The regioselective synthesis of spirooxindolo pyrrolidines and pyrrolizidines via three-component reactions of acrylamides and aroylacrylic acids with isatins and α-amino acids

Beilstein J. Org. Chem. 2014, 10, 117–126.
http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-10-8

The three-component condensation of equimolar amounts of isatins 1, α-amino acids 2 and acrylamides 3 in boiling aqueous methanol (1:3) afforded the spirooxindoles 4a–4g in moderate to excellent yields (Table 1). The reaction times largely depend on the reactivity of the employed α-amino acid. The longest reaction time (7 h) was found for sarcosine, while the fastest reaction (40 min) was found for proline as a substrate (Table 1, entries 1 and 3).

Table 1: Three-component synthesis of spirooxindoles 4a–4g.

entry	compound	R1	R2	R3	R4	R5	yield (%)	time
1	4a	H	Br	CH3	H	H	31	7 h
2	4b	H	NO2	CH2CH2CH2		H	85	3 h
3	4c	H	NO2	CH2CH2CH2		CH3	37	40 min
4	4d	H	Br	CH2SCH2		H	42	1 h
5	4e	H	NO2	CH2SCH2		H	60	6 h
6	4f	4-CH2C6H4Cl	H	CH2SCH2		H	38	2 h
7	4g	CH3	Br	CH2CH2CH2		CH3	58	2 h

The 1,3-dipolar cycloaddition of unsymmetrical dipolarophiles such as acrylamides can occur via the two pathways A and B leading to the formation of the regioisomers 4 and 4’. In our case, spirooxindol 4 is exclusively formed. All new cycloadducts obtained by the above method were characterized by mass spectrometry, 1H and13C NMR, and elemental analyses. The regiochemical outcome of the cycloaddition was unambiguously confirmed by NOE experiments in 1H NMR as well as later by a single crystal X-ray structure analysis of the cycloadduct 4a.

The 1H NMR spectra of compounds 4b–4d have two multiplets at 4.07–3.72 ppm for 7a’-CH and 3.50–3.35 ppm for 2’-CH (compound 4b) or 6’-CH (compound 4d) and a singlet at 1.45 ppm for 2’-CCH3 of compound 4c. The relative stereochemistry of compounds 4b–4d was established by NOE cross peaks between 7a’-CH and 2’(6’-CH) and 2’-CCH3. Also, multiplets for 7a’-CH and 2’-(6’-CH) and singlet for 2’-CCH3 show correlation signals to the neighboring methylene groups. Additionally, the absence of the NOE cross peak of 4-CH of the isatin nucleus and 2’(6’-CH) or 2’-CCH3 of the pyrrolizidine moiety was indicative for the assigned relative stereochemistry. Therefore, the relative stereochemistry could be as shown in Figure 1.

Figure 1: The NOE correlations of the signals in 1H NMR spectra of compounds 4b–4d.

The NH-proton of the oxindole moiety appeared as a singlet between 10.38–10.86 ppm. The 13C NMR spectra of compounds 4a–4g showed characteristic peaks at 71–73 ppm due to the spiro carbon nucleus.

The structure of compound 4a was determined by an X-ray diffraction study of a single crystal and supports the structure deduced from NMR spectroscopy (Figure 2).

Figure 2: Molecular structure of spirooxindole 4a according to X-ray diffraction data.