In the Laboratory
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Multicomponent Reactions A Convenient Undergraduate Organic Chemistry Experiment
Ricardo Bossio,1 Stefano Marcaccini,* and Roberto Pepino CNR, Dipartimento di Chimica Organica Ugo Schiff, Università di Firenze, Via Gino Capponi 9, I-50121 Firenze, Italy; *
[email protected] Carlos F. Marcos* Departamento de Química Orgánica, Facultad de Veterinaria, Universidad de Extremadura. Avenida de la Universidad s/n, E-10071 Cáceres, Spain; *
[email protected] Multicomponent reactions involving isocyanides (1) include the Passerini reaction (2, 3) and the Ugi reactions (4). In the Passerini reaction, an isocyanide is treated with a carboxylic acid and an aldehyde or a ketone, to give an α-acyloxyamide. If ammonia or a primary amine is added to the mixture, the product is the corresponding bisamide, and the reaction is known as the Ugi 4-component condensation (U-4CC). Surprisingly, despite the considerable synthetic potential and didactic interest of these now classical reactions, their study has rarely been included in undergraduate organic chemistry courses. Here we present two experiments for the synthesis of a β-lactam (5) and a succinimide (6 ), based on a 4-component Ugi condensation. The reactions involved are interesting both for the theoretical, mechanistic, and synthetic concepts and for the laboratory techniques that the students learn while completing the experiments. In a of two-step sequence using simple, commercially available starting materials it is possible to obtain complex organic structures that are present in natural products and pharmaceuticals. A subtle difference in electronic richness in the intermediate explains the formation of one product or the other. Examination of the reaction mechanisms illustrates examples of nucleophilic attack, imide formation, abstraction of acidic protons, reaction intermediates, rearrangements, ring closure, and selective reactions when many different functional groups are present in the same molecule. The experiments also show the preparation of chiral products from a mixture of achiral reagents. The study of the 1H NMR and IR spectra is quite instructive because the β-lactam and the succinimide, though structurally similar, show very clear characteristic signals, which permit identification of both compounds. The approach offers an excellent training to solve real structure elucidation problems. All the reactions involved are high yielding and easy to carry out, reagents and solvent are readily available, and
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reaction products are conveniently purified by crystallization. The experimental procedures for both syntheses are identical except for the choice of the starting amine 4. The first step (Scheme I) consists in a four-component Ugi condensation between (E )-cinnamaldehyde (1), chloroacetic acid (2), cyclohexyl isocyanide (3), and amines 4. Ph
+
CHO
+ c-C6H11NC:
CO2H
Cl
NH2
R
MeOH 20 ˚C, 24 h
4a,b
3
2
1
+
Ph
Ph
Nc-C6H11
CHNR NR 6a,b
5a,b
Nc-C6H11 Ph
CONHc-C6H11
Ph
O
N
Cl
R
RHN
O
O
Cl 7a,b
8a,b
a: R = C6H5 ; b: R = 4-(NO2)C6H4
Scheme I A U-4CC condensation yielding a suitable precursor for the synthesis of 4- or 5-member heterocycles.
This affords the key intermediate (E)-2-[(N-chloroacetyl-Nsubstituted)amino]-4-phenyl-but-3-enoic acid N-cyclohexylamides 8. The mechanism of this reaction, shown in Scheme I, starts with the formation of the imine 5 from the aldehyde 1 and the primary amine 4. Then attack of the isocyanide 3 occurs on the imine 5 and the carboxylic acid 2, as shown, to yield the reaction intermediate 7, which finally suffers acyl rearrangement to give the product 8.
Journal of Chemical Education • Vol. 77 No. 3 March 2000 • JChemEd.chem.wisc.edu
In the Laboratory
Upon treatment with a methanol solution of potassium hydroxide, compounds 8 undergo a ring-closure reaction to give the β-lactams 9 (Scheme II). In the case of using the relatively electron-rich aniline 4a, the product 9a is perfectly stable and is isolated in a high yield. CONHc-C6H11
Ph KOH, MeOH 8a
20 ˚C, 2 h
N C6H5
O 9a
c - C6H11 CONc-C6H11
Ph
N
O
O
KOH, MeOH 8b
20 ˚C, 30 min
N p-(NO2)C6H4
O 9b
Ph
N
H
p-(NO2)C6H4 10
Scheme II Base-promoted ring closure of 8 affords the formation of a 4- or a 5-member heterocycle, depending on the electronic nature of substituent R.
