Organic Letters
Letter
a
Scheme 1. Gold(I)-Catalyzed Addition of
Heteronucleophiles As Well As 1,2-Migration and This
Approach
Table 1. Optimization of the Conditions
Time
(h)
Yield of 2a
b
Entry
Catalyst
Solvent T (°C)
(%)
1
2
3
4
5
AuCl
AuCl3
Ph3PAuCl/AgOTf
IPrAuCl/AgOTf
JohnPhosAuCl/
AgOTf
DCE
DCE
DCE
DCE
DCE
60
60
60
60
60
12
12
12
12
12
0
0
39
71
81
6
7
8
9
(tBuP)3AuCl/AgOTf
Cat. A/AgOTf
Cat. B/AgOTf
Cat. C/AgOTf
JohnPhosAuCl/
AgNTf2
DCE
DCE
DCE
DCE
DCE
60
60
60
60
60
12
12
12
12
12
56
55
52
49
89
10
11
12
13
14
JohnPhosAuCl/
AgSbF6
JohnPhosAuCl/
AgBF4
JohnPhosAuCl/
Ag2CO3
JohnPhosAuCl/
AgNTf2
DCE
DCE
DCE
DCE
60
60
60
rt
12
12
12
3
61
43
45
89
a
All reactions were run with 0.05 mmol of Ugi adduct 1a, 5 mol %
b
catalyst, and 1.0 mL of DCE in a sealed flask. Isolated yields Cat. A:
Chloro[2-di-tert-butyl(2′,4′,6′-triisopropylbiphenyl)phophine]gold-
(I); Cat. B: Chloro[2-(dicyclohexylphosphino)biphenyl]gold(I); Cat.
C: Chloro[di(1-adamantyl)-2-dimethylaminophenylphosphine]gold-
(I).
construction of diverse indolizidine scaffolds (Scheme 1f).
Through the tandem nucleophilic cyclization/enyne cyclo-
isomerization/1,2-migration sequence, the regiospecific and
convergent synthesis of pyrrolo[1,2-b]isoquinolines are
achieved under mild conditions.
Our studies commenced by examining the gold(I)-catalyzed
1,2-aryl migration of 1a. Screening of various gold catalysts
(Table 1, entries 1−9) revealed that in situ generated
JohnPhosAuOTf is the most efficient one (entry 5). Employing
JohnPhosAuCl with other chloride scavengers such as AgNTf2,
AgSbF6, AgBF4, or Ag2CO3 assured that AgNTf2 is the best
one (entries 10−13). To our delight, the reaction worked well
at room temperature delivering product 2a in 89% yield (entry
14). The structure of 2a has been confirmed by X-ray
After optimization of the reaction conditions, various
substrates were subjected to this process to examine the
scope and limitations (Scheme 2). We first examined the
substituent effect (R1) of the migrating phenyl group. Both the
ortho and meta-methoxyl phenyl appeared to be a good
migrating group, delivering the corresponding products in 81%
and 82% yields (2b and 2c). The substrate with a para-
dimethylamine phenyl showed complete conversion in 3 h
delivering the product in 33% yield (2d). Other electron-
donating groups, such as methyl, n-pentyl, and tert-butyl in the
para position of the migrating phenyl group, gave complete
conversion in 6 h at rt with moderate to good yields (2e−2i).
However, substrates with an electron-withdrawing group on
the migrating phenyl group hardly gave complete conversion at
rt. Whe the temperature was increased to 60 °C for 3 h,
substrates bearing a para-fluoro or a para-chlorophenyl group
gave complete conversion with moderate yields (2j and 2k).
Notably, a para-trifluoromethyl phenyl group also underwent
the migration, although delivering the product in a low 39%
yield (2l).
With a 6′-methoxylnaphtyl migrating group, the reaction
smoothly delivered the target product in 85% yield at rt for 3 h
(2m). The substrate with thiophenyl as the migrating group
had to be heated to 60 °C for 3 h, leading to the corresponding
product in 68% yield (2n). Due to steric effects, the substrate
bearing a tert-butyl as the migrating group could not deliver the
target product even when heated at 100 °C (2o). To our
delight, when the reaction was performed at 60 °C, both the
cyclohexyl (2p) and the cyclopropyl (2q), having a secondary
sp3 migrating carbon, performed well. Encouraged by these
results, we next tried substrate bearing a benzyl as the
migrating group. This substrate could give the corresponding
product in 43% yield at 60 °C for 3 h (2r). We also tried a
substrate with a cyclohexmethyl, i.e., a primary sp3 carbon as
the migrating group. Under the same conditions, product 2s
was isolated in 41% yield. We further evaluated the substrate
with a terminal alkyne to test whether hydrogen could perform
as a migrating group (2t). However, we did not obtain the
expected product 2t. Next, the scope of this reaction was
further explored using substrates bearing different R2
substituents. Various alkyl (2u−2w), aryl (2y−2z), and
heteroaryl (2x) groups performed well. Finally, we examined
the effect of the benzylamine substituents (R3 and R4).
B
Org. Lett. XXXX, XXX, XXX−XXX