Design and synthesis of novel indoline-(thio)urea hybrids

Figures & data

Figure 1. Some proline, pyrrolidine-type and indoline-type organocatalysts.

Scheme 1. Synthesis of 11a/b from indoline (8).

Figure 2. Structures of another type-target indoline/indole-based chiral catalyst candidates.

Scheme 2. Attempts to synthesize rac-23/24.

Scheme 3. Synthesis of (S,S)-12a/b.

Scheme 4. Attempts to synthesize (S)-13a/14a and a proposed mechanism for the formation of 11a.

Figure 3. Structures of target indoline-based chiral catalyst candidates.

Scheme 5. Synthesis of 29a/b and 30a/b.

Scheme 6. Synthesis of 31a/b.

Table 1. Catalyst screening for the asymmetric Michael addition of indole (38) to β-nitrostyrene (39).^a

Entry	Catalyst	Temperature (^oC)	Time (h)	Yield (%)^b	er (%)^c
1	–	50	12	NR	–
2	10a	50	12	NR	–
3	10b	50	12	82	50.7:49.3
4	11a	50	12	NR	–
5	11b	50	12	NR	–
6	12a	50	12	85	49.5:50.5
7	12b	50	12	NR	–
8	13a	50	12	81	49.6:50.4
9	13b	50	12	NR	–
10	29a	25	48	93	50.1:49.9
11	29b	25	48	91	50.5:49.5
12	30a	25	48	89	50.2:49.8
13	30b	25	48	91	50.4:49.6
14	31a	25	48	90	50.7:49.3
15	31b	25	48	91	50.2:49.8

^a The reactions were performed with 0.1 mmol of 38, 0.1 mmol of 39, 10 mol% of catalyst in 1 mL of toluene.

^b Isolated yield after thin-layer chromatography on silica gel.

^c Determined using HPLC on chiral OD-H column.

NR: no reaction.

Figure 4. Structures of Michael adducts 41–42.

Table 2. Catalyst screening for the asymmetric Morita–Baylis–Hillman (MBH) reaction of 2-cyclohexen-1-one (43) with benzaldehydes (44 and 45).^a

Entry	Catalyst	BA	Yield (%)^b	er (%)^c	Entry	BA	Yield (%)^b	er (%)^c
1	–	43	NR	–	10	44	NR	–
2	10a		NR	–	11		85	50.3:49.7
3	10b		NR	–	12		83	50.8:49.2
4	11a		90	49.6:50.4	13		87	51.3:48.7
5	11b		91	49.1:50.9	14		88	52.5:47.5
6	12a		93	51.6:48.4	15		90	50.5:49.5
7	12b		94	49.5:50.5	16		90	51.1:48.9
8	13a		95	51.4:48.6	17		96	52.8:47.2
9	13b		95	50.8:49.2	18		94	50.7:49.3

^a The reactions were performed with 0.1 mmol of 43, 0.1 mmol of 44 (or 45), 30 mol% of catalyst in 1 mL of toluene.

^b Isolated yield after thin-layer chromatography on silica gel.

^c Determined by HPLC on chiral OD-H column.

NR: no reaction.

Figure 5. Proposed activation modes between electrophiles and catalysts.

Figure 6. Possible transition states for Michael addition reaction and MBH reaction.

Figure 7. Free energy profile for 12a and 30a catalyzed and uncatalyzed Michael addition reaction of indole (38) to β-nitrostyrene (39). M06-2X/6-31 + G(d,p) with IEF-PCM in toluene; free energies in kcal/mol at 298 K and 1 atm. Results for TS-S, TS-12a-S and TS-30a-S are shown in parenthesis.

Figure 8. Optimized transition states and activation barriers (ΔG^‡) for asymmetric Michael addition of 38 to 39 using catalyst 12a. M06-2X/6-31 + G(d,p) with IEF-PCM in toluene at 298 K and 1 atm, critical distances in Å.

Figure 9. Optimized transition states and activation barriers (ΔG^‡) for the Michael addition of 38 to 39 catalyzed by 30a. M06-2X/6-31 + G(d,p) with IEF-PCM in toluene at 298 K and 1 atm, critical distances in Å.

Figure 10. Proposed phenyl functionalized catalysts 48. M06-2X/6-31 + G(d,p) with IEF-PCM in toluene at 298 K and 1 atm.

Figure 11. Optimized TSs and relative free energies for asymmetric Michael addition of 38 to 39 using catalyst 48. M06-2X/6-31 + G(d,p) with IEF-PCM in toluene at 298 K and 1 atm, critical distances in Å.