Efficient and regioselective synthesis of functionalized pyrroles by cyclocondensation of 1,3-dicarbonyl dianions with α-azidoketones

Article abstract of DOI:10.1039/b207840f

The cyclocondensation of 1,3-dicarbonyl dianions with α-azidoketones regioselectively afforded 2-alkylidenepyrrolidines which were transformed into functionalized pyrroles by treatment with acid.

Full text of DOI:10.1039/b207840f

Efficient and regioselective synthesis of functionalized pyrroles by
cyclocondensation of 1,3-dicarbonyl dianions with a-azidoketones
Peter Langer* and Ilia Freifeld
Institut für Chemie und Biochemie der Ernst-Moritz-Arndt-Universität Greifswald, Soldmannstr. 16,
D-17487 Greifswald, Germany. E-mail: peter.langer@uni-greifswald.de; Fax: (+49) 3834-864373
Received (in Cambridge, UK) 9th August 2002, Accepted 20th September 2002
First published as an Advance Article on the web 14th October 2002
The cyclocondensation of 1,3-dicarbonyl dianions with a-
azidoketones regioselectively afforded 2-alkylidenepyrroli-
dines which were transformed into functionalized pyrroles
by treatment with acid.
Functionalized pyrroles and 2-alkylidenepyrrolidines are pre-
sent in a number of pharmacologically relevant natural and
unnatural products and represent useful synthetic intermediates.
2-Alkylidenepyrrolidines have been used as key intermediates
during the synthesis of mitomycin antitumor antibiotics pos-
sessing antibacterial activity.1 Functionalized pyrroles are
building blocks of natural tetrapyrrole pigments,2 such as
porphobilinogen or bilirubin, and various other natural products
and their analogues.3 The pyrrole zomepirac possesses analgetic
and antiphlogistic activity and has clinical applications. Substi-
tuted oligopyrroles are of interest in the field of material
sciences.
Pyrroles have been prepared mainly by using the classic
Knorr procedure which proceeds by initial formation of a
carbon–nitrogen and subsequent formation of a carbon–carbon
bond.4 The synthesis of alkyl-substituted pyrroles by this
method is problematic, since regioisomers are generally formed
for non-stabilized enamine intermediates. The classic Hantzsch
procedure also relies on the formation of enamines.4d The
regioselectivity strongly depends on the substituents of the
Scheme 1 Synthesis of 4a and 5a: i, 2.4 equiv. LDA, THF, 0 °C; ii, 278 ?
20 °C; iii, PPh3, 24 h, 45 °C; iv, TFA, CH2Cl2, 1 h, 20 °C.
starting materials.
The proposed biosynthetic pathway of natural products such
as porphobilinogen relies on the formation of a carbon–carbon
rather than a carbon–nitrogen bond in the first step.5 Only very
few biomimetic pyrrole syntheses have been reported so far.6
Herein, we wish to report what are, to the best of our knowledge,
the first cyclocondensations of 1,3-dicarbonyl dianions7 with a-
azidoketones which can be considered as masked a-aminoke-
tones.8 These biomimetic transformations afforded function-
alized 2-alkylidenepyrrolidines and pyrroles with very good
regioselectivity.
Our initial attempts to induce a condensation of acetoacetate
d4 synthons with a-azidocarbonyl derivatives were unsuccess-
ful. The Lewis acid mediated reaction of 3-azidobutan-2-one
(2a) with 1-ethoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene, an
electroneutral equivalent of the dianion of ethyl acetoacetate
(1a), resulted in formation of a complex mixture from which the
desired open-chain product 3a could be isolated, however, in
only low yield (Scheme 1). Although condensations of simple
silyl enol ethers with a-azidoketals have been reported,6a the
reaction of 1-ethoxy-1,3-bis(trimethylsilyloxy)-1,3-butadiene
with a-azidoketals proved unsuccessful. The problem was
eventually solved by application of the free dianion of 1a which
was generated by 2.4 equiv. of LDA. The condensation of
dilithiated 1a with 2a afforded the alcohol 3a in good yield. The
formation of the dianion allowed the functionalization of the
terminal (rather than the central) carbon atom of 1a. The
reaction proceeded with excellent regio- and chemoselectivity.
