Synthesis of phenanthridines via palladium-catalyzed picolinamide-directed sequential C-H functionalization

Article abstract of DOI:10.3762/bjoc.9.102

We report a new synthesis of phenanthridines based on palladium-catalyzed picolinamide-directed sequential C-H functionalization reactions starting from readily available benzylamine and aryl iodide precursors. Under the catalysis of Pd(OAc)₂, the ortho- C-H bond of benzylpicolinamides is first arylated with an aryl iodide. The resulting biaryl compound is then subjected to palladium- catalyzed picolinamide-directed intramolecular dehydrogenative C-H amination with PhI(OAc)₂ oxidant to form the corresponding cyclized dihydrophenanthridines. The benzylic position of these dihydrophenanthridines could be further oxidized with Cu(OAc)₂, removing the picolinamide group and providing phenathridine products. The cyclization and oxidation could be carried out in a single step and afford phenathridines in moderate to good yields.

Full text of DOI:10.3762/bjoc.9.102

Synthesis of phenanthridines via palladium-catalyzed
picolinamide-directed sequential
C–H functionalization
Ryan Pearson1, Shuyu Zhang1, Gang He1, Nicola Edwards2
and Gong Chen*1
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2013, 9, 891–899.
1Department of Chemistry, The Pennsylvania State University,
University Park, Pennsylvania 16802, United States of America and
2Department of Chemistry, The Pennsylvania State University,
Worthington Scranton, Dunmore, Pennsylvania 18512, United States
of America
doi:10.3762/bjoc.9.102
Received: 04 March 2013
Accepted: 18 April 2013
Published: 08 May 2013
Email:
This article is part of the Thematic Series "Transition-metal and
organocatalysis in natural product synthesis".
Gong Chen* - guc11@psu.edu
* Corresponding author
Guest Editors: D. Y.-K. Chen and D. Ma
Keywords:
© 2013 Pearson et al; licensee Beilstein-Institut.
License and terms: see end of document.
C–H functionalization; palladium; phenanthridine; picolinamide
Abstract
We report a new synthesis of phenanthridines based on palladium-catalyzed picolinamide-directed sequential C–H functionaliza-
tion reactions starting from readily available benzylamine and aryl iodide precursors. Under the catalysis of Pd(OAc)2, the ortho-
C–H bond of benzylpicolinamides is first arylated with an aryl iodide. The resulting biaryl compound is then subjected to palla-
dium-catalyzed picolinamide-directed intramolecular dehydrogenative C–H amination with PhI(OAc)2 oxidant to form the corres-
ponding cyclized dihydrophenanthridines. The benzylic position of these dihydrophenanthridines could be further oxidized with
Cu(OAc)2, removing the picolinamide group and providing phenathridine products. The cyclization and oxidation could be carried
out in a single step and afford phenathridines in moderate to good yields.
Introduction
Phenanthridines and 5,6-dihydro-phenanthridines are important tionalization of carbon–hydrogen (C–H) bonds have also
core structures found in a variety of natural products and func- emerged as viable strategies for synthesizing phenanthridines
tional molecules (Scheme 1A) [1-8]. Synthetic methods for [23-25]. Despite these advances, construction of phenan-
their preparation include the classical Pictet–Hubert conden- thridines with complex substitution patterns remains difficult
sation [9], radical-mediated reactions [10-13], metal-catalyzed and often requires lengthy and inefficient synthetic sequences.
cross-couplings [14-18], cycloadditions [19], and others [20- Herein, we report a novel method for phenanthridine synthesis
22]. More recently, methods based on the metal-catalyzed func- based on sequential palladium-catalyzed picolinamide
891

Beilstein J. Org. Chem. 2013, 9, 891–899.
Scheme 1: Representative phenanthridine compounds and our synthetic strategy based on Pd-catalyzed sequential C–H functionalizations.
(PA)-directed C–H functionalization reactions beginning from arene group to form cyclized dihydrophenanthridines, which
easily accessible PA-protected benzylamine and aryl iodide could be further converted to phenanthridine products under
precursors.
oxidative conditions. Ideally, we hoped to perform both the
intramolecular C–H amination and subsequent oxidation in a
single step [36].
Results and Discussion
New synthetic strategy for phenanthridine compounds. The
picolinamide (PA) group has been shown to be an excellent Arylation of 2-methoxybenzyl picolinamide 1 with
directing group for a range of Pd-catalyzed C–H functionaliza- 4-iodoanisole (2) under various conditions. We commenced
tion reactions [26-35]. In 2005, the Daugulis laboratory first the study by investigating the arylation of 2-methoxybenzyl
reported that the ortho-C(sp2)−H bond of benzylpicolinamides picolinamide 1 with 4-iodoanisole (2) under various conditions
could be arylated with aryl iodides under Ag-promoted (Table 1) to form our desired arylated product 3. Our initial
Pd-catalyzed conditions [26]. In 2012, our laboratory [28] as attempt under the original Pd(OAc)2-catalyzed AgOAc-
well as that of Daugulis [27] independently reported that promoted solvent-free condition afforded the desired arylated
picolinamide substrates can undergo intramolecular dehydro- product 3 in good yield (Table 1, entry 1). This method,
genative C–H amination reactions to afford medium-sized however, required the use of expensive silver salt as an additive
N-heterocycles under the catalysis of Pd(OAc)2 with PhI(OAc)2 and high reaction temperature (150 °C). We next sought to
oxidant. These discoveries led us to explore whether we could replace the silver salts with cheaper reagents and lower the reac-
develop a new strategy for synthesizing phenanthridines. As tion temperature [12]. Not surprisingly, the arylation yield
outlined in Scheme 1B, we envisioned that ortho-arylated dropped significantly when the reaction was performed in
benzylamine picolinamides could undergo an intramolecular toluene solvent at 120 °C (Table 1, entry 2). Addition of PivOH
amination at the ortho ε-C–H position of the newly installed (0.3 equiv) gave little improvement (Table 1, entries 3 and 4).
892

Beilstein J. Org. Chem. 2013, 9, 891–899.
Table 1: Optimization of the Pd-catalyzed ortho-C–H arylation of benzylpicolinamide. All screening reactions were carried out in a 10 mL glass vial on
a 0.2 mmol scale.
entry
additives (equiv)
temperature (°C)
solvent
yield of 3 (%)a
1
2
AgOAc (1.5)
150
120
120
120
120
120
120
120
120
90
no solvent
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
76
AgOAc (1.5)
6
3
AgOAc (1.5), PivOH (0.3)
PivOH (0.3)
3
5
4
5
K2CO3 (2)
57
6
PivOH (0.3), K2CO3 (2)
PivOH (0.3), KHCO3 (2)
AcOH (0.3), KHCO3 (2)
oPBAc (0.3), KHCO3 (2)
PivOH (0.3), KHCO3 (2)
90
7
95 (91)b
78
8
9
84
10
29
aYields are based on 1H NMR analysis of the reaction mixture after workup; bIsolated yield; coPBA: ortho-phenylbenzoic acid.
To our delight, the desired arylation reaction was largely intramolecular dehydrogenative amination of ε-C(sp2)–H bonds
restored with the application of 2 equiv of K2CO3 at 120 °C for [37-45]. To our delight, treatment of 3 in the presence of
24 h (Table 1, entry 5). Furthermore, an excellent yield was 5 mol % of Pd(OAc)2 and 2 equiv of PhI(OAc)2 in toluene at
obtained when K2CO3 was replaced with KHCO3 and 0.3 equiv 120 °C for 24 h gave the desired dihydrophenanthridine 16 in
of PivOH was applied (Table 1, entry 7). The most effective good yield (Table 2, entry 1). In addition, a further oxidized
carboxylate ligand and solvent was found to be PivOH and phenanthridine 17 was obtained as a side product. Compound
toluene, respectively.
17 is presumably generated through the PhI(OAc)2-mediated
oxidation of the benzylic C–H bond to form a phenanthri-
The determination of the scope of this reaction with dinium intermediate 18, which then undergoes a removal of the
benzylpicolinamide and aryl iodide substrates. With the opti- PA group. Encouraged by these observations, we proceeded to
mized conditions in hand, we next explored the scope of explore whether the cyclization and oxidation steps can be
benzylpicolinamide and aryl iodide substrates (Figure 1). The performed in one step to give the phenanthridines in a shorter
electronic properties of benzylpicolinamide and aryl iodides had procedure. A variety of oxidants, such as 1,4-benzoquinone
little influence on the reactivity, as benzylpicolinamide and aryl (BQ), KMnO4, ceric ammonium nitrate (CAN), and copper
iodide substrates bearing electron-donating and withdrawing salts were examined [46]. The combination of PhI(OAc)2
substituents react in good yields (3, 8, and 12). Significantly (2 equiv) and Cu(OAc)2 (2 equiv) afforded the phenanthridine
decreased arylation yield was observed for ortho-substituted product 17 in highest yield (Table 2, entry 7). The yield can be
aryl iodides (e.g., 9). The sterics of the benzylpicolinamides is further improved using 10 mol % of Pd(OAc)2 catalyst
also important for the regioselectivity of the arylation reaction. (Table 2, entry 8). In a control experiment, dihydrophenanthri-
For instance, the less hindered ortho position is preferentially dine 16 was oxidized with the application of Cu(OAc)2
arylated (e.g., 14) when a meta substitutent is present on the (2 equiv) in toluene at 120 °C for 24 h, forming 17 in excellent
benzylpicolinamide. Aryl bromides are much less reactive yield. We believe that PhI(OAc)2 serves as the oxidant for the
compared with aryl iodide substrates 4. This is in accordance initial Pd-catalyzed intramolecular C–H amination step, in
with results on the Pd-catalyzed PA-directed arylation of more which a PdII/IV catalytic manifold might be operative.
inert C(sp3)−H bonds [29].
Cu(OAc)2 is responsible for the subsequent oxidation of the
benzylic C–H bond of dihydrophenanthridine.
Cyclization of biaryl compounds to form dihydrophenan-
thridines. Next, we investigated the cyclization of biaryl com- Extension of the cyclization–oxidation step to other arylated
pounds to form dihydrophenanthridines via Pd-catalyzed picolinamide substrates. The coupled cyclization–oxidation
893

Beilstein J. Org. Chem. 2013, 9, 891–899.
