Direct α-arylation of α-amino carbonyl compounds with indoles using visible light photoredox catalysis

Article abstract of DOI:10.1021/jo301691h

A general and mild method for the construction of functionalized 2-(1H-indol-3-yl)-2-amino-carbonyl compounds was achieved, which represents the first example of direct α-arylation of α-amino carbonyl compounds with indoles using the visible light photoredox catalysis strategy.

Full text of DOI:10.1021/jo301691h

Article
pubs.acs.org/joc
Direct α‑Arylation of α‑Amino Carbonyl Compounds with Indoles
Using Visible Light Photoredox Catalysis
Zhi-Qiang Wang,†,‡ Ming Hu,†,‡ Xiao-Cheng Huang,†,‡ Lu-Bing Gong,†,‡ Ye-Xiang Xie,†
and Jin-Heng Li*,†
†State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical Engineering, Hunan University,
Changsha 410082, China
‡Key Laboratory of Chemical Biology & Traditional Chinese Medicine Research (Ministry of Education), Hunan Normal University,
Changsha 410081, China
S
* Supporting Information
ABSTRACT: A general and mild method for the construction
of functionalized 2-(1H-indol-3-yl)-2-amino-carbonyl com-
pounds was achieved, which represents the first example of
direct α-arylation of α-amino carbonyl compounds with
indoles using the visible light photoredox catalysis strategy.
Scheme 1. Direct α-Arylation Using the Cu-Catalyzed C−H
INTRODUCTION
■
Oxidation Strategy
The α-amino carbonyl motif is an important structure
component of multitudinous natural products and biomole-
cules.1,2 For these reasons, many mild, general and efficient
methods have been well-established for accessing this important
motif. However, despite progress in the field, transition metal-
catalyzed functionalization of α-C−H bond in α-amino
carbonyl compounds remains one of the biggest challenges
because there are some highly reactive functional groups, such
as a free N−H bond and a carbonyl group, often resulting in
some competitive reactions.1−4 In particular, methods for α-
arylation of α-amino carbonyls are rare and are more limited:
the α-arylation reaction often requires a base to in situ generate
the carbonyl enolate by α-deprotonation, thereby reacting with
expensive aryl sources (often aryl halides or pseudohalides)
with the aid of transition metal catalysts.3
A general synthesis of nonnaturally α-arylated amino
carbonyl compounds from cleavage of α-C−H bond without
the aid of bases would greatly expand the methods that are
available for their preparation. Very recently, we report a new,
mild base-free copper-catalyzed α-arylation of α-amino carbon-
yls with indoles in the presence of TBHP through a C−H
oxidation strategy.4 However, 2-(1H-indol-3-yl)-2-imino-car-
bonyls and 2-(1H-indol-3-yl)-2-oxo-carbonyls, not α-amino
carbonyl products, were selectively obtained as the terminal
products under argon or air atmosphere (Scheme 1).
indoles leading to 2-(1H-indol-3-yl)-2-amino-carbonyl com-
pounds. However, these reaction conditions cannot be
employed for α-arylation of α-amino carbonyl compounds
with either indole or even 1-benzylindole.
These compelled us to screen other viable reaction
conditions. After a series of trials, we found a new visible-
light photoredox catalysis strategy for 2-(1H-indol-3-yl)-2-
amino-carbonyl compounds synthesis by direct α-arylation
between α-amino carbonyl compounds and indoles with the aid
of Ru(bpy)3Cl2, 5 W blue LEDs light and O2, avoiding both the
use of bases and the conversion of the amino groups into imino
groups in the products (Scheme 2).5,6 It is noteworthy that the
products containing an indole unit would be valuable in
chemical synthesis because indole derivatives are important
motifs of numerous natural products, pharmaceutical molecules
and functional materials.7
RESULTS AND DISCUSSION
■
Very recently, Stephenson and co-workers reported that
Ru(bpy)3Cl2-catalyzed Friedel−Crafts amidoalkylation was
achieved by oxidation of dialkylamides using an oxidant
persulfate6n under the visible light at room temperature, via a
reactive N-acyliminium intermediate (Scheme 2).6 Although
this protocol is not consistent with either indole or 1-
methylindole with low yields,6n we envision that it may be
applied to α-arylation of α-amino carbonyl compounds with
The reaction between 1H-indole (1a) and 1-phenyl-2-
(phenylamino)ethanone (2a) was chosen to screen the optimal
conditions, and the results are summarized in Table 1. In the
presence of Ru(bpy)3Cl2, O2 and 37 W compact fluorescent
Received: August 9, 2012
Published: September 17, 2012
© 2012 American Chemical Society
8705
dx.doi.org/10.1021/jo301691h | J. Org. Chem. 2012, 77, 8705−8711

The Journal of Organic Chemistry
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Scheme 2. Direct Arylation with Indoles Using Visible Light Photoredox Catalysis
a
Table 1. Screening Optimal Conditions
9−11). While both CH2ClCH2Cl and toluene displayed a lower
effect, the reaction in MeCN still gave moderate yield. Notably,
only a trace of product 3 was observed in the absence of O2
(entry 12). Finally, the reaction at room temperature was
tested: it could take place, but a low yield was isolated in 48 h
(entry 13).
As shown in Scheme 3, we have probed the scope of both
indoles 1 and α-amino carbonyls 2 for this oxidative α-arylation
under the optimal reaction conditions. In the presence of indole
(1a), Ru(bpy)3Cl2, O2 and 5 W blue LEDs light, a number of
other arylamino groups in α-amino carbonyls 2 were initially
investigated (Products 4−10). For 1-phenyl-2-aminoethanones
having Me-substituted phenylamino groups, the order of the
reactivity is para > meta > ortho in terms of yields (Products 4−
6). The results demonstrated that substituents, such as
phenylamino, p-tolylamino, p-methoxyphenylamion and 2,3-
dihydro-1H-inden-5-ylamino groups, in 2-amino-1-p-tolyletha-
nones were compatible with the optimal conditions (Products
7−10). Interestingly, halo substituents, Cl and F, on the aryl
ring of the arylethanone moiety were consistent with the
optimal conditions, thereby facilitating additional modifications
at the halogenated positions (Products 12 and 13). It was
noted that ethyl 2-(p-tolylamino)acetate, an amino ester, was
successfully reacted with indole (1a), Ru(bpy)3Cl2 and O2
under 5 W blue LEDs light, providing the desired product 14 in
50% yield.
entry
[M] (mol %)
solvent
CH2Cl2
isolated yield (%)
b
1
Ru(bpy)3Cl2 (10)
Ru(bpy)3Cl2 (3)
Ru(bpy)3Cl2 (15)
32
26
b
2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2ClCH2Cl
MeCN
b
3
34
b
4
0
c
5
Ru(bpy)3Cl2 (10)
Ru(bpy)3Cl2 (10)
Ir(ppy)3 (10)
0
6
60
7
30
8
Eosin Y (10)
37
9
Ru(bpy)3Cl2 (10)
Ru(bpy)3Cl2 (10)
Ru(bpy)3Cl2 (10)
Ru(bpy)3Cl2 (10)
Ru(bpy)3Cl2 (10)
trace
54
10
11
toluene
CH2Cl2
CH2Cl2
6
d
12
trace
20
e
13
a
Reaction conditions: 1a (0.3 mmol), 2a (2.5 equiv), [M], O2 (1 atm)
and solvent (2 mL) with 5 W blue LEDs light at 40 °C for 48 h.
