Indoles are one of the most ubiquitous nitrogen-containing heterocycles. Indolo[2,1-
a]isoquinolines represent an important class of polycyclic fused indoles, and are present in a variety of bioactive molecules and pharmaceuticals, and materials (
Fig. 1) [
1–
5]. In the past, considerable efforts have been made in constructing indolo[2,1-
a]isoquinoline skeletons using various strategies, including radical [
6–
29] or metal-catalyzed [
30–
37] cascade cyclization processes. A Pd-catalyzed tandem Heck process also presents a powerful approach to this class of molecules [
38–
46] particularly for skeletons with additional fused ring(s) [
47–
50]. An introduction of a fused nitrogen heterocycle like pyrrole fused indolo[2,1-
a]isoquinoline (
6) would provide new structural diversities for the biological activities, and little has been reported for such type of molecules.
Previously, we have found that a five-membered azacycle can be generated by reacting a pallada(Ⅱ)cycle (
7) with di–
tert-butyldiaziridinone (
8) (
Scheme 1) [
51,
52]. The reaction likely proceeded
via four-membered pallada(Ⅳ)cycle
9 with simultaneous formation of two C—N bonds [
51–
64]. This bisamination process provides unique opportunities for the synthesis of structurally diverse
N-heterocycles. Now we report that pyrrole fused indolo[2,1-
a]isoquinolines (
6) can be efficiently constructed from indole
12 by such reaction process
via tandem Heck/C—H activation/amination through pallada(Ⅱ)cycle intermediate
13 (
Scheme 2).
Indole
12a was used as the test substrate for initial studies. Various phosphine ligands were examined with 5 mol% Pd(OAc)
2, and 2.0 equiv. of di–
tert-butyldiaziridinone (
8) in toluene at 110 ℃ (
Table 1, entries 1–11) (for more details, see Table S1 in Supporting information). The ligand was found to be important to the reaction. The highest yield (58%) was obtained with PPhCy
2 (
Table 1, entry 7). Further investigation with additional Pd catalysts (
Table 1, entries 12–14) and solvents (
Table 1, entries 15–18) (for more details, see Table S1) did not lead to any improvement. It appeared that the reaction process was sensitive to the reaction temperature. The reaction went to completion at 130 ℃ while no product was observed at 90 ℃ (
Table 1 entry 20
vs. entry 19). At 130 ℃, the reaction was completed within 4 h (
Table 1, entry 21).
With the optimized reaction conditions, the substrate scope was subsequently investigated with a variety of indole substrates. As shown in
Scheme 3, the reaction can be extended to various substituted 1-methacryloyl indoles, giving the corresponding pyrrole fused indolo[2,1-
a]isoquinolines
6a-6j in 43%−99% isolated yields. High yield was also obtained with 1-(2-benzylacryloyl)indole (
Scheme 3,
6k). A lower yield was obtained in the case of 1-(2-phenylacryloyl) indole (
Scheme 3,
6l). 1-(2-Methylallyl) indoles were also effective for the reaction, giving the corresponding pyrrole fused indolo[2,1-
a]isoquinolines
6m-6o in 81%−95% yields. Significantly lower yield was obtained when the methyl group on the olefin was replaced with the methyl ester group (
Scheme 3,
6p). The reaction can also be applied to propargyl indoles to give the corresponding pyrrole fused indolo[2,1-
a]isoquinolines
6q and
6r in 63%−70% yields with modified reaction conditions. The reaction process was not effective to indole
12s tethered with 3-methylbut-3-en-1-yl group (one carbon longer), giving a messy mixture under the reaction conditions. With modified conditions, indolo[3,2-
b]indole
14s was isolated in 77% yield (
Scheme 4) [
65–
80]. This reaction process also proceeded well with
N-Me, Et, and Bn substituted indoles
12v-
x, giving the corresponding indolo[3,2-
b]indole
14v-x in 96%−98% yields (
Scheme 4). Further studies showed that seven-membered ring product
6y can be isolated in 50% yield when the corresponding indole with a methyl at the indole's C-3 position (
12y) used (
Scheme 5).
As exemplified with
6m, the reaction proceeded well at gram scale (
Scheme 6). Several synthetic transformations were also carried out with
6m. The
tert–butyl group can be removed with CF
3SO
3H/cyclohexane to give compound
15 in 76% yield. The benzylation of
6m with benzaldehyde, I
2 and Et
3SiH led to compound
16 in 82% yield [
81]. The formylation of
6m with 1 equiv. of POCl
3 afforded aldehyde
17 in 70% yield [
82]. Bisaldehyde
18 can be obtained in 50% yield when excess of POCl
3 used.
A precise understanding of the reaction mechanism awaits further study. On the basis of earlier studies [
51–
57], a plausible catalytic cycle is outlined in
Scheme 7 (with
12a as an example). The oxidative addition of Pd(0) to
12a led to Pd intermediate
19, which subsequently underwent an intramolecular carbopalladation to form alkyl Pd species
20. Pallada(Ⅱ)cycle
13 was then generated from
20 via aryl C—H activation [
83–
101]. The oxidative addition of
13 to di–
tert-butyldiaziridinone (
8) gave four-membered pallada(Ⅳ)cycle
21, which afforded pallada(Ⅳ)nitrene species
22 upon release of
tBuNCO. At the end, pyrrole fused indolo[2,1-
a]isoquinoline
6a was formed from
22 via two consecutive reductive eliminations with regeneration of the Pd catalyst.
In the case of
12s (
Scheme 8), the formation of a seven-membered ring from Pd intermediate
23 was apparently unfavorable (path a). Instead,
23 could undergo a C—H activation at C-3 under proper reaction conditions to give pallada(Ⅱ)cycle
26 [
102–
106], which was aminated with di–
tert-butyldiaziridinone (
8) to form indolo[3,2-
b]indole
14s (path b) [
53]. The introduction of a methyl group at the indole's C-3 position suppressed path b and shifted the outcome towards the formation of the seven-membered ring product.
In summary, we have developed an efficient Pd-catalyzed sequential Heck/C—H activation/amination reaction process with alkene-tethered indole derivatives and di–tert-butyldiaziridinone, providing a variety of pyrrole fused indolo[2,1-a]isoquinoline polycycles bearing various functional groups. The reaction process provides ready access to structurally diverse indolo[2,1-a]isoquinoline compounds for biologically studies. In addition, indolo[3,2-b]indoles can be efficiently formed by varying N-substituents of indole substrates. The current work further illustrates the versatility of the diaziridinone for the construction of N-heterocycles. Further expansion of its synthetic utility is currently underway.
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