Figure 1: Substrate scope of the Pd-catalyzed PA-directed C–H arylation reaction. All reactions were carried out in a 10 mL glass vial on a 0.2 mmol
scale; yields are based on the isolated product.
step detailed above was then used to synthesize phenan- show intense blue fluorescence. We expect our synthetic
thridines from other arylated picolinamide substrates (Figure 2). strategy will afford access to phenanthridines bearing varied
In general, electron-rich arene motifs, installed by C–H substitution patterns, enabling applications in biology and ma-
arylation, gave a higher yield of phenanthridine products; elec- terials science.
tron-deficient substrates provide a lower yield. For instance,
substrate 8 with a para-nitro group failed to give any cyclized Conclusion
product under the standard conditions. Substrates with moder- In summary, we have developed a readily applicable two-step
ately electron-withdrawing groups, such as 20 bearing a para- method for the synthesis of phenanthridines from easily acces-
ester group, reacted in moderate yield. The electronic prop- sible benzylamine picolinamides and aryl iodides. In the
erties of the benzylpicolinamide scaffold had much less influ- first step, an improved protocol allows us to carry out the
ence on the reaction. For example, product 22 bearing an ortho- Pd-catalyzed PA-directed C–H arylation reaction without the
CF3 substituent was obtained in 51% yield. Finally, it is use of expensive silver additives. In the second step, applica-
noteworthy that all of the above phenanthridine products tion of PhI(OAc)2 and Cu(OAc)2 oxidant under the catalysis of
894

Beilstein J. Org. Chem. 2013, 9, 891–899.
Table 2: Formation of phenanthridine 17 in a single step by Pd-catalyzed intramolecular C–H amination followed by oxidation. All screening reactions
were carried out in a 10 mL glass vial on a 0.2 mmol scale.
entry
Pd(OAc)2 (mol %)
additives (equiv)
yield (%)a
16
17
1
2
3
4
5
6
7
8
5
5
PhI(OAc)2 (2)
40
23
35
56
37
29
17
15
5
PhI(OAc)2 (2), AcOH (2)
PhI(OAc)2 (2), BQ (2)
PhI(OAc)2 (2), KMnO4 (2)
PhI(OAc)2 (2), CAN (2)
PhI(OAc)2 (2), CuCl2 (2)
PhI(OAc)2 (2), Cu(OAc)2 (2)
PhI(OAc)2 (2), Cu(OAc)2 (2)
8
10
5
5
3
5
25
5
34
5
51
10
62 (58)b
aYields are based on 1H NMR analysis of the reaction mixture after workup; bIsolated yield.
Figure 2: Substrate scope of this phenanthridine synthesis. All reactions were carried out in a 10 mL glass vial on a 0.2 mmol scale; yields are based
on isolated product.
Pd(OAc)2 affords phenanthridines in moderate to good yields. Experimental
Applications of this method to the synthesis of more complex General conditions: All commercial materials were used as
phenanthridines with novel photophysical properties are cur- received unless otherwise noted. All solvents were obtained
rently underway.
from a JC Meyer solvent dispensing system and used without
895

Beilstein J. Org. Chem. 2013, 9, 891–899.
further purification. Flash chromatography was performed using 6.8 Hz, 1H), 7.35 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 8.3 Hz, 2H),
230–400 mesh SiliaFlash 60® silica gel (Silicycle Inc.). 6.97 (d, J = 8.2 Hz, 1H), 6.89 (d, J = 7.7 Hz, 1H), 4.59 (d,
PhI(OAc)2 (98%, Aldrich), Pd(OAc)2 (98%, Aldrich) were used J = 5.5 Hz, 2H), 3.95 (s, 3H); 13C NMR (CDCl3, 75.5 MHz) δ
in the Pd-catalyzed reactions. NMR spectra were recorded on 163.3, 158.7, 150.1, 148.0, 142.5, 139.4, 137.1, 131.3, 130.9,
Bruker CDPX-300, DPX-300, DPX-400 instruments and cali- 128.6, 125.9, 123.5, 122.4, 122.1, 121.6, 109.9, 55.8, 36.7;
brated by using residual solvent peaks as the internal reference. HRMS (m/z): [M + H]+ calcd for C20H18BrN2O2, 397.0552;
Multiplicities are recorded as: s = singlet, d = doublet, found, 397.0561.
t = triplet, dd = doublet of doublets, m = multiplet. High-resolu-
tion ESI mass experiments were operated on a Waters LCT Compound 5. 1H NMR (CDCl3, 400 MHz) δ 8.51 (d,
Premier instrument.
J = 4.0 Hz, 1H), 8.33 (s, 1H), 8.15 (d, J = 7.6 Hz, 1H), 8.08 (d,
J = 8.0 Hz, 1H), 7.80 (t, J = 7.6 Hz, 1H), 7.44–7.34 (m, 4H),
Standard procedure for the Pd-catalyzed ortho C–H 6.97 (d, J = 8.0 Hz, 1H), 6.90 (d, J = 7.6 Hz, 1H), 4.58 (d,
arylation reaction: A mixture of picolinamide 1 [30] (48 mg, J = 5.2 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H); 13C NMR (CDCl3,
0.2 mmol, 1 equiv), aryl iodide 2 (94 mg, 0.4 mmol, 2 equiv), 75 MHz) δ 166.9, 163.3, 158.7, 150.2, 148.0, 145.2, 142.9,
Pd(OAc)2 (2.2 mg, 0.01 mmol, 0.05 equiv), KHCO3 (40 mg, 137.2, 129.5, 129.3, 129.0, 128.6, 125.9, 123.5, 122.3, 122.2,
0.4 mmol, 2.0 equiv), and PivOH (6 mg, 0.06 mmol, 0.3 equiv) 110.0, 55.8, 52.1, 36.6; HRMS (m/z): [M + H]+ calcd for
in anhydrous toluene (4 mL) in a 10 mL glass vial (purged with C22H21N2O4, 377.1501; found, 377.1509.
