An efficient pyrroline annulation of glycine imine with enones

Abstract

We describe here a single-step synthesis of substituted 1-pyrrolines from N-(4-chlorobenzylidene)-glycine methyl ester and enones which combines conversion of the Michael adducts to 1-pyrrolines with separation between the products on silica gel column chromatography.

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The 1,3-dipolar cycloaddition reactions are fundamental processes in organic synthesis for the construction of five-membered heterocyclic rings.¹ In this field, the 1,3-dipolar cycloaddition of azomethine ylides is a powerful method for the synthesis of substituted pyrrolidines, in which the electron-deficient C=C bond (for example of an enone) is used as the dipolarophile (Scheme 1, path A).^2,3 While major advances have been made in the [3 + 2] cycloaddition and exemplified the diversity in dipolarophiles^4–7 and non-traditional reaction channels over the past decade,⁸ there has been no report on evaluating the reactivity of azomethine ylides in the synthesis of 1-pyrrolines in detail.^2–9

Scheme 1 [3 + 2] cycloaddition versus pyrroline annulation.

During our studies on reactions initiated by Michael addition,^10,11 it was found for the first time that a variety of substituted 1-pyrrolines can be synthesized under very mild reaction conditions in a single-step by combing use with a reaction-separation methodology.¹² Herein, we describe this efficient method involving Michael addition of N-(4-chlorobenzylidene)-glycine methyl ester with various enones in the presence of a catalytic amounts of DBU (DBU = 1,8-diazabicyclo-[5.4.0]undec-7-ene) and conversion of the Michael adducts to the corresponding substituted 1-pyrrolines and separation between the products on silica gel column chromatography (Scheme 1, path B).

In our investigation of the reaction of 4-chlorochalcone 1a with glycine imines 2 under various conditions (Table 1), the catalyst screening showed that DBU was an efficient catalyst for the conjugate addition of N-(4-chlorobenzylidene)-glycine methyl ester 2a to 1a to give the adduct 4a.⁹ For example, catalyzed by DBU (20 mol%), the reaction of 1a (1.0 mmol) and 2a (1.2 equiv) in THF (5 mL) at room temperature was completed in 5 h (monitored by TLC). Surprisingly, 1-pyrroline 3a instead of the adduct 4a was obtained in 92% yield as a diastereomeric mixture¹³ (trans/cis = 1.5/1.0, entry 1) after silica gel column chromatography (EtOAc/petroleum ether, 1/10 as eluent; for details, see ESI†).¹⁴ The above result ensures that the process, including conversion of adduct 4a to 1-pyrroline 3a and 4-chlorobenzaldehyde via deprotection, dehydrative cyclization and separation between 3a and 4-chlorobenzaldehyde can be combined using silica gel column chromatography (Scheme 1, path B).

Table 1 Reactions of 1a with 2 under various conditions^a

Entry	2	Solvent	Base (equiv.)	t/h	Yield(%)^b (trans/cis)
a Reaction conditions: 1a (1.0 mmol) and 2 (1.2 equiv.) in solvent (5 mL, analytical grade) at room temperature. b Isolated yield. c Absolute THF was used. d THF (5 mL)/H2O (0.05 mL). e THF (4 mL)/H2O (0.5 mL).
1	2a	THF	DBU (0.2)	5	92 (3a) (1.5/1.0)
2	2a	THF	DBU (0.1)	9	72 (3a) (1.3/1.0)
3	2a	THF	DBU (0.1)	24	73 (3a) (1.3/1.0)
4	2a	THF	Et3N (0.2)	24	complex mixture
5	2a	THF	K2CO3 (0.2)	24	84 (5a)
6	2a	THF	NaOH (0.2)	24	82 (5a)
7	2a	Dioxane	DBU (0.2)	12	90 (3a) (1.6/1.0)
8	2a	CH2Cl2	DBU (0.2)	24	89 (3a) (1.2/1.0)
9	2a	DMF	DBU (0.2)	24	69 (3a) (1.1/1.0)
10	2a	EtOH	DBU (0.2)	24	62 (5a) 33 (3a) (1.3/1.0)
11^c	2a	THF	DBU (0.2)	5	92 (3a) (1.4/1.0)
12^c^,^d	2a	THF/H2O	DBU (0.2)	5	85 (3a) (1.3/1.0) 9 (5a)
13^c^,^e	2a	THF/H2O	DBU (0.2)	5	78 (3a) (1.1/1.0) 17 (5a)
14	2b	THF	DBU (0.2)	48	85 (3a) (1.2/1.0)
15	2c	THF	DBU (0.2)	48	50 (3a) (1.1/1.0)