Ru(bpy)3Cl2 = tris(2,2′-bipyridine)ruthenium dichloride, Ir(ppy)3 =
b
tris(2-phenylpyridine)iridium(III). With 37 W compact fluorescent
c
d
e
light. Without additional visible light. Under argon atmosphere. At
room temperature.
The optimal conditions were found to be viable for a wide
range of indoles 1 with high substituents compatibility: several
substituents, including Me, Br, Cl, acryl, Et and aryl groups, on
the aromatic ring of indoles 1 were well-tolerated in the
presence of 1-p-tolyl-2-(m-tolylamino)ethanone (Products 15−
24). For example, treatment of Me-substituted indole with 1-p-
tolyl-2-(m-tolylamino)ethanone, Ru(bpy)3Cl2, O2 and 5 W blue
LEDs light afforded the corresponding products 15 and 19 in
62 and 67% yields, respectively. The introduction of Br, Cl or
olefin into this system makes this methodology more useful for
the preparation of pharmaceuticals and natural products
(Products 16−18). Gratifyingly, substituents, Me or aryl, at
the 2-position of indoles were also compatible with the optimal
conditions (Products 21−24). In the presence of Ru(bpy)3Cl2,
O2 and 5 W blue LEDs light, 2-methyl-1H-indole successfully
underwent the arylation reaction with 1-p-tolyl-2-(m-
tolylamino)ethanone leading to the desired product 21 in
light, 1H-indole (1a) was treated with 1-phenyl-2-
(phenylamino)ethanone (2a) at 40 °C smoothly, affording
the desired product 3 in 32% yield after 48 h (Table 1, entry 1).
Encouraged by these results, the amount of Ru(bpy)3Cl2 was
investigated: the yield was lowered to 26% yield at 3 mol %
Ru(bpy)3Cl2 (entry 2), and identical results to those of 10 mol
% Ru(bpy)3Cl2 were observed when 15 mol % Ru(bpy)3Cl2
was added (entry 3). It is noteworthy that the reaction cannot
take place without either Ru(bpy)3Cl2 or additional visible light
(entries 4 and 5). Gratifyingly, the yield was enhanced sharply
to 60% using 5 W blue LEDs light instead of 37 W compact
fluorescent light (entry 6). Two other visible-light photoredox
catalysts, Ir(ppy)3 and Eosin Y, were subsequently examined,
and screening revealed that they were inferior to Ru(bpy)3Cl2
(entries 7 and 8). Among the effect of solvents examined, it
turned out that CH2Cl2 was the most effective solvent (entries
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Scheme 3. Direct α-Arylation of α-Amino Carbonyl
Scheme 4. Control Experiments
Compounds (2) with Indoles (1) Using Visible Light
a
Photoredox Catalysis
GC yield of product 28b together with 42% GC yield of
product 29b were isolated after 12 h (eq 2). Both products 28b
and 29b could also be furnished even without Ru(bpy)3Cl2,
albeit with a yield significantly lower than that with
Ru(bpy)3Cl2 (eq 2). Notably, blue LEDs light play an
important role in this reaction: only traces of the target
products 28b and 29b were observed without blue LEDs light
(eq 2). Consequently, we deduce that Ru(bpy)3Cl2 combined
with visible light is employed to only catalyze the formation of
imines.6m As expected, treatment of indole (1a) with ethyl 2-
(p-tolylimino)acetate (28b) offered the desired product 3 in
the absence of both Ru catalysts and additional light (eq 3).8
Consequently, a possible mechanism as outlined in Scheme 5
is proposed.5,6,8 Initially, the active Ru(bpy)3 species is
2+
Scheme 5. Possible Mechanism
a
Reaction conditions: 1 (0.3 mmol), 2 (2.5 equiv), Ru(bpy)3Cl2 (10
mol %), O2 (1 atm) and CH2Cl2 (2 mL) with 5 W blue LEDs light at
40 °C for 48−72 h.
good yield. Screening revealed that indoles with a phenyl, 4-
MeC6H4 or 4-BrC6H4 group also displayed high reactivity
under the same conditions, furnishing the target products 22−
24 in good yields. Finally, substituents on the nitrogen atom of
the indole moiety were tested (Products 25−27). While 1-alkyl
indoles (1-Me or 1-Bn) were successfully reacted with 1-p-tolyl-
2-(m-tolylamino)ethanone, Ru(bpy)3Cl2, O2 and 5 W blue
LEDs light in good yields (Products 25 and 26), 1-Ac-
substitued indole has no reactivity (Product 27).
Some control experiments were carried out to elucidate the
mechanism (Scheme 4). The results in eq 1 disclosed that the
addition of TBHP disfavored the reaction. In the presence of
Ru(bpy)3Cl2, TBHP, O2 and 5 W blue LEDs light, treatment of
indole (1a) with 1-phenyl-2-(phenylamino)ethanone (2a)
afforded product 3 in a low yield together with some
unidentified byproduct. Interestingly, the GC−MS analysis
results disclosed that without indoles ethyl 2-(p-tolylamino)-
acetate (2b) could be converted into ethyl 2-(p-tolylimino)-
acetate (28b) and ethyl 2-oxo-2-(p-tolylamino)acetate (29b) in
the presence of Ru(bpy)3Cl2, O2 and 5 W blue LEDs light: 49%
2+•
converted to the excited state Ru(bpy)3 by irradiating with
visible light. Subsequently, a single electron transfer (SET)
2+•
from the excited state Ru(bpy)3
to 1-phenyl-2-
(phenylamino)ethanone 2a takes place to offer the radical
5,6
+
intermediate A and Ru(bpy)3 . The radical intermediate A
readily undergoes the deprotonation reaction leading to imine
intermediate B.6m Finally, the reaction of indole (1a) with
intermediate B affords the desired product 3,8 and the active
Ru(bpy)3 species is regenerated from the oxidation of
Ru(bpy)3 with O2 to start a new catalytic cycle.
2+
+
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Article
(5), 65 (15); HRMS (EI) for C23H20N2O (M+) calcd 340.1576, found
340.1572.
CONCLUSIONS
■
In summary, we have established a general and mild method for
constructing numerous functionalized 2-(1H-indol-3-yl)-2-
amino-carbonyl compounds via direct α-arylation of α-amino
carbonyl compounds with indoles using the visible-light
photoredox catalysis strategy. This new protocol has several
attractive features, including (i) a low operating temperature
(40 °C) without the requirement of bases, ligands or dangerous
peroxides (TBHP), (ii) high functional group tolerance and
broad substrate scope, and (iii) simple operation by visible-light
photoredox catalysis. Importantly, it opens a new door to
synthesize natural and nonnatural α-amino carbonyl com-
pounds by the introduction of the heterocycle unit into them,
which makes the obtanied α-amino carbonyl compounds more
valuable with some special complex bioactivities.
