An expedient synthesis of pyrrole derivatives by reaction of lithiated methoxyallenes with imines

Article abstract of DOI:10.1055/s-1999-2966

Addition of lithiated methoxyallene 2 to imines provided the expected allenyl amines in good yield. These could be cyclized with base or with silver nitrate to a variety of 2,5-dihydropyrrole derivatives. Selected examples describe their conversion to pyrrolidin-3-ones or 3-methoxypyrroles. Most importantly, this [3+2] cyclization method could also be applied to the synthesis of 2,5-disubstituted derivatives such as 26-28 and also to the preparation of the enantiopure compound 23.

Full text of DOI:10.1055/s-1999-2966

LETTER
1871
An Expedient Synthesis of Pyrrole Derivatives by Reaction of Lithiated
Methoxyallenes with Imines
Marlyse Okala Amombo, Arndt Hausherr, Hans-Ulrich Reissig1*
Institut für Organische Chemie der Technischen Universität Dresden, D-01062 Dresden, Germany
Fax +49(0)351/463-7030; E-mail: Hans.Reissig@chemie.tu-dresden.de
Received 27 August 1999
Abstract: Addition of lithiated methoxyallene 2 to imines provided
the expected allenyl amines in good yield. These could be cyclized
with base or with silver nitrate to a variety of 2,5-dihydropyrrole de-
rivatives. Selected examples describe their conversion to pyrroli-
din-3-ones or 3-methoxypyrroles. Most importantly, this [3+2]
cyclization method could also be applied to the synthesis of 2,5-
disubstituted derivatives such as 26-28 and also to the preparation
of the enantiopure compound 23.
Key words: methoxyallene, imine, allenyl amine, 2,5-dihydropyr-
role, pyrrolidin-3-one, 3-methoxypyrrole
Syntheses of pyrrole derivatives are of great importance
due to their presence in numerous biologically active
compounds.2 Therefore, many routes leading to this class
of heterocycles have been developed.3 In addition, certain
electron-rich pyrrole derivatives are of interest because of
their redox behaviour and their ability to provide polypyr-
roles.4 Lithiated methoxyallene 2 is an extremely valuable
building block for the synthesis of oxygen and nitrogen
heterocycles.5 With carbonyl compounds it provides furan
derivatives after cyclization,6 whereas its reaction with ni-
trones leads to 1,2-oxazines.7 Surprisingly, no additions to
simple imines have been reported,8 which should furnish
pyrrole derivatives. A recent publication describing reac-
tions of 2 with SAMP-hydrazones providing enantiopure
3-methoxy-2,5-dihydropyrrole derivatives9 prompts us to
report our results with various imines.10
Scheme 1
Lithiated methoxyallene 2 was generated by the standard
procedure employing n-butyllithium at -40 °C, and after
addition of N-tosylimine 111 followed by aqueous workup
and purification the primary adduct 3 was obtained in
67% yield (Scheme 1). This intermediate could be hydro-
lyzed with acid to afford an a,ß-unsaturated ketone10 or,
more interestingly, converted into a-amino ester 4 by ozo-
nolysis.12
In analogy to the behaviour of the carbonyl adducts6 cy-
clization of 3 employing 0.15 equivalents of potassium
tert-butoxide in DMSO furnished the desired pyrrole de-
rivative 6 in 84% yield. Since an excess of base converts
6 into 5, the isomerization 3Æ6 is better performed by us-
ing of 0.27 equivalents of silver nitrate in acetone13 which
gave a yield of 93%.14 Cyclization of 3 and elimination of
toluene sulfinate from intermediate 6 proceeded by use of
1.5 equivalents of KOtBu and furnished 3-methoxy-2-
phenylpyrrole (5) in 71% yield. This compound was also
formed by heating the primarily obtained lithium salt of 3
in DMSO. An obvious subsequent transformation of 2,5-
dihydropyrrole derivative 6 is the hydrolysis of its enol
ether moiety; treatment of 6 with 2N aqueous sulfuric acid
provided pyrrolidinone 7 in 96% yield. Analogous exper-
iments were successfully performed with N-tosyl imines
derived from pivalaldehyde and cinnamyl aldehyde. Hav-
ing established that highly reactive imines such as 1 be-
have similarly to carbonyl compounds, we studied less
reactive N-aryl and N-alkyl imines. Scheme 2 presents se-
lected examples of the additions of 2 to readily available
imines 8, 10, 12, 15, and 17. Cyclization either with silver
nitrate or under basic conditions cleanly afforded the ex-
pected pyrrole derivatives 9, 11, 16 and 18 in good to ex-
cellent overall yields, whereas tricyclic compound 13 was
accompanied by the dehydrogenated product 14. Of par-
ticular interest is the smooth formation of double adducts
such as 18 (1:1 mixture of diastereomers) since com-
pounds of this type may be valuable components of su-
pramolecular systems.