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Based on the above procedure which combines the reaction of 1a with a glycine imine with reaction-separation methodology, a series of experiments were performed with the aim to evaluate the reactivity of glycine imines under different conditions. It was found that lower DBU loading (10 mol%) led to decreased yields of 3a (entries 2 and 3). In the above experiments (entries 1–3), the corresponding 1,3-dipolar adduct pyrrolidine 5a was not detected. However, a complex mixture was obtained when triethylamine (20 mol%) was selected as the catalyst (entry 4). In comparison, the 1,3-dipolar adduct 5a was produced in high yield by using potassium carbonate (20 mol%) and sodium hydroxide (20 mol%) as the catalyst, respectively (entries 5 and 6). These results indicate that the reaction pathways of glycine imine 2a with 1a could be altered completely depending on the base used.¹⁵

A significant solvent effect was also observed. Similar with the results in THF solvent (entry 1), 3a could be obtained in high yields in dioxane and dichloromethane solvents, respectively, although with longer reaction times (entry 1 versus entries 7 and 8). With DMF as the solvent, 3a was formed in relatively lower yield (entry 9). However, with ethanol as the solvent, the 1,3-dipolar adduct 5a was obtained as the major product (62%) and 3a as the minor product (33%), indicating that the conjugate addition of 2a to 1a is unfavorable in a protic solvent (entry 10). Furthermore, it was observed that 3a could be obtained in excellent yields by using either analytical grade THF or absolute THF as the solvent (entry 1 versus 11). In comparison, 5a could be obtained in low yields when the reaction of 1a and 2a was carried out in the mixed solvent of THF–H₂O and the amounts of 5a increased with an increase of water concentration (entries 12 and 13).

Investigations of substituent effects (monitored by TLC) indicate that glycine imines 2b (Ar = Ph) and 2c (Ar = 4-MeC₆H₄) markedly decrease the reaction rate of the Michael addition (entries 14 and 15 versus entry 1). However, under identical conditions the reaction of 1a with glycine imine 2d having a more electron-deficient aryl group (Ar = 4-pyridyl) led to complete decomposition of the glycine imine. These results show that glycine imine 2a with a suitable electron-deficient aryl group reacts at a faster rate.

The above experiments indicate that 1-pyrroline 3a can be prepared in “a single step” since both the conversion of Michael adduct 4a to 1-pyrroline 3a and the separation between 3a and 4-chlorobenzaldehyde occur in the process of column chromatography (Scheme 1, path B). Significantly, the efficient synthesis of 2,4,5-trisubstituted 1-pyrroline 3a can also be attributed to the proper choice of solvent and especially the catalyst. In addition, substituent effect (the aryl group of glycine imines 2) significantly affects the reaction rate of the conjugate addition (Table 1).

With optimal conditions (Table 1, entry 1) in hand, the scope of the reaction was examined. As described in Table 2, a broad range of enones 1 is compatible with this operationally simple procedure. Chalcone 1d (Table 2, entry 4), chalcones 1 with electron-deficient (1a–1c, Table 2, entries 1–3) and electron-rich aryl groups (1e–1g, Table 2, entries 5–7) and (E)-3-(furan-2-yl)-1-phenylprop-2-en-1-one (1h, Table 2, entry 8) can give the corresponding substituted 1-pyrrolines 3a–3h in excellent yields. The generality of the reaction was further demonstrated by the synthesis of 3i–3s in high to excellent yields through the reaction of 2a with enones 1i–1s, which bear a variety of R and R¹ substituents, respectively (entries 9–19).¹⁶ It was observed that alkyl enone 1t can also give the corresponding 1-pyrroline 3t in moderate yield (entry 20).