2-(1H-Indol-3-yl)-1-phenyl-2-(o-tolylamino)ethanone (6). 43.9
1
mg, yield 43%. Yellow oil: H NMR (500 MHz, DMSO-d6) δ 11.15
(brs, 1H), 8.21 (d, J = 7.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.64 (s,
1H), 7.55 (t, J = 7.5 Hz, 1H), 7.45 (t, J = 7.5 Hz, 2H), 7.33 (d, J = 7.5
Hz, 1H), 7.08−6.95 (m, 4H), 6.88 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 7.5
Hz, 1H), 6.53 (t, J = 7.5 Hz, 1H), 5.31 (d, J = 7.5 Hz, 1H), 2.20 (s,
3H); 13C NMR (125 MHz, DMSO-d6) δ 197.5, 145.1, 136.9, 135.3,
133.9, 130.4, 129.2 (2C), 127.2, 126.8, 125.9, 122.5, 121.9, 119.8,
119.3, 117.1, 112.5, 111.6, 110.9, 55.3, 17.8; LRMS (EI 70 ev) m/z
(%) 340 (M+, 1), 322 (1), 233 (15), 204 (19), 130 (11), 106 (27), 77
(18), 40 (100); HRMS (EI) for C23H20N2O (M+) calcd 340.1576,
found 340.1572.
2-(1H-Indol-3-yl)-2-(phenylamino)-1-p-tolylethanone (7). 56.1
1
mg, yield 55%. Yellow oil: H NMR (500 MHz, DMSO-d6) δ 11.09
(brs, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 7.5 Hz, 1H), 7.47 (s,
1H), 7.30 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.06−6.98 (m,
4H), 6.78 (d, J = 8.0 Hz, 2H), 6.55 (d, J = 7.5 Hz, 1H), 6.50 (t, J = 7.5
Hz, 1H), 6.15 (d, J = 7.5 Hz, 1H), 2.30 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 197.2, 148.0, 144.2, 136.8, 133.1, 129.9, 129.7, 129.1
(2C), 126.2, 126.1, 121.8, 119.7, 119.5, 116.6, 113.5, 112.2, 111.2,
55.0, 21.6; LRMS (EI 70 ev) m/z (%) 340 (M+, 1), 339 (1), 221
(100), 207 (6), 91 (10), 77 (4), 51 (15); HRMS (EI) for C23H20N2O
(M+) calcd 340.1576, found 340.1570.
EXPERIMENTAL SECTION
■
General Considerations. The H and 13C NMR spectra were
1
recorded in CDCl3 or DMSO-d6 solvents on 500 MHz spectrometer
using TMS as internal standard. HRMS was measured using a
Finnigan MAT95XP-HRMS analyzer in an EI mode. Melting points
determined are uncorrected.
Typical Experimental Procedure for the Ru-Catalyzed Direct
α-Arylation of α-Amino Carbonyl Compounds with Indoles. To
a Schlenk tube were added indole 1 (0.3 mmol), a-amino carbonyl 2
(2.5 equiv), Ru(bpy)2Cl2 (10 mol %), and CH2Cl2 (2 mL). Then the
tube was charged with O2 (1 atm), and illuminated with 5 W blue LED
at 40 °C (oil bath temperature) for the indicated time until complete
consumption of starting material as monitored by TLC and GC−MS
analysis. After the reaction was finished, the reaction mixture was
cooled to room temperature, diluted in diethyl ether, and washed with
brine. The aqueous phase was re-extracted with diethyl ether. The
combined organic extracts were dried over Na2SO4 and concentrated
in a vacuum, and the resulting residue was purified by silica gel column
chromatography (hexane/ethyl acetate = 5:1) to afford the desired
product.
2-(1H-Indol-3-yl)-1-p-tolyl-2-(p-tolylamino)ethanone (8). 70.1
1
mg, yield 66%. Yellow oil: H NMR (500 MHz, DMSO-d6) δ 11.05
(brs, 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.44 (s,
1H), 7.29 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 7.5 Hz, 2H), 7.04 (t, J = 7.5
Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 8.0 Hz, 2H), 6.70 (d, J =
7.5 Hz, 2H), 6.51 (d, J = 7.5 Hz, 1H), 5.89 (d, J = 7.5 Hz, 1H), 2.30 (s,
3H), 2.10 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 197.3, 145.7,
144.1, 136.7, 133.1, 129.7, 129.6, 129.1, 126.1, 125.0, 121.7, 119.7,
119.5, 113.7 (2C), 112.1, 111.3, 55.2, 21.6, 20.5; LRMS (EI 70 ev) m/
z (%)354 (M+, 1), 353 (1),, 338 (3), 235 (100), 204 (7), 118 (30), 91
(25), 40 (13); HRMS (EI) for C24H22N2O (M+) calcd 354.1732,
found 354.1728.
2-(1H-Indol-3-yl)-2-(4-methoxyphenylamino)-1-p-tolylethanone
(9). 68.8 mg, yield 62%. Yellow oil: 1H NMR (500 MHz, DMSO-d6) δ
11.05 (brs, 1H), 8.04 (d, J = 7.5 Hz, 2H), 7.75 (d, J = 8.0 Hz, 1H),
7.44 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz, 2H), 7.04 (t,
J = 8.0 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.75 (d, J = 8.5 Hz, 2H), 6.65
(d, J = 8.5 Hz, 2H), 6.49 (d, J = 8.0 Hz, 1H), 5.74 (d, J = 8.0 Hz, 1H),
3.59 (s, 3H), 2.30 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 197.5,
151.5, 144.1, 142.1, 136.7, 133.2, 129.7, 129.1, 126.1 (2C), 121.7,
119.7, 119.4, 114.8, 114.7, 112.1, 111.4, 55.7 (2C), 21.6; LRMS (EI 70
ev) m/z (%) 370 (M+, 1), 369 (1), 368 (2), 251 (55), 219 (17), 204
(20), 123 (41), 108 (52), 80 (121), 40 (100); HRMS (EI) for
C24H22N2O2 (M+) calcd 370.1681, found 370.1676.
2-(1H-Indol-3-yl)-1-phenyl-2-(phenylamino)ethanone (3). 58.7
mg, yield 60%. Yellow oil: H NMR (500 MHz, DMSO-d6) δ 11.09
1
(brs, 1H), 8.14 (d, J = 8.0 Hz, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.55 (t, J
= 7.0 Hz, 1H), 7.47−7.43 (m, 3H), 7.30 (d, J = 8.0 Hz, 1H), 7.07−
6.88 (m, 4H), 6.78 (d, J = 8.0 Hz, 2H), 6.58 (d, J = 8.0 Hz, 1H), 6.51
(t, J = 7.5 Hz, 1H), 6.13 (d, J = 7.5 Hz, 1H); 13C NMR (125 MHz,
DMSO-d6) δ 197.6, 147.9, 136.7, 133.6, 129.1 (2C), 128.9, 126.2,
126.1, 121.8, 119.6, 119.5, 116.6, 113.5 (2C), 112.1, 110.9, 55.2;
LRMS (EI 70 ev) m/z (%) 326 (M+, 1), 324 (4), 281 (3), 253 (3),
219 (100), 165 (6), 142 (5), 116 (7), 77 (24), 51 (9); HRMS (EI) for
C22H18N2O (M+) calcd 326.1419, found 326.1415.