N2, sealed with PTFE cap) was heated at 120 °C for 24 h. The
reaction mixture was filtered through a short pad of celite and Compound 6. 1H NMR (CDCl3, 300 MHz) δ 8.51 (d,
concentrated in vacuo. The resulting residue was purified by J = 4.2 Hz, 1H), 8.34 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H),
silica-gel flash chromatography (hexanes/EtOAc 3:1) to give 7.40–7.31 (m, 1H), 6.98–6.91 (m, 5H), 4.66 (d, J = 5.4 Hz, 2H),
the product 3 as a pale white solid (64 mg, 91%). Compounds 3.94 (s, 3H), 3.79 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ 163.8,
4–15 were prepared from the known precursors [30] by using 159.7, 159.0, 150.7, 148.4, 144.4, 142.3, 137.6, 129.7, 128.9,
the standard C–H arylation procedure.
126.3, 124.0, 123.0, 122.6, 122.1, 114.9, 113.8, 110.1, 55.3,
55.6, 37.2; HRMS (m/z): [M + H]+ calcd for C21H21N2O3,
Standard procedure for the Pd-catalyzed cyclization and 349.1552; found, 349.1564.
oxidation reaction to form phenanthridines: A mixture of
picolinamide 3 (70 mg, 0.2 mmol, 1 equiv), Pd(OAc)2 (4.4 mg, Compound 7. 1H NMR (CDCl3, 300 MHz) δ 8.53 (d,
0.02 mmol, 0.1 equiv), PhI(OAc)2 (129 mg, 0.4 mmol, J = 4.2 Hz, 1H), 8.34 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H),
2.0 equiv), and Cu(OAc)2 (72 mg, 0.4 mmol, 2 equiv) in anhy- 7.84–7.80 (m, 1H), 7.40–7.29 (m, 2H), 6.96–6.80 (m, 5H),
drous toluene (4 mL) in a 10 mL glass vial (purged with N2, 6.00 (s, 2H), 4.64 (d, J = 5.4 Hz, 1H), 3.96 (s, 3H);
sealed with PTFE cap) was heated at 120 °C for 24 h. The reac- 13C NMR (CDCl3, 75 MHz) δ 163.4, 158.7, 150.3, 148.0,
tion mixture was filtered through a short pad of celite and 147.4, 146.9, 143.7, 137.1, 134.4, 128.4, 125.8, 123.7, 122.8,
concentrated in vacuo. The resulting residue was purified by 122.7, 122.2, 109.9, 109.5, 108.1, 101.0, 55.8, 36.8; HRMS
silica gel flash chromatography (hexanes/EtOAc 4:1) to give the (m/z): [M + H]+ calcd for C21H20N2O4, 363.1345; found,
product 17 as a pale white solid (28 mg, 58%). Compounds 363.1355.
19–24 were prepared by using the standard cyclization–oxi-
dation procedure.
Compound 8. 1H NMR (CDCl3, 300 MHz) δ 8.53 (d,
J = 4.1 Hz, 1H), 8.41 (s, 1H), 8.29 (d, J = 8.8 Hz, 2H), 8.16 (d,
Compound 3. 1H NMR (CDCl3, 300 MHz) δ 8.53 (d, J = 7.8 Hz, 1H), 7.85 (td, J = 7.7, 1.6 Hz, 1H), 7.55 (d,
J = 4.2 Hz, 1H), 8.40 (s, 1H), 8.21 (d, J = 7.5 Hz, 1H), J = 8.7 Hz, 2H), 7.42–7.34 (m, 2H), 7.03 (d, J = 8.2 Hz, 1H),
7.85–7.80 (m, 1H), 7.42–7.30 (m, 3H), 6.99–6.93 (m, 4H), 4.65 6.89 (d, J = 7.7 Hz, 1H), 4.58 (d, J = 5.7 Hz, 2H), 3.98 (s, 3H);
(d, J = 5.4 Hz, 2H), 3.95 (s, 3H), 3.85 (s, 3H); 13C NMR 13C NMR (CDCl3, 75.5 MHz) δ 163.4, 158.8, 150.0, 148.1,
(CDCl3, 75 MHz) δ 163.3, 158.8, 158.6, 150.2, 147.9, 143.6, 147.4, 147.1, 141.4, 137.3, 130.4, 128.9, 126.1, 123.7, 123.5,
137.1, 132.7, 130.3, 128.3, 125.8, 123.4, 122.7, 122.1, 113.6, 122.2, 122.2, 110.7, 56.0, 36.6; HRMS (m/z): [M + H]+ calcd
109.1, 55.7, 55.2, 36.8; HRMS (m/z): [M + H]+ calcd for for C20H18N3O4, 364.1297; found, 364.1292.
