A novel one-pot pyrrole synthesis via a coupling-isomerization-stetter-paal-knorr sequence

Article abstract of DOI:10.1021/ol0165185

Equation presented 1,2,3,5-Tetrasubstituted pyrroles can be synthesized in good yields in a one-pot, three-step, four-component process by a coupling-isomerization-Stetter reaction-Paal-Knorr sequence of an electron-poor (hetero)aryl halide, a terminal propargyl alcohol, an aldehyde, and a primary amine. The structures of the 1,4-diketone 4f and the pyrrole 6b were additionally supported by X-ray structure analyses.

Full text of DOI:10.1021/ol0165185

ORGANIC
LETTERS
2001
Vol. 3, No. 21
3297-3300
A Novel One-Pot Pyrrole Synthesis via a
Coupling−Isomerization−Stetter−Paal−Knorr
Sequence†
Roland U. Braun, Kirsten Zeitler,‡ and Thomas J. J. Mu1ller*
Department Chemie, Ludwig-Maximilians-UniVersita¨t Mu¨nchen,
Butenandtstr. 5-13 (Haus F), D-81377 Mu¨nchen, Germany
tom@cup.uni-muenchen.de
Received July 30, 2001
ABSTRACT
1,2,3,5-Tetrasubstituted pyrroles can be synthesized in good yields in a one-pot, three-step, four-component process by a coupling−isomerization−
Stetter reaction−Paal−Knorr sequence of an electron-poor (hetero)aryl halide, a terminal propargyl alcohol, an aldehyde, and a primary amine.
The structures of the 1,4-diketone 4f and the pyrrole 6b were additionally supported by X-ray structure analyses.
One-pot multicomponent processes have recently gained a
considerable and steadily increasing academic, economic, and
ecological interest because they address very fundamental
principles of synthetic efficiency and reaction design.1
Additionally, the prospect of extending one-pot reactions into
combinatorial and solid-phase syntheses1c,2 promises mani-
fold opportunities for developing novel lead structures of
pharmaceuticals, catalysts, and even novel molecule based
materials. With a palladium-copper-catalyzed domino cross-
coupling-isomerization sequence of electron-poor halogen-
substituted π-systems and 1-aryl prop-2-yn-1-ols furnishing
1,3-di(hetero)aryl enones (i.e., chalcones)3 we have recently
found a very efficient entry to three-component one-pot
syntheses of pyrrolidines,3 pyrimidines,4 and 1,5-benzohet-
eroazepines5 (Scheme 1).
clic classes can be readily accessed. Among numerous
heterocycles the pyrrole core has always been one of the
most prominent since it constitutes important classes of
natural products,6 synthetic pharmaceuticals,6c and electrically
conducting materials such as polypyrroles.7 In particular,
1,2,3,5-tetrasubstituted pyrroles are highly biologically active
and have proven to display antibacterial,8 antiviral (also anti-
HIV-1),9 antiinflammatory,10 and antioxidant11 activity and
to inhibit cytokine-mediated diseases.12 Thus, applying our
Scheme 1. One-Pot Syntheses of Pyrazolines, Pyrimidines,
and Benzoheteroazepines Based upon a Coupling-Isomerization
Sequence
Considering the mild reaction conditions, quite a number
of generic structures of pharmaceutically relevant heterocy-
† Dedicated to Prof. Dr. Rolf Gleiter on the occasion of his 65th birthday.
‡ X-ray crystal structure analysis.
(1) (a) Ugi, I.; Do¨mling, A.; Werner, B. J. Heterocycl. Chem. 2000, 37,
647. (b) Posner, G. H. Chem. ReV. 1986, 86, 831. (c) Weber, L.; Illgen, K.;
Almstetter, M. Synlett 1999, 366.
(2) Kobayashi, S. Chem. Soc. ReV. 1999, 28, 1.
(3) Mu¨ller, T. J. J.; Ansorge, M.; Aktah, D. Angew. Chem., Int. Ed. 2000,
39, 1253.
(4) Mu¨ller, T. J. J.; Braun, R.; Ansorge, M. Org. Lett. 2000, 2, 1967.
10.1021/ol0165185 CCC: $20.00 © 2001 American Chemical Society
Published on Web 09/18/2001

