Tandem 1,5-migration/Michael reactions to prepare adducts of pyrazolone derivatives: protecting group-directed rearrangement

Abstract

A tandem 1,5-migration/Michael reaction of pyrazoline has been described, which results in different multiply-substituted pyrazolone derivatives with excellent yields controlled by protecting group.

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In recent years, migration reactions have received much attention.¹ Particularly, migration reactions in tandem processes have led to the development of diverse and versatile synthetic methods.² Migration occurs in some organic reactions, which may be of value or a disadvantage for the strategies desired in synthesis.³ So, control of the stereochemistry is of high interest and is still a challenging problem in migration processes, especially for the stereoselective construction of molecules with remote centers.⁴ Furthermore, this moiety usually exists in many heterocyclic natural products and medicines.⁵ Generally, the migration can be observed under different reaction conditions.⁶ On the other hand, this isomerization occurs in the reaction of compounds with dramatically different core structures.⁷ However, the control of the remote migration reaction with a similar core structure under the same reaction conditions remains unexplored.

Pyrazolone derivatives, representing an important class of five-membered-ring lactams, have exhibited a variety of applications as pharmaceutical agents,⁸ synthetic scaffolds in combinatorial and medicinal chemistry.⁹ Especially, pyrazolin-5-ones derivatives have been well known as analgesic and antipyretic agents.¹⁰ In this respect, the development of a facile and excellent strategy for the synthesis of new pyrazolin-5-ones derivatives seems to be attractive and highly interesting. However, the reactions of pyrazolin-5-ones still have not been well documented.¹¹ In particular, there was only one example about the pyrazolin-5-ones used as precursors in a tandem process.¹² Herein, we reported a facile tandem 1,5-migration/Michael reaction of 3-substituted pyrazolines with nitroalkenes. The resultant different pyrazoline derivatives were obtained through different processes controlled by the protecting group on the oxygen atom of pyrazolines under the same reaction conditions. The current reaction also provides an easy access to multiply-substituted pyrazolin-5-one derivatives from readily available starting materials.

Initially, we used pyrazoline 1a and nitrostyrene 4a as model substrates with DMAP as catalyst. We assumed that the reaction proceeds through the designed route, as shown in pathway a in Scheme 1. However, no desired adducts were obtained from the reaction after 12 h. Surprisingly, the reaction was found to proceed through pathway b, and resulted in compound 5a with 95% yield. This suggested that the reagent 1a undergoes the arrangement in the presence of Lewis base, and the benzyloxycarbonyl protecting group migrated from an oxygen atom to a nitrogen atom. A similar rearrangement was also found in the previous report with Lewis acid as catalyst.¹³

Scheme 1 Reaction of pyrazoline 1a with nitrostyrene 4a.

To improve the reaction efficiency, several other catalysts were used for the reaction (Table 1). No reaction was detected at all when no catalyst was used in the reaction (entry 2). Although other base catalysts also could promote the reaction, the resulting yields were dramatically lower (entries 3–8). Then, the optimization with DMAP as catalyst was focused on the screening of solvent, and CH₂Cl₂ was found to be the best choice. Notably, when acetonitrile or acetone was employed in this reaction, the reaction time was much longer with a dramatic decrease in yields (entries 12–13). The further optimization found that the catalyst loading amount could be lowered to 1 mol% without any appreciable drop in reactivity and yield after 12 h (entry 15). However, when the catalyst loading increased to 50%, the corresponding adduct 5a was obtained with only 28% yield (entry 16).