C21H21N2O3, 349.1552; found, 349.1546.
Compound 9. 1H NMR (CDCl3, 300 MHz) δ 8.53 (d,
Compound 4. 1H NMR (CDCl3, 300 MHz) δ 8.52 (d, J = 4.2 Hz, 1H), 8.32 (s, 1H), 8.18–8.16 (m, 1H), 7.85–7.80 (m,
J = 4.5 Hz, 1H), 8.36 (s, 1H), 8.19 (d, J = 7.8 Hz, 1H), 7.84 (td, 1H), 7.38–7.30 (m, 4H), 7.25–7.13 (m, 2H), 7.02–6.92 (m, 2H),
J = 7.8, 1.4 Hz, 1H), 7.55 (d, J = 8.3 Hz, 2H), 7.41 (dd, J = 5.0, 4.64–4.90 (m, 2H), 3.98 (s, 3H); 13C NMR (CDCl3, 75 MHz) δ
896

Beilstein J. Org. Chem. 2013, 9, 891–899.
163.8, 161.2, 158.9, 150.7, 148.4, 137.8, 137.6, 132.0, 129.9, 122.0, 113.5, 55.0, 41.1, 20.9; HRMS (m/z): [M + H]+ calcd for
128.9, 126.2, 125.2, 124.5, 123.3, 122.6, 115.9, 115.8, 110.7, C21H21N2O2, 333.1603; found, 333.1609.
56.22, 37.2; HRMS (m/z): [M + H]+ calcd for C20H18FN2O2,
337.1352; found, 337.1364.
Compound 15. 1H NMR (CDCl3, 300 MHz) δ 8.45 (d,
J = 4.7 Hz, 1H), 8.01 (d, J = 7.8 Hz, 1H), 7.78 (m, 2H), 7.42 (s,
Compound 10. 1H NMR (CDCl3, 300 MHz) δ 8.51 (d, 2H), 7.37 (m, 1H), 7.30 (d, J = 8.7 Hz, 4H), 6.90 (d, J = 8.7 Hz,
J = 4.0 Hz, 1H), 8.25 (s, 1H), 8.17 (d, J = 7.8 Hz, 1H), 7.84 (td, 4H), 4.47 (d, J = 5.1 Hz, 2H), 3.79 (s, 6H); 13C NMR (CDCl3,
J = 7.7, 1.7 Hz, 1H), 7.73 (d, J = 8.3 Hz, 2H), 7.66 (d, 75.5 MHz) δ 162.9, 159.1, 149.5, 147.8, 145.2, 137.0, 132.3,
J = 8.3 Hz, 1H), 7.41–7.36 (m, 1H), 7.32–7.24 (m, 3H), 7.17 (d, 132.2, 132.1, 129.9, 125.9, 121.8, 121.0, 113.8, 55.2, 39.0;
J = 8.3 Hz, 1H), 7.06 (s, 1H), 6.94 (d, J = 8.2 Hz, 1H), 6.88 (d, HRMS (m/z): [M + H]+ calcd for C27H24Br3N2O3, 503.0970;
J = 7.4 Hz, 1H), 4.57 (d, J = 5.4 Hz, 2H), 3.95 (t, J = 8.8 Hz, found, 503.0975.
2H), 3.92 (s, 3H), 2.93 (t, J = 8.4 Hz, 2H), 2.37 (s, 3H);
13C NMR (CDCl3, 75.5 MHz) δ 163.3, 158.7, 150.2, 148.1, Compound 17. 1H NMR (CDCl3, 300 MHz) δ 9.72 (s, 1H),
144.1, 143.4, 141.3, 137.2, 136.1, 133.9, 131.8, 129.8, 128.7, 8.45 (d, J = 9.0 Hz, 1H), 8.08 (d, J = 8.2 Hz, 1H), 7.75 (t,
128.5, 127.3, 126.2, 125.9, 123.5, 122.6, 122.1, 114.5, 109.5, J = 8.1 Hz, 1H), 7.61 (d, J = 2.6 Hz, 1H), 7.33–7.29 (m, 1H),
55.8, 50.1, 36.7, 27.8, 21.5; HRMS (m/z): [M + H]+ calcd for 6.99 (d, J = 7.8 Hz, 1H), 4.09 (s, 3H), 4.00 (s, 3H); 13C NMR
C29H18N3O4S, 514.1801; found: 514.1813.
(CDCl3, 75.5 MHz) δ 160.5, 157.5, 149.1, 147.2, 134.6, 132.1,
124.3, 118.5, 117.1, 113.8, 110.1, 105.9, 56.2, 56.0; HRMS
Compound 11. 1H NMR (CDCl3, 300 MHz) δ 8.54 (d, (m/z): [M + H]+ calcd for C15H14NO2, 240.1025; found,
J = 3.9 Hz, 1H), 8.21 (d, J = 7.5 Hz, 2H), 7.88–7.83 (m, 1H), 240.1030.