coupling-isomerization concept toward the synthesis of
pyrroles it can be easily envisioned that 1,2,3,5-substituted
pyrroles should be accessible by combining a Stetter reaction,
furnishing the 1,4-diketones,13 and a subsequent Paal-Knorr
cyclocondensation (Scheme 2).6a,b,d Here, we wish to com-
coupling in boiling triethylamine.15 In all cases the beige to
yellow 1,2,4-tri(hetero)aryl-1,4-diketones 4 were obtained in
75-88% yield (Table 1).16
The NMR spectroscopic data support the formation of the
1,4-diketones, in particular, in the 1H NMR spectra of 4 by
the indicative appearance of the ABM-spin system with the
characteristic geminal and vicinal coupling constants for the
3
3
methylene group resonances (2J ) 18.0, J ) 4.3, J ) 9.6
Hz) and the vicinal coupling constants for the methine
resonances (3J ) 4.4, 3J ) 9.6 Hz). Furthermore, the structure
of 4 was unambiguously supported by an X-ray crystal
structure analysis (Figure 1) of compound 4f17 (Table 1, entry
6).
Scheme 2. Retrosynthetic Concept for a Four-Component
Pyrrole Synthesis
municate first synthetic studies on a novel one-pot pyrrole
synthesis based upon a coupling-isomerization-Stetter-
Paal-Knorr sequence.
First, we tested the compatibility of the Stetter addition
of aldehydes to the in situ formed chalcone functionality.
Thus, we submitted p-bromo benzonitrile (1a) or 2-bromo
pyridine (1b), (hetero)aryl propynols 2,14 and after some
reaction time (hetero)aryl aldehydes 3 in the presence of a
thiazolium salt to the reaction conditions of the Sonogashira
(5) Braun, R. U.; Zeitler, K.; Mu¨ller, T. J. J. Org. Lett. 2000, 2, 4181.
(6) For excellent reviews, see: (a) Gossauer, A. Die Chemie der Pyrrole;
Springer-Verlag: Berlin, Heidelberg, New York, 1974. (b) Gossauer, A.
In Houben-Weyl, Methoden der Organischen Chemie; Kreher, R., Ed.; G.
Thieme Verlag: Stuttgart, 1994; Bd. E6a, p 556. (c) Gribble, G. W. In
ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon Press: Oxford, New York, Toronto,
Sydney, Paris, Frankfurt, 1996; Vol. 2, p 207. (d) Sundberg, R. J. In
ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C. W.,
Scriven, E. F. V., Eds.; Pergamon Press: Oxford, New York, Toronto,
Sydney, Paris, Frankfurt, 1996; Vol. 2, 119. (e) Fu¨rstner, A. Synlett 1999,
1523.
Figure 1. ORTEP plot of compound 4f.
Finally, we have combined the one-pot coupling-isomer-
ization-Stetter reaction with the fourth step, i.e., a Paal-
Knorr pyrrole reaction for designing a novel four-component
pyrrole synthesis. Thus, applying p-bromo benzonitrile (1a)
and 1-phenyl propyn-1-ol (2a) to the conditions of the
chalcone formation, after some reaction time adding (hetero)-
(7) For an interesting review, see: MacDiarmid, A. G. Synth. Met. 1997,
84, 27.
(8) Daidone, G.; Maggio, B.; Schillaci, D. Pharmazie 1990, 45, 441.
(9) (a) Almerico, A. M.; Diana, P.; Barraja, P.; Dattolo, G.; Mingoia,
F.; Loi, A. G.; Scintu, F.; Milia, C.; Puddu, I.; La Colla, P. Farmaco 1998,
53, 33. (b) Almerico, A. M.; Diana, P.; Barraja, P.; Dattolo, G.; Mingoia,
F.; Putzolu, M.; Perra, G.; Milia, C.; Musiu, C.; Marongiu, M. E. Farmaco
1997, 52, 667.
(10) (a) Kimura, T.; Kawara, A.; Nakao, A.; Ushiyama, S.; Shimozato,
T.; Suzuki, K. PCT Int. Appl. WO 0001688 A1 20000113, 2000. (b) Kaiser,
D. G.; Glenn, E. M. J. Pharm. Sci. 1972, 61, 1908.
(15) Typical Procedure (4d). (Table 1, entry 4) A magnetically stirred
solution of 182 mg (1.00 mmol) of 4-bromo benzonitrile (1a), 139 mg (1.05
mmol) of 1-phenyl propyn-1-ol (2a), 14 mg (0.02 mmol) of Pd(PPh3)2Cl2,
and 2 mg (0.01 mmol) of CuI in 5 mL of degassed triethylamine under
nitrogen was heated to reflux temperature for 16 h. After the mixture cooled
to room temperature, 115 mg (1.20 mmol) of furfural (3d) and 57 mg (0.2
mmol) of the thiazolium salt were added, and the reaction mixture was
heated to reflux temperature for 8 h. After being allowed to cool the mixture
was filtered, solvents were removed from the filtrate in vacuo, and the
residue was recrystallized from ethanol to give 261 mg (81%) of analytically
pure 4d as light yellow crystals, mp 179 °C. 1H NMR (CDCl3, 300 MHz):
δ 3.36 (dd, J ) 4.3, 18.0 Hz, 1 H), 4.13 (dd, J ) 9.6, 18.0 Hz, 1 H), 5.21
(dd, J ) 4.4, 9.6 Hz, 1 H), 6.53 (dd, J ) 1.7, 3.6 Hz, 1 H), 7.27 (m, 1 H),
7.42-7.63 (m, 8 H), 7.96 (d, J ) 7.2 Hz, 2 H). 13C NMR (CDCl3, 75
MHz): δ 42.5 (CH2), 48.8 (CH), 111.8 (Cquat), 112.9 (CH), 118.8 (CH),
118.9 (Cquat), 128.4 (CH), 129.0 (CH), 129.5 (CH), 133.0 (CH), 133.8 (CH),
136.4 (Cquat), 143.9 (Cquat), 147.2 (CH), 152.2 (Cquat), 186.9 (Cquat), 197.3
(Cquat). MS (70 eV, m/z %): 329 (M+, 17), 224 (M+ - C6H5CO, 11), 105
(C6H5CO, 40), 95 (C4H3CO, 100). Anal. Calcd for C21H15NO3 (329.4): C,
76.58; H, 4.59; N, 4.25. Found: C, 76.54; H, 4.69; N, 4.19.
(11) Lehuede, J.; Fauconneau, B.; Barrier, L.; Ourakow, M.; Piriou, A.;
Vierfond, J.-M. Eur. J. Med. Chem. 1999, 34, 991.
(12) (a) Kawai, A.; Kawai, M.; Murata, Y.; Takada, J.; Sakakibara, M.
PCT Int. Appl. WO 9802430 A1 19980122, 1998. (b) De Laszlo, S. E.;
Liverton, N. J.; Ponticello, G. S.; Selnick, H. G.; Mantlo, N. B. U.S. Patent
5837719 A 19981117, 1998. (c) De Laszlo, S. E.; Liverton, N. J.; Ponticello,
G. S.; Selnick, H. G.; Mantlo, N. B. U.S. Patent 5792778 A 19980811,
1998. (d) De Laszlo, S. E.; Chang, L. L.; Kim, D.; Mantlo, N. B. PCT Int.
Appl. WO 9716442 A1 19970509, 1997.
(13) (a) Stetter, H.; Kuhlmann, H.; Haese, W. Org. Synth. 1987, 65, 26.
(b) Stetter, H.; Kuhlmann, H. Org. React. 1991, 40, 407. (c) Stetter, H.
Angew. Chem., Int. Ed. Engl. 1976, 15, 639.
(14) The propynols 5 were synthesized according to Krause, N.; Seebach,
D. Chem. Ber. 1987, 120, 1845.
(16) All compounds have been fully characterized spectroscopically and
by correct elemental analysis or HRMS, respectively
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Org. Lett., Vol. 3, No. 21, 2001