Table 1 Optimization of reaction conditions^a

Entry	Catalyst	Amount (mol%)	Solvent	Time (h)	Yield (%)^c
a Reaction conditions: 1a (0.5 mmol), 4a (0.75 mmol), solvent (2 mL) at room temperature. b Tetramethylguanidine. c Isolated yields.
1	DMAP	10	CH2Cl2	12	95
2	No	—	CH2Cl2	24	NR
3	DIPEA	10	CH2Cl2	24	28
4	DABCO	10	CH2Cl2	72	34
5	DBU	10	CH2Cl2	72	45
6	TMG^b	10	CH2Cl2	72	32
7	Et3N	10	CH2Cl2	24	21
8	Pyridine	10	CH2Cl2	24	17
9	DMAP	10	CHCl3	12	78
10	DMAP	10	DME	12	92
11	DMAP	10	Toluene	12	80
12	DMAP	10	Acetone	72	48
13	DMAP	10	CH3CN	72	45
14	DMAP	5	CH2Cl2	12	95
15	DMAP	1	CH2Cl2	12	92
16	DMAP	50	CH2Cl2	12	28

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After the optimized condition was established, we began to examine the substrate scope of the tandem reaction with pyrazolines 1 and nitroolefins 4 (Table 2). Generally, the reaction could proceed smoothly to generate multiply-substituted pyrazolin-5-one derivatives. For all the probed nitroolefins, those with one halogen on the aromatic ring could participate better in the reaction (entries 3–5), resulting in the desired products with higher yields (92%–95%). Contrasting with electronic features, steric features have a greater effect on the chemical yields. The reactions gave sharply lower yields when the phenyl ring was changed to a 1-naphthyl ring (81% yield, entry 8). More significantly, the reaction of the substrates with a heteroaromatic ring also proceeded well, affording the desired product with good yields (entries 9–10). We further checked the effects of substituents on the nitrogen atom of the pyrazolines on this reaction. To our delight, the reaction also proceeded well to give the desired products in excellent yields (entries 11–13). Results in Table 2 disclosed that the variation of R¹ substituent on pyrazolines and aromatic ring of nitrostyrenes was not the key factor for the migration.

Table 2 Scope of nitroolefins 4 with pyrazoline 1^a

Entry	Ar	R^1	Product	Yield (%)^b
a Reaction conditions: 1 (0.5 mmol), 4 (0.75 mmol), solvent (2 mL) at room temperature. b Isolated yields.
1	C6H5	C6H5	5a	92
2	4-MeC6H4	C6H5	5b	92
3	2-FC6H4	C6H5	5c	92
4	4-ClC6H4	C6H5	5d	95
5	4-BrC6H4	C6H5	5e	95
6	4-OMeC6H4	C6H5	5f	92
7	3-OMeC6H4	C6H5	5g	95
8	1-Naphthyl	C6H5	5h	81
9	2-Furyl	C6H5	5i	83
10	2-Thienyl	C6H5	5j	76
11	C6H5	4-ClC6H4	5k	92
12	2-FC6H4	4-ClC6H4	5l	93
13	2-ClC6H4	4-ClC6H4	5m	94

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To investigate the cause for the 1,5-migration, reactions of pyrazolines with other usual alkoxycarbonyl protecting groups were performed under the optimized conditions (Table 3). After careful characterizations, we found that the alkoxycarbonyl protecting group also migrated from the oxygen atom to the nitrogen atom for all cases. We were also glad to see that the reactions could proceed smoothly, and resulted in excellent yields for all the nitrostyrene derivatives within 12 h. In addition, heterocyclic substrates also reacted well with pyrazolines to give the desired products with slightly lower yields (entries 8 and 9). The absolute stereochemistry of these products was confirmed by single-crystal X-ray analysis of 6j (Fig. 1).

Fig. 1 ORTEP diagram showing of compound 6j.

Table 3 Scope of nitroolefins with pyrazoline 2^a

Entry	Ar	R^1	R^2	Product	Yield (%)^b
a Reaction conditions: pyrazolines 2 (0.5 mmol), nitroolefin 4 (0.75 mmol), CH2Cl2 (2 mL), 1 mol% DMAP. b Isolated yields.
1	C6H5	C6H5	Boc	6a	90
2	4-FC6H4	C6H5	Boc	6b	92
3	4-ClC6H4	C6H5	Boc	6c	94
4	4-BrC6H4	C6H5	Boc	6d	98
5	4-OMeC6H4	C6H5	Boc	6e	98
6	2-ClC6H4	C6H5	Boc	6f	96
7	1-Naphthyl	C6H5	Boc	6g	82
8	2-Furyl	C6H5	Boc	6h	65
9	2-Thienyl	C6H5	Boc	6i	70
10	C6H5	4-ClC6H4	Boc	6j	94
11	4-ClC6H4	4-ClC6H4	Boc	6k	95
12	4-BrC6H4	4-ClC6H4	Boc	6l	92
13	C6H5	C6H5	EtOCO	6m	98

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Then we continued to scan the reaction parameters for the key factor for the migration. We used the pyrazol-5-yl acetates 3 as substrates to perform the reaction under the optimized condition (entry 1, Table 4). Surprisingly, when the nitrogen protecting group was changed into acetyl, the starting materials were totally converted into the regular Michael product and no migration product was detected. Notably, the similar products were found for all probed nitroolefins with high yields. The chemical structures of these no migration products have been confirmed by single-crystal X-ray analysis of 7h (Fig. 2). As the results show in Table 4, the variation of the protecting group of pyrazolines directly led to different products, and the migration did not occur during the process.

Fig. 2 ORTEP diagram showing of compound 7h.

Table 4 Scope of nitroolefins with pyrazoline 3^a

Entry	Ar	R^1	R^2	Product	Yield (%)^b
a Reaction conditions: pyrazol-5-yl-acetate 3 (0.5 mmol), nitroolefin 4 (0.75 mmol), CH2Cl2 (2 mL), 1 mol% DMAP. b Isolated yields. c DBU was used as catalyst.
1	C6H5	C6H5	H	7a	95
2	C6H5	2-ClC6H4	H	7b	92
3	C6H5	4-ClC6H4	H	7c	94
4	C6H5	4-MeC6H4	H	7d	73
5	C6H5	2-FC6H4	H	7e	82
6	C6H5	3-FC6H4	H	7f	88
7	C6H5	4-FC6H4	H	7g	83
8	4-ClC6H4	4-BrC6H4	Me	7h	52^c

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On the basis of the above results, a tandem migration/Michael mechanism has been proposed for the current process as shown in Scheme 2. The initial step is the DMAP-catalyzed generation of enolate A. Then there is the Michael addition of intermediate A to nitrostyrene, giving the intermediate B, which also exists as tautomeric form C. The intermediate C undergoes an O-carboxylation process to form the no migration adducts 7, when the R group is a methyl. However, the reaction will proceed through N-carboxylation to give the migration adducts 5 or 6, when the R group is an alkoxy group. A similar process could be found in the previous report from Fu's group.¹⁴

Scheme 2 The proposed mechanism.

Conclusions

In summary, we developed a facile and highly efficient tandem 1,5-migration/Michael reaction of pyrazolines to nitroolefins, resulting in different multiply 4-substituted-5-pyrazolone derivatives. The protecting group in pyrazolines controlled the migration, to give the different adducts with excellent yields. The present reaction provides a straightforward solution to the challenging problem of generating pyrazolone derivatives. Studies exploring the asymmetric manner for this reaction with organocatalysts are actively underway in our laboratory.

Acknowledgements

We gratefully acknowledge the financial support from the National Natural Science Foundation of China (No. 21102071) and the Fundamental Research Funds for the Central Universities (No. 1107020522 and No. 1082020502). The Jiangsu 333 program (for Pan) and Changzhou Jin-Feng-Huang program (for Han) are also acknowledged.

References

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Footnote

† Electronic Supplementary Information (ESI) available: experimental procedures, full spectroscopic data for new compounds and single-crystal X-ray diffraction analysis of 2a, 6j and 7h. CCDC reference numbers 861353, 874014 and 874398. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c2ra21549g

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