7.46–7.41 (m, 2 H), 7.34–7.23 (m, 4 H), 6.96 (d, J = 8.7 Hz,
1H), 4.72 (d, J = 5.4 Hz, 1H), 8.86 (s, 3H); 13C NMR (CDCl3, Compound 19. 1H NMR (CDCl3, 400 MHz) δ 9.68 (s, 1H),
75 MHz) δ 163.5, 159.1, 149.8, 148.0, 144.9, 137.2, 135.8, 8.33 (m, 2H), 8.04 (d, J = 8.3 Hz, 1H), 7.75 (m, 2H), 7.04 (d,
132.9, 132.4, 130.1, 129.2, 128.7, 128.6, 126.0, 122.2, 113.8, J = 7.9 Hz, 1H), 4.05 (s, 3H); 13C NMR (CDCl3, 75.5 MHz) δ
55.2, 39.6; HRMS (m/z): [M + H]+ calcd for C20H18ClN2O2, 157.6, 149.5, 145.7, 133.8, 132.5, 132.2, 130.1, 124.3, 122.5,
353.1057; found, 353.1067.
117.4, 113.7, 107.2, 55.9; HRMS (m/z): [M + H]+ calcd for
C14H11BrNO, 228.0024; found, 228.0032.
Compound 12. 1H NMR (CDCl3, 300 MHz) δ 8.50 (d,
J = 4.8 Hz, 1H), 8.14 (d, J = 7.8 Hz, 1H), 7.93 (s, 1H), Compound 20. 1H NMR (CDCl3, 300 MHz) δ 9.75 (s, 1H),
7.83–7.74 (m, 2H), 7.50–7.39 (m, 3H), 7.28–7.22 (m, 2H), 6.89 8.84 (s, 1H), 8.54 (d, J = 8.7 Hz, 1H), 8.24 (d, J = 7.5 Hz, 1H),
(d, J = 8.7 Hz, 2H), 4.71 (d, J = 4.5 Hz, 1H), 3.82 (s, 3H); 8.14 (d, J = 8.4 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 7.09 (d,
13C NMR (CDCl3, 75 MHz) δ 163.0, 159.1, 149.6, 148.0, J = 8.1 Hz, 1H), 4.06 (s, 3H), 4.01 (s, 3H); 13C NMR (CDCl3,
145.6, 137.1, 134.6, 133.5, 131.9, 130.1, 129.9, 127.8, 126.0, 75 MHz) δ 166.8, 157.4, 149.2, 144.0, 133.2, 132.1, 132.0,
125.4, 122.1, 113.8, 55.2, 38.2; HRMS (m/z): [M + H]+ calcd 130.1, 127.0, 126.7, 122.9, 117.9, 114.2, 107.8, 55.8, 52.4;
for C21H18F3N2O2, 387.1320; found, 387.1328.
HRMS (m/z): [M + H]+ calcd for C16H13NO3, 268.0974, found,
268.0970.
Compound 13. 1H NMR (CDCl3, 300 MHz) δ 8.51 (d,
J = 4.2 Hz, 1H), 8.18 (d, J = 7.8 Hz, 2H), 7.83–7.79 (m, 1H), Compound 21. 1H NMR (CDCl3, 300 MHz) δ 9.59 (s, 1H),
7.42–7.38 (m, 1H), 7.33–7.30 (m, 3H), 7.11 (d, J = 7.5 Hz, 2H), 8.46 (d, J = 9.0 Hz, 1H), 8.29 (d, J = 8.4 Hz, 1H), 7.82–7.74 (m,
6.97 (d, J = 8.7 Hz, 2H), 4.68 (d, J = 5.4 Hz, 2H), 3.84 (s, 3H); 1H), 7.64 (s, 1H), 7.37–7.26 (m, 2H), 4.01 (s, 3H); 13C NMR
13C NMR (CDCl3, 75 MHz) δ 163.7, 160.4, 159.1, 149.7, (CDCl3, 75 MHz) δ 160.6, 147.4, 146.6, 134.6, 131.7, 131.6,
147.9, 144.4, 137.1, 131.6, 130.1, 128.9, 128.7, 126.0, 122.6, 123.8, 118.7, 117.4, 117.3, 111.1, 110.8, 110.1, 55.7; HRMS
122.1, 114.3, 113.8, 55.2, 35.6; HRMS (m/z): [M + H]+ calcd (m/z): [M + H]+ calcd for C14H10FNO, 228.0825; found,
for C20H18FN2O2, 337.1352; found, 337.1357.
228.0830.
Compound 14. 1H NMR (CDCl3, 300 MHz) δ 8.50 (d, Compound 22. 1H NMR (CDCl3, 300 MHz) δ 9.62 (s, 1H),
J = 4.5 Hz, 1H), 8.27–8.21 (m, 2H), 7.82 (t, J = 7.5 Hz, 1H), 8.72 (d, J = 8.4 Hz, 1H), 8.47 (d, J = 9.0 Hz, 1H), 7.95 (d,
7.41–7.29 (m, 4H), 7.19 (dd, J = 14.1 and 7.8 Hz, 2H), 6.98 (d, J = 7.2 Hz, 1H), 7.85 (t, J = 8.1 Hz, 1H), 7.62 (d, J = 2.4 Hz,
J = 8.4 Hz, 2H), 4.64 (d, J = 6.0 Hz, 2H), 3.84 (s, 3H), 2.38 (s, 1H), 7.36 (dd, J = 9.0 Hz and 2.7 Hz, 1H), 4.01 (s, 3H);
3H); 13C NMR (CDCl3, 75 MHz) δ 163.8, 158.5, 149.6, 147.8, 13C NMR (CDCl3, 75 MHz) δ 160.7, 149.3, 145.8, 133.8,
138.4, 137.0, 136.9, 135.2, 132.8, 130.0, 129.1, 127.9, 125.9, 129.5, 125.8, 124.4, 124.3, 123.4, 122.2, 119.1, 117.6, 109.8,
897

Beilstein J. Org. Chem. 2013, 9, 891–899.