2-(2,3-Dihydro-1H-inden-5-ylamino)-2-(1H-indol-3-yl)-1-p-tolyle-
2-(1H-Indol-3-yl)-1-phenyl-2-(p-tolylamino)ethanone (4). 59.2
mg, yield 58%. Yellow oil: H NMR (500 MHz, DMSO-d6) δ 11.07
1
1
thanone (10). 65.0 mg, yield 57%. Brown oil: H NMR (500 MHz,
DMSO-d6) δ 11.04 (brs, 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.73 (d, J = 8.0
Hz, 1H), 7.43 (s, 1H), 7.29 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.0 Hz,
2H), 7.04 (t, J = 7.5 Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.86 (d, J = 8.0
Hz, 1H), 6.80 (s, 1H), 6.58 (d, J = 7.5 Hz, 1H), 6.51 (d, J = 7.5 Hz,
1H), 6.85 (d, J = 7.5 Hz, 1H), 2.71−2.63(m, 4H), 2.30 (s, 3H), 1.93−
1.87 (m, 2H); 13C NMR (125 MHz, DMSO-d6) δ 197.4, 146.7, 144.5,
144.1, 136.7, 133.2, 131.7, 129.7 (2C), 129.1, 126.1 (2C), 124.6, 121.7,
119.7, 119.4, 112.1, 111.4, 109.7, 55.4, 33.1, 31.9, 25.7, 21.6; LRMS
(EI 70 ev) m/z (%) 380 (M+, 1), 379 (2), 378 (7), 259 (100), 234
(15), 144 (29), 115 (25), 40 (98); HRMS (EI) for C26H24N2O (M+)
calcd 380.1889, found 380.1885.
(brs, 1H), 8.13 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.54 (t, J
= 7.5 Hz, 1H), 7.45−7.43 (m, 3H), 7.30 (d, J = 8.0 Hz, 1H), 7.05 (t, J
= 8.0 Hz, 1H), 6.99 (t, J = 8.0 Hz, 1H), 6.83 (d, J = 8.0 Hz, 2H), 6.70
(d, J = 8.0 Hz, 2H), 6.55 (d, J = 7.0 Hz, 1H), 5.92 (d, J = 8.0 Hz, 1H),
2.10 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 197.8, 145.7, 136.8,
135.7, 133.6, 129.6, 129.1, 128.9, 126.2, 126.1, 125.1, 121.8, 119.7,
119.5, 113.7, 112.1, 111.1, 55.4, 20.6; LRMS (EI 70 ev) m/z (%) 340
(M+, 1), 339 (1), 233 (100), 207 (12), 91 (13), 77 (4), 65 (11);
HRMS (EI) for C23H20N2O (M+) calcd 340.1576, found 340.1571.
2-(1H-Indol-3-yl)-1-phenyl-2-(m-tolylamino)ethanone (5). 52.0
1
mg, yield 51%. Yellow oil: H NMR (500 MHz, DMSO-d6) δ 11.09
2-(1H-Indol-3-yl)-1-p-tolyl-2-(m-tolylamino)ethanone (11). 75.4
(brs, 1H), 8.15 (d, J = 7.5 Hz, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.56 (t, J
= 7.5 Hz, 1H), 7.47−7.44 (m, 3H), 7.31 (d, J = 8.0 Hz, 1H), 7.06 (t, J
= 7.5 Hz, 1H), 7.00 (t, J = 7.5 Hz, 1H), 6.91 (t, J = 8.0 Hz, 1H), 6.63
(s, 1H), 6.60−6.57 (m, 2H), 6.34 (d, J = 7.5 Hz, 1H), 6.03 (d, J = 7.5
Hz, 1H), 2.14 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 197.7,
147.9, 138.0, 135.7, 133.7, 129.1, 129.0, 128.9, 126.2, 126.1, 121.8,
119.7, 119.5, 117.6, 114.3, 112.2, 111.1, 110.7, 55.2, 21.8; LRMS (EI
70 ev) m/z (%) 340 (M+, 1), 339 (1), 233 (100), 207 (20), 91 (8), 77
1
mg, yield 71%. Yellow oil: H NMR (500 MHz, DMSO-d6) δ 11.06
(brs, 1H), 8.04 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 8.0 Hz, 1H), 7.45 (s,
1H), 7.29 (d, J = 8.0 Hz, 1H), 7.24 (d, J = 8.5 Hz, 2H), 7.04 (t, J = 7.5
Hz, 1H), 6.98 (t, J = 7.5 Hz, 1H), 6.82 (d, J = 8.0 Hz, 2H), 6.70 (d, J =
8.0 Hz, 2H), 6.52 (d, J = 8.0 Hz, 1H), 5.91 (d, J = 8.0 Hz, 1H), 2.30 (s,
3H), 2.10 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 197.4, 145.7,
144.1, 136.7, 133.2, 129.7 (2C), 129.6, 129.1, 126.2, 126.1, 125.1,
8708
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Article
121.7, 119.7, 119.5, 113.8 (2C), 112.1, 111.3, 55.2, 21.6, 20.6; LRMS
(EI 70 ev) m/z (%) 354 (M+, 1), 353 (1), 352 (1), 338 (2), 235 (100),
204 (14), 118 (35), 91 (28), 77 (18), 40 (13); HRMS (EI) for
C24H22N2O (M+) calcd 354.1732, found 354.1729.
127.2, 124.2, 121.7, 119.1, 117.7, 114.3, 113.6, 111.3, 110.8, 54.8, 21.8,
21.6; LRMS (EI 70 ev) m/z (%) 388 (M+, 1), 269 (41), 253 (5, -Cl),
207 (4), 164 (17), 119 (27), 91 (26), 65 (9), 40 (100); HRMS (EI)
for C24H21ClN2O (M+) calcd 388.1342, found 388.1337.
1-(4-Chlorophenyl)-2-(1H-indol-3-yl)-2-(m-tolylamino)ethanone
(12). 56.1 mg, yield 50%. Yellow oil: 1H NMR (500 MHz, DMSO-d6)
δ 11.09 (brs, 1H), 8.14 (d, J = 8.5 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H),
7.51 (d, J = 8.5 Hz, 2H), 7.45 (s, 1H), 7.30 (d, J = 8.5 Hz, 1H), 7.05 (t,
J = 8.5 Hz, 1H), 6.99 (t, J = 7.5 Hz, 1H), 6.89 (t, J = 7.5 Hz, 1H), 6.62
(s, 1H), 6.59−6.54 (m, 2H), 6.34 (d, J = 7.5 Hz, 1H), 6.04 (d, J = 7.5
Hz, 1H), 2.13 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 196.8,
147.8, 138.6, 138.1, 136.8, 134.3, 131.6, 130.9, 129.2, 129.0, 126.3,
126.0, 121.8, 119.6 (2C), 117.7, 114.3, 112.2, 110.8, 55.3, 21.8; LRMS
(EI 70 ev) m/z (%) 376 (M++2, 1), 374 (1), 373 (1), 372 (3), 269
(4), 233 (100), 204 (5), 144 (51), 91 (28), 65 (14), 40 (34); HRMS
(EI) for C23H19ClN2O (M+) calcd 374.1186, found 374.1181.
