Angewandte
Chemie
Table 1: Optimization of divergent conditions.[a]
Among transition metal catalyzed carbonylations, the ligand
often plays a key role in accelerating the CO insertion.[7] Very
recently, the elegant work from Beller and co-workers showed
that the regioselectivity of palladium-catalyzed alkoxycarbo-
nylation can be controlled through different ligands.[8] Con-
sidering the different coordinative modes of aryne (p
coordination) and CO (s coordination) to the center metal,
the regioselectivity may be predominantly tuned by the
electronic and steric effects of the ligand. On the other hand,
the rate of aryne release from o-(trimethylsilyl)aryl triflates
can be controlled through selection of the fluoride source.[9]
Since selectivity is the key challenge, controllable multipath
MCRs often show great efficiency in divergent synthesis.[10]
Herein, we report a regiodivergent aryne MCR to afford two
classes of alkaloid scaffolds controlled through selection of
ligand and the releasing rate of aryne (Scheme 1E).
With this concept, we commenced our study by inves-
tigating N-methy-2-iodoaniline (1a) and benzyne precursor
(2a). The reaction was first performed in the presence of
Pd(OAc)2, K2CO3, and KF in toluene at 1008C, which
generated the desired product 3a in 10% yield (Table 1,
entry 1). To promote the solubility of the inorganic salt in the
system, MeCN was applied (entry 2) to give 3a in 33% yield
with 4a formation in 20% yield as well. A slightly increased
yield (39%) of 3a was obtained by changing the fluoride
source to CsF. To increase the generation rate of benzyne,
phase transfer catalysts were tested to improve the selectivity
of the reaction, and TBAI was found to produce the best yield
(entries 4–6). In view of iodide anions serving as ligands in Pd-
catalyzed reactions, KI was also tested as an additive, but no
improvement was observed (entry 7). When 10% of water
was added, 3a could be afforded in 69% yield without
formation of 4a (entry 8). Further study showed that a diluted
concentration could help to afford 3a as the single product in
85% yield (entry 9). To our delight, the acridone product 4a
turned to be the major product when electron-abundant
bidentate ligand dppm was applied for stabilizing the catalyst,
which demonstrated the ligand acceleration of carbonyl
insertion (entry 10). To confirm ligand effect and the influ-
ence of nitrogen coordination to the catalytic center, N-
benzyl-2-iodoaniline was tested with and without dppm,
resulting in a better yield of 4a in the presence of dppm
when reacting for 24 h (entries 11 and 12). Other bidentate
phosphine ligands such as dppe, dppp, and dppb could not
replace dppm for selectivity (entry 13–15), revealing the
effect of the ligand bite angle on the insertion rate of CO.[11]
Better yields were obtained by slowing down the rate of
benzyne generation (entries 16 and 17). Three equivalents of
benzyne precursor was used as the best choice for 4a
formation in 82% yield (entry 18).
Entry
R
Ligand Additive Solvent
“F”
Yield of Yield of
reagent 3 [%][b] 4 [%][b]
1
2
3
4
5
6
7
8
Me
Me
Me
Me
Me
Me
Me
Me
–
–
–
–
–
–
–
–
–
–
–
toluene
MeCN
MeCN
MeCN
MeCN
KF
KF
10
33
39
49
45
42
40
69
nd
20
21
18
15
17
25
nd
CsF
CsF
CsF
CsF
CsF
CsF
TBAI
TBAB
TEBAc
KI
MeCN
MeCN
TBAI
MeCN/
10% H2O
MeCN/
10% H2O
MeCN/
10% H2O
MeCN/
10% H2O
MeCN/
10% H2O
MeCN/
10% H2O
MeCN/
10% H2O
MeCN/
10% H2O
MeCN/
10% H2O
MeCN
9[c]
Me
–
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
–
CsF
CsF
CsF
CsF
KF
85
trace
76
nd
30
10
Me dppm
11[d] Bn
12[d] Bn dppm
13[d] Bn
–
nd
trace
43
35
dppe
21
14[d] Bn dppp
15[d] Bn dppb
16[d] Bn dppm
KF
35
trace
trace
39
KF
trace
trace
CsF
17[d] Bn dppm
–
–
KF
KF
trace
66
18[d,e] Bn dppm
MeCN
trace
82
[a] Reaction conditions: iodoaniline (0.1 mmol), benzyne precursor
(0.15 mmol), Pd(OAc)2 (0.01 mmol), ligand (0.01 mmol), additive
(0.02 mmol), “F” reagent (0.3 mmol), K2CO3 (0.3 mmol), CO balloon,
solvent (1 mL), 1008C, 12 h. [b] Yields of the isolated products. [c] 2 mL
of solvents was used. [d] Reacted for 24 h. [e] Benzyne precursor
(0.30 mmol) was used. TBAI=tetrabutylammonium iodide, TBAB=te-
trabutylammonium bromide, TEBAC=benzyl triethylammonium chlo-
ride, dppm=bis(diphenylphosphino)methane, dppe=bis(diphenyl-
phosphino)ethane, dppp=bis(diphenylphosphino)propane,
dppb=bis(diphenylphosphino)butane.
smoothly in this transformation (3i). In particular, 3l was
afforded without regioisomers, and the structure was con-
firmed by X-ray diffraction.[12] On the other hand, a set of
substituted acridones were obtained in overwhelming selec-
tivity under conditions B (4a–n). Electron-poor ester group
was tolerated and the structure of corresponding acridones
was confirmed by X-ray as well (4n).[12] Different acridone
alkaloids analogues were obtained by utilizing o-silyl aryltri-
flates bearing naturally frequently existing methoxy (4o) and
3,4-methylenedioxy groups (4p).
As we mentioned, penathridiones and acridones are
important natural product scaffolds which show biological
activities. We therefore extended the methodology to natural
product synthesis (Scheme 2). The acridone alkaloid 2,3-
methylenedioxy-10-methyl-9-acridanone 5 was afforded by
The results shown in Table 2 demonstrate that this
approach has a great potential in the divergent synthesis of
functionalized phenanthridinones and acridones. As shown in
the left part of Table 2, both electron-rich and electron-
deficient iodoanilines could be efficiently transformed to the
corresponding phenanthridinone products in good yields with
the R group substituted both at positions 4 and 5 (3a–l).
Notably, substrates bearing aryl bromide moieties, which
were prone to oxidative addition with Pd0 proceeded
,
Angew. Chem. Int. Ed. 2015, 54, 14960 –14964
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim