Abstract
A novel Pd(0)-catalyzed sequential C–N bond formation process via allylic and aromatic C–H amination of α-methylstyrenes with di-tert-butyldiaziridinone, giving spirocyclic indolines in good yields is described. Four C–N bonds and one spiro quaternary carbon are generated in a single operation.
C–N bond formation is very important in organic synthesis, and various effective methods have been developed.1 Direct C–H amination presents an attractive approach to construct C–N bonds and remains an active area.2 In our earlier studies on the Pd(0)-catalyzed diamination3,4 of olefins with di-tert-butyldiaziridinone (1),5,6 we have found that terminal olefins 2 (R = CH2CH2R2) can be aminated at allylic and homoallylic carbons to give diamination products 3 (Scheme 1).4 This diamination process likely proceeds via a diene intermediate, generated from the terminal olefin via allylic C–H activation to form a π-allyl Pd complex and subsequent β-hydride elimination.4 In our efforts to further explore the reactivity of diaziridinone, we have investigated terminal olefins which lack homoallylic hydrogens and thus cannot form dienes under the reaction conditions. During such studies, it has been found that spirocyclic indolines 4 can be obtained when α-methylstyrenes were treated with di-tert-butyldiaziridinone (1) and a Pd(0) catalyst (Scheme 1).7 The reaction likely proceeds via a novel C–H activation and C–N bond formation process. Herein, we wish to report our preliminary studies on this subject.
Scheme 1.
Our initial studies were carried out with α-methylstyrene (2a) as the test substrate. Treating 2a with di-tert-butyldiaziridinone (1) and 10 mol % Pd(PPh3)4 under neat conditions at 85 °C for 24 h gave spirocyclic indoline 4a in 18% yield (Table 1, entry 1). The yield was increased to 51% when di-tert-butyldiaziridinone (1) was added slowly over 10 h via syringe pump (Table 1, entry 2). The yield was further improved with addition of PPh3 ligand to the reaction system, with 20 mol % PPh3 being optimal (Table1, entries 3–5). No reaction was observed with PPh3 alone (Table 1, entry 6). The reaction was also investigated with Pd2(dba)3 as catalyst (Table 1, entries 7–14). No product was formed without additional ligand (Table 1, entry 7). The nature of the ligand has a dramatic effect on the product yield. Among the ligands examined, PPh3 gave the highest yield (Table 1, entry 8), and essentially no product was obtained with P(o-tolyl)3, dppp, or BINAP (Table 1, entries 11, 13, and 14).
Table 1.
Studies on Reaction Conditions.a
 | |||
|---|---|---|---|
| entry | catalyst | ligand (x mol %) | yieldb |
| 1 | Pd(PPh3)4 | – | 18 |
| 2 | Pd(PPh3)4 | – | 51 |
| 3 | Pd(PPh3)4 | PPh3 (10 mol %) | 58 |
| 4 | Pd(PPh3)4 | PPh3 (20 mol %) | 75 |
| 5 | Pd(PPh3)4 | PPh3 (30 mol %) | 62 |
| 6 | – | PPh3 (60 mol %) | 0 |
| 7 | Pd2(dba)3 | – | 0 |
| 8 | Pd2(dba)3 | PPh3 (60 mol %) | 65 |
| 9 | Pd2(dba)3 | P(p-MeO-Ph)3 (60 mol %) | 36 |
| 10 | Pd2(dba)3 | P(p-tolyl)3 (60 mol %) | 51 |
| 11 | Pd2(dba)3 | P(o-tolyl)3 (60 mol %) | 0 |
| 12 | Pd2(dba)3 | P(p-F3C-Ph)3 (60 mol %) | 35 |
| 13 | Pd2(dba)3 | dppp (30 mol %) | 0 |
| 14 | Pd2(dba) | BINAP (30 mol %) | 0 |
All reactions were carried out with olefin 2a (0.40 mmol), di-tert-butyldiaziridinone (1) (1.60 mmol), Pd(PPh3)4 (0.040 mmol) or Pd2(dba)3 (0.020 mmol), and appropriate phosphine ligand at 85 °C under Ar for 24 h unless otherwise stated. For entry 1, di-tert-butyldiaziridinone (1) was added in one portion. For entries 2−14, di-tert-butyldiaziridinone (1) was slowly added over 10 h via syringe pump.
Isolated yield based on olefin 2a.
As shown in Table 2, the reaction process can be extended to various para-, meta-, di-, and tri-substituted α-methylstyrenes 2b–2p, giving the corresponding spirocyclic indoline products 4b–4p in 56–83% yield (Table 2, entries 2–16). For entries 10–15, the reaction generally occurred at the less sterically hindered position (the X-ray data of 4j and 4n, see Supporting Information). In the cases of entries 10, 11, 13, and 15, the reactions proceeded with high regioselectivity (>20:1).
Table 2.