In contrast, when using an aromatic amine containing an electron-withdrawing group on the benzene ring, for example 4-nitroaniline, the β-lactam 9b spontaneously rearranges in the reaction conditions to give the 5-member succinimide 10 as shown in Scheme II. The fact that 4-nitroaniline is a better leaving group than aniline makes the difference, allowing the rearrangement in just one of the cases. Fine tuning of the electron richness of the starting amine permits formation of the 4- or 5-member heterocycles described. The IR spectrum of β-lactam 9a presents a broad peak at 3292 cm᎑1, characteristic of amine NH stretching, and two strong peaks at 1756 and 1651 cm᎑1, corresponding to C= O stretching of, respectively, lactam and amide carbonyls. The IR of succinimide 10 shows a similar NH signal, but also two peaks of different intensity at 1776 and 1699 cm᎑1, which are characteristic stretching signals of carbonyls in 5-member succinimides. The proton NMR spectrum of β-lactam 9a shows 10 aromatic hydrogens between 7.5 and 7.1 ppm, an AB system at 7.03 and 6.57 ppm corresponding to the vinylic hydrogens, a broad multiplet at around 6 ppm corresponding to the NH group, a multiplet at 3.91 ppm corresponding to the cyclohexyl CH attached to the nitrogen, a second AB system at 3.47 and 3.27 ppm corresponding to the ring methylene group, and 10 cyclohexyl hydrogens between 2 and 1 ppm. The NMR spectrum of succinimide 10 is quite similar, with 9 aromatic protons, AB systems for the vinylic hydrogens and the ring CH2, and the characteristic signals corresponding to the cyclohexyl ring. The NH signal is a broad singlet shifted to higher magnetic field with respect to the homologous signal in β-lactam 9a. Experimental Procedure The reactions can be performed in test tubes, small flasks, or small beakers. If the reaction vessels are not provided with suitable joints, they can be stoppered with Parafilm. Additions are made by means of Pasteur pipets. Stirring is provided by means of a magnetic stirring plate.
Synthesis of ( E)-2-[( N-Chloroacetyl-N-phenyl)amino]4-phenylbut-3-enoic Acid N-Cyclohexylamide (8a) A solution of chloroacetic acid (2) (95 mg, 1.0 mmol) in methanol (0.3 mL) is added to a well-stirred solution of aniline (4a) (93 mg, 1.0 mmol) in methanol (0.2 mL). The resulting solution is treated as quickly as possible with a solution of (E )-cinnamaldehyde (1) (132 mg, 1.0 mmol) in methanol (0.3 mL) and then with a solution of cyclohexyl isocyanide (3) (109 mg, 1.0 mmol) in methanol (0.3 mL). The resulting mixture is stirred for 24 h at room temperature and then cooled in an ice–water bath, filtered by suction, and washed with cold isopropanol (0.5–1 mL) and isopropyl ether (0.5–1 mL) to give about 250 mg (61% yield) of 8a as a white solid; mp 174–175 °C. If desired, the product may be recrystallized from ethanol, but it is usually pure enough to perform the next reaction.
Synthesis of ( E)-2-{[ N-Chloroacetyl-N-(4-nitrophenyl)]amino}-4-phenylbut-3-enoic Acid N-Cyclohexylamide (5b) A solution of chloroacetic acid (2) (95 mg, 1.0 mmol) in methanol (0.3 mL) is added to a well-stirred solution of 4-nitroaniline (4b) (138 mg, 1.0 mmol) in methanol (0.2 mL). The resulting solution is treated as quickly as possible with a solution of (E )-cinnamaldehyde (1) (132 mg, 1.0 mmol) in methanol (0.3 mL) and then with a solution of cyclohexyl isocyanide (3) (109 mg, 1.0 mmol) in methanol (0.3 mL). The resulting mixture is stirred for 24 h at room temperature and then cooled in an ice–water bath, filtered by suction, and washed with cold isopropanol (0.5–1 mL) and isopropyl ether (0.5–1 mL) to give 350 mg (74% yield) of 8b as a white solid; mp 193–194 °C (dec). If desired, the product may be recrystallized from a mixture of ethanol and N,N-dimethylformamide, but it is usually pure enough to perform the next reaction. Synthesis of ( E)-1-Phenyl-N-cyclohexyl-2-(1-phenylethen-2-yl)-4-oxazetidine-2-carboxamide (9a) Compound 8a (205 mg, 0.5 mmol) is added to a solution of KOH (1 mL, 0.54 mmol) prepared from 300 mg of KOH and methanol to complete a volume of 10 mL. The resulting mixture is stirred at room temperature for 2 h and then cooled in an ice–water bath and filtered by suction. The collected solid is washed with water and dried to give 150 mg (80% yield) of the β-lactam 9a as a white solid; mp 189–190 °C. If desired, the product may be recrystallized from ethanol. Synthesis of ( E)-1-Cyclohexyl-3-(4-nitrophenylamino)2,5-dioxo-3-(1-phenylethen-2-yl)-1,2,3,4tetrahydropyrrol (10) Compound 8b (228 mg, 0.5 mmol) is added to a solution of KOH (1 mL, 0.54 mmol) prepared from 300 mg of KOH and methanol to complete a volume of 10 mL. The resulting mixture is stirred at room temperature for 30 min and then cooled in an ice–water bath and filtered by suction. The collected solid is washed with water and dried to give 120 mg (55% yield) of the succinimide 10 as a pale yellow solid; mp 216-218 °C. If desired, the product may be recrystallized from a mixture of ethanol and N,N-dimethylformamide.