14.Yanada, R.; Hashimoto, K.; Tokizane, R.; Miwa, Y.; Minami, H.;
Yanada, K.; Ishikura, M.; Takemoto, Y. J. Org. Chem. 2008, 73,
5135–5138. doi:10.1021/jo800474c
55.6; HRMS (m/z): [M + H]+ calcd for C15H12F3NO, 278.0793;
found, 278.0797.
15.Donaldson, L. R.; Haigh, D.; Hulme, A. N. Tetrahedron 2008, 64,
4468–4477. doi:10.1016/j.tet.2008.02.044
Compound 23. 1H NMR (CDCl3, 300 MHz) δ 9.72 (s, 1H),
8.46–8.42 (m, 2H), 7.72–7.62 (m, 3H), 7.35 (dd, J = 9.0 and
2.4 Hz, 1H), 4.02 (s, 3H); 13C NMR (CDCl3, 75 MHz, ppm) δ
160.5, 150.1, 146.1, 134.5, 133.9, 131.0, 126.9, 123.6, 122.3,
120.4, 118.8, 117.1, 109.9, 55.6; HRMS (m/z): [M + H]+ calcd
for C14H11ClNO, 244.0529; found, 244.0534.
16.Candito, D. A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48,
6713–6716. doi:10.1002/anie.200902400
17.Gerfaud, T.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed. 2009, 48,
572–577. doi:10.1002/anie.200804683
18.Zhang, L.; Ang, G. Y.; Chiba, S. Org. Lett. 2010, 12, 3682–3685.
doi:10.1021/ol101490n
19.Sripada, L.; Teske, J. A.; Deiters, A. Org. Biomol. Chem. 2008, 6,
263–265. doi:10.1039/b716519f
Compound 24. 1H NMR (CDCl3, 300 MHz) δ 9.23 (s, 1H),
8.48–8.42 (m, 2H), 7.82 (s, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.62
(s, 1H), 7.34–7.30 (m, 1H), 4.02 (s, 3H), 2.62 (s, 3H); 13C NMR
(CDCl3, 75 MHz) δ 160.2, 154.2, 146.3, 137.4, 136.7, 133.4,
131.1, 128.5, 123.6, 121.7, 118.2, 118.4, 110.3, 56.0, 21.9;
HRMS (m/z): [M + H]+ calcd for C15H13NO, 244.1075; found,
244.1079.
20.Shou, W.-G.; Yang, Y.-Y.; Wang, Y.-G. J. Org. Chem. 2006, 71,
9241–9243. doi:10.1021/jo061648i
21.Budén, M. E.; Dorn, V. B.; Gamba, M.; Pierini, A. B.; Rossi, R. A.
J. Org. Chem. 2010, 75, 2206–2218. doi:10.1021/jo9025918
22.Wu, Y.; Wong, S. M.; Mao, F.; Chan, T. L.; Kwong, F. Y. Org. Lett.
2012, 14, 5306–5309. doi:10.1021/ol302489n
23.Shabashov, D.; Daugulis, O. J. Org. Chem. 2007, 72, 7720–7725.
doi:10.1021/jo701387m
24.Maestri, G.; Larraufie, M.-H.; Derat, É.; Ollivier, C.; Fensterbank, L.;
Lacôte, E.; Malacria, M. Org. Lett. 2010, 12, 5692–5695.
doi:10.1021/ol102509n
Acknowledgements
We gratefully thank The Pennsylvania State University, NSF
(CAREER CHE-1055795), and ACS-PRF (51705-DNI1) for
financial support of this work.
25.Peng, J.; Chen, T.; Chen, C.; Li, B. J. Org. Chem. 2011, 76,
9507–9513. doi:10.1021/jo2017108
26.Zaitsev, V. G.; Shabashov, D.; Daugulis, O. J. Am. Chem. Soc. 2005,
127, 13154–13155. doi:10.1021/ja054549f
References
27.Nadres, E. T.; Daugulis, O. J. Am. Chem. Soc. 2012, 134, 7–9.
doi:10.1021/ja210959p
1. Theobald, R. S.; Schofield, K. Chem. Rev. 1950, 46, 170–189.
doi:10.1021/cr60143a004
28.Tran, L. D.; Popov, I.; Daugulis, O. J. Am. Chem. Soc. 2012, 134,
18237–18240. doi:10.1021/ja3092278
2. Kock, I.; Heber, D.; Weide, M.; Wolschendorf, U.; Clement, B.
J. Med. Chem. 2005, 48, 2772–2777. doi:10.1021/jm0490888
3. Zhang, J.; Lakowicz, J. R. J. Phys. Chem. B 2005, 109, 8701–8706.
doi:10.1021/jp046016j
29.He, G.; Chen, G. Angew. Chem., Int. Ed. 2011, 50, 5192–5196.
doi:10.1002/anie.201100984
30.Zhao, Y.; Chen, G. Org. Lett. 2011, 13, 4850–4853.
doi:10.1021/ol201930e
4. Stevens, N.; O’Connor, N.; Vishwasrao, H.; Samaroo, D.;
Kandel, E. R.; Akins, D. L.; Drain, C. M.; Turro, N. J. J. Am. Chem. Soc.