The diastereoselectivity (3+1) was only moderate, but irrelevant
to pyrrole synthesis (vide infra). To avoid extensive side
reactions, such as polymerization, deprotonation and reduction
of 2a, a number of parameters had to be optimized.† This
included the reaction time, temperature, stoichiometry and
concentration.
Hydrogenation of 3a (H2, Pd/C) directly afforded the desired
2-alkylidenepyrrolidine 4a by deprotection and subsequent
nucleophilic attack of the amino onto the carbonyl group (15%
yield).† The yield could be greatly improved by use of PPh3
(70%). The cyclocondensation proceeded by a domino
Staudinger-aza-Wittig reaction with subsequent migration of
the double bond. The product was formed with good Z-
selectivity, due to formation of an intramolecular hydrogen
bond N–H…O. Treatment of a CH2Cl2 solution of 4a with TFA
gave the desired alkyl-substituted pyrrole 5a by elimination of
water and migration of the exocyclic double bond.
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CHEM. COMMUN., 2002, 2668–2669
This journal is © The Royal Society of Chemistry 2002

Table 1 Products and yields
major isomer): d = 1.14–1.32 (m, 9 H, 3 3 CH3), 2.78 (m, 2 H, 4-H),
3.39–3.65 (m, 1 H, 6-H), 3.54 (s, 2 H, 2-H), 4.20 (q, J = 7 Hz, 2 H,
CH2CH3). 13C NMR (50.3 MHz, CDCl3): d = 13.35, 14.05, 23.77 (CH3),
49.34, 50.79, 61.56 (CH2), 64.21 (CH), 74.31 (C), 166.79, 203.91 (CNO).
MS (DCI, 70 eV): 261 ([M + NH4]+, 40), 216 (24), 200 (40), 190 (100), 147
(40).
Entry
R1
R2
R3
R4
3 [%]a
4 [%]a 5 [%]a
a
b
c
d
e
f
g
h
i
H
H
H
H
OMe
OMe
Me
Et
H
H
H
H
H
H
H
H
H
H
OEt
OEt
Me
H
Me
H
Me
H
Me
H
Me
H
H
H
Me
H
55
57
69
60
51
53
50
51
71
70
51
60
73
71
70
68
76
65
81
78
76
72
—
78
—
—
65
72
46
71
0
0
0
OtBu
OtBu
OMe
OMe
OMe
OEt
NEt2
OEt
OEt
Ethyl (4,5-dimethyl-pyrrolidin-2-ylidene)acetate (4a): to a THF solution
(10 ml) of 3a (0.2 g, 0.82 mmol) was added PPh3 (0.258 g, 0.98 mmol) at
20 °C and the reaction mixture was stirred for 24 h at 45 °C. The solution
was cooled to ambient and water (50 ml) was added. The organic and the
aqueous layer were separated and the latter was extracted with CH2Cl2 (3 3
50 ml). The combined organic layers were extracted with brine, dried
(Na2SO4), filtered and the solvent of the filtrate was removed in vacuo. The
residue was purified by chromatography (silica gel, ether–petroleum ether
= 1+2) to give 4a as a yellow oil (114 mg, 70%, mixture of diastereomers).
1H NMR (250 MHz, CDCl3): d = 1.04–1.38 (m, 9 H, 3 3 CH3), 2.64 (m,
2 H, ring-CH2), 3.60, 3.70 (2 3 q, J = 6 Hz, 1 H, CHCH3, diastereomers),
4.13 (q, J = 7 Hz, 2 H, CH2CH3), 4.52, 4.54 (2 3 s, 1 H, CNCH,
diastereomers), 7.74, 7.81 (2 3 br, 1 H, NH). 13C NMR (50.3 MHz, CDCl3):
d = 13.18, 14.64, 17.27, 21.85, 23.26 (CH3), 45.98, 47.38, 58.54, 58.57
(CH2), 62.75, 64.36, 78.25, 78.41 (CH), 110.42, 110.43 (C), 162.43
(CNCO2Et), 170.43 (CNO). MS (EI, 70 eV): 199 (M+, 100), 184 (26), 156
(84), 154 (64), 110 (47); the exact molecular mass for C10H17O3N m/z =
199.1208 ± 2 mD (M+) was confirmed by HRMS (EI, 70 eV).