1-(4-Fluorophenyl)-2-(1H-indol-3-yl)-2-(m-tolylamino)ethanone
(13). 48.3 mg, yield 45%. Yellow oil: 1H NMR (500 MHz, DMSO-d6)
δ 11.08 (brs, 1H), 8.23−8.21 (m, 2H), 7.73 (d, J = 7.5 Hz, 1H), 7.60
(s, 1H), 7.31−7.25 (m, 3H), 7.05 (t, J = 7.5 Hz, 1H), 6.99 (t, J = 7.5
Hz, 1H), 6.90 (t, J = 8.0 Hz, 1H), 6.62 (s, 1H), 6.59−6.54 (m, 2H),
6.34 (d, J = 7.0 Hz, 1H), 6.01 (t, J = 7.5 Hz, 1H), 2.13 (s, 3H); 13C
NMR (125 MHz, DMSO-d6) δ 196.9, 147.8, 138.0, 136.7, 132.3,
132.0, 131.9, 129.0, 126.1, 121.8, 119.6, 119.5, 117.7, 116.2, 116.0,
114.3, 112.1, 111.0, 110.7, 55.3, 21.8; LRMS (EI 70 ev) m/z (%) 358
(M+, 1), 251 (5), 235 (26), 130 (24), 107 (18), 66 (15), 40 (100);
HRMS (EI) for C23H19FN2O (M+) calcd 358.1481, found 358.1474.
Ethyl 2-(1H-indol-3-yl)-2-(p-tolylamino)acetate (14). 46.2 mg,
(E)-Methyl 3-(3-(2-oxo-2-p-tolyl-1-(m-tolylamino)ethyl)-1H-indol-
5-yl)acrylate (18). 73.6 mg, yield 56%. Yellow solid: mp 136.7−138.9
°C (uncorrected); 1H NMR (500 MHz, DMSO-d6) δ 11.07 (brs, 1H),
8.16 (s, 1H), 8.06 (d, J = 8.5 Hz, 2H), 7.75 (d, J = 11.0 Hz, 1H), 7.51
(s, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.32 (d, J = 9.0 Hz, 1H), 7.26 (d, J =
8.0 Hz, 2H), 6.90 (t, J = 8.0 Hz, 1H), 6.66 (s, 1H), 6.58−6.63 (m,
2H), 6.54 (s, 1H), 6.34 (d, J = 7.0 Hz, 1H), 6.15 (d, J = 8.0 Hz, 1H),
3.74 (s, 3H), 2.31 (s, 3H), 2.13 (s, 3H); 13C NMR (125 MHz, DMSO-
d6) δ 197.1, 167.5, 147.8, 147.0, 144.1, 138.0 (2C), 133.0, 129.7, 129.0,
128.9, 127.4, 126.4, 125.7, 121.7 (2C), 117.6, 114.6, 114.3, 112.6,
112.5, 110.8, 54.7, 51.6, 21.7, 21.5; LRMS (EI 70 ev) m/z (%) 438
(M+, 1), 317 (44), 214 (80), 119 (48), 107 (52), 77 (12), 40 (100);
HRMS (EI) for C28H26N2O3 (M+) calcd 438.1943, found 438.1940.
2-(6-Methyl-1H-indol-3-yl)-1-p-tolyl-2-(p-tolylamino)ethanone
(19). 73.9 mg, yield 67%. Yellow oil: 1H NMR (500 MHz, DMSO-d6)
δ 10.88 (brs, 1H), 8.01 (d, J = 8.0 Hz, 2H), 7.61 (d, J = 8.0 Hz, 1H),
7.33 (s, 1H), 7.23 (d, J = 8.0 Hz, 2H), 7.07 (s, 1H), 6.81 (d, J = 7.5
Hz, 3H), 6.68 (d, J = 8.0 Hz, 2H), 6.46 (d, J = 7.5 Hz, 1H), 5.84 (d, J
= 8.0 Hz, 1H), 2.33 (s, 3H), 2.30 (s, 3H), 2.09 (s, 3H); 13C NMR
(125 MHz, DMSO-d6) δ 197.3, 145.6, 144.0, 137.1, 133.2, 130.7,
129.6, 129.5, 129.0, 125.3, 125.0, 124.0, 121.2, 119.3, 113.7, 111.8,
111.2, 55.3, 21.7, 21.5, 20.5; LRMS (EI 70 ev) m/z (%) 368 (M+, 1),
261 (39), 249 (100), 218 (38), 144 (52), 106 (86), 65 (27), 40 (88);
HRMS (EI) for C25H24N2O (M+) calcd 368.1889, found 368.1885.
2-(7-Ethyl-1H-indol-3-yl)-1-p-tolyl-2-(m-tolylamino)ethanone
(20). 75.6 mg, yield 66%. Brown solid: mp 112.6−115.4 °C
1
yield 50%. Yellow oil: H NMR (500 MHz, DMSO-d6) δ 11.11 (brs,
1H), 7.68 (d, J = 7.5 Hz, 1H), 7.42 (s, 1H), 7.37 (d, J = 8.0 Hz, 1H),
7.10 (t, J = 7.5 Hz, 1H), 7.01 (t, J = 7.5 Hz, 1H), 6.89 (d, J = 8.0 Hz,
2H), 6.61 (d, J = 8.5 Hz, 2H), 5.90 (d, J = 7.5 Hz, 1H), 5.32 (d, J = 8.0
Hz, 1H), 4.16−4.09 (m, 1H), 4.06−3.99 (m, 1H), 2.14 (s, 3H), 1.11
(t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ 173.1, 145.7,
136.7, 129.7, 126.2, 125.5, 124.7, 121.9, 119.6, 119.4, 113.4, 112.1,
111.3, 61.0, 54.1, 20.6, 14.6; LRMS (EI 70 ev) m/z (%) 308 (15), 235
(100), 118 (40), 107 (49), 66 (27), 40 (78); HRMS (EI) for
C19H20N2O2 (M+) calcd 308.1525, found 308.1522.