Table 2 Synthesis of 1-pyrrolines 3^a

Entry	R1	R	t/h	3	Yield (%)^b (trans/cis)
a General reaction conditions: 1 (1.0 mmol) and 2a (1.2 equiv.) in THF (5 mL) at room temperature followed by a reaction-separation methodology on silica gel column. b Isolated yield.
1	Ph	4-ClC6H4	5.0	3a	92 (1.5/1.0)
2	Ph	4-FC6H4	5.5	3b	94 (2.4/1.0)
3	Ph	4-NO2C6H4	1.5	3c	90 (1.3/1.0)
4	Ph	Ph	7.5	3d	93 (1.4/1.0)
5	Ph	4-MeC6H4	8.5	3e	93 (1.6/1.0)
6	Ph	4-MeOC6H4	9.5	3f	94 (1.4/1.0)
7	Ph	3,4-O2CH2C6H3	3.0	3g	91 (1.3/1.0)
8	Ph	2-Furyl	2.5	3h	94 (1.2/1.0)
9	Ph	C6H5CH=CH	1.5	3i	89 (1.1/1.0)
10	Ph	Me	4.0	3j	90 (1.1/1.0)
11	Ph	H	3.0	3k	93
12	4-MeC6H4	4-ClC6H4	4.5	3l	87 (1.6/1.0)
13	4-BrC6H4	4-ClC6H4	3.5	3m	82 (1.4/1.0)
14	Me	4-ClC6H4	24	3n	91 (1.3/1.0)
15	Et	4-ClC6H4	26	3o	91 (1.3/1.0)
16	Me	4-FC6H4	24	3p	90 (1.4/1.0)
17	Me	Ph	26	3q	90 (1.6/1.0)
18	Me	4-MeC6H4	27	3r	93 (1.7/1.0)
19	Me	4-MeOC6H4	29	3s	94 (1.5/1.0)
20	Me	Me	20	3t	53 (1.4/1.0)

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The above reaction (Table 2) provides a straightforward route to substituted 1-pyrrolines from easily available substrates under very mild reaction conditions.^9,17 Encouraged by the success of the 1-pyrroline synthesis between glycine imine 2a and various enones 1 (Table 2), the efficiency and generality of this procedure was tested by variations in the 1,3-dielectrophiles. Fortunately, when cinnamoyl ketene dithioacetals 6a–6f were used,^10,11 the corresponding 1-pyrrolines 7a–7f were obtained in high yields under mild reaction conditions, as shown in Scheme 2. In these reactions, the ketene dithioacetal moiety was intact.

Scheme 2 Synthesis of 1-pyrrolines 7.

Furthermore, 1-pyrrolines 9a–9c were prepared in excellent yields from the reaction of glycine imine 2a with (E)-1-(1-benzoylcyclopropyl)-3-arylprop-2-en-1-ones 8a–8c.^11a,18 In these reactions, the cyclopropane ring remains intact (Scheme 3). From the above experimental results, it can be seen that glycine imine 2a can act as an efficient reagent in the single-step pyrroline annulation, in which the enone moiety of 1 (Table 2), 6 (Scheme 2), and 8 (Scheme 3) act as a 1,3-dielectrophile.

Scheme 3 Synthesis of 1-pyrrolines 9.

Finally, the reactions of glycine imine 2e with 4-chlorochalcone 1a and 4-nitrochalcone 1c were examined (monitored by TLC, Scheme 4). Under identical reaction conditions as described for the conjugate addition (Table 1, entry 1) for 24 h (2e with 1a) and 10 h (2e with 1c), Michael adduct 4a′ and 4c′ were obtained in 96 and 94% isolate yields, respectively, after silica gel column purification (EtOAc/petroleum ether, 1/16 as eluent). These results mean that adduct 4a′ and 4c′ are insensitive to silica gel chromatography and thus display apparently different reactivity among glycine imines (and adducts 4) bearing different imine units.

Scheme 4 The reaction of 1a with 2e.

In conclusion, an efficient method for the single-step synthesis of substituted 1-pyrrolines has been developed. By this method, a wide range of 1-pyrrolines having various substituents at 2- and 4-positions were synthesized in high to excellent yields (28 examples, 68–94% yields) from readily available glycine imine and various enones under very mild conditions. In this reaction (E)-methyl 2-(4-chlorobenzylideneamino)acetate 2a exhibited a relatively higher reactivity than other glycine imines tested. In addition, this new procedure has the advantage of allowing conversion of Michael adducts to 1-pyrrolines during the separation process and thus avoiding the use of acid (for hydrolysis to cleave protecting group) and base (for dehydrative cyclization) as most commonly involved in the synthesis of 1-pyrrolines starting from glycine imines. Further studies are in progress.

We gratefully acknowledge the National Natural Sciences Foundation of China (21072027 and 21172030) and the Project-sponsored by SRF for ROCS, SEM for financial support.

References

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Footnote

† Electronic Supplementary Information (ESI) available: Detailed experimental procedures, analytical and spectral data for all the new compounds. CCDC 844259 (3d). See DOI: 10.1039/c2ra20697h/

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