Synlett 1999, No. 12, 1871–1874 ISSN 0936-5214 © Thieme Stuttgart · New York

1872
M. O. Amombo et al.
LETTER
Scheme 3
Initial experiments were devoted to the preparation of 5-
alkyl substituted pyrrole derivatives using this route.
Thus, 1-methoxy-1,2-heptadiene could successfully be
employed for this purpose.19 However, it turned out that 1-
methoxy-2-heptyne (24)20 allows an even more efficient
approach (Scheme 4). Its deprotonation and treatment
with KOtBu/HMPA followed by addition of N-tosyl imi-
ne 1 provided allene 25 as a mixture of diastereomers
(1:1) in 50% yield. The base catalyzed cyclization of 25a/
25b afforded a mixture of 2,5-dihydropyrrole derivatives
28a (47%) and 28b (10%); a small amount of 25b was re-
isolated.21 This experiment demonstrates that pyrrole for-
mation is not hampered by the terminal substituent at the
methoxyallene moiety although it proceeds more slowly.
Scheme 2
We also started to prepare enantiopure compounds fol-
lowing this approach (Scheme 3). A phenethyl group at
the imine nitrogen present in 19 induced almost no diaste-
reomeric excess as demonstrated by formation of 20 (ratio
of diastereomers 56:44). However, (R)-glyceraldehyde
derived imine 2115 reacted with lithiated methoxyallene 2
with excellent diastereofacial selectivity. Only syn com-
pounds 22 and 23 were formed as a 1:1 mixture.16 The cy-
clization was completed with silver nitrate to provide
enantiopure 2,5-dihydropyrrole derivative 23 in 57%
yield. The syn-configuration was anticipated according to
literature precedence17 and proven by comparison with a
compound obtained by an independent route;18 in addi-
tion, an X-ray analysis of the analog N-phenyl derivative
unequivocally demonstrated the relative configuration of
these compounds.
Diastereomer 28a was smoothly transformed into 2,5-cis-
substituted pyrrolidin-3-one 26 by acid treatment, or into
5-butyl-3-methoxy-2-phenylpyrrole (27) by base promot-
ed elimination. These high yielding processes demon-
strate that the cyclizations of allenyl amines22 as described
in this letter should allow the preparation of a variety of
highly substituted and functionalized pyrrole derivatives.
First examples of this [3+2] cyclization method also re-
veal that control of relative and absolute configuration is
possible.
Synlett 1999, No. 12, 1871–1874 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Pyrrole Derivatives from Lithiated Methoxyallenes and Imines
1873
(4) a) A. Merz, T. Meyer, Synthesis 1999, 94-99. b) A. Merz, J.
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(5) For a recent review see: H.-U. Reissig, S. Hormuth, W.
Schade, M. Okala Amombo, T. Watanabe, R. Pulz, A.
Hausherr, R. Zimmer, J. Heterocyclic Chem. 2000, in press.
For general reviews on the reactivity of alkoxyallenes see: a)
R. Zimmer, Synthesis 1993, 165-178. b) R. Zimmer, F. A.
Khan, J. Prakt. Chem. 1996, 338, 92-94.
(6) Initial work: a) S. Hoff, L. Brandsma, J. F. Arens, Recl. Trav.
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(7) W. Schade, H.-U. Reissig, Synlett 1999, 632-634.