2008, 130, 7182–7183. doi:10.1021/ja8008924
31.He, G.; Zhao, Y.; Zhang, S.; Lu, C.; Chen, G. J. Am. Chem. Soc. 2012,
134, 3–6. doi:10.1021/ja210660g
5. Chen, J.-J.; Li, K.-T.; Yang, D.-Y. Org. Lett. 2011, 13, 1658–1661.
doi:10.1021/ol200117b
32.Zhang, S.-Y.; He, G.; Zhao, Y.; Wright, K.; Nack, W. A.; Chen, G.
J. Am. Chem. Soc. 2012, 134, 7313–7316. doi:10.1021/ja3023972
33.He, G.; Lu, C.; Zhao, Y.; Nack, W. A.; Chen, G. Org. Lett. 2012, 14,
2944–2947. doi:10.1021/ol301352v
6. Barthelmes, H. U.; Niederberger, E.; Roth, T.; Schulte, K.; Tang, W. C.;
Boege, F.; Fiebig, H. H.; Eisenbrand, G.; Marko, D. Br. J. Cancer 2001,
85, 1585–1591. doi:10.1054/bjoc.2001.2142
34.Zhao, Y.; He, G.; Nack, W. A.; Chen, G. Org. Lett. 2012, 14,
2948–2951. doi:10.1021/ol301214u
7. Bailly, C.; Arafa, R. K.; Tanious, F. A.; Laine, W.; Tardy, C.;
Lansiaux, A.; Colson, P.; Boykin, D. W.; Wilson, W. D. Biochemistry
2005, 44, 1941–1952. doi:10.1021/bi047983n
35.Zhang, S.-Y.; He, G.; Nack, W. A.; Zhao, Y.; Li, Q.; Chen, G.
J. Am. Chem. Soc. 2013, 135, 2124–2127. doi:10.1021/ja312277g
36.Thansandote, P.; Lautens, M. Chem.–Eur. J. 2009, 15, 5874–5883.
doi:10.1002/chem.200900281
8. Park, G. Y.; Wilson, J. J.; Song, Y.; Lippard, S. J.
Proc. Natl. Acad. Sci. U. S. A. 2012, 109, 11987–11992.
doi:10.1073/pnas.1207670109
37.Zaitsev, V. G.; Daugulis, O. J. Am. Chem. Soc. 2005, 127, 4156–4157.
doi:10.1021/ja050366h
9. Pictet, A.; Hubert, A. Ber. Dtsch. Chem. Ges. 1896, 29, 1182–1189.
doi:10.1002/cber.18960290206
38.Shabashov, D.; Daugulis, O. Org. Lett. 2005, 7, 3657–3659.
doi:10.1021/ol051255q
10.Alonso, R.; Campos, P. J.; García, B.; Rodríguez, M. A. Org. Lett.
2006, 8, 3521–3523. doi:10.1021/ol061258i
39.Tsang, W. C. P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005,
127, 14560–14561. doi:10.1021/ja055353i
11.McBurney, R. T.; Slawin, A. M. Z.; Smart, L. A.; Yu, Y.; Walton, J. C.
Chem. Commun. 2011, 47, 7974–7976. doi:10.1039/c1cc12720a
12.Linsenmeier, A. M.; William, C. M.; Bräse, S. J. Org. Chem. 2011, 76,
9127–9132. doi:10.1021/jo201542x
40.Inamoto, K.; Saito, T.; Katsuno, M.; Sakamoto, T.; Hiroya, K. Org. Lett.
2007, 9, 2931–2934. doi:10.1021/ol0711117
41.Wasa, M.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058–14059.
doi:10.1021/ja807129e
13.Tobisu, M.; Koh, K.; Furukawa, T.; Chatani, N. Angew. Chem., Int. Ed.
2012, 51, 11363–11366. doi:10.1002/anie.201206115
898

Beilstein J. Org. Chem. 2013, 9, 891–899.
42.Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.;
Gaunt, M. J. J. Am. Chem. Soc. 2008, 130, 16184–16186.
doi:10.1021/ja806543s
43.Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
10806–10807. doi:10.1021/ja904709b
44.Tan, Y.; Hartwig, J. F. J. Am. Chem. Soc. 2010, 132, 3676–3677.
doi:10.1021/ja100676r
45.Cho, S. H.; Yoon, J.; Chang, S. J. Am. Chem. Soc. 2011, 133,
5996–6005. doi:10.1021/ja111652v
46.Li, W.-R.; Hsu, N.-M.; Chou, H.-H.; Lin, S. T.; Lin, Y.-S.
Chem. Commun. 2000, 401–402. doi:10.1039/a909236f
License and Terms
This is an Open Access article under the terms of the
Creative Commons Attribution License
(http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic
Chemistry terms and conditions:
(http://www.beilstein-journals.org/bjoc)
The definitive version of this article is the electronic one
which can be found at:
doi:10.3762/bjoc.9.102
899