Indresh
Kumar
*ab,
Nisar A.
Mir
a,
Panduga
Ramaraju
a and
Basant P.
Wakhloo
c
aDepartment of Chemistry, Birla Institute of Technology & Science, Pilani 333 031, Rajasthan, India. E-mail: indresh.chemistry@gmail.com; indresh.kumar@bits-pilani.ac.in; Fax: +91 1596 244183; Tel: +91 1596 245073 Ext. 276
bSchool of Biology & Chemistry, College of Science, Shri Mata Vaishno Devi University, Katra 182 320, India
cInstrumentional Division, IIIM-CSIR Lab, Jammu 180 001, India
First published on 8th August 2012
A robust method for the synthesis of substituted pyrrole-3-carboxaldehydes from N-PMP aldimines and succinaldehyde is reported. This reaction involves an organocatalytic direct Mannich reaction, and an acid catalyzed cyclization and oxidative aromatization sequence with high yields (up to 82%).
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Fig. 1 Direct approaches to substituted pyrroles from 1,4-dicarbonyls. |
However, the problems and limitations, such as the harsh cyclization conditions,5g associated with the Paal–Knorr method have driven the development of other methods, which mainly rely on cycloaddition,6 multi-component,7 and metal-mediated reactions.8 Although there are a few indirect routes,9a–c none of the methods offer direct access to substituted pyrrole-3-carboxaldehyde,9d even though these compounds are important synthetic intermediates.10a–c Direct substitution at the C-3 position of pyrrole,10d,e particularly, direct formylation at C-3, remains a challenge because electrophilic substitutions mainly occur at the C-2 position. Therefore, a general strategy to synthesize pyrrole-3-carboxaldehydes from simple building blocks with a minimal number of overall synthetic steps is highly desirable. Additionally, it is also motivating to develop a new method with variation, where 1,4-dicarbonyl compounds serve as the source of the three ring atoms and the other two atoms of the pyrrole moiety could be obtained from imines (eqn (2), Fig. 1).
Organocatalytic cascade reactions involving two or more selective transformations using single/multiple catalysis, serve as powerful tools to conserve energy and minimize the number of synthetic operations.11 With the idea of cascade synthesis for pyrroles in mind, we reasoned that a simple catalytic route for substituted pyrrole-3-carboxaldehydes could be developed from succinaldehyde and imines. Although, imines have been used earlier to synthesize pyrroles,12 to the best of our knowledge, this is the first report to employ such building blocks: aldimines and succinaldehyde. Herein, we report an entirely new synthetic method for the synthesis of substituted pyrrole-3-carboxyaldehdyes, which consists of the following steps viz. a direct Mannich reaction, followed by acid catalyzed cyclization and oxidative aromatization, as a two-step sequence.
As part of our recent interest in the development of synthetic methods for heterocyclic compounds,13 we anticipated that an aqueous solution of succinaldehyde 3,14 a synthetically useful 1,4-dicarbonyl unit, might participate in a cascade sequence similar to aqueous glutaraldehyde used by Hayashi and co-workers for other reactions.15 The optimization study for this direct approach to synthesize pyrrole-3-carboxaldehdye were conducted using N-PMP aldimine 2a pre-formed from p-nitrobenzaldehyde as shown in Table 1.
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Entry | 3 (x M sol.)b | Steps | Conditionsa | Yield (%)c |
a (i) Imine 2 (0.3 mmol), 3 (× M sol, 0.9 mmol), 1 (20 mol%), solvent (3.0 mL); (ii) CH3CO2H (50 mol%, 0.15 mmol), solvent (3.0 mL) DDQ (1.1 eq). b See the ESI.† c Isolated yields refer to 2 (after two steps). d 1 (10 mol%). e CH3CO2H (not added). f Pyrrolidine (20 mol%), CH3CO2H (20 mol%) were used in place of 1. | ||||
1 | 6 M | i | DMF, rt, 10 h | |
ii | DMF, rt, 24 h | <20 | ||
2 | 6 M | i | DMF, rt, 10 h | |
ii | benzene, 40 -C, 6 h | 51 | ||
3 | 6 M | i | CH3CN, rt, 12h | |
ii | CH3CN, 40 -C, 6 h | 34 | ||
4 | 6 M | i | DMSO, rt, 9 h | |
ii | DMSO, 40 -C, 6 h | <20 | ||
5 | 6 M | i | DMSO, rt, 9 h | |
ii | benzene, 40 -C, 6 h | 54 | ||
6 | 6 M | i | DMSO, rt, 9 h | |
ii | Toluene, 60 -C, 4 h | 62 | ||
7 | 4 M | i | DMSO, rt, 7 h | |
ii | Toluene, 60 -C, 4 h | 73 | ||
8 | 3 M | i | DMSO, rt, 6 h | |
ii | Toluene, 70 -C, 2 h | 82 | ||
9d | 3 M | i | DMSO, rt, 10 h | |
ii | Toluene, 70 -C, 2 h | 63 | ||
10 | 2 M | i | DMSO, rt, 6 h | |
ii | Toluene, 70 -C, 2 h | 65 | ||
11e | 3 M | i | DMSO, rt, 6 h | |
ii | Toluene, 70 -C, 2 h | 49 | ||
12f | 3 M | i | DMSO, rt, 12 h | |
ii | Toluene, 70 -C, 2 h | 43 |
During the initial experimental studies, we found that proline 1 catalyzed the direct Mannich reaction of aqueous succinaldehyde 3 with imine 2a, followed by acid catalyzed cyclization and DDQ mediated aromatization as a two-step sequence to afford substituted pyrrole 3-carboxaldehyde 4a in high yield (entry 8, Table 1). The amount of water present alters the course of the reaction (entry 6–8 and 10, Table 1), similar to that discussed earlier by Barbas and others for direct organocatalytic Mannich reactions.16 Additionally, we also examined other solvent combinations (entry 1–6, Table 1) and found that DMSO/toluene was optimal for this two-step process. Furthermore, decreasing the catalyst loading (entry 9, Table 1), and using a different catalytic system (entry 12, Table 1), led to prolonged reaction times with reduced yield due to the lability of the imine in the presence of water. The reaction proceeded with low yield in the absence of acid (entry 11, Table 1), which shows that the presence of acid is essential for enhancing the rate of the intramolecular cyclization. Thus, we preferred to perform this two-step sequence with the optimized conditions (entry 8, Table 1).