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(9) V. Breuil-Desvergnes, P. Compain, J.-M. Vatéle, J. Goré,
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(10) M. Okala Amombo, Diplomarbeit, Technische Universität
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(11) a) R. Albrecht, G. Kresze, B. Mlakar, Chem. Ber. 1964, 97,
483-489. b) B. M. Trost, C. Marrs, J. Org. Chem. 1991, 56,
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(12) For a related approach see: M. Braun, K. Opdenbusch, Liebigs
Ann. 1997, 141-145.
Scheme 4
(13) J. A. Marshall, G. S. Bartley, J. Org. Chem. 1994, 59, 7169-
7171. Also see: A. Claesson, K. Sahlberg, K. Luthman, Acta
Chem. Scand. 1979, B33, 303.
(14) Typical procedure, 1+2Æ3Æ6: Lithiated methoxyallene 2
was generated under an atmosphere of dry argon by treating a
solution of 687 mg (9.80 mmol) methoxyallene in 20 ml of
THF at -40 °C with 4.00 ml (8.82 mmol) of n-BuLi (2.2 M in
hexane). After 5 min a solution of 1.70 g (6.54 mmol) of 1 in
7 ml of THF was added over a period of 5 min, the mixture
was stirred for 2 h at -40 to -20 °C and quenched with 20 ml
of H2O. Warming to room temperature was followed by
extraction with diethyl ether (3 x 20 ml) and drying of the
combined extracts (Na2SO4). Removal of the solvent in vacuo
yielded 2.15 g (99%) of crude 3 as a brown solid, which was
purified by washing with diethyl ether. Compound 3 was
obtained as a yellow solid (1.44 g, 67%, m. p. 100-101 °C).
For analytical data see ref.10
Acknowledgement
Generous support of this work by the Deutsche Forschungsgemein-
schaft (Graduiertenkolleg: “Struktur-Eigenschafts-Beziehungen bei
Heterocyclen”) and the Fonds der Chemischen Industrie (Kekulé
fellowship for A. Hausherr) is most gratefully acknowlegded. We
thank Dr. Stephan Hormuth for preliminary experiments with 1 and
2 and Dr. Margit Gruner for measurements and help during interpre-
tation of numerous 2D-NMR spectra.
References and Notes
(1) New address: Institut für Chemie, Freie Universität Berlin,
Takustr. 3, 14195 Berlin
Cyclization of 3: To 300 mg (0.91 mmol) of allene 3 in 7 ml
of acetone was added 42 mg (0.25 mmol) of AgNO3, and the
resulting mixture was stirred in the dark under argon at room
temperature for 3 h. The mixture was filtered through a pad of
celite with ethyl acetate. The filtrate was concentrated to
afford pure 2,5-dihydropyrrole 6 as a yellow solid (280 mg,
93%, m. p. 155-157 °C).
(2) For recent examples see: K. Ishii, H. Ohno, Y. Takemoto, T.
Ibuka, Synlett 1999, 228-230 and references cited.
(3) Reviews: a) R. J. Sundberg in Comprehensive Heterocyclic
Chemistry (Eds. A. R. Katritzky, C. W. Rees), p. 313-376,
Pergamon, Oxford 1984. b) G. P. Beau in Pyrroles (Ed. R. A.
Jones), The Chemistry of Heterocyclic Compounds (Eds. E. C.
Taylor, A. Weissberger), p. 105-294, Wiley: New York 1990.
c) R. J. Sundberg in Comprehensive Heterocyclic Chemistry II
(Eds. A. R. Katritzky, C. W. Rees, E. F. V. Scriven), p. 119-
206, Pergamon: Oxford 1996. d) S. E. Korostova, A. I.
Mikhaleva, A. M. Vasil’tsov, B. A. Trofimov, Russ. J. Org.
Chem. (Engl. Transl.) 1998, 34, 911-948. e) S. E. Korostova,
A. I. Mikhaleva, A. M. Vasil’tsov, B. A. Trofimov, Russ. J.
Org. Chem. (Engl. Transl.) 1998, 34, 1691-1714. f) For a
recent synthesis employing electron-deficient allene
derivatives and imines: Z. Xu, X. Lu, J. Org. Chem. 1998, 63,
5031-5041.