0
70
75
79
81
32
42b
91
88
H
Me
Bn
j
k
l
H
H
–CH2CH2O–
m
n
–(CH2)3–
–(CH2)3–
OEt
OEt
a Isolated yields. All pyrrolidines 4 (except for 4b,d) were obtained as
diastereomeric mixtures (ds = 5+1–1.5+1, assignment arbitrary). b A small
amount of a prototropic isomer is contained in 5l.
To study the preparative scope of the new methodology the
substituents of the 1,3-dicarbonyl compound and of the a-
azidoketone were systematically varied (Table 1). The reaction
of the dianion of 1a with a-azidoacetone (2b) gave 3b which
was transformed into pyrrolidine 4b and pyrrole 5b. Starting
with t-butyl acetoacetate (1b), pyrrolidines 4c–d were prepared.
Treatment of 4c–d with TFA resulted in decomposition. The
cyclocondensation of 2a,b with dilithiated methyl 4-methox-
yacetoacetate (1c) afforded the Z-configured pyrrolidines 4e–f
in good yields and as diastereomeric mixtures. The correspond-
ing pyrroles were again not available, due to destruction of the
substrate. Starting with methyl 3-oxopentanoate (1d) and ethyl
3-oxohexanoate (1e), pyrrolidines 4g–h and pyrroles 5g–h
(containing additional ring substituents) were prepared. The
reaction of 2a with dilithiated N,N-diethylacetylacetic amide
(1f) gave 3i which directly afforded pyrrole 5i upon treatment
with PPh3. The cyclocondensation of ethyl 2-methylacetoace-
tate (1g) with 2b afforded pyrrolidine 4j and pyrrole 5j
(containing an additional substituent at the side-chain). Sim-
ilarly, pyrrole 5k was prepared from ethyl 2-benzylacetoacetate
(1h). The use of cyclic substrates was next studied. Starting with
2-acetyl-g-butyrolactone (1i), pyrrolidine 4l and pyrrole 5l were
prepared. The cyclocondensation of 2a,b with dilithiated ethyl
cyclohexanone-2-carboxylate (1j) gave pyrrolidines 4m–n
which were transformed into the bicyclic pyrroles 5m–n.
P. L. thanks Professor A. de Meijere for his support. Financial
support by the Fonds der Chemischen Industrie e. V. (Liebig-
scholarship and funds for P. L.) and by the Deutsche
Forschungsgemeinschaft (Heisenberg-scholarship for P. L.) is
gratefully acknowledged.
Ethyl (4,5-dimethyl-pyrrol-2-yl)acetate (5a): to a CH2Cl2 solution (10
ml) of 4a (0.095 g, 0.52 mmol) was slowly added TFA (0.5 ml) and the
solution was stirred at 20 °C for 1 h. The solvent and the acid were removed
in vacuo and the residue was purified by chromatography (silica gel, ether–
petroleum ether = 1+10) to give 5a as a red oil (40 mg, 46%). 1H NMR (250
MHz, CDCl3): d = 1.31 (t, J = 7 Hz, 3 H, CH2CH3), 1.99 (s, 3 H, CH3),
2.26 (s, 3 H, CH3), 3.58 (s, 2 H, CH2CO2Et), 4.18 (q, J = 7 Hz, 2 H,
CH2CH3), 5.78 (s, 1 H, CH), 8.17 (br, 1 H, NH). 13C NMR (50.3 MHz,
CDCl3): d = 10.71, 10.89, 14.14 (CH3), 33.29, 60.99 (CH2), 109.03 (CH),
114.00, 120.39, 123.61, 171.41 (C). MS (EI, 70 eV): 181 (M+, 23), 108
(100); the exact molecular mass for C10H15O2N m\z = 181.1103 ± 2 mD
(M+) was confirmed by HRMS (EI, 70 eV). All new compounds were
characterized spectroscopically and gave correct elemental analyses and/or
high resolution mass data.
1 Mitomycins: (a) J. R. Luly and H. Rapoport, J. Am. Chem. Soc., 1983,
105, 2859; (b) J. Rebek Jr., S. H. Shaber, Y.-K. Shue, J.-C. Gehret and S.
Zimmerman, J. Org. Chem., 1984, 49, 5164.