With the optimal conditions in hand, we next examined the generality of this developed transformation by employing various N-PMP aldimines and the results are summarized in Table 2. The reaction proceeded with high yields in case of electron-deficient arylimines (entry 1–9, Table 2). However, when using imines pre-formed from 2-substituted benzaldehydes (entry 5, 6, Table 2) and naphthaldehydes (entry 11, 12, Table 2), reactions were rather slow with lower yields, perhaps owing to steric crowding. Not only aryl imines, but hetero-aryl imines also resulted in products with high yields (entry 13–16, Table 2), while the reactions with an alkenyl imine (entry 17, Table 2) and an in situ generated imine from formaldehyde (entry 18, Table 2) were sluggish, which resulted in low yields. In the case of electron-rich aryl imine and alkyl imine (entry 19 and 20, Table 2), the desired products were not obtained.
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Entry | Product (4)a/time (h)b/yield (%)c | Entry | Product (4)a/time (h)b/yield (%)c |
a (i) Imine 2 (0.3 mmol), 3 (3 M sol., 0.9 mmol), 1 (20 mol%), DMSO (3.0 mL), (ii) toluene (3.0 mL). b Time for Mannich reaction catalyzed by 1 (20 mol%). c Isolated yields refer to 2 (≤10% of aldehyde obtain in all the cases due to cleavage of imine). d Aldimines were prepared in situ. | |||
1 |
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11 |
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2 |
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12 |
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3 |
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13 |
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4 |
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14 |
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5 |
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15 |
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6 |
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16 |
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7 |
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17 |
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8 |
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18d |
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9 |
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19 |
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10 |
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20d |
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Based on our initial study and the literature precedents on proline catalyzed Mannich reactions, the following stepwise mechanism is proposed to account for this reaction. As shown in Scheme 1, the in situ generated enamine 5, generated from succinaldehyde 2 and proline 1, reacts with the N-PMP aldimine 3via a direct Mannich reaction to produce 6. The intermediate 6 undergoes intramolecular cyclization to hemiaminal 7 with the simultaneous regeneration of proline 1. Hemiaminal 7 underwent acid catalyzed dehydration and DDQ mediated aromatization to afford the substituted pyrrole 3-carboxaldehyde 4.
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Scheme 1 Mechanism for the two-step synthesis of pyrrole-3-carboxaldehyde 4. |
The presented two-step protocol also works very well at the preparative scale (2.0 mmol) of aldimines; resulting pyrroles 4 possessing the aldehyde functionality are important synthetic intermediates for further functionalization. A Wittig-reaction of 4j provided the corresponding α,β-unsaturated ester 9, and the trichloro-triazine (TCT) mediated dehydration17 of in situ generated oxime from 4j produced the corresponding nitrile compound 10 with high yields (Scheme 2).
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Scheme 2 Synthetic transformation of pyrrole 3-carboxaldeyhde 4j. |
In conclusion, we have developed a new and direct method for the synthesis of substituted pyrrole-3-carboxaldehydes from readily available precursors such as N-PMP aldimines and succinaldehyde. The presented two-step protocol involves an organocatalytic Mannich reaction, followed by intramolecular cyclization and oxidative aromatization as a two-step sequence under mild conditions. In general, this method provides a new route to synthesizing substituted pyrroles from 1,4-dicarbonyl compounds, in addition to the Paal–Knorr condensation. Further applications of this methodology for the synthesis of densely substituted pyrroles is currently under investigation in our lab and will be presented in due course.
Footnotes |
† Electronic Supplementary Information (ESI) available: For experimental procedures and characterization data of new compounds. See DOI: 10.1039/c2ra21258g |
‡ This article is dedicated to Prof. H. Ila for her contribution to heterocyclic chemistry. |
This journal is © The Royal Society of Chemistry 2012 |