Substrate Scope.a
 | |||
|---|---|---|---|
| entry | substrate (2) | product (4) | yield (%)b |
 |
 |
||
| 1 | 2a, X = H | 4a | 75 |
| 2 | 2b, X = OMe | 4b | 81 |
| 3 | 2c, X = Me | 4c | 71 |
| 4 | 2d, X = i-Pr | 4d | 70 |
| 5 | 2e, X = t-Bu | 4e | 61 |
| 6 | 2f, X = F | 4f | 73 |
| 7 | 2g, X = Cl | 4g | 69 |
| 8 | 2h, X = Br | 4h | 63 |
| 9 | 2i, X = CO2Me | 4i | 81 |
 |
 |
||
| 10 | 2j, X = OMe | 4j | 79 |
| 11 | 2k, X = Me | 4k | 74 |
| 12 | 2l, X = Cl | 4l | 68 |
| 13 | 2m, X = Br | 4m | 64 |
| 14 |  |
 |
70 |
| 15 |  |
 |
56 |
| 16 |  |
 |
83 |
All reactions were carried out with olefin 2 (0.40 mmol), di-tert-butyldiaziridinone (1) (1.60 mmol) (added over 10 h via syringe pump), Pd(PPh3)4 (0.040 mmol), and PPh3 (0.080 mmol) at 85 °C under Ar for 24 h (total).
Isolated yield. The ratio of the regioisomers was determined to be >20:1 (for entries 10, 11, 13, and 15), 8:1 (for entry 12), and 10:1 (for entry 14) by 1H NMR analysis of the crude reaction mixture.
While a precise understanding of the reaction mechanism awaits further study, a plausible catalytic pathway is proposed in Scheme 2. The Pd(0) first inserts into the N–N bond of di-tert-butyldiaziridinone (1) to give four-membered Pd(II) species 5, which then forms complex 6 with α-methylstyrene (2a). Abstraction of an allylic hydrogen from 6 leads to π-allyl Pd complex 7,8,9 which affords allyl urea-ligated Pd(0) intermediate 8 via reductive elimination.10 Reaction of intermediate 8 with another equivalent of 1 provides 9, which undergoes a Pd(II)-catalyzed cyclization to give 10.11,12 Subsequently, 10 undergoes an intramolecular aromatic C–H activation to form urea 11 and pallada(II)cycle 12,13 which inserts into the N–N bond of 1 to give pallada(IV)cycle 13. Reductive elimination of pallada(IV)cycle 13 leads to eight-membered pallada(II)cycle 14a and/or 14b (pathway a), which is transformed to 16a and/or 16b by releasing tert-butyl isocyanate (15).14 Upon reductive elimination, 16a and/or 16b is converted to spirocyclic indoline 4a with the regeneration of the Pd(0) catalyst. Alternatively, pallada(IV)cycle 13 releases a molecule of tert-butyl isocyanate (15) to form Pd(IV)-nitrene 1715 (pathway b), which undergoes two consecutive reductive eliminations to give product 4a via 16a and/or 16b and to regenerate the Pd(0) catalyst.
Scheme 2.
Proposed Catalytic Cycle.
To gain some insight into the reaction mechanism, additional experiments were performed (Schemes 3). When deuterium-labeled α-methylstyrene 2a–d was subjected to the standard reaction conditions, equal amounts of indoline products 4a–d and 4a–d’ were obtained in 50% yield (Scheme 3, eq. 1). This result suggests that π-allyl Pd complex 7 is very likely to be involved in this process. Attempts to isolate any reaction intermediates were unsuccessful. Allyl urea 18 was subsequently prepared and subjected to the reaction conditions. It was found that 18 did cyclize to provide indoline 4a (eq. 2), which is also in agreement with the reaction mechanism described in Scheme 2. A known palladacycle 1916 was also prepared and was found to be catalytically active. Treating α-methylstyrene (2a) with di-tert-butyldiaziridinone (1) in the presence of 10 mol % 19 and 60 mol % PPh3 at 85 °C for 24 h gave indoline 4a in 77% yield along with small amounts of indoline 20 (eq. 3). When stoichiometric amounts of 19 were used, indolines 4a and 20 were obtained in 72% and 76% yield, respectively. These results suggest that palladacycle 12 is a likely intermediate in the catalytic cycle and can be converted into the indoline 4a.
Scheme 3.
In summary, we have discovered a novel Pd(0)-catalyzed C–N bond formation process of α-methylstyrenes with di-tert-butyldiaziridinone (1) via sequential allylic and aromatic C–H amination. Various α-methylstyrenes can be converted to spirocyclic indolines in good yields with the generation of four C–N bonds and one spiro quaternary carbon in a single operation. The ability of di-tert-butyldiaziridinone to be oxidatively inserted into a R2Pd(II) species further illustrates its versatile reactivity and opens up more opportunities for new reaction development with this class of compounds. Such studies are currently underway.
Supplementary Material
Acknowledgment
We are grateful for the generous financial support from the General Medical Sciences of the National Institutes of Health (GM083944-06).
Footnotes
Supporting Information Available. Experimental procedure, characterization of all compounds, and crystallographic information file for compound 4a, 4j and 4n. This material is available free of charge via the Internet at http://pubs.acs.org.
References
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