Analytical data of 6: 1H NMR (CDCl3, 300 MHz): d = 7.51 (d,
J = 8.2 Hz, 2 H, Tos), 7.26 (s, 5 H, Ph), 7.18 (d, J = 8.2 Hz, 2
H, Tos), 5.25-5.22 (m, 1 H, 4-H), 4.57 (q, J = 1.6 Hz, 1 H, 2-
H), 4.30-4.25 (m, 2 H, 5-H), 3.50 (s, 3 H, OMe), 2.38 (s, 3 H,
Me).
13C NMR (CDCl3, 75.5 MHz): d = 156.6 (s, C-3), 143.1,
139.4, 135.4 (3 s, i-C), 129.4, 128.3, 128.0, 127.6, 127.3 (5 d,
Ar, Ph), 89.0 (d, C-4), 67.3 (d, C-2), 57.3 (q, OMe), 52.3 (t, C-
5), 21.5 (q, Me). - IR (KBr): n = 3100-3000 cm-1 ( = C-H),
3000-2840 (C-H), 1670-1600 (C=C), 1350-1310, 1160-1120
Synlett 1999, No. 12, 1871–1874 ISSN 0936-5214 © Thieme Stuttgart · New York

1874
M. O. Amombo et al.
LETTER
(19) A. Hausherr, unpublished results, Technische Universität
(SO2), 1250 (C-O). - C18H19NO3S (329.4) Calcd. C 65.63, H
5.81, N 4.25, S 9.73; found C 65.73, H 5.89, N 4.27, S 9.48.
Dresden 1999.
(15) J. Yoshimura, Y. Ohgo, T. Sato, J. Am. Chem. Soc. 1964, 86,
3858-3862. Also see: L. Battistini, F. Zanardi, G. Rassu, P.
Spanu, G. Pelosi, G. G. Fava, M. B. Ferrari, G. Casiraghi,
Tetrahedron: Asymmetry 1997, 8, 2975-2987.
(16) Primary adducts with an N-alkyl substituent such as 22 seem
to undergo faster cyclization to 2,5-dihydropyrrole
derivatives.
(20) Performed in analogy to L. Brandsma, H. D. Verkruijsse, W.
Verboom, P. E. Van Riju, J. Organomet. Chem. 1982, 232,
C1-C4.
(21) The cyclization of 25 is probably stereospecific. Thus,
diastereomer 25a provides only cis-substituted 28a whereas
the slower reacting 25b gives trans-isomer 28b. Details will
be presented in a full paper.
(17) For additions of organometallic reagents to this imine see: ref.
15. For general reviews on stereoselective additions to imines
see: a) N. Risch, M. Arend in Stereoselective Synthesis of
Organic Compounds/Methods of Organic Chemistry
(Houben-Weyl), 4th Ed., Vol. E21b (Eds.: G. Helmchen, R. W.
Hoffmann, J. Mulzer, E. Schaumann), Thieme, Stuttgart 1995,
p. 1833-2010. b) D. Enders, U. Reinhold, Tetrahedron:
Asymmetry 1997, 8, 1895-1946. c) R. Bloch, Chem. Rev.
1998, 98, 1407-1438.
(22) For related 5-endo-trig cyclizations of allenyl amines
furnishing 2,5-dihydropyrrole derivatives see: a) J. S. Prasad,
L. S. Liebeskind, Tetrahedron Lett. 1988, 29, 4253-4256.
b) J. S. Prasad, L. S. Liebeskind, Tetrahedron Lett. 1988, 29,
4257-4260. c) K. Schierle, R. Vahle, E. Steckhan, Eur. J. Org.
Chem. 1998, 509-514. d) H. Ohno, A. Toda, Y. Miwa, T.
Taga, E. Osawa, Y. Yamaoka, N. Fujii, T. Ibuka, J. Org.
Chem. 1999, 64, 2992-2993.
(18) A 1,2-oxazine with syn-configuration could be converted into
23. T. Watanabe, unpublished results, Technische Universität
Dresden 1998.
Article Identifier:
1437-2096,E;1999,0,12,1871,1874,ftx,en;G21599ST.pdf
Synlett 1999, No. 12, 1871–1874 ISSN 0936-5214 © Thieme Stuttgart · New York