2 For natural tetrapyrrole pigments such as bilirubin, see: (a) H. Falk, The
Chemistry of Linear Oligopyrroles and Bile Pigments, Springer-Verlag,
Wien, 1989, p. 355; (b) C. J. Dutton, C. J. R. Fookes and A. R. Battersby,
J. Chem. Soc., Chem. Commun., 1983, 1237; (c) F.-P. Montforts and U.
M. Schwartz, Angew. Chem., 1985, 97, 767; F.-P. Montforts and U. M.
Schwartz, Angew. Chem., Int. Ed. Engl., 1985, 24, 775.
3 For other natural products, see: (a) G. Stork, Y. Nakahara, Y. Nakahara
and W. J. Greenlee, J. Am. Chem. Soc., 1978, 100, 7775; (b) G. Stork and
E. Nakamura, J. Am. Chem. Soc., 1983, 105, 5510. For the application of
unsubstituted 2-alkylidenepyrrolidinones to the synthesis of camptothe-
cin, see (c) W. Shen, C. A. Coburn, W. G. Bornmann and S. J.
Danishefsky, J. Org. Chem., 1993, 58, 611. See also (d) A. Müller, A.
Maier, R. Neumann and G. Maas, Eur. J. Org. Chem., 1998, 1177.
4 (a) R. J. Sundberg, in Comprehensive Heterocyclic Chemistry, ed. C. W.
Bird and G. W. H. Cheeseman, Pergamon Press, Oxford, 1984, vol. 4, p.
331. For alternative approaches, see (b) P.-K. Chiu, K.-H. Lui, P. N.
Maini and M. P. Sammes, J. Chem. Soc., Chem. Commun., 1987, 109; (c)
D. H. R. Barton, J. Kervagoret and S. Z. Zard, Tetrahedron, 1990, 46,
7587; (d) T. Eicher and S. Hauptmann, Chemie der Heterocyclen.,
Thieme Verlag, Stuttgart. 1994, p. 94.
Notes and references
†
Typical experimental procedures: Ethyl 3-oxo-5-methyl-5-hydroxy-
6-azidoheptanoate (3a): To a THF solution (35 ml) of diisopropylamine
(0.92 g, 9.2 mmol) was added nBuLi (3.9 ml, 9.2 mmol, 23% solution in
hexane) at 0 °C. After stirring for 15 min 1a (0.51 g, 3.9 mmol) was added
and the solution was stirred for 1 h at 0 °C. A THF solution (5 ml) of 2a (400
mg, 3.54 mmol) was added at 278 °C and the reaction mixture was warmed
to ambient temperature over 12 h. After stirring for 3 h at 20 °C a saturated
aqueous solution of NH4Cl (50 ml) was added, the organic layer was
separated and the aqueous layer was extracted with Et2O (2 3 70 ml) and
with CH2Cl2 (2 3 50 ml). The combined organic layers were extracted with
brine, dried (Na2SO4), filtered and the solvent of the filtrate was removed in
vacuo. The residue was purified by chromatography (silica gel, ether–
petroleum ether (bp 40–70 °C) = 1+4 ? 1+3) to give 3a as a yellow oil (471
mg, 55%, 3+1 mixture of diastereomers). 1H NMR (250 MHz, CDCl3,
5 G. F. Barnard, R. Itoh, L. Hohberger and D. Shemin, J. Biol. Chem., 1977,
252, 8965.
6 (a) H. Bertschy, A. Meunier and R. Neier, Angew. Chem., 1990, 102, 828;
H. Bertschy, A. Meunier and R. Neier, Angew. Chem., Int. Ed. Engl.,
1990, 29, 777. For aza-Wittig reactions, see (b) F.-P. Montforts, U. M.
Schwartz and G. Mai, Liebigs Ann. Chem., 1990, 1037. For reactions of
dianions with aziridines, see (c) B. Lygo, Synlett, 1993, 765.
7 L. Weiler, J. Am. Chem. Soc., 1970, 92, 6702.
8 For reviews of work from our laboratory, see: (a) P. Langer, Chem. Eur.
J., 2001, 7, 3858; (b) P. Langer and M. Döring, Eur. J. Org. Chem., 2002,
221; (c) P. Langer, Synthesis, 2002, 441.
CHEM. COMMUN., 2002, 2668–2669
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