Table 1. Three-Component 1,4-Diketone Synthesis Based upon a Coupling-Isomerization-Stetter-Acylation Sequencea
a Reaction conditions: 1.0 equiv of the (hetero)aryl halide 1, 1.05 equiv of the propargyl alcohol 2, 0.02 equiv of (Ph3P)2PdCl2, 0.01 equiv of CuI, 1.2
equiv of the aldehyde 3, 0.2 equiv of the thiazolium salt, and NEt3 (5 mL/mmol halide). b Yields refer to isolated yields of compounds 4 after recrystallization
estimated to be 95% pure as determined by NMR spectroscopy and elemental analysis.
aryl aldehydes 3 in the presence of a thiazolium salt to the
reaction mixture, and finally adding primary amines 5 or
ammonium chloride in the presence of acetic acid, the
pyrroles 6 were formed in moderate yields as a result of a
coupling-isomerization-Stetter-Paal-Knorr sequence (Table
2).18,16
The formation of the pyrroles is strongly supported by the
NMR spectra, in particular, in the 13C NMR spectra of 6 by
the indicative appearance of the quaternary C-3 resonance
at δ 108 and the C-4 methine carbon signal at δ 109 of the
pyrrole core. In addition, the structure of 6 was unambigu-
ously supported by an X-ray crystal structure analysis (Figure
2) of compound 6b (Table 2, entry 2).17
In conclusion, we could show that the mild reaction
conditions of the coupling-isomerization sequence of electron-
poor (hetero)aryl halides with 1-aryl propargyl alcohols
giving rise to chalcones can be extended to a one-pot three-
component synthesis of 1,4-diketones (Stetter reaction) and,
even further, to a one-pot four-component pyrrole synthesis
in the sense of a coupling-isomerization-Stetter-Paal-
Knorr sequence. Further studies directed to extend these one-
Org. Lett., Vol. 3, No. 21, 2001
3299

