. P. Org. Prep. Proced. Int. 1993, 25,
15. For some more recent examples, see, for instance: (b) Molander, G.
A.; McKie, J. A. J. Org. Chem. 1993, 58, 7216. (c) Alberola, A.; Gonza´lez
Ortega, A.; Sa´daba, M. L.; San˜udo, C. Tetrahedron 1999, 55, 6555. (d)
Alberola, A.; AÄ lvaro, R.; Gonza´lez Ortega, A.; Sa´daba, M. L.; San˜udo, C.
Tetrahedron 1999, 55, 13211. (e) Satyamurthi, N.; Singh, J.; Aidhen, I. S.
Synthesis 2000, 375.(f) Wang, X.-J.; Tan, J.; Zhang, L. Org. Lett. 2000, 2,
3107. (g) Suh, Y.-G.; Jung, J.-K.; Seo, S.-Y.; Min, K.-H.; Shin, D.-Y.; Lee,
Y.-S.; Park, O.-H. J. Org. Chem. 2002, 67, 1691.
(6) Aidhen, I. S.; Ahuja, J. R. Tetrahedron Lett. 1992, 33, 5431.
(7) Selnick, H. G.; Radzilowski, E. M.; Ponticello, G. S. Tetrahedron
Lett. 1991, 32, 721.
(8) Hinkley, S. F. R.; Perry, N. B.; Weavers, R. T. Tetrahedron Lett.
1994, 35, 3775.
(12) Iodobenzyl bromides 1 were prepared from the corresponding
benzylic alcohols in two steps. Aromatic iodination of benzylic alcohols
was carried out with I2/CF3CO2Ag in CHCl3 (Janssen, D. E.; Wilson, C.
V. Organic Syntheses; Wiley: New York, 1963; Collect. Vol. IV, p 547)
and was completely regioselective in all cases except e, where a minor
amount of 5-iodo regioisomer was obtained. Subsequent bromination was
accomplished PBr3 in CHCl2 for cases a-f (Charlton, J. L.; Alauddin, M.
M. J. Org. Chem. 1986, 51, 3490), or with HBr (45%) for case f. For
representative experimental procedures and characterization data, see the
Supporting Information.
(13) This concept has been invoked to explain the enhancement of
metalation in hydrogen-metal, metal-metal (Beak, P.; Meyers, A. I. Acc.
Chem. Res. 1986, 19, 356), or halogen-metal exchanges (Beak, P.; Musick,
T.; Liu, C.; Cooper, T.; Gallagher, D. J. J. Org. Chem. 1993, 58, 7330).
(9) Souchet, M.; Clark, R. D. Synlett 1990, 151.
(10) Sha, C.-K.; Hong, A.-W.; Huang, C.-M. Org. Lett. 2001, 3, 2177.
(11) Sha, C.-K.; Huang, S.-J.; Zhan, Z.-P J. Org. Chem. 2002, 67, 831.
1116
Org. Lett., Vol. 5, No. 7, 2003

of the intermediate generated after cyclization by formation
of an internal chelate (Scheme 2).
Table 2. Synthesis of Fused Indolizidinones
To extend the scope of this Parham-type cycliacylation,
we tested the feasibility of using heteroaryllithium com-
pounds to access various fused indolizidinone skeletons. For
this purpose, we chose thiophene and quinoline ring systems
that incorporated N,N-diethylamido and N-methoxy-N-me-
thylamido groups as internal electrophiles. Thus, tenylpyr-
roles 4a,b and quinolinylmethylpyrroles 6a,b were prepared
by standard procedures and submitted to Parham conditions
(Scheme 3). As indicated above, two sets of experiments
method Aa
method Bb
yield (%)
entry
substrate
product
yield (%)
1
2
3
4
4a
4b
6a
6b
5
5
7
7
42d
71
28e
61e
c,d
49
f
20
a Method A: t-BuLi (2.2 equiv), -78 °C, 6 h. b Method B: t-BuLi (2.2
equiv), -78 °C, 6 h; f rt. c No cyclization product was obtained. 88% of
deiodinated tenylpyrrole was isolated. d 3 equiv of t-BuLi was used. e n-
BuLi (2.2 equiv), -90 °C, 5 min. f No cyclization product was obtained.
Deiodinated quinolinylmethylpyrrole was isolated (23%).
Scheme 3
obtained from 6b. However, cyclization of 6b took place
rapidly and efficiently when the heteroaryllithium was
generated with n-BuLi at lower temperature and for a shorter
period of time (-90 °C, 5 min) (entry 4).
In summary, it has been shown that N-(o-iodobenzyl)-
pyrrole-2-carboxyamides tolerate lithium-iodine exchange
reaction conditions, allowing the efficient construction of the
indolizinone nucleus. The N-methoxy-N-methylcarbamoyl
group behaves as an excellent internal electrophile, improving
the results obtained with other amides. This procedure has
also been extended to heteroaryllithums, opening a new route
to heterocyclic systems with potential pharmacological
properties that could compete with previously reported
strategies.14
Acknowledgment. Financial support from Gobierno
Vasco (PI-1999-165), MCYT (BQU2000-0223), and Uni-
versidad del Pa´ıs Vasco is gratefully acknowledged. We also
thank MEC for a grant (J.R.).
were carried out. Heteroaryllithiums were generated with
t-BuLi (2.2 equiv) at - 78 °C and the reaction quenched at
low temperature (method A) or allowed to warm before
quenching (method B). Results are summarized in Table 2.
As shown for benzylpyrroles, in these substrates the N-
methyl-N-methoxycarbamoyl group turned out to be more
efficient internal electrophile than the N,N-diethylcarbamoyl
group in the metalation-cyclization sequence. Thus better
yields of thieno[3,2-f]indolizinone 5 and pyrroloacridinone
7 were obtained from 4b and 6b, respectively (entries 2 and
4). Besides, in both cases cyclization occurred more ef-
ficiently when the reaction was quenched at low temperature
(method A vs method B). No cyclization products were
obtained when heteroaryllithiums derived from 4a and 6a
were allowed to reach rt. In the case of quinolinylmeth-
ylpyrroles 6a,b, decomposition was observed when treated
with t-BuLi at -78 °C, and only a low yield of 7 was
Supporting Information Available: Experimental pro-
cedures and characterization data of compounds 1d, 2d, 3a-
g, 5, and 7. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL034194+
(14) Pyrrolo[1, 2-b]isoquinolines have been synthesized by (a) addition
of ortho-lithiated benzamides to the carbonyl group of the N-benzylpyrrole-
2-carbaldehyde: Iwao, M.; Mahalanabis, K. K.; Watanabe, M.; de Silva,
S. O.; Snieckus, V. Tetrahedron 1983, 39, 1955. (b) Cyclisation of amidyl
radicals derived from O-acylhydroxamic acid derivatives: Clark, A. J.; Filik,
R. P.; Peacock, J. L.; Thomas, G. H. Synlett 1999, 441. (c) Photocyclization
of 1-benzyl-1-pyrrolinium salts: Cho, I.-S.; Tu, C.-L.; Mariano, P. S. J.
Am. Chem. Soc. 1990, 112, 3594. (d) Thieno[3,2-f]indolizinones have been
prepared by classical Friedel-Crafts acylation: Decroix, B.; Morel, J. J.
Heterocycl. Chem. 1991, 28, 81.
Org. Lett., Vol. 5, No. 7, 2003
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