JChemEd.chem.wisc.edu • Vol. 77 No. 3 March 2000 • Journal of Chemical Education
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In the Laboratory
Spectral Data
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β-Lactam 9a: IR (KBr) ν: 3292 (NH), 1756 (lactam C= O), 1651 (amide C= O) cm᎑1. 1 H NMR (CDCl3, 250 MHz) δ 7.51–7.14 (10 H, m, ArH), 7.03 (1 H, d, J = 16.4 Hz, PhCH= CH), 6.57 (1 H, d, J = 16.4 Hz, PhCH= CH), 6.07 (1 H, m, NH), 3.91 (1 H, m, CHNH), 3.47 and 3.27 (2 H, AB, J = 15.1 Hz, CH2), 1.93–0.99 (10 H, m, cyclohexyl) ppm.
Supplemental material for this article is available in this issue of JCE Online.
Succinimide 10: IR (KBr) ν: 3334 (NH), 2930, 1776 (succinimide C= O), 1699 (succinimide C= O), 1325 (NO2), 1311 (NO2) cm᎑1. 1 H NMR (CDCl3, 250 MHz) δ 8.04–6.47 (9 H, m, ArH), 6.62 (1 H, d, J = 16.0 Hz, PhCH= CH), 6.07 (1 H, d, J = 16.0 Hz, PhCH= CH), 5.49 (1 H, br.s, NH), 3.97 (1 H, m, CHNH), 3.30 and 3.00 (2 H, AB, J = 17.5 Hz, CH2), 2.10–1.11 (10 H, m, cyclohexyl) ppm. Acknowledgments We thank José Delgado Muriel and Ana Fernández Gacio for obtaining the NMR spectra. We also gratefully acknowledge financial support from the Dirección General de Enseñanza Superior of Spain (DGDES Project ref. PB96-0101) and the Consejería de Educación de la Junta de Extremadura y Fondo Social Europeo (ref. IPR98C017).
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Supplemental Material
Note 1. Ricardo Bossio died on 15 September 1999, shortly after the submission of this paper. He will be sorely missed by his friends and colleagues at Florence and Cáceres.
Literature Cited 1. For a recent review on the use of isocyanides in heterocyclic synthesis, see: Marcaccini, S.; Torroba, T. Org. Prep. Proc. Int. 1993, 25, 141–208. 2. Passerini, M. Gazz. Chim. Ital. 1921, 51II, 126, 181; 1922, 52I, 432; 1923, 53, 331, 410; 1924, 54, 529, 540; 1925, 55, 721. 3. Passerini, M.; Ragni, G. Gazz. Chim. Ital. 1926, 56, 826; 1931, 61, 964. 4. See for example: Ugi, I. Isonitrile Chemistry; Academic: New York, 1971. Ugi, I. Angew. Chem. Int. Ed. Engl. 1982, 21, 810. Ugi, I.; Dömling, A.; Hörl, W. Endeavour 1994, 18, 115, and references therein. 5. Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R. Tetrahedron Lett. 1997, 38, 2519. 6. Bossio, R.; Marcos, C. F.; Marcaccini, S.; Pepino, R. Synthesis 1997, 1389.
Journal of Chemical Education • Vol. 77 No. 3 March 2000 • JChemEd.chem.wisc.edu