Table 2. Four-Component Pyrrole Synthesis Based upon a
Coupling-Isomerization-Stetter-Paal-Knorr Sequencea
Figure 2. ORTEP plot of compound 6b.
Acknowledgment. The financial support of the Fonds
der Chemischen Industrie and the Dr.-Otto-Ro¨hm Geda¨cht-
nisstiftung is gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and characterization of compounds 4 and 6. Tables
of data collection parameters, bond lengths and angles,
positional and thermal parameters, and least-squares planes
for 4f and 6b. This material is available free of charge via
the Internet at http://pubs.acs.org.
OL0165185
(17) Crystallographic data (excluding structure factors) for the structures
reported in this paper have been deposited with the Cambridge Crystal-
lographic Data Centre as supplementary publication no. CCDC-167866 (4f)
and no. CCDC-167867 (6b). Copies of the data can be obtained free of
charge on application to CCDC, 12 Union Road, Cambridge CB2 1EZ,
U.K. (Fax: + 44-1223/336-033. E-mail: deposit@ccdc.cam.ac.uk).
(18) Typical Procedure (6b). (Table 2, entry 2) According to ref 15
the coupling-isomerization-Stetter sequence was performed with 364 mg
(2.00 mmol) of 1a, 278 mg (2.1 mmol) of 2a, 44 mg (0.04 mmol) of Pd-
(PPh3)2Cl2, 4 mg (0.02 mmol) of CuI, 230 mg (2.40 mmol) of 3d, and 114
mg (0.4 mmol) of thiazolium salt in 4 mL of triethylamine. After the mixture
cooled, 857 mg (8 mmol) of benzylamine (5a) and 2.5 mL of acetic acid
were added, and the mixture was heated to reflux temperature for 5 d. After
cooling and aqueous workup the residue was chromatographed on silica
gel (ethyl acetate/hexanes 1:6), and the residue was recrystallized from
ethanol to give 444 mg (55%) of analytically pure 6b as colorless crystals,
mp 104-105 °C. 1H NMR (CDCl3, 300 MHz): δ 5.14 (s, 2 H), 6.15 (d, J
) 3.1 Hz, 1 H), 6.36 (dd, J ) 1.8, 3.2 Hz, 1 H), 6.55 (s, 1 H), 6.81-6.84
(m, 2 H), 7.18-7.25 (m, 3 H), 7.31-7.36 (m, 7 H), 7.43 (d, J ) 1.4 Hz,
1 H), 7.50 (d, J ) 8.4 Hz, 2 H). 13C NMR (CDCl3, 75 MHz): δ 48.9
(CH2), 108.8 (Cquat), 109.2 (CH), 111.2 (CH), 112.1 (CH), 119.4 (Cquat),
122.3 (Cquat), 124.6 (Cquat), 125.9 (CH), 127.1 (CH), 127.6 (CH), 127.9
(CH) 128.5 (CH), 128.55 (CH), 129.1 (CH), 132.1 CH), 132.5 (Cquat), 137.4
(Cquat), 138.6 (Cquat), 140.6 (Cquat., 143.0 (CH), 145.1 (Cqua.). MS (70 eV,
m/z(%): 400 (M+, 86), 309 (M+ - C6H5CH2, 100), 91 (C6H5CH2, 32).
Anal. Calcd for C28H20N2O (400.5): C, 83.98; H, 5.03; N, 7.00. Found:
C, 83.88; H, 4.96; N, 6.97.
a Reaction conditions: 1.0 equiv of the aryl halide 1a, 1.05 equiv of the
propargyl alcohol 2a, 0.02 equiv of (Ph3P)2PdCl2, 0.01 equiv of CuI, 1.2
equiv of the aldehyde 3, 0.2 equiv of the thiazolium salt, NEt3 (2.5 mL/
mmol halide), 1.2 equiv of the amine 5, and acetic acid (2.5 mL/5 mL
amine). b Yields refer to isolated yields of compounds 6 after recrystalli-
zation estimated to be 95% pure as determined by NMR spectroscopy and
elemental analysis. c The acetylation occurred under the reaction conditions.
d Nitrogen was transferred from glycine amide.
pot heterocycle syntheses to pharmaceutically and electroni-
cally interesting systems such as oligopyrroles are currently
underway.
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Org. Lett., Vol. 3, No. 21, 2001