Organic Letters
Letter
a
Protoberberine and Protonitidine Alkaloids
Scheme 2. Synthesis of A−C−D Rings
both protoberberine and protonitidine alkaloids with the
abscission on B ring due to the distinct connection of the B
ring among the A−B−C−D rings. Thus, disassembling the B
ring via C−N bond breakage for protoberberine and C−C
bond cleavage for protonitidine uniformed the mutual
intermediate containing the A−C−D ring linked on the N-
adjacent position of isoquinoline, which can be afforded
through the aryl−heteroaryl cross coupling between aryl borate
and halo-substituted isoquinoline. The annular boronic acid (A
ring) with a better coupling activity and selectivity could be
cross-linked with the C−D ring, simultaneously reserving a
carbon chain for the B ring. A polysubstituted isoquinoline
a
Reagents and conditions are as follows: (i) I (1.0 equiv), AgOTFA
2
(
1.0 equiv), THF, rt or − 78 °C, 12 h or 6 h. (ii) Pd(dba) (5 mol %),
2
X-phos (10 mol %), (Bpin) (1.5 equiv), Na CO (5.0 equiv),
2
2
3
toluene/EtOH (v/v) = 1:1, 110 °C, 12 h. (iii) tBuOK (3.0 equiv),
toluene, rt, 12 h; X = Cl and R = H, 72%; X = Br and R = H, 70%; X =
Cl and R = Me, 74%. (iv) [Ir(COD)Cl]2 (5 mol %), bis(2-
dicyclohexylphosphinophenyl)ether (3 mol %), Sc(OTf) (10 mol
%), MeOH, 60 °C, 12 h, then MeI (1.2 equiv), K CO (2.0 equiv),
THF, reflux, 58%. (v) [Ir(COD)Cl]2 (5 mol %), bis(2-
3
2 3
dicyclohexylphosphinophenyl)ether (3 mol %), Sc(OTf) (10 mol
3
%
), MeOH, 60 °C, 12 h, then PMB-Cl (1.2 equiv), TBAI (20 mol %),
(
C−D ring) library can be established via the [4 + 2]-
K CO (3.0 equiv), THF, reflux, 52%. (vi) (a) [Ir(COD)Cl] (5 mol
2
3
2
cycloaddition reaction of 3,4-pyridyne and diene. 3,4-Pyridyne
28
%), bis(2-dicyclohexylphosphinophenyl)ether (3 mol %), Sc(OTf)
10 mol %), MeOH, 60 °C, 12 h, then BBr (3.0 equiv), DCM, −78
3
(C ring) orignates from hypervalent iodonium salts in situ.
(
3
Preinstalled chlorine on the N-adjacent position not only
strengthened the selectivity of the deprotonation but also
reserved a cross coupling linkage in advance. The diene partner
to −30 °C, 3 h; (b) CH Br (1.0 equiv), K CO (1.5 equiv), DMSO,
9
2
2
2
3
0 °C, two steps, 15%. (vii) (a) BBr (2.0 equiv), DCM, −78 °C, 3 h,
3
then MeI (1.2 equiv), K CO (2.0 equiv), THF, reflux, 65%; (b)
2
3
(
D ring) was the ideal choice not only for the matching the
Cu(acac) (10 mol %), BHMPO (12 mol %), LiOH·H O (3.0 equiv),
2
2
electronic properties of its HOMO orbital with the LUMO of
pyridyne but also for its selectivity due to the rigid
configuration via orbital overlapping. Preinstallation of Br on
position 3 allows isoquinoline to be diversely substituted.
As depicted in Scheme 2A, four kinds of annular boronic
acids B-1, B-2, B-3, and B-4 were readily afforded through
iodization and boronation with substituted phenethyl alcohol
as starting source. The stable cyclic boronic lactone is the key
partner not only for the highly selective coupling but also for
the B-ring cyclization. Since the protonation of iodide was
prone occurring, the desired boronation was achieved with the
help of the coordination from the alcoholic hydroxyl to boron.
Eight kinds of 3-haloisoquinolines were smoothly obtained
with the gram-scale preparation of annular boronic acids in
DMSO/H
2
O (v/v) = 4:1, 100 °C, 24 h, 72%; (c) PMB-Cl (1.5
equiv), TBAI (20 mol %), K CO (3.0 equiv), THF, reflux, 86%.
2
3
(
viii) (a) oxone (1.5 equiv), bis(4-fluorophenyl)-methanone (1.0
equiv), NaHCO (3.0 equiv), MeCN/H O (v/v) = 1:1, rt, 24 h, then
3
2
BBr (3.0 equiv), DCM, −78 °C, 3 h, 35%; (b) zinc power (30.0
3
equiv), NaHCO (5.0 equiv), EtOH/THF (v/v) = 4/1, 80 °C, 12 h;
3
(
(
c) MnO (3.0 equiv), THF, 12 h; (c) CH Br (1.0 equiv), K CO
2 2 2 2 3
1.5 equiv), DMSO, 90 °C, two steps, 21%. (ix) BBr (2.0 equiv),
3
DCM, −78 °C 3 h, then Me SO (1.2 equiv), K CO (2.0 equiv),
2
4
2
3
acetone, 60 °C, 55%. (x) BBr (2.0 equiv), DCM, −78 °C, 3 h; MeI
3
(1.2 equiv), K CO (2.0 equiv), THF, reflux, 68%. (xi) [Ir(COD)Cl]
2
3
2
(5 mol %), bis(2-dicyclohexylphosphinophenyl)ether (3 mol %),
Sc(OTf) (10 mol %), MeOH, 50 °C, 24 h, then MeI (1.2 equiv),
3
K CO (2.0 equiv), THF, reflux, 42%. (xii) [Ir(COD)Cl] (5 mol %),
2
3
2
bis(2-dicyclohexylphosphinophenyl)ether (3 mol %), Sc(OTf) (10
3
2
9
mol %), MeOH, 50 °C, 12 h, then PMB-Cl (1.2 equiv), TBAI (20
Scheme 2B. 2-Halopyridyl(anisole)iodonium salt was sub-
jected to potassium tert-butoxide in toluene, generating
pyridyne in situ that caused a [4 + 2]-cycloaddition with 3-
bromofuran at room temperature to afford 3-halo-6-bromo-
mol %), K CO (3.0 equiv), THF, reflux, 45%.
2
3
the compound 2a-1. With the cascade catalysis of iridium(I)
and scandium(III), 2a-1 was converted to the intermediate 3-
chloro-7-methoxy-5,8-dihydro-5,8-epoxyisoquinoline via cross
coupling with methanol, followed by highly selective ring-
5
,8-dihydro-5,8-epoxyisoquinoline and 3-halo-7-bromo-5,8-
dihydro-5,8-epoxyisoquinoline. Four different types of sub-
stituted 3-chloro-isoquinolines were collectively afforded from
1
328
Org. Lett. 2021, 23, 1327−1332