2-(5-Methyl-1H-indol-3-yl)-1-p-tolyl-2-(p-tolylamino)ethanone
(15). 68.4 mg, yield 62%. Yellow oil: 1H NMR (500 MHz, DMSO-d6)
δ 10.91 (brs, 1H), 8.02 (d, J = 7.5 Hz, 2H), 7.51 (s, 1H), 7.36 (s, 1H),
7.24 (d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 1H), 6.86−6.88 (m, 1H),
6.82 (d, J = 8.0 Hz, 2H), 6.68 (d, J = 8.0 Hz, 2H), 6.45 (d, J = 8.0 Hz,
1H), 5.85 (d, J = 8.0 Hz, 1H), 2.36 (s, 3H), 2.30 (s, 3H), 2.10 (s, 3H);
13C NMR (125 MHz, DMSO-d6) δ 197.4, 145.7, 144.0, 135.1, 133.2,
129.8, 129.6, 129.5, 129.0, 127.9, 126.3, 126.1, 125.0, 123.3, 119.1,
113.6, 111.8, 110.7, 55.3, 21.8, 21.5, 20.5; LRMS (EI 70 ev) m/z (%)
368 (M+, 1), 249 (100), 218 (41), 158 (17), 144 (43), 106 (87), 65
(29), 40 (26); HRMS (EI) for C25H24N2O (M+) calcd 368.1889,
found 368.1885.
2-(5-Bromo-1H-indol-3-yl)-1-p-tolyl-2-(m-tolylamino)ethanone
(16). 71.3 mg, yield 55%. Yellow oil: 1H NMR (500 MHz, DMSO-d6)
δ 11.26 (brs, 1H), 8.05 (d, J = 8.0 Hz, 2H), 7.93 (s, 1H), 7.53 (s, 1H),
7.25−7.28 (m, 3H), 7.14−7.16 (m, 1H), 6.89 (t, J = 7.5 Hz, 1H), 6.64
(s, 1H), 6.59 (d, J = 8.0 Hz, 1H), 6.54 (d, J = 8.0 Hz, 1H), 6.33 (d, J =
7.5 Hz, 1H), 6.09 (d, J = 8.0 Hz, 1H), 2.31 (s, 3H), 2.13 (s, 3H); 13C
NMR (125 MHz, DMSO-d6) δ 197.2, 147.8, 144.2, 138.0, 135.4, 129.7
(2C), 129.1, 129.0, 127.9, 127.7, 124.2, 122.1, 117.6, 114.3, 114.1,
112.2, 111.2, 110.8, 54.8, 21.8, 21.5; LRMS (EI 70 ev) m/z (%) 434
(M++2, 1), 432 (M+,1), 313 (46), 208 (12), 119 (36), 91 (33), 65
(13), 40 (100); HRMS (EI) for C24H21BrN2O (M+) calcd 432.0837,
found 432.0834.
1
(uncorrected); H NMR (500 MHz, DMSO-d6) δ 11.03 (brs, 1H),
8.04 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.42 (s, 1H), 7.24
(d, J = 7.5 Hz, 2H), 6.93 (t, J = 7.5 Hz, 1H), 6.87 (d, J = 7.0 Hz, 1H),
6.82 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 8.0 Hz, 2H), 6.50 (d, J = 7.0 Hz,
1H), 5.89 (d, J = 7.5 Hz, 1H), 2.78−2.74 (m, 2H), 2.30 (s, 3H), 2.10
(s, 3H), 1.20 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, DMSO-d6) δ
197.3, 145.7, 144.1, 135.4, 133.2, 129.8, 129.7, 129.6, 129.1, 127.5,
126.0, 125.8, 125.0, 120.4, 119.8, 117.3, 114.5, 113.7, 111.7, 55.3, 24.1,
21.6, 20.6, 14.7; LRMS (EI 70 ev) m/z (%) 382 (M+, 1), 261 (100),
158 (31), 119 (40), 91 (41), 40 (50); HRMS (EI) for C26H26N2O
(M+) calcd 382.2045, found 382.2041.
2-(2-Methyl-1H-indol-3-yl)-1-p-tolyl-2-(m-tolylamino)ethanone
(21). 71.8 mg, yield 65%. Yellow solid: mp 125.4−128.1 °C
1
(uncorrected); H NMR (500 MHz, DMSO-d6) δ 10.94 (brs, 1H),
7.91 (d, J = 8.0 Hz, 2H), 7.70−7.65 (m, 1H), 7.21 (d, J = 8.5 Hz, 2H),
7.17−7.15 (m, 1H), 6.97−6.93 (m, 2H), 6.88 (t, J = 8.0 Hz, 1H), 6.56
(s, 1H), 6.52 (d, J = 8.0 Hz, 1H), 6.40 (d, J = 7.0 Hz, 1H), 6.32 (d, J =
7.5 Hz, 1H), 5.91 (d, J = 7.0 Hz, 1H), 2.46 (s, 3H), 2.28 (s, 3H),; 2.11
(s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 196.5, 147.7, 143.8, 137.9,
135.6, 134.8, 133.7, 129.6, 128.9, 128.6, 127.2, 120.7, 119.3, 118.7,
117.5, 114.3, 111.0, 110.8, 106.4, 54.8, 21.8, 21.5, 12.4; LRMS (EI 70
ev) m/z (%) 368 (M+, 1), 261 (24), 249 (100), 218 (14), 119 (22),
107 (37), 65 (14), 40 (73); HRMS (EI) for C25H24N2O (M+) calcd
368.1889, found 368.1883.
2-(2-Phenyl-1H-indol-3-yl)-1-p-tolyl-2-(m-tolylamino)ethanone
(22). 96.8 mg, yield 75%. Yellow solid: mp 140.6−144.5 °C
1
(uncorrected); H NMR (500 MHz, DMSO-d6) δ 11.63 (brs, 1H),
7.64 (d, J = 7.5 Hz, 2H), 7.50−7.60 (m, 3H), 7.51 (t, J = 7.5 Hz, 1H),
7.46 (d, J = 8.5 Hz, 2H), 7.35 (d, J = 8.0 Hz, 1H), 7.08 (t, J = 7.5 Hz,
1H), 7.03 (d, J = 8.0 Hz, 2H), 6.98 (t, J = 7.5 Hz, 1H), 6.85 (d, J = 8.0
Hz, 2H), 6.50 (d, J = 8.5 Hz, 2H), 6.23 (d, J = 7.0 Hz, 1H), 6.16 (d, J
= 7.0 Hz, 1H), 2.21 (s, 3H), 2.13 (s, 3H); 13C NMR (125 MHz,
DMSO-d6) δ 196.5, 147.2, 145.8, 143.9, 137.6, 136.6, 133.3, 132.5,
129.7, 129.5, 129.5, 128.9, 128.8, 128.1, 127.0, 125.1, 122.1, 120.4,
119.9, 113.1, 111.9, 107.2, 56.3, 21.4, 20.5; LRMS (EI 70 ev) m/z (%)
430 (M+, 1), 323 (23), 311 (100), 204 (18), 119 (28), 91 (25), 65 (8),
40 (19); HRMS (EI) for C30H26N2O (M+) calcd 430.2045, found
430.2040.
2-(5-Chloro-1H-indol-3-yl)-1-p-tolyl-2-(m-tolylamino)ethanone
(17). 71.0 mg, yield 61%. Yellow oil: 1H NMR (500 MHz, DMSO-d6)
δ 11.25 (brs, 1H), 8.06 (d, J = 8.0 Hz, 2H), 7.79 (s, 1H), 7.56 (s, 1H),
7.31 (d, J = 8.5 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.04 (d, J = 9.0 Hz,
1H), 6.90 (t, J = 7.5 Hz, 1H), 6.64 (s, 1H), 6.59 (d, J = 8.0 Hz, 1H),
6.55 (d, J = 7.5 Hz, 1H), 6.33 (d, J = 7.5 Hz, 1H), 6.09 (d, J = 7.5 Hz,
1H), 2.31 (s, 3H), 2.13 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ
197.2, 147.8, 144.2, 138.0, 135.2, 133.0, 129.7, 129.1, 129.0, 128.0,
1-p-Tolyl-2-(2-p-tolyl-1H-indol-3-yl)-2-(m-tolylamino)ethanone
(23). 79.9 mg, yield 60%. Yellow solid: mp 155.8−158.2 °C
8709
dx.doi.org/10.1021/jo301691h | J. Org. Chem. 2012, 77, 8705−8711

The Journal of Organic Chemistry
Article
1
(uncorrected); H NMR (500 MHz, DMSO-d6) δ 11.55 (brs, 1H),
ACKNOWLEDGMENTS
■
7.55−7.53 (m, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.39 (d, J = 7.5 Hz, 2H),
7.33 (d, J = 8.0 Hz, 1H), 7.08−7.04 (m, 3H), 6.97 (t, J = 7.5 Hz, 1H),
6.91 (t, J = 8.0 Hz, 1H), 6.42 (s, 1H), 6.38 (d, J = 7.5 Hz, 2H), 6.35 (d,
J = 8.0 Hz, 1H), 6.29 (d, J = 7.0 Hz, 1H), 6.16 (d, J = 7.0 Hz, 1H),
2.41 (s, 3H), 2.22 (s, 3H), 2.12 (s, 3H); 13C NMR (125 MHz, DMSO-
d6) δ 196.4, 148.0, 143.9, 138.4, 138.1, 137.7, 136.5, 133.3, 130.1,
129.6, 129.5, 129.1, 128.7, 128.1, 127.0, 122.0, 120.2, 119.8, 117.6,
113.8, 111.8, 110.1, 106.7, 56.1, 21.8, 21.4, 21.3; LRMS (EI 70 ev) m/z
(%) 444 (M+, 1), 337 (24), 325 (100), 220 (27), 208 (14), 119 (27),
107 (22), 65 (7), 40 (47); HRMS (EI) for C31H28N2O (M+) calcd
444.2202, found 444.2198.
We thank the National Natural Science Foundation of China
(No. 21172060) and Fundamental Research Funds for the
Central Universities (Hunan University) for financial support.
REFERENCES
■
(1) For selected reviews, see: (a) Hunt, S. Chemistry and Biochemistry
of the Amino Acids; Barrett, G. C., Ed.; Chapman and Hall: London,
1985, p 55. (b) Ohfune, Y. Acc. Chem. Res. 1992, 25, 360. (c) Gellman,
S. H. Acc. Chem. Res. 1998, 31, 173.
2-(2-(4-Bromophenyl)-1H-indol-3-yl)-1-p-tolyl-2-(m-tolylamino)-
(2) (a) Obrecht, D.; Altorfer, M.; Lehmann, C.; Schonholzer, P.;
̈
ethanone (24). 77.7 mg, yield 51%. Yellow solid: mp 171.7−174.5 °C
Muller, K. J. Org. Chem. 1996, 61, 4080. (b) Obrecht, D.; Bohdal, U.;
̈
1
(uncorrected); H NMR (500 MHz, DMSO-d6) δ 11.65 (brs, 1H),
Broger, C.; Bur, D.; Lehmann, C.; Ruffieux, R.; Schonholzer, P.;
̈
7.78 (d, J = 8.0 Hz, 2H), 7.56−7.59 (m, 3H), 7.49 (d, J = 8.0 Hz, 2H),
7.35 (d, J = 8.0 Hz, 1H), 7.06−7.11 (m, 3H), 7.00 (t, J = 7.0 Hz, 1H),
6.91 (t, J = 8.0 Hz, 1H), 6.44 (s, 1H), 6.38 (d, J = 7.5 Hz, 2H), 6.30 (d,
J = 7.0 Hz, 1H), 6.17 (d, J = 7.5 Hz, 1H), 2.22 (s, 3H), 2.12 (s, 3H);
13C NMR (125 MHz, DMSO-d6) δ 196.4, 147.9, 143.9, 138.2, 136.6,
136.3, 133.4, 132.5, 131.7, 130.8, 129.5, 129.1, 128.2, 127.0, 122.4,
122.3, 120.4, 120.0, 117.7, 114.0, 111.9, 110.2, 107.6, 55.9, 21.8, 21.4;
LRMS (EI 70 ev) m/z (%) 508 (M+, 1), 389 (100), 284 (21), 205
(30), 119 (27), 91 (35), 40 (44); HRMS (EI) for C30H25BrN2O (M+)
calcd 508.1150, found 508.1147.
Spiegler, C.; Muller, K. Helv. Chim. Acta 1995, 78, 563. (c) Schoepp,
̈
D. D.; Jane, D. E.; Monn, J. A. Neuropharmacology 1999, 38, 1431.
(d) Takahashi, A.; Naganawa, H.; Ikeda, D.; Okami, Y. Tetrahedron
1991, 47, 3621. (e) Schirlin, D.; Gerhart, F.; Hornsperger, J. M.;
Hamon, M.; Wagner, J.; Jung, M. J. J. Med. Chem. 1988, 31, 30.
(f) Walsh, J. J.; Metzler, D. E.; Powell, D.; Jacobson, R. A. J. Am. Chem.
Soc. 1980, 102, 7136. (g) Beenen, M. A.; Weix, D. J.; Ellman, J. A. J.
Am. Chem. Soc. 2006, 128, 6304. (h) Zhao, L.; Li, C.-J. Angew. Chem.
Int, Ed. 2008, 47, 7075.
(3) For reviews and papers on α-arylation of α-amino carbonyl
compounds under basic conditions, see: (a) Williams, R. M.; Hendrix,
J. A. Chem. Rev. 1992, 92, 889. (b) Culkin, D.; Hartwig, J. F. Acc.
Chem. Res. 2003, 36, 234. (c) Miura, M.; Nomura, M. Top. Curr. Chem.
2002, 219, 211. (d) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082.
(e) Gaertzen, O.; Buchwald, S. L. J. Org. Chem. 2002, 67, 465. (f) Liu,
X.; Hartwig, J. F. Org. Lett. 2003, 5, 1915. (g) Lee, S.; Beare, N. A.;
Hartwig, J. F. J. Am. Chem. Soc. 2001, 123, 8410. (h) Sigman, M. S.;
Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 5315. (i) Sigman, M. S.;
Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120, 4901. (j) Reddy, K. L.;
Sharpless, K. B. J. Am. Chem. Soc. 1998, 120, 1207. (k) Chaari, M.;
Jenhi, A.; Lavergne, J.-P.; Viallefont, P. Tetrahedron 1991, 47, 4619.
(l) O’Donnell, M. J.; Bennett, W. D.; Jacobsen, W. N.; Ma, Y.;
Huffman, J. C. Tetrahedron Lett. 1989, 30, 3909. (m) Trost, B. M.;
Aeiza, X. J. Am. Chem. Soc. 1999, 121, 10727. (n) Hocek, M.
Heterocycles 2004, 63, 1673. (o) Marsden, S. P.; Watson, E. L.; Raw, S.
A. Org. Lett. 2008, 10, 2905.
2-(1-Methyl-1H-indol-3-yl)-1-p-tolyl-2-(m-tolylamino)ethanone
(25). 73.9 mg, yield 67%. Yellow solid: mp 90.1−91.1 °C
1
(uncorrected); H NMR (500 MHz, DMSO-d6) δ 8.03 (d, J = 8.0
Hz, 2H), 7.79 (t, J = 8.0 Hz, 1H), 7.40 (s, 1H), 7.33 (d, J = 8.5 Hz,
1H), 7.24 (d, J = 7.5 Hz, 2H), 7.12 (t, J = 7.5 Hz, 1H), 7.04 (t, J = 7.5
Hz, 1H), 6.83 (d, J = 8.0 Hz, 2H), 6.69 (d, J = 7.5 Hz, 2H), 6.52 (d, J
= 6.5 Hz, 1H), 5.89 (d, J = 7.5 Hz, 1H), 3.68 (s, 3H), 2.30 (s, 3H),;
2.10 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 197.3, 145.7, 144.2,
137.2, 133.1, 130.0, 129.8, 129.7, 129.6, 129.1, 126.6, 125.1, 121.8,
119.9, 119.8, 119.7, 113.7, 110.6, 110.4, 54.8, 32.9, 21.6, 20.6; LRMS
(EI 70 ev) m/z (%) 368 (M+, 1), 350 (1), 249 (84), 144 (18), 91 (21),
58 (11), 40 (100); HRMS (EI) for C25H24N2O (M+) calcd 368.1889,
found 368.1887.
2-(1-Benzyl-1H-indol-3-yl)-1-p-tolyl-2-(m-tolylamino)ethanone
(26). 75.9 mg, yield 57%. Yellow solid: mp 133.7−135.5 °C
1
(uncorrected); H NMR (500 MHz, DMSO-d6) δ 8.03 (d, J = 8.0
Hz, 2H), 7.73 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.33 (d, J = 8.0 Hz,
1H), 7.25 (d, J = 8.0 Hz, 2H), 7.20−7.19 (m, 3H), 7.06−6.98 (m,
4H), 6.83 (d, J = 8.0 Hz, 2H), 6.71 (d, J = 8.0 Hz, 2H), 6.54 (d, J = 8.0
Hz, 1H), 5.95 (d, J = 8.0 Hz, 1H), 5.33 (s, 2H), 2.32 (s, 3H),; 2.11 (s,
3H); 13C NMR (125 MHz, DMSO-d6) δ 197.4, 145.6, 144.1, 138.5,
136.6, 133.2, 130.1, 129.6, 129.5, 129.1, 128.9, 127.7, 127.3, 125.1,
122.0, 120.1, 119.8, 113.8, 111.3, 110.8, 55.3, 49.4, 21.6, 20.6; LRMS
(EI 70 ev) m/z (%) 444 (M+, 1), 426 (2), 325 (100), 220 (15), 118
(12), 91 (84), 65 (10), 40 (7); HRMS (EI) for C31H28N2O (M+) calcd
444.2202, found 444.2195.
(4) Wu, J.-C.; Song, R.-J.; Wang, Z.-Q.; Huang, X.-C.; Xie, Y.-X.; Li,
J.-H. Angew. Chem., Int. Ed. 2012, 51, 3453.
(5) For special reviews on visible-light photoredox catalysis, see:
(a) Zeitler, K. Angew. Chem., Int. Ed. 2009, 48, 9785. (b) Yoon, T. P.;
Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527. (c) Narayanam, J. M. R.;
Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102. (d) Teply, F.
́
Collect. Czech. Chem. Commun. 2011, 76, 859. (e) Tucker, J. W.;
Stephenson, C. R. J. J. Org. Chem. 2012, 77, 1617.
(6) For papers on the C(sp3)−H functionalization using visible-light
Ethyl 2-oxo-2-(p-tolylamino)acetate (29b).9 26.1 mg, yield 42%.
́ ́
photoredox catalysis, see: (a) Condie, A. G.; Gonzalez-Gomez, J.;
1
Yellow oil: H NMR (500 MHz, CDCl3) δ 8.84 (s, 1H), 7.53−7.51
Stephenson, C. R. J. J. Am. Chem. Soc. 2010, 132, 1464. (b) Freeman,
D. B.; Furst, L.; Condie, A. G.; Stephenson, C. R. J. Org. Lett. 2012, 14,
94. (c) Zou, Y.-Q.; Lu, L.-Q.; Fu, L.; Chang, N.-J.; Rong, J.; Chen, J.-
R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2011, 50, 7171. (d) Xuan, J.;
Cheng, Y.; An, J.; Lu, L.-Q.; Zhang, X.-X.; Xiao, W.-J. Chem. Commun.
2011, 47, 8337. (e) Xie, Z.; Wang, C.; de Krafft, K. E.; Lin, W. J. Am.
Chem. Soc. 2011, 133, 2056. (f) Zhu, M.; Zheng, N. Synthesis 2011,
2223. (g) Rueping, M.; Leonori, D.; Poisson, T. Chem. Commun. 2011,
(m, 2H), 7.17 (d, J = 8.0 Hz, 2H), 4.43−4.39 (m, 2H), 2.33 (s, 3H),
1.42 (t, J = 7.0 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 161.1, 153.7,
135.3, 133.8, 129.7, 119.8, 63.6, 20.9, 14.0; LRMS (EI 70 ev) m/z (%)
207 (M+, 63), 134 (67), 106 (100), 91 (28), 51 (7).
ASSOCIATED CONTENT
■
S
* Supporting Information
47, 9615. (h) Hari, D. P.; Konig, B. Org. Lett. 2011, 13, 3852.
̈
Computational details and copies of spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(i) Rueping, M.; Zhu, S.; Koenigs, R. M. Chem. Commun. 2011, 47,
8679. (j) Su, F.; Mathew, S. C.; Moehlmann, L.; Antonietti, M.; Wang,
X.; Blechert, S. Angew. Chem., Int. Ed. 2011, 50, 657. (k) Rueping, M.;
Zoller, J.; Fabry, D. C.; Poscharny, K.; Koenigs, R. M.; Weirich, T. E.
Chem.Eur. J. 2012, 18, 3478. (l) Miyake, Y.; Nakajima, K.;
Nishibayashi, Y. J. Am. Chem. Soc. 2012, 134, 3338. (m) Tucker, J.
W.; Narayanam, J. M. R.; Shah, P. S.; Stephenson, C. R. J. Chem.
Commun. 2011, 47, 5040. (n) Dai, C.; Meschini, F.; Narayanam, J. M.
R.; Stephenson, C. R. J. J. Org. Chem. 2012, 77, 4425.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jhli@hnu.edu.cn.
Notes
The authors declare no